Biomolecules

15 pages, 2692 KiB

Open AccessArticle

Structural Analyses on the Deamidation of N-Terminal Asn in the Human N-Degron Pathway

by Joon Sung Park, Jae-Young Lee, Yen Thi Kim Nguyen, Nae-Won Kang, Eun Kyung Oh, Dong Man Jang, Hyun-Jung Kim, Dae-Duk Kim and Byung Woo Han

Biomolecules 2020, 10(1), 163; https://doi.org/10.3390/biom10010163 - 20 Jan 2020

Cited by 10 | Viewed by 4336

Abstract

The N-degron pathway is a proteolytic system in which a single N-terminal amino acid acts as a determinant of protein degradation. Especially, degradation signaling of N-terminal asparagine (Nt-Asn) in eukaryotes is initiated from its deamidation by N-terminal asparagine amidohydrolase 1 (NTAN1) into aspartate. [...] Read more.

The N-degron pathway is a proteolytic system in which a single N-terminal amino acid acts as a determinant of protein degradation. Especially, degradation signaling of N-terminal asparagine (Nt-Asn) in eukaryotes is initiated from its deamidation by N-terminal asparagine amidohydrolase 1 (NTAN1) into aspartate. Here, we have elucidated structural principles of deamidation by human NTAN1. NTAN1 adopts the characteristic scaffold of CNF1/YfiH-like cysteine hydrolases that features an α-β-β sandwich structure and a catalytic triad comprising Cys, His, and Ser. In vitro deamidation assays using model peptide substrates with varying lengths and sequences showed that NTAN1 prefers hydrophobic residues at the second-position. The structures of NTAN1-peptide complexes further revealed that the recognition of Nt-Asn is sufficiently organized to produce high specificity, and the side chain of the second-position residue is accommodated in a hydrophobic pocket adjacent to the active site of NTAN1. Collectively, our structural and biochemical analyses of the substrate specificity of NTAN1 contribute to understanding the structural basis of all three amidases in the eukaryotic N-degron pathway. Full article

(This article belongs to the Section Molecular Structure and Dynamics)

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12 pages, 2037 KiB

Open AccessArticle

Back to GroEL-Assisted Protein Folding: GroES Binding-Induced Displacement of Denatured Proteins from GroEL to Bulk Solution

by Victor Marchenkov, Andrey Gorokhovatsky, Natalia Marchenko, Tanya Ivashina and Gennady Semisotnov

Biomolecules 2020, 10(1), 162; https://doi.org/10.3390/biom10010162 - 20 Jan 2020

Cited by 6 | Viewed by 4126

Abstract

The main events in chaperone-assisted protein folding are the binding and ligand-induced release of substrate proteins. Here, we studied the location of denatured proteins previously bound to the GroEL chaperonin resulting from the action of the GroES co-chaperonin in the presence of Mg-ATP. [...] Read more.

The main events in chaperone-assisted protein folding are the binding and ligand-induced release of substrate proteins. Here, we studied the location of denatured proteins previously bound to the GroEL chaperonin resulting from the action of the GroES co-chaperonin in the presence of Mg-ATP. Fluorescein-labeled denatured proteins (α-lactalbumin, lysozyme, serum albumin, and pepsin in the presence of thiol reagents at neutral pH, as well as an early refolding intermediate of malate dehydrogenase) were used to reveal the effect of GroES on their interaction with GroEL. Native electrophoresis has demonstrated that these proteins tend to be released from the GroEL-GroES complex. With the use of biotin- and fluorescein-labeled denatured proteins and streptavidin fused with luciferase aequorin (the so-called streptavidin trap), the presence of denatured proteins in bulk solution after GroES and Mg-ATP addition has been confirmed. The time of GroES-induced dissociation of a denatured protein from the GroEL surface was estimated using the stopped-flow technique and found to be much shorter than the proposed time of the GroEL ATPase cycle. Full article

(This article belongs to the Special Issue Protein Folding and Quality Control Mechanisms - In Memory of Prof. Oleg B. Ptitsyn (1929-1999))

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19 pages, 790 KiB

Open AccessReview

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

by Terezia Kiskova, Peter Kubatka, Dietrich Büsselberg and Monika Kassayova

Biomolecules 2020, 10(1), 161; https://doi.org/10.3390/biom10010161 - 19 Jan 2020

Cited by 69 | Viewed by 7949

Abstract

Despite intensive research, malignant brain tumors are among the most difficult to treat due to high resistance to conventional therapeutic approaches. High-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma, are among the most devastating and rapidly growing cancers. Despite the ability of standard [...] Read more.

Despite intensive research, malignant brain tumors are among the most difficult to treat due to high resistance to conventional therapeutic approaches. High-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma, are among the most devastating and rapidly growing cancers. Despite the ability of standard treatment agents to achieve therapeutic concentrations in the brain, malignant gliomas are often resistant to alkylating agents. Resveratrol is a plant polyphenol occurring in nuts, berries, grapes, and red wine. Resveratrol crosses the blood‒brain barrier and may influence the central nervous system. Moreover, it influences the enzyme isocitrate dehydrogenase and, more importantly, the resistance to standard treatment via various mechanisms, such as O6-methylguanine methyltransferase. This review summarizes the anticancer effects of resveratrol in various types of brain cancer. Several in vitro and in vivo studies have presented promising results; however, further clinical research is necessary to prove the therapeutic efficacy of resveratrol in brain cancer treatment. Full article

(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)

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24 pages, 1124 KiB

Open AccessReview

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

by Oliwia Koszła, Katarzyna M. Targowska-Duda, Ewa Kędzierska and Agnieszka A. Kaczor

Biomolecules 2020, 10(1), 160; https://doi.org/10.3390/biom10010160 - 19 Jan 2020

Cited by 16 | Viewed by 6538

Abstract

Schizophrenia (SZ) is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, and is not satisfactorily treated by current antipsychotics. Progress in understanding the basic pathomechanism of the disease has been hampered by the lack of appropriate models. In order to [...] Read more.

Schizophrenia (SZ) is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, and is not satisfactorily treated by current antipsychotics. Progress in understanding the basic pathomechanism of the disease has been hampered by the lack of appropriate models. In order to develop modern drugs against SZ, efficient methods to study them in in vitro and in vivo models of this disease are required. In this review a short presentation of current hypotheses and concepts of SZ is followed by a description of current progress in the field of SZ experimental models. A critical discussion of advantages and limitations of in vitro models and pharmacological, genetic, and neurodevelopmental in vivo models for positive, negative, and cognitive symptoms of the disease is provided. In particular, this review concerns the important issue of how cellular and animal systems can help to meet the challenges of modeling the disease, which fully manifests only in humans, as experimental studies of SZ in humans are limited. Next, it is emphasized that novel clinical candidates should be evaluated in animal models for treatment-resistant SZ. In conclusion, the plurality of available in vitro and in vivo models is a consequence of the complex nature of SZ, and there are extensive possibilities for their integration. Future development of more efficient antipsychotics reflecting the pleiotropy of symptoms in SZ requires the incorporation of various models into one uniting model of the multifactorial disorder and use of this model for the evaluation of new drugs. Full article

(This article belongs to the Section Molecular Medicine)

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16 pages, 3130 KiB

Open AccessArticle

Preparation, Characterization, and Immuno-Enhancing Activity of Polysaccharides from Glycyrrhiza uralensis

by Adila Aipire, Pengfei Yuan, Alimu Aimaier, Shanshan Cai, Mahepali Mahabati, Jun Lu, Tianlei Ying, Baohong Zhang and Jinyao Li

Biomolecules 2020, 10(1), 159; https://doi.org/10.3390/biom10010159 - 19 Jan 2020

Cited by 34 | Viewed by 4860

Abstract

Glycyrrhiza uralensis is a Chinese herbal medicine with various bioactivities. Three fractions (GUPS-I, GUPS-II and GUPS-III) of G. uralensis polysaccharides (GUPS) were obtained with molecular weights of 1.06, 29.1, and 14.9 kDa, respectively. The monosaccharide compositions of GUPS-II and GUPS-III were similar, while [...] Read more.

Glycyrrhiza uralensis is a Chinese herbal medicine with various bioactivities. Three fractions (GUPS-I, GUPS-II and GUPS-III) of G. uralensis polysaccharides (GUPS) were obtained with molecular weights of 1.06, 29.1, and 14.9 kDa, respectively. The monosaccharide compositions of GUPS-II and GUPS-III were similar, while that of GUPS-I was distinctively different. The results of scanning electron microscopy, FT-IR, and NMR suggested that GUPS-II and GUPS-III were flaky with a smooth surface and contained α- and β-glycosidic linkages, while GUPS-I was granulated and contained only α-glycosidic linkages. Moreover, GUPS-II and GUPS-III exhibited better bioactivities on the maturation and cytokine production of dendritic cells (DCs) in vitro than that of GUPS-I. An in vivo experiment showed that only GUPS-II significantly enhanced the maturation of DCs. These results indicate that GUPS-II has the potential to be used in combination with cancer immunotherapy to enhance the therapeutic effect. Full article

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10 pages, 2456 KiB

Open AccessArticle

Anti-Migratory and Pro-Apoptotic Properties of Parvifloron D on Triple-Negative Breast Cancer Cells

by Nuno Saraiva, João G. Costa, Catarina Reis, Nuno Almeida, Patrícia Rijo and Ana Sofia Fernandes

Biomolecules 2020, 10(1), 158; https://doi.org/10.3390/biom10010158 - 19 Jan 2020

Cited by 11 | Viewed by 3568

Abstract

Medicinal plants are important sources of new bioactive compounds with potential anticancer activity. Parvifloron D (ParvD) is an abietane diterpenoid, isolated in high amounts from Plectranthus ecklonii Benth. Previous reports have suggested potential therapeutic properties for ParvD. ParvD has shown pro-apoptotic and cytotoxic [...] Read more.

Medicinal plants are important sources of new bioactive compounds with potential anticancer activity. Parvifloron D (ParvD) is an abietane diterpenoid, isolated in high amounts from Plectranthus ecklonii Benth. Previous reports have suggested potential therapeutic properties for ParvD. ParvD has shown pro-apoptotic and cytotoxic effects in leukemia and melanoma cell lines. However, to the best of our knowledge, there are no studies in triple-negative breast cancer (TNBC) models. TNBC is a breast cancer subtype characterized by an aggressive behavior with poor clinical outcomes and weak overall therapeutic responses to the current treatment options. This work aimed at evaluating the anticancer effect of ParvD in MDA-MB-231 cells, a model of human TNBC. To obtain sufficient amounts of purified ParvD the efficiency of several extraction methods was compared. ParvD (0.1–10 µM) decreased cell viability in a concentration-dependent manner. Treatment with ParvD (5 µM) significantly increased the percentage of apoptotic nuclei and exposure to 3 µM ParvD increased the sub-G1 population. Since altered cell adherence, migration, and invasion are determinant processes for the formation of metastases, the effect of ParvD on these cellular processes was tested. Although treatment with ParvD (1 µM) had no effect on cell-substrate attachment, ParvD (1 µM) significantly reduced cell chemotaxis and invasion. This is the first report describing the proapoptotic effect of ParvD in TNBC cells. Moreover, for the first time we have shown that ParvD reduces cell motility, unraveling potential anti-metastatic properties. Full article

(This article belongs to the Special Issue Selected Papers from Bio.Natural Meeting 2019)

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18 pages, 2888 KiB

Open AccessArticle

A Combined Proteomics, Metabolomics and In Vivo Analysis Approach for the Characterization of Probiotics in Large-Scale Production

by Laura Bianchi, Luca Laghi, Virginia Correani, Emily Schifano, Claudia Landi, Daniela Uccelletti and Benedetta Mattei

Biomolecules 2020, 10(1), 157; https://doi.org/10.3390/biom10010157 - 18 Jan 2020

Cited by 21 | Viewed by 4938

Abstract

The manufacturing processes of commercial probiotic strains may be affected in different ways in the attempt to optimize yield, costs, functionality, or stability, influencing gene expression, protein patterns, or metabolic output. Aim of this work is to compare different samples of a high [...] Read more.

The manufacturing processes of commercial probiotic strains may be affected in different ways in the attempt to optimize yield, costs, functionality, or stability, influencing gene expression, protein patterns, or metabolic output. Aim of this work is to compare different samples of a high concentration (450 billion bacteria) multispecies (8 strains) formulation produced at two different manufacturing sites, United States of America (US) and Italy (IT), by applying a combination of functional proteomics, metabolomics, and in vivo analyses. Several protein-profile differences were detected between IT- and US-made products, with Lactobacillus paracasei, Streptococcus thermophilus, and Bifidobacteria being the main affected probiotics/microorganisms. Performing proton nuclear magnetic spectroscopy (¹H-NMR), some discrepancies in amino acid, lactate, betaine and sucrose concentrations were also reported between the two products. Finally, we investigated the health-promoting and antiaging effects of both products in the model organism Caenorhabditis elegans. The integration of omics platforms with in vivo analysis has emerged as a powerful tool to assess manufacturing procedures. Full article

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16 pages, 3122 KiB

Open AccessArticle

Synthesis of Chitosan-Polyvinyl Alcohol Biopolymers to Eliminate Fluorides from Water

by Cecilia Judith Valdez-Alegría, Rosa María Fuentes-Rivas, José Luis García-Rivas, Rosa Elvira Zavala Arce, María de la Luz Jiménez Núñez and Beatriz García-Gaitán

Biomolecules 2020, 10(1), 156; https://doi.org/10.3390/biom10010156 - 18 Jan 2020

Cited by 12 | Viewed by 3626

Abstract

The fluoride content in groundwater varies depending on geological configuration. Fluoride problems tend to occur in places where these minerals are most abundant in rocks. The objective of the present work was to synthesize four biopolymers based on chitosan-polyvinyl alcohol (Ch-PVA) cross-linked with [...] Read more.

The fluoride content in groundwater varies depending on geological configuration. Fluoride problems tend to occur in places where these minerals are most abundant in rocks. The objective of the present work was to synthesize four biopolymers based on chitosan-polyvinyl alcohol (Ch-PVA) cross-linked with sodium tripolyphosphate pentabasic (TPP) and ethylene glycol diglycidyl ether (EGDE) and determine their ability to remove fluoride from water. The characterization of the Ch-PVA beads was performed by way of Scanning Electron Microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR). The percentage of humidity and the point of zero charge were determined. The Ch-PVA beads showed a surface area of 63.87 m² g⁻¹, a pore size of 7.6 nm, a point of zero charge of 7.4, and 98.6% humidity. The kinetic adsorption study was adjusted to the pseudo-second-order model and the adsorption equilibrium data were adjusted to the Freundlich adsorption isotherm, showing a maximum fluoride adsorption capacity of 12.64 mg g⁻¹ at pH 7 and 30 °C, for the beads of Ch-PVA-NaOH-TPP. According to the thermodynamic parameters: −∆G°, +∆H° and −∆S°, fluoride adsorption is spontaneous, endothermic in nature and there is no random energy change in the solid/liquid interface during the adsorption process. Full article

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11 pages, 4222 KiB

Open AccessArticle

Rheopectic Behavior for Aqueous Solutions of Megamolecular Polysaccharide Sacran

by Fitri Adila Amat Yusof, Miho Yamaki, Mika Kawai, Maiko K. Okajima, Tatsuo Kaneko and Tetsu Mitsumata

Biomolecules 2020, 10(1), 155; https://doi.org/10.3390/biom10010155 - 17 Jan 2020

Cited by 11 | Viewed by 4013

Abstract

The rheopectic behavior of sacran aqueous solutions, a natural giant molecular polysaccharide with a molecular weight of 1.6 × 10⁷ g/mol, was investigated. When a low shear was applied to 1.0 wt.% sacran solution, the shear viscosity increased from 7.2 to 34 [...] Read more.

The rheopectic behavior of sacran aqueous solutions, a natural giant molecular polysaccharide with a molecular weight of 1.6 × 10⁷ g/mol, was investigated. When a low shear was applied to 1.0 wt.% sacran solution, the shear viscosity increased from 7.2 to 34 Pa·s. The increment in the viscosity was enhanced as the shear rate decreased. The shear viscosity was independent of the time at a shear rate of 0.8 s⁻¹; simultaneously, thixotropic behavior was observed at shear rates higher than 1.0 s⁻¹. A crossover was observed at 0.15 wt.% for the concentration dependence of both the viscosity increase and zeta potential, which was the vicinity of the helix transition concentration or gelation concentration. It was clear that the molecular mechanism for the rheopexy was different at lower and higher regions of the crossover concentration. Full article

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16 pages, 1023 KiB

Open AccessReview

The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

by Michele Provenzano, Michele Andreucci, Carlo Garofalo, Teresa Faga, Ashour Michael, Nicola Ielapi, Raffaele Grande, Paolo Sapienza, Stefano de Franciscis, Pasquale Mastroroberto and Raffaele Serra

Biomolecules 2020, 10(1), 154; https://doi.org/10.3390/biom10010154 - 17 Jan 2020

Cited by 68 | Viewed by 5090

Abstract

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate [...] Read more.

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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16 pages, 1607 KiB

Open AccessArticle

Valorization of Flaxseed Oil Cake Residual from Cold-Press Oil Production as a Material for Preparation of Spray-Dried Functional Powders for Food Applications as Emulsion Stabilizers

by Emilia Drozłowska, Łukasz Łopusiewicz, Monika Mężyńska and Artur Bartkowiak

Biomolecules 2020, 10(1), 153; https://doi.org/10.3390/biom10010153 - 17 Jan 2020

Cited by 27 | Viewed by 6023

Abstract

Flaxseed oil cake extract (residual from cold-press oil production and rich in proteins and polysaccharides) was evaluated as a potential substrate for the preparation of spray-dried powders with emulsifying activity. Three variants of powders were obtained using different spray-drying process inlet temperatures: 160 [...] Read more.

Flaxseed oil cake extract (residual from cold-press oil production and rich in proteins and polysaccharides) was evaluated as a potential substrate for the preparation of spray-dried powders with emulsifying activity. Three variants of powders were obtained using different spray-drying process inlet temperatures: 160 °C, 180 °C, and 200 °C. The influence of temperature on physicochemical features (water holding capacity, oil binding capacity, water activity, solubility, color, chemical composition, antioxidant activity, and surface morphology) of the powders was estimated. Additionally, the emulsifying activity of the powders and the stability of oil-in-water emulsions prepared with their various content (0.5%, 1%, and 3%) were determined. Results showed that inlet temperature had significant influence on all physicochemical and functional properties of the powders. Increased inlet temperature decreased solubility and antioxidant activity but increased water-holding capacity, oil-binding capacity, and emulsifying activity. The emulsions prepared with the powder obtained at 200 °C showed the highest stability. SEM images showed the production of relatively spherical particles which were folded or wrinkled with a lot of dentures. This study could open a promising pathway for producing natural and plant-based spray-dried powders for food applications as emulsion stabilizers. Full article

(This article belongs to the Special Issue Biomolecules from Plant Residues)

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18 pages, 795 KiB

Open AccessReview

Retinoic Acid: A Key Regulator of Lung Development

by Hugo Fernandes-Silva, Henrique Araújo-Silva, Jorge Correia-Pinto and Rute S Moura

Biomolecules 2020, 10(1), 152; https://doi.org/10.3390/biom10010152 - 17 Jan 2020

Cited by 40 | Viewed by 9091

Abstract

Retinoic acid (RA) is a key molecular player in embryogenesis and adult tissue homeostasis. In embryo development, RA plays a crucial role in the formation of different organ systems, namely, the respiratory system. During lung development, there is a spatiotemporal regulation of RA [...] Read more.

Retinoic acid (RA) is a key molecular player in embryogenesis and adult tissue homeostasis. In embryo development, RA plays a crucial role in the formation of different organ systems, namely, the respiratory system. During lung development, there is a spatiotemporal regulation of RA levels that assures the formation of a fully functional organ. RA signaling influences lung specification, branching morphogenesis, and alveolarization by regulating the expression of particular target genes. Moreover, cooperation with other developmental pathways is essential to shape lung organogenesis. This review focuses on the events regulated by retinoic acid during lung developmental phases and pulmonary vascular development; also, it aims to provide a snapshot of RA interplay with other well-known regulators of lung development. Full article

(This article belongs to the Special Issue Retinoids in Embryonic Development)

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35 pages, 26304 KiB

Open AccessReview

Recent Advances in the Synthesis of Coumarin Derivatives from Different Starting Materials

by Melita Lončarić, Dajana Gašo-Sokač, Stela Jokić and Maja Molnar

Biomolecules 2020, 10(1), 151; https://doi.org/10.3390/biom10010151 - 16 Jan 2020

Cited by 119 | Viewed by 19560

Abstract

The study of coumarin dates back to 1820 when coumarin was first extracted from tonka bean by Vogel. Compounds containing coumarin backbone are a very important group of compounds due to their usage in pharmacy and medicine. Properties and biological activities of coumarin [...] Read more.

The study of coumarin dates back to 1820 when coumarin was first extracted from tonka bean by Vogel. Compounds containing coumarin backbone are a very important group of compounds due to their usage in pharmacy and medicine. Properties and biological activities of coumarin derivatives have a significant role in the development of new drugs. Therefore, many different methods and techniques are developed in order to synthesize coumarin derivatives. Coumarin derivatives could be obtained from different starting materials with various methods but with big differences in yield. This review summarized various methods, techniques and reaction conditions for synthesis of coumarins from different compounds such as aldehydes, phenols, ketones and carboxylic acids. Full article

(This article belongs to the Special Issue Perspectives of Coumarins)

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16 pages, 2428 KiB

Open AccessArticle

Identification of miRNAs Enriched in Extracellular Vesicles Derived from Serum Samples of Breast Cancer Patients

by Patricia M. M. Ozawa, Evelyn Vieira, Débora S. Lemos, Ingrid L. Melo Souza, Silvio M. Zanata, Vânia C. Pankievicz, Thalita R. Tuleski, Emanuel M. Souza, Pryscilla F. Wowk, Cícero de Andrade Urban, Flavia Kuroda, Rubens S. Lima, Rodrigo C. Almeida, Daniela F. Gradia, Iglenir J. Cavalli, Luciane R. Cavalli, Danielle Malheiros and Enilze M. S. F. Ribeiro

Biomolecules 2020, 10(1), 150; https://doi.org/10.3390/biom10010150 - 16 Jan 2020

Cited by 47 | Viewed by 6164

Abstract

MicroRNAs derived from extracellular vesicles (EV-miRNAs) are circulating miRNAs considered as potential new diagnostic markers for cancer that can be easily detected in liquid biopsies. In this study, we performed RNA sequencing analysis as a screening strategy to identify EV-miRNAs derived from serum [...] Read more.

MicroRNAs derived from extracellular vesicles (EV-miRNAs) are circulating miRNAs considered as potential new diagnostic markers for cancer that can be easily detected in liquid biopsies. In this study, we performed RNA sequencing analysis as a screening strategy to identify EV-miRNAs derived from serum of clinically well-annotated breast cancer (BC) patients from the south of Brazil. EVs from three groups of samples (healthy controls (CT), luminal A (LA), and triple-negative (TNBC)) were isolated from serum using a precipitation method and analyzed by RNA-seq (screening phase). Subsequently, four EV-miRNAs (miR-142-5p, miR-150-5p, miR-320a, and miR-4433b-5p) were selected to be quantified by quantitative real-time PCR (RT-qPCR) in individual samples (test phase). A panel composed of miR-142-5p, miR-320a, and miR-4433b-5p distinguished BC patients from CT with an area under the curve (AUC) of 0.8387 (93.33% sensitivity, 68.75% specificity). The combination of miR-142-5p and miR-320a distinguished LA patients from CT with an AUC of 0.9410 (100% sensitivity, 93.80% specificity). Interestingly, decreased expression of miR-142-5p and miR-150-5p were significantly associated with more advanced tumor grades (grade III), while the decreased expression of miR-142-5p and miR-320a was associated with a larger tumor size. These results provide insights into the potential application of EVs-miRNAs from serum as novel specific markers for early diagnosis of BC. Full article

(This article belongs to the Special Issue microRNA Biomarkers in Clinical Study)

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17 pages, 3577 KiB

Open AccessArticle

Activation of mGluR5 and NMDA Receptor Pathways in the Rostral Ventrolateral Medulla as a Central Mechanism for Methamphetamine-Induced Pressor Effect in Rats

by Chih-Chia Lai, Chi Fang, Chung-Yi Kuo, Ya-Wen Wu and Hsun-Hsun Lin

Biomolecules 2020, 10(1), 149; https://doi.org/10.3390/biom10010149 - 16 Jan 2020

Cited by 9 | Viewed by 3455

Abstract

Acute hypertension produced by methamphetamine (MA) is well known, mainly by the enhancement of catecholamine release from sympathetic terminals. However, the central pressor mechanism of the blood-brain-barrier-penetrating molecule remains unclear. We used radio-telemetry and femoral artery cannulation to monitor the mean arterial pressure [...] Read more.

Acute hypertension produced by methamphetamine (MA) is well known, mainly by the enhancement of catecholamine release from sympathetic terminals. However, the central pressor mechanism of the blood-brain-barrier-penetrating molecule remains unclear. We used radio-telemetry and femoral artery cannulation to monitor the mean arterial pressure (MAP) in conscious free-moving and urethane-anesthetized rats, respectively. Expression of Fos protein (Fos) and phosphorylation of N-methyl-D-aspartate receptor subunit GluN1 in the rostral ventrolateral medulla (RVLM) were detected using Western blot analysis. ELISA was carried out for detection of protein kinase C (PKC) activity in the RVLM. MA-induced glutamate release in the RVLM was assayed using in vivo microdialysis and HPLC. Systemic or intracerebroventricular (i.c.v.) administration of MA augments the MAP and increases Fos expression, PKC activity, and phosphorylated GluN1-ser 896 (pGluN1-ser 896) in the RVLM. However, direct microinjection of MA into the RVLM did not change the MAP. Unilateral microinjection of a PKC inhibitor or a metabotropic glutamate receptor 5 (mGluR5) antagonist into the RVLM dose-dependently attenuated the i.c.v. MA-induced increase in MAP and pGluN1-ser 896. Our data suggested that MA may give rise to glutamate release in the RVLM further to the activation of mGluR5-PKC pathways, which would serve as a central mechanism for the MA-induced pressor effect. Full article

(This article belongs to the Special Issue NMDA Receptor in Health and Diseases)

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44 pages, 2277 KiB

Open AccessReview

Biofunctionalization of Natural Fiber-Reinforced Biocomposites for Biomedical Applications

by Tânia D. Tavares, Joana C. Antunes, Fernando Ferreira and Helena P. Felgueiras

Biomolecules 2020, 10(1), 148; https://doi.org/10.3390/biom10010148 - 16 Jan 2020

Cited by 118 | Viewed by 9434

Abstract

In the last ten years, environmental consciousness has increased worldwide, leading to the development of eco-friendly materials to replace synthetic ones. Natural fibers are extracted from renewable resources at low cost. Their combination with synthetic polymers as reinforcement materials has been an important [...] Read more.

In the last ten years, environmental consciousness has increased worldwide, leading to the development of eco-friendly materials to replace synthetic ones. Natural fibers are extracted from renewable resources at low cost. Their combination with synthetic polymers as reinforcement materials has been an important step forward in that direction. The sustainability and excellent physical and biological (e.g., biocompatibility, antimicrobial activity) properties of these biocomposites have extended their application to the biomedical field. This paper offers a detailed overview of the extraction and separation processes applied to natural fibers and their posterior chemical and physical modifications for biocomposite fabrication. Because of the requirements for biomedical device production, specialized biomolecules are currently being incorporated onto these biocomposites. From antibiotics to peptides and plant extracts, to name a few, this review explores their impact on the final biocomposite product, in light of their individual or combined effect, and analyzes the most recurrent strategies for biomolecule immobilization. Full article

(This article belongs to the Section Biological and Bio- Materials)

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21 pages, 5203 KiB

Open AccessArticle

Combined Kinetin and Spermidine Treatments Ameliorate Growth and Photosynthetic Inhibition in Vigna angularis by Up-Regulating Antioxidant and Nitrogen Metabolism under Cadmium Stress

by Mohammad Abass Ahanger, Usman Aziz, Abdulaziz Alsahli, Mohammed Nasser Alyemeni and Parvaiz Ahmad

Biomolecules 2020, 10(1), 147; https://doi.org/10.3390/biom10010147 - 16 Jan 2020

Cited by 90 | Viewed by 4601

Abstract

Pot experiments were conducted to investigate the probable beneficial role of the individual as well as combined application of kinetin (50 μM Kn) and spermidine (200 μM Spd) on Vigna angularis under cadmium (Cd) stress. Cd treatment reduced growth by declining the content [...] Read more.

Pot experiments were conducted to investigate the probable beneficial role of the individual as well as combined application of kinetin (50 μM Kn) and spermidine (200 μM Spd) on Vigna angularis under cadmium (Cd) stress. Cd treatment reduced growth by declining the content of chlorophylls and carotenoids, photosynthesis, and gas exchange parameters. Exogenously, Kn and Spd application enhanced the photosynthetic parameters and up-regulated the antioxidant system by improving the activities of antioxidant enzymes and the content of non-enzymatic components. In addition, the application of Kn and Spd resulted in significant improvement in the content of sugars, proline, and glycine betaine, ameliorating the decline in relative water content. Oxidative stress parameters including hydrogen peroxide, superoxide, lipid peroxidation, lipoxygenase activity, and electrolyte leakage increased due to Cd stress; however, the application of Kn and Spd imparted a significant decline in all these parameters. Further, reduced Cd uptake was also observed due to Kn and Spd application. Total phenols and flavonoids also increased due to Kn and Spd treatments under normal as well as Cd stress conditions, which may have further helped with the elimination of reactive oxygen species. Reduction in the activity of nitrate reductase and the content of nitrogen was ameliorated due to the exogenous application of Kn and Spd. Therefore, the exogenous application of Kn and Spd benefited Vigna angularis counteracting the damaging effects of Cd stress by up-regulating the tolerance mechanisms, including antioxidant and osmolyte metabolism. Full article

(This article belongs to the Special Issue Phytohormones)

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22 pages, 358 KiB

Open AccessReview

Can Medicinal Plants and Bioactive Compounds Combat Lipid Peroxidation Product 4-HNE-Induced Deleterious Effects?

by Fei-Xuan Wang, Hong-Yan Li, Yun-Qian Li and Ling-Dong Kong

Biomolecules 2020, 10(1), 146; https://doi.org/10.3390/biom10010146 - 16 Jan 2020

Cited by 6 | Viewed by 5337

Abstract

The toxic reactive aldehyde 4-hydroxynonenal (4-HNE) belongs to the advanced lipid peroxidation end products. Accumulation of 4-HNE and formation of 4-HNE adducts induced by redox imbalance participate in several cytotoxic processes, which contribute to the pathogenesis and progression of oxidative stress-related human disorders. [...] Read more.

The toxic reactive aldehyde 4-hydroxynonenal (4-HNE) belongs to the advanced lipid peroxidation end products. Accumulation of 4-HNE and formation of 4-HNE adducts induced by redox imbalance participate in several cytotoxic processes, which contribute to the pathogenesis and progression of oxidative stress-related human disorders. Medicinal plants and bioactive natural compounds are suggested to be attractive sources of potential agents to mitigate oxidative stress, but little is known about the therapeutic potentials especially on combating 4-HNE-induced deleterious effects. Of note, some investigations clarify the attenuation of medicinal plants and bioactive compounds on 4-HNE-induced disturbances, but strong evidence is needed that these plants and compounds serve as potent agents in the prevention and treatment of disorders driven by 4-HNE. Therefore, this review highlights the pharmacological basis of these medicinal plants and bioactive compounds to combat 4-HNE-induced deleterious effects in oxidative stress-related disorders, such as neurotoxicity and neurological disorder, eye damage, cardiovascular injury, liver injury, and energy metabolism disorder. In addition, this review briefly discusses with special attention to the strategies for developing potential therapies by future applications of these medicinal plants and bioactive compounds, which will help biological and pharmacological scientists to explore the new vistas of medicinal plants in combating 4-HNE-induced deleterious effects. Full article

(This article belongs to the Special Issue Phytochemical Omics in Medicinal Plants)

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36 pages, 509 KiB

Open AccessEditorial

Acknowledgement to Reviewers of Biomolecules in 2019

by Biomolecules Editorial Office

Biomolecules 2020, 10(1), 145; https://doi.org/10.3390/biom10010145 - 16 Jan 2020

Viewed by 3713

Abstract

Full article

17 pages, 1618 KiB

Open AccessReview

Mechanistic Pathways and Molecular Targets of Plant-Derived Anticancer ent-Kaurane Diterpenes

by Md. Shahid Sarwar, Yi-Xuan Xia, Zheng-Ming Liang, Siu Wai Tsang and Hong-Jie Zhang

Biomolecules 2020, 10(1), 144; https://doi.org/10.3390/biom10010144 - 16 Jan 2020

Cited by 44 | Viewed by 5634

Abstract

Since the first discovery in 1961, more than 1300 ent-kaurane diterpenoids have been isolated and identified from different plant sources, mainly the genus Isodon. Chemically, they consist of a perhydrophenanthrene subunit and a cyclopentane ring. A large number of reports describe [...] Read more.

Since the first discovery in 1961, more than 1300 ent-kaurane diterpenoids have been isolated and identified from different plant sources, mainly the genus Isodon. Chemically, they consist of a perhydrophenanthrene subunit and a cyclopentane ring. A large number of reports describe the anticancer potential and mechanism of action of ent-kaurane compounds in a series of cancer cell lines. Oridonin is one of the prime anticancer ent-kaurane diterpenoids that is currently in a phase-I clinical trial in China. In this review, we have extensively summarized the anticancer activities of ent-kaurane diterpenoids according to their plant sources, mechanistic pathways, and biological targets. Literature analysis found that anticancer effect of ent-kauranes are mainly mediated through regulation of apoptosis, cell cycle arrest, autophagy, and metastasis. Induction of apoptosis is associated with modulation of BCL-2, BAX, PARP, cytochrome c, and cleaved caspase-3, -8, and -9, while cell cycle arrest is controlled by cyclin D1, c-Myc, p21, p53, and CDK-2 and -4. The most common metastatic target proteins of ent-kauranes are MMP-2, MMP-9, VEGF, and VEGFR whereas LC-II and mTOR are key regulators to induce autophagy. Full article

(This article belongs to the Special Issue Phytochemical Omics in Medicinal Plants)

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15 pages, 2159 KiB

Open AccessArticle

Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

by Paulina Podkalicka, Olga Mucha, Szczepan Kruczek, Anna Biela, Kalina Andrysiak, Jacek Stępniewski, Maciej Mikulski, Michał Gałęzowski, Kamil Sitarz, Krzysztof Brzózka, Alicja Józkowicz, Józef Dulak and Agnieszka Łoboda

Biomolecules 2020, 10(1), 143; https://doi.org/10.3390/biom10010143 - 16 Jan 2020

Cited by 15 | Viewed by 4426

Abstract

Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic [...] Read more.

Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)—an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed. Full article

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

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16 pages, 2161 KiB

Open AccessArticle

In Vivo Quantitative Estimation of DNA-Dependent Interaction of Sox2 and Oct4 Using BirA-Catalyzed Site-Specific Biotinylation

by Arman Kulyyassov and Vasily Ogryzko

Biomolecules 2020, 10(1), 142; https://doi.org/10.3390/biom10010142 - 16 Jan 2020

Cited by 6 | Viewed by 4270

Abstract

Protein–protein interactions of core pluripotency transcription factors play an important role during cell reprogramming. Cell identity is controlled by a trio of transcription factors: Sox2, Oct4, and Nanog. Thus, methods that help to quantify protein–protein interactions may be useful for understanding the mechanisms [...] Read more.

Protein–protein interactions of core pluripotency transcription factors play an important role during cell reprogramming. Cell identity is controlled by a trio of transcription factors: Sox2, Oct4, and Nanog. Thus, methods that help to quantify protein–protein interactions may be useful for understanding the mechanisms of pluripotency at the molecular level. Here, a detailed protocol for the detection and quantitative analysis of in vivo protein–protein proximity of Sox2 and Oct4 using the proximity-utilizing biotinylation (PUB) method is described. The method is based on the coexpression of two proteins of interest fused to a biotin acceptor peptide (BAP)in one case and a biotin ligase enzyme (BirA) in the other. The proximity between the two proteins leads to more efficient biotinylation of the BAP, which can be either detected by Western blotting or quantified using proteomics approaches, such as a multiple reaction monitoring (MRM) analysis. Coexpression of the fusion proteins BAP-X and BirA-Y revealed strong biotinylation of the target proteins when X and Y were, alternatively, the pluripotency transcription factors Sox2 and Oct4, compared with the negative control where X or Y was green fluorescent protein (GFP), which strongly suggests that Sox2 and Oct4 come in close proximity to each other and interact. Full article

(This article belongs to the Section Molecular Biology)

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11 pages, 1834 KiB

Open AccessArticle

Simultaneous Suppression of Two Distinct Serotonin N-Acetyltransferase Isogenes by RNA Interference Leads to Severe Decreases in Melatonin and Accelerated Seed Deterioration in Rice

by Ok Jin Hwang and Kyoungwhan Back

Biomolecules 2020, 10(1), 141; https://doi.org/10.3390/biom10010141 - 15 Jan 2020

Cited by 26 | Viewed by 3284

Abstract

Serotonin N-acetyltransferase (SNAT) is the penultimate enzyme in the melatonin biosynthetic pathway, in which serotonin is converted into N-acetylserotonin (NAS) in plants. To date, two SNAT isogenes with low amino acid sequence homologies have been identified. Their [...] Read more.

Serotonin N-acetyltransferase (SNAT) is the penultimate enzyme in the melatonin biosynthetic pathway, in which serotonin is converted into N-acetylserotonin (NAS) in plants. To date, two SNAT isogenes with low amino acid sequence homologies have been identified. Their single suppression in rice has been reported, but their double suppression in rice has not yet been attempted. Here, we generated double-suppression transgenic rice (snat1+2) using the RNA interference technique. The snat1+2 exhibited retarded seedling growths in conjunction with severe decreases in melatonin compared to wild-types and single-suppression rice plants (snat1 or snat2). The laminar angle was decreased in the snat1+2 rice compared to that of the wild-types and snat1, but was comparable to that of snat2. The reduced germination speed in the snat1+2 was comparable to that of snat2. Seed-aging testing revealed that snat1 was the most severely deteriorated, followed by snat1+2 and snat2, suggesting that melatonin is positively involved in seed longevity. Full article

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

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15 pages, 618 KiB

Open AccessArticle

Long-Term Effect of Combination of Creatine Monohydrate Plus β-Hydroxy β-Methylbutyrate (HMB) on Exercise-Induced Muscle Damage and Anabolic/Catabolic Hormones in Elite Male Endurance Athletes

by Julen Fernández-Landa, Diego Fernández-Lázaro, Julio Calleja-González, Alberto Caballero-García, Alfredo Córdova, Patxi León-Guereño and Juan Mielgo-Ayuso

Biomolecules 2020, 10(1), 140; https://doi.org/10.3390/biom10010140 - 15 Jan 2020

Cited by 19 | Viewed by 10789

Abstract

Creatine monohydrate (CrM) and β-hydroxy β-methylbutyrate (HMB) are widely studied ergogenic aids. However, both supplements are usually studied in an isolated manner. The few studies that have investigated the effect of combining both supplements on exercise-induced muscle damage (EIMD) and hormone status have [...] Read more.

Creatine monohydrate (CrM) and β-hydroxy β-methylbutyrate (HMB) are widely studied ergogenic aids. However, both supplements are usually studied in an isolated manner. The few studies that have investigated the effect of combining both supplements on exercise-induced muscle damage (EIMD) and hormone status have reported controversial results. Therefore, the main purpose of this study was to determine the effect and degree of potentiation of 10 weeks of CrM plus HMB supplementation on EIMD and anabolic/catabolic hormones. This study was a double-blind, placebo-controlled trial where participants (n = 28) were randomized into four different groups: placebo group (PLG; n = 7), CrM group (CrMG; 0.04 g/kg/day of CrM; n = 7), HMB group (HMBG; 3 g/day of HMB; n = 7), and CrM-HMB group (CrM-HMBG; 0.04 g/kg/day of CrM plus 3 g/day of HMB; n = 7). Before (baseline, T1) and after 10 weeks of supplementation (T2), blood samples were collected from all rowers. There were no significant differences in the EIMD markers (aspartate aminotransferase, lactate dehydrogenase, and creatine kinase) among groups. However, we observed significant differences in CrM-HMBG with respect to PLG, CrMG, and HMBG on testosterone (p = 0.006; η²p = 0.454) and the testosterone/cortisol ratio (T/C; p = 0.032; η²p = 0.349). Moreover, we found a synergistic effect of combined supplementation on testosterone (CrM-HMBG = −63.85% vs. CrMG + HMBG = −37.89%) and T/C (CrM-HMBG = 680% vs. CrMG + HMBG = 57.68%) and an antagonistic effect on cortisol (CrM-HMBG = 131.55% vs. CrMG + HMBG = 389.99%). In summary, the combination of CrM plus HMB showed an increase in testosterone and T/C compared with the other groups after 10 weeks of supplementation. Moreover, this combination presented a synergistic effect on testosterone and T/C and an antagonistic effect on cortisol compared with the sum of individual or isolated supplementation. Full article

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15 pages, 2893 KiB

Open AccessArticle

Oxidative Stress-Induced DNA Damage and Apoptosis in Clove Buds-Treated MCF-7 Cells

by Martin Kello, Peter Takac, Peter Kubatka, Tomas Kuruc, Klaudia Petrova and Jan Mojzis

Biomolecules 2020, 10(1), 139; https://doi.org/10.3390/biom10010139 - 14 Jan 2020

Cited by 34 | Viewed by 4893

Abstract

In recent decades, several spices have been studied for their potential in the prevention and treatment of cancer. It is documented that spices have antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. The main mechanisms of spices action included apoptosis induction, proliferation, migration and invasion [...] Read more.

In recent decades, several spices have been studied for their potential in the prevention and treatment of cancer. It is documented that spices have antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. The main mechanisms of spices action included apoptosis induction, proliferation, migration and invasion of tumour inhibition, and sensitization of tumours to radiotherapy and chemotherapy. In this study, the ability of clove buds extract (CBE) to induce oxidative stress, DNA damage, and stress/survival/apoptotic pathways modulation were analysed in MCF-7 cells. We demonstrated that CBE treatment induced intrinsic caspase-dependent cell death associated with increased oxidative stress mediated by oxygen and nitrogen radicals. We showed also the CBE-mediated release of mitochondrial pro-apoptotic factors, signalling of oxidative stress-mediated DNA damage with modulation of cell antioxidant SOD (superoxide dismutase) system, and modulation activity of the Akt, p38 MAPK, JNK and Erk 1/2 pathways. Full article

(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)

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28 pages, 13171 KiB

Open AccessReview

A Review of the Structure–Activity Relationship of Natural and Synthetic Antimetastatic Compounds

by Su Ki Liew, Sharan Malagobadan, Norhafiza M. Arshad and Noor Hasima Nagoor

Biomolecules 2020, 10(1), 138; https://doi.org/10.3390/biom10010138 - 14 Jan 2020

Cited by 64 | Viewed by 6397

Abstract

There are innumerable anticancer compounds derived from either natural or synthetic origins. Many of these compounds have been further developed through structural modifications to not only inhibit cancer cell growth but also to exert an antimetastatic effect. This is achieved by attaching different [...] Read more.

There are innumerable anticancer compounds derived from either natural or synthetic origins. Many of these compounds have been further developed through structural modifications to not only inhibit cancer cell growth but also to exert an antimetastatic effect. This is achieved by attaching different substituents to generate different structure–activity relationships. This review highlights the effectiveness of different functional groups known to have antimigration and antiproliferation activities, such as fluoro, methoxy, methyl, amino, hydroxy, nitro, bromo, chloro, methylamino, ethoxy, carbonyl, iodo, and trifluoromethyl groups. Additionally, the positioning of these functional groups plays an important role in their anticancer activities, which was evident in one of our studies comparing analogues of a natural compound. Thus, this review suggests future recommendations for the design and development of improved anticancer drugs with higher efficacy. Full article

(This article belongs to the Special Issue Antitumor Agents from Natural Sources)

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19 pages, 820 KiB

Open AccessReview

Microglia Mediated Neuroinflammation: Focus on PI3K Modulation

by Antonia Cianciulli, Chiara Porro, Rosa Calvello, Teresa Trotta, Dario Domenico Lofrumento and Maria Antonietta Panaro

Biomolecules 2020, 10(1), 137; https://doi.org/10.3390/biom10010137 - 14 Jan 2020

Cited by 115 | Viewed by 9593

Abstract

Immune activation in the central nervous system involves mostly microglia in response to pathogen invasion or tissue damage, which react, promoting a self-limiting inflammatory response aimed to restore homeostasis. However, prolonged, uncontrolled inflammation may result in the production by microglia of neurotoxic factors [...] Read more.

Immune activation in the central nervous system involves mostly microglia in response to pathogen invasion or tissue damage, which react, promoting a self-limiting inflammatory response aimed to restore homeostasis. However, prolonged, uncontrolled inflammation may result in the production by microglia of neurotoxic factors that lead to the amplification of the disease state and tissue damage. In particular, specific inducers of inflammation associated with neurodegenerative diseases activate inflammatory processes that result in the production of a number of mediators and cytokines that enhance neurodegenerative processes. Phosphoinositide 3-kinases (PI3Ks) constitute a family of enzymes regulating a wide range of activity, including signal transduction. Recent studies have focused attention on the intracellular role of PI3K and its contribution to neurodegenerative processes. This review illustrates and discusses recent findings about the role of this signaling pathway in the modulation of microglia neuroinflammatory responses linked to neurodegeneration. Finally, we discuss the modulation of PI3K as a potential therapeutic approach helpful for developing innovative therapeutic strategies in neurodegenerative diseases. Full article

(This article belongs to the Section Biological Factors)

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14 pages, 6617 KiB

Open AccessArticle

Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration

by Shanmugam Muruganandan, Xiujun Fan, Sabita Dhal and Nihar R. Nayak

Biomolecules 2020, 10(1), 136; https://doi.org/10.3390/biom10010136 - 14 Jan 2020

Cited by 17 | Viewed by 6185

Abstract

The human endometrium undergoes sequential phases of shedding of the upper functionalis zone during menstruation, followed by regeneration of the functionalis zone from the remaining basalis zone cells, and secretory differentiation under the influence of the ovarian steroid hormones estradiol (E2) and progesterone [...] Read more.

The human endometrium undergoes sequential phases of shedding of the upper functionalis zone during menstruation, followed by regeneration of the functionalis zone from the remaining basalis zone cells, and secretory differentiation under the influence of the ovarian steroid hormones estradiol (E2) and progesterone (P4). This massive tissue regeneration after menstruation is believed to arise from endometrial stromal and epithelial stem cells residing in the basal layer of the endometrium. Although many endometrial pathologies are thought to be associated with defects in these stem cells, studies on their identification and regulation are limited, primarily due to lack of easily accessible animal models, as these processes are unique to primates. Here we describe a robust new method to study endometrial regeneration and differentiation processes using human endometrial tissue slice cultures incorporating an air-liquid interface into a 3D matrix scaffold of type I collagen gel, allowing sustained tissue viability over three weeks. The 3D collagen gel-embedded endometrial tissue slices in a double-dish culture system responded to ovarian steroid hormones, mimicking the endometrial changes that occur in vivo during the menstrual cycle. These changes included the E2-induced upregulation of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in all endometrial compartments and were markedly suppressed by both P4 and E2 plus P4 treatments. There were also distinct changes in endometrial morphology after E2 and P4 treatments, including subnuclear vacuolation and luminal secretions in glands as well as decidualization of stromal cells, typical characteristics of a progestational endometrium in vivo. This long-term slice culture method provides a unique in vivo-like microenvironment for the study of human endometrial functions and remodeling during early pregnancy and experiments on stem cell populations involved in endometrial regeneration and remodeling. Furthermore, this model has the potential to enable studies on several endometrial diseases, including endometrial cancers and pregnancy complications associated with defects in endometrial remodeling. Full article

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23 pages, 570 KiB

Open AccessReview

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

by Rosario Avolio, Danilo Swann Matassa, Daniela Criscuolo, Matteo Landriscina and Franca Esposito

Biomolecules 2020, 10(1), 135; https://doi.org/10.3390/biom10010135 - 14 Jan 2020

Cited by 52 | Viewed by 7993

Abstract

Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based [...] Read more.

Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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14 pages, 2312 KiB

Open AccessArticle

Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

by Anna L. Gharibyan, Tohidul Islam, Nina Pettersson, Solmaz A. Golchin, Johanna Lundgren, Gabriella Johansson, Mélany Genot, Nina Schultz, Malin Wennström and Anders Olofsson

Biomolecules 2020, 10(1), 134; https://doi.org/10.3390/biom10010134 - 14 Jan 2020

Cited by 15 | Viewed by 3897

Abstract

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different [...] Read more.

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant. Full article

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