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Volume 22
Issue 4
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Int. J. Mol. Sci., Volume 22, Issue 4 (February-2 2021) – 726 articles

Cover Story (view full-size image): Despite the existing prevention campaigns, cervical cancer remains a leading cause of cancer-related deaths in women worldwide. Progress in finding adequate treatment solutions has been slow in the last years, especially for the patients with recurrent or metastatic disease. Consensus dictates that immunotherapy for cervical cancer holds great promise but currently does not live up to its full effect. We discuss the potential of PD-1 targeting therapy for cervical cancer, how it opens doors for personalized treatment, and which clinical trials are aiming to further exploit this approach in cervical cancer. View this paper
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13 pages, 7652 KiB  
Review
Therapeutic Rationale for Endotoxin Removal with Polymyxin B Immobilized Fiber Column (PMX) for Septic Shock
by Hisataka Shoji and Steven M. Opal
Int. J. Mol. Sci. 2021, 22(4), 2228; https://doi.org/10.3390/ijms22042228 - 23 Feb 2021
Cited by 17 | Viewed by 5396
Abstract
Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented [...] Read more.
Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicenter, randomized and controlled trial. Following the findings derived from a large sepsis clinical trial with PMX in North America, a new trial is ongoing to determine if PMX has a long-term survival benefit when administered to septic patients. Another approach to support a survival benefit from intervention with PMX is to utilize a detailed analysis available from a large clinical data base. The endotoxin adsorption capacity of PMX columns in vitro and the effectiveness of PMX columns can be further demonstrable in animal models. The capability of PMX and details of its mechanism of action to intervene in the sepsis cascade and impede organ dysfunction in septic patients is not fully understood. The surface antigen expression in monocytes and neutrophils are improved after PMX therapy. Immunomodulatory effects as a result of endotoxin removal and/or other mechanisms of action have been suggested. These effects and other potential immune effects may explain some of the improved effects upon organ dysfunction of sepsis and septic shock patients. Endotoxemia may be involved in the pathophysiology of other diseases than sepsis. A rapid diagnostic method to detect and target endotoxemia could allow us to practice precision medicine and expand the clinical indications of endotoxin removal therapy. Full article
(This article belongs to the Special Issue Diagnostic Challenge and Therapeutic Approaches in Human Sepsis Based on the Appearance of Endotoxemia and Beta-D-Glucanemia)
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23 pages, 4314 KiB  
Article
Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: A Feature Selection Approach
by Simona De Summa, Antonio Palazzo, Mariapia Caputo, Rosa Maria Iacobazzi, Brunella Pilato, Letizia Porcelli, Stefania Tommasi, Angelo Virgilio Paradiso and Amalia Azzariti
Int. J. Mol. Sci. 2021, 22(4), 2227; https://doi.org/10.3390/ijms22042227 - 23 Feb 2021
Cited by 3 | Viewed by 3195
Abstract
Prostate cancer is one of the most common malignancies in men. It is characterized by a high molecular genomic heterogeneity and, thus, molecular subtypes, that, to date, have not been used in clinical practice. In the present paper, we aimed to better stratify [...] Read more.
Prostate cancer is one of the most common malignancies in men. It is characterized by a high molecular genomic heterogeneity and, thus, molecular subtypes, that, to date, have not been used in clinical practice. In the present paper, we aimed to better stratify prostate cancer patients through the selection of robust long non-coding RNAs. To fulfill the purpose of the study, a bioinformatic approach focused on feature selection applied to a TCGA dataset was used. In such a way, LINC00668 and long non-coding(lnc)-SAYSD1-1, able to discriminate ERG/not-ERG subtypes, were demonstrated to be positive prognostic biomarkers in ERG-positive patients. Furthermore, we performed a comparison between mutated prostate cancer, identified as “classified”, and a group of patients with no peculiar genomic alteration, named “not-classified”. Moreover, LINC00920 lncRNA overexpression has been linked to a better outcome of the hormone regimen. Through the feature selection approach, it was found that the overexpression of lnc-ZMAT3-3 is related to low-grade patients, and three lncRNAs: lnc-SNX10-87, lnc-AP1S2-2, and ADPGK-AS1 showed, through a co-expression analysis, significant correlation values with potentially druggable pathways. In conclusion, the data mining of publicly available data and robust bioinformatic analyses are able to explore the unknown biology of malignancies. Full article
(This article belongs to the Special Issue Role of ncRNAs Classes as Biomarkers for Diagnostic and Prognosis in Cancer)
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22 pages, 16857 KiB  
Article
Mutation of GGMP Repeat Segments of Plasmodium falciparum Hsp70-1 Compromises Chaperone Function and Hop Co-Chaperone Binding
by Stanley Makumire, Tendamudzimu Harmfree Dongola, Graham Chakafana, Lufuno Tshikonwane, Cecilia Tshikani Chauke, Tarushai Maharaj, Tawanda Zininga and Addmore Shonhai
Int. J. Mol. Sci. 2021, 22(4), 2226; https://doi.org/10.3390/ijms22042226 - 23 Feb 2021
Cited by 15 | Viewed by 3643
Abstract
Parasitic organisms especially those of the Apicomplexan phylum, harbour a cytosol localised canonical Hsp70 chaperone. One of the defining features of this protein is the presence of GGMP repeat residues sandwiched between α-helical lid and C-terminal EEVD motif. The role of the GGMP [...] Read more.
Parasitic organisms especially those of the Apicomplexan phylum, harbour a cytosol localised canonical Hsp70 chaperone. One of the defining features of this protein is the presence of GGMP repeat residues sandwiched between α-helical lid and C-terminal EEVD motif. The role of the GGMP repeats of Hsp70s remains unknown. In the current study, we introduced GGMP mutations in the cytosol localised Hsp70-1 of Plasmodium falciparum (PfHsp70-1) and a chimeric protein (KPf), constituted by the ATPase domain of E. coli DnaK fused to the C-terminal substrate binding domain of PfHsp70-1. A complementation assay conducted using E. coli dnaK756 cells demonstrated that the GGMP motif was essential for chaperone function of the chimeric protein, KPf. Interestingly, insertion of GGMP motif of PfHsp70-1 into DnaK led to a lethal phenotype in E. coli dnaK756 cells exposed to elevated growth temperature. Using biochemical and biophysical assays, we established that the GGMP motif accounts for the elevated basal ATPase activity of PfHsp70-1. Furthermore, we demonstrated that this motif is important for interaction of the chaperone with peptide substrate and a co-chaperone, PfHop. Our findings suggest that the GGMP may account for both the specialised chaperone function and reportedly high catalytic efficiency of PfHsp70-1. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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14 pages, 14050 KiB  
Article
Regulation of Glucose Metabolism by MuRF1 and Treatment of Myopathy in Diabetic Mice with Small Molecules Targeting MuRF1
by Siegfried Labeit, Stephanie Hirner, Julijus Bogomolovas, André Cruz, Moldir Myrzabekova, Anselmo Moriscot, Thomas Scott Bowen and Volker Adams
Int. J. Mol. Sci. 2021, 22(4), 2225; https://doi.org/10.3390/ijms22042225 - 23 Feb 2021
Cited by 16 | Viewed by 3870
Abstract
The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog. MuRF1 and MuRF2-KO [...] Read more.
The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog. MuRF1 and MuRF2-KO (knockout) mice have elevated serum glucose, elevated triglycerides, and reduced glucose tolerance. In addition, MuRF2-KO mice have a reduced tolerance to a fat-rich diet. Western blot and enzymatic studies on MuRF1-KO skeletal muscle showed perturbed FoxO-Akt signaling, elevated Akt-Ser-473 activation, and downregulated oxidative mitochondrial metabolism, indicating potential mechanisms for MuRF1,2-dependent glucose and fat metabolism regulation. Consistent with this, the adenoviral re-expression of MuRF1 in KO mice normalized Akt-Ser-473, serum glucose, and triglycerides. Finally, we tested the MuRF1/2 inhibitors MyoMed-205 and MyoMed-946 in a mouse model for type 2 diabetes mellitus (T2DM). After 28 days of treatment, T2DM mice developed progressive muscle weakness detected by wire hang tests, but this was attenuated by the MyoMed-205 treatment. While MyoMed-205 and MyoMed-946 had no significant effects on serum glucose, they did normalize the lymphocyte–granulocyte counts in diabetic sera as indicators of the immune response. Thus, small molecules directed to MuRF1 may be useful in attenuating skeletal muscle strength loss in T2DM conditions. Full article
(This article belongs to the Special Issue Skeletal Muscle Organelle Maintenance in Health and Disease: From Molecular Mechanisms to Practical Recommendations)
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26 pages, 1399 KiB  
Review
Development of Antimicrobial Phototreatment Tolerance: Why the Methodology Matters
by Aleksandra Rapacka-Zdonczyk, Agata Wozniak, Joanna Nakonieczna and Mariusz Grinholc
Int. J. Mol. Sci. 2021, 22(4), 2224; https://doi.org/10.3390/ijms22042224 - 23 Feb 2021
Cited by 21 | Viewed by 4429
Abstract
Due to rapidly growing antimicrobial resistance, there is an urgent need to develop alternative, non-antibiotic strategies. Recently, numerous light-based approaches, demonstrating killing efficacy regardless of microbial drug resistance, have gained wide attention and are considered some of the most promising antimicrobial modalities. These [...] Read more.
Due to rapidly growing antimicrobial resistance, there is an urgent need to develop alternative, non-antibiotic strategies. Recently, numerous light-based approaches, demonstrating killing efficacy regardless of microbial drug resistance, have gained wide attention and are considered some of the most promising antimicrobial modalities. These light-based therapies include five treatments for which high bactericidal activity was demonstrated using numerous in vitro and in vivo studies: antimicrobial blue light (aBL), antimicrobial photodynamic inactivation (aPDI), pulsed light (PL), cold atmospheric plasma (CAP), and ultraviolet (UV) light. Based on their multitarget activity leading to deleterious effects to numerous cell structures—i.e., cell envelopes, proteins, lipids, and genetic material—light-based treatments are considered to have a low risk for the development of tolerance and/or resistance. Nevertheless, the most recent studies indicate that repetitive sublethal phototreatment may provoke tolerance development, but there is no standard methodology for the proper evaluation of this phenomenon. The statement concerning the lack of development of resistance to these modalities seem to be justified; however, the most significant motivation for this review paper was to critically discuss existing dogma concerning the lack of tolerance development, indicating that its assessment is more complex and requires better terminology and methodology. Full article
(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)
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4 pages, 165 KiB  
Editorial
The Self-Assembly and Design of Polyfunctional Nanosystems
by Ruslan Kashapov and Lucia Zakharova
Int. J. Mol. Sci. 2021, 22(4), 2223; https://doi.org/10.3390/ijms22042223 - 23 Feb 2021
Cited by 1 | Viewed by 1991
Abstract
The current task of the molecular sciences is to create unique nanostructured materials with a given structure and with specific physicochemical properties on the basis of the existing wide range of molecules of natural and synthetic origin. A promising and inexpensive way to [...] Read more.
The current task of the molecular sciences is to create unique nanostructured materials with a given structure and with specific physicochemical properties on the basis of the existing wide range of molecules of natural and synthetic origin. A promising and inexpensive way to obtain nanostructured materials is the spontaneous self-assembly of molecular building blocks during random collisions in real dispersive systems in solution and at interfaces. This editorial aims to summarize the major points from the 11 scientific papers that contributed to the special issue “The Self-Assembly and Design of Polyfunctional Nanosystems”, assessing the modern self-assembly potential and strategies for maintaining sustainable development of the nanoindustry. Full article
(This article belongs to the Special Issue The Self-Assembly and Design of Polyfunctional Nanosystems)
15 pages, 2333 KiB  
Communication
KRASG12C Can Either Promote or Impair Cap-Dependent Translation in Two Different Lung Adenocarcinoma Cell Lines
by George Kyriakopoulos, Vicky Katopodi, Ilias Skeparnias, Eleni G. Kaliatsi, Katerina Grafanaki and Constantinos Stathopoulos
Int. J. Mol. Sci. 2021, 22(4), 2222; https://doi.org/10.3390/ijms22042222 - 23 Feb 2021
Cited by 3 | Viewed by 3089
Abstract
KRASG12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS oncogenic signaling is responsible for modulation of tumor microenvironment, with translation factors being among the most prominent deregulated targets. In the [...] Read more.
KRASG12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS oncogenic signaling is responsible for modulation of tumor microenvironment, with translation factors being among the most prominent deregulated targets. In the present study, we used TALENs to edit EGFRWT CL1-5 and A549 cells for integration of a Tet-inducible KRASG12C expression system. Subsequent analysis of both cell lines showed that cap-dependent translation was impaired in CL1-5 cells via involvement of mTORC2 and NF-κB. In contrast, in A549 cells, which additionally harbor the KRASG12S mutation, cap-dependent translation was favored via recruitment of mTORC1, c-MYC and the positive regulation of eIF4F complex. Downregulation of eIF1, eIF5 and eIF5B in the same cell line suggested a stringency loss of start codon selection during scanning of mRNAs. Puromycin staining and polysome profile analysis validated the enhanced translation rates in A549 cells and the impaired cap-dependent translation in CL1-5 cells. Interestingly, elevated translation rates were restored in CL1-5 cells after prolonged induction of KRASG12C through an mTORC1/p70S6K-independent way. Collectively, our results suggest that KRASG12C signaling differentially affects the regulation of the translational machinery. These differences could provide additional insights and facilitate current efforts to effectively target KRAS. Full article
(This article belongs to the Section Molecular Oncology)
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11 pages, 1678 KiB  
Communication
Alternative to Poly(2-isopropyl-2-oxazoline) with a Reduced Ability to Crystallize and Physiological LCST
by Wojciech Wałach, Agnieszka Klama-Baryła, Anna Sitkowska, Agnieszka Kowalczuk and Natalia Oleszko-Torbus
Int. J. Mol. Sci. 2021, 22(4), 2221; https://doi.org/10.3390/ijms22042221 - 23 Feb 2021
Cited by 12 | Viewed by 2399
Abstract
In this work, we sought to examine whether the presence of alkyl substituents randomly distributed within the main chain of a 2-isopropyl-2-oxazoline-based copolymer will decrease its ability to crystallize when compared to its homopolymer. At the same time, we aimed to ensure an [...] Read more.
In this work, we sought to examine whether the presence of alkyl substituents randomly distributed within the main chain of a 2-isopropyl-2-oxazoline-based copolymer will decrease its ability to crystallize when compared to its homopolymer. At the same time, we aimed to ensure an appropriate hydrophilic/lipophilic balance in the copolymer and maintain the phase transition in the vicinity of the human body temperature. For this reason, copolymers of 2-ethyl-4-methyl-2-oxazoline and 2-isopropyl-2-oxazoline were synthesized. The thermoresponsive behavior of the copolymers in water, the influence of salt on the cloud point, the presence of hysteresis of the phase transition and the crystallization ability in a water solution under long-term heating conditions were studied by turbidimetry. The ability of the copolymers to crystallize in the solid state, and their thermal properties, were analyzed by differential scanning calorimetry and X-ray diffractometry. A cytotoxicity assay was used to estimate the viability of human fibroblasts in the presence of the obtained polymers. The results allowed us to demonstrate a nontoxic alternative to poly(2-isopropyl-2-oxazoline) (PiPrOx) with a physiological phase transition temperature (LCST) and a greatly reduced tendency to crystallize. The synthesis of 2-oxazoline polymers with such well-defined properties is important for future biomedical applications. Full article
(This article belongs to the Section Macromolecules)
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Graphical abstract

16 pages, 2171 KiB  
Article
Structural Determinants of Substrate Specificity of SplF Protease from Staphylococcus aureus
by Natalia Stach, Abdulkarim Karim, Przemyslaw Golik, Radoslaw Kitel, Katarzyna Pustelny, Natalia Gruba, Katarzyna Groborz, Urszula Jankowska, Sylwia Kedracka-Krok, Benedykt Wladyka, Marcin Drag, Adam Lesner and Grzegorz Dubin
Int. J. Mol. Sci. 2021, 22(4), 2220; https://doi.org/10.3390/ijms22042220 - 23 Feb 2021
Cited by 7 | Viewed by 2906
Abstract
Accumulating evidence suggests that six proteases encoded in the spl operon of a dangerous human pathogen, Staphylococcus aureus, may play a role in virulence. Interestingly, SplA, B, D, and E have complementary substrate specificities while SplF remains to be characterized in this [...] Read more.
Accumulating evidence suggests that six proteases encoded in the spl operon of a dangerous human pathogen, Staphylococcus aureus, may play a role in virulence. Interestingly, SplA, B, D, and E have complementary substrate specificities while SplF remains to be characterized in this regard. Here, we describe the prerequisites of a heterologous expression system for active SplF protease and characterize the enzyme in terms of substrate specificity and its structural determinants. Substrate specificity of SplF is comprehensively profiled using combinatorial libraries of peptide substrates demonstrating strict preference for long aliphatic sidechains at the P1 subsite and significant selectivity for aromatic residues at P3. The crystal structure of SplF was provided at 1.7 Å resolution to define the structural basis of substrate specificity of SplF. The obtained results were compared and contrasted with the characteristics of other Spl proteases determined to date to conclude that the spl operon encodes a unique extracellular proteolytic system. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 3347 KiB  
Article
Runx3 Induces a Cell Shape Change and Suppresses Migration and Metastasis of Melanoma Cells by Altering a Transcriptional Profile
by Ning Wang, Haiying Zhang, Xiulin Cui, Chao Ma, Linghui Wang and Wenguang Liu
Int. J. Mol. Sci. 2021, 22(4), 2219; https://doi.org/10.3390/ijms22042219 - 23 Feb 2021
Cited by 4 | Viewed by 2887
Abstract
Runt-related transcription factor-3 (Runx3) is a tumor suppressor, and its contribution to melanoma progression remains unclear. We previously demonstrated that Runx3 re-expression in B16-F10 melanoma cells changed their shape and attenuated their migration. In this study, we found that Runx3 re-expression in B16-F10 [...] Read more.
Runt-related transcription factor-3 (Runx3) is a tumor suppressor, and its contribution to melanoma progression remains unclear. We previously demonstrated that Runx3 re-expression in B16-F10 melanoma cells changed their shape and attenuated their migration. In this study, we found that Runx3 re-expression in B16-F10 cells also suppressed their pulmonary metastasis. We performed microarray analysis and uncovered an altered transcriptional profile underlying the cell shape change and the suppression of migration and metastasis. This altered transcriptional profile was rich in Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) annotations relevant to adhesion and the actin cytoskeleton and included differentially expressed genes for some major extracellular matrix (ECM) proteins as well as genes that were inversely associated with the increase in the metastatic potential of B16-F10 cells compared to B16-F0 melanoma cells. Further, we found that this altered transcriptional profile could have prognostic value, as evidenced by myelin and lymphocyte protein (MAL) and vilin-like (VILL). Finally, Mal gene expression was correlated with metastatic potential among the cells and was targeted by histone deacetylase (HDAC) inhibitors in B16-F10 cells, and the knockdown of Mal gene expression in B16-F0 cells changed their shape and enhanced the migratory and invasive traits of their metastasis. Our study suggests that self-entrapping of metastatic Runx3-negative melanoma cells via adhesion and the actin cytoskeleton could be a powerful therapeutic strategy. Full article
(This article belongs to the Section Molecular Oncology)
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13 pages, 1433 KiB  
Review
Chemistry and Toxicology of Major Bioactive Substances in Inocybe Mushrooms
by Jiri Patocka, Ran Wu, Eugenie Nepovimova, Martin Valis, Wenda Wu and Kamil Kuca
Int. J. Mol. Sci. 2021, 22(4), 2218; https://doi.org/10.3390/ijms22042218 - 23 Feb 2021
Cited by 32 | Viewed by 7050
Abstract
Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It attracts the attention of researchers, especially in the aspects of toxin composition, toxic mechanism and [...] Read more.
Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It attracts the attention of researchers, especially in the aspects of toxin composition, toxic mechanism and toxin application in poisonous mushroom. Inocybe is a large genus of mushrooms and contains toxic substances including muscarine, psilocybin, psilocin, aeruginascin, lectins and baeocystin. In order to prevent and remedy mushroom poisoning, it is significant to clarify the toxic effects and mechanisms of these bioactive substances. In this review article, we summarize the chemistry, most known toxic effects and mechanisms of major toxic substances in Inocybe mushrooms, especially muscarine, psilocybin and psilocin. Their available toxicity data (different species, different administration routes) published formerly are also summarized. In addition, the treatment and medical application of these toxic substances in Inocybe mushrooms are also discussed. We hope that this review will help understanding of the chemistry and toxicology of Inocybe mushrooms as well as the potential clinical application of its bioactive substances to benefit human beings. Full article
(This article belongs to the Special Issue Natural and Synthetic Toxins: Molecular Aspects and Development Treatment Strategy)
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15 pages, 1867 KiB  
Review
The Multifaceted Role of CMA in Glioma: Enemy or Ally?
by Alessia Lo Dico, Cristina Martelli, Cecilia Diceglie and Luisa Ottobrini
Int. J. Mol. Sci. 2021, 22(4), 2217; https://doi.org/10.3390/ijms22042217 - 23 Feb 2021
Cited by 7 | Viewed by 3747
Abstract
Chaperone-mediated autophagy (CMA) is a catabolic pathway fundamental for cell homeostasis, by which specific damaged or non-essential proteins are degraded. CMA activity has three main levels of regulation. The first regulatory level is based on the targetability of specific proteins possessing a KFERQ-like [...] Read more.
Chaperone-mediated autophagy (CMA) is a catabolic pathway fundamental for cell homeostasis, by which specific damaged or non-essential proteins are degraded. CMA activity has three main levels of regulation. The first regulatory level is based on the targetability of specific proteins possessing a KFERQ-like domain, which can be recognized by specific chaperones and delivered to the lysosomes. Target protein unfolding and translocation into the lysosomal lumen constitutes the second level of CMA regulation and is based on the modulation of Lamp2A multimerization. Finally, the activity of some accessory proteins represents the third regulatory level of CMA activity. CMA’s role in oncology has not been fully clarified covering both pro-survival and pro-death roles in different contexts. Taking all this into account, it is possible to comprehend the actual complexity of both CMA regulation and the cellular consequences of its activity allowing it to be elected as a modulatory and not only catabolic machinery. In this review, the role covered by CMA in oncology is discussed with a focus on its relevance in glioma. Molecular correlates of CMA importance in glioma responsiveness to treatment are described to identify new early efficacy biomarkers and new therapeutic targets to overcome resistance. Full article
(This article belongs to the Special Issue Microautophagy)
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13 pages, 2613 KiB  
Article
Targeting lncRNA H19/miR-29b/COL1A1 Axis Impedes Myofibroblast Activities of Precancerous Oral Submucous Fibrosis
by Cheng-Chia Yu, Yi-Wen Liao, Pei-Ling Hsieh and Yu-Chao Chang
Int. J. Mol. Sci. 2021, 22(4), 2216; https://doi.org/10.3390/ijms22042216 - 23 Feb 2021
Cited by 37 | Viewed by 3364
Abstract
Oral submucous fibrosis (OSF) is known as a potentially malignant disorder, which may result from chemical irritation due to areca nuts (such as arecoline). Emerging evidence suggests that fibrogenesis and carcinogenesis are regulated by the interaction of long noncoding RNAs (lncRNAs) and microRNAs. [...] Read more.
Oral submucous fibrosis (OSF) is known as a potentially malignant disorder, which may result from chemical irritation due to areca nuts (such as arecoline). Emerging evidence suggests that fibrogenesis and carcinogenesis are regulated by the interaction of long noncoding RNAs (lncRNAs) and microRNAs. Among these regulators, profibrotic lncRNA H19 has been found to be overexpressed in several fibrosis diseases. Here, we examined the expression of H19 in OSF specimens and its functional role in fibrotic buccal mucosal fibroblasts (fBMFs). Our results indicate that the aberrantly overexpressed H19 contributed to higher myofibroblast activities, such as collagen gel contractility and migration ability. We also demonstrated that H19 interacted with miR-29b, which suppressed the direct binding of miR-29b to the 3′-untranslated region of type I collagen (COL1A1). We showed that ectopic expression of miR-29b ameliorated various myofibroblast phenotypes and the expression of α-smooth muscle actin (α-SMA), COL1A1, and fibronectin (FN1) in fBMFs. In OSF tissues, we found that the expression of miR-29b was downregulated and there was a negative correlation between miR-29b and these fibrosis markers. Lastly, we demonstrate that arecoline stimulated the upregulation of H19 through the transforming growth factor (TGF)-β pathway. Altogether, this study suggests that increased TGF-β secretion following areca nut chewing may induce the upregulation of H19, which serves as a natural sponge for miR-29b and impedes its antifibrotic effects. Full article
(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)
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12 pages, 1356 KiB  
Article
GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease
by Silvia Cerri, Cristina Ghezzi, Gerardo Ongari, Stefania Croce, Micol Avenali, Roberta Zangaglia, Donato A. Di Monte, Enza Maria Valente and Fabio Blandini
Int. J. Mol. Sci. 2021, 22(4), 2215; https://doi.org/10.3390/ijms22042215 - 23 Feb 2021
Cited by 20 | Viewed by 3918
Abstract
Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are [...] Read more.
Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD. Full article
(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)
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27 pages, 1792 KiB  
Article
How Are the Flower Structure and Nectar Composition of the Generalistic Orchid Neottia ovata Adapted to a Wide Range of Pollinators?
by Emilia Brzosko, Andrzej Bajguz, Magdalena Chmur, Justyna Burzyńska, Edyta Jermakowicz, Paweł Mirski and Piotr Zieliński
Int. J. Mol. Sci. 2021, 22(4), 2214; https://doi.org/10.3390/ijms22042214 - 23 Feb 2021
Cited by 12 | Viewed by 3607
Abstract
Plant-pollinator interactions significantly influence reproductive success (RS) and drive the evolution of pollination syndromes. In the context of RS, mainly the role of flower morphology is touched. The importance of nectar properties is less studied, despite its significance in pollination effectiveness. Therefore, the [...] Read more.
Plant-pollinator interactions significantly influence reproductive success (RS) and drive the evolution of pollination syndromes. In the context of RS, mainly the role of flower morphology is touched. The importance of nectar properties is less studied, despite its significance in pollination effectiveness. Therefore, the aim of this study was to test selection on flower morphology and nectar chemistry in the generalistic orchid Neottia ovata. In 2019–2020, we measured three floral displays and six flower traits, pollinaria removal (PR), female reproductive success (FRS), and determined the soil properties. The sugars and amino acids (AAs) were analyzed using the HPLC method. Data were analyzed using multiple statistical methods (boxplots, ternary plot, one-way ANOVA, Kruskal-Wallis test, and PCA). Variation of flower structure and nectar chemistry and their weak correlation with RS confirms the generalistic character of N. ovata. In particular populations, different traits were under selection. PR was high and similar in all populations in both years, while FRS was lower and varied among populations. Nectar was dominated by glucose, fructose, and included 28 AAs (Ala and Glu have the highest content). Sugars and AAs influenced mainly FRS. Among soil parameters, carbon and carbon:nitrogen ratio seems to be the most important in shaping flower structure and nectar chemistry. Full article
(This article belongs to the Special Issue Orchid Biochemistry 2.0)
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25 pages, 2315 KiB  
Review
Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease
by Natalia Diaz-Garrido, Cecilia Cordero, Yenifer Olivo-Martinez, Josefa Badia and Laura Baldomà
Int. J. Mol. Sci. 2021, 22(4), 2213; https://doi.org/10.3390/ijms22042213 - 23 Feb 2021
Cited by 37 | Viewed by 6129
Abstract
Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling [...] Read more.
Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here. Full article
(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease)
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26 pages, 2988 KiB  
Review
KRAB-ZFP Transcriptional Regulators Acting as Oncogenes and Tumor Suppressors: An Overview
by Joanna Sobocińska, Sara Molenda, Marta Machnik and Urszula Oleksiewicz
Int. J. Mol. Sci. 2021, 22(4), 2212; https://doi.org/10.3390/ijms22042212 - 23 Feb 2021
Cited by 51 | Viewed by 5798
Abstract
Krüppel-associated box zinc finger proteins (KRAB-ZFPs) constitute the largest family of transcriptional factors exerting co-repressor functions in mammalian cells. In general, KRAB-ZFPs have a dual structure. They may bind to specific DNA sequences via zinc finger motifs and recruit a repressive complex through [...] Read more.
Krüppel-associated box zinc finger proteins (KRAB-ZFPs) constitute the largest family of transcriptional factors exerting co-repressor functions in mammalian cells. In general, KRAB-ZFPs have a dual structure. They may bind to specific DNA sequences via zinc finger motifs and recruit a repressive complex through the KRAB domain. Such a complex mediates histone deacetylation, trimethylation of histone 3 at lysine 9 (H3K9me3), and subsequent heterochromatization. Nevertheless, apart from their repressive role, KRAB-ZFPs may also co-activate gene transcription, likely through interaction with other factors implicated in transcriptional control. KRAB-ZFPs play essential roles in various biological processes, including development, imprinting, retroelement silencing, and carcinogenesis. Cancer cells possess multiple genomic, epigenomic, and transcriptomic aberrations. A growing number of data indicates that the expression of many KRAB-ZFPs is altered in several tumor types, in which they may act as oncogenes or tumor suppressors. Hereby, we review the available literature describing the oncogenic and suppressive roles of various KRAB-ZFPs in cancer. We focused on their association with the clinicopathological features and treatment response, as well as their influence on the cancer cell phenotype. Moreover, we summarized the identified upstream and downstream molecular mechanisms that may govern the functioning of KRAB-ZFPs in a cancer setting. Full article
(This article belongs to the Special Issue Transcription Factors in Cancer)
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13 pages, 3323 KiB  
Article
Identification of Active Site Residues of the Siderophore Synthesis Enzyme PvdF and Evidence for Interaction of PvdF with a Substrate-Providing Enzyme
by Priya Philem, Torsten Kleffmann, Sinan Gai, Bill C. Hawkins, Sigurd M. Wilbanks and Iain L. Lamont
Int. J. Mol. Sci. 2021, 22(4), 2211; https://doi.org/10.3390/ijms22042211 - 23 Feb 2021
Cited by 4 | Viewed by 2702
Abstract
The problematic opportunistic pathogen Pseudomonas aeruginosa secretes a siderophore, pyoverdine. Pyoverdine scavenges iron needed by the bacteria for growth and for pathogenicity in a range of different infection models. PvdF, a hydroxyornithine transformylase enzyme, is essential for pyoverdine synthesis, catalysing synthesis of formylhydroxyornithine [...] Read more.
The problematic opportunistic pathogen Pseudomonas aeruginosa secretes a siderophore, pyoverdine. Pyoverdine scavenges iron needed by the bacteria for growth and for pathogenicity in a range of different infection models. PvdF, a hydroxyornithine transformylase enzyme, is essential for pyoverdine synthesis, catalysing synthesis of formylhydroxyornithine (fOHOrn) that forms part of the pyoverdine molecule and provides iron-chelating hydroxamate ligands. Using a mass spectrometry assay, we confirm that purified PvdF catalyses synthesis of fOHOrn from hydroxyornithine and formyltetrahydrofolate substrates. Site directed mutagenesis was carried out to investigate amino acid residues predicted to be required for enzymatic activity. Enzyme variants were assayed for activity in vitro and also in vivo, through measuring their ability to restore pyoverdine production to a pvdF mutant strain. Variants at two putative catalytic residues N168 and H170 greatly reduced enzymatic activity in vivo though did not abolish activity in vitro. Change of a third residue D229 abolished activity both in vivo and in vitro. A change predicted to block entry of N10-formyltetrahydrofolate (fTHF) to the active site also abolished activity both in vitro and in vivo. A co-purification assay showed that PvdF binds to an enzyme PvdA that catalyses synthesis of hydroxyornithine, with this interaction likely to increase the efficiency of fOHOrn synthesis. Our findings advance understanding of how P. aeruginosa synthesises pyoverdine, a key factor in host–pathogen interactions. Full article
(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)
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37 pages, 2005 KiB  
Review
Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment
by Rebecca Raue, Ann-Christin Frank, Shahzad Nawaz Syed and Bernhard Brüne
Int. J. Mol. Sci. 2021, 22(4), 2210; https://doi.org/10.3390/ijms22042210 - 23 Feb 2021
Cited by 34 | Viewed by 6349
Abstract
The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional [...] Read more.
The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside. Full article
(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)
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23 pages, 3736 KiB  
Article
Divalent Cation Modulation of Ion Permeation in TMEM16 Proteins
by Dung M. Nguyen, Hwoi Chan Kwon and Tsung-Yu Chen
Int. J. Mol. Sci. 2021, 22(4), 2209; https://doi.org/10.3390/ijms22042209 - 23 Feb 2021
Cited by 7 | Viewed by 3068
Abstract
Intracellular divalent cations control the molecular function of transmembrane protein 16 (TMEM16) family members. Both anion channels (such as TMEM16A) and phospholipid scramblases (such as TMEM16F) in this family are activated by intracellular Ca2+ in the low µM range. In addition, intracellular [...] Read more.
Intracellular divalent cations control the molecular function of transmembrane protein 16 (TMEM16) family members. Both anion channels (such as TMEM16A) and phospholipid scramblases (such as TMEM16F) in this family are activated by intracellular Ca2+ in the low µM range. In addition, intracellular Ca2+ or Co2+ at mM concentrations have been shown to further potentiate the saturated Ca2+-activated current of TMEM16A. In this study, we found that all alkaline earth divalent cations in mM concentrations can generate similar potentiation effects in TMEM16A when applied intracellularly, and that manipulations thought to deplete membrane phospholipids weaken the effect. In comparison, mM concentrations of divalent cations minimally potentiate the current of TMEM16F but significantly change its cation/anion selectivity. We suggest that divalent cations may increase local concentrations of permeant ions via a change in pore electrostatic potential, possibly acting through phospholipid head groups in or near the pore. Monovalent cations appear to exert a similar effect, although with a much lower affinity. Our findings resolve controversies regarding the ion selectivity of TMEM16 proteins. The physiological role of this mechanism, however, remains elusive because of the nearly constant high cation concentrations in cytosols. Full article
(This article belongs to the Special Issue Ca2+-Activated Chloride Channels and Phospholipid Scramblases)
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18 pages, 6433 KiB  
Communication
Exploring Molecular Contacts of MUC1 at CIN85 Binding Interface to Address Future Drug Design Efforts
by Maria Rita Gulotta, Serena Vittorio, Rosaria Gitto, Ugo Perricone and Laura De Luca
Int. J. Mol. Sci. 2021, 22(4), 2208; https://doi.org/10.3390/ijms22042208 - 23 Feb 2021
Cited by 1 | Viewed by 2386
Abstract
The modulation of protein-protein interactions (PPIs) by small molecules represents a valuable strategy for pharmacological intervention in several human diseases. In this context, computer-aided drug discovery techniques offer useful resources to predict the network of interactions governing the recognition process between protein partners, [...] Read more.
The modulation of protein-protein interactions (PPIs) by small molecules represents a valuable strategy for pharmacological intervention in several human diseases. In this context, computer-aided drug discovery techniques offer useful resources to predict the network of interactions governing the recognition process between protein partners, thus furnishing relevant information for the design of novel PPI modulators. In this work, we focused our attention on the MUC1-CIN85 complex as a crucial PPI controlling cancer progression and metastasis. MUC1 is a transmembrane glycoprotein whose extracellular domain contains a variable number of tandem repeats (VNTRs) regions that are highly glycosylated in normal cells and under-glycosylated in cancer. The hypo-glycosylation fosters the exposure of the backbone to new interactions with other proteins, such as CIN85, that alter the intracellular signalling in tumour cells. Herein, different computational approaches were combined to investigate the molecular recognition pattern of MUC1-CIN85 PPI thus unveiling new structural information useful for the design of MUC1-CIN85 PPI inhibitors as potential anti-metastatic agents. Full article
(This article belongs to the Section Molecular Informatics)
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Graphical abstract

24 pages, 4836 KiB  
Article
Differential Effects of STCH and Stress-Inducible Hsp70 on the Stability and Maturation of NKCC2
by Dalal Bakhos-Douaihy, Elie Seaayfan, Sylvie Demaretz, Martin Komhoff and Kamel Laghmani
Int. J. Mol. Sci. 2021, 22(4), 2207; https://doi.org/10.3390/ijms22042207 - 23 Feb 2021
Cited by 11 | Viewed by 3376
Abstract
Mutations in the Na-K-2Cl co-transporter NKCC2 lead to type I Bartter syndrome, a life-threatening kidney disease. We previously showed that export from the ER constitutes the limiting step in NKCC2 maturation and cell surface expression. Yet, the molecular mechanisms involved in this process [...] Read more.
Mutations in the Na-K-2Cl co-transporter NKCC2 lead to type I Bartter syndrome, a life-threatening kidney disease. We previously showed that export from the ER constitutes the limiting step in NKCC2 maturation and cell surface expression. Yet, the molecular mechanisms involved in this process remain obscure. Here, we report the identification of chaperone stress 70 protein (STCH) and the stress-inducible heat shock protein 70 (Hsp70), as two novel binding partners of the ER-resident form of NKCC2. STCH knock-down increased total NKCC2 expression whereas Hsp70 knock-down or its inhibition by YM-01 had the opposite effect. Accordingly, overexpressing of STCH and Hsp70 exerted opposite actions on total protein abundance of NKCC2 and its folding mutants. Cycloheximide chase assay showed that in cells over-expressing STCH, NKCC2 stability and maturation are heavily impaired. In contrast to STCH, Hsp70 co-expression increased NKCC2 maturation. Interestingly, treatment by protein degradation inhibitors revealed that in addition to the proteasome, the ER associated degradation (ERAD) of NKCC2 mediated by STCH, involves also the ER-to-lysosome-associated degradation pathway. In summary, our data are consistent with STCH and Hsp70 having differential and antagonistic effects with regard to NKCC2 biogenesis. These findings may have an impact on our understanding and potential treatment of diseases related to aberrant NKCC2 trafficking and expression. Full article
(This article belongs to the Section Biochemistry)
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13 pages, 2054 KiB  
Review
Macrophage Function and the Role of GSK3
by Sarvatit Patel and Geoff H. Werstuck
Int. J. Mol. Sci. 2021, 22(4), 2206; https://doi.org/10.3390/ijms22042206 - 23 Feb 2021
Cited by 20 | Viewed by 4582
Abstract
Macrophages are present in nearly all vertebrate tissues, where they respond to a complex variety of regulatory signals to coordinate immune functions involved in tissue development, metabolism, homeostasis, and repair. Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed protein kinase that plays [...] Read more.
Macrophages are present in nearly all vertebrate tissues, where they respond to a complex variety of regulatory signals to coordinate immune functions involved in tissue development, metabolism, homeostasis, and repair. Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed protein kinase that plays important roles in multiple pathways involved in cell metabolism. Dysregulation of GSK3 has been implicated in several prevalent metabolic disorders, and recent findings have highlighted the importance of GSK3 activity in the regulation of macrophages, especially with respect to the initiation of specific pathologies. This makes GSK3 a potential therapeutic target for the development of novel drugs to modulate immunometabolic responses. Here, we summarize recent findings that have contributed to our understanding of how GSK3 regulates macrophage function, and we discuss the role of GSK3 in the development of metabolic disorders and diseases. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part III)
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17 pages, 1939 KiB  
Article
Rainbow Trout (Oncorhynchus mykiss) Na+/H+ Exchangers tNhe3a and tNhe3b Display Unique Inhibitory Profiles Dissimilar from Mammalian NHE Isoforms
by Salvatore Blair, Xiuju Li, Debajyoti Dutta, Danuta Chamot, Larry Fliegel and Greg Goss
Int. J. Mol. Sci. 2021, 22(4), 2205; https://doi.org/10.3390/ijms22042205 - 23 Feb 2021
Cited by 10 | Viewed by 2536
Abstract
Freshwater fishes maintain an internal osmolality of ~300 mOsm, while living in dilute environments ranging from 0 to 50 mOsm. This osmotic challenge is met at least partially, by Na+/H+ exchangers (NHE) of fish gill and kidney. In this study, [...] Read more.
Freshwater fishes maintain an internal osmolality of ~300 mOsm, while living in dilute environments ranging from 0 to 50 mOsm. This osmotic challenge is met at least partially, by Na+/H+ exchangers (NHE) of fish gill and kidney. In this study, we cloned, expressed, and pharmacologically characterized fish-specific Nhes of the commercially important species Oncorhynchus mykiss. Trout (t) Nhe3a and Nhe3b isoforms from gill and kidney were expressed and characterized in an NHE-deficient cell line. Western blotting and immunocytochemistry confirmed stable expression of the tagged trout tNhe proteins. To measure NHE activity, a transient acid load was induced in trout tNhe expressing cells and intracellular pH was measured. Both isoforms demonstrated significant activity and recovered from an acute acid load. The effect of the NHE transport inhibitors amiloride, EIPA (5-(N-ethyl-N-isopropyl)-amiloride), phenamil, and DAPI was examined. tNhe3a was inhibited in a dose-dependent manner by amiloride and EIPA and tNhe3a was more sensitive to amiloride than EIPA, unlike mammalian NHE1. tNhe3b was inhibited by high concentrations of amiloride, while even in the presence of high concentrations of EIPA (500 µM), some activity of tNhe3b remained. Phenamil and DAPI were ineffective at inhibiting tNhe activity of either isoform. The current study aids in understanding the pharmacology of fish ion transporters. Both isoforms display inhibitory profiles uniquely different from mammalian NHEs and show resistance to inhibition. Our study allows for more direct interpretation of past, present, and future fish-specific sodium transport studies, with less reliance on mammalian NHE data for interpretation. Full article
(This article belongs to the Section Biochemistry)
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17 pages, 8210 KiB  
Review
The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance
by Simon Grootendorst, Jonathan de Wilde, Birgit van Dooijeweert, Annelies van Vuren, Wouter van Solinge, Roger Schutgens, Richard van Wijk and Marije Bartels
Int. J. Mol. Sci. 2021, 22(4), 2204; https://doi.org/10.3390/ijms22042204 - 23 Feb 2021
Cited by 6 | Viewed by 4092
Abstract
Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due [...] Read more.
Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis 2.0)
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13 pages, 1093 KiB  
Review
Current Understanding of Role of Vesicular Transport in Salt Secretion by Salt Glands in Recretohalophytes
by Chaoxia Lu, Fang Yuan, Jianrong Guo, Guoliang Han, Chengfeng Wang, Min Chen and Baoshan Wang
Int. J. Mol. Sci. 2021, 22(4), 2203; https://doi.org/10.3390/ijms22042203 - 23 Feb 2021
Cited by 20 | Viewed by 4183
Abstract
Soil salinization is a serious and growing problem around the world. Some plants, recognized as the recretohalophytes, can normally grow on saline–alkali soil without adverse effects by secreting excessive salt out of the body. The elucidation of the salt secretion process is of [...] Read more.
Soil salinization is a serious and growing problem around the world. Some plants, recognized as the recretohalophytes, can normally grow on saline–alkali soil without adverse effects by secreting excessive salt out of the body. The elucidation of the salt secretion process is of great significance for understanding the salt tolerance mechanism adopted by the recretohalophytes. Between the 1950s and the 1970s, three hypotheses, including the osmotic potential hypothesis, the transfer system similar to liquid flow in animals, and vesicle-mediated exocytosis, were proposed to explain the salt secretion process of plant salt glands. More recently, increasing evidence has indicated that vesicular transport plays vital roles in salt secretion of recretohalophytes. Here, we summarize recent findings, especially regarding the molecular evidence on the functional roles of vesicular trafficking in the salt secretion process of plant salt glands. A model of salt secretion in salt gland is also proposed. Full article
(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues 2.0)
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18 pages, 7197 KiB  
Article
Overexpression of miR-1306-5p, miR-3195, and miR-3914 Inhibits Ameloblast Differentiation through Suppression of Genes Associated with Human Amelogenesis Imperfecta
by Hiroki Yoshioka, Yin-Ying Wang, Akiko Suzuki, Meysam Shayegh, Mona V. Gajera, Zhongming Zhao and Junichi Iwata
Int. J. Mol. Sci. 2021, 22(4), 2202; https://doi.org/10.3390/ijms22042202 - 23 Feb 2021
Cited by 10 | Viewed by 3060
Abstract
Amelogenesis imperfecta is a congenital form of enamel hypoplasia. Although a number of genetic mutations have been reported in humans, the regulatory network of these genes remains mostly unclear. To identify signatures of biological pathways in amelogenesis imperfecta, we conducted bioinformatic analyses on [...] Read more.
Amelogenesis imperfecta is a congenital form of enamel hypoplasia. Although a number of genetic mutations have been reported in humans, the regulatory network of these genes remains mostly unclear. To identify signatures of biological pathways in amelogenesis imperfecta, we conducted bioinformatic analyses on genes associated with the condition in humans. Through an extensive search of the main biomedical databases, we found 56 genes in which mutations and/or association/linkage were reported in individuals with amelogenesis imperfecta. These candidate genes were further grouped by function, pathway, protein–protein interaction, and tissue-specific expression patterns using various bioinformatic tools. The bioinformatic analyses highlighted a group of genes essential for extracellular matrix formation. Furthermore, advanced bioinformatic analyses for microRNAs (miRNAs), which are short non-coding RNAs that suppress target genes at the post-transcriptional level, predicted 37 candidates that may be involved in amelogenesis imperfecta. To validate the miRNA–gene regulation association, we analyzed the target gene expression of the top seven candidate miRNAs: miR-3195, miR-382-5p, miR-1306-5p, miR-4683, miR-6716-3p, miR-3914, and miR-3935. Among them, miR-1306-5p, miR-3195, and miR-3914 were confirmed to regulate ameloblast differentiation through the regulation of genes associated with amelogenesis imperfecta in AM-1 cells, a human ameloblastoma cell line. Taken together, our study suggests a potential role for miRNAs in amelogenesis imperfecta. Full article
(This article belongs to the Special Issue Gene Networks That Control Cell Proliferation and Differentiation)
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26 pages, 8897 KiB  
Review
Advances in Targeting HPV Infection as Potential Alternative Prophylactic Means
by Sinead Carse, Martina Bergant and Georgia Schäfer
Int. J. Mol. Sci. 2021, 22(4), 2201; https://doi.org/10.3390/ijms22042201 - 23 Feb 2021
Cited by 12 | Viewed by 6702
Abstract
Infection by oncogenic human papillomavirus (HPV) is the primary cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle- income countries (LMIC). Concurrent infection with Human Immunodeficiency Virus (HIV) further increases the risk of [...] Read more.
Infection by oncogenic human papillomavirus (HPV) is the primary cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle- income countries (LMIC). Concurrent infection with Human Immunodeficiency Virus (HIV) further increases the risk of HPV infection and exacerbates disease onset and progression. Highly effective prophylactic vaccines do exist to combat HPV infection with the most common oncogenic types, but the accessibility to these in LMIC is severely limited due to cost, difficulties in accessing the target population, cultural issues, and maintenance of a cold chain. Alternative preventive measures against HPV infection that are more accessible and affordable are therefore also needed to control cervical cancer risk. There are several efforts in identifying such alternative prophylactics which target key molecules involved in early HPV infection events. This review summarizes the current knowledge of the initial steps in HPV infection, from host cell-surface engagement to cellular trafficking of the viral genome before arrival in the nucleus. The key molecules that can be potentially targeted are highlighted, and a discussion on their applicability as alternative preventive means against HPV infection, with a focus on LMIC, is presented. Full article
(This article belongs to the Special Issue Human Papillomavirus from Lab to Life: Insights from Molecular Researches)
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21 pages, 31051 KiB  
Article
Structural Communication between the E. coli Chaperones DnaK and Hsp90
by Matthew P. Grindle, Ben Carter, John Paul Alao, Katherine Connors, Riina Tehver and Andrea N. Kravats
Int. J. Mol. Sci. 2021, 22(4), 2200; https://doi.org/10.3390/ijms22042200 - 23 Feb 2021
Cited by 7 | Viewed by 3606
Abstract
The 70 kDa and 90 kDa heat shock proteins Hsp70 and Hsp90 are two abundant and highly conserved ATP-dependent molecular chaperones that participate in the maintenance of cellular homeostasis. In Escherichia coli, Hsp90 (Hsp90Ec) and Hsp70 (DnaK) directly interact [...] Read more.
The 70 kDa and 90 kDa heat shock proteins Hsp70 and Hsp90 are two abundant and highly conserved ATP-dependent molecular chaperones that participate in the maintenance of cellular homeostasis. In Escherichia coli, Hsp90 (Hsp90Ec) and Hsp70 (DnaK) directly interact and collaborate in protein remodeling. Previous work has produced a model of the direct interaction of both chaperones. The locations of the residues involved have been confirmed and the model has been validated. In this study, we investigate the allosteric communication between Hsp90Ec and DnaK and how the chaperones couple their conformational cycles. Using elastic network models (ENM), normal mode analysis (NMA), and a structural perturbation method (SPM) of asymmetric and symmetric DnaK-Hsp90Ec, we extract biologically relevant vibrations and identify residues involved in allosteric signaling. When one DnaK is bound, the dominant normal modes favor biological motions that orient a substrate protein bound to DnaK within the substrate/client binding site of Hsp90Ec and release the substrate from the DnaK substrate binding domain. The presence of one DnaK molecule stabilizes the entire Hsp90Ec protomer to which it is bound. Conversely, the symmetric model of DnaK binding results in steric clashes of DnaK molecules and suggests that the Hsp90Ec and DnaK chaperone cycles operate independently. Together, this data supports an asymmetric binding of DnaK to Hsp90Ec. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 1806 KiB  
Review
Exercise–Linked Irisin: Consequences on Mental and Cardiovascular Health in Type 2 Diabetes
by Ricardo Augusto Leoni De Sousa, Alex Cleber Improta-Caria and Bruno Solano de Freitas Souza
Int. J. Mol. Sci. 2021, 22(4), 2199; https://doi.org/10.3390/ijms22042199 - 23 Feb 2021
Cited by 49 | Viewed by 8796
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with insulin resistance and hyperglycemia. Chronic exposure to a T2DM microenvironment with hyperglycemia, hyperinsulinemia, oxidative stress and increased levels of proinflammatory mediators, has negative consequences to the cardiovascular system and mental health. Therefore, [...] Read more.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with insulin resistance and hyperglycemia. Chronic exposure to a T2DM microenvironment with hyperglycemia, hyperinsulinemia, oxidative stress and increased levels of proinflammatory mediators, has negative consequences to the cardiovascular system and mental health. Therefore, atherosclerotic cardiovascular diseases (CVD) and mental health issues have been strongly associated with T2DM. Lifestyle modifications, including physical exercise training, are necessary to prevent T2DM development and its associated complications. It is widely known that the regular practice of exercise provides several physiological benefits to subjects with T2DM, such as managing glycemic and blood pressure levels. Different types of exercise, from aerobic to resistance training, are effective to improve mental health and cognitive function in T2DM. Irisin is a myokine produced in response to exercise, which has been pointed as a relevant mechanism of action to explain the benefits of exercise on cardiovascular and mental health in T2DM patients. Here, we review emerging clinical and experimental evidence about exercise-linked irisin consequences to cardiovascular and mental health in T2DM. Full article
(This article belongs to the Section Molecular Neurobiology)
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