Biomolecules

17 pages, 1216 KiB

Open AccessReview

Treatment Options for Motor and Non-Motor Symptoms of Parkinson’s Disease

by Frank C. Church

Biomolecules 2021, 11(4), 612; https://doi.org/10.3390/biom11040612 - 20 Apr 2021

Cited by 111 | Viewed by 22595

Parkinson’s disease (PD) usually presents in older adults and typically has both motor and non-motor dysfunctions. PD is a progressive neurodegenerative disorder resulting from dopaminergic neuronal cell loss in the mid-brain substantia nigra pars compacta region. Outlined here is an integrative medicine and [...] Read more.

Parkinson’s disease (PD) usually presents in older adults and typically has both motor and non-motor dysfunctions. PD is a progressive neurodegenerative disorder resulting from dopaminergic neuronal cell loss in the mid-brain substantia nigra pars compacta region. Outlined here is an integrative medicine and health strategy that highlights five treatment options for people with Parkinson’s (PwP): rehabilitate, therapy, restorative, maintenance, and surgery. Rehabilitating begins following the diagnosis and throughout any additional treatment processes, especially vis-à-vis consulting with physical, occupational, and/or speech pathology therapist(s). Therapy uses daily administration of either the dopamine precursor levodopa (with carbidopa) or a dopamine agonist, compounds that preserve residual dopamine, and other specific motor/non-motor-related compounds. Restorative uses strenuous aerobic exercise programs that can be neuroprotective. Maintenance uses complementary and alternative medicine substances that potentially support and protect the brain microenvironment. Finally, surgery, including deep brain stimulation, is pursued when PwP fail to respond positively to other treatment options. There is currently no cure for PD. In conclusion, the best strategy for treating PD is to hope to slow disorder progression and strive to achieve stability with neuroprotection. The ultimate goal of any management program is to improve the quality-of-life for a person with Parkinson’s disease. Full article

(This article belongs to the Special Issue Parkinson’s Disease and Associated Disorders)

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41 pages, 1105 KiB

Open AccessFeature PaperReview

Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development

by Giulia Massaro, Amy F. Geard, Wenfei Liu, Oliver Coombe-Tennant, Simon N. Waddington, Julien Baruteau, Paul Gissen and Ahad A. Rahim

Biomolecules 2021, 11(4), 611; https://doi.org/10.3390/biom11040611 - 20 Apr 2021

Cited by 35 | Viewed by 7989

Abstract

Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy [...] Read more.

Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy represents a feasible option to address the unmet medical need of these patients. This article provides a comprehensive overview of the current state of the field, reviewing the most used viral gene delivery vectors in the context of lysosomal storage disorders, a selection of relevant pre-clinical studies and ongoing clinical trials within recent years. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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15 pages, 1601 KiB

Open AccessArticle

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

by Sylwester Głowacki, Ewelina Synowiec, Marzena Szwed, Monika Toma, Tomasz Skorski and Tomasz Śliwiński

Biomolecules 2021, 11(4), 610; https://doi.org/10.3390/biom11040610 - 20 Apr 2021

Cited by 14 | Viewed by 3312

Abstract

Chronic myeloid leukemia (CML) develops due to the presence of the BCR-ABL1 protein, a target of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), used in a CML therapy. CML eradication is a challenge due to developing resistance to TKIs. BCR-ABL1 induces endogenous [...] Read more.

Chronic myeloid leukemia (CML) develops due to the presence of the BCR-ABL1 protein, a target of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), used in a CML therapy. CML eradication is a challenge due to developing resistance to TKIs. BCR-ABL1 induces endogenous oxidative stress leading to genomic instability and development of TKI resistance. Model CML cells susceptible or resistant to IM, as well as wild-type, non-cancer cells without the BCR-ABL1 protein were treated with IM, hydrogen peroxide (H₂O₂) as a model trigger of external oxidative stress, or with IM+H₂O₂. Accumulation of reactive oxygen species (ROS), DNA damage, activity of selected antioxidant enzymes and glutathione (GSH), and mitochondrial potential (MMP) were assessed. We observed increase in ROS accumulation in BCR-ABL1 positive cells and distinct levels of ROS accumulation in IM-susceptible cells when compared to IM-resistant ones, as well as increased DNA damage caused by IM action in sensitive cells. Depletion of GSH levels and a decreased activity of glutathione peroxidase (GPx) in the presence of IM was higher in the cells susceptible to IM. IM-resistant cells showed an increase of catalase activity and a depletion of MMP. BCR-ABL1 kinase alters ROS metabolism, and IM resistance is accompanied by the changes in activity of GPx, catalase, and alterations in MMP. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 5533 KiB

Open AccessArticle

A Homozygous Dab1^−/− Is a Potential Novel Cause of Autosomal Recessive Congenital Anomalies of the Mice Kidney and Urinary Tract

by Anita Racetin, Natalija Filipović, Mirela Lozić, Masaki Ogata, Larissa Gudelj Ensor, Nela Kelam, Petra Kovačević, Koichiro Watanabe, Yu Katsuyama, Mirna Saraga-Babić, Merica Glavina Durdov and Katarina Vukojević

Biomolecules 2021, 11(4), 609; https://doi.org/10.3390/biom11040609 - 20 Apr 2021

Cited by 13 | Viewed by 2985

Abstract

This study aimed to explore morphology changes in the kidneys of Dab1^−/− (yotari) mice, as well as expression patterns of reelin, NOTCH2, LC3B, and cleaved caspase3 (CASP3) proteins, as potential determinants of normal kidney formation and function. We assumed that Dab1 [...] Read more.

This study aimed to explore morphology changes in the kidneys of Dab1^−/− (yotari) mice, as well as expression patterns of reelin, NOTCH2, LC3B, and cleaved caspase3 (CASP3) proteins, as potential determinants of normal kidney formation and function. We assumed that Dab1 functional inactivation may cause disorder in a wide spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Animals were sacrificed at postnatal days P4, P11, and P14. Paraffin-embedded kidney tissues were sectioned and analyzed by immunohistochemistry using specific antibodies. Kidney specimens were examined by bright-field, fluorescence, and electron microscopy. Data were analyzed by two-way ANOVA and t-tests. We noticed that yotari kidneys were smaller in size with a reduced diameter of nephron segments and thinner cortex. TEM microphotographs revealed foot process effacement in the glomeruli (G) of yotari mice, whereas aberrations in the structure of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) were not observed. A significant increase in reelin expression, NOTCH2, LC3B and cleaved CASP3 proteins was observed in the glomeruli of yotari mice. Renal hypoplasia in conjunction with foot process effacement and elevation in the expression of examined proteins in the glomeruli revealed CAKUT phenotype and loss of functional kidney tissue of yotari. Full article

(This article belongs to the Special Issue Biomolecules in Development and Diseases of Urogenital System)

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7 pages, 2875 KiB

Open AccessEditorial

Protein Intrinsic Disorder and Evolvability of MERS-CoV

by Vladimir N. Uversky, Elrashdy M. Redwan and Abdullah A. Aljadawi

Biomolecules 2021, 11(4), 608; https://doi.org/10.3390/biom11040608 - 20 Apr 2021

Cited by 3 | Viewed by 2180

Abstract

Middle East Respiratory Syndrome (MERS) is a viral respiratory disease caused by one of the human coronaviruses, MERS-CoV [...] Full article

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34 pages, 21908 KiB

Open AccessEditor’s ChoiceReview

SARS-CoV-2 M^pro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

by Andrea Citarella, Angela Scala, Anna Piperno and Nicola Micale

Biomolecules 2021, 11(4), 607; https://doi.org/10.3390/biom11040607 - 19 Apr 2021

Cited by 120 | Viewed by 12260

Abstract

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective [...] Read more.

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO’s main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (M^pro) are becoming more and more promising candidates. M^pro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 M^pro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 M^pro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds. Full article

(This article belongs to the Special Issue State-of-the-Art Highlighting Antiviral Therapy and Viral Diseases Diagnosis in Italy 2020–2021)

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14 pages, 2381 KiB

Open AccessArticle

The Effect of a Unique Region of Parvovirus B19 Capsid Protein VP1 on Endothelial Cells

by Ieva Rinkūnaitė, Egidijus Šimoliūnas, Daiva Bironaitė, Rasa Rutkienė, Virginija Bukelskienė, Rolandas Meškys and Julius Bogomolovas

Biomolecules 2021, 11(4), 606; https://doi.org/10.3390/biom11040606 - 19 Apr 2021

Cited by 2 | Viewed by 2693

Abstract

Parvovirus B19 (B19V) is a widespread human pathogen possessing a high tropism for erythroid precursor cells. However, the persistence or active replication of B19V in endothelial cells (EC) has been detected in diverse human pathologies. The VP1 unique region (VP1u) of the viral [...] Read more.

Parvovirus B19 (B19V) is a widespread human pathogen possessing a high tropism for erythroid precursor cells. However, the persistence or active replication of B19V in endothelial cells (EC) has been detected in diverse human pathologies. The VP1 unique region (VP1u) of the viral capsid has been reported to act as a major determinant of viral tropism for erythroid precursor cells. Nevertheless, the interaction of VP1u with EC has not been studied. We demonstrate that recombinant VP1u is efficiently internalized by rats’ pulmonary trunk blood vessel-derived EC in vitro compared to the human umbilical vein EC line. The exposure to VP1u was not acutely cytotoxic to either human- or rat-derived ECs, but led to the upregulation of cellular stress signaling-related pathways. Our data suggest that high levels of circulating B19V during acute infection can cause endothelial damage, even without active replication or direct internalization into the cells. Full article

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8 pages, 290 KiB

Open AccessArticle

Antibacterial Activity and Reversal of Multidrug Resistance of Tumor Cells by Essential Oils from Fresh Leaves, Flowers, and Stems of Montanoa quadrangularis Schultz Bipontinus (Asteraceae) Collected in Mérida—Venezuela

by Janne Rojas, Gautier Mark-Arthur Ndong Ntoutoume, Patrick Martin and Marielba Morillo

Biomolecules 2021, 11(4), 605; https://doi.org/10.3390/biom11040605 - 19 Apr 2021

Cited by 7 | Viewed by 2211

Abstract

Essential oils obtained by hydrodistillation of Montanoa quadrangularis leaves, flowers, and stems were analyzed by GC and GC/MS techniques revealing myrcene, limonene, β-phellandrene, and sabinene among the main components. The aim of the present study was to evaluate the MDR modulator activity on [...] Read more.

Essential oils obtained by hydrodistillation of Montanoa quadrangularis leaves, flowers, and stems were analyzed by GC and GC/MS techniques revealing myrcene, limonene, β-phellandrene, and sabinene among the main components. The aim of the present study was to evaluate the MDR modulator activity on human MDR1 gene transfected mouse lymphoma cell line and the antimicrobial activity on the essential oils obtained from different parts of the species under investigation. The results revealed that MQL caused a similar increase in the fluorescence activity of the cells at 0.02 μL/mL comparing to the Verapamil^® value. The antimicrobial assay was carried out according to the disc diffusion method. Five different bacterial strains (Staphylococcus epidermidis, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli AG 100, and Escherichia coli AG100A) were treated with the essential oils and the zones of inhibition were determined on TSA plates and TSA agar plates supplemented with Tween 20. MQF and MQL showed activity against B. subtilis, S. epidermidis, and E. coli AG 100A while MQS was only active against E. coli AG 100A on TSA agar plates experiment. In case of TSA agar plates supplemented with 0.1 v/v% Tween 20 detergent, MQF showed inhibition on B. subtilis, S. epidermidis, and E. coli AG 100A; MQL was active against B. subtilis, E. coli AG 100, and E. coli AG 100A while MQS was only active against E. coli AG 100A. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

12 pages, 2873 KiB

Open AccessArticle

Dual Role for Astroglial Copper-Assisted Polyamine Metabolism during Intense Network Activity

by Zsolt Szabó, Márton Péter, László Héja and Julianna Kardos

Biomolecules 2021, 11(4), 604; https://doi.org/10.3390/biom11040604 - 19 Apr 2021

Cited by 7 | Viewed by 3270

Abstract

Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by [...] Read more.

Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by reverse operation of the astroglial GABA transporter, induced by Glu-Na⁺ symport. GABA, released from astrocytes, is synthesized from the polyamine (PA) putrescine and this process involves copper amino oxidase. Through this pathway, putrescine can be considered as an important source of inhibitory signaling that counterbalances epileptic discharges. Putrescine, however, is also a precursor for spermine that is known to enhance gap junction channel communication and, consequently, supports long-range Ca²⁺ signaling and contributes to spreading of excitatory activity through the astrocytic syncytium. Recently, we presented the possibility of neuron-glia redox coupling through copper (Cu⁺/Cu²⁺) signaling and oxidative putrescine catabolism. In the current work, we explore whether the Cu⁺/Cu²⁺ homeostasis is involved in astrocytic control on neuronal excitability by regulating PA catabolism. We provide supporting experimental data underlying this hypothesis. We show that the blockade of copper transporter (CTR1) by AgNO₃ (3.6 µM) prevents GABA transporter-mediated tonic inhibitory currents, indicating causal relationship between copper (Cu⁺/Cu²⁺) uptake and the catabolism of putrescine to GABA in astrocytes. In addition, we show that MnCl₂ (20 μM), an inhibitor of the divalent metal transporter DMT1, also prevents the astrocytic Glu-GABA exchange. Furthermore, we observed that facilitation of copper uptake by added CuCl₂ (2 µM) boosts tonic inhibitory currents. These findings corroborate the hypothesis that modulation of neuron-glia coupling by copper uptake drives putrescine → GABA transformation, which leads to subsequent Glu-GABA exchange and tonic inhibition. Findings may in turn highlight the potential role of copper signaling in fine-tuning the activity of the tripartite synapse. Full article

(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)

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27 pages, 13157 KiB

Open AccessReview

Podophyllotoxin: History, Recent Advances and Future Prospects

by Zinnia Shah, Umar Farooq Gohar, Iffat Jamshed, Aamir Mushtaq, Hamid Mukhtar, Muhammad Zia-UI-Haq, Sebastian Ionut Toma, Rosana Manea, Marius Moga and Bianca Popovici

Biomolecules 2021, 11(4), 603; https://doi.org/10.3390/biom11040603 - 19 Apr 2021

Cited by 108 | Viewed by 11940

Abstract

Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of [...] Read more.

Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of treating cytokine storm in COVID-19 patients. Podophyllotoxin and its naturally occurring congeners have low bioavailability and almost all these initially discovered compounds cause systemic toxicity and development of drug resistance. Moreover, the production of synthetic derivatives that could suffice for the clinical limitations of these naturally occurring compounds is not economically feasible. These challenges demanded continuous devotions towards improving the druggability of these drugs and continue to seek structure-optimization strategies. The discovery of renewable sources including microbial origin for podophyllotoxin is another possible approach. This review focuses on the exigency of innovation and research required in the global R&D and pharmaceutical industry for podophyllotoxin and related compounds based on recent scientific findings and market predictions. Full article

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10 pages, 14750 KiB

Open AccessArticle

Regulation of Phosphoinositide Levels in the Retina by Protein Tyrosine Phosphatase 1B and Growth Factor Receptor-Bound Protein 14

by Raju V. S. Rajala, Austin McCauley, Rahul Rajala, Kenneth Teel and Ammaji Rajala

Biomolecules 2021, 11(4), 602; https://doi.org/10.3390/biom11040602 - 19 Apr 2021

Cited by 1 | Viewed by 2394

Abstract

Protein tyrosine kinases and protein phosphatases play a critical role in cellular regulation. The length of a cellular response depends on the interplay between activating protein kinases and deactivating protein phosphatases. Protein tyrosine phosphatase 1B (PTP1B) and growth factor receptor-bound protein 14 (Grb14) [...] Read more.

Protein tyrosine kinases and protein phosphatases play a critical role in cellular regulation. The length of a cellular response depends on the interplay between activating protein kinases and deactivating protein phosphatases. Protein tyrosine phosphatase 1B (PTP1B) and growth factor receptor-bound protein 14 (Grb14) are negative regulators of receptor tyrosine kinases. However, in the retina, we have previously shown that PTP1B inactivates insulin receptor signaling, whereas phosphorylated Grb14 inhibits PTP1B activity. In silico docking of phosphorylated Grb14 and PTP1B indicate critical residues in PTP1B that may mediate the interaction. Phosphoinositides (PIPs) are acidic lipids and minor constituents in the cell that play an important role in cellular processes. Their levels are regulated by growth factor signaling. Using phosphoinositide binding protein probes, we observed increased levels of PI(3)P, PI(4)P, PI(3,4)P₂, PI(4,5)P2, and PI(3,4,5)P₃ in PTP1B knockout mouse retina and decreased levels of these PIPs in Grb14 knockout mouse retina. These observations suggest that the interplay between PTP1B and Grb14 can regulate PIP metabolism. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

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17 pages, 2853 KiB

Open AccessArticle

Central Alteration in Peripheral Neuropathy of Trembler-J Mice: Hippocampal pmp22 Expression and Behavioral Profile in Anxiety Tests

by Juan Pablo Damián, Lucia Vázquez Alberdi, Lucía Canclini, Gonzalo Rosso, Silvia Olivera Bravo, Mariana Martínez, Natalia Uriarte, Paul Ruiz, Miguel Calero, María Vittoria Di Tomaso and Alejandra Kun

Biomolecules 2021, 11(4), 601; https://doi.org/10.3390/biom11040601 - 19 Apr 2021

Cited by 7 | Viewed by 3153

Abstract

Charcot–Marie–Tooth (CMT) type 1 disease is the most common human hereditary demyelinating neuropathy. Mutations in pmp22 cause about 70% of all CMT1. Trembler-J (TrJ/+) mice are an animal model of CMT1E, having the same spontaneous pmp22 mutation that is found in humans. We [...] Read more.

Charcot–Marie–Tooth (CMT) type 1 disease is the most common human hereditary demyelinating neuropathy. Mutations in pmp22 cause about 70% of all CMT1. Trembler-J (TrJ/+) mice are an animal model of CMT1E, having the same spontaneous pmp22 mutation that is found in humans. We compared the behavior profile of TrJ/+ and +/+ (wild-type) in open-field and elevated-plus-maze anxiety tests. In these tests, TrJ/+ showed an exclusive head shake movement, a lower frequency of rearing, but a greater frequency of grooming. In elevated-plus-maze, TrJ/+ defecate more frequently, performed fewer total entries, and have fewer entries to closed arms. These hippocampus-associated behaviors in TrJ/+ are consistent with increased anxiety levels. The expression of pmp22 and soluble PMP22 were evaluated in E17-hippocampal neurons and adult hippocampus by in situ hybridization and successive immunohistochemistry. Likewise, the expression of pmp22 was confirmed by RT-qPCR in the entire isolated hippocampi of both genotypes. Moreover, the presence of aggregated PMP22 was evidenced in unmasked granular hippocampal adult neurons and shows genotypic differences. We showed for the first time a behavior profile trait associated with anxiety and a differential expression of pmp22/PMP22 in hippocampal neurons of TrJ/+ and +/+ mice, demonstrating the involvement at the central level in an animal model of peripheral neuropathy (CMT1E). Full article

(This article belongs to the Special Issue Recent Advances and Future Prospectives for Experimental Models of Neurodegenerative Diseases)

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32 pages, 1382 KiB

Open AccessFeature PaperReview

Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes

by Marta Valenza, Roberta Facchinetti, Giorgia Menegoni, Luca Steardo and Caterina Scuderi

Biomolecules 2021, 11(4), 600; https://doi.org/10.3390/biom11040600 - 19 Apr 2021

Cited by 17 | Viewed by 6167

Abstract

The available treatments for patients affected by Alzheimer’s disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms [...] Read more.

The available treatments for patients affected by Alzheimer’s disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms of AD known so far, based on which different therapeutic tools have been designed. Then, we focus on a specific approach that is targeting astrocytes. Indeed, these non-neuronal brain cells respond to any insult, injury, or disease of the brain, including AD. The study of astrocytes is complicated by the fact that they exert a plethora of homeostatic functions, and their disease-induced changes could be context-, time-, and disease specific. However, this complex but fervent area of research has produced a large amount of data targeting different astrocytic functions using pharmacological approaches. Here, we review the most recent literature findings that have been published in the last five years to stimulate new hypotheses and ideas to work on, highlighting the peculiar ability of palmitoylethanolamide to modulate astrocytes according to their morpho-functional state, which ultimately suggests a possible potential disease-modifying therapeutic approach for AD. Full article

(This article belongs to the Special Issue Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease)

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16 pages, 2564 KiB

Open AccessArticle

EPHA3 Contributes to Epigenetic Suppression of PTEN in Radioresistant Head and Neck Cancer

by Song-Hee Kim, Byung-Chul Kang, Daseul Seong, Won-Hyeok Lee, Jae-Hee An, Hyoung-Uk Je, Hee-Jeong Cha, Hyo-Won Chang, Sang-Yoon Kim, Seong-Who Kim and Myung-Woul Han

Biomolecules 2021, 11(4), 599; https://doi.org/10.3390/biom11040599 - 18 Apr 2021

Cited by 10 | Viewed by 2959

Abstract

EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro [...] Read more.

EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro and in vivo. In this study, we investigated the mechanisms of PTEN regulation through EPHA3-related signaling. Increased DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2) levels, along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, correlated with decreased levels of PTEN in radioresistant head and neck cancer cells. Furthermore, PTEN is regulated in two ways: DNMT1-mediated DNA methylation, and EZH2-mediated histone methylation through EPHA3/C-myc signaling. Our results suggest that EPHA3 could display a novel regulatory mechanism for the epigenetic regulation of PTEN in radioresistant head and neck cancer cells. Full article

(This article belongs to the Special Issue Prevention, Diagnosis and Therapy of HNSCC (Head and Neck Squamous Cell Carcinoma))

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15 pages, 16174 KiB

Open AccessArticle

Comparison of the Benzanthrone Luminophores: They Are Not Equal for Rapid Examination of Parafasciolopsis fasciolaemorpha (Trematoda: Digenea)

by Ilze Rubenina, Inese Gavarane, Elena Kirilova, Ligita Mezaraupe and Muza Kirjusina

Biomolecules 2021, 11(4), 598; https://doi.org/10.3390/biom11040598 - 18 Apr 2021

Cited by 9 | Viewed by 2712

Abstract

Luminescent derivatives of benzanthrone are becoming more useful based on their light-absorbing and fluorescent-emitting properties. Our previous studies showed that luminescent staining properties of the same benzanthrone dye differ for variable parasite samples. Therefore, two types of benzanthrone dyes were prepared. One has [...] Read more.

Luminescent derivatives of benzanthrone are becoming more useful based on their light-absorbing and fluorescent-emitting properties. Our previous studies showed that luminescent staining properties of the same benzanthrone dye differ for variable parasite samples. Therefore, two types of benzanthrone dyes were prepared. One has a strongly basic amidine group and a halogen atom, and the other has an amide moiety and a tertiary amine group. Trematoda Parafasciolopsis fasciolaemorpha is a liver fluke of a moose (Alces alces) and has a significant influence on the health and abundance of the moose population. Staining protocols for parasite P. fasciolaemorpha specific organ or organ systems imaging are mostly time-consuming and labor-intensive. The study aimed to compare the fixation technique and the staining protocol by synthesized benzanthrone luminescent dyes to determine detailed morphology, anatomical arrangement of the organ systems and gross organization of the muscle layers of P. fasciolaemorpha using confocal laser scanning microscopy. Luminophores were tested for samples fixed in different fixatives. Developed dyes and staining protocol resulting in imaging of all parts of trematode without additional sample preparation procedures, which usually are required for parasite examination. Obtained results confirmed that the most qualitative results could be reached using 3-N-(2-piperidinylacetamido)benzanthrone dye which has amide moiety and a tertiary amine group. Based on obtained results, 3-N-(2-piperidinylacetamido)benzanthrone gave more qualitative parasite visualization than 2-bromo-3-N-(N′,N′-dimethylformamidino)benzanthrone. Full article

(This article belongs to the Special Issue Biomolecules in Complex Biological and Biochemical Systems – Selected Papers from ICBB2019)

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22 pages, 4854 KiB

Open AccessArticle

Structural Basis for the C-Terminal Domain of Mycobacterium tuberculosis Ribosome Maturation Factor RimM to Bind Ribosomal Protein S19

by Haoran Zhang, Qiuxiang Zhou, Chenyun Guo, Liubin Feng, Huilin Wang, Xinli Liao and Donghai Lin

Biomolecules 2021, 11(4), 597; https://doi.org/10.3390/biom11040597 - 18 Apr 2021

Cited by 4 | Viewed by 2764

Abstract

Multidrug-resistant tuberculosis (TB) is a serious threat to public health, calling for the development of new anti-TB drugs. Chaperon protein RimM, involved in the assembly of ribosomal protein S19 into 30S ribosomal subunit during ribosome maturation, is a potential drug target for TB [...] Read more.

Multidrug-resistant tuberculosis (TB) is a serious threat to public health, calling for the development of new anti-TB drugs. Chaperon protein RimM, involved in the assembly of ribosomal protein S19 into 30S ribosomal subunit during ribosome maturation, is a potential drug target for TB treatment. The C-terminal domain (CTD) of RimM is primarily responsible for binding S19. However, both the CTD structure of RimM from Mycobacterium tuberculosis (MtbRimM_CTD) and the molecular mechanisms underlying MtbRimM_CTD binding S19 remain elusive. Here, we report the solution structure, dynamics features of MtbRimM_CTD, and its interaction with S19. MtbRimM_CTD has a rigid hydrophobic core comprised of a relatively conservative six-strand β-barrel, tailed with a short α-helix and interspersed with flexible loops. Using several biophysical techniques including surface plasmon resonance (SPR) affinity assays, nuclear magnetic resonance (NMR) assays, and molecular docking, we established a structural model of the MtbRimM_CTD–S19 complex and indicated that the β4-β5 loop and two nonconserved key residues (D105 and H129) significantly contributed to the unique pattern of MtbRimM_CTD binding S19, which might be implicated in a form of orthogonality for species-dependent RimM–S19 interaction. Our study provides the structural basis for MtbRimM_CTD binding S19 and is beneficial to the further exploration of MtbRimM as a potential target for the development of new anti-TB drugs. Full article

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16 pages, 5684 KiB

Open AccessArticle

Effect of Surface Roughness on Aggregation of Polypeptide Chains: A Monte Carlo Study

by Nguyen Truong Co and Mai Suan Li

Biomolecules 2021, 11(4), 596; https://doi.org/10.3390/biom11040596 - 18 Apr 2021

Cited by 10 | Viewed by 4291

Abstract

The self-assembly of amyloidogenic peptides and proteins into fibrillar structures has been intensively studied for several decades, because it seems to be associated with a number of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Therefore, understanding the molecular mechanisms of this phenomenon [...] Read more.

The self-assembly of amyloidogenic peptides and proteins into fibrillar structures has been intensively studied for several decades, because it seems to be associated with a number of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Therefore, understanding the molecular mechanisms of this phenomenon is important for identifying an effective therapy for the corresponding diseases. Protein aggregation in living organisms very often takes place on surfaces like membranes and the impact of a surface on this process depends not only on the surface chemistry but also on its topology. Our goal was to develop a simple lattice model for studying the role of surface roughness in the aggregation kinetics of polypeptide chains and the morphology of aggregates. We showed that, consistent with the experiment, an increase in roughness slows down the fibril formation, and this process becomes inhibited at a very highly level of roughness. We predicted a subtle catalytic effect that a slightly rough surface promotes the self-assembly of polypeptide chains but does not delay it. This effect occurs when the interaction between the surface and polypeptide chains is moderate and can be explained by taking into account the competition between energy and entropy factors. Full article

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13 pages, 2093 KiB

Open AccessArticle

Exploration of Galectin Ligands Displayed on Gram-Negative Respiratory Bacterial Pathogens with Different Cell Surface Architectures

by María A. Campanero-Rhodes, Ioanna Kalograiaki, Begoña Euba, Enrique Llobet, Ana Ardá, Jesús Jiménez-Barbero, Junkal Garmendia and Dolores Solís

Biomolecules 2021, 11(4), 595; https://doi.org/10.3390/biom11040595 - 18 Apr 2021

Cited by 6 | Viewed by 3257

Abstract

Galectins bind various pathogens through recognition of distinct carbohydrate structures. In this work, we examined the binding of four human galectins to the Gram-negative bacteria Klebsiella pneumoniae (Kpn) and non-typeable Haemophilus influenzae (NTHi), which display different surface glycans. In particular, Kpn cells are [...] Read more.

Galectins bind various pathogens through recognition of distinct carbohydrate structures. In this work, we examined the binding of four human galectins to the Gram-negative bacteria Klebsiella pneumoniae (Kpn) and non-typeable Haemophilus influenzae (NTHi), which display different surface glycans. In particular, Kpn cells are covered by a polysaccharide capsule and display an O-chain-containing lipopolysaccharide (LPS), whereas NTHi is not capsulated and its LPS, termed lipooligosacccharide (LOS), does not contain O-chain. Binding assays to microarray-printed bacteria revealed that galectins-3, -4, and -8, but not galectin-1, bind to Kpn and NTHi cells, and confocal microscopy attested binding to bacterial cells in suspension. The three galectins bound to array-printed Kpn LPS. Moreover, analysis of galectin binding to mutant Kpn cells evidenced that the O-chain is the docking point for galectins on wild type Kpn. Galectins-3, -4, and -8 also bound the NTHi LOS. Microarray-assisted comparison of the binding to full-length and truncated LOSs, as well as to wild type and mutant cells, supported LOS involvement in galectin binding to NTHi. However, deletion of the entire LOS oligosaccharide chain actually increased binding to NTHi cells, indicating the availability of other ligands on the bacterial surface, as similarly inferred for Kpn cells devoid of both O-chain and capsule. Altogether, the results illustrate galectins’ versatility for recognizing different bacterial structures, and point out the occurrence of so far overlooked galectin ligands on bacterial surfaces. Full article

(This article belongs to the Special Issue Galectins: Their Network and Roles in Infection/Immunity/Tumor Growth Control 2021)

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16 pages, 1443 KiB

Open AccessReview

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

by Elizabeth Martínez-Rojo, Laura Cristina Berumen, Guadalupe García-Alcocer and Jesica Escobar-Cabrera

Biomolecules 2021, 11(4), 594; https://doi.org/10.3390/biom11040594 - 18 Apr 2021

Cited by 22 | Viewed by 7861

Abstract

Bladder cancer (urothelial carcinoma) is one of the most frequently diagnosed neoplasms, with an estimated half a million new cases and 200,000 deaths per year worldwide. This pathology mainly affects men. Men have a higher risk (4:1) of developing bladder cancer than women. [...] Read more.

Bladder cancer (urothelial carcinoma) is one of the most frequently diagnosed neoplasms, with an estimated half a million new cases and 200,000 deaths per year worldwide. This pathology mainly affects men. Men have a higher risk (4:1) of developing bladder cancer than women. Cigarette smoking and exposure to chemicals such as aromatic amines, and aniline dyes have been established as risk factors for bladder cancer and may contribute to the sex disparity. Male internal genitalia, including the urothelium and prostate, are derived from urothelial sinus endoderm; both tissues express the androgen receptor (AR). Several investigations have shown evidence that the AR plays an important role in the initiation and development of different types of cancer including bladder cancer. In this article, we summarize the available data that help to explain the role of the AR in the development and progression of bladder cancer, as well as the therapies used for its treatment. Full article

(This article belongs to the Section Molecular Medicine)

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12 pages, 923 KiB

Open AccessFeature PaperReview

Bone Morphogenetic Proteins and Diabetic Retinopathy

by Khaled Elmasry, Samar Habib, Mohamed Moustafa and Mohamed Al-Shabrawey

Biomolecules 2021, 11(4), 593; https://doi.org/10.3390/biom11040593 - 18 Apr 2021

Cited by 9 | Viewed by 3739

Abstract

Bone morphogenetic proteins (BMPs) play an important role in bone formation and repair. Recent studies underscored their essential role in the normal development of several organs and vascular homeostasis in health and diseases. Elevated levels of BMPs have been linked to the development [...] Read more.

Bone morphogenetic proteins (BMPs) play an important role in bone formation and repair. Recent studies underscored their essential role in the normal development of several organs and vascular homeostasis in health and diseases. Elevated levels of BMPs have been linked to the development of cardiovascular complications of diabetes mellitus. However, their particular role in the pathogenesis of microvascular dysfunction associated with diabetic retinopathy (DR) is still under-investigated. Accumulated evidence from our and others’ studies suggests the involvement of BMP signaling in retinal inflammation, hyperpermeability and pathological neovascularization in DR and age-related macular degeneration (AMD). Therefore, targeting BMP signaling in diabetes is proposed as a potential therapeutic strategy to halt the development of microvascular dysfunction in retinal diseases, particularly in DR. The goal of this review article is to discuss the biological functions of BMPs, their underlying mechanisms and their potential role in the pathogenesis of DR in particular. Full article

(This article belongs to the Special Issue Neurovascular Injury in Diabetic Retinopathy; Experimental Models, Pathophysiology and Potential new Therapeutic Targets)

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19 pages, 3095 KiB

Open AccessArticle

Involvement of Opioid System and TRPM8/TRPA1 Channels in the Antinociceptive Effect of Spirulina platensis

by Mariana A. Freitas, Amanda Vasconcelos, Elaine C. D. Gonçalves, Eduarda G. Ferrarini, Gabriela B. Vieira, Donatella Cicia, Maíra Cola, Raffaele Capasso and Rafael C. Dutra

Biomolecules 2021, 11(4), 592; https://doi.org/10.3390/biom11040592 - 17 Apr 2021

Cited by 71 | Viewed by 4427

Abstract

Spirulina platensis is a “super-food” and has attracted researchers’ attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3–300 mg/kg, [...] Read more.

Spirulina platensis is a “super-food” and has attracted researchers’ attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3–300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED₅₀ = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders. Full article

(This article belongs to the Collection Pharmacology of Medicinal Plants)

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9 pages, 273 KiB

Open AccessFeature PaperArticle

The Initial Course of IL1β, IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α with Regard to Severity Grade in Acute Pancreatitis

by Hanna Sternby, Hannes Hartman, Henrik Thorlacius and Sara Regnér

Biomolecules 2021, 11(4), 591; https://doi.org/10.3390/biom11040591 - 17 Apr 2021

Cited by 25 | Viewed by 2428

Abstract

Clinical reports on early immune dysregulation in acute pancreatitis (AP) are scarce. Herein we investigate the initial temporal development of selected biomarkers. Blood samples were taken at 0–24 and 25–48 h after onsets of AP were acquired. Mean values and temporal intermediate difference [...] Read more.

Clinical reports on early immune dysregulation in acute pancreatitis (AP) are scarce. Herein we investigate the initial temporal development of selected biomarkers. Blood samples were taken at 0–24 and 25–48 h after onsets of AP were acquired. Mean values and temporal intermediate difference (delta-values) of IL-1β, IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α were calculated. Differences between severity groups, predictive capacity of the biomarkers and association with severe disease were analyzed. Paired comparison of samples (n = 115) taken at 0–24 and 25–48 h after onsets of AP showed a change over time for IL-1β, IL-6, IL-8 and IL-10 (p < 0.05) and a significant difference between severity groups after 24 h. In ROC-analysis an IL-6 cut-off level of 196.6 pg/mL could differentiate severe AP (sensitivity 81.9, specificity 91.3). The delta-values of IL-1β and IL-6 were significantly associated with severe outcomes (odds ratios 1.085 and 1.002, respectively). Data of this work demonstrate a distinct change in IL-1β, IL-8, IL-10 and IL-6 over the first 48 h after onset of AP. The temporal development of biomarkers can assist in the early stratification of the disease. Herein IL-1β and IL-6 were associated with severe disease, however the prognostic capacity of investigated biomarkers is low. Full article

(This article belongs to the Special Issue Pancreatitis and Its Complications—Call for Accurate Biomarkers)

13 pages, 1936 KiB

Open AccessArticle

A Multi-Enzyme Cascade Reaction for the Production of 2′3′-cGAMP

by Martin Becker, Patrick Nikel, Jennifer N. Andexer, Stephan Lütz and Katrin Rosenthal

Biomolecules 2021, 11(4), 590; https://doi.org/10.3390/biom11040590 - 16 Apr 2021

Cited by 24 | Viewed by 4410

Abstract

Multi-enzyme cascade reactions for the synthesis of complex products have gained importance in recent decades. Their advantages compared to single biotransformations include the possibility to synthesize complex molecules without purification of reaction intermediates, easier handling of unstable intermediates, and dealing with unfavorable thermodynamics [...] Read more.

Multi-enzyme cascade reactions for the synthesis of complex products have gained importance in recent decades. Their advantages compared to single biotransformations include the possibility to synthesize complex molecules without purification of reaction intermediates, easier handling of unstable intermediates, and dealing with unfavorable thermodynamics by coupled equilibria. In this study, a four-enzyme cascade consisting of ScADK, AjPPK2, and SmPPK2 for ATP synthesis from adenosine coupled to the cyclic GMP-AMP synthase (cGAS) catalyzing cyclic GMP-AMP (2′3′-cGAMP) formation was successfully developed. The 2′3′-cGAMP synthesis rates were comparable to the maximal reaction rate achieved in single-step reactions. An iterative optimization of substrate, cofactor, and enzyme concentrations led to an overall yield of 0.08 mole 2′3′-cGAMP per mole adenosine, which is comparable to chemical synthesis. The established enzyme cascade enabled the synthesis of 2′3′-cGAMP from GTP and inexpensive adenosine as well as polyphosphate in a biocatalytic one-pot reaction, demonstrating the performance capabilities of multi-enzyme cascades for the synthesis of pharmaceutically relevant products. Full article

(This article belongs to the Special Issue Biotechnological and Biomedical Applications of Enzymes Involved in the Synthesis of Nucleosides and Nucleotides)

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23 pages, 5198 KiB

Open AccessReview

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions

by Valeria Consoli, Valeria Sorrenti, Salvo Grosso and Luca Vanella

Biomolecules 2021, 11(4), 589; https://doi.org/10.3390/biom11040589 - 16 Apr 2021

Cited by 138 | Viewed by 10876

Abstract

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies [...] Read more.

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

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8 pages, 1471 KiB

Open AccessCommunication

Assessing Various Control Samples for Microarray Gene Expression Profiling of Laryngeal Squamous Cell Carcinoma

by Adam Ustaszewski, Magdalena Kostrzewska-Poczekaj, Joanna Janiszewska, Malgorzata Jarmuz-Szymczak, Malgorzata Wierzbicka, Joanna Marszal, Reidar Grénman and Maciej Giefing

Biomolecules 2021, 11(4), 588; https://doi.org/10.3390/biom11040588 - 16 Apr 2021

Cited by 2 | Viewed by 2445

Abstract

Selection of optimal control samples is crucial in expression profiling tumor samples. To address this issue, we performed microarray expression profiling of control samples routinely used in head and neck squamous cell carcinoma studies: human bronchial and tracheal epithelial cells, squamous cells obtained [...] Read more.

Selection of optimal control samples is crucial in expression profiling tumor samples. To address this issue, we performed microarray expression profiling of control samples routinely used in head and neck squamous cell carcinoma studies: human bronchial and tracheal epithelial cells, squamous cells obtained by laser uvulopalatoplasty and tumor surgical margins. We compared the results using multidimensional scaling and hierarchical clustering versus tumor samples and laryngeal squamous cell carcinoma cell lines. A general observation from our study is that the analyzed cohorts separated according to two dominant factors: “malignancy”, which separated controls from malignant samples and “cell culture-microenvironment” which reflected the differences between cultured and non-cultured samples. In conclusion, we advocate the use of cultured epithelial cells as controls for gene expression profiling of cancer cell lines. In contrast, comparisons of gene expression profiles of cancer cell lines versus surgical margin controls should be treated with caution, whereas fresh frozen surgical margins seem to be appropriate for gene expression profiling of tumor samples. Full article

(This article belongs to the Special Issue Genetics and Molecular Biology of Head and Neck Cancer)

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15 pages, 10602 KiB

Open AccessArticle

Modulation of the Antioxidant Defense System by Exogenous l-Glutamic Acid Application Enhances Salt Tolerance in Lentil (Lens culinaris Medik.)

by Jannatul Fardus, Md. Shahadat Hossain and Masayuki Fujita

Biomolecules 2021, 11(4), 587; https://doi.org/10.3390/biom11040587 - 16 Apr 2021

Cited by 30 | Viewed by 3480

Abstract

Salt stress greatly disturbs the growth, morpho-physiological, and biochemical performance of plants. However, different physiological processes and acclimation mechanisms can be induced under stress, while some of them can be modulated by the appropriate chemical stimulus. The objective of this study was to [...] Read more.

Salt stress greatly disturbs the growth, morpho-physiological, and biochemical performance of plants. However, different physiological processes and acclimation mechanisms can be induced under stress, while some of them can be modulated by the appropriate chemical stimulus. The objective of this study was to evaluate the impact of exogenous pretreatment with 10 mM l-glutamic acid (l-Glu) on the physiological and biochemical parameters of lentil (Lensculinaris Medik.) under 110 mM NaCl stress. Salt stress inhibited the growth and reduced the photosynthetic pigment (chlorophylls and carotenoids) level, water content, and survival of lentil seedlings during recovery from the stress. Salt stress also induced oxidative damage, as indicated by higher hydrogen peroxide and malonaldehyde contents and electrolyte leakage, by interrupting the antioxidant defense system and promoting the accumulation of toxic levels of Na⁺. However, l-Glu pretreatment mitigated the salt-induced damage in lentil seedlings by reducing the accumulation of Na⁺, maintaining ion homeostasis, and increasing the activities of antioxidant enzymes (catalase and ascorbate peroxidase). As a result, salt-induced oxidative damage was reduced, seedling growth and photosynthetic pigment contents were enhanced, and the survival rate of the lentil seedlings was improved in response to salt stress, indicating an ameliorative role for l-Glu in lentil seedling growth under salt stress. Full article

(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)

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22 pages, 2960 KiB

Open AccessArticle

Multi-Enzymatic Cascades in the Synthesis of Modified Nucleosides: Comparison of the Thermophilic and Mesophilic Pathways

by Ilja V. Fateev, Maria A. Kostromina, Yuliya A. Abramchik, Barbara Z. Eletskaya, Olga O. Mikheeva, Dmitry D. Lukoshin, Evgeniy A. Zayats, Maria Ya. Berzina, Elena V. Dorofeeva, Alexander S. Paramonov, Alexey L. Kayushin, Irina D. Konstantinova and Roman S. Esipov

Biomolecules 2021, 11(4), 586; https://doi.org/10.3390/biom11040586 - 16 Apr 2021

Cited by 14 | Viewed by 4814

Abstract

A comparative study of the possibilities of using ribokinase → phosphopentomutase → nucleoside phosphorylase cascades in the synthesis of modified nucleosides was carried out. Recombinant phosphopentomutase from Thermus thermophilus HB27 was obtained for the first time: a strain producing a soluble form of [...] Read more.

A comparative study of the possibilities of using ribokinase → phosphopentomutase → nucleoside phosphorylase cascades in the synthesis of modified nucleosides was carried out. Recombinant phosphopentomutase from Thermus thermophilus HB27 was obtained for the first time: a strain producing a soluble form of the enzyme was created, and a method for its isolation and chromatographic purification was developed. It was shown that cascade syntheses of modified nucleosides can be carried out both by the mesophilic and thermophilic routes from D-pentoses: ribose, 2-deoxyribose, arabinose, xylose, and 2-deoxy-2-fluoroarabinose. The efficiency of 2-chloradenine nucleoside synthesis decreases in the following order: Rib (92), dRib (74), Ara (66), F-Ara (8), and Xyl (2%) in 30 min for mesophilic enzymes. For thermophilic enzymes: Rib (76), dRib (62), Ara (32), F-Ara (<1), and Xyl (2%) in 30 min. Upon incubation of the reaction mixtures for a day, the amounts of 2-chloroadenine riboside (thermophilic cascade), 2-deoxyribosides (both cascades), and arabinoside (mesophilic cascade) decreased roughly by half. The conversion of the base to 2-fluoroarabinosides and xylosides continued to increase in both cases and reached 20-40%. Four nucleosides were quantitatively produced by a cascade of enzymes from D-ribose and D-arabinose. The ribosides of 8-azaguanine (thermophilic cascade) and allopurinol (mesophilic cascade) were synthesized. For the first time, D-arabinosides of 2-chloro-6-methoxypurine and 2-fluoro-6-methoxypurine were synthesized using the mesophilic cascade. Despite the relatively small difference in temperatures when performing the cascade reactions (50 and 80 °C), the rate of product formation in the reactions with Escherichia coli enzymes was significantly higher. E. coli enzymes also provided a higher content of the target products in the reaction mixture. Therefore, they are more appropriate for use in the polyenzymatic synthesis of modified nucleosides. Full article

(This article belongs to the Special Issue Biotechnological and Biomedical Applications of Enzymes Involved in the Synthesis of Nucleosides and Nucleotides)

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17 pages, 1758 KiB

Open AccessReview

Matrix Metalloproteinases and Arterial Hypertension: Role of Oxidative Stress and Nitric Oxide in Vascular Functional and Structural Alterations

by Alejandro F. Prado, Rose I. M. Batista, Jose E. Tanus-Santos and Raquel F. Gerlach

Biomolecules 2021, 11(4), 585; https://doi.org/10.3390/biom11040585 - 16 Apr 2021

Cited by 43 | Viewed by 5569

Abstract

Various pathophysiological mechanisms have been implicated in hypertension, but those resulting in vascular dysfunction and remodeling are critical and may help to identify critical pharmacological targets. This mini-review article focuses on central mechanisms contributing to the vascular dysfunction and remodeling of hypertension, increased [...] Read more.

Various pathophysiological mechanisms have been implicated in hypertension, but those resulting in vascular dysfunction and remodeling are critical and may help to identify critical pharmacological targets. This mini-review article focuses on central mechanisms contributing to the vascular dysfunction and remodeling of hypertension, increased oxidative stress and impaired nitric oxide (NO) bioavailability, which enhance vascular matrix metalloproteinase (MMP) activity. The relationship between NO, MMP and oxidative stress culminating in the vascular alterations of hypertension is examined. While the alterations of hypertension are not fully attributable to these pathophysiological mechanisms, there is strong evidence that such mechanisms play critical roles in increasing vascular MMP expression and activity, thus resulting in abnormal degradation of extracellular matrix components, receptors, peptides, and intracellular proteins involved in the regulation of vascular function and structure. Imbalanced vascular MMP activity promotes vasoconstriction and impairs vasodilation, stimulating vascular smooth muscle cells (VSMC) to switch from contractile to synthetic phenotypes, thus facilitating cell growth or migration, which is associated with the deposition of extracellular matrix components. Finally, the protective effects of MMP inhibitors, antioxidants and drugs that enhance vascular NO activity are briefly discussed. Newly emerging therapies that address these essential mechanisms may offer significant advantages to prevent vascular remodeling in hypertensive patients. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease in the Times of COVID-19)

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22 pages, 5002 KiB

Open AccessReview

Cation Transporters of Candida albicans—New Targets to Fight Candidiasis?

by Marina Volkova, Anastasia Atamas, Alexey Tsarenko, Andrey Rogachev and Albert Guskov

Biomolecules 2021, 11(4), 584; https://doi.org/10.3390/biom11040584 - 16 Apr 2021

Cited by 7 | Viewed by 3749

Abstract

Candidiasis is the wide-spread fungal infection caused by numerous strains of yeast, with the prevalence of Candida albicans. The current treatment of candidiasis is becoming rather ineffective and costly owing to the emergence of resistant strains; hence, the exploration of new possible [...] Read more.

Candidiasis is the wide-spread fungal infection caused by numerous strains of yeast, with the prevalence of Candida albicans. The current treatment of candidiasis is becoming rather ineffective and costly owing to the emergence of resistant strains; hence, the exploration of new possible drug targets is necessary. The most promising route is the development of novel antibiotics targeting this pathogen. In this review, we summarize such candidates found in C. albicans and those involved in the transport of (metal) cations, as the latter are essential for numerous processes within the cell; hence, disruption of their fluxes can be fatal for C. albicans. Full article

(This article belongs to the Collection Feature Papers in Biochemistry)

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12 pages, 997 KiB

Open AccessArticle

GPCR-Based Bioactive Peptide Screening Using Phage-Displayed Peptides and an Insect Cell System for Insecticide Discovery

by Man-Yeon Choi and Robert K. Vander Meer

Biomolecules 2021, 11(4), 583; https://doi.org/10.3390/biom11040583 - 16 Apr 2021

Cited by 10 | Viewed by 6887

Abstract

The discovery of new insecticides improves integrated pest management (IPM), but is usually a long high-risk process with a low probability of success. For over two decades, insect neuropeptides (NPs) and their G-protein coupled receptors (GPCRs) have been considered as biological targets for [...] Read more.

The discovery of new insecticides improves integrated pest management (IPM), but is usually a long high-risk process with a low probability of success. For over two decades, insect neuropeptides (NPs) and their G-protein coupled receptors (GPCRs) have been considered as biological targets for insect pest control, because they are involved in almost all physiological processes associated with insect life stages. A key roadblock to success has been the question of how large volume chemical libraries can be efficiently screened for active compounds. New genomic and proteomic tools have advanced and facilitated the development of new approaches to insecticide discovery. In this study, we report a novel GPCR-based screening technology that uses millions of short peptides randomly generated by bacteriophages, and a method using an insect Sf9 cell expression system. The fire ant is a good model system, since bioactive peptides have been identified for a specific GPCR. The novel small peptides could interfere with the target GPCR-ligand functions. Therefore, we refer to this new mechanism as “receptor interference” (RECEPTORi). The GPCR-based bioactive peptide screening method offers multiple advantages. Libraries of phage-displayed peptides (~10⁹ peptides) are inexpensive. An insect cell-based screening system rapidly leads to target specific GPCR agonists or antagonists in weeks. Delivery of bioactive peptides to target pests can be flexible, such as topical, ingestion, and plant-incorporated protectants. A variety of GPCR targets are available, thus minimizing the development of potential insecticide resistance. This report provides the first proof-of-concept for the development of novel arthropod pest management strategies using neuropeptides, and GPCRs. Full article

(This article belongs to the Special Issue Insect Receptors: Biochemical, Physiological and Molecular Studies)

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