Compounds with Medicinal Value

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Applied Sciences applsci	2.5	5.3	2011	18.4 Days	CHF 2400
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	13.9 Days	CHF 2900
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Antibiotics antibiotics	4.3	7.3	2012	15.8 Days	CHF 2900

1 pages, 146 KiB

Open AccessCorrection

Correction: Nazeer et al. Bacterial-Specific Aggregation and Killing of Immunomodulatory Host Defense Peptides. Pharmaceuticals 2021, 14, 839

by Nauman Nazeer, Juan Carlos Rodriguez-Lecompte and Marya Ahmed

Pharmaceuticals 2024, 17(10), 1359; https://doi.org/10.3390/ph17101359 - 11 Oct 2024

Viewed by 532

Abstract

In the original publication [...] Full article

(This article belongs to the Topic Compounds with Medicinal Value)

18 pages, 645 KiB

Open AccessArticle

Antimicrobial and Cytotoxic Cyathane-Xylosides from Cultures of the Basidiomycete Dentipellis fragilis

by Winnie Chemutai Sum, Nico Mitschke, Hedda Schrey, Kathrin Wittstein, Harald Kellner, Marc Stadler and Josphat Clement Matasyoh

Antibiotics 2022, 11(8), 1072; https://doi.org/10.3390/antibiotics11081072 - 8 Aug 2022

Cited by 19 | Viewed by 3328

Abstract

In our continued search for biologically active metabolites from cultures of rare Basidiomycota species, we found eight previously undescribed cyathane-xylosides from submerged cultures of Dentipellis fragilis, which were named dentifragilins A–H. In addition, the known cyathane derivatives striatal D and laxitextine A [...] Read more.

In our continued search for biologically active metabolites from cultures of rare Basidiomycota species, we found eight previously undescribed cyathane-xylosides from submerged cultures of Dentipellis fragilis, which were named dentifragilins A–H. In addition, the known cyathane derivatives striatal D and laxitextine A were isolated. All compounds were characterized by high-resolution electrospray ionization mass spectrometry (HR-ESIMS) as well as by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Several of the compounds exhibited significant activities in standardized cell-based assays for the determination of antimicrobial and cytotoxic effects. The discovery of cyathanes in the genus Dentipellis has chemotaxonomic implications, as this class of diterpenoids has already been shown to be characteristic for mycelial cultures of the related genera Hericium and Laxitextum, which are classified as Dentipellis in the family Hericiaceae. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 3787 KiB

Open AccessEditor’s ChoiceArticle

Astaxanthin Carotenoid Modulates Oxidative Stress in Adipose-Derived Stromal Cells Isolated from Equine Metabolic Syndrome Affected Horses by Targeting Mitochondrial Biogenesis

by Malwina Mularczyk, Nabila Bourebaba, Krzysztof Marycz and Lynda Bourebaba

Biomolecules 2022, 12(8), 1039; https://doi.org/10.3390/biom12081039 - 27 Jul 2022

Cited by 10 | Viewed by 3928

Abstract

Astaxanthin is gaining recognition as a natural bioactive component. This study aimed to test whether astaxanthin could protect adipose-derived stromal stem cells (ASCs) from apoptosis, mitochondrial dysfunction and oxidative stress. Phaffia rhodozyma was used to extract astaxanthin, whose biocompatibility was tested after 24, [...] Read more.

Astaxanthin is gaining recognition as a natural bioactive component. This study aimed to test whether astaxanthin could protect adipose-derived stromal stem cells (ASCs) from apoptosis, mitochondrial dysfunction and oxidative stress. Phaffia rhodozyma was used to extract astaxanthin, whose biocompatibility was tested after 24, 48 and 72 h of incubation with the cells; no harmful impact was found. ASCs were treated with optimal concentrations of astaxanthin. Several parameters were examined: cell viability, apoptosis, reactive oxygen levels, mitochondrial dynamics and metabolism, superoxide dismutase activity, and astaxanthin’s antioxidant capacity. A RT PCR analysis was performed after each test. The astaxanthin treatment significantly reduced apoptosis by modifying the normalized caspase activity of pro-apoptotic pathways (p21, p53, and Bax). Furthermore, by regulating the expression of related master factors SOD1, SOD2, PARKIN, PINK 1, and MFN 1, astaxanthin alleviated the oxidative stress and mitochondrial dynamics failure caused by EMS. Astaxanthin restored mitochondrial oxidative phosphorylation by stimulating markers associated with the OXPHOS machinery: COX4I1, COX4I2, UQCRC2, NDUFA9, and TFAM. Our results suggest that astaxanthin has the potential to open new possibilities for potential bio-drugs to control and suppress oxidative stress, thereby improving the overall metabolic status of equine ASCs suffering from metabolic syndrome. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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39 pages, 7183 KiB

Open AccessArticle

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

by Nahed N. E. El-Sayed, Magdi E. A. Zaki, Sami A. Al-Hussain, Abir Ben Bacha, Malika Berredjem, Vijay H. Masand, Zainab M. Almarhoon and Hanaa S. Omar

Pharmaceuticals 2022, 15(7), 891; https://doi.org/10.3390/ph15070891 - 19 Jul 2022

Cited by 22 | Viewed by 3365

Abstract

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant [...] Read more.

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC₅₀ values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC₅₀ values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski’s rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 6685 KiB

Open AccessArticle

Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives

by Vincent Montero, Marc Montana, Omar Khoumeri, Florian Correard, Marie-Anne Estève and Patrice Vanelle

Pharmaceuticals 2022, 15(7), 781; https://doi.org/10.3390/ph15070781 - 23 Jun 2022

Cited by 5 | Viewed by 2917

Abstract

The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane [...] Read more.

The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers cis and trans. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, trans derivatives were observed to display better activities than cis derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC₅₀ = 2.49 ± 1.33 μM and IC₅₀ = 3.96 ± 2.03 μM for compound 11a and IC₅₀ = 5.3 ± 2.12 μM and IC₅₀ = 7.12 ± 1.59 μM for compound 11b against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 1326 KiB

Open AccessArticle

Purification, Characterization and Evaluation of the Antitumoral Activity of a Phospholipase A2 from the Snake Bothrops moojeni

by Breno Emanuel Farias Frihling, Ana Paula de Araújo Boleti, Caio Fernando Ramalho de Oliveira, Simone Camargo Sanches, Pedro Henrique de Oliveira Cardoso, Newton Verbisck, Maria Lígia Rodrigues Macedo, Paula Helena Santa Rita, Cristiano Marcelo Espinola Carvalho and Ludovico Migliolo

Pharmaceuticals 2022, 15(6), 724; https://doi.org/10.3390/ph15060724 - 7 Jun 2022

Cited by 11 | Viewed by 3074

Abstract

Nature presents a wide range of biomolecules with pharmacological potential, including venomous animal proteins. Among the protein components from snake venoms, phospholipases (PLA₂) are of great importance for the development of new anticancer compounds. Thus, we aimed to evaluate the PLA [...] Read more.

Nature presents a wide range of biomolecules with pharmacological potential, including venomous animal proteins. Among the protein components from snake venoms, phospholipases (PLA₂) are of great importance for the development of new anticancer compounds. Thus, we aimed to evaluate the PLA₂ anticancer properties from Bothrops moojeni venom. The crude venom was purified through three chromatographic steps, monitored by enzymatic activity and SDS-PAGE (12%). The purified PLA₂ denominated BmPLA2 had its molecular mass and N-terminal sequence identified by mass spectrometry and Edman degradation, respectively. BmPLA2 was assayed against human epithelial colorectal adenocarcinoma cells (Caco-2), human rhabdomyosarcoma cells (RD) and mucoepidermoid carcinoma of the lung (NCI-H292), using human fibroblast cells (MRC-5) and microglia cells (BV-2) as a cytotoxicity control. BmPLA2 presented 13,836 Da and a 24 amino acid-residue homologue with snake PLA₂, which showed a 90% similarity with other Bothrops moojeni PLA₂. BmPLA2 displayed an IC₅₀ of 0.6 µM against Caco-2, and demonstrated a selectivity index of 1.85 (compared to MRC-5) and 6.33 (compared to BV-2), supporting its selectivity for cancer cells. In conclusion, we describe a new acidic phospholipase, which showed antitumor activity and is a potential candidate in the development of new biotechnological tools. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 985 KiB

Open AccessReview

Phytotherapy: A Solution to Decrease Antifungal Resistance in the Dental Field

by Katherine Cuenca-León, Edisson-Mauricio Pacheco-Quito, Yanela Granda-Granda, Eleonor Vélez-León and Aránzazu Zarzuelo-Castañeda

Biomolecules 2022, 12(6), 789; https://doi.org/10.3390/biom12060789 - 4 Jun 2022

Cited by 8 | Viewed by 4665

Abstract

The pathologies produced by fungi in the oral cavity in recent decades have become a health problem, with factors such as an imbalance of the local microbiota being the cause for their propagation. Conventional antifungal treatments, instead of being beneficial, have generated alterations [...] Read more.

The pathologies produced by fungi in the oral cavity in recent decades have become a health problem, with factors such as an imbalance of the local microbiota being the cause for their propagation. Conventional antifungal treatments, instead of being beneficial, have generated alterations that have led to antifungal resistance. The aim of this study was to investigate and describe phytotherapy resources as a possible solution to oral antifungal resistance. A bibliographic search was carried out on platforms such as PubMed, Scopus, ScienceDirect, Web of Science, and Google scholar. A total of 248 scientific articles were obtained, of which 108 met the inclusion criteria. Microorganisms of fungal origin currently show resistance to the different antifungals of conventional use, which is undoubtedly altering the oral health of human beings, but there are new therapeutic possibilities such as the active principles of various natural species. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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20 pages, 4332 KiB

Open AccessArticle

Dopamine D₂ and Serotonin 5-HT_1A Dimeric Receptor-Binding Monomeric Antibody scFv as a Potential Ligand for Carrying Drugs Targeting Selected Areas of the Brain

by Agata Kowalik, Mateusz Majerek, Krzysztof Mrowiec, Joanna Solich, Agata Faron-Górecka, Olga Woźnicka, Marta Dziedzicka-Wasylewska and Sylwia Łukasiewicz

Biomolecules 2022, 12(6), 749; https://doi.org/10.3390/biom12060749 - 26 May 2022

Cited by 3 | Viewed by 3177

Abstract

Targeted therapy uses multiple ways of ensuring that the drug will be delivered to the desired site. One of these ways is an encapsulation of the drug and functionalization of the surface. Among the many molecules that can perform such a task, the [...] Read more.

Targeted therapy uses multiple ways of ensuring that the drug will be delivered to the desired site. One of these ways is an encapsulation of the drug and functionalization of the surface. Among the many molecules that can perform such a task, the present work focused on the antibodies of single-chain variable fragments (scFvs format). We studied scFv, which specifically recognizes the dopamine D₂ and serotonin 5-HT_1A receptor heteromers. The scFv_D2–5-HT1A protein was analyzed biochemically and biologically, and the obtained results indicated that the antibody is properly folded and non-toxic and can be described as low-immunogenic. It is not only able to bind to the D₂–5-HT_1A receptor heteromer, but it also influences the cAMP signaling pathway and—when surfaced on nanogold particles—it can cross the blood–brain barrier in in vitro models. When administered to mice, it decreased locomotor activity, matching the effect induced by clozapine. Thus, we are strongly convinced that scFvD₂–5-HT_1A, which was a subject of the present investigation, is a promising targeting ligand with the potential for the functionalization of nanocarriers targeting selected areas of the brain. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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20 pages, 4302 KiB

Open AccessEditor’s ChoiceArticle

Anti-Inflammatory Effects of GM1 Ganglioside on Endotoxin-Induced Uveitis in Rats

by Tzu-Heng Weng, Chang-Chih Ke and Yuahn-Sieh Huang

Biomolecules 2022, 12(5), 727; https://doi.org/10.3390/biom12050727 - 21 May 2022

Cited by 3 | Viewed by 3542

Abstract

Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide [...] Read more.

Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide (LPS). GM1 was injected intraperitoneally for three consecutive days prior to the LPS injection. Twenty-four hours after the LPS injection, the integrity of the blood-aqueous barrier was evaluated by determining the protein concentration and number of infiltrating cells in the aqueous humor (AqH). Immunohistochemical and Western blot analyses of the iris-ciliary body (ICB) were performed to evaluate the effect of GM1 on the LPS-induced expression of cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1). The effect of GM1 on proinflammatory mediators and signaling cascades was examined in LPS-stimulated RAW 264.7 cells using Western blotting and immunofluorescence staining to further clarify the underlying anti-inflammatory mechanism. Results: GM1 significantly reduced the protein concentration and number of infiltrating cells in the AqH of rats with EIU. GM1 also decreased the LPS-induced expression of the ICAM-1 and COX-2 proteins in the ICB. In RAW 264.7 cells, GM1 inhibited the proinflammatory mediators induced by LPS, including inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and this inhibitory effect was potentially mediated by suppressing reactive oxygen species (ROS)-mediated activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). Conclusions: Based on this study, GM1 may be a potential anti-inflammatory agent for ocular inflammatory diseases. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 3594 KiB

Open AccessArticle

Integrin/TGF-β1 Inhibitor GLPG-0187 Blocks SARS-CoV-2 Delta and Omicron Pseudovirus Infection of Airway Epithelial Cells In Vitro, Which Could Attenuate Disease Severity

by Kelsey E. Huntington, Lindsey Carlsen, Eui-Young So, Matthias Piesche, Olin Liang and Wafik S. El-Deiry

Pharmaceuticals 2022, 15(5), 618; https://doi.org/10.3390/ph15050618 - 17 May 2022

Cited by 16 | Viewed by 4122

Abstract

As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with [...] Read more.

As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate the blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced the inhibition of pseudovirus infection by GLPG-0187. Because integrins activate transforming growth factor beta (TGF-β) signaling, we compared the plasma levels of active and total TGF-β in COVID-19+ patients. The plasma TGF-β1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. Moreover, the inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and it may mitigate COVID-19 severity through decreased TGF-β1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 5005 KiB

Open AccessArticle

ZnO/Ag Nanocomposites with Enhanced Antimicrobial Activity

by Jaime Gonzalez Cuadra, Loredana Scalschi, Begonya Vicedo, Maxim Guc, Víctor Izquierdo-Roca, Samuel Porcar, Diego Fraga and Juan B. Carda

Appl. Sci. 2022, 12(10), 5023; https://doi.org/10.3390/app12105023 - 16 May 2022

Cited by 25 | Viewed by 4417

Abstract

In this study, ZnO/Ag nanocomposites were synthesized using a facile chemical route involving metallic precursors of zinc acetate dehydrate and silver acetate, and dissolving the two metallic precursors in EtOH. The final concentration of the solution was 0.4 M. The different nanocomposites were [...] Read more.

In this study, ZnO/Ag nanocomposites were synthesized using a facile chemical route involving metallic precursors of zinc acetate dehydrate and silver acetate, and dissolving the two metallic precursors in EtOH. The final concentration of the solution was 0.4 M. The different nanocomposites were synthesized using different atomic percentages of silver to compare the amount of silver nanoparticles with the bactericidal power of the nanocomposites. They were prepared at concentrations of 0, 1, 3, 5, 7, and 10 at%. The as-prepared nanocomposites were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM) and scanning transmission electron microscopy (STEM) to study their structural and morphological properties. SEM showed that there is a clear effect of Ag on the size of the ZnO particles, since when silver percentages of 1 at% are included, the grain size obtained is much smaller than that of the ZnO synthesis. The effect is maintained for 3, 5, 7, and 10 at% silver. Transmission electron microscopy (TEM) compositional mapping confirms the presence of spherical nanoparticles in the synthesized samples. The size of the nanoparticles ranges from about 10 to about 30 nm. In addition, UV-Vis and Raman spectroscopy were performed to obtain structural details. The different samples show an increase in the absorption in the visible range due to the incorporation of the silver NPs. Measurement of the antimicrobial activity was tested against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) It is shown that zinc oxide has bactericidal power for these two groups of bacteria and also that when it is used together with silver NP, this effect improves, eliminating more than 90% of inoculated bacteria. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 2105 KiB

Open AccessArticle

Artemisia dracunculus L. Ethanolic Extract and an Isolated Component, DMC2, Ameliorate Inflammatory Signaling in Pancreatic β-Cells via Inhibition of p38 MAPK

by Peter Smoak, Susan J. Burke, Thomas M. Martin, Heidi M. Batdorf, Z. Elizabeth Floyd and J. Jason Collier

Biomolecules 2022, 12(5), 708; https://doi.org/10.3390/biom12050708 - 15 May 2022

Cited by 4 | Viewed by 2397

Abstract

Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. [...] Read more.

Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. Herein, we described the use of 2′,4′-dihydroxy-4-methoxydihydrochalcone (DMC2), a bioactive molecule isolated from an ethanolic extract of Artemisia dracunculus L., as a novel anti-inflammatory agent. The ethanolic extract, termed PMI 5011, reduced IL-1β-mediated NF-κB activity. DMC2 retained this ability, indicating this compound as the likely source of anti-inflammatory activity within the overall PMI 5011 extract. We further examined NF-κB activity using promoter-luciferase reporter constructs, Western blots, mRNA abundance, and protein secretion. Specifically, we found that PMI 5011 and DMC2 each reduced the ability of IL-1β to promote increases in the expression of the Ccl2 and Ccl20 genes. These genes encode proteins that promote immune cell recruitment and are secreted by β-cells in response to IL-1β. Phosphorylation of IκBα and the p65 subunit of NF-κB were not reduced by either PMI 5011 or DMC2; however, phosphorylation of p38 MAPK was blunted in the presence of DMC2. Finally, we observed that while PMI 5011 impaired glucose-stimulated insulin secretion, insulin output was preserved in the presence of DMC2. In conclusion, PMI 5011 and DMC2 reduced inflammation, but only DMC2 did so with the preservation of glucose-stimulated insulin secretion. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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10 pages, 3854 KiB

Open AccessBrief Report

Significant Sex Differences in the Efficacy of the CSF1R Inhibitor-PLX5622 on Rat Brain Microglia Elimination

by Aviv Sharon, Hadas Erez and Micha E. Spira

Pharmaceuticals 2022, 15(5), 569; https://doi.org/10.3390/ph15050569 - 2 May 2022

Cited by 16 | Viewed by 3275

Abstract

Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor [...] Read more.

Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R). The inhibition of CSF1R by brain-permeant PLX5622 in the chow eliminates, within 5–10 days, ~90% of the microglia in female and male mice, thereby enabling the investigation of the roles of the microglia in health and pathological mice models. Because of a prevailing “impression” that PLX5622 is ineffective in rats, it has hardly been used in studies of adult rats. Here, we report that effective microglia elimination by PLX5622-chow in rats is highly sex-dependent. Our observations provide missing information for the limited use and interpretation of PLX5622 in biomedical studies of the microglia in rat models. The sex differences that are too often overlooked must be carefully considered and clearly emphasized. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 3297 KiB

Open AccessArticle

Antifungal Thiazolidines: Synthesis and Biological Evaluation of Mycosidine Congeners

by Igor B. Levshin, Alexander Y. Simonov, Sergey N. Lavrenov, Alexey A. Panov, Natalia E. Grammatikova, Alexander A. Alexandrov, Eslam S. M. O. Ghazy, Nikita A. Savin, Peter V. Gorelkin, Alexander S. Erofeev and Vladimir I. Polshakov

Pharmaceuticals 2022, 15(5), 563; https://doi.org/10.3390/ph15050563 - 1 May 2022

Cited by 17 | Viewed by 3779

Abstract

Novel derivatives of Mycosidine (3,5-substituted thiazolidine-2,4-diones) are synthesized by Knoevenagel condensation and reactions of thiazolidines with chloroformates or halo-acetic acid esters. Furthermore, 5-Arylidene-2,4-thiazolidinediones and their 2-thioxo analogs containing halogen and hydroxy groups or di(benzyloxy) substituents in 5-benzylidene moiety are tested for antifungal activity [...] Read more.

Novel derivatives of Mycosidine (3,5-substituted thiazolidine-2,4-diones) are synthesized by Knoevenagel condensation and reactions of thiazolidines with chloroformates or halo-acetic acid esters. Furthermore, 5-Arylidene-2,4-thiazolidinediones and their 2-thioxo analogs containing halogen and hydroxy groups or di(benzyloxy) substituents in 5-benzylidene moiety are tested for antifungal activity in vitro. Some of the synthesized compounds exhibit high antifungal activity, both fungistatic and fungicidal, and lead to morphological changes in the Candida yeast cell wall. Based on the use of limited proteomic screening and toxicity analysis in mutants, we show that Mycosidine activity is associated with glucose transport. This suggests that this first-in-class antifungal drug has a novel mechanism of action that deserves further study. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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26 pages, 5935 KiB

Open AccessArticle

Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX-2

by Povilas Kavaliauskas, Felipe Stambuk Opazo, Waldo Acevedo, Ruta Petraitiene, Birutė Grybaitė, Kazimieras Anusevičius, Vytautas Mickevičius, Sergey Belyakov and Vidmantas Petraitis

Pharmaceuticals 2022, 15(5), 541; https://doi.org/10.3390/ph15050541 - 27 Apr 2022

Cited by 15 | Viewed by 3462

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing [...] Read more.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds 9–16 showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood–brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 6203 KiB

Open AccessArticle

Administration of Hookworm Excretory/Secretory Proteins Improves Glucose Tolerance in a Mouse Model of Type 2 Diabetes

by Zainab Khudhair, Rafid Alhallaf, Ramon M. Eichenberger, Matt Field, Lutz Krause, Javier Sotillo and Alex Loukas

Biomolecules 2022, 12(5), 637; https://doi.org/10.3390/biom12050637 - 26 Apr 2022

Cited by 12 | Viewed by 3465

Abstract

Diabetes is recognised as the world’s fastest growing chronic condition globally. Helminth infections have been shown to be associated with a lower prevalence of type 2 diabetes (T2D), in part due to their ability to induce a type 2 immune response. Therefore, to [...] Read more.

Diabetes is recognised as the world’s fastest growing chronic condition globally. Helminth infections have been shown to be associated with a lower prevalence of type 2 diabetes (T2D), in part due to their ability to induce a type 2 immune response. Therefore, to understand the molecular mechanisms that underlie the development of T2D-induced insulin resistance, we treated mice fed on normal or diabetes-promoting diets with excretory/secretory products (ES) from the gastrointestinal helminth Nippostrongylus brasiliensis. We demonstrated that treatment with crude ES products from adult worms (AES) or infective third-stage larvae (L3ES) from N. brasiliensis improved glucose tolerance and attenuated body weight gain in mice fed on a high glycaemic index diet. N. brasiliensis ES administration to mice was associated with a type 2 immune response measured by increased eosinophils and IL-5 in peripheral tissues but not IL-4, and with a decrease in the level of IL-6 in adipose tissue and corresponding increase in IL-6 levels in the liver. Moreover, treatment with AES or L3ES was associated with significant changes in the community composition of the gut microbiota at the phylum and order levels. These data highlight a role for N. brasiliensis ES in modulating the immune response associated with T2D, and suggest that N. brasiliensis ES contain molecules with therapeutic potential for treating metabolic syndrome and T2D. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 1900 KiB

Open AccessArticle

Cobalt Bis-Dicarbollide Enhances Antibiotics Action towards Staphylococcus epidermidis Planktonic Growth Due to Cell Envelopes Disruption

by Eva Vaňková, Kristýna Lokočová, Petra Kašparová, Romana Hadravová, Ivana Křížová, Olga Maťátková, Jan Masák and Václav Šícha

Pharmaceuticals 2022, 15(5), 534; https://doi.org/10.3390/ph15050534 - 26 Apr 2022

Cited by 11 | Viewed by 2727

Abstract

The emergence of antibiotic resistance in opportunistic pathogens represents a huge problem, the solution for which may be a treatment with a combination of multiple antimicrobial agents. Sodium salt of cobalt bis-dicarbollide (COSAN.Na) is one of the very stable, low-toxic, amphiphilic boron-rich sandwich [...] Read more.

The emergence of antibiotic resistance in opportunistic pathogens represents a huge problem, the solution for which may be a treatment with a combination of multiple antimicrobial agents. Sodium salt of cobalt bis-dicarbollide (COSAN.Na) is one of the very stable, low-toxic, amphiphilic boron-rich sandwich complex heteroboranes. This compound has a wide range of potential applications in the biological sciences due to its antitumor, anti-HIV-1, antimicrobial and antibiofilm activity. Our study confirmed the ability of COSAN.Na (in the concentration range 0.2–2.48 µg/mL) to enhance tetracycline, erythromycin, and vancomycin action towards Staphylococcus epidermidis planktonic growth with an additive or synergistic effect (e.g., the combination of 1.24 µg/mL COSAN.Na and 6.5 µg/mL TET). The effective inhibitory concentration of antibiotics was reduced up to tenfold most efficiently in the case of tetracycline (from 65 to 6.5 µg/mL). In addition, strong effect of COSAN.Na on disruption of the cell envelopes was determined using propidium iodide uptake measurement and further confirmed by transmission electron microscopy. The combination of amphiphilic COSAN.Na with antibiotics can therefore be considered a promising way to overcome antibiotic resistance in Gram-positive cocci. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 2221 KiB

Open AccessArticle

Possible Association between the Use of Proton Pump Inhibitors and H₂ Receptor Antagonists, and Esophageal Cancer: A Nested Case–Control Study Using a Korean National Health Screening Cohort

by Hyo Geun Choi, Hong Kyu Lee, Ho Suk Kang, Hyun Lim, Joo-Hee Kim, Ji Hee Kim, Nan Young Kim, Seong-Jin Cho, Eun Sook Nam, Kyueng-Whan Min and Mi Jung Kwon

Pharmaceuticals 2022, 15(5), 517; https://doi.org/10.3390/ph15050517 - 22 Apr 2022

Cited by 13 | Viewed by 3709

Abstract

Although safety concerns regarding proton pump inhibitor (PPI)/H2-receptor antagonists (H2RA) in the incident esophageal cancer have been raised, the Asian-based report is unclear. We investigated the estimated likelihood of incident esophageal cancer—its mortality depending on prior history of PPI/H2RA use—and gastroesophageal reflux disease [...] Read more.

Although safety concerns regarding proton pump inhibitor (PPI)/H2-receptor antagonists (H2RA) in the incident esophageal cancer have been raised, the Asian-based report is unclear. We investigated the estimated likelihood of incident esophageal cancer—its mortality depending on prior history of PPI/H2RA use—and gastroesophageal reflux disease (GERD) in Koreans. Using the Korean National Health Insurance Service-Health Screening Cohort data (2002–2015), a case–control study was retrospectively conducted, including 811 patients with incident esophageal cancer and 3244 controls matched with sex, age, income, and residence. Propensity score overlap weighting was adjusted to balance the baseline covariates. Overlap propensity score-weighted logistic regression analyses were assessed to determine associations of the prior exposure of PPI/H2RA (current vs. past) and the medication duration (<30-, 30–90-, vs. ≥90-days) with incident esophageal cancer and its mortality among the total participants or those with/without the GERD episodes, after adjusting for multiple covariates including PPI/H2RA. The current exposure to either PPI or H2RA showed higher odds for incident esophageal cancer than the nonuser group ([13.23; 95%CI 10.25–17.06] and [4.34; 95%CI 3.67–5.14], respectively), especially in all adults over the age of 40 years without GERD. Both current and past exposures to PPI showed a decreased probability of mortality compared with those of the nonuser group ([0.62; 95%CI 0.45–0.86] and [0.41; 95%CI 0.25–0.67], respectively). However, current or past exposure to H2RA harbored the mutually different likelihoods for mortality depending on the presence of GERD and old age. This study carefully speculates on the possible link between PPI/H2RA and incident esophageal cancer in the Korean population. Mortality appears to be affected by certain risk factors depending on drug types, exposure history, old age, and the presence of GERD. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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22 pages, 4477 KiB

Open AccessArticle

Design and Synthesis of a Novel 4-aryl-N-(2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide DGG200064 Showed Therapeutic Effect on Colon Cancer through G2/M Arrest

by Eun-Sil Lee, Nayeon Kim, Joon Hee Kang, Aizhan Abdildinova, Seon-Hyeong Lee, Myung Hwi Lee, Nam Sook Kang, Tae-Sung Koo, Soo-Youl Kim and Young-Dae Gong

Pharmaceuticals 2022, 15(5), 502; https://doi.org/10.3390/ph15050502 - 20 Apr 2022

Cited by 5 | Viewed by 3177

Abstract

Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its [...] Read more.

Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its properties, compound DGG200064 was tested in vivo through a xenograft mouse model of colorectal cancer using HCT116 cells. The in vivo results showed high cell growth inhibition efficacy. Our results confirmed that the newly synthesized DGG200064 inhibits the growth of colorectal cancer cells by inducing G2/M arrest. Unlike the known cell cycle inhibitors, DGG200064 (GI₅₀ = 12 nM in an HCT116 cell-based assay) induced G2/M arrest by selectively inhibiting the interaction of FBXW7 and c-Jun proteins. Additionally, the physicochemical properties of the lead compounds were analyzed. Based on the results of the study, we suggested further development of DGG200064 as a novel oral anti-colorectal cancer drug. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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22 pages, 10315 KiB

Open AccessArticle

Comparative Studies on the Antioxidant, Antifungal, and Wound Healing Activities of Solenostemma arghel Ethyl Acetate and Methanolic Extracts

by Fatma F. Abdel-Motaal, Zainab M. Maher, Samah F. Ibrahim, Amany El-Mleeh, Maged Behery and Asmaa A. Metwally

Appl. Sci. 2022, 12(9), 4121; https://doi.org/10.3390/app12094121 - 19 Apr 2022

Cited by 10 | Viewed by 6486

Abstract

Various herbal compounds are used for medical purposes due to their safety, as there are no or minimal side effects. This study was performed to assess the wound healing and antioxidant activities of ethyl acetate (EtOAc) and methanolic extract (MeoH) of Solenostemma arghel [...] Read more.

Various herbal compounds are used for medical purposes due to their safety, as there are no or minimal side effects. This study was performed to assess the wound healing and antioxidant activities of ethyl acetate (EtOAc) and methanolic extract (MeoH) of Solenostemma arghel (S. arghel). Their antifungal activities were also evaluated against isolated swabs of equine wounds. They underwent GC-MS analysis for the characterization of both extracts. For wound healing evaluation, forty-five male albino rats were divided into three groups; the control group was treated with normal saline, and the other two groups were treated with S. arghel EtOAc and MeoH extract gels, respectively. The wounds were examined clinicopathologically and immunohistochemistry on the 3rd, 7th, and 14th days post-wounding. GC-Ms analysis of S. arghel recorded fifty-one volatile organic compounds (VOCs) within EtOAc extraction and thirty VOCs in MeoH extract. VOCs represented in EtOAc extract showed higher antioxidant activity and better and faster wound healing than VOCs of MeOH extract. The treated groups showed improved wound healing clinically and pathologically in comparison with the control group as they decreased the wound surface area (WSA) and percent (WSA%) and increased the wound contraction percent (WC%), epithelization, fibroblast proliferation with neovascularization, and reduced the inflammatory reaction. Moreover, the treated groups showed higher expression of vascular endothelial growth factor (VEGF) compared with the control. The EtOAc extract showed higher antifungal activity against Penicillium funiculosum, P. jensenii, M. cinctum, and Candida albicans, which were isolated from infected clinical equine wounds, than MeOH extract. The treated groups showed improved wound healing clinically and pathologically in comparison with the control group as they decreased the wound surface area (WSA) and percent (WSA%) and increased the wound contraction percent (WC%), epithelization, fibroblast proliferation with neovascularization, and reduced the inflammatory reaction. Moreover, the treated groups showed higher expression of vascular endothelial growth factor (VEGF) compared with the control. Additionally, the two extract gels showed promising healing of equine wounds. In conclusion, the study recommended the use of S. arghel EtOAc extract as it was proven to promote wound healing compared with MeoH extract. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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18 pages, 4342 KiB

Open AccessArticle

Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway

by Dandan Chen, Yanan Duan, Shuxiang Yu, Xinwen Zhang, Ni Li and Jingya Li

Pharmaceuticals 2022, 15(4), 469; https://doi.org/10.3390/ph15040469 - 13 Apr 2022

Cited by 6 | Viewed by 3378

Abstract

Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, [...] Read more.

Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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20 pages, 1135 KiB

Open AccessReview

Recent Advances in Green Synthesis, Characterization, and Applications of Bioactive Metallic Nanoparticles

by Shabaaz J. P. Begum, S. Pratibha, Janhvi M. Rawat, Divya Venugopal, Prashant Sahu, Abhilash Gowda, Kamal A. Qureshi and Mariusz Jaremko

Pharmaceuticals 2022, 15(4), 455; https://doi.org/10.3390/ph15040455 - 8 Apr 2022

Cited by 88 | Viewed by 7408

Abstract

Nanoparticles (NPs) are elements derived from a cluster of atoms with one or more dimensions in the nanometer scale in the range of 1–100 nm. The bio nanofabrication of metallic NPs is now an important dynamic area of research, with major significance in [...] Read more.

Nanoparticles (NPs) are elements derived from a cluster of atoms with one or more dimensions in the nanometer scale in the range of 1–100 nm. The bio nanofabrication of metallic NPs is now an important dynamic area of research, with major significance in applied research. Biogenic synthesis of NPs is more desirable than physical and chemical synthesis due to its eco-friendliness, non-toxicity, lower energy consumption, and multifunctional nature. Plants outperform microorganisms as reducing agents as they contain large secondary biomolecules that accelerate the reduction and stability of the NPs. The produced NPs can then be studied spectroscopically (UV-Visible, XRD, Raman, IR, etc.) and microscopically (SEM, TEM, AFM, etc.). The biological reduction of a metallic ion or its oxide to a nanoparticle is quick, simple, and may be scaled up at room temperature and pressure. The rise in multi-drug resistant (MDR) microbes due to the immoderate use of antibiotics in non-infected patients is a major cause of morbidity and mortality in humans. The contemporary development of a new class of antibiotics with different mechanisms of action to kill microbes is crucial. Metals and their oxides are extremely toxic to microbes at unprecedentedly low concentrations. In addition, prevailing infections in plants and animals are raising significant concerns across the globe. NPs’ wide range of bioactivity makes them ideal antimicrobial agents in agricultural and medical fields. The present review outlines the synthesis of metallic NPs from botanicals, which enables the metals to be in a stabilized form even after ionization. It also presents a valuable database on the biofunctionalization of synthesized NPs for further drug development. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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7 pages, 1672 KiB

Open AccessArticle

Biosynthesis of (±)-Differolide, an Antioxidant Isolate from Streptomyces qaidamensis S10^T

by Yujie Wu, Wei Zhang, Kan Jiang, Xue Yu, Shiyu Wu, Guangxiu Liu and Tuo Chen

Appl. Sci. 2022, 12(8), 3741; https://doi.org/10.3390/app12083741 - 8 Apr 2022

Viewed by 1837

Abstract

Streptomyces from unexplored or underexplored environments may be an essential source of discoveries of bioactive molecules. One such example is Streptomyces qaidamensis S10^T, which was isolated from a sand sample collected in Qaidam Basin, Qinghai Province, China. Here, we report [...] Read more.

Streptomyces from unexplored or underexplored environments may be an essential source of discoveries of bioactive molecules. One such example is Streptomyces qaidamensis S10^T, which was isolated from a sand sample collected in Qaidam Basin, Qinghai Province, China. Here, we report on (±)-differolide, an antioxidant isolated from S. qaidamensis, and verified with scavenging experiments on 2,2-diphenyl-1-picrylhydrazyl (DPPH). The biosynthetic gene cluster responsible for synthesizing the compound was also identified using comparative genomic methods. These results provide a basis for further study of the biological activities of (±)-differolide, which also make it possible to develop as an antioxidant medicine. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 3778 KiB

Open AccessArticle

Synthesis, Characterization and Biological Activities of New Schiff Base Compound and Its Lanthanide Complexes

by Abdel-Aziz Abu-Yamin, Maisa Siddiq Abduh, Sultan Ayesh Mohammed Saghir and Naif Al-Gabri

Pharmaceuticals 2022, 15(4), 454; https://doi.org/10.3390/ph15040454 - 7 Apr 2022

Cited by 47 | Viewed by 4447

Abstract

The thermal condensation of 3-(2-Furyl)acrolein with 2-Amino-6-ethoxybenzothiazole generated a new Schiff base, (1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-imine (L), with general formula of C₁₆H₁₄N₂O₂S. Also, a series of lanthanide complexes of gadolinium, samarium, and neodymium (La– [...] Read more.

The thermal condensation of 3-(2-Furyl)acrolein with 2-Amino-6-ethoxybenzothiazole generated a new Schiff base, (1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-imine (L), with general formula of C₁₆H₁₄N₂O₂S. Also, a series of lanthanide complexes of gadolinium, samarium, and neodymium (La–Lc) were synthesized utilizing acetonitrile as the solvent and triethylamine as a buffer and catalyst. Based on elemental analysis, mass spectroscopy, and FTIR analysis, all of the Bis-(1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-iminetri-nitratolanthanide(III) complexes with the general formula [LnL₂(NO₃)₃]·H₂O are solids with a 2:1 molar ratio (ligand: metal). Based on conductivity estimates, they are nonelectrolytes and monoatomic paramagnetic according to the magnetic moment measurements, and one mole of lattice water was found after thermal gravimetric measurements and FTIR analysis. Therefore, the lanthanide complexes show a ten-coordination structure with a deformed bicapped square antiprismatic. The Schiff base and its complexes were screened for their antimicrobial, antifungal, antioxidant, and antitumor properties. Their antimicrobial and antifungal activities were strong, and they also produced good antioxidant and antitumor effects. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 1929 KiB

Open AccessArticle

Antibacterial Fractions from Erodium cicutarium Exposed—Clinical Strains of Staphylococcus aureus in Focus

by Vanja Ljoljić Bilić, Uroš M. Gašić, Dušanka Milojković-Opsenica, Hrvoje Rimac, Jadranka Vuković Rodriguez, Josipa Vlainić, Diana Brlek-Gorski and Ivan Kosalec

Antibiotics 2022, 11(4), 492; https://doi.org/10.3390/antibiotics11040492 - 6 Apr 2022

Cited by 3 | Viewed by 2899

Abstract

Followed by a buildup of its phytochemical profile, Erodium cicutarium is being subjected to antimicrobial investigation guided with its ethnobotanical use. The results of performed in vitro screening on Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans strains, show that E. cicutarium [...] Read more.

Followed by a buildup of its phytochemical profile, Erodium cicutarium is being subjected to antimicrobial investigation guided with its ethnobotanical use. The results of performed in vitro screening on Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans strains, show that E. cicutarium has antimicrobial activity, with a particular emphasis on clinical S. aureus strains—both the methicillin sensitive (MSSA) and the methicillin resistant (MRSA) S. aureus. Experimental design consisted of general methods (the serial microdilution broth assay and the agar well diffusion assay), as well as observing bactericidal/bacteriostatic activity through time (the “time-kill” assay), investigating the effect on cell wall integrity and biofilm formation, and modulation of bacterial hemolysis. Observed antibacterial activity from above-described methods led to further activity-guided fractionation of water and methanol extracts using bioautography coupled with UHPLC-LTQ OrbiTrap MS⁴. It was determined that active fractions are predominantly formed by gallic acid derivatives and flavonol glycosides. Among the most active phytochemicals, galloyl-shikimic acid was identified as the most abundant compound. These results point to a direct connection between galloyl-shikimic acid and the observed E. cicutarium antibacterial activity, and open several new research approaches for future investigation. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 1600 KiB

Open AccessArticle

Discovery of 5,7-Dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one with Lipid Lowering Effects in Hepatocytes

by Yi-Han Chang, Chia-Hung Yen, Chih-Chung Lai, Hsuan-Yu Lai and Hsin-Yi Hung

Pharmaceuticals 2022, 15(4), 449; https://doi.org/10.3390/ph15040449 - 4 Apr 2022

Cited by 2 | Viewed by 2643

Abstract

The population with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing. However, no medicine is indicated for treating these diseases clinically nowadays. Therefore, there is an urgent need to develop a new drug to overcome NAFLD and NASH. Capillarisin, a [...] Read more.

The population with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing. However, no medicine is indicated for treating these diseases clinically nowadays. Therefore, there is an urgent need to develop a new drug to overcome NAFLD and NASH. Capillarisin, a 2-phenoxychromone originating from Artemisia capillaris Thunb., is well-known for its liver-protective effects. As a result, a series of 2-phenoxychromones was prepared and evaluated for its protective activity against lipid droplet formation in oleic acid (OA)-treated Huh7 cells by means of high-content screening. In the light of the results, the compounds with trimethoxy groups on the phenyl ring possessed better inhibitory properties against lipid accumulation in Huh7 cells, compared to other functional groups on the same ring. Nonetheless, the compounds with a hydroxy group at the C-5 position of the chromone exhibited apparent cytotoxicity. Finally, the active compound, 5,7-dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one (7e), with an IC₅₀ value of 32.2 ± 2.1 μM against lipid accumulation and no significant cytotoxicity, reduced the accumulation of lipid droplets by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) to facilitate the catabolism of fat, which shows promise for further optimization to manage NAFLD and NASH. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 3755 KiB

Open AccessArticle

Preclinical Efficacy and Toxicity Analysis of the Pan-Histone Deacetylase Inhibitor Gossypol for the Therapy of Colorectal Cancer or Hepatocellular Carcinoma

by Mascha Mayer, Alexander Berger, Christian Leischner, Olga Renner, Markus Burkard, Alexander Böcker, Seema Noor, Timo Weiland, Thomas S. Weiss, Christian Busch, Ulrich M. Lauer, Stephan C. Bischoff and Sascha Venturelli

Pharmaceuticals 2022, 15(4), 438; https://doi.org/10.3390/ph15040438 - 1 Apr 2022

Cited by 13 | Viewed by 3756

Abstract

Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors [...] Read more.

Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5–50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 2700 KiB

Open AccessArticle

A Novel Allosteric Inhibitor Targets PLK1 in Triple Negative Breast Cancer Cells

by Jankiben R. Patel, Prasad Thangavelu, Renee M. Terrell, Bridg’ette Israel, Arindam Basu Sarkar, A. Michael Davidson, Kun Zhang, Rahul Khupse and Syreeta L. Tilghman

Biomolecules 2022, 12(4), 531; https://doi.org/10.3390/biom12040531 - 31 Mar 2022

Cited by 5 | Viewed by 3201

Abstract

While Polo-like kinase 1 (PLK1) inhibitors have shown promise in clinical settings for treating triple-negative breast cancer tumors and other solid tumors, they are limited by their ability to bind non-selectively to the ATP kinase domain. Therefore, we sought to develop a PLK1 [...] Read more.

While Polo-like kinase 1 (PLK1) inhibitors have shown promise in clinical settings for treating triple-negative breast cancer tumors and other solid tumors, they are limited by their ability to bind non-selectively to the ATP kinase domain. Therefore, we sought to develop a PLK1 allosteric inhibitor targeting the PLK1 T-loop (a switch responsible for activation) and evaluate its effects in triple-negative breast cancer cells. A novel compound, RK-10, was developed based on an in silico model, and its effects on specificity, viability, migration, and cell cycle regulation in MCF-10A and MDA-MB 231 cells were evaluated. When MDA-MB 231 cells were treated with 0–50 µg/mL RK-10, phospho-PLK1 (Thr-210) was decreased in cells cultured adherently and cells cultured as mammospheres. RK-10 significantly inhibited viability after 24 h; however, by 48 h, 25–50 µM RK-10 caused >50% reduction. RK-10 attenuated wound healing by up to 99.7% and caused S and G2/M cell cycle arrest, which was associated with increased p21 expression. We developed a novel allosteric inhibitor which mediates anti-proliferative and anti-migratory properties through targeting phospho-PLK1 (Thr-210) in mammospheres and causing S phase and G2/M cell cycle arrest. Further development of PLK1 allosteric inhibitors may be a promising approach for TNBC treatment. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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10 pages, 1633 KiB

Open AccessArticle

Rosmarinic Acid Attenuates the Lipopolysaccharide-Provoked Inflammatory Response of Vascular Smooth Muscle Cell via Inhibition of MAPK/NF-κB Cascade

by Ching-Pei Chen, You-Cian Lin, Yu-Hui Peng, Han-Min Chen, Jiun-Tsai Lin and Shao-Hsuan Kao

Pharmaceuticals 2022, 15(4), 437; https://doi.org/10.3390/ph15040437 - 31 Mar 2022

Cited by 15 | Viewed by 3108

Abstract

Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflammatory and antioxidant activities. Here, we further investigate the anti-inflammatory effect of RA on rat A7r5 aortic smooth muscle cells with exposure to lipopolysaccharide (LPS). Our findings showed that low-dose [...] Read more.

Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflammatory and antioxidant activities. Here, we further investigate the anti-inflammatory effect of RA on rat A7r5 aortic smooth muscle cells with exposure to lipopolysaccharide (LPS). Our findings showed that low-dose RA (10–25 μM) did not influence the cell viability and morphology of A7r5 cells and significantly inhibited LPS-induced mRNA expression of the pro-inflammatory mediators TNFα, IL-8, and inducible NO synthase (iNOS). Consistently, RA reduced the production of TNFα, IL-8, and NO by A7r5 cells with exposure to LPS. Signaling cascade analysis showed that LPS induced activation of Erk, JNK, p38 mitogen-activated protein kinase (MAPK), and NF-κB, and RA treatments attenuated the activation of the three MAPKs and NF-κB. Moreover, cotreatment with RA and Erk, JNK, p38 MAPK, or NF-κB inhibitors further downregulated the mRNA expression of TNFα, IL-8, and iNOS, and decreased the production of TNFα, IL-8, and NO by A7r5 cells. Taken together, these findings indicate that RA may ameliorate the LPS-provoked inflammatory response of vascular smooth muscle cells by inhibition of MAPK/NF-κB signaling. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 3436 KiB

Open AccessArticle

ZLN005 Alleviates In Vivo and In Vitro Renal Fibrosis via PGC-1α-Mediated Mitochondrial Homeostasis

by Pengfei Zhu, Haijian Ma, Shichao Cui, Xiqiao Zhou, Weilong Xu, Jiangyi Yu and Jingya Li

Pharmaceuticals 2022, 15(4), 434; https://doi.org/10.3390/ph15040434 - 31 Mar 2022

Cited by 11 | Viewed by 4003

Abstract

Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the [...] Read more.

Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the development of CKD. ZLN005 is a novel peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) activator from our laboratory. To explore whether ZLN005 can protect against CKD in vivo and in vitro, a unilateral ureteral obstruction (UUO) model and TGF-β1-treated renal tubular epithelial cells (TECs), respectively, were used in this study. We found that ZLN005-administrated UUO mice showed less kidney damages than control mice, as indicated by the reduced expression of fibrotic biomarkers in the kidney of UUO mice. ZLN005 treatment also alleviated the TGF-β1-induced fibrotic phenotype and lipid accumulation in TECs. Our study demonstrated ZLN005 treatment improved mitochondrial homeostasis at least partially via the activation of PGC-1α, thus maintaining mitochondria function and energy homeostasis. In summary, ZLN005 treatment ameliorates UUO-induced renal fibrosis, providing conceptional support for mitochondria-targeting therapies for chronic kidney disease. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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34 pages, 1758 KiB

Open AccessReview

Insights into Recent Studies on Biotransformation and Pharmacological Activities of Ginsenoside Rd

by Xiaoping Song, Lina Wang and Daidi Fan

Biomolecules 2022, 12(4), 512; https://doi.org/10.3390/biom12040512 - 28 Mar 2022

Cited by 28 | Viewed by 5769

Abstract

It is well known that ginsenosides—major bioactive constituents of Panax ginseng—are attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities. In recent decades, nearly 300 studies on the pharmacological activities [...] Read more.

It is well known that ginsenosides—major bioactive constituents of Panax ginseng—are attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities. In recent decades, nearly 300 studies on the pharmacological activities of Rd—as a potential treatment for a variety of diseases—have been published. However, no specific, comprehensive reviews have been documented to date. The present review not only summarizes the in vitro and in vivo studies on the health benefits of Rd, including anti-cancer, anti-diabetic, anti-inflammatory, neuroprotective, cardioprotective, ischemic stroke, immunoregulation, and other pharmacological effects, it also delves into the inclusion of potential molecular mechanisms, providing an overview of future prospects for the use of Rd in the treatment of chronic metabolic diseases and neurodegenerative disorders. Although biotransformation, pharmacokinetics, and clinical studies of Rd have also been reviewed, clinical trial data of Rd are limited; the only data available are for its treatment of acute ischemic stroke. Therefore, clinical evidence of Rd should be considered in future studies. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 1162 KiB

Open AccessArticle

The Novel Analogue of Modafinil CE-158 Protects Social Memory against Interference and Triggers the Release of Dopamine in the Nucleus Accumbens of Mice

by Karl Ebner, Simone B. Sartori, Rita Murau, Fabian Kopel, Predrag Kalaba, Vladimir Dragačević, Johann J. Leban, Nicolas Singewald, Mario Engelmann and Gert Lubec

Biomolecules 2022, 12(4), 506; https://doi.org/10.3390/biom12040506 - 27 Mar 2022

Cited by 7 | Viewed by 3642

Abstract

Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male [...] Read more.

Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male mice. Systemic administration of CE-158 1 h before the social learning event prevented the impairment of social-recognition memory following retroactive interference 3 h after the learning session of a juvenile conspecific. This effect was dose-dependent, as mice treated with 10 mg/kg, but not with 1 mg/kg CE-158, were able to discriminate between the novel and familiar conspecific despite the presentation of an interference stimulus, both 3 h and 6 h post learning. However, when 10 mg/kg of the drug was administered after learning, CE-158 failed to prevent social memory from interference. Paralleling these behavioral effects, the systemic administration of 10 mg/kg CE-158 caused a rapid and sustained elevation of extracellular dopamine in the nucleus accumbens, a brain area where dopaminergic signaling plays a key role in learning and memory function, of freely moving mice, while 1 mg/kg was not sufficient for altering dopamine levels. Taken together, our findings suggest promnestic effects of the novel dopamine-transporter-inhibitor CE-158 in a social recognition memory test that may be in part mediated via increased dopamine-neurotransmission in the nucleus accumbens. Thus, selective-dopamine-transporter-inhibitors such as CE-158 may represent interesting drug candidates for the treatment of memory complaints observed in humans with cognitive impairments and dementia. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 1550 KiB

Open AccessArticle

Natural Phaeosphaeride A Derivatives Overcome Drug Resistance of Tumor Cells and Modulate Signaling Pathways

by Victoria Abzianidze, Natalia Moiseeva, Diana Suponina, Sofya Zakharenkova, Nadezhda Rogovskaya, Lidia Laletina, Alvin A. Holder, Denis Krivorotov, Alexander Bogachenkov, Alexander Garabadzhiu, Anton Ukolov and Vyacheslav Kosorukov

Pharmaceuticals 2022, 15(4), 395; https://doi.org/10.3390/ph15040395 - 24 Mar 2022

Cited by 3 | Viewed by 2671

Abstract

In the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds [...] Read more.

In the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds on the activation of intracellular kinase cascades in A431 cells. MILLIPLEX MAP Multi-Pathway Magnetic Bead 9-Plex was used, which allowed for the simultaneous detection of the following nine phosphorylated protein markers of the main intracellular signaling pathways: a universal transcription factor that controls the expression of immune-response genes, apoptosis and cell cycle NFκB (pS536); cAMP-dependent transcription factor (CREB (pS133); mitogen-activated kinase p38 (pT180/pY182); stress-activated protein kinase JNK (pT183/pY185); ribosomal SK; transcription factors STAT3 (pS727) and STAT5A/B (pY694/699); protein kinase B (Akt) (pS473); and kinase regulated by extracellular signals ERK1/2 (pT185/pY187). The effect of various concentrations of PPA derivatives on the cell culture was studied using xCelligence RTCA equipment. The compounds were found to modulate JNK, ERK1/2, and p38 signaling pathways. The set of activated kinase cascades suggests that oxidative stress is the main probable mechanism of the toxic action of PPA derivatives. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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9 pages, 1102 KiB

Open AccessArticle

Juniper communis L. Essential Oils from Western Romanian Carpathians: Bio-Structure and Effective Antibacterial Activity

by Eugenia Dumitrescu, Florin Muselin, Carmen S. Dumitrescu, Sergiu A. Orasan-Alic, Răzvan F. Moruzi, Alexandru O. Doma, Erieg A. Mohamed and Romeo T. Cristina

Appl. Sci. 2022, 12(6), 2949; https://doi.org/10.3390/app12062949 - 14 Mar 2022

Cited by 12 | Viewed by 3807

Abstract

The antibacterial activity of four bacterial standard strains that are naturally encountered in humans and animals was investigated by using bioactive compounds from commercial essential oils of Juniperus communis that were collected from the Western Romanian Carpathians. The Juniper communis essential oils, volatile [...] Read more.

The antibacterial activity of four bacterial standard strains that are naturally encountered in humans and animals was investigated by using bioactive compounds from commercial essential oils of Juniperus communis that were collected from the Western Romanian Carpathians. The Juniper communis essential oils, volatile compounds, were recognized through the GC–MS methodology by comparing identified spectra with those held in the NIST 02, Wiley 275 library. The ratio of each component was calculated based on the peak areas of the GC, without utilizing correction factors. The CLSI standardized micro-dilution was used to determine antimicrobial activity, employing 10⁻³ dilutions of fresh culture, with inoculums equivalent to a standard of 0.5 McFarland being prepared for testing. Four bacterial strains, Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), and Streptococcus pyogenes (ATCC 19615), were investigated, using 96-well micro-dilution plates. Over each micro-dilution well, the essential oils were poured, introducing gradually 2, 4, 8, and 10 µL/well, respectively. The results were expressed as ±SEM and analyzed by one-way ANOVA with Bonferroni’s multiple comparison test, considering the differences statistically provided when p < 0.05 or lower. The juniper essential oil originating from the Western Romanian Carpathians is rich in four main volatile compounds: β-pinene (34.02%), 1α-pinene (30.43%), p-cymol (20.25%), and β-myrcene (10.20%). The juniper communis essential oil reduced bacterial density for all four strains tested, but compared to Gram-negative bacteria, in our case; a considerably higher antibacterial effectiveness was detected for Gram-positives, with peak reduction of Staphylococcus aureus, recommending the Romanian essential oil as a beneficial antibacterial resource. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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18 pages, 4861 KiB

Open AccessArticle

Discovery of APL-1030, a Novel, High-Affinity Nanofitin Inhibitor of C3-Mediated Complement Activation

by Joshua Garlich, Mathieu Cinier, Anne Chevrel, Anaëlle Perrocheau, David J. Eyerman, Mark Orme, Olivier Kitten and Lukas Scheibler

Biomolecules 2022, 12(3), 432; https://doi.org/10.3390/biom12030432 - 11 Mar 2022

Cited by 8 | Viewed by 5259

Abstract

Uncontrolled complement activation contributes to multiple immune pathologies. Although synthetic compstatin derivatives targeting C3 and C3b are robust inhibitors of complement activation, their physicochemical and molecular properties may limit access to specific organs, development of bifunctional moieties, and therapeutic applications requiring transgenic expression. [...] Read more.

Uncontrolled complement activation contributes to multiple immune pathologies. Although synthetic compstatin derivatives targeting C3 and C3b are robust inhibitors of complement activation, their physicochemical and molecular properties may limit access to specific organs, development of bifunctional moieties, and therapeutic applications requiring transgenic expression. Complement-targeting therapeutics containing only natural amino acids could enable multifunctional pharmacology, gene therapies, and targeted delivery for underserved diseases. A Nanofitin library of hyperthermophilic protein scaffolds was screened using ribosome display for C3/C3b-targeting clones mimicking compstatin pharmacology. APL-1030, a recombinant 64-residue Nanofitin, emerged as the lead candidate. APL-1030 is thermostable, binds C3 (K_D, 1.59 nM) and C3b (K_D, 1.11 nM), and inhibits complement activation via classical (IC₅₀ = 110.8 nM) and alternative (IC₅₀ = 291.3 nM) pathways in Wieslab assays. Pharmacologic activity (determined by alternative pathway inhibition) was limited to primate species of tested sera. C3b-binding sites of APL-1030 and compstatin were shown to overlap by X-ray crystallography of C3b-bound APL-1030. APL-1030 is a novel, high-affinity inhibitor of primate C3-mediated complement activation developed from natural amino acids on the hyperthermophilic Nanofitin platform. Its properties may support novel drug candidates, enabling bifunctional moieties, gene therapy, and tissue-targeted C3 pharmacologics for diseases with high unmet need. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 2154 KiB

Open AccessReview

Assessment of Avermectins-Induced Toxicity in Animals

by Muhammad Salman, Rao Zahid Abbas, Khalid Mehmood, Riaz Hussain, Sehar Shah, Mehwish Faheem, Tean Zaheer, Asghar Abbas, Bernardo Morales, Ina Aneva and José L. Martínez

Pharmaceuticals 2022, 15(3), 332; https://doi.org/10.3390/ph15030332 - 9 Mar 2022

Cited by 37 | Viewed by 8131

Abstract

Macrocyclic lactones, particularly the avermectins, have completely revolutionized the approaches aimed at control of parasites. These avermectins are the most widely used anti-parasitic drugs in veterinary field with sales exceeding one billion US dollars annually. However, before clinical usage, their safety evaluation in [...] Read more.

Macrocyclic lactones, particularly the avermectins, have completely revolutionized the approaches aimed at control of parasites. These avermectins are the most widely used anti-parasitic drugs in veterinary field with sales exceeding one billion US dollars annually. However, before clinical usage, their safety evaluation in the animals is a major critical factor that must be considered. Many studies have reported the negative effects of avermectins like ivermectin, abamectin, doramectin, and eprinomectin on the host animals. These harmful effects arise from avermectins targeting GABA and glutamate-gated chloride channels present both in the parasites and the host animals. In this review, various modes of avermectins action along with the negative effects on the host like nephrotoxicity, hepatotoxicity, neurotoxicity, reproductive toxicity, and endocrine disruption were discussed in detail. Furthermore, other important issues like ecotoxicity, drug resistance, and drug residues in milk associated with avermectins usage were also discussed, which need special attention. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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11 pages, 1483 KiB

Open AccessArticle

Investigation of the Quality of the 12 Most-Used Antibiotics Available in Retail Private Pharmacies in Rwanda

by Thomas Bizimana, Védaste Kagisha, Jean Baptiste Nyandwi, Alain Katembezi Nyirimigabo, Raymond Muganga, Marie Françoise Mukanyangezi and Egide Kayitare

Antibiotics 2022, 11(3), 329; https://doi.org/10.3390/antibiotics11030329 - 2 Mar 2022

Cited by 6 | Viewed by 4998

Abstract

Using poor-quality antibiotics leads to increased risk of the development of microorganism-resistant strains, treatment failure, loss of confidence in health systems, and associated socio-economic impacts. The prevalence of poor-quality antibiotics has been found to be high in some of the Low and Middle-Income [...] Read more.

Using poor-quality antibiotics leads to increased risk of the development of microorganism-resistant strains, treatment failure, loss of confidence in health systems, and associated socio-economic impacts. The prevalence of poor-quality antibiotics has been found to be high in some of the Low and Middle-Income Countries (LMICs), but no data were available on the situation in Rwanda. This study was conducted to obtain data and inform health professionals on the quality of the 12 most-used selected antibiotics from private retail pharmacies in Rwanda. The investigation was conducted on 232 batches collected from randomly selected private retail pharmacies in all provinces of Rwanda, and concerned only with visual inspection and assay tests. Visual inspection was performed using a tool adopted by the International Pharmaceutical Federation (FIP) to identify manufacturing defects. An assay test quantified the Active Pharmaceutical Ingredient (API) in each collected batch using high-performance liquid chromatography (HPLC) coupled with an ultraviolet-visible (UV) detector, and the results were reported as the percentage content of the amount of APIs stated on the label. A total of 232 batches were analyzed, manufactured in 10 countries; the main country of manufacture was Kenya, with almost half of the batches (49.6%). The results of the visual inspection did not show the presence of counterfeit/ falsified antibiotics on the Rwandan market in this study but revealed weaknesses in labeling: more than 90% of the analyzed batches of the 12 antibiotics did not present the dosage statement on their label, and the complete list of excipients was missing in more than 20% of the analyzed batches. The assay test using HPLC confirmed the presence of APIs in 100% of the analyzed batches. However, moderate deviations from acceptable ranges of the API content defined by M. M. Nasr & C. M. Stanley in 2006 for erythromycin and the United States Pharmacopoeia 2018 for the other 11 molecules were found. The failure rate to meet the quality requirements in terms of the percentage content of active pharmaceutical ingredients declared on the labels was estimated at 8.2% in total, with 3.9% and 4.3% containing more and less than the amount of APIs stated on the labels respectively. The most-represented antibiotics on the Rwandan market were amoxicillin, co-trimoxazole and cloxacillin. No counterfeit antibiotics were found in this study. However, substandard batches with moderate deviations were found, suggesting that regular quality control of antibiotics is needed in Rwanda. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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25 pages, 11596 KiB

Open AccessReview

Staphyloxanthin as a Potential Novel Target for Deciphering Promising Anti-Staphylococcus aureus Agents

by Rana A. Elmesseri, Sarra E. Saleh, Heba M. Elsherif, Ibrahim S. Yahia and Khaled M. Aboshanab

Antibiotics 2022, 11(3), 298; https://doi.org/10.3390/antibiotics11030298 - 23 Feb 2022

Cited by 30 | Viewed by 4933

Abstract

Staphylococcus aureus is a fatal Gram-positive pathogen threatening numerous cases of hospital-admitted patients worldwide. The emerging resistance of the pathogen to several antimicrobial agents has pressurized research to propose new strategies for combating antimicrobial resistance. Novel strategies include targeting the virulence factors of [...] Read more.

Staphylococcus aureus is a fatal Gram-positive pathogen threatening numerous cases of hospital-admitted patients worldwide. The emerging resistance of the pathogen to several antimicrobial agents has pressurized research to propose new strategies for combating antimicrobial resistance. Novel strategies include targeting the virulence factors of S. aureus. One of the most prominent virulence factors of S. aureus is its eponymous antioxidant pigment staphyloxanthin (STX), which is an auspicious target for anti-virulence therapy. This review provides an updated outline on STX and multiple strategies to attenuate this virulence factor. The approaches discussed in this article focus on bioprospective and chemically synthesized inhibitors of STX, inter-species communication and genetic manipulation. Various inhibitor molecules were found to exhibit appreciable inhibitory effect against STX and hence would be able to serve as potential anti-virulence agents for clinical use. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 3223 KiB

Open AccessArticle

Solids Turn into Liquids—Liquid Eutectic Systems of Pharmaceutics to Improve Drug Solubility

by Mafalda C. Sarraguça, Paulo R. S. Ribeiro, Cláudia Nunes and Catarina Leal Seabra

Pharmaceuticals 2022, 15(3), 279; https://doi.org/10.3390/ph15030279 - 23 Feb 2022

Cited by 11 | Viewed by 3270

Abstract

The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is [...] Read more.

The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is commonly called Therapeutic Deep Eutectic Systems (THEDES). THEDES has been gaining attention due to their properties such as non-toxicity, biodegradability, and being non-expensive and easy to prepare. Since the knowledge of the solid liquid diagram of the mixture and the ideal eutectic point is necessary to ascertain if a mixture is a deep eutectic or just a eutectic mixture that is liquid at ambient temperature, the systems studied in this work are called Therapeutic Liquid Eutectic Systems (THELES). Therefore, the strategy proposed in this work is to improve the solubility of chlorpropamide and tolbutamide by preparing THELES. Both APIs are sulfonylurea compounds used for the treatment of type 2 diabetes mellitus and have low solubility in water. To prepare the THELES, several coformers were tested, namely, tromethamine, L(+)-arginine, L-tryptophan, citric acid, malic acid, ascorbic acid, and p-aminobenzoic acid, in molar ratios of 1:1 and 1:2. To improve viscosity, water was added in different molar ratios to all systems. THELES were characterized by mid-infrared spectroscopy (MIR), and differential scanning calorimetry. Their viscosity, solubility, and permeability were also determined. Their stability at room temperature and 40 °C was accessed by MIR. Cytocompatibility was performed by metabolic activity and cell lysis evaluation, according to ISO10993-5:2009, and compared with the crystalline APIs. THELES with TRIS were successfully synthesized for both APIs. Results showed an increased solubility without a decrease in the permeability of the APIs in the THELES when compared with the pure APIs. The THELES were also considered stable for 8 weeks at ambient temperature. The cells studied showed that the THELES were not toxic for the cell lines used. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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35 pages, 9600 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition

by Mater H. Mahnashi, Fardous F. El-Senduny, Mohammed Abdulrahman Alshahrani and Mahrous A. Abou-Salim

Pharmaceuticals 2022, 15(2), 246; https://doi.org/10.3390/ph15020246 - 18 Feb 2022

Cited by 11 | Viewed by 3596

Abstract

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 [...] Read more.

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds 12a–c and 14a had the best MGI%, among the tested compounds. The target fluorinated compound 12b, as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC₅₀ values of 11.5, 11.6, and 13 µM against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound 12b (IC₅₀ = 0.092 µM) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC₅₀ = 0.049 µM). Furthermore, the ability of compound 12b in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound 12b decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for E-cadherin and N-cadherin showed lower expression of the neuronal N-cadherin and increased expression of epithelial E-cadherin, indicating the ability of 12b to suppress metastasis. Furthermore, 12b-treated HepG2 cells expressed a low level of anti-apoptotic BCL-2 and over-expressed proapoptotic Bax genes, respectively. Using the DAF-FM DA fluorescence probe, compound 12b produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of 12b with sorafenib. Interestingly, the drug-likeness properties of compound 12b met the expectations of Pfizer’s rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 2733 KiB

Open AccessArticle

Zinc-Substituted Pheophorbide A Is a Safe and Efficient Antivascular Photodynamic Agent

by Milena J. Szafraniec, Monika Toporkiewicz and Andrzej Gamian

Pharmaceuticals 2022, 15(2), 235; https://doi.org/10.3390/ph15020235 - 16 Feb 2022

Cited by 6 | Viewed by 2699

Abstract

The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to [...] Read more.

The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to cancer cells, which may necessitate the use of relatively high doses. Here we show that zinc pheophorbide a is very effective against vascular endothelial cells, even in its albumin-complexed form. Albumin complexation increases the lysosomal accumulation of the drug, thus enhancing its efficiency. Zinc pheophorbide a at nanomolar concentrations induces endothelial cell death via apoptosis, which in many cases is considered a desirable cell death mode because of its anti-inflammatory effect. Additionally, we demonstrate that in comparison to tumor cells, endothelial cells are much more susceptible to photodynamic treatment with the use of the investigated compound. Our findings demonstrate that zinc pheophorbide a is a very promising photosensitizer for use in vascular-targeted photodynamic therapy against solid tumors, acting as a vascular shutdown inducer. It can also possibly find application in the treatment of a range of vascular disorders. Numerous properties of zinc pheophorbide a are comparable or even more favorable than those of the well-known photosensitizer of a similar structure, palladium bacteriopheophorbide (TOOKAD^®). Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 3961 KiB

Open AccessArticle

Carpaine Promotes Proliferation and Repair of H9c2 Cardiomyocytes after Oxidative Insults

by Suhaini Sudi, Yee-Zheng Chin, Nur Syafinaz Wasli, Siat-Yee Fong, Sadia Choudhury Shimmi, Siew-Eng How and Caroline Sunggip

Pharmaceuticals 2022, 15(2), 230; https://doi.org/10.3390/ph15020230 - 15 Feb 2022

Cited by 6 | Viewed by 3628

Abstract

Carpaine has long been identified as the major alkaloid in Carica papaya leaves that possess muscle relaxant properties. Limited study on the molecular signaling properties of carpaine urges us to conduct this study that aims to elucidate the mechanism underlying the cardioprotective effect [...] Read more.

Carpaine has long been identified as the major alkaloid in Carica papaya leaves that possess muscle relaxant properties. Limited study on the molecular signaling properties of carpaine urges us to conduct this study that aims to elucidate the mechanism underlying the cardioprotective effect of carpaine in embryonic cardiomyocytes of the H9c2 cell line. The 50% inhibitory concentration (IC₅₀) of carpaine was first determined using a colorimetric MTT assay to establish the minimum inhibitory concentration for the subsequent test. Using a 1 µM carpaine treatment, a significant increase in the H9c2 proliferation rate was observed following 24 and 48 h of incubation. A Western blot analysis also revealed that carpaine promotes the upregulation of the cell cycle marker proteins cyclin D1 and PCNA. Carpaine-induced H9c2 cell proliferation is mediated by the activation of the FAK-ERK1/2 and FAK-AKT signaling pathways. In the setting of ischemia-reperfusion injury (IRI), carpaine provided a significant protective role to recover the wounded area affected by the hydrogen peroxide (H₂O₂) treatment. Furthermore, the oxidative-stress-induced reduction in mitochondrial membrane potential (MMP) and overproduction of reactive oxygen species (ROS) were attenuated by carpaine treatment. The current study revealed a novel therapeutic potential of carpaine in promoting in vitro cardiomyocyte proliferation and repair following injury. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 2309 KiB

Open AccessReview

Novel Nutraceutical Compounds in Alzheimer Prevention

by Ricardo Benjamin Maccioni, Camila Calfío, Andrea González and Valentina Lüttges

Biomolecules 2022, 12(2), 249; https://doi.org/10.3390/biom12020249 - 3 Feb 2022

Cited by 35 | Viewed by 8812

Abstract

Alzheimer’s disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative [...] Read more.

Alzheimer’s disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean shilajit. Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 1496 KiB

Open AccessArticle

Myricetin Increases Circulating Adropin Level after Activation of Glucagon-like Peptide 1 (GLP-1) Receptor in Type-1 Diabetic Rats

by Ying-Xiao Li, Kai-Chun Cheng, I-Min Liu and Ho-Shan Niu

Pharmaceuticals 2022, 15(2), 173; https://doi.org/10.3390/ph15020173 - 31 Jan 2022

Cited by 13 | Viewed by 3798

Abstract

Myricetin is a common plant-derived flavonoid, considered an agonist of glucagon-like peptide 1 (GLP-1) receptor. It improves glycemic control and helps reduce body weight in diabetic subjects. The potential mechanisms of action of myricetin in this context might be enhancing the secretion of [...] Read more.

Myricetin is a common plant-derived flavonoid, considered an agonist of glucagon-like peptide 1 (GLP-1) receptor. It improves glycemic control and helps reduce body weight in diabetic subjects. The potential mechanisms of action of myricetin in this context might be enhancing the secretion of β-endorphin (BER) to activate peripheral μ-opioid receptors. Moreover, adropin is a nutritionally regulated peptide hormone, which regulates energy metabolism, and plays a role in ameliorating diabetes. Because their mechanisms of insulin sensitivity are closely related, we hypothesized that myricetin may interact with adropin and plasma BER. The present study investigated the glucose-lowering effect of acute and chronic treatments of myricetin in type-1 diabetic rats. Plasma BER and adropin levels were determined by enzyme-linked immunosorbent assay (ELISA). The secretion of BER was measured in rats who received adrenalectomy. The changes in adropin gene (Enho) or mRNA level of GLP-1 receptor were measured using qPCR analysis. The results showed that myricetin dose-dependently increased plasma BER and adropin levels like the reduction of hyperglycemia after bolus injection as acute treatment. In addition, these effects of myricetin were inhibited by the antagonist of GLP-1 receptor. Moreover, in HepG2 cell line, myricetin induced GLP-1 receptor activation, which modulated the expression of adropin. In diabetic rats, the plasma adropin increased by myricetin is mainly through endogenous β-endorphin after activation of GLP-1 receptor via bolus injection as acute treatment. Additionally, chronic treatment with myricetin increased adropin secretion in diabetic rats. In conclusion, our results provide a new finding that activation of opioid μ-receptor in the liver may enhance circulating adropin in animals. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 60464 KiB

Open AccessArticle

Two Red Sea Sponge Extracts (Negombata magnifica and Callyspongia siphonella) Induced Anticancer and Antimicrobial Activity

by Hussein A. El-Naggar, Mansour A. E. Bashar, Islam Rady, Mohammad S. El-Wetidy, Waleed B. Suleiman, Fatimah O. Al-Otibi, Sara A. Al-Rashed, Lamiaa M. Abd El-Maoula, El-Sayed S. Salem, Enas M. H. Attia and Sayed Bakry

Appl. Sci. 2022, 12(3), 1400; https://doi.org/10.3390/app12031400 - 28 Jan 2022

Cited by 23 | Viewed by 4556

Abstract

Bioactive compounds extracted from marine organisms showed several biological activities. The present study is an extension of our earlier studies where we assessed the antiproliferative and pro-apoptotic activities of ethanol, methylene chloride, ethyl acetate, acetone, and chloroform crude extracts of sponges: Negombata magnifica [...] Read more.

Bioactive compounds extracted from marine organisms showed several biological activities. The present study is an extension of our earlier studies where we assessed the antiproliferative and pro-apoptotic activities of ethanol, methylene chloride, ethyl acetate, acetone, and chloroform crude extracts of sponges: Negombata magnifica (NmE) and Callyspongia siphonella (CsE) against cancer cells. Herein, we are extending our previous findings on both sponge species depending on an alternative methanol extraction method with more advanced molecular biochemical insights as additional proof for anticancer and antimicrobial activity of N. magnifica and C. siphonella. Therefore, sponge specimens were collected during winter 2020 from the Dahab region at the Gulf of Aqaba. Each sponge was macerated with methanol to obtain the crude extracts; NmE and CsE. GC–MS analysis presented a total of 117 chemical compounds; 37 bioactive, 11 represented previously as constituents for a natural organism, and 69 had no biological activities. NmE dose-dependently inhibited the growth of HepG2, MCF-7, and Caco-2 carcinoma cell lines compared to CsE, which unfortunately has no antiproliferative activity against the same cancer cells. NmE was found to induce G0/G1 cell cycle arrest in HepG2 cells with its inhibition for CDK6, Cyclins D1, and E1 in HepG2, MCF-7, and Caco-2 cells. NmE also activated ROS production in HepG2 cells and induced apoptosis in HepG2, MCF-7, and Caco-2 cells via an increase in pro-apoptotic protein Bax, caspase-3, and cleavage PARP, and a decrease in anti-apoptotic protein BCL2. Unlike its anticancer potential, CsE exhibited clear superior results as an antimicrobial agent with a wider range against six microbial strains, whereas NmE showed a positive antibacterial activity against only two strains. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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10 pages, 7939 KiB

Open AccessArticle

Treatment of Bone Defects Resulted after Excision of Enchondroma of the Hand in 15 Patients, Comparing the Techniques of Autologous Bone Graft, Injectable Bone Substitute and Spontaneous Healing

by Petru Ciobanu, Andrian Panuta, Iulian Radu, Norin Forna, Stefanita Arcana, Razvan Tudor, Alexandru Covaciu, Victor Niculescu, Vladimir Poroch and Bogdan Puha

Appl. Sci. 2022, 12(3), 1300; https://doi.org/10.3390/app12031300 - 26 Jan 2022

Cited by 6 | Viewed by 7093

Abstract

Background: Enchondroma is the most common benign bone tumor of the hand. Surgical excision of the tumor using curettage is the treatment of choice. The management of the resulting defects is still a controversial topic in the literature. Methods: This retrospective study includes [...] Read more.

Background: Enchondroma is the most common benign bone tumor of the hand. Surgical excision of the tumor using curettage is the treatment of choice. The management of the resulting defects is still a controversial topic in the literature. Methods: This retrospective study includes 15 patients diagnosed with solitary enchondroma in the hand bones: eight cases with type A, three cases with type B and four cases with type D according to Takigawa classification. The aim of this study was to compare the course and outcome in the three patient groups treated by curettage associated with natural consolidation of the bone defect, autologous bone graft or injectable synthetic bone substitute in association with plate and screw osteosynthesis. Results: Outcomes were assessed using the DASH score (mean score 2.5) and TAM score (excellent in all patients) with no significant functional differences between the three groups. Defects managed with k-IBS^® injectable bone substitute were associated with shorter operating time, simpler surgical technique and less postoperative pain assessed by VAS score. Conclusion: The use of k-IBS^® bone substitute is efficient and less technically demanding than autologous bone grafting. The Takigawa classification could be a good indicator for treatment choice. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 3039 KiB

Open AccessArticle

Aescin Protects against Experimental Benign Prostatic Hyperplasia and Preserves Prostate Histomorphology in Rats via Suppression of Inflammatory Cytokines and COX-2

by Mohamed Raafat, Amr A. Kamel, Alaa H. Shehata, Al-Shaimaa F. Ahmed, Asmaa M. A. Bayoumi, Rabab A. Moussa, Mohammed A. S. Abourehab and Mahmoud El-Daly

Pharmaceuticals 2022, 15(2), 130; https://doi.org/10.3390/ph15020130 - 22 Jan 2022

Cited by 19 | Viewed by 5625

Abstract

Background: Benign prostatic hyperplasia (BPH) is the most common urogenital condition in aging males, while inflammation and tissue proliferation constitute the main pathophysiological factors. The adverse effects of currently available BPH medications limit patient compliance. We tested the protective effect of aescin against [...] Read more.

Background: Benign prostatic hyperplasia (BPH) is the most common urogenital condition in aging males, while inflammation and tissue proliferation constitute the main pathophysiological factors. The adverse effects of currently available BPH medications limit patient compliance. We tested the protective effect of aescin against the development of BPH in rats. Methods: A total of 18 male Wistar rats were divided into 3 groups: control (sesame oil 1 mL/kg, s.c.); BPH (testosterone oenanthate 3 mg/kg, s.c., in sesame oil), and BPH-aescin rats (testosterone oenanthate 3 mg/kg, s.c. + aescin 10 mg/kg/day, p.o.). All treatments continued for 4 weeks. Serum and prostatic samples were harvested for biochemical and histopathological examination. Results: Induction of BPH by testosterone increased the prostate weight and prostate weight index, serum testosterone, prostate expression of inflammatory (IL-1β, TNF-α, and COX-2), and proliferative markers (PCNA and TGF-β1). Concurrent treatment with aescin decreased the testosterone-induced increase in prostatic IL-1β, TNF-α, and COX-2 expression by 47.9%, 71.2%, and 64.4%, respectively. Moreover, aescin reduced the prostatic proliferation markers TGF-β1 and PCNA by 58.3% and 71.9%, respectively, and normalized the prostate weight. Conclusion: The results of this study showed, for the first time, that aescin protected against the development of experimental BPH in rats via its anti-inflammatory and antiproliferative effects. These findings warrant further studies to clinically repurpose aescin in the management of BPH. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 2790 KiB

Open AccessArticle

Benzaldehyde Attenuates the Fifth Stage Larval Excretory–Secretory Product of Angiostrongylus cantonensis-Induced Injury in Mouse Astrocytes via Regulation of Endoplasmic Reticulum Stress and Oxidative Stress

by Kuang-Yao Chen, Yi-Ju Chen, Chien-Ju Cheng, Kai-Yuan Jhan and Lian-Chen Wang

Biomolecules 2022, 12(2), 177; https://doi.org/10.3390/biom12020177 - 21 Jan 2022

Cited by 7 | Viewed by 3206

Abstract

Excretory–secretory products (ESPs) are the main research targets for investigating the hosts and helminths interaction. Parasitic worms can migrate to parasitic sites and avoid the host immune response by secreting this product. Angiostrongylus cantonensis is an important food-borne zoonotic parasite that causes severe [...] Read more.

Excretory–secretory products (ESPs) are the main research targets for investigating the hosts and helminths interaction. Parasitic worms can migrate to parasitic sites and avoid the host immune response by secreting this product. Angiostrongylus cantonensis is an important food-borne zoonotic parasite that causes severe neuropathological damage and symptoms, including eosinophilic meningitis or meningoencephalitis in humans. Benzaldehydes are organic compounds composed of a benzene ring and formyl substituents. This compound has anti-inflammatory and antioxidation properties. Previous studies showed that 3-hydroxybenzaldehyde (3-HBA) and 4-hydroxybenzaldehyde (4-HBA) can reduce apoptosis in A. cantonensis ESP-treated astrocytes. These results on the protective effect underlying benzaldehyde have primarily focused on cell survival. The study was designed to investigate the molecular mechanisms of endoplasmic reticulum stress (ER stress) and oxidative stress in astrocytes in A. cantonensis ESP-treated astrocytes and to evaluate the therapeutic consequent of 3-HBA and 4-HBA. First, we initially established the RNA-seq dataset in each group, including normal, ESPs, ESPs + 3-HBA, and ESPs + 4-HBA. We also found that benzaldehyde (3-HBA and 4-HBA) can stimulate astrocytes to express ER stress-related molecules after ESP treatment. The level of oxidative stress could also be decreased in astrocytes by elevating antioxidant activity and reducing ROS generation. These results suggested that benzaldehyde may be a potential therapeutic compound for human angiostrongyliasis to support brain cell survival by inducing the expression levels of ER stress- and oxidative stress-related pathways. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 2931 KiB

Open AccessArticle

Synthesis and Anti-Hepatoma Activities of U12 Derivatives Arresting G0/G1 Phase and Inducing Apoptosis by PI3K/AKT/mTOR Pathway

by Renjing Yang, Chunchun Du, Ting Cao, Guanghui Wang, Xin Jiang, Jun Gao, Ting Lin, Cuiling Sun, Rong Ding, Wenjing Tian and Haifeng Chen

Pharmaceuticals 2022, 15(1), 107; https://doi.org/10.3390/ph15010107 - 17 Jan 2022

Cited by 3 | Viewed by 3223

Abstract

Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural [...] Read more.

Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural modification and optimization of U12 were further investigated and twelve U12 derivatives were synthesized by substitution, esterification and amidation reactions. The evaluation of the cytotoxicity of synthetic derivatives against hepatoma cell lines (HepG2) indicated that U12-I, U12a-d and U12h showed more effective cytotoxic effects on the growth of HepG2 cells than U12, and the preliminary structure–activity relationship was discussed. Among them, U12a exhibited the most potent anti-hepatocellular carcinoma activity. Mechanism studies indicated that U12a inhibited HepG2 cell proliferation by arresting the G0/G1 phase, and suppressed the activation of the PI3K/AKT/mTOR pathway. Further studies showed that U12a induced HepG2 cells apoptosis through activating the caspase signaling pathway. Furthermore, U12a evidently inhibits the growth of HepG2-derived tumor xenografts in vivo without observable adverse effects. Thus, U12a might be considered as a promising candidate for the treatment of hepatocellular carcinoma. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 1682 KiB

Open AccessArticle

Antifungal Activity of Natural Compounds vs. Candida spp.: A Mixture of Cinnamaldehyde and Eugenol Shows Promising In Vitro Results

by Ilaria Maria Saracino, Claudio Foschi, Matteo Pavoni, Renato Spigarelli, Maria Chiara Valerii and Enzo Spisni

Antibiotics 2022, 11(1), 73; https://doi.org/10.3390/antibiotics11010073 - 8 Jan 2022

Cited by 37 | Viewed by 4637

Abstract

Candida spp. are commensal organisms of the skin, mucous membranes, gastrointestinal tract, blood, and vagina of animals and humans. In recent decades, the incidence of human fungal infections has increased, with Candida spp. (mainly C. albicans) infections being the most frequent, and [...] Read more.

Candida spp. are commensal organisms of the skin, mucous membranes, gastrointestinal tract, blood, and vagina of animals and humans. In recent decades, the incidence of human fungal infections has increased, with Candida spp. (mainly C. albicans) infections being the most frequent, and the treatment of fungal infections is still a clinical challenge. Colonization of the human gastrointestinal tract by Candida spp. is significant because infections (e.g., candidemia and vulvovaginal candidiasis) frequently arise from commensal microorganisms. The aim of this study was to test in vitro the antifungal activity and the eventual synergistic effect of five pure components of essential oils: cinnamaldehyde, α-pinene, limonene, eucalyptol, and eugenol. These compounds were tested on 18 Candida strains (15 C. albicans, 2 C. glabrata, and 1 C. lusitaniae) derived from a culture collection of vaginal clinical strains. Methods: Fungistatic activity was evaluated using the disk diffusion method. For fungicidal activity, microdilution and time–kill curve protocols were set up. The checkerboard method was chosen to evaluate a possible synergistic effect of these compounds when mixed. Results: Cinnamaldehyde and eugenol gave the best results, inhibiting all the Candida strains and showing a highly additive effect (FICI 0.625). The cinnamaldehyde inhibition zone (IZ), MIC, and MFC means were 69 mm, 50.05 mg/L, and 109.26 mg/L respectively. Cinnamaldehyde led to the total loss of viable Candida cells within 4 h. Eugenol IZ, MIC, and MFC means were 35.2 mm, 455.42 mg/L, and 690.09 mg/L, respectively. Eugenol led to the total loss of viable fungal cells within 1 h. Treatment with α-pinene inhibited 88.9% of Candida strains, with an IZ mean of 21.2 mm, a MIC mean of 195.41 mg/L, and a MFC mean of 251.27 mg/L; this compound led to the total loss of viable fungal cells only after 24 h. Limonene inhibited only 33.3% of the tested strains and eucalyptol did not produce an inhibition halo, so these compounds were not tested further. Conclusions: These characteristics, together with the well-known safety of cinnamaldehyde and eugenol for human use, make these two natural compounds the perfect candidates for the treatment of candidiasis. This was a pilot study, the purpose of which was to evaluate the best composition of a mixture to be used against intestinal and vulvovaginal candidiasis; in vivo studies are needed to confirm these very encouraging results. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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11 pages, 2344 KiB

Open AccessArticle

Persimmon Leaves (Diospyros kaki) Extract Enhances the Viability of Human Corneal Endothelial Cells by Improving Na⁺-K⁺-ATPase Activity

by Ramsha Afzal and Hyung Bin Hwang

Pharmaceuticals 2022, 15(1), 72; https://doi.org/10.3390/ph15010072 - 6 Jan 2022

Cited by 2 | Viewed by 2560

Abstract

The Na⁺/K⁺-ATPase, present in the basolateral membrane of human corneal endothelial cells (HCECs), is known to play an important role for corneal transparency. Na⁺/K⁺-ATPase dysfunction is one of the major causes of corneal decompensation. The [...] Read more.

The Na⁺/K⁺-ATPase, present in the basolateral membrane of human corneal endothelial cells (HCECs), is known to play an important role for corneal transparency. Na⁺/K⁺-ATPase dysfunction is one of the major causes of corneal decompensation. The ethanol extract of Diospyros kaki (EEDK) has been reported to increase corneal cell viability. Thus, we treated HCECs with EEDK and studied its effects on HCECs survival and Na⁺/K⁺-ATPase against cytotoxic drugs like staurosporine (ST) and ouabain (OU). Firstly, survival assays, (MTT assay and live dead-imaging) showed that decreased HCECs viability by ST and OU was significantly recovered by EEDK co-treatment. Secondly, Na⁺/K⁺-ATPase activity assays revealed that EEDK enhanced Na⁺/K⁺-ATPase enzymatic activity (* p < 0.01) with/without ST and OU. Finally, Na⁺/K⁺-ATPase expression analysis (Western Blot and confocal microscopy) demonstrated that EEDK treatment with/without ST and OU facilitates Na⁺/K⁺-ATPase expression in HCECs. Taken together, our findings led us to the conclusion that EEDK might aid HCECs survival in vitro by increasing the activity and expression of Na⁺/K⁺-ATPase enzyme. Since Na⁺/K⁺-ATPase activity is important to maintain cellular function of HCECs, we suggest that EEDK can be a potential effective agent against corneal edema and related corneal disorders. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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26 pages, 36015 KiB

Open AccessReview

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

by Jyothi Dhuguru, Eugene Zviagin and Rachid Skouta

Pharmaceuticals 2022, 15(1), 66; https://doi.org/10.3390/ph15010066 - 4 Jan 2022

Cited by 51 | Viewed by 13751

Abstract

Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their [...] Read more.

Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are β-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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25 pages, 3614 KiB

Open AccessReview

Some Common Medicinal Plants with Antidiabetic Activity, Known and Available in Europe (A Mini-Review)

by Monika Przeor

Pharmaceuticals 2022, 15(1), 65; https://doi.org/10.3390/ph15010065 - 4 Jan 2022

Cited by 56 | Viewed by 7685

Abstract

Diabetes is a metabolic disease that affected 9.3% of adults worldwide in 2019. Its co-occurrence is suspected to increase mortality from COVID-19. The treatment of diabetes is mainly based on the long-term use of pharmacological agents, often expensive and causing unpleasant side effects. [...] Read more.

Diabetes is a metabolic disease that affected 9.3% of adults worldwide in 2019. Its co-occurrence is suspected to increase mortality from COVID-19. The treatment of diabetes is mainly based on the long-term use of pharmacological agents, often expensive and causing unpleasant side effects. There is an alarming increase in the number of pharmaceuticals taken in Europe. The aim of this paper is to concisely collect information concerning the few antidiabetic or hypoglycaemic raw plant materials that are present in the consciousness of Europeans and relatively easily accessible to them on the market and sometimes even grown on European plantations. The following raw materials are discussed in this mini-review: Morus alba L., Cinnamomum zeylanicum J.Presl, Trigonella foenum-graecum L., Phaseolus vulgaris L., Zingiber officinale Rosc., and Panax ginseng C.A.Meyer in terms of scientifically tested antidiabetic activity and the presence of characteristic biologically active compounds and their specific properties, including antioxidant properties. The characteristics of these raw materials are based on in vitro as well as in vivo studies: on animals and in clinical studies. In addition, for each plant, the possibility to use certain morphological elements in the light of EFSA legislation is given. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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20 pages, 5218 KiB

Open AccessArticle

Immobilized Bisphosphonates as Potential Inhibitors of Bioprosthetic Calcification: Effects on Various Xenogeneic Cardiovascular Tissues

by Irina Y. Zhuravleva, Anna A. Dokuchaeva, Elena V. Karpova, Tatyana P. Timchenko, Anatoly T. Titov, Svetlana S. Shatskaya and Yuliya F. Polienko

Biomedicines 2022, 10(1), 65; https://doi.org/10.3390/biomedicines10010065 - 29 Dec 2021

Cited by 4 | Viewed by 2131

Abstract

Calcification is the major factor limiting the clinical use of bioprostheses. It may be prevented by the immobilization of bisphosphonic compounds (BPs) on the biomaterial. In this study, we assessed the accumulation and structure of calcium phosphate deposits in collagen-rich bovine pericardium (Pe) [...] Read more.

Calcification is the major factor limiting the clinical use of bioprostheses. It may be prevented by the immobilization of bisphosphonic compounds (BPs) on the biomaterial. In this study, we assessed the accumulation and structure of calcium phosphate deposits in collagen-rich bovine pericardium (Pe) and elastin-rich porcine aortic wall (Ao) and bovine jugular vein wall (Ve) cross-linked with glutaraldehyde (GA) or diepoxy compound (DE). These tissues were then modified with pamidronic (PAM) acid or 2-(2′-carboxyethylamino)ethylidene-1,1-bisphosphonic (CEABA) acid. Tissue transformations were studied using Fourier-transform infrared spectroscopy. After subcutaneous implantation of the biomaterials in 220 rats, calcification dynamics were examined using atomic absorption spectrophotometry, light microscopy after von Kossa staining, and scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy The calcium content in all GA-cross-linked tissues and DE-cross-linked Ao increased to 100–160 mg/g on day 60 after implantation. BPs prevented the accumulation of phosphates on the surface of all materials and most effectively inhibited calcification in GA-cross-linked Ao and DE-cross-linked Pe. PAM containing -OH in the R1 group was more effective than CEABA containing -H in R1. The calcification-inhibitory effect of BPs may be realized through their ability to block nucleation and prevent the growth of hydroxyapatite crystals. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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37 pages, 1911 KiB

Open AccessReview

Nigella sativa L. Phytochemistry and Pharmacological Activities: A Review (2019–2021)

by Mohammed Dalli, Oussama Bekkouch, Salah-eddine Azizi, Ali Azghar, Nadia Gseyra and Bonglee Kim

Biomolecules 2022, 12(1), 20; https://doi.org/10.3390/biom12010020 - 23 Dec 2021

Cited by 64 | Viewed by 10312

Abstract

Medicinal and aromatic plants are mainly characterized by the presence of different bioactive compounds which exhibit various therapeutic activities. In order to investigate the different pharmacological properties of different Nigella sativa extracts, a multitude of research articles published in the period between 2019 [...] Read more.

Medicinal and aromatic plants are mainly characterized by the presence of different bioactive compounds which exhibit various therapeutic activities. In order to investigate the different pharmacological properties of different Nigella sativa extracts, a multitude of research articles published in the period between 2019 and 2021 were obtained from different databases (Scopus, Science Direct, PubMed, and Web of Science), and then explored and analyzed. The analysis of the collected articles allows us to classify the phytochemicals and the pharmacological activities through their underlying molecular mechanisms, as well as to explore the pharmacological activities exhibited by several identified compounds in Nigella sativa which allow a better understanding, and better elucidation, of the bioactive compounds responsible for the pharmacological effects. Also shown are the existence of other bioactive compounds that are still unexplored and could be of great interest. This review could be taken as a guide for future studies in the field. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 1963 KiB

Open AccessArticle

Screening of the Promising Direct Thrombin Inhibitors from Haematophagous Organisms. Part I: Recombinant Analogues and Their Antithrombotic Activity In Vitro

by Maria A. Kostromina, Elena A. Tukhovskaya, Elvira R. Shaykhutdinova, Gulsara A. Slashcheva, Alina M. Ismailova, Victor A. Palikov, Yuliya A. Palikova, Igor A. Dyachenko, Irina N. Kravchenko, Elena S. Sadovnikova, Nadezhda I. Novikova, Natalia A. Perepechenova, Evgeniy A. Zayats, Yuliya A. Abramchik, Dmitry D. Lykoshin, Andrey N. Mamaev, Elena V. Grigorieva, Andrey P. Momot, Arkady N. Murashev and Roman S. Esipov

Biomedicines 2022, 10(1), 11; https://doi.org/10.3390/biomedicines10010011 - 22 Dec 2021

Cited by 5 | Viewed by 3996

Abstract

The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis(desirudin), being the first-known and most [...] Read more.

The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis(desirudin), being the first-known and most well-studied natural anticoagulant, along with recombinant analogs of haemadin from the leech Haemadipsa sylvestris, variegin from the tick Amblyomma variegatum, and anophelin from Anopheles albimanus. These polypeptides were chosen due to their high specificity and affinity for thrombin, as well as their distinctive inhibitory mechanisms. We have developed a universal scheme for the biotechnological production of these recombinant peptides as pharmaceutical substances. The anticoagulant activities of these peptides were compared using the thrombin amidolytic activity assay and prolongation of coagulation time (thrombin time, prothrombin time, and activated partial thromboplastin time) in mouse and human plasma. The preliminary results obtained suggest haemadin as the closest analog of recombinant hirudin-1, the active substance of the medicinal product Iprivask (Aventis Pharmaceuticals, USA) for the prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery. In contrast, variegin can be regarded as a natural analog of bivalirudin (Angiomax, The Medicines Company), a synthetic hirudin-1 derivative certified for the treatment of patients undergoing percutaneous coronary intervention and of patients with unstable angina pectoris after percutaneous transluminal coronary angioplasty. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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32 pages, 6738 KiB

Open AccessArticle

New Heterocyclic Combretastatin A-4 Analogs: Synthesis and Biological Activity of Styryl-2(3H)-benzothiazolones

by Gjorgji Atanasov, Rusi I. Rusew, Vladimir M. Gelev, Christo D. Chanev, Rosica Nikolova, Boris L. Shivachev, Ognyan I. Petrov and Margarita D. Apostolova

Pharmaceuticals 2021, 14(12), 1331; https://doi.org/10.3390/ph14121331 - 20 Dec 2021

Cited by 4 | Viewed by 4313

Abstract

Here, we describe the synthesis, characterization, and biological activities of a series of 26 new styryl-2(3H)-benzothiazolone analogs of combretastatin-A4 (CA-4). The cytotoxic activities of these compounds were tested in several cell lines (EA.hy926, A549, BEAS-2B, MDA-MB-231, HT-29, MCF-7, and MCF-10A), and the relations [...] Read more.

Here, we describe the synthesis, characterization, and biological activities of a series of 26 new styryl-2(3H)-benzothiazolone analogs of combretastatin-A4 (CA-4). The cytotoxic activities of these compounds were tested in several cell lines (EA.hy926, A549, BEAS-2B, MDA-MB-231, HT-29, MCF-7, and MCF-10A), and the relations between structure and cytotoxicity are discussed. From the series, compound (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzothiazolone (26Z) exhibits the most potent cytotoxic activity (IC₅₀ 0.13 ± 0.01 µM) against EA.hy926 cells. 26Z not only inhibits vasculogenesis but also disrupts pre-existing vasculature. 26Z is a microtubule-modulating agent and inhibits a spectrum of angiogenic events in EA.hy926 cells by interfering with endothelial cell invasion, migration, and proliferation. 26Z also shows anti-proliferative activity in CA-4 resistant cells with the following IC₅₀ values: HT-29 (0.008 ± 0.001 µM), MDA-MB-231 (1.35 ± 0.42 µM), and MCF-7 (2.42 ± 0.48 µM). Cell-cycle phase-specific experiments show that 26Z treatment results in G2/M arrest and mitotic spindle multipolarity, suggesting that drug-induced centrosome amplification could promote cell death. Some 26Z-treated adherent cells undergo aberrant cytokinesis, resulting in aneuploidy that perhaps contributes to drug-induced cell death. These data indicate that spindle multipolarity induction by 26Z has an exciting chemotherapeutic potential that merits further investigation. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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28 pages, 11136 KiB

Open AccessReview

A Review on Microbial Products and Their Perspective Application as Antimicrobial Agents

by Alka Rani, Khem Chand Saini, Felix Bast, Sunita Varjani, Sanjeet Mehariya, Shashi Kant Bhatia, Neeta Sharma and Christiane Funk

Biomolecules 2021, 11(12), 1860; https://doi.org/10.3390/biom11121860 - 10 Dec 2021

Cited by 41 | Viewed by 7227

Abstract

Microorganisms including actinomycetes, archaea, bacteria, fungi, yeast, and microalgae are an auspicious source of vital bioactive compounds. In this review, the existing research regarding antimicrobial molecules from microorganisms is summarized. The potential antimicrobial compounds from actinomycetes, particularly Streptomyces spp.; archaea; fungi including endophytic, [...] Read more.

Microorganisms including actinomycetes, archaea, bacteria, fungi, yeast, and microalgae are an auspicious source of vital bioactive compounds. In this review, the existing research regarding antimicrobial molecules from microorganisms is summarized. The potential antimicrobial compounds from actinomycetes, particularly Streptomyces spp.; archaea; fungi including endophytic, filamentous, and marine-derived fungi, mushroom; and microalgae are briefly described. Furthermore, this review briefly summarizes bacteriocins, halocins, sulfolobicin, etc., that target multiple-drug resistant pathogens and considers next-generation antibiotics. This review highlights the possibility of using microorganisms as an antimicrobial resource for biotechnological, nutraceutical, and pharmaceutical applications. However, more investigations are required to isolate, separate, purify, and characterize these bioactive compounds and transfer these primary drugs into clinically approved antibiotics. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 1370 KiB

Open AccessArticle

The Selective Serotonin 2A Receptor Antagonist Sarpogrelate Prevents Cardiac Hypertrophy and Systolic Dysfunction via Inhibition of the ERK1/2–GATA4 Signaling Pathway

by Kana Shimizu, Yoichi Sunagawa, Masafumi Funamoto, Hiroki Honda, Yasufumi Katanasaka, Noriyuki Murai, Yuto Kawase, Yuta Hirako, Takahiro Katagiri, Harumi Yabe, Satoshi Shimizu, Nurmila Sari, Hiromichi Wada, Koji Hasegawa and Tatsuya Morimoto

Pharmaceuticals 2021, 14(12), 1268; https://doi.org/10.3390/ph14121268 - 5 Dec 2021

Cited by 9 | Viewed by 4224

Abstract

Drug repositioning has recently emerged as a strategy for developing new treatments at low cost. In this study, we used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy. We identified the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT [...] Read more.

Drug repositioning has recently emerged as a strategy for developing new treatments at low cost. In this study, we used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy. We identified the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT_2A) receptor antagonist, and investigated the drug’s anti-hypertrophic effect in cultured cardiomyocytes and its effect on heart failure in vivo. Primary cultured cardiomyocytes pretreated with sarpogrelate were stimulated with angiotensin II, endothelin-1, or phenylephrine. Immunofluorescence staining showed that sarpogrelate suppressed the cardiomyocyte hypertrophy induced by each of the stimuli. Western blotting analysis revealed that 5-HT_2A receptor level was not changed by phenylephrine, and that sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. C57BL/6J male mice were subjected to transverse aortic constriction (TAC) surgery followed by daily oral administration of sarpogrelate for 8 weeks. Echocardiography showed that 5 mg/kg of sarpogrelate suppressed TAC-induced cardiac hypertrophy and systolic dysfunction. Western blotting revealed that sarpogrelate suppressed TAC-induced phosphorylation of ERK1/2 and GATA4. These results indicate that sarpogrelate suppresses the development of heart failure and that it does so at least in part by inhibiting the ERK1/2–GATA4 signaling pathway. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 27779 KiB

Open AccessArticle

Mechanism of Action of the Sesquiterpene Compound Helenalin in Rhabdomyosarcoma Cells

by Hakmin Mun and Helen Elizabeth Townley

Pharmaceuticals 2021, 14(12), 1258; https://doi.org/10.3390/ph14121258 - 2 Dec 2021

Cited by 6 | Viewed by 3313

Abstract

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in paediatric patients. Relapsed or refractory RMS shows very low 5-year survival rates, which urgently necessitates new chemotherapy agents. Herein, the sesquiterpene lactone, helenalin, was investigated as a new potential therapeutic agent against the [...] Read more.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in paediatric patients. Relapsed or refractory RMS shows very low 5-year survival rates, which urgently necessitates new chemotherapy agents. Herein, the sesquiterpene lactone, helenalin, was investigated as a new potential therapeutic agent against the embryonal RMS (eRMS) and alveolar RMS (aRMS) cells. We have evaluated in vitro antiproliferative efficacy of helenalin on RMS cells by the MTT and wound healing assay, and estimated several cell death pathways by flow cytometry, confocal microscopy and immunoblotting. It was shown that helenalin was able to increase reactive oxygen species levels, decrease mitochondrial membrane potential, trigger endoplasmic reticulum stress and deactivate the NF-κB pathway. Confirmation was obtained through the use of antagonistic compounds which alleviated the effects of helenalin in the corresponding pathways. Our findings demonstrate that oxidative stress is the pivotal mechanism of action of helenalin in promoting RMS cell death in vitro. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 1322 KiB

Open AccessArticle

Dissolution of Biofilm Secreted by Three Different Strains of Pseudomonas aeruginosa with Bromelain, N-Acetylcysteine, and Their Combinations

by Carly J. Carter, Krishna Pillai, Samina Badar, Ahmed H. Mekkawy, Javed Akhter, Thomas Jefferies, Sarah J. Valle and David L. Morris

Appl. Sci. 2021, 11(23), 11388; https://doi.org/10.3390/app112311388 - 1 Dec 2021

Cited by 1 | Viewed by 4291

Abstract

Bacterial infection of hernia mesh with the formation of biofilms presents a barrier to antibiotic treatment with subsequent surgical intervention and hospitalization. Hence, in the current study, we examined the effect of BromAc, a mucolytic agent, on the dissolution of biofilm formed by [...] Read more.

Bacterial infection of hernia mesh with the formation of biofilms presents a barrier to antibiotic treatment with subsequent surgical intervention and hospitalization. Hence, in the current study, we examined the effect of BromAc, a mucolytic agent, on the dissolution of biofilm formed by three different strains of Pseudomonas aeruginosa. Pseudomonas aeruginosa was carefully grown on hernia mesh and treated with various concentrations of bromelain, NAC, and their combinations at 37 °C over 4 h in vitro. Then, the biofilm dissolution activities of the agents were evaluated. Moreover, the combination index (CI) was analyzed to determine the synergy of the bromelain and NAC combination. The results indicated that biofilms were more susceptible to degradation by bromelain, whilst NAC showed growth enhancement in two of the strains. However, in combination (BromAc), the three strains were dramatically affected by the agents, with more than 80% debridement fir a suitable combination of bromelain and NAC that was also strain-specific. Hence, the current study shows that the biofilms formed by these three strains of Pseudomonas aeruginosa were adversely affected by a single treatment of BromAc, with more than 80% debridement, indicating that subsequent treatment may abolish the biofilm completely. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 5024 KiB

Open AccessArticle

7,7″-Dimethoxyagastisflavone Inhibits Proinflammatory Cytokine Release and Inflammatory Cell Recruitment through Modulating ERα Signaling

by Yi-Shin Wu, Chian-Ruei Chen, Yun-Ting Yeh, Han-Huei Lin, Yin-Hsuan Peng and Yu-Ling Lin

Biomedicines 2021, 9(12), 1778; https://doi.org/10.3390/biomedicines9121778 - 26 Nov 2021

Cited by 2 | Viewed by 2203

Abstract

Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7″-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var. Hicksii, has previously been evaluated for its antiproliferative and antineoplastic effects in cancer cells. In [...] Read more.

Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7″-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var. Hicksii, has previously been evaluated for its antiproliferative and antineoplastic effects in cancer cells. In this study, the effects of DMGF on the cytokine production and cell migration of inflammatory macrophages were investigated. The inhibition of cytokine and chemokine production by DMGF in LPS-treated macrophages was analyzed by a multiplex cytokine assay. Then, the integrin molecules used for cell adhesion and regulators of actin polymerization were observed by RT-PCR and recorded using confocal imaging. The DMGF interaction with estrogen receptor α (ERα) was modeled structurally by molecular docking and validated by an ERα reporter assay. DMGF inhibited TNF-α, IL-1β, and IL-6 production in LPS-induced macrophages. DMGF also inhibited inflammatory macrophage migration by downregulating the gene and protein expression of adhesion molecules (LFA-1 and VLA4) and regulators of actin assembly (Cdc42-Rac1 pathway). DMGF might interact with the ligand-binding domain of ERα and downregulate its transcriptional activity. These results indicated that DMGF effectively inhibited the production of proinflammatory cytokines and the recruitment of inflammatory cells through downregulating ERα signaling. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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10 pages, 2244 KiB

Open AccessArticle

Targeting Mycobacterial F-ATP Synthase C-Terminal α Subunit Interaction Motif on Rotary Subunit γ

by Amaravadhi Harikishore, Chui-Fann Wong, Priya Ragunathan, Dennis Litty, Volker Müller and Gerhard Grüber

Antibiotics 2021, 10(12), 1456; https://doi.org/10.3390/antibiotics10121456 - 26 Nov 2021

Cited by 10 | Viewed by 3119

Abstract

Mycobacteria regulate their energy (ATP) levels to sustain their survival even in stringent living conditions. Recent studies have shown that mycobacteria not only slow down their respiratory rate but also block ATP hydrolysis of the F-ATP synthase (α₃:β₃:γ:δ:ε:a [...] Read more.

Mycobacteria regulate their energy (ATP) levels to sustain their survival even in stringent living conditions. Recent studies have shown that mycobacteria not only slow down their respiratory rate but also block ATP hydrolysis of the F-ATP synthase (α₃:β₃:γ:δ:ε:a:b:b’:c₉) to maintain ATP homeostasis in situations not amenable for growth. The mycobacteria-specific α C-terminus (α533-545) has unraveled to be the major regulative of latent ATP hydrolysis. Its deletion stimulates ATPase activity while reducing ATP synthesis. In one of the six rotational states of F-ATP synthase, α533-545 has been visualized to dock deep into subunit γ, thereby blocking rotation of γ within the engine. The functional role(s) of this C-terminus in the other rotational states are not clarified yet and are being still pursued in structural studies. Based on the interaction pattern of the docked α533-545 region with subunit γ, we attempted to study the druggability of the α533-545 motif. In this direction, our computational work has led to the development of an eight-featured α533-545 peptide pharmacophore, followed by database screening, molecular docking, and pose selection, resulting in eleven hit molecules. ATP synthesis inhibition assays using recombinant ATP synthase as well as mycobacterial inverted membrane vesicles show that one of the hits, AlMF1, inhibited the mycobacterial F-ATP synthase in a micromolar range. The successful targeting of the α533-545-γ interaction motif demonstrates the potential to develop inhibitors targeting the α site to interrupt rotary coupling with ATP synthesis. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 1337 KiB

Open AccessReview

The New Role of AMP-Activated Protein Kinase in Regulating Fat Metabolism and Energy Expenditure in Adipose Tissue

by Qun Wang, Jiayi Sun, Mengyu Liu, Yaqi Zhou, Lei Zhang and Yanzhang Li

Biomolecules 2021, 11(12), 1757; https://doi.org/10.3390/biom11121757 - 24 Nov 2021

Cited by 36 | Viewed by 4779

Abstract

Obesity is characterized by excessive accumulation of fat in the body, which is triggered by a body energy intake larger than body energy consumption. Due to complications such as cardiovascular diseases, type 2 diabetes (T2DM), obstructive pneumonia and arthritis, as well as high [...] Read more.

Obesity is characterized by excessive accumulation of fat in the body, which is triggered by a body energy intake larger than body energy consumption. Due to complications such as cardiovascular diseases, type 2 diabetes (T2DM), obstructive pneumonia and arthritis, as well as high mortality, morbidity and economic cost, obesity has become a major health problem. The global prevalence of obesity, and its comorbidities is escalating at alarming rates, demanding the development of additional classes of therapeutics to reduce the burden of disease further. As a central energy sensor, the AMP-activated protein kinase (AMPK) has recently been elucidated to play a paramount role in fat synthesis and catabolism, especially in regulating the energy expenditure of brown/beige adipose tissue and the browning of white adipose tissue (WAT). This review discussed the role of AMPK in fat metabolism in adipose tissue, emphasizing its role in the energy expenditure of brown/beige adipose tissue and browning of WAT. A deeper understanding of the role of AMPK in regulating fat metabolism and energy expenditure can provide new insights into obesity research and treatment. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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18 pages, 2463 KiB

Open AccessReview

Eclipta prostrata (L.) L. (Asteraceae): Ethnomedicinal Uses, Chemical Constituents, and Biological Activities

by Deepak Timalsina and Hari Prasad Devkota

Biomolecules 2021, 11(11), 1738; https://doi.org/10.3390/biom11111738 - 22 Nov 2021

Cited by 62 | Viewed by 13293

Abstract

Eclipta prostrata (L.) L. (Syn.: Eclipta alba (L.) Hassak, Family: Asteraceae) is an important medicinal plant in the tropical and subtropical regions. It is widely used in treating various diseases of skin, liver and stomach in India, Nepal, Bangladesh, and other countries. The [...] Read more.

Eclipta prostrata (L.) L. (Syn.: Eclipta alba (L.) Hassak, Family: Asteraceae) is an important medicinal plant in the tropical and subtropical regions. It is widely used in treating various diseases of skin, liver and stomach in India, Nepal, Bangladesh, and other countries. The main aim of this review was to collect and analyze the available information on traditional uses, phytoconstituents, and biological activities of E. prostrata. The scientific information was collected from the online bibliographic databases such as Scopus, MEDLINE/PubMed, Google Scholar, SciFinder, etc. and books and proceedings. The active phytochemicals were coumestan derivatives, phenolic acid derivatives, flavonoids, triterpenoid and steroid saponins, substituted thiophenes, etc. Various extracts and isolated compounds of E. prostrata showed a wide range of biological activities such as antimicrobial, anticancer, hepatoprotective, neuroprotective and hair growth promoting activities. Relatively a few studies have been performed to reveal the exact phytoconstituents responsible for their corresponding pharmacological activities. Future studies should focus on detailed mechanism based studies using animal models and clinical studies. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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18 pages, 1597 KiB

Open AccessArticle

Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome

by Wenche Stensen, Ulli Rothweiler, Richard Alan Engh, Melissa R. Stasko, Ilya Bederman, Alberto C. S. Costa, Anders Fugelli and John S. Mjøen Svendsen

Pharmaceuticals 2021, 14(11), 1170; https://doi.org/10.3390/ph14111170 - 17 Nov 2021

Cited by 11 | Viewed by 3834

Abstract

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. [...] Read more.

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer’s disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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18 pages, 1919 KiB

Open AccessArticle

Biological Activity Evaluation and In Silico Studies of Polyprenylated Benzophenones from Garcinia celebica

by Yenni Pintauli Pasaribu, Arif Fadlan, Sri Fatmawati and Taslim Ersam

Biomedicines 2021, 9(11), 1654; https://doi.org/10.3390/biomedicines9111654 - 10 Nov 2021

Cited by 14 | Viewed by 3287

Abstract

This study aimed to isolate polyprenylated benzophenones from the rootbark of Garcinia celebica and assess their activities in vitro and in silico. The antioxidant activity was evaluated by the DPPH, ABTS, and FRAP methods. The cytotoxicity was evaluated against HeLa, MCF-7, A549, and [...] Read more.

This study aimed to isolate polyprenylated benzophenones from the rootbark of Garcinia celebica and assess their activities in vitro and in silico. The antioxidant activity was evaluated by the DPPH, ABTS, and FRAP methods. The cytotoxicity was evaluated against HeLa, MCF-7, A549, and B16 cancer cell lines. The antiplasmodial activity was performed against the chloroquine-sensitive Plasmodium falciparum strain 3D7. Molecular docking was analyzed on alpha-estrogen receptor (3ERT) and P. falciparum lactate dehydrogenase enzyme (1CET). The prediction of ADMET for the compounds was also studied. For the first time, (-)-cycloxanthochymol, isoxanthochymol, and xanthochymol were isolated from the root bark of Garcinia celebica. The antioxidant and cytotoxicity evaluation showed that all benzophenones exhibited antioxidant activity compared to gallic acid and quercetin as positive controls and also exhibited strong activity against HeLa, MCF-7, A549, and B16 cell lines compared to cisplatin as the positive control. The antiplasmodial evaluation showed that isoxanthochymol exhibited activity against the chloroquine-sensitive P. falciparum strain 3D7. In addition, the in silico molecular docking study supported in vitro activities. The ADMET analysis also indicated the isolated benzophenones are potential oral drug candidates. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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8 pages, 1723 KiB

Open AccessArticle

Glycyrol Alone or in Combination with Gefitinib Is Effective against Gefitinib-Resistant HCC827GR Lung Cancer Cells

by Shuang Zhao, Shangyun Lu, Lihong Fan and Hongbo Hu

Appl. Sci. 2021, 11(22), 10526; https://doi.org/10.3390/app112210526 - 9 Nov 2021

Cited by 1 | Viewed by 2088

Abstract

Gefitinib has been clinically demonstrated to be effective in the first-line setting for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired therapeutic resistance to gefitinib almost unavoidably develops, posing a major hurdle for its clinical utilization. Our previous study showed [...] Read more.

Gefitinib has been clinically demonstrated to be effective in the first-line setting for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired therapeutic resistance to gefitinib almost unavoidably develops, posing a major hurdle for its clinical utilization. Our previous study showed that glycyrol (GC), a representative of coumarin compounds isolated from the medicinal plant licorice, was effective against A549 lung cancer cells in both cell culture and a murine xenograft model. In this follow-up study, we evaluated the effect of glycyrol against gefitinib-resistant NSCLC and its ability to overcome the resistance using gefitinib-resistant HCC827GR cells. Results showed that glycyrol was effective against HCC827GR cells in both in vitro and in vivo. Moreover, glycyrol was able to significantly increase the sensitivity of HCC827GR cells to gefitinib, mechanistically associated with inactivating MET, which is a known important contributor to the resistance of HCC827GR cells to gefitinib. The findings of the present study suggest that glycyrol holds potential to be developed as a novel agent against gefitinib-resistant NSCLC. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 582 KiB

Open AccessReview

Antibacterial Effects of Modified Implant Abutment Surfaces for the Prevention of Peri-Implantitis—A Systematic Review

by Marie-Elise Jennes, Michael Naumann, Simon Peroz, Florian Beuer and Franziska Schmidt

Antibiotics 2021, 10(11), 1350; https://doi.org/10.3390/antibiotics10111350 - 5 Nov 2021

Cited by 16 | Viewed by 3504

Abstract

The aim of the present study was to systematically review studies investigating antibacterial implant abutment surfaces or coatings, which may suppress bacterial growth to prevent plaque-induced peri-implant inflammatory disease. Data were collected after identification of case, assay/laboratory procedure, predicate/reference standard and outcome (CAPO). [...] Read more.

The aim of the present study was to systematically review studies investigating antibacterial implant abutment surfaces or coatings, which may suppress bacterial growth to prevent plaque-induced peri-implant inflammatory disease. Data were collected after identification of case, assay/laboratory procedure, predicate/reference standard and outcome (CAPO). Seven hundred and twenty (720) records were identified through data base searching. After screening nine publications fulfilled inclusion criteria and were included. The following surfaces/coatings showed antibacterial properties: Electrochemical surface modification of titanium by the anodic spark deposition technique; doxycycline coating by cathodic polarization; silver coating by DC plasma sputter; titanium nitride; zirconium nitride and microwave assistant nano silver coating. Since the current state of the literature is rather descriptive, a meta-analysis was not performed. While several abutment coatings showed to have antibacterial capacity, some of them also influenced the behavior of investigated human cells. None of the studies investigated the long-term effect of surface modifications. Since surface changes are the main contributing factor in the development of antibacterial effects, the biodegradation behavior must be characterized to understand its durability. To date there is no effective structure, material or strategy to avoid peri-implant inflammation used as clinical routine. Furthermore, clinical studies are scarce. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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28 pages, 11365 KiB

Open AccessEditor’s ChoiceArticle

New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors

by Momen R. Fareed, Mai E. Shoman, Mohammed I. A. Hamed, Mohamed Badr, Hanin A. Bogari, Sameh S. Elhady, Tarek S. Ibrahim, Gamal El-Din A. Abuo-Rahma and Taha F. S. Ali

Pharmaceuticals 2021, 14(11), 1114; https://doi.org/10.3390/ph14111114 - 30 Oct 2021

Cited by 14 | Viewed by 3636

Abstract

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against [...] Read more.

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC₅₀ value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC₅₀ = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC₅₀ of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC₅₀s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC₅₀ = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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11 pages, 2340 KiB

Open AccessArticle

Effect of Selected Silyl Groups on the Anticancer Activity of 3,4-Dibromo-5-Hydroxy-Furan-2(5H)-One Derivatives

by Radoslaw Kitel, Anna Byczek-Wyrostek, Katarzyna Hopko, Anna Kasprzycka and Krzysztof Walczak

Pharmaceuticals 2021, 14(11), 1079; https://doi.org/10.3390/ph14111079 - 25 Oct 2021

Cited by 14 | Viewed by 2827

Abstract

The pharmacological effects of carbon to silicon bioisosteric replacements have been widely explored in drug design and medicinal chemistry. Here, we present a systematic investigation of the impact of different silyl groups on the anticancer activity of mucobromic acid (MBA) bearing furan-2(5H [...] Read more.

The pharmacological effects of carbon to silicon bioisosteric replacements have been widely explored in drug design and medicinal chemistry. Here, we present a systematic investigation of the impact of different silyl groups on the anticancer activity of mucobromic acid (MBA) bearing furan-2(5H)-one core. We describe a comprehensive characterization of obtained compounds with respect to their anticancer potency and selectivity towards cancer cells. All four novel compounds exert stronger antiproliferative activity than MBA. Moreover, 3b induce apoptosis in colon cancer cell lines. A detailed investigation of the mechanism of action revealed that 3b activity stems from the down-regulation of survivin and the activation of caspase-3. Furthermore, compound 3b attenuates the clonogenic potential of HCT-116 cells. Interestingly, we also found that depending on the type of the silyl group, compound selectivity towards cancer cells could be precisely controlled. Collectively, we demonstrated the utility of silyl groups for adjusting both the potency and selectivity of silicon-containing compounds. These data reveal a link between the types of silyl group and compound potency, which could have bearings for the design of novel silicon-based anticancer drugs. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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35 pages, 11730 KiB

Open AccessArticle

Aspirin-Based Organoiron Dendrimers as Promising Anti-Inflammatory, Anticancer, and Antimicrobial Drugs

by Alaa S. Abd-El-Aziz, Maysun R. Benaaisha, Amani A. Abdelghani, Rabin Bissessur, Laila H. Abdel-Rahman, Ahmed M. Fayez and Doaa Abou El-ezz

Biomolecules 2021, 11(11), 1568; https://doi.org/10.3390/biom11111568 - 22 Oct 2021

Cited by 17 | Viewed by 3024

Abstract

Designing nanocarriers with actions directed at a specific organ or tissue is a very promising strategy since it can significantly reduce the toxicity of a bioactive drug. In this study, an organometallic dendrimer was used to synthesize a biocompatible drug delivery system by [...] Read more.

Designing nanocarriers with actions directed at a specific organ or tissue is a very promising strategy since it can significantly reduce the toxicity of a bioactive drug. In this study, an organometallic dendrimer was used to synthesize a biocompatible drug delivery system by attaching aspirin to the periphery of the dendrimer. Our goal is to enhance the bioavailability and anticancer activity of aspirin and reduce its toxicity through successive generations of organoiron dendrimers. The biological activity of aspirin-based dendrimer complexes was evaluated. The result of antimicrobial activity of the synthesized dendrimers also demonstrated an increase in their antimicrobial activity with increased generation of the dendrimers for most types of microorganisms. This study reveals for the first time that organoiron dendrimers linked with aspirin exhibit an excellent Gram-negative activity comparable to the reference drug Gentamicin. All synthesized dendrimers were tested for their anticancer activity against breast cancer cell lines (MCF-7), hepatocellular cell lines (Hep-G2), and a non-cancer cell line, Human Embryonic Kidney (HEK293), using the MTT cell viability assay and compared against a standard anticancer drug, Doxorubicin. Compounds G3-D9-Asp and G4-D12-Asp exhibited noticeable activity against both cell lines, both of which were more effective than aspirin itself. In addition, the in vivo anti-inflammatory activity and histopathology of swollen paws showed that the designed aspirin-based dendrimers displayed significant anti-inflammatory activity; however, G2-D6-Asp showed the best anti-inflammatory activity, which was more potent than the reference drug aspirin during the same period. Moreover, the coupling of aspirin to the periphery of organoiron dendrimers showed a significant reduction in the toxicity of aspirin on the stomach. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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18 pages, 3475 KiB

Open AccessReview

Immunomodulatory Effects of a Concoction of Natural Bioactive Compounds—Mechanistic Insights

by Vani Gangwar, Amar Garg, Karan Lomore, Kalyani Korla, Shruthi S. Bhat, Raghavendra P. Rao, Mohamed Rafiq, Rajesh Kumawath, Babu V. Uddagiri and Venkatesh V. Kareenhalli

Biomedicines 2021, 9(11), 1522; https://doi.org/10.3390/biomedicines9111522 - 22 Oct 2021

Cited by 29 | Viewed by 4130

Abstract

Natural bioactive compounds derived from plant-based products are known for their biological immunomodulatory activities. They possess systemic pleiotropic effects, minimal side effects, and very low toxicities. Plant-based bioactive compounds have tremendous potential as natural therapeutic entities against various disease conditions and act as [...] Read more.

Natural bioactive compounds derived from plant-based products are known for their biological immunomodulatory activities. They possess systemic pleiotropic effects, minimal side effects, and very low toxicities. Plant-based bioactive compounds have tremendous potential as natural therapeutic entities against various disease conditions and act as anti-inflammatory, antioxidant, anti-mutagenic, anti-microbial, anti-viral, anti-tumour, anti-allergic, neuroprotective, and cardioprotective agents. A herbal formulation extract including five biologically active compounds: Apigenin, Quercetin, Betulinic acid, Oleanolic acid, and β-Sitosterol can impart several immunomodulatory effects. In this review, we systematically present the impact of these compounds on important molecular signaling pathways, including inflammation, immunity, redox metabolism, neuroinflammation, neutropenia, cell growth, apoptosis, and cell cycle. The review corroborates the beneficial effect of these compounds and shows considerable potential to be used as a safer, more cost-effective treatment for several diseases by affecting the major nodal points of various stimulatory pathways. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 804 KiB

Open AccessEditor’s ChoiceReview

Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention

by Pratibha Pandey, Fahad Khan, Huda A. Qari and Mohammad Oves

Pharmaceuticals 2021, 14(11), 1069; https://doi.org/10.3390/ph14111069 - 22 Oct 2021

Cited by 64 | Viewed by 8645

Abstract

Cancer is a complex ailment orchestrated by numerous intrinsic and extrinsic pathways. Recent research has displayed a deep interest in developing plant-based cancer therapeutics for better management of the disease and limited side effects. A wide range of plant-derived compounds have been reported [...] Read more.

Cancer is a complex ailment orchestrated by numerous intrinsic and extrinsic pathways. Recent research has displayed a deep interest in developing plant-based cancer therapeutics for better management of the disease and limited side effects. A wide range of plant-derived compounds have been reported for their anticancer potential in the quest of finding an effective therapeutic approach. Rutin (vitamin P) is a low-molecular weight flavonoid glycoside (polyphenolic compound), abundantly present in various vegetables, fruits (especially berries and citrus fruits), and medicinal herbs. Numerous studies have delineated several pharmacological properties of rutin such as its antiprotozoal, antibacterial, anti-inflammatory, antitumor, antiviral, antiallergic, vasoactive, cytoprotective, antispasmodic, hypolipidemic, antihypertensive, and antiplatelet properties. Specifically, rutin-mediated anticancerous activities have been reported in several cancerous cell lines, but the most common scientific evidence, encompassing several molecular processes and interactions, including apoptosis pathway regulation, aberrant cell signaling pathways, and oncogenic genes, has not been thoroughly studied. In this direction, we attempted to project rutin-mediated oncogenic pathway regulation in various carcinomas. Additionally, we also incorporated advanced research that has uncovered the notable potential of rutin in the modulation of several key cellular functions via interaction with mRNAs, with major emphasis on elucidating direct miRNA targets of rutin as well as the process needed to transform these approaches for developing novel therapeutic interventions for the treatment of several cancers. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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18 pages, 2761 KiB

Open AccessArticle

Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

by Kyoung Song, Nirmal Rajasekaran, Chaithanya Chelakkot, Hun Seok Lee, Seung-Mann Paek, Hobin Yang, Lina Jia, Hee Geon Park, Woo Sung Son, Yu-Jin Kim, Joon-Seok Choi, Hae Min Jeong, Young-Ger Suh, Hwayoung Yun and Young Kee Shin

Pharmaceuticals 2021, 14(10), 1060; https://doi.org/10.3390/ph14101060 - 19 Oct 2021

Cited by 6 | Viewed by 4375

Abstract

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells [...] Read more.

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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12 pages, 2504 KiB

Open AccessArticle

Unprecedented Monoterpenoid Polyprenylated Acylphloroglucinols with a Rare 6/6/5/4 Tetracyclic Core, Enhanced MCF-7 Cells’ Sensitivity to Camptothecin by Inhibiting the DNA Damage Response

by Xiang-Zhong Liu, Mi Zhou, Chun-Chun Du, Hong-Hong Zhu, Xi Lu, Shou-Lun He, Guang-Hui Wang, Ting Lin, Wen-Jing Tian and Hai-Feng Chen

Biomedicines 2021, 9(10), 1473; https://doi.org/10.3390/biomedicines9101473 - 14 Oct 2021

Cited by 8 | Viewed by 2690

Abstract

(±)-Hypersines A–C (1–3), the three pairs of enantiomerically pure monoterpenoid polyprenylated acylphloroglucinols with an unprecedented 6/6/5/4 fused ring system, were isolated from Hypericum elodeoides. Their structures, including absolute configurations, were elucidated by comprehensive spectroscopic data, single-crystal X-ray diffraction, [...] Read more.

(±)-Hypersines A–C (1–3), the three pairs of enantiomerically pure monoterpenoid polyprenylated acylphloroglucinols with an unprecedented 6/6/5/4 fused ring system, were isolated from Hypericum elodeoides. Their structures, including absolute configurations, were elucidated by comprehensive spectroscopic data, single-crystal X-ray diffraction, and quantum chemical calculations. The plausible, biosynthetic pathway of 1–3 was proposed. Moreover, the bioactivity evaluation indicated that 1a might be a novel DNA damage response inhibitor, and could enhance MCF-7 cell sensitivity to the anticancer agent, camptothecin. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 1481 KiB

Open AccessArticle

Bis-thiobarbiturates as Promising Xanthine Oxidase Inhibitors: Synthesis and Biological Evaluation

by João L. Serrano, Diana Lopes, Melani J. A. Reis, Renato E. F. Boto, Samuel Silvestre and Paulo Almeida

Biomedicines 2021, 9(10), 1443; https://doi.org/10.3390/biomedicines9101443 - 11 Oct 2021

Cited by 10 | Viewed by 2668

Abstract

Xanthine oxidase (XO) is the enzyme responsible for the conversion of endogenous purines into uric acid. Therefore, this enzyme has been associated with pathological conditions caused by hyperuricemia, such as the disease commonly known as gout. Barbiturates and their congeners thiobarbiturates represent a [...] Read more.

Xanthine oxidase (XO) is the enzyme responsible for the conversion of endogenous purines into uric acid. Therefore, this enzyme has been associated with pathological conditions caused by hyperuricemia, such as the disease commonly known as gout. Barbiturates and their congeners thiobarbiturates represent a class of heterocyclic drugs capable of influencing neurotransmission. However, in recent years a very large group of potential pharmaceutical and medicinal applications have been related to their structure. This great diversity of biological activities is directly linked to the enormous opportunities found for chemical change off the back of these findings. With this in mind, sixteen bis-thiobarbiturates were synthesized in moderate to excellent reactional yields, and their antioxidant, anti-proliferative, and XO inhibitory activity were evaluated. In general, all bis-thiobarbiturates present a good antioxidant performance and an excellent ability to inhibit XO at a concentration of 30 µM, eight of them are superior to those observed with the reference drug allopurinol (Allo), nevertheless they were not as effective as febuxostat. The most powerful bis-thiobarbiturate within this set showed in vitro IC₅₀ of 1.79 μM, which was about ten-fold better than Allo inhibition, together with suitable low cytotoxicity. In silico molecular properties such as drug-likeness, pharmacokinetics, and toxicity of this promising barbiturate were also analyzed and herein discussed. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 3453 KiB

Open AccessArticle

Quercetin Completely Ameliorates Hypoxia–Reoxygenation-Induced Pathophysiology Severity in NY1DD Transgenic Sickle Mice: Intrinsic Mild Steady State Pathophysiology of the Disease in NY1DD Is Also Reversed

by Sangeetha Thangaswamy, Craig A. Branch, Kamalakar Ambadipudi and Seetharama A. Acharya

Biomolecules 2021, 11(10), 1473; https://doi.org/10.3390/biom11101473 - 6 Oct 2021

Cited by 7 | Viewed by 2578

Abstract

The vaso-occlusive crisis (VOC) is a major complication of sickle cell disease (SCD); thus, strategies to ameliorate vaso-occlusive episodes are greatly needed. We evaluated the therapeutic benefits of quercetin in a SCD transgenic sickle mouse model. This disease model exhibited very mild disease [...] Read more.

The vaso-occlusive crisis (VOC) is a major complication of sickle cell disease (SCD); thus, strategies to ameliorate vaso-occlusive episodes are greatly needed. We evaluated the therapeutic benefits of quercetin in a SCD transgenic sickle mouse model. This disease model exhibited very mild disease pathophysiology in the steady state. The severity of the disease in the NY1DD mouse was amplified by subjecting mice to 18 h of hypoxia followed by 3 h of reoxygenation. Quercetin (200 mg/kg body weight) administered to hypoxia challenged NY1DD mice in a single intraperitoneal (i.p.) dose at the onset of reoxygenation completely ameliorated all hypoxia reoxygenation (H/R)-induced pathophysiology. Additionally, it ameliorated the mild intrinsic steady state pathophysiology. These results are comparable with those seen with semisynthetic supra plasma expanders. In control mice, C57BL/6J, hypoxia reoxygenation-induced vaso-occlusion was at significantly lower levels than in NY1DD mice, reflecting the role of sickle hemoglobin (HbS) in inducing vaso-occlusion; however, the therapeutic benefits from quercetin were significantly muted. We suggest that these findings represent a unique genotype of the NY1DD mice, i.e., the presence of high oxygen affinity red blood cells (RBCs) with chimeric HbS, composed of mouse α-chain and human β^S-chain, as well as human α-chain and mouse β-chain (besides HbS). The anti-anemia therapeutic benefits from high oxygen affinity RBCs in these mice exert disease severity modifications that synergize with the therapeutic benefits of quercetin. Combining the therapeutic benefits of high oxygen affinity RBCs generated in situ by chemical or genetic manipulation with the therapeutic benefits of antiadhesive therapies is a novel approach to treat sickle cell patients with severe pathophysiology. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 1830 KiB

Open AccessArticle

Evaluation of the Antioxidant, Antidiabetic, and Antiplasmodial Activities of Xanthones Isolated from Garcinia forbesii and Their In Silico Studies

by Johanis Wairata, Edwin Risky Sukandar, Arif Fadlan, Adi Setyo Purnomo, Muhammad Taher and Taslim Ersam

Biomedicines 2021, 9(10), 1380; https://doi.org/10.3390/biomedicines9101380 - 2 Oct 2021

Cited by 28 | Viewed by 4040

Abstract

This study aimed to isolate xanthones from Garcinia forbesii and evaluated their activity in vitro and in silico. The isolated compounds were evaluated for their antioxidant activity by DPPH, ABTS and FRAP methods. The antidiabetic activity was performed against α-glucosidase and α-amylase [...] Read more.

This study aimed to isolate xanthones from Garcinia forbesii and evaluated their activity in vitro and in silico. The isolated compounds were evaluated for their antioxidant activity by DPPH, ABTS and FRAP methods. The antidiabetic activity was performed against α-glucosidase and α-amylase enzymes. The antiplasmodial activity was evaluated using Plasmodium falciparum strain 3D7 sensitive to chloroquine. Molecular docking analysis on the human lysosomal acid-alpha-glucosidase enzyme (5NN8) and P. falciparum lactate dehydrogenase enzyme (1CET) and prediction of ADMET for the active compound, were also studied. For the first time, lichexanthone (1), subelliptenone H (2), 12b-hydroxy-des-D-garcigerrin A (3), garciniaxanthone B (4) and garcigerin A (5) were isolated from the CH₂Cl₂ extract of the stem bark of G. forbesii. Four xanthones (Compounds 2–5) showed strong antioxidant activity. In vitro α-glucosidase test showed that Compounds 2 and 5 were more active than the others, while Compound 4 was the strongest against α-amylase enzymes. In vitro antiplasmodial evaluation revealed that Compounds 2 and 3 showed inhibitory activity on P. falciparum. Molecular docking studies confirmed in vitro activity. ADMET predictions suggested that Compounds 1–5 were potential candidates for oral drugs. The isolated 2–5 can be used as promising phytotherapy in antidiabetic and antiplasmodial treatment. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 3103 KiB

Open AccessTechnical Note

Optimization of Synthesis of the Amino Lipid ECO for Effective Delivery of Nucleic Acids

by Andrew L. Schilb, Josef H. Scheidt, Amita M. Vaidya, Zhanhu Sun, Da Sun, Sangjoon Lee and Zheng-Rong Lu

Pharmaceuticals 2021, 14(10), 1016; https://doi.org/10.3390/ph14101016 - 2 Oct 2021

Cited by 6 | Viewed by 2550

Abstract

Nucleic acids are promising for a variety of therapies, such as cancer therapy and the gene therapy of genetic disorders. The therapeutic efficacy of nucleic acids is reliant on the ability of their efficient delivery to the cytosol of the target cells. Amino [...] Read more.

Nucleic acids are promising for a variety of therapies, such as cancer therapy and the gene therapy of genetic disorders. The therapeutic efficacy of nucleic acids is reliant on the ability of their efficient delivery to the cytosol of the target cells. Amino lipids have been developed to aid in the cytosolic delivery of nucleic acids. This work reports a new and efficient synthetic pathway for the lipid carrier, (1-aminoethyl) iminobis [N-(oleicylcysteinyl-1-amino-ethyl)propionamide] (ECO). The previous synthesis of the ECO was inefficient and presented poor product quality control. A solution-phase synthesis of the ECO was explored, and each intermediate product was characterized with better quality control. The ECO was synthesized with a relatively high yield and high purity. The formulations of the ECO nanoparticles were made with siRNA, miRNA, or plasmid DNA, and characterized. The transfection efficiency of the nanoparticles was evaluated in vitro over a range of N/P ratios. The nanoparticles were consistent in size with previous formulations and had primarily a positive zeta potential. The ECO/siLuc nanoparticles resulted in potent luciferase silencing with minimal cytotoxicity. The ECO/miR-200c nanoparticles mediated the efficient delivery of miR-200c into the target cells. The ECO/pCMV-GFP nanoparticles resulted in substantial GFP expression upon transfection. These results demonstrate that the solution-phase synthetic pathway produced pure ECO for the efficient intracellular delivery of nucleic acids without size limitation. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 5519 KiB

Open AccessArticle

Phenotypic Switching of B16F10 Melanoma Cells as a Stress Adaptation Response to Fe3O4/Salicylic Acid Nanoparticle Therapy

by Ion Mîndrilă, Andrei Osman, Bogdan Mîndrilă, Maria Cristina Predoi, Dan Eduard Mihaiescu and Sandra Alice Buteică

Pharmaceuticals 2021, 14(10), 1007; https://doi.org/10.3390/ph14101007 - 30 Sep 2021

Cited by 11 | Viewed by 3151

Abstract

Melanoma is a melanocyte-derived skin cancer that has a high heterogeneity due to its phenotypic plasticity, a trait that may explain its ability to survive in the case of physical or molecular aggression and to develop resistance to therapy. Therefore, the therapy modulation [...] Read more.

Melanoma is a melanocyte-derived skin cancer that has a high heterogeneity due to its phenotypic plasticity, a trait that may explain its ability to survive in the case of physical or molecular aggression and to develop resistance to therapy. Therefore, the therapy modulation of phenotypic switching in combination with other treatment modalities could become a common approach in any future therapeutic strategy. In this paper, we used the syngeneic model of B16F10 melanoma implanted in C57BL/6 mice to evaluate the phenotypic changes in melanoma induced by therapy with iron oxide nanoparticles functionalized with salicylic acid (SaIONs). The results of this study showed that the oral administration of the SaIONs aqueous dispersion was followed by phenotypic switching to highly pigmented cells in B16F10 melanoma through a cytotoxicity-induced cell selection mechanism. The hyperpigmentation of melanoma cells by the intra- or extracellular accumulation of melanic pigment deposits was another consequence of the SaIONs therapy. Additional studies are needed to assess the reversibility of SaIONs-induced phenotypic switching and the impact of tumor hyperpigmentation on B16F10 melanoma’s progression and metastasis abilities. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 3188 KiB

Open AccessArticle

Freeze-Drying Ethylcellulose Microparticles Loaded with Etoposide for In Vitro Fast Dissolution and In Vitro Cytotoxicity against Cancer Cell Types, MCF-7 and Caco-2

by Ahmed A. H. Abdellatif, Mashari A. Aldhafeeri, Waleed H. Alharbi, Fahad H. Alharbi, Waleed Almutiri, Mohammed A. Amin, Mohammed F. Aldawsari and Hamzah M. Maswadeh

Appl. Sci. 2021, 11(19), 9066; https://doi.org/10.3390/app11199066 - 29 Sep 2021

Cited by 3 | Viewed by 3282

Abstract

The aim of this study was to improve the solubility of etoposide–ethylcellulose (ET–ETO) microparticles using the freeze-drying technique. Ethylcellulose (EC) microparticles loaded with etoposide (ETO) were prepared with different drug–polymer molar ratios of 1:1, 1:3, 1:6, and 1:20 by the solvent evaporation method. [...] Read more.

The aim of this study was to improve the solubility of etoposide–ethylcellulose (ET–ETO) microparticles using the freeze-drying technique. Ethylcellulose (EC) microparticles loaded with etoposide (ETO) were prepared with different drug–polymer molar ratios of 1:1, 1:3, 1:6, and 1:20 by the solvent evaporation method. The size of the prepared microparticles was 0.088 µm. The results showed that the amount of ETO encapsulated into the microparticles was 387.3, 365.0, 350.0, and 250 µg/50 mg microparticles for microparticles with drug–polymer ratios of 1:1, 1:3, 1:6, and 1:20, respectively. The FT-IR spectra showed no chemical interaction between ETO and the polymer in the solid state. The results obtained from the dissolution experiment showed that the freeze-dried microparticles were stable in 0.1 N HCl (gastric pH) for 2 h. At pH 7.4, the ETO release was 60 to 70% within the first 15 min and approximately 100% within 30 min. Results from the application of different dissolution models showed that the equations that best fit the dissolution data for the ET–ETO microparticles at pH 7.4 were the Higuchi and Peppas model equations. The in vitro cytotoxicity assay of free ETO and freeze-dried microspheres prepared in this study with a drug–polymer ratio of 1:1 was performed in two mammalian cancer cell lines, MCF-7 (for bone cancer of the mammary organ) and Caco-2 (for mammalian epithelial colorectal adenocarcinoma). The results showed that the half-maximal inhibitory concentrations (IC50 values) for ETO and freeze-dried ET–ETO microparticles were 18.6 µM and 27.1 µM, respectively. In conclusion, freeze-dried ET–ETO is a promising formulation for developing a fast-dissolving form of ETO with a significant antiproliferative activity against the tested cell lines used in this study. It is a promising formulation for local duodenal area targeting. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 1618 KiB

Open AccessEditor’s ChoiceReview

A Proteomic View of Cellular and Molecular Effects of Cannabis

by Morteza Abyadeh, Vivek Gupta, Joao A. Paulo, Veer Gupta, Nitin Chitranshi, Angela Godinez, Danit Saks, Mafruha Hasan, Ardeshir Amirkhani, Matthew McKay, Ghasem H. Salekdeh, Paul A. Haynes, Stuart L. Graham and Mehdi Mirzaei

Biomolecules 2021, 11(10), 1411; https://doi.org/10.3390/biom11101411 - 27 Sep 2021

Cited by 20 | Viewed by 7480

Abstract

Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known [...] Read more.

Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known as cannabinoids against several diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease, schizophrenia and glaucoma; these have prompted changes in medicinal cannabis legislation. The relaxation of legal restrictions and increased socio-cultural acceptance has led to its increase in both medicinal and recreational usage. Several biochemically active components of cannabis have a range of effects on the biological system. There is an urgent need for more research to better understand the molecular and biochemical effects of cannabis at a cellular level, to understand fully its implications as a pharmaceutical drug. Proteomics technology is an efficient tool to rigorously elucidate the mechanistic effects of cannabis on the human body in a cell and tissue-specific manner, drawing conclusions associated with its toxicity as well as therapeutic benefits, safety and efficacy profiles. This review provides a comprehensive overview of both in vitro and in vivo proteomic studies involving the cellular and molecular effects of cannabis and cannabis-derived compounds. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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20 pages, 5178 KiB

Open AccessArticle

Preparation of Soluble Complex of Curcumin for the Potential Antagonistic Effects on Human Colorectal Adenocarcinoma Cells

by Jamal Moideen Muthu Mohamed, Ali Alqahtani, Barkat A. Khan, Adel Al Fatease, Taha Alqahtani, Krishnaraju Venkatesan, Fazil Ahmad, Bashar I. Alzghoul and Ali Alamri

Pharmaceuticals 2021, 14(9), 939; https://doi.org/10.3390/ph14090939 - 19 Sep 2021

Cited by 21 | Viewed by 3152

Abstract

This study was designed to investigate the effects of curcumin (CMN) soluble complex (SC) prepared by melt casting (HM) and hot-melt extrusion (HME) technology. Phase solubility (PS) study, in silico molecular modeling, aqueous solubility, drug release, and physicochemical investigation including a novel dyeing [...] Read more.

This study was designed to investigate the effects of curcumin (CMN) soluble complex (SC) prepared by melt casting (HM) and hot-melt extrusion (HME) technology. Phase solubility (PS) study, in silico molecular modeling, aqueous solubility, drug release, and physicochemical investigation including a novel dyeing test was performed to obtain an optimized complex by a central composite design (CCD). The results show that the HME-SC produces better improvements towards solubility (0.852 ± 0.02), dissolution (91.87 ± 0.21% at 30 min), with an ideal stability constant (309 and 377 M⁻¹ at 25 and 37 °C, respectively) and exhibits A_L type of isotherm indicating 1:1 stoichiometry. Intermolecular hydrogen bonding involves the formation of SC, which does not undergo any chemical modification, followed by the complete conversion of the amorphous form which was identified by XRD. The in vitro cytotoxicity showed that IC₅₀ was achieved in the SW480 (72 µM.mL⁻¹) and Caco-2 (40 µM.mL⁻¹) cells while that of pure CMN ranged from 146 to 116 µM/mL⁻¹. Apoptosis studies showed that cell death is primarily due to apoptosis, with a low rate of necrosis. In vivo toxicity, confirmed by the zebrafish model, exhibited the safety of the HME-SC. In conclusion, the HME-SC potentially enhances the solubility and cytotoxicity to the treatment of colorectal cancer (CRC). Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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10 pages, 845 KiB

Open AccessArticle

Involvement of Angiogenesis in the Pathogenesis of Coronary Aneurysms

by Sylwia Iwańczyk, Tomasz Lehmann, Artur Cieślewicz, Artur Radziemski, Katarzyna Malesza, Michał Wrotyński, Paweł Piotr Jagodziński, Marek Grygier, Maciej Lesiak and Aleksander Araszkiewicz

Biomedicines 2021, 9(9), 1269; https://doi.org/10.3390/biomedicines9091269 - 19 Sep 2021

Cited by 9 | Viewed by 2673

Abstract

The present study aimed to evaluate the plasma concentration of pro and antiangiogenic factors and their role in the pathogenesis of coronary artery abnormal dilation (CAAD). We measured the plasma concentration of matrix metalloproteinase-8 (MMP-8), transforming growth factor beta 1 (TGF-β1), Angiopoietin-2, vascular [...] Read more.

The present study aimed to evaluate the plasma concentration of pro and antiangiogenic factors and their role in the pathogenesis of coronary artery abnormal dilation (CAAD). We measured the plasma concentration of matrix metalloproteinase-8 (MMP-8), transforming growth factor beta 1 (TGF-β1), Angiopoietin-2, vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) using a sandwich ELISA technique in the plasma of patients with coronary artery abnormal dilation (CAAD, Group 1), coronary artery disease (CAD, Group 2), and normal coronary arteries (NCA, Group 3). Patients suffering from CAAD showed significantly higher plasma concentrations of VEGF (p = 0.002) than those from the control group. Both pathological angiogenesis and inflammation appear to be crucial in the pathogenesis of aneurysmal dilatation of the coronary arteries. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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11 pages, 2370 KiB

Open AccessArticle

Microwave-Assisted, One-Pot Synthesis of Doxycycline under Heterogeneous Catalysis in Water

by Fabio Bucciol, Elia Maffeis, Emanuela Calcio Gaudino, László Jicsinszky, Silvia Tagliapietra, Alessandro Barge, Cristina Prandi and Giancarlo Cravotto

Antibiotics 2021, 10(9), 1084; https://doi.org/10.3390/antibiotics10091084 - 8 Sep 2021

Cited by 1 | Viewed by 3859

Abstract

The selective synthesis of active pharmaceutical molecules is a challenging issue, particularly when attempting to make the reactions even more sustainable. The present work focuses on the microwave-assisted hydrogenolysis of oxytetracycline to selectively produce α-doxycycline. Although the combination of microwave irradiation and a [...] Read more.

The selective synthesis of active pharmaceutical molecules is a challenging issue, particularly when attempting to make the reactions even more sustainable. The present work focuses on the microwave-assisted hydrogenolysis of oxytetracycline to selectively produce α-doxycycline. Although the combination of microwave irradiation and a heterogeneous rhodium catalyst provided good conversions, the selective synthesis of active α-doxycycline was only achieved when an oxytetracycline-cyclodextrin complex was used as the starting material, giving the desired product at 34.0% yield in a one-step reaction under very mild conditions. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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7 pages, 1495 KiB

Open AccessArticle

Mitoxantrone Shows In Vitro, but Not In Vivo Antiviral Activity against Human Respiratory Syncytial Virus

by Patricia G. de la Sota, Elena Lorente, Laura Notario, Carmen Mir, Oscar Zaragoza and Daniel López

Biomedicines 2021, 9(9), 1176; https://doi.org/10.3390/biomedicines9091176 - 7 Sep 2021

Cited by 1 | Viewed by 2664

Abstract

Human respiratory syncytial virus (HRSV) is the most common cause of severe respiratory infections in infants and young children, often leading to hospitalization. In addition, this virus poses a serious health risk in immunocompromised individuals and the elderly. HRSV is also a major [...] Read more.

Human respiratory syncytial virus (HRSV) is the most common cause of severe respiratory infections in infants and young children, often leading to hospitalization. In addition, this virus poses a serious health risk in immunocompromised individuals and the elderly. HRSV is also a major nosocomial hazard in healthcare service units for patients of all ages. Therefore, the development of antiviral treatments against HRSV is a global health priority. In this study, mitoxantrone, a synthetic anthraquinone with previously reported in vitro antiprotozoal and antiviral activities, inhibits HRSV replication in vitro, but not in vivo in a mice model. These results have implications for preclinical studies of some drug candidates. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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9 pages, 1390 KiB

Open AccessArticle

Efficiency of Bromelain-Enriched Enzyme Mixture (NexoBrid™) in the Treatment of Burn Wounds

by Mihaela Pertea, Vladimir Poroch, Petru Ciobanu, Alexandru Filip, Natalia Velenciuc, Sorinel Lunca, Andrian Panuta, Mihaela Buna-Arvinte, Stefana Luca and Bogdan Veliceasa

Appl. Sci. 2021, 11(17), 8134; https://doi.org/10.3390/app11178134 - 2 Sep 2021

Cited by 12 | Viewed by 5416

Abstract

Background: The use of bromelain for the removal of eschar in deep burns is considered to be effective because it does not affect the unaffected skin and leaves a clean dermis after use. The main objective of this study is to find out [...] Read more.

Background: The use of bromelain for the removal of eschar in deep burns is considered to be effective because it does not affect the unaffected skin and leaves a clean dermis after use. The main objective of this study is to find out whether bromelain is a good alternative to surgical debridement. In order to achieve that, we aim to evaluate its indications, limitations, and safety measures. Methods: The current study was conducted on a group of 30 patients with deep burn lesions, aged 20 to 56 years, from which 15 underwent enzymatic debridement and 15 patients acted as a control group in which primary surgical debridement was used. The mixture of enzymes enriched in bromelain, meant to dissolve burn eschar, was provided by NexoBrid™. The inclusion criteria were in agreement with the manufacturer’s protocols, but the application protocol was slightly modified in order to implement a better intern protocol and to assess its efficiency. Results: Complete eschar debridement was obtained in 13 of the 15 cases, from which 10 patients went through spontaneous healing and 3 needed to be covered with a skin graft. In the other 2 cases, partial eschar debridement was associated with surgical debridement and coverage with split-thickness skin graft in the same operation. The results obtained in the two groups were assessed with the Vancouver Scar Scale. Conclusions: Even though early excision followed by coverage with split-thickness skin graft remains the gold standard for the treatment of deep burns, enzymatic debridement can provide a series of advantages when the inclusion and exclusion criteria are respected. Bromelain is an alternative to surgical debridement that provides speed, tissue selectivity, safety, and less blood loss. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 3041 KiB

Open AccessArticle

Syzygium aromaticum Extracts as a Potential Antibacterial Inhibitors against Clinical Isolates of Acinetobacter baumannii: An In-Silico-Supported In-Vitro Study

by Abdelhamed Mahmoud, Magdy M. Afifi, Fareed El Shenawy, Wesam Salem and Basem H. Elesawy

Antibiotics 2021, 10(9), 1062; https://doi.org/10.3390/antibiotics10091062 - 1 Sep 2021

Cited by 7 | Viewed by 3696

Abstract

Imipenem is the most efficient antibiotic against Acinetobacter baumannii infection, but new research has shown that the organism has also developed resistance to this agent. A. baumannii isolates from a total of 110 clinical samples were identified by multiplex PCR. The antibacterial activity [...] Read more.

Imipenem is the most efficient antibiotic against Acinetobacter baumannii infection, but new research has shown that the organism has also developed resistance to this agent. A. baumannii isolates from a total of 110 clinical samples were identified by multiplex PCR. The antibacterial activity of Syzygium aromaticum multiple extracts was assessed following the GC-Mass spectra analysis. The molecular docking study was performed to investigate the binding mode of interactions of guanosine (Ethanolic extract compound) against Penicillin- binding proteins 1 and 3 of A. baumannii. Ten isolates of A. baumannii were confirmed to carry recA and iutA genes. Isolates were multidrug-resistant containing bla_TEM and Bla_SHV. The concentrations (0.04 to 0.125 mg mL⁻¹) of S. aromaticum ethanolic extract were very promising against A. baumannii isolates. Even though imipenem (0.02 mg mL⁻¹) individually showed a great bactericidal efficacy against all isolates, the in-silico study of guanosine, apioline, eugenol, and elemicin showed acceptable fitting to the binding site of the A. baumannii PBP1 and/or PBP3 with highest binding energy for guanosine between −7.1 and −8.1 kcal/mol respectively. Moreover, it formed π-stacked interactions with the residue ARG76 at 4.14 and 5.6, Å respectively. These findings might support the in vitro study and show a substantial increase in binding affinity and enhanced physicochemical characteristics compared to imipenem. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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20 pages, 3689 KiB

Open AccessArticle

Lignosulfonic Acid Sodium Is a Noncompetitive Inhibitor of Human Factor XIa

by Srabani Kar, Page Bankston, Daniel K. Afosah and Rami A. Al-Horani

Pharmaceuticals 2021, 14(9), 886; https://doi.org/10.3390/ph14090886 - 31 Aug 2021

Cited by 13 | Viewed by 3364

Abstract

The anticoagulant activity of lignosulfonic acid sodium (LSAS), a non-saccharide heparin mimetic, was investigated in this study. LSAS is a relatively safe industrial byproduct with similar polyanionic characteristics to that of heparin. Human plasma clotting assays, fibrin polymerization testing, and enzyme inhibition assays [...] Read more.

The anticoagulant activity of lignosulfonic acid sodium (LSAS), a non-saccharide heparin mimetic, was investigated in this study. LSAS is a relatively safe industrial byproduct with similar polyanionic characteristics to that of heparin. Human plasma clotting assays, fibrin polymerization testing, and enzyme inhibition assays were exploited to investigate the anticoagulant activity of LSAS. In normal human plasma, LSAS selectively doubled the activated partial thromboplastin time (APTT) at ~308 µg/mL. Equally, LSAS doubled APTT at ~275 µg/mL in antithrombin-deficient plasma. Yet, LSAS doubled APTT at a higher concentration of 429 µg/mL using factor XI-deficient plasma. LSAS did not affect FXIIIa-mediated fibrin polymerization at 1000 µg/mL. Enzyme assays revealed that LSAS inhibits factor XIa (FXIa) with an IC₅₀ value of ~8 μg/mL. LSAS did not inhibit thrombin, factor IXa, factor Xa, factor XIIIa, chymotrypsin, or trypsin at the highest concentrations tested and demonstrated significant selectivity against factor XIIa and plasmin. In Michaelis–Menten kinetics, LSAS decreased the V_MAX of FXIa hydrolysis of a tripeptide chromogenic substrate without significantly changing its K_M indicating an allosteric inhibition mechanism. The inhibitor also disrupted the generation of FXIa–antithrombin complex, inhibited factor XIIa-mediated and thrombin-mediated activation of the zymogen factor XI to FXIa, and competed with heparin for binding to FXIa. Its action appears to be reversed by protamine sulfate. Structure–activity relationship studies demonstrated the advantageous selectivity and allosteric behavior of LSAS over the acetylated and desulfonated derivatives of LSAS. LSAS is a sulfonated heparin mimetic that demonstrates significant anticoagulant activity in human plasma. Overall, it appears that LSAS is a potent, selective, and allosteric inhibitor of FXIa with significant anticoagulant activity in human plasma. Altogether, this study introduces LSAS as a promising lead for further development as an anticoagulant. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 2045 KiB

Open AccessCommunication

Synthesis and Biological Evaluation of Honokiol Derivatives Bearing 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones as Potential Viral Entry Inhibitors against SARS-CoV-2

by Yong Guo, Jie-Ru Meng, Jia-Zheng Liu, Ting Xu, Zhi-Yuan Zheng, Zhi-Hong Jiang and Li-Ping Bai

Pharmaceuticals 2021, 14(9), 885; https://doi.org/10.3390/ph14090885 - 31 Aug 2021

Cited by 13 | Viewed by 3674

Abstract

The 2019 coronavirus disease (COVID-19) caused by SARS-CoV-2 virus infection has posed a serious danger to global health and the economy. However, SARS-CoV-2 medications that are specific and effective are still being developed. Honokiol is a bioactive component from Magnoliae officinalis Cortex with [...] Read more.

The 2019 coronavirus disease (COVID-19) caused by SARS-CoV-2 virus infection has posed a serious danger to global health and the economy. However, SARS-CoV-2 medications that are specific and effective are still being developed. Honokiol is a bioactive component from Magnoliae officinalis Cortex with damp-drying effect. To develop new potent antiviral molecules, a series of novel honokiol analogues were synthesized by introducing various 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones to its molecule. In a SARS-CoV-2 pseudovirus model, all honokiol derivatives were examined for their antiviral entry activities. As a result, 6a and 6p demonstrated antiviral entry effect with IC₅₀ values of 29.23 and 9.82 µM, respectively. However, the parental honokiol had a very weak antiviral activity with an IC₅₀ value more than 50 µM. A biolayer interfero-metry (BLI) binding assay and molecular docking study revealed that 6p binds to human ACE2 protein with higher binding affinity and lower binding energy than the parental honokiol. A competitive ELISA assay confirmed the inhibitory effect of 6p on SARS-CoV-2 spike RBD’s binding with ACE2. Importantly, 6a and 6p (TC₅₀ > 100 μM) also had higher biological safety for host cells than honokiol (TC₅₀ of 48.23 μM). This research may contribute to the discovery of potential viral entrance inhibitors for the SARS-CoV-2 virus, although 6p’s antiviral efficacy needs to be validated on SARS-CoV-2 viral strains in a biosafety level 3 facility. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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22 pages, 4344 KiB

Open AccessArticle

Lactococcus lactis Delivery of Surface Layer Protein A Protects Mice from Colitis by Re-Setting Host Immune Repertoire

by Ananta Prasad Arukha, Christian Furlan Freguia, Meerambika Mishra, Jyoti K. Jha, Subhashinie Kariyawasam, Neil A. Fanger, Ellen M. Zimmermann, Gary R. Fanger and Bikash Sahay

Biomedicines 2021, 9(9), 1098; https://doi.org/10.3390/biomedicines9091098 - 29 Aug 2021

Cited by 8 | Viewed by 4194

Abstract

Inflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation comprised of Crohn’s disease and ulcerative colitis. Centers for Disease Control and Prevention report that 1.3% of the population of the United States (approximately 3 million people) were affected by the disease in 2015, [...] Read more.

Inflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation comprised of Crohn’s disease and ulcerative colitis. Centers for Disease Control and Prevention report that 1.3% of the population of the United States (approximately 3 million people) were affected by the disease in 2015, and the number keeps increasing over time. IBD has a multifactorial etiology, from genetic to environmental factors. Most of the IBD treatments revolve around disease management, by reducing the inflammatory signals. We previously identified the surface layer protein A (SlpA) of Lactobacillus acidophilus that possesses anti-inflammatory properties to mitigate murine colitis. Herein, we expressed SlpA in a clinically relevant, food-grade Lactococcus lactis to further investigate and characterize the protective mechanisms of the actions of SlpA. Oral administration of SlpA-expressing L. lactis (R110) mitigated the symptoms of murine colitis. Oral delivery of R110 resulted in a higher expression of IL-27 by myeloid cells, with a synchronous increase in IL-10 and cMAF in T cells. Consistent with murine studies, human dendritic cells exposed to R110 showed exquisite differential gene regulation, including IL-27 transcription, suggesting a shared mechanism between the two species, hence positioning R110 as potentially effective at treating colitis in humans. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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12 pages, 3093 KiB

Open AccessArticle

Adenine Inhibits the Invasive Potential of DLD-1 Human Colorectal Cancer Cell via the AMPK/FAK Axis

by Chien-Wei Huang, You-Cian Lin, Chia-Hung Hung, Han-Min Chen, Jiun-Tsai Lin, Chau-Jong Wang and Shao-Hsuan Kao

Pharmaceuticals 2021, 14(9), 860; https://doi.org/10.3390/ph14090860 - 27 Aug 2021

Cited by 6 | Viewed by 3300

Abstract

Tumor metastasis is a major cause of death of patients with colorectal cancer (CRC). Our previous findings show that adenine has antiproliferation activity against tumor cells. However, whether adenine reduces the invasiveness of DLD-1 and SW480 CRC cells has not been thoroughly explored. [...] Read more.

Tumor metastasis is a major cause of death of patients with colorectal cancer (CRC). Our previous findings show that adenine has antiproliferation activity against tumor cells. However, whether adenine reduces the invasiveness of DLD-1 and SW480 CRC cells has not been thoroughly explored. In this study, we aimed to explore the effects of adenine on the invasion potential of DLD-1 cells. Our findings showed that adenine at concentrations of ≤200 μM did not influence the cell viability of DLD-1 and SW480 CRC cells. By contrast, adenine reduced the migratory potential of the CRC cells. Moreover, it decreased the invasion capacity of the CRC cells in a dose-dependent manner. We further observed that adenine downregulated the protein levels of tissue plasminogen activator, matrix metalloproteinase-9, Snail, TWIST, and vimentin, but upregulated the tissue inhibitor of metalloproteinase-1 expression in DLD-1 cells. Adenine decreased the integrin αV level and reduced the activation of integrin-associated signaling components, including focal adhesion kinase (FAK), paxillin, and Src in DLD-1 cells. Further observations showed that adenine induced AMP-activated protein kinase (AMPK) activation and inhibited mTOR phosphorylation in DLD-1 cells. The knockdown of AMPK restored the reduced integrin αV level and FAK/paxillin/Src signaling inhibited by adenine in DLD-1 cells. Collectively, these findings reveal that adenine reduces the invasion potential of DLD-1 cells through the AMPK/integrin/FAK axis, suggesting that adenine may have anti-metastatic potential in CRC cells. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 1470 KiB

Open AccessReview

Therapeutic Potential of Curcumin as an Antimycobacterial Agent

by Nilakshi Barua and Alak Kumar Buragohain

Biomolecules 2021, 11(9), 1278; https://doi.org/10.3390/biom11091278 - 26 Aug 2021

Cited by 25 | Viewed by 5210

Abstract

Curcumin is the principal curcuminoid obtained from the plant Curcuma longa and has been extensively studied for its biological and chemical properties. Curcumin displays a vast range of pharmacological properties, including antimicrobial, anti-inflammatory, antioxidant, and antitumor activity. Specifically, curcumin has been linked to [...] Read more.

Curcumin is the principal curcuminoid obtained from the plant Curcuma longa and has been extensively studied for its biological and chemical properties. Curcumin displays a vast range of pharmacological properties, including antimicrobial, anti-inflammatory, antioxidant, and antitumor activity. Specifically, curcumin has been linked to the improvement of the outcome of tuberculosis. There are many reviews on the pharmacological effects of curcumin; however, reviews of the antitubercular activity are comparatively scarcer. In this review, we attempt to discuss the different aspects of the research on the antitubercular activity of curcumin. These include antimycobacterial activity, modulation of the host immune response, and enhancement of BCG vaccine efficacy. Recent advances in the antimycobacterial activity of curcumin synthetic derivatives, the role of computer aided drug design in identifying curcumin targets, the hepatoprotective role of curcumin, and the dosage and toxicology of curcumin will be discussed. While growing evidence supports the use of curcumin and its derivatives for tuberculosis therapy, further preclinical and clinical investigations are of pivotal importance before recommending the use of curcumin formulations in public health. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 3003 KiB

Open AccessArticle

Bacterial-Specific Aggregation and Killing of Immunomodulatory Host Defense Peptides

by Nauman Nazeer, Juan Carlos Rodriguez-Lecompte and Marya Ahmed

Pharmaceuticals 2021, 14(9), 839; https://doi.org/10.3390/ph14090839 - 24 Aug 2021

Cited by 8 | Viewed by 2868 | Correction

Abstract

This study involves the design and development of disulfide bridge-linked antimicrobial peptides using the host defense protein Angiogenin 4 (chAng4) as a template. The mini peptides derived from chAng4 (mCA4s) were evaluated for their antibacterial efficacies in various pathogenic bacterial strains, and the [...] Read more.

This study involves the design and development of disulfide bridge-linked antimicrobial peptides using the host defense protein Angiogenin 4 (chAng4) as a template. The mini peptides derived from chAng4 (mCA4s) were evaluated for their antibacterial efficacies in various pathogenic bacterial strains, and the role of the oxidation state of thiols in the peptide sequence and its implication on antibacterial properties were explored. A remarkable property of these synthetic mCA4 peptides is their capability to flocculate bacteria and mediate bacterial-specific killing, in the absence of any other external stimulus. mCA4s were further evaluated for their cellular uptake, hemolytic activities, toxicities, and immunomodulatory activities in different eukaryotic cell lines. The results indicate that disulfide bridge-containing cationic amphipathic peptides show superior antibacterial efficacies, are nontoxic and nonhemolytic, and mediate bacterial flocculation and killing, in the absence of external stimuli. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 12178 KiB

Open AccessArticle

Gastroprotection against Rat Ulcers by Nephthea Sterol Derivative

by Tarik A. Mohamed, Abdelsamed I. Elshamy, Mahmoud A. A. Ibrahim, Mohamed A. M. Atia, Rania F. Ahmed, Sherin K. Ali, Karam A. Mahdy, Shifaa O. Alshammari, Ahmed M. Al-Abd, Mahmoud F. Moustafa, Abdel Razik H. Farrag and Mohamed-Elamir F. Hegazy

Biomolecules 2021, 11(8), 1247; https://doi.org/10.3390/biom11081247 - 21 Aug 2021

Cited by 8 | Viewed by 3520

Abstract

Different species belonging to the genus Nephthea (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine [...] Read more.

Different species belonging to the genus Nephthea (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine the anti-ulcer activity of 4α,24-dimethyl-5α-cholest-8β,18-dihydroxy,22E-en-3β-ol (ST-1) isolated from samples of a Nephthea species. This in vivo study was supported by in silico molecular docking and protein–protein interaction techniques. Oral administration of ST-1 reduced rat stomach ulcers with a concurrent increase in gastric mucosa. Molecular docking calculations against the H⁺/K⁺-ATPase transporter showed a higher binding affinity of ST-1, with a docking score value of −9.9 kcal/mol and a pK_i value of 59.7 nM, compared to ranitidine (a commercial proton pump inhibitor, which gave values of −6.2 kcal/mol and 27.9 µM, respectively). The combined PEA-reactome analysis results revealed promising evidence of ST-1 potency as an anti-ulcer compound through significant modulation of the gene set controlling the PI3K signaling pathway, which subsequently plays a crucial role in signaling regarding epithelialization and tissue regeneration, tissue repairing and tissue remodeling. These results indicate a probable protective role for ST-1 against ethanol-induced gastric ulcers. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 657 KiB

Open AccessArticle

Analyses of the Compositions, Antioxidant Capacities, and Tyrosinase-Inhibitory Activities of Extracts from Two New Varieties of Chrysanthemum morifolium Ramat Using Four Solvents

by Yen Hua Chen, Sheng Lei Yan, Jane Yii Wu, Chang Wei Hsieh, Sue Hong Wang and Ming Shiun Tsai

Appl. Sci. 2021, 11(16), 7631; https://doi.org/10.3390/app11167631 - 19 Aug 2021

Cited by 5 | Viewed by 2770

Abstract

Chrysanthemum morifolium Ramat is traditionally used as both medicine and food in China. In this study, extracts of C. morifolium Ramat Hang Ju No. 1 (No. 1) and No. 2 (No. 2) were produced using four different solvents: 95% ethanol, ethyl acetate, n-hexane [...] Read more.

Chrysanthemum morifolium Ramat is traditionally used as both medicine and food in China. In this study, extracts of C. morifolium Ramat Hang Ju No. 1 (No. 1) and No. 2 (No. 2) were produced using four different solvents: 95% ethanol, ethyl acetate, n-hexane and distilled water. In total, eight types of extracts were analyzed for extraction yields and total flavonoids, polyphenols, glycans, reducing sugars, and chlorogenic acids. The antioxidant capacities and tyrosinase-inhibitory activities of these extracts were also determined. Among them, the ethanolic extract of No. 1 (No. 1A) had the highest levels of total flavonoids (16.71 mg rutin equivalent/g dry weight (DW)), polyphenols (7.07 mg gallic acid equivalent/g DW), and chlorogenic acids (6595.46 μg/g DW) and the water extract of No. 1 (No. 1D) had the highest levels of total glycans (9.24 mg/g DW), and reducing sugars (23.32 μg/g DW). In terms of antioxidant capacity, No. 1A (1.0 mg/mL) demonstrated the best 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (96.2 ± 0.4%), ferrous ion chelating ability (55.44 ± 0.03%), and reducing power (0.988 ± 0.003). No. 1D (1.0 mg/mL) showed the highest tyrosinase inhibitory activity (39.34 ± 0.03%). From these results, high levels of total flavonoids and polyphenols correlate with antioxidant capacity. Moreover, high levels of total chlorogenic acid in No. 1A and No. 1D correlate with high levels of tyrosinase inhibitory activity. Therefore, No. 1A has the potential to be used in daily health drinks, foods and skin whitening products. These results can be applied to similar flower plant extracts. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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22 pages, 7384 KiB

Open AccessArticle

Regulation of the HTRA2 Protease Activity by an Inhibitory Antibody-Derived Peptide Ligand and the Influence on HTRA2-Specific Protein Interaction Networks in Retinal Tissues

by Carsten Schmelter, Kristian Nzogang Fomo, Natarajan Perumal, Norbert Pfeiffer and Franz H. Grus

Biomedicines 2021, 9(8), 1013; https://doi.org/10.3390/biomedicines9081013 - 13 Aug 2021

Cited by 9 | Viewed by 3236

Abstract

The mitochondrial serine protease HTRA2 has many versatile biological functions ranging from being an important regulator of apoptosis to being an essential component for neuronal cell survival and mitochondrial homeostasis. Loss of HTRA2 protease function is known to cause neurodegeneration, whereas overactivation of [...] Read more.

The mitochondrial serine protease HTRA2 has many versatile biological functions ranging from being an important regulator of apoptosis to being an essential component for neuronal cell survival and mitochondrial homeostasis. Loss of HTRA2 protease function is known to cause neurodegeneration, whereas overactivation of its proteolytic function is associated with cell death and inflammation. In accordance with this, our group verified in a recent study that the synthetic peptide ASGYTFTNYGLSWVR, encoding the hypervariable sequence part of an antibody, showed a high affinity for the target protein HTRA2 and triggered neuroprotection in an in vitro organ culture model for glaucoma. To unravel this neuroprotective mechanism, the present study showed for the first time that the synthetic CDR1 peptide significantly (p < 0.01) inhibited the proteolytic activity of HTRA2 up to 50% using a specific protease function assay. Furthermore, using state-of-the-art co-immunoprecipitation technologies in combination with high-resolution MS, we identified 50 significant protein interaction partners of HTRA2 in the retina of house swine (p < 0.01; log₂ fold change > 1.5). Interestingly, 72% of the HTRA2-specific interactions (23 of 31 binders) were inhibited by additional treatment with UCF-101 (HTRA2 protease inhibitor) or the synthetic CDR peptide. On the other hand, the remaining 19 binders of HTRA2 were exclusively identified in the UCF101 and/or CDR group. However, many of the interactors were involved in the ER to Golgi anterograde transport (e.g., AP3D1), aggrephagy (e.g., PSMC1), and the pyruvate metabolism/citric acid cycle (e.g., SHMT2), and illustrated the complex protein interaction networks of HTRA2 in neurological tissues. In conclusion, the present study provides, for the first time, a comprehensive protein catalogue of HTRA2-specific interaction partners in the retina, and will serve as reference map in the future for studies focusing on HTRA2-mediated neurodegeneration. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 2847 KiB

Open AccessArticle

Structural and Functional Insights into the Biofilm-Associated BceF Tyrosine Kinase Domain from Burkholderia cepacia

by Michal Mayer, Yulia Matiuhin, Mickal Nawatha, Orly Tabachnikov, Inbar Fish, Nili Schutz, Hay Dvir and Meytal Landau

Biomolecules 2021, 11(8), 1196; https://doi.org/10.3390/biom11081196 - 12 Aug 2021

Cited by 2 | Viewed by 3661

Abstract

BceF is a bacterial tyrosine kinase (BY-kinase) from Burkholderia cepacia, a Gram-negative bacterium accountable for respiratory infections in immunocompromised and cystic fibrosis patients. BceF is involved in the production of exopolysaccharides secreted to the biofilm matrix and promotes resistant and aggressive infections. [...] Read more.

BceF is a bacterial tyrosine kinase (BY-kinase) from Burkholderia cepacia, a Gram-negative bacterium accountable for respiratory infections in immunocompromised and cystic fibrosis patients. BceF is involved in the production of exopolysaccharides secreted to the biofilm matrix and promotes resistant and aggressive infections. BY-kinases share no homology with mammalian kinases, and thereby offer a means to develop novel and specific antivirulence drugs. Here, we report the crystal structure of the BceF kinase domain at 1.85 Å resolution. The isolated BceF kinase domain is assembled as a dimer in solution and crystallized as a dimer in the asymmetric unit with endogenous adenosine-diphosphate bound at the active sites. The low enzymatic efficiency measured in solution may be explained by the partial obstruction of the active sites at the crystallographic dimer interface. This study provides insights into self-assembly and the specific activity of isolated catalytic domains. Several unique variations around the active site compared to other BY-kinases may allow for structure-based design of specific inhibitors to target Burkholderia cepacia virulence. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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11 pages, 1860 KiB

Open AccessArticle

Bioavailability and Antidiabetic Activity of Gliclazide-Loaded Cubosomal Nanoparticles

by Mohamed Nasr, Saud Almawash, Ahmed Al Saqr, Alaa Y. Bazeed, Sameh Saber and Heba I. Elagamy

Pharmaceuticals 2021, 14(8), 786; https://doi.org/10.3390/ph14080786 - 9 Aug 2021

Cited by 25 | Viewed by 4192

Abstract

In this study, gliclazide-loaded cubosomal particles were prepared for improving the oral bioavailability and antidiabetic activity of gliclazide. Four formulations of gliclazide-loaded cubosomal nanoparticles dispersions were prepared by the emulsification method using four different concentrations of glyceryl monooleate (GMO) and poloxamer 407 (P407) [...] Read more.

In this study, gliclazide-loaded cubosomal particles were prepared for improving the oral bioavailability and antidiabetic activity of gliclazide. Four formulations of gliclazide-loaded cubosomal nanoparticles dispersions were prepared by the emulsification method using four different concentrations of glyceryl monooleate (GMO) and poloxamer 407 (P407) as the stabilizer. The prepared formulations were in vitro and in vivo evaluated. In vitro, the prepared gliclazide-loaded cubosomal dispersions exhibited disaggregated regular poly-angular particles with a nanometer-sized particle range from 220.60 ± 1.39 to 234.00 ± 2.90 nm and entrapped 73.84 ± 3.03 to 88.81 ± 0.94 of gliclazide. In vitro gliclazide release from cubosomal nanoparticles revealed an initially higher drug release during the first 2 h in acidic pH medium; subsequently, a comparatively higher drug release in alkaline medium relative to gliclazide suspension was observed. An in vivo absorption study in rats revealed a two-fold increase in the bioavailability of gliclazide cubosomal formulation relative to plain gliclazide suspension. Moreover, the study of in vivo hypoglycemic activity indicated that a higher percentage reduction in glucose level was observed after the administration of gliclazide cubosomal nanoparticles to rats. In conclusion, gliclazide-loaded cubosomal nanoparticles could be a promising delivery system for improving the oral absorption and antidiabetic activity of gliclazide. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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24 pages, 7769 KiB

Open AccessReview

Role of Phytonutrients in Nutrigenetics and Nutrigenomics Perspective in Curing Breast Cancer

by Tanima Bhattacharya, Soumam Dutta, Rokeya Akter, Md. Habibur Rahman, Chenmala Karthika, Hechanur Puttappa Nagaswarupa, Hanabe Chowdappa Ananda Murthy, Ovidiu Fratila, Roxana Brata and Simona Bungau

Biomolecules 2021, 11(8), 1176; https://doi.org/10.3390/biom11081176 - 9 Aug 2021

Cited by 46 | Viewed by 10153

Abstract

Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in the development and progression of BC. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence [...] Read more.

Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in the development and progression of BC. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence that certain phytonutrients are able to modulate gene expression at transcriptional and post-transcriptional levels. Such phytonutrients may also be beneficial to prevent and treat BC. In this review, we will focus on the nutrigenomic effects of various phytochemicals including polyphenols, phytosterols, terpenoids, alkaloids, and other compounds from different sources. Overall, these phytonutrients are found to inhibit BC cell proliferation, differentiation, invasion, metastasis, angiogenesis, and induce apoptotic cell death by targeting various molecular pathways. They also alter epigenetic mechanisms and enhance the chemosensitivity and radiosensitivity of cancer cells. Such phytochemicals may be used for the effective management of BC patients in the clinical setting in the future. The present article aims to summarize the specific molecular pathways involved in the genetic effects of phytochemicals in BC. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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15 pages, 2379 KiB

Open AccessArticle

Lepidium sativum Sprouts Grown under Elevated CO₂ Hyperaccumulate Glucosinolates and Antioxidants and Exhibit Enhanced Biological and Reduced Antinutritional Properties

by Modhi O. Alotaibi, Galal Khamis, Hamada AbdElgawad, Afrah E. Mohammed, Mohamed S. Sheteiwy, Mudawi M. Elobeid and Ahmed M. Saleh

Biomolecules 2021, 11(8), 1174; https://doi.org/10.3390/biom11081174 - 9 Aug 2021

Cited by 14 | Viewed by 3246

Abstract

The nutritional and health-promoting properties of plants are largely determined by their tissue chemistry. Tuning growth conditions could affect the accumulation of phytochemicals and, therefore, enhance the biological activities. Herein, the impact of elevated CO₂ (eCO₂; 620 µmol CO₂ [...] Read more.

The nutritional and health-promoting properties of plants are largely determined by their tissue chemistry. Tuning growth conditions could affect the accumulation of phytochemicals and, therefore, enhance the biological activities. Herein, the impact of elevated CO₂ (eCO₂; 620 µmol CO₂ mol⁻¹ air) on growth and chemical composition of sprouts of three Lepidium sativum cultivars (Haraz, Khider and Rajab) was investigated. Changes in the sprout actions against some human chronic diseases were evaluated. eCO₂ induced biomass accumulation (1.46-, 1.47- and 2-fold in Haraz, Khider and Rajab, respectively) and pigment accumulation and reduced the level of antinutrients in L. sativum cultivars. Compared to the control, eCO₂ induced total glucosinolate accumulation (0.40-, 0.90- and 1.29-fold in Khider, Haraz and Rajab, respectively), possibly through increased amino acid production, and their hydrolysis by myrosinase. In line with increased polyphenol production, improved phenylalanine ammonia lyase activity was observed. The antioxidant, anti-inflammatory, hypocholesterolemic, antibacterial and anticancer activities of the produced sprouts were significantly improved by sprouting and eCO₂ exposure. PCA indicated that the cultivars showed interspecific responses. Thus, the present study confirms the synergistic effect of sprouting with eCO₂ exposure as a promising approach to produce more bioactive L. sativum sprouts. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 5354 KiB

Open AccessReview

Micro- and Nano-Based Transdermal Delivery Systems of Photosensitizing Drugs for the Treatment of Cutaneous Malignancies

by Isabella Portugal, Sona Jain, Patrícia Severino and Ronny Priefer

Pharmaceuticals 2021, 14(8), 772; https://doi.org/10.3390/ph14080772 - 6 Aug 2021

Cited by 13 | Viewed by 4697

Abstract

Photodynamic therapy is one of the more unique cancer treatment options available in today’s arsenal against this devastating disease. It has historically been explored in cutaneous lesions due to the possibility of focal/specific effects and minimization of adverse events. Advances in drug delivery [...] Read more.

Photodynamic therapy is one of the more unique cancer treatment options available in today’s arsenal against this devastating disease. It has historically been explored in cutaneous lesions due to the possibility of focal/specific effects and minimization of adverse events. Advances in drug delivery have mostly been based on biomaterials, such as liposomal and hybrid lipoidal vesicles, nanoemulsions, microneedling, and laser-assisted photosensitizer delivery systems. This review summarizes the most promising approaches to enhancing the photosensitizers’ transdermal delivery efficacy for the photodynamic treatment for cutaneous pre-cancerous lesions and skin cancers. Additionally, discussions on strategies and advantages in these approaches, as well as summarized challenges, perspectives, and translational potential for future applications, will be discussed. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 26599 KiB

Open AccessArticle

Synthesis, Structural Investigations, Molecular Docking, and Anticancer Activity of Some Novel Schiff Bases and Their Uranyl Complexes

by Hanan B. Howsaui, Amal S. Basaleh, Magda H. Abdellattif, Walid M. I. Hassan and Mostafa A. Hussien

Biomolecules 2021, 11(8), 1138; https://doi.org/10.3390/biom11081138 - 2 Aug 2021

Cited by 34 | Viewed by 4310

Abstract

Three novel 2-aminopyrazine Schiff bases derived from salicylaldehyde derivatives and their uranyl complexes were synthesized and characterized by elemental analysis, UV-vis, FTIR, molar conductance, and thermal gravimetric analysis (TGA). The proposed structures were optimized using density functional theory (DFT/B3LYP) and 6–311G ∗(d,p) basis [...] Read more.

Three novel 2-aminopyrazine Schiff bases derived from salicylaldehyde derivatives and their uranyl complexes were synthesized and characterized by elemental analysis, UV-vis, FTIR, molar conductance, and thermal gravimetric analysis (TGA). The proposed structures were optimized using density functional theory (DFT/B3LYP) and 6–311G ∗(d,p) basis sets. All uranyl complexes are soluble in DMSO and have low molar conductance, which indicates that all the complexes are nonelectrolytes. The DNA binding of those Schiff bases and their uranyl complexes was studied using UV-vis spectroscopy, and screening of their ability to bind to calf thymus DNA (CT-DNA) showed that the complexes interact with CT-DNA through an intercalation mode, for which the K_b values ranged from 1 × 10⁶ to 3.33 × 10⁵ M⁻¹. The anticancer activities of the Schiff base ligands and their uranyl complexes against two ovarian (Ovcar-3) and melanoma cell lines (M14) were investigated, and the results indicated that uranyl complexes exhibit better results than the Schiff base ligands. Molecular docking identified the distance, energy account, type, and position of links contributing to the interactions between these complexes and two different cancer proteins (3W2S and 2OPZ). Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 2352 KiB

Open AccessArticle

Potential Therapeutic Applications of Synthetic Conotoxin s-cal14.2b, Derived from Californiconus californicus, for Treating Type 2 Diabetes

by Pavel H. Lugo-Fabres, Leslie M. Otero-Sastre, Johanna Bernáldez-Sarabia, Tanya A. Camacho-Villegas, Noemi Sánchez-Campos, Janeth Serrano-Bello, Luis A. Medina, Saé Muñiz-Hernández, Lizbeth de la Cruz, Isabel Arenas, Antonio Barajas-Martínez, David E. Garcia, Linda Nuñez-Garcia, Jorge González-Canudas and Alexei F. Licea-Navarro

Biomedicines 2021, 9(8), 936; https://doi.org/10.3390/biomedicines9080936 - 1 Aug 2021

Cited by 7 | Viewed by 3912

Abstract

The FDA’s approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or [...] Read more.

The FDA’s approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or ligands alter normal physiological functions, as in metabolic diseases such as Type 2 diabetes. In this study, the synthetic cal14.2b (s-cal14.2b) from the unusual Californiconus californicus demonstrated bioactivity on NIT-1 insulinoma cell lines stimulating insulin secretion detecting by high performance liquid chromatography (HPLC). Accordingly, s-cal14.2b increased the Ca_V1.2/1.3 channel-current by 35 ± 4% with a recovery τ of 10.3 ± 4 s in primary cell culture of rat pancreatic β-cells. The in vivo results indicated a similar effect of insulin secretion on mice in the glucose tolerance curve model by reducing the glucose from 500 mg/dL to 106 mg/dL in 60 min, compared to the negative control of 325 mg/dL at the same time. The PET-SCAN with radiolabeling 99mTc-s-cal14.2b demonstrated biodistribution and accumulation in rat pancreas with complete depuration in 24 h. These findings show the potential therapeutic use of s-cal14.2b in endocrinal pathologies such as early stages of Type 2 Diabetes where the pancreas’s capability to produce insulin is still effective. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 2450 KiB

Open AccessArticle

Carica papaya Leaf Extract Silver Synthesized Nanoparticles Inhibit Dengue Type 2 Viral Replication In Vitro

by Antonia Windkouni Bere, Omuyundo Mulati, James Kimotho and Florence Ng’ong’a

Pharmaceuticals 2021, 14(8), 718; https://doi.org/10.3390/ph14080718 - 26 Jul 2021

Cited by 26 | Viewed by 7055

Abstract

The current global occurrence of dengue infection annually is approximately 400 million, with a case fatality rate of 2.5%. However, there are no antiviral agents. Carica papaya leaf extract is known for its medicinal value, due to the presence of organic compounds that [...] Read more.

The current global occurrence of dengue infection annually is approximately 400 million, with a case fatality rate of 2.5%. However, there are no antiviral agents. Carica papaya leaf extract is known for its medicinal value, due to the presence of organic compounds that possess antimicrobial, anti-inflammatory, and antioxidant activities. This study determined the anti-dengue effect of C. papaya leaf extract silver synthesized nanoparticles. In this study, aqueous and non-aqueous extractions were carried out, followed by the synthesis of silver nanoparticles as well as characterization through Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy. The in vitro anti-dengue effect was evaluated using a focus reduction neutralization test on kidney Vero E2 cell lines. In silico studies involved molecular docking to determine the potential interactions between the bioactive compounds in C. papaya leaf extract and the viral NS5 protein. C. papaya leaf methanol extract silver synthesized nanoparticle was the most promising with an IC₅₀ of 9.20 µg/mL. Molecular docking showed 5,7 dimethoxycoumarin as the best ligand, with binding energy of −7.75 kcal/mol, indicating high affinity for the NS5 protein. These results highlight that C. papaya leaf methanol extract silver synthesized nanoparticles could be used to inhibit dengue virus type 2 viral replication. However, we recommend further studies to determine their toxicity and the safety profiles. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 2623 KiB

Open AccessArticle

Development and Characterization of a Novel Peptide—Drug Conjugate with DM1 for Treatment of FGFR2-Positive Tumors

by Yayu Wang, Yadan Li, Jieqiong Cao, Qilin Meng, Xiaocen Li, Yibo Zhang, Kit S. Lam, An Hong, Ruiwu Liu and Xiaojia Chen

Biomedicines 2021, 9(8), 849; https://doi.org/10.3390/biomedicines9080849 - 21 Jul 2021

Cited by 10 | Viewed by 3976

Abstract

A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide–drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) [...] Read more.

A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide–drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 °C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide–drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B–DM1 can be developed into a potential PDC for tumor treatment in the future. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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25 pages, 2029 KiB

Open AccessFeature PaperReview

Phytomedicines Targeting Cancer Stem Cells: Therapeutic Opportunities and Prospects for Pharmaceutical Development

by Piyush Kumar Gupta, Mrunmayee Saraff, Rekha Gahtori, Nidhi Negi, Surya Kant Tripathi, Jatin Kumar, Sanjay Kumar, Saad Hamad Aldhayan, Sugapriya Dhanasekaran, Mosleh Mohammad Abomughaid, Kamal Dua, Rohit Gundamaraju, Shreesh Ojha, Janne Ruokolainen, Niraj Kumar Jha and Kavindra Kumar Kesari

Pharmaceuticals 2021, 14(7), 676; https://doi.org/10.3390/ph14070676 - 15 Jul 2021

Cited by 16 | Viewed by 6507

Abstract

The presence of small subpopulations of cells within tumor cells are known as cancer stem cells (CSCs). These cells have been the reason for metastasis, resistance with chemotherapy or radiotherapy, and tumor relapse in several types of cancers. CSCs underwent to epithelial–mesenchymal transition [...] Read more.

The presence of small subpopulations of cells within tumor cells are known as cancer stem cells (CSCs). These cells have been the reason for metastasis, resistance with chemotherapy or radiotherapy, and tumor relapse in several types of cancers. CSCs underwent to epithelial–mesenchymal transition (EMT) and resulted in the development of aggressive tumors. CSCs have potential to modulate numerous signaling pathways including Wnt, Hh, and Notch, therefore increasing the stem-like characteristics of cancer cells. The raised expression of drug efflux pump and suppression of apoptosis has shown increased resistance with anti-cancer drugs. Among many agents which were shown to modulate these, the plant-derived bioactive agents appear to modulate these key regulators and were shown to remove CSCs. This review aims to comprehensively scrutinize the preclinical and clinical studies demonstrating the effects of phytocompounds on CSCs isolated from various tumors. Based on the available convincing literature from preclinical studies, with some clinical data, it is apparent that selective targeting of CSCs with plants, plant preparations, and plant-derived bioactive compounds, termed phytochemicals, may be a promising strategy for the treatment of relapsed cancers. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 3489 KiB

Open AccessArticle

A High-Throughput Metabolic Microarray Assay Reveals Antibacterial Effects of Black and Red Raspberries and Blackberries against Helicobacter pylori Infection

by Candace Goodman, Katrina N. Lyon, Aitana Scotto, Cyra Smith, Thomas A. Sebrell, Andrew B. Gentry, Ganesh Bala, Gary D. Stoner and Diane Bimczok

Antibiotics 2021, 10(7), 845; https://doi.org/10.3390/antibiotics10070845 - 12 Jul 2021

Cited by 13 | Viewed by 4265

Abstract

Helicobacter pylori infection is commonly treated with a combination of antibiotics and proton pump inhibitors. However, since H. pylori is becoming increasingly resistant to standard antibiotic regimens, novel treatment strategies are needed. Previous studies have demonstrated that black and red berries may have [...] Read more.

Helicobacter pylori infection is commonly treated with a combination of antibiotics and proton pump inhibitors. However, since H. pylori is becoming increasingly resistant to standard antibiotic regimens, novel treatment strategies are needed. Previous studies have demonstrated that black and red berries may have antibacterial properties. Therefore, we analyzed the antibacterial effects of black and red raspberries and blackberries on H. pylori. Freeze-dried powders and organic extracts from black and red raspberries and blackberries were prepared, and high-performance liquid chromatography was used to measure the concentrations of anthocyanins, which are considered the major active ingredients. To monitor antibiotic effects of the berry preparations on H. pylori, a high-throughput metabolic growth assay based on the Biolog system was developed and validated with the antibiotic metronidazole. Biocompatibility was analyzed using human gastric organoids. All berry preparations tested had significant bactericidal effects in vitro, with MIC₉₀ values ranging from 0.49 to 4.17%. Antimicrobial activity was higher for extracts than powders and appeared to be independent of the anthocyanin concentration. Importantly, human gastric epithelial cell viability was not negatively impacted by black raspberry extract applied at the concentration required for complete bacterial growth inhibition. Our data suggest that black and red raspberry and blackberry extracts may have potential applications in the treatment and prevention of H. pylori infection but differ widely in their MICs. Moreover, we demonstrate that the Biolog metabolic assay is suitable for high-throughput antimicrobial susceptibility screening of H. pylori. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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10 pages, 2191 KiB

Open AccessArticle

Comparative EPR Study on the Scavenging Effect of Methotrexate with the Isomers of Its Photoswitchable Derivative

by Zsolt Preisz, Nóra Hartvig, Balázs Bognár, Tamás Kálai and Sándor Kunsági-Máté

Pharmaceuticals 2021, 14(7), 665; https://doi.org/10.3390/ph14070665 - 11 Jul 2021

Cited by 3 | Viewed by 3077

Abstract

The scavenging effect of the antimetabolite dihydrofolate reductase inhibitor methotrexate (MTX) and the isomers of its photoswitchable derivate, cis- and trans-phototrexate (PHX), have been compared by ESR spectroscopy, with the application of a cyclic hydroxylamine spin probe. The results showed the [...] Read more.

The scavenging effect of the antimetabolite dihydrofolate reductase inhibitor methotrexate (MTX) and the isomers of its photoswitchable derivate, cis- and trans-phototrexate (PHX), have been compared by ESR spectroscopy, with the application of a cyclic hydroxylamine spin probe. The results showed the most pronounced scavenging effect in the presence of trans-phototrexate (trans-PHX). At a low concentration (100 µM) cis-PHX also showed a greater scavenging effect than the parent molecule MTX. Direct antioxidant properties of the investigated molecules were measured by ABTS scavenging assay, which showed no significant difference between trans-PHX and cis-PHX, but both of the isomers of PHX showed a higher antioxidant capacity than MTX. These findings imply that trans-PHX may have more pronounced anti-inflammatory and tissue-protective effects than MTX, despite the lack of its cytotoxic, antineoplastic effect. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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12 pages, 2832 KiB

Open AccessArticle

Identification of HSP47 Binding Site on Native Collagen and Its Implications for the Development of HSP47 Inhibitors

by Haiyan Cai, Parvathy Sasikumar, Gemma Little, Dominique Bihan, Samir W. Hamaia, Aiwu Zhou, Jonathan M. Gibbins and Richard W. Farndale

Biomolecules 2021, 11(7), 983; https://doi.org/10.3390/biom11070983 - 3 Jul 2021

Cited by 12 | Viewed by 4887

Abstract

HSP47 (heat shock protein 47) is a collagen-specific molecular chaperone that is essential for procollagen folding and function. Previous studies have shown that HSP47 binding requires a critical Arg residue at the Y position of the (Gly-Xaa-Yaa) repeats of collagen; however, the exact [...] Read more.

HSP47 (heat shock protein 47) is a collagen-specific molecular chaperone that is essential for procollagen folding and function. Previous studies have shown that HSP47 binding requires a critical Arg residue at the Y position of the (Gly-Xaa-Yaa) repeats of collagen; however, the exact binding sites of HSP47 on native collagens are not fully defined. To address this, we mapped the HSP47 binding sites on collagens through an ELISA binding assay using collagen toolkits, synthetic collagen peptides covering the entire amino acid sequences of collagen types II and III assembled in triple-helical conformation. Our results showed that HSP47 binds to only a few of the GXR motifs in collagen, with most of the HSP47 binding sites identified located near the N-terminal part of the triple-helical region. Molecular modelling and binding energy calculation indicated that residues flanking the key Arg in the collagen sequence also play an important role in defining the high-affinity HSP47 binding site of collagen. Based on this binding mode of HSP47 to collagen, virtual screening targeting both the Arg binding site and its neighboring area on the HSP47 surface, and a subsequent bioassay, we identified two novel compounds with blocking activity towards HSP47 binding of collagen. Overall, our study revealed the native HSP47 binding sites on collagen and provided novel information for the design of small-molecule inhibitors of HSP47. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 5038 KiB

Open AccessArticle

Therapeutic Potential of Luteolin on Impaired Wound Healing in Streptozotocin-Induced Rats

by Li-You Chen, Hsin-Lin Cheng, Yu-Hsiang Kuan, Tang-Jun Liang, Yun-Yi Chao and Hsing-Chun Lin

Biomedicines 2021, 9(7), 761; https://doi.org/10.3390/biomedicines9070761 - 30 Jun 2021

Cited by 54 | Viewed by 5392

Abstract

Long-term hyperglycemia may lead to diabetic microvascular and macrovascular complications that can affect the peripheral vascular system, particularly in wound healing capacity. Impaired angiogenesis and delayed wound healing are significant clinically. Luteolin (3′, 4′, 5, 7-tetrahydroxyflavone) is a naturally occurring flavonoid that is [...] Read more.

Long-term hyperglycemia may lead to diabetic microvascular and macrovascular complications that can affect the peripheral vascular system, particularly in wound healing capacity. Impaired angiogenesis and delayed wound healing are significant clinically. Luteolin (3′, 4′, 5, 7-tetrahydroxyflavone) is a naturally occurring flavonoid that is ubiquitously found in plants. Recent evidence has shown that luteolin is an anti-inflammatory and anti-oxidative agent. However, the effect of systemic luteolin administration on diabetic wound restoration remains unclear. Herein, we explored the effectiveness of luteolin for improving delayed and impaired healing of skin wound and further clarified the underlying mechanisms. The results indicated that luteolin significantly attenuates blood glucose concentration, improves impaired healing and accelerates re-epithelization of skin wound in streptozotocin (STZ)-induced diabetic rats. Histopathological staining and immunoblotting revealed an inhibitory effect of luteolin on inflammatory cell and cytokine production. We also observed remarkable decreases in protein expressions of inflammatory factors including matrix metalloproteinase (MMP)-9, tumor necrosis factor (TNF)-α, interleukin (IL-6), and IL1-β and downregulation of nuclear factor (NF)-κB, as well as increases in anti-oxidative enzymes such as superoxide dismutase 1 (SOD1) and glutathione peroxidase (GSH-Px) induced by nuclear factor erythroid 2-related factor (Nrf)-2 following luteolin supplementation. Furthermore, luteolin decreased the expression of vascular endothelial growth factor (VEGF) and increased the expression of ubiquitin carboxy-terminal hydrolase (UCH)-L1, as evidenced by angiogenesis and neuronal regeneration in completely healed wound. In conclusion, systemic administration of luteolin promotes wound restoration by ameliorating inflammation and oxidative stress through the inactivation of NF-κB and upregulation of Nrf2 in STZ-induced diabetic rats. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 1217 KiB

Open AccessArticle

Rifamycin W Analogues from Amycolatopsis mediterranei S699 Δrif-orf5 Strain

by Yanrong Shi, Feng Ye, Yuliang Song, Xiaochun Zhang, Chunhua Lu and Yuemao Shen

Biomolecules 2021, 11(7), 920; https://doi.org/10.3390/biom11070920 - 22 Jun 2021

Cited by 8 | Viewed by 3308

Abstract

Rifamycin W, the most predominant intermediate in the biosynthesis of rifamycin, needs to undergo polyketide backbone rearrangement to produce rifamycin B via an oxidative cleavage of the C-12/C-29 double bond. However, the mechanism of this putative oxidative cleavage has not been characterized yet. [...] Read more.

Rifamycin W, the most predominant intermediate in the biosynthesis of rifamycin, needs to undergo polyketide backbone rearrangement to produce rifamycin B via an oxidative cleavage of the C-12/C-29 double bond. However, the mechanism of this putative oxidative cleavage has not been characterized yet. Rif-Orf5 (a putative cytochrome P450 monooxygenase) was proposed to be involved in the cleavage of this olefinic moiety of rifamycin W. In this study, the mutant strain Amycolatopsis mediterranei S699 Δrif-orf5 was constructed by in-frame deleting the rif-orf5 gene to afford thirteen rifamycin W congeners (1–13) including seven new ones (1–7). Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data and high-resolution ESI mass spectra. Presumably, compounds 1–4 were derivatized from rifamycin W via C-5/C-11 retro-Claisen cleavage, and compounds 1–3, 9 and 10 featured a hemiacetal. Compounds 5–7 and 11 showed oxygenations at various sites of the ansa chain. In addition, compounds 1–3 exhibited antibacterial activity against Staphylococcus aureus with minimal inhibitory concentration (MIC) values of 5, 40 and 0.5 µg/mL, respectively. Compounds 1 and 3 showed modest antiproliferative activity against HeLa and Caco-2 cells with half maximal inhibitory concentration (IC₅₀) values of about 50 µM. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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12 pages, 1350 KiB

Open AccessArticle

Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics

by Kirsten E. Knoll, Zander Lindeque, Adetomiwa A. Adeniji, Carel B. Oosthuizen, Namrita Lall and Du Toit Loots

Antibiotics 2021, 10(6), 693; https://doi.org/10.3390/antibiotics10060693 - 10 Jun 2021

Cited by 11 | Viewed by 3793

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the current [...] Read more.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the current anti-TB drugs, exacerbated by lack of patient adherence due to drug toxicity. The aforementioned highlights the urgent need for new anti-TB compounds with different antimycobacterial mechanisms of action to those currently being used. An N-alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against Mtb, while also exhibiting low cytotoxicity and excellent pharmacokinetic characteristics. Its exact mechanism of action, however, is still unknown. Considering this, we used GCxGC-TOFMS and well described metabolomic approaches to analyze and compare the metabolic alterations of Mtb treated with decoquinate derivative RMB041 by comparison to non-treated Mtb controls. The most significantly altered pathways in Mtb treated with this drug include fatty acid metabolism, amino acid metabolism, glycerol metabolism, and the urea cycle. These changes support previous findings suggesting this drug acts primarily on the cell wall and secondarily on the DNA metabolism of Mtb. Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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17 pages, 865 KiB

Open AccessReview

Resveratrol Production in Yeast Hosts: Current Status and Perspectives

by Gehad G. Ibrahim, Jinyong Yan, Li Xu, Min Yang and Yunjun Yan

Biomolecules 2021, 11(6), 830; https://doi.org/10.3390/biom11060830 - 2 Jun 2021

Cited by 14 | Viewed by 5981

Abstract

Resveratrol is a plant secondary metabolite known for its therapeutic applications as an antioxidant, anti-cancer, anti-inflammatory, anti-aging, cardio-protective, and neuroprotective agent. Topical formulas of resveratrol are also used for skin disease management and in cosmetic industries. Due to its importance, high resveratrol production [...] Read more.

Resveratrol is a plant secondary metabolite known for its therapeutic applications as an antioxidant, anti-cancer, anti-inflammatory, anti-aging, cardio-protective, and neuroprotective agent. Topical formulas of resveratrol are also used for skin disease management and in cosmetic industries. Due to its importance, high resveratrol production is urgently required. Since the last decade, intensive efforts have been devoted to obtaining resveratrol from microorganisms by pathway and metabolic engineering. Yeasts were proven to be excellent host candidates for resveratrol production. In addition to the similar intracellular compartments between yeasts and plants, yeasts exhibit the ability to express genes coding for plant-derived enzymes and to perform post-translational modification. Therefore, this review summarizes the attempts to use yeasts as a platform for resveratrol synthesis as the next promising route in producing high titers of resveratrol from genetically engineered strains. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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13 pages, 1097 KiB

Open AccessReview

Cannabinoid Activity—Is There a Causal Connection to Spasmolysis in Clinical Studies?

by Daniel Joseph and Johannes Schulze

Biomolecules 2021, 11(6), 826; https://doi.org/10.3390/biom11060826 - 1 Jun 2021

Cited by 5 | Viewed by 3476

Abstract

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may [...] Read more.

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. Methods: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. Results: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies (“enriched” studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3–4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. Conclusions: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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23 pages, 9172 KiB

Open AccessReview

An Overview of Antimicrobial Compounds from African Edible Insects and Their Associated Microbiota

by Cynthia M. Mudalungu, Chrysantus M. Tanga, Segenet Kelemu and Baldwyn Torto

Antibiotics 2021, 10(6), 621; https://doi.org/10.3390/antibiotics10060621 - 22 May 2021

Cited by 20 | Viewed by 6227

Abstract

The need for easily biodegradable and less toxic chemicals in drug development and pest control continues to fuel the exploration and discovery of new natural molecules. Like certain plants, some insects can also respond rapidly to microbial infections by producing a plethora of [...] Read more.

The need for easily biodegradable and less toxic chemicals in drug development and pest control continues to fuel the exploration and discovery of new natural molecules. Like certain plants, some insects can also respond rapidly to microbial infections by producing a plethora of immune-induced molecules that include antibacterial and antifungal peptides/polypeptides (AMPs), among other structurally diverse small molecules. The recent recognition that new natural product-derived scaffolds are urgently needed to tackle life-threatening pathogenic infections has been prompted by the health threats posed by multidrug resistance. Although many researchers have concentrated on the discovery of AMPs, surprisingly, edible insect-produced AMPs/small molecules have received little attention. This review will discuss the recent advances in the identification and bioactivity analysis of insect AMPs, with a focus on small molecules associated with the microbiota of selected African edible insects. These molecules could be used as templates for developing next-generation drugs to combat multidrug-resistant pathogens. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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21 pages, 5637 KiB

Open AccessArticle

Potent Antimicrobial and Antibiofilm Activities of Feleucin-K3 Analogs Modified by α-(4-Pentenyl)-Ala against Multidrug-Resistant Bacteria

by Xiaomin Guo, Tiantian Yan, Jing Rao, Xin Yue, Xiong Pei, Jiahui Deng, Wangsheng Sun, Wenle Yang, Bangzhi Zhang and Junqiu Xie

Biomolecules 2021, 11(5), 761; https://doi.org/10.3390/biom11050761 - 19 May 2021

Cited by 12 | Viewed by 3186

Abstract

The dramatic increase in antimicrobial resistance (AMR) highlights an urgent need to develop new antimicrobial therapies. Thus, antimicrobial peptides (AMPs) have emerged as promising novel antibiotic alternatives. Feleucin-K3 is an amphiphilic α-helical nonapeptide that has powerful antimicrobial activity. In our previous study, it [...] Read more.

The dramatic increase in antimicrobial resistance (AMR) highlights an urgent need to develop new antimicrobial therapies. Thus, antimicrobial peptides (AMPs) have emerged as promising novel antibiotic alternatives. Feleucin-K3 is an amphiphilic α-helical nonapeptide that has powerful antimicrobial activity. In our previous study, it was found that the fourth residue of Feleucin-K3 is important for antimicrobial activity. After α-(4-pentenyl)-Ala was introduced into this position, both the antimicrobial activity and stability were greatly improved. Herein, to improve the limitations of Feleucin-K3, this unnatural amino acid was further introduced into different positions of Feleucin-K3. Among these synthetic Feleucin-K3 analogs, the N-terminal-substituted analog Feleucin-K65 (K65) and C-terminal-substituted analog Feleucin-K70 (K70) had preferable antimicrobial activity. In particular, their antimicrobial activities against multidrug-resistant bacteria were more potent than that of antibiotics. The stabilities of these peptides in salt and serum environments were improved compared with those of Feleucin-K3. In addition, these analogs had low hemolytic activity and AMR. More importantly, they effectively inhibited biofilm formation and exhibited considerable efficacy compared with traditional antibiotics against biofilm infection caused by methicillin-resistant Staphylococcus aureus (MRSA). In antimicrobial mechanism studies, K65 and K70 mainly permeated the outer membrane and depolarized the cytoplasmic membrane, resulting in cellular component leakage and cell death. In summary, analogs K65 and K70 are potential antimicrobial alternatives to solve the antibiotic crisis. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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