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Int. J. Mol. Sci., Volume 24, Issue 6 (March-2 2023) – 949 articles

Cover Story (view full-size image): The discovery of new therapies for colorectal cancer (CRC) is of increased relevance. Despite the described antitumorigenic properties of microbiota-derived short-chain fatty acids (SCFAs), their influence on the tumor microenvironment is poorly understood. Since the tumor microenvironment affects the patients’ treatment and prognosis, the aim of this review was to explore what is known about the SCFA effects on the tumor microenvironment. It is reported that SCFAs promote immune cell differentiation, inhibit inflammation and angiogenesis, sustain the basement membrane’s integrity and modulate the intestinal pH. CRC patients have lower concentrations of SCFAs than healthy individuals, so increasing the SCFA levels by modulating the intestinal microbiota represents an important therapeutic strategy for CRC patients. View this paper
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13 pages, 1029 KiB  
Review
Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus
by Jelena Rakocevic, Milan Dobric, Rada Vucic, Matija Furtula, Ivan Zaletel, Katarina Milutinovic, Ana Ilijevski, Milica Labudovic Borovic, Miloje Tomasevic and Milos Bajcetic
Int. J. Mol. Sci. 2023, 24(6), 6012; https://doi.org/10.3390/ijms24066012 - 22 Mar 2023
Viewed by 2286
Abstract
The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) enzyme interferes with the metabolism of low-density lipoprotein (LDL) cholesterol. Inhibition of PCSK9 results in lower LDL cholesterol levels, which can be achieved by different molecular pathways. Monoclonal antibodies targeting circulating PCSK9 have shown strong and [...] Read more.
The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) enzyme interferes with the metabolism of low-density lipoprotein (LDL) cholesterol. Inhibition of PCSK9 results in lower LDL cholesterol levels, which can be achieved by different molecular pathways. Monoclonal antibodies targeting circulating PCSK9 have shown strong and persistent effects on lowering the LDL cholesterol level, while reducing the risk of future cardiovascular events. However, this therapy requires once- or twice-monthly administration in the form of subcutaneous injection. This dosing regimen might impact the therapy adherence in cardiovascular patients who often require multiple drugs with different dosing intervals. Small interfering ribonucleic acid (siRNA) represents a promising therapy approach for patients with elevated LDL cholesterol level despite optimized background statin therapy. Inclisiran is a synthesized siRNA which inhibits PCSK9 synthesis in the liver and provides sustained and durable lowering of LDL cholesterol with twice-yearly application and a good tolerability profile. Herein, we present an overview of the current available data and critical review of the major clinical trials which assessed safety and efficacy of inclisiran in different groups of patients with elevated LDL cholesterol level. Full article
(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)
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19 pages, 4206 KiB  
Article
Generation and Next-Generation Sequencing-Based Characterization of a Large Human Combinatorial Antibody Library
by Hye Lim Choi, Ha Rim Yang, Ha Gyeong Shin, Kyusang Hwang, Ji Woong Kim, Ji Hyun Lee, Taehoon Ryu, Yushin Jung and Sukmook Lee
Int. J. Mol. Sci. 2023, 24(6), 6011; https://doi.org/10.3390/ijms24066011 - 22 Mar 2023
Cited by 2 | Viewed by 2683
Abstract
Antibody phage display is a key technology for the discovery and development of target-specific monoclonal antibodies (mAbs) for use in research, diagnostics, and therapy. The construction of a high-quality antibody library, with larger and more diverse antibody repertoires, is essential for the successful [...] Read more.
Antibody phage display is a key technology for the discovery and development of target-specific monoclonal antibodies (mAbs) for use in research, diagnostics, and therapy. The construction of a high-quality antibody library, with larger and more diverse antibody repertoires, is essential for the successful development of phage display-derived mAbs. In this study, a large human combinatorial single-chain variable fragment library (1.5 × 1011 colonies) was constructed from Epstein–Barr virus-infected human peripheral blood mononuclear cells stimulated with a combination of two of the activators of human B cells, the Toll-like receptor 7/8 agonist R848 and interleukin-2. Next-generation sequencing analysis with approximately 1.9 × 106 and 2.7 × 106 full-length sequences of heavy chain variable (VH) and κ light chain variable (Vκ) domains, respectively, revealed that the library consists of unique VH (approximately 94%) and Vκ (approximately 91%) sequences with greater diversity than germline sequences. Lastly, multiple unique mAbs with high affinity and broad cross-species reactivity could be isolated from the library against two therapeutically relevant target antigens, validating the library quality. These findings suggest that the novel antibody library we have developed may be useful for the rapid development of target-specific phage display-derived recombinant human mAbs for use in therapeutic and diagnostic applications. Full article
(This article belongs to the Special Issue From Omics to Therapeutic Targets in Cancer)
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25 pages, 1894 KiB  
Review
Sex Differences in Tryptophan Metabolism: A Systematic Review Focused on Neuropsychiatric Disorders
by Mariana Lapo Pais, João Martins, Miguel Castelo-Branco and Joana Gonçalves
Int. J. Mol. Sci. 2023, 24(6), 6010; https://doi.org/10.3390/ijms24066010 - 22 Mar 2023
Cited by 5 | Viewed by 3272
Abstract
Tryptophan (Tryp) is an essential amino acid and the precursor of several neuroactive compounds within the central nervous system (CNS). Tryp metabolism, the common denominator linking serotonin (5-HT) dysfunctions and neuroinflammation, is involved in several neuropsychiatric conditions, including neurological, neurodevelopmental, neurodegenerative, and psychiatric [...] Read more.
Tryptophan (Tryp) is an essential amino acid and the precursor of several neuroactive compounds within the central nervous system (CNS). Tryp metabolism, the common denominator linking serotonin (5-HT) dysfunctions and neuroinflammation, is involved in several neuropsychiatric conditions, including neurological, neurodevelopmental, neurodegenerative, and psychiatric diseases. Interestingly, most of those conditions occur and progress in a sex-specific manner. Here, we explore the most relevant observations about the influence of biological sex on Tryp metabolism and its possible relation to neuropsychiatric diseases. Consistent evidence suggests that women have a higher susceptibility than men to suffer serotoninergic alterations due to changes in the levels of its precursor Tryp. Indeed, female sex bias in neuropsychiatric diseases is involved in a reduced availability of this amino acid pool and 5-HT synthesis. These changes in Tryp metabolism could lead to sexual dimorphism on the prevalence and severity of some neuropsychiatric disorders. This review identifies gaps in the current state of the art, thus suggesting future research directions. Specifically, there is a need for further research on the impact of diet and sex steroids, both involved in this molecular mechanism as they have been poorly addressed for this topic. Full article
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10 pages, 1110 KiB  
Communication
A Compendium of AR Splice Variants in Metastatic Castration-Resistant Prostate Cancer
by Khrystany T. Isebia, Martijn P. Lolkema, Guido Jenster, Ronald de Wit, John W. M. Martens and Job van Riet
Int. J. Mol. Sci. 2023, 24(6), 6009; https://doi.org/10.3390/ijms24066009 - 22 Mar 2023
Cited by 1 | Viewed by 1479
Abstract
Treatment-induced AR alterations, including AR alternative splice variants (AR-Vs), have been extensively linked to harboring roles in primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer and therefore have gained momentum. Our aim was to uniformly determine recurrent AR-Vs [...] Read more.
Treatment-induced AR alterations, including AR alternative splice variants (AR-Vs), have been extensively linked to harboring roles in primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer and therefore have gained momentum. Our aim was to uniformly determine recurrent AR-Vs in metastatic castration-resistant prostate cancer (mCRPC) using whole transcriptome sequencing in order to assess which AR-Vs might hold potential diagnostic or prognostic relevance in future research. This study reports that in addition to the promising AR-V7 as a biomarker, AR45 and AR-V3 were also seen as recurrent AR-Vs and that the presence of any AR-V could be associated with higher AR expression. With future research, these AR-Vs may therefore harbor similar or complementary roles to AR-V7 as predictive and prognostic biomarkers in mCRPC or as proxies for abundant AR expression. Full article
(This article belongs to the Special Issue Molecular Research of Urology 2022)
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20 pages, 7330 KiB  
Article
CHIR99021-Treated Osteocytes with Wnt Activation in 3D-Printed Module Form an Osteogenic Microenvironment for Enhanced Osteogenesis and Vasculogenesis
by Yisheng Luo, Yangxi Liu, Bo Wang and Xiaolin Tu
Int. J. Mol. Sci. 2023, 24(6), 6008; https://doi.org/10.3390/ijms24066008 - 22 Mar 2023
Cited by 1 | Viewed by 1842
Abstract
Finding a bone implant that has high bioactivity that can safely drive stem cell differentiation and simulate a real in vivo microenvironment is a challenge for bone tissue engineering. Osteocytes significantly regulate bone cell fate, and Wnt-activated osteocytes can reversely regulate bone formation [...] Read more.
Finding a bone implant that has high bioactivity that can safely drive stem cell differentiation and simulate a real in vivo microenvironment is a challenge for bone tissue engineering. Osteocytes significantly regulate bone cell fate, and Wnt-activated osteocytes can reversely regulate bone formation by regulating bone anabolism, which may improve the biological activity of bone implants. To achieve a safe application, we used the Wnt agonist CHIR99021 (C91) to treat MLO-Y4 for 24 h, in a co-culture with ST2 for 3 days after withdrawal. We found that the expression of Runx2 and Osx increased, promoted osteogenic differentiation, and inhibited adipogenic differentiation in the ST2 cells, and these effects were eliminated by the triptonide. Therefore, we hypothesized that C91-treated osteocytes form an osteogenic microenvironment (COOME). Subsequently, we constructed a bio-instructive 3D printing system to verify the function of COOME in 3D modules that mimic the in vivo environment. Within PCI3D, COOME increased the survival and proliferation rates to as high as 92% after 7 days and promoted ST2 cell differentiation and mineralization. Simultaneously, we found that the COOME-conditioned medium also had the same effects. Therefore, COOME promotes ST2 cell osteogenic differentiation both directly and indirectly. It also promotes HUVEC migration and tube formation, which can be explained by the high expression of Vegf. Altogether, these results indicate that COOME, combined with our independently developed 3D printing system, can overcome the poor cell survival and bioactivity of orthopedic implants and provide a new method for clinical bone defect repair. Full article
(This article belongs to the Special Issue Novel Osteogenic Molecules and Delivery Methods for Bone Regeneration)
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13 pages, 327 KiB  
Perspective
The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease
by Christodoula Kourtidou and Konstantinos Tziomalos
Int. J. Mol. Sci. 2023, 24(6), 6007; https://doi.org/10.3390/ijms24066007 - 22 Mar 2023
Cited by 3 | Viewed by 1576
Abstract
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears [...] Read more.
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears to induce oxidative stress, inflammation and fibrosis in the diabetic kidney. In the present review, we summarize the current knowledge on the association between histone modification and DKD. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)
20 pages, 964 KiB  
Article
Studying the Geroprotective Properties of YAP/TAZ Signaling Inhibitors on Drosophila melanogaster Model
by Denis A. Golubev, Nadezhda V. Zemskaya, Anastasia A. Gorbunova, Daria V. Kukuman, Alexey Moskalev and Mikhail V. Shaposhnikov
Int. J. Mol. Sci. 2023, 24(6), 6006; https://doi.org/10.3390/ijms24066006 - 22 Mar 2023
Viewed by 1951
Abstract
The transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the main downstream effectors of the evolutionarily conserved Hippo signaling pathway. YAP/TAZ are implicated in the transcriptional regulation of target genes that are involved in a wide range of [...] Read more.
The transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the main downstream effectors of the evolutionarily conserved Hippo signaling pathway. YAP/TAZ are implicated in the transcriptional regulation of target genes that are involved in a wide range of key biological processes affecting tissue homeostasis and play dual roles in the aging process, depending on the cellular and tissue context. The aim of the present study was to investigate whether pharmacological inhibitors of Yap/Taz increase the lifespan of Drosophila melanogaster. Real-time qRT-PCR was performed to measure the changes in the expression of Yki (Yorkie, the Drosophila homolog of YAP/TAZ) target genes. We have revealed a lifespan-increasing effect of YAP/TAZ inhibitors that was mostly associated with decreased expression levels of the wg and E2f1 genes. However, further analysis is required to understand the link between the YAP/TAZ pathway and aging. Full article
(This article belongs to the Section Biochemistry)
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12 pages, 1855 KiB  
Article
Simultaneous Electrochemical Detection of LDL and MDA-LDL Using Antibody-Ferrocene or Anthraquinone Conjugates Coated Magnetic Beads
by Daria Rudewicz-Kowalczyk and Iwona Grabowska
Int. J. Mol. Sci. 2023, 24(6), 6005; https://doi.org/10.3390/ijms24066005 - 22 Mar 2023
Viewed by 1625
Abstract
The simultaneous detection of atherosclerotic cardiovascular disease (ACSVD) biomarkers was recently of great scientific interest. In this work, magnetic beads-based immunosensors for the simultaneous detection of low density lipoprotein (LDL) and malondialdehyde-modified low density lipoprotein (MDA-LDL) were presented. The approach proposed was based [...] Read more.
The simultaneous detection of atherosclerotic cardiovascular disease (ACSVD) biomarkers was recently of great scientific interest. In this work, magnetic beads-based immunosensors for the simultaneous detection of low density lipoprotein (LDL) and malondialdehyde-modified low density lipoprotein (MDA-LDL) were presented. The approach proposed was based on the formation of two types of specific immunoconjugates consisting of monoclonal antibodies: anti-LDL or anti-MDA-LDL, together with redox active molecules: ferrocene and anthraquinone, respectively, coated on magnetic beads (MBs). The decrease in redox agent current in the concentration range: 0.001–1.0 ng/mL for LDL and 0.01–10.0 ng/mL for MDA-LDL, registered by square wave voltammetry (SWV), was observed upon the creation of complex between LDL or MDA-LDL and appropriate immunoconjugates. The detection limits of 0.2 ng/mL for LDL and 0.1 ng/mL for MDA-LDL were estimated. Moreover, the results of selectivity against the possible interferents were good, as human serum albumin (HSA) and high density lipoprotein (HDL), stability and recovery studies demonstrated the potential of platform proposed for early prognosis and diagnosis of ASCVD. Full article
(This article belongs to the Special Issue Biosensors for the Early Diagnosis of High-Impact Human Diseases)
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17 pages, 3821 KiB  
Article
Unraveling the Aquaporin-3 Inhibitory Effect of Rottlerin by Experimental and Computational Approaches
by Inês Paccetti-Alves, Marta S. P. Batista, Catarina Pimpão, Bruno L. Victor and Graça Soveral
Int. J. Mol. Sci. 2023, 24(6), 6004; https://doi.org/10.3390/ijms24066004 - 22 Mar 2023
Cited by 1 | Viewed by 1790
Abstract
The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and [...] Read more.
The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC50 in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design. Full article
(This article belongs to the Special Issue Channels and Transporters in Cells and Tissue 4.0)
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14 pages, 3177 KiB  
Article
Efficient Knocking Out of the Organophosphorus Insecticides Degradation Gene opdB in Cupriavidus nantongensis X1T via CRISPR/Cas9 with Red System
by Yufei Zhang, Yuehan Geng, Shengyang Li, Taozhong Shi, Xin Ma, Rimao Hua and Liancheng Fang
Int. J. Mol. Sci. 2023, 24(6), 6003; https://doi.org/10.3390/ijms24066003 - 22 Mar 2023
Cited by 3 | Viewed by 1816
Abstract
Cupriavidus nantongensis X1T is a type strain of the genus Cupriavidus, that can degrade eight kinds of organophosphorus insecticides (OPs). Conventional genetic manipulations in Cupriavidus species are time-consuming, difficult, and hard to control. The clustered regularly interspaced short palindromic repeat (CRISPR)/associated [...] Read more.
Cupriavidus nantongensis X1T is a type strain of the genus Cupriavidus, that can degrade eight kinds of organophosphorus insecticides (OPs). Conventional genetic manipulations in Cupriavidus species are time-consuming, difficult, and hard to control. The clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (Cas9) system has emerged as a powerful tool for genome editing applied in prokaryotes and eukaryotes due to its simplicity, efficiency, and accuracy. Here, we combined CRISPR/Cas9 with the Red system to perform seamless genetic manipulation in the X1T strain. Two plasmids, pACasN and pDCRH were constructed. The pACasN plasmid contained Cas9 nuclease and Red recombinase, and the pDCRH plasmid contained the dual single-guide RNA (sgRNA) of organophosphorus hydrolase (OpdB) in the X1T strain. For gene editing, two plasmids were transferred to the X1T strain and a mutant strain in which genetic recombination had taken place, resulting in the targeted deletion of opdB. The incidence of homologous recombination was over 30%. Biodegradation experiments suggested that the opdB gene was responsible for the catabolism of organophosphorus insecticides. This study was the first to use the CRISPR/Cas9 system for gene targeting in the genus Cupriavidus, and it furthered our understanding of the process of degradation of organophosphorus insecticides in the X1T strain. Full article
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16 pages, 3706 KiB  
Article
Mitochondrial Metabolism and EV Cargo of Endothelial Cells Is Affected in Presence of EVs Derived from MSCs on Which HIF Is Activated
by Federica Zanotti, Ilaria Zanolla, Martina Trentini, Elena Tiengo, Tommaso Pusceddu, Danilo Licastro, Margherita Degasperi, Sara Leo, Elena Tremoli, Letizia Ferroni and Barbara Zavan
Int. J. Mol. Sci. 2023, 24(6), 6002; https://doi.org/10.3390/ijms24066002 - 22 Mar 2023
Cited by 6 | Viewed by 1627
Abstract
Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have attracted growing interest as a possible novel therapeutic agent for the management of different cardiovascular diseases (CVDs). Hypoxia significantly enhances the secretion of angiogenic mediators from MSCs as well as sEVs. The [...] Read more.
Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have attracted growing interest as a possible novel therapeutic agent for the management of different cardiovascular diseases (CVDs). Hypoxia significantly enhances the secretion of angiogenic mediators from MSCs as well as sEVs. The iron-chelating deferoxamine mesylate (DFO) is a stabilizer of hypoxia-inducible factor 1 and consequently used as a substitute for environmental hypoxia. The improved regenerative potential of DFO-treated MSCs has been attributed to the increased release of angiogenic factors, but whether this effect is also mediated by the secreted sEVs has not yet been investigated. In this study, we treated adipose-derived stem cells (ASCs) with a nontoxic dose of DFO to harvest sEVs (DFO-sEVs). Human umbilical vein endothelial cells (HUVECs) treated with DFO-sEVs underwent mRNA sequencing and miRNA profiling of sEV cargo (HUVEC-sEVs). The transcriptomes revealed the upregulation of mitochondrial genes linked to oxidative phosphorylation. Functional enrichment analysis on miRNAs of HUVEC-sEVs showed a connection with the signaling pathways of cell proliferation and angiogenesis. In conclusion, mesenchymal cells treated with DFO release sEVs that induce in the recipient endothelial cells molecular pathways and biological processes strongly linked to proliferation and angiogenesis. Full article
(This article belongs to the Special Issue Molecular Research on Heart Protection)
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12 pages, 2271 KiB  
Article
Composition of Particulate Matter and Bacterial Community in Gut Contents and Surrounding Sediments of Three Sipunculan Species (Siphonosoma australe, Phascolosoma arcuatum, and Sipunculus nudus)
by Chunsheng Liu, Chuang Liu, Fei Gao, Aimin Wang, Haiqing Wang, Yumei Yang and Linwen He
Int. J. Mol. Sci. 2023, 24(6), 6001; https://doi.org/10.3390/ijms24066001 - 22 Mar 2023
Cited by 1 | Viewed by 1120
Abstract
Siphonosoma australe, Phascolosoma arcuatum, and Sipunculus nudus are three important sipunculan species in tropical intertidal zones. In this study, the particle size, organic matter content, and bacterial community composition in the gut contents of three different sipunculans and their surrounding sediments were [...] Read more.
Siphonosoma australe, Phascolosoma arcuatum, and Sipunculus nudus are three important sipunculan species in tropical intertidal zones. In this study, the particle size, organic matter content, and bacterial community composition in the gut contents of three different sipunculans and their surrounding sediments were analyzed. The grain size fractions of sipunculans’ guts were significantly different from those of their surrounding sediments; particle size fractions < 500 μm were favored by the sipunculans. As for the total organic matter (TOM), higher contents of organic matter were observed in the guts than in the surrounding sediments in all three sipunculan species. The bacterial community composition of all the samples was investigated by 16S rRNA gene sequencing, in which a total of 8974 OTUs were obtained from 24 samples based on a 97% threshold. The predominant phylum identified from the gut contents of three sipunculans was Planctomycetota, while the predominant phylum in their surrounding sediments was Proteobacteria. At the genus level, the most abundant genus was Sulfurovum (average 4.36%) in the surrounding sediments, while the most abundant genus was Gplla (average 12.76%) in the gut contents. The UPGMA tree showed that the samples from the guts of three different sipunculans and their surrounding sediments were clustered separately into two groups, which showed that these three sipunculans had a different bacterial community composition with their surrounding sediments. The grain size and total organic matter (TOM) had the greatest impacts on the bacterial community composition at both the phylum and genus levels. In conclusion, the differences in particle size fractions, organic matter content, and bacterial community composition between the gut contents and surrounding sediments in these three sipunculan species might be caused by their selective ingestion. Full article
(This article belongs to the Section Molecular Microbiology)
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22 pages, 4285 KiB  
Article
Influence of Scaffold Microarchitecture on Angiogenesis and Regulation of Cell Differentiation during the Early Phase of Bone Healing: A Transcriptomics and Histological Analysis
by Julien Guerrero, Ekaterina Maevskaia, Chafik Ghayor, Indranil Bhattacharya and Franz E. Weber
Int. J. Mol. Sci. 2023, 24(6), 6000; https://doi.org/10.3390/ijms24066000 - 22 Mar 2023
Cited by 3 | Viewed by 1434
Abstract
The early phase of bone healing is a complex and poorly understood process. With additive manufacturing, we can generate a specific and customizable library of bone substitutes to explore this phase. In this study, we produced tricalcium phosphate-based scaffolds with microarchitectures composed of [...] Read more.
The early phase of bone healing is a complex and poorly understood process. With additive manufacturing, we can generate a specific and customizable library of bone substitutes to explore this phase. In this study, we produced tricalcium phosphate-based scaffolds with microarchitectures composed of filaments of 0.50 mm in diameter, named Fil050G, and 1.25 mm named Fil125G, respectively. The implants were removed after only 10 days in vivo followed by RNA sequencing (RNAseq) and histological analysis. RNAseq results revealed upregulation of adaptive immune response, regulation of cell adhesion, and cell migration-related genes in both of our two constructs. However, significant overexpression of genes linked to angiogenesis, regulation of cell differentiation, ossification, and bone development was observed solely in Fil050G scaffolds. Moreover, quantitative immunohistochemistry of structures positive for laminin revealed a significantly higher number of blood vessels in Fil050G samples. Furthermore, µCT detected a higher amount of mineralized tissue in Fil050G samples suggesting a superior osteoconductive potential. Hence, different filament diameters and distances in bone substitutes significantly influence angiogenesis and regulation of cell differentiation involved in the early phase of bone regeneration, which precedes osteoconductivity and bony bridging seen in later phases and as consequence, impacts the overall clinical outcome. Full article
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15 pages, 3618 KiB  
Article
Mitochondrial Methionyl-tRNA Formyltransferase Deficiency Alleviates Metaflammation by Modulating Mitochondrial Activity in Mice
by Xiaoxiao Sun, Suyuan Liu, Jiangxue Cai, Miaoxin Yang, Chenxuan Li, Meiling Tan and Bin He
Int. J. Mol. Sci. 2023, 24(6), 5999; https://doi.org/10.3390/ijms24065999 - 22 Mar 2023
Viewed by 1423
Abstract
Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such [...] Read more.
Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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17 pages, 977 KiB  
Review
Blue Light—Ocular and Systemic Damaging Effects: A Narrative Review
by Răzvan-Geo Antemie, Ovidiu Ciprian Samoilă and Simona Valeria Clichici
Int. J. Mol. Sci. 2023, 24(6), 5998; https://doi.org/10.3390/ijms24065998 - 22 Mar 2023
Cited by 1 | Viewed by 3034
Abstract
Light is a fundamental aspect of our lives, being involved in the regulation of numerous processes in our body. While blue light has always existed in nature, with the ever-growing number of electronic devices that make use of short wavelength (blue) light, the [...] Read more.
Light is a fundamental aspect of our lives, being involved in the regulation of numerous processes in our body. While blue light has always existed in nature, with the ever-growing number of electronic devices that make use of short wavelength (blue) light, the human retina has seen increased exposure to it. Because it is at the high-energy end of the visible spectrum, many authors have investigated the theoretical harmful effects that it poses to the human retina and, more recently, the human body, given the discovery and characterization of the intrinsically photosensitive retinal ganglion cells. Many approaches have been explored, with the focus shifting throughout the years from examining classic ophthalmological parameters, such as visual acuity, and contrast sensitivity to more complex ones seen on electrophysiological assays and optical coherence tomographies. The current study aims to gather the most recent relevant data, reveal encountered pitfalls, and suggest future directions for studies regarding local and/or systemic effects of blue light retinal exposures. Full article
(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)
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13 pages, 1664 KiB  
Article
Kaempferol Suppresses the Activation of Mast Cells by Modulating the Expression of FcεRI and SHIP1
by Kazuki Nagata, Sanae Araumi, Daisuke Ando, Naoto Ito, Miki Ando, Yuki Ikeda, Miki Takahashi, Sakura Noguchi, Yayoi Yasuda, Nobuhiro Nakano, Tomoaki Ando, Mutsuko Hara, Takuya Yashiro, Masakazu Hachisu and Chiharu Nishiyama
Int. J. Mol. Sci. 2023, 24(6), 5997; https://doi.org/10.3390/ijms24065997 - 22 Mar 2023
Cited by 6 | Viewed by 1920
Abstract
In the present study, we evaluated the effects of kaempferol on bone marrow-derived mast cells (BMMCs). Kaempferol treatment significantly and dose-dependently inhibited IgE-induced degranulation, and cytokine production of BMMCs under the condition that cell viability was maintained. Kaempferol downregulated the surface expression levels [...] Read more.
In the present study, we evaluated the effects of kaempferol on bone marrow-derived mast cells (BMMCs). Kaempferol treatment significantly and dose-dependently inhibited IgE-induced degranulation, and cytokine production of BMMCs under the condition that cell viability was maintained. Kaempferol downregulated the surface expression levels of FcεRI on BMMCs, but the mRNA levels of FcεRIα, β, and γ-chains were not changed by kaempferol treatment. Furthermore, the kaempferol-mediated downregulation of surface FcεRI on BMMCs was still observed when protein synthesis or protein transporter was inhibited. We also found that kaempferol inhibited both LPS- and IL-33-induced IL-6 production from BMMCs, without affecting the expression levels of their receptors, TLR4 and ST2. Although kaempferol treatment increased the protein amount of NF-E2-related factor 2 (NRF2)—a master transcription factor of antioxidant stress—in BMMCs, the inhibition of NRF2 did not alter the suppressive effect of kaempferol on degranulation. Finally, we found that kaempferol treatment increased the levels of mRNA and protein of a phosphatase SHIP1 in BMMCs. The kaempferol-induced upregulation of SHIP1 was also observed in peritoneal MCs. The knockdown of SHIP1 by siRNA significantly enhanced IgE-induced degranulation of BMMCs. A Western blotting analysis showed that IgE-induced phosphorylation of PLCγ was suppressed in kaempferol-treated BMMCs. These results indicate that kaempferol inhibited the IgE-induced activation of BMMCs by downregulating FcεRI and upregulating SHIP1, and the SHIP1 increase is involved in the suppression of various signaling-mediated stimulations of BMMCs, such as those associated with TLR4 and ST2. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma 2.0)
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9 pages, 1733 KiB  
Article
Lymphocyte-to-C-Reactive Protein (LCR) Ratio Is Not Accurate to Predict Severity and Mortality in Patients with COVID-19 Admitted to the ED
by Laure Abensur Vuillaume, François Lefebvre, Axel Benhamed, Amandine Schnee, Mathieu Hoffmann, Fernanda Godoy Falcao, Nathan Haber, Jonathan Sabah, Charles-Eric Lavoignet and Pierrick Le Borgne
Int. J. Mol. Sci. 2023, 24(6), 5996; https://doi.org/10.3390/ijms24065996 - 22 Mar 2023
Cited by 2 | Viewed by 1475
Abstract
Health care systems worldwide have been battling the ongoing COVID-19 pandemic. Since the beginning of the COVID-19 pandemic, Lymphocytes and CRP have been reported as markers of interest. We chose to investigate the prognostic value of the LCR ratio as a marker of [...] Read more.
Health care systems worldwide have been battling the ongoing COVID-19 pandemic. Since the beginning of the COVID-19 pandemic, Lymphocytes and CRP have been reported as markers of interest. We chose to investigate the prognostic value of the LCR ratio as a marker of severity and mortality in COVID-19 infection. Between 1 March and 30 April 2020, we conducted a multicenter, retrospective cohort study of patients with moderate and severe coronavirus disease 19 (COVID-19), all of whom were hospitalized after being admitted to the Emergency Department (ED). We conducted our study in six major hospitals of northeast France, one of the outbreak’s epicenters in Europe. A total of 1035 patients with COVID-19 were included in our study. Around three-quarters of them (76.2%) presented a moderate form of the disease, while the remaining quarter (23.8%) presented a severe form requiring admission to the ICU. At ED admission, the median LCR was significantly lower in the group presenting severe disease compared to that with moderate disease (versus 6.24 (3.24–12) versus 12.63 ((6.05–31.67)), p < 0.001). However, LCR was neither associated with disease severity (OR: 0.99, CI 95% (0.99–1)), p = 0.476) nor mortality (OR: 0.99, CI 95% (0.99–1)). In the ED, LCR, although modest, with a threshold of 12.63, was a predictive marker for severe forms of COVID-19. Full article
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22 pages, 1724 KiB  
Review
Neutrophil Extracellular Traps and Cancer: Trapping Our Attention with Their Involvement in Ovarian Cancer
by María Castaño, Sarai Tomás-Pérez, Eva González-Cantó, Cristina Aghababyan, Andrea Mascarós-Martínez, Nuria Santonja, Alejandro Herreros-Pomares, Julia Oto, Pilar Medina, Martin Götte, Bárbara Andrea Mc Cormack, Josep Marí-Alexandre and Juan Gilabert-Estellés
Int. J. Mol. Sci. 2023, 24(6), 5995; https://doi.org/10.3390/ijms24065995 - 22 Mar 2023
Cited by 6 | Viewed by 3292
Abstract
Neutrophils, the most abundant circulating leukocytes, play a well-known role in defense against pathogens through phagocytosis and degranulation. However, a new mechanism involving the release of neutrophil extracellular traps (NETs) composed of DNA, histones, calprotectin, myeloperoxidase, and elastase, among others, has been described. [...] Read more.
Neutrophils, the most abundant circulating leukocytes, play a well-known role in defense against pathogens through phagocytosis and degranulation. However, a new mechanism involving the release of neutrophil extracellular traps (NETs) composed of DNA, histones, calprotectin, myeloperoxidase, and elastase, among others, has been described. The so-called NETosis process can occur through three different mechanisms: suicidal, vital, and mitochondrial NETosis. Apart from their role in immune defense, neutrophils and NETs have been involved in physiopathological conditions, highlighting immunothrombosis and cancer. Notably, neutrophils can either promote or inhibit tumor growth in the tumor microenvironment depending on cytokine signaling and epigenetic modifications. Several neutrophils’ pro-tumor strategies involving NETs have been documented, including pre-metastatic niche formation, increased survival, inhibition of the immune response, and resistance to oncologic therapies. In this review, we focus on ovarian cancer (OC), which remains the second most incidental but the most lethal gynecologic malignancy, partly due to the presence of metastasis, often omental, at diagnosis and the resistance to treatment. We deepen the state-of-the-art on the participation of NETs in OC metastasis establishment and progression and their involvement in resistance to chemo-, immuno-, and radiotherapies. Finally, we review the current literature on NETs in OC as diagnostic and/or prognostic markers, and their contribution to disease progression at early and advanced stages. The panoramic view provided in this article might pave the way for enhanced diagnostic and therapeutic strategies to improve the prognosis of cancer patients and, specifically, OC patients. Full article
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22 pages, 2656 KiB  
Review
Nanobodies: A Review of Generation, Diagnostics and Therapeutics
by Bo-kyung Jin, Steven Odongo, Magdalena Radwanska and Stefan Magez
Int. J. Mol. Sci. 2023, 24(6), 5994; https://doi.org/10.3390/ijms24065994 - 22 Mar 2023
Cited by 43 | Viewed by 11326
Abstract
Nanobodies, also referred to as single domain-based VHHs, are antibody fragments derived from heavy-chain only IgG antibodies found in the Camelidae family. Due to their small size, simple structure, high antigen binding affinity, and remarkable stability in extreme conditions, nanobodies possess the potential [...] Read more.
Nanobodies, also referred to as single domain-based VHHs, are antibody fragments derived from heavy-chain only IgG antibodies found in the Camelidae family. Due to their small size, simple structure, high antigen binding affinity, and remarkable stability in extreme conditions, nanobodies possess the potential to overcome several of the limitations of conventional monoclonal antibodies. For many years, nanobodies have been of great interest in a wide variety of research fields, particularly in the diagnosis and treatment of diseases. This culminated in the approval of the world’s first nanobody based drug (Caplacizumab) in 2018 with others following soon thereafter. This review will provide an overview, with examples, of (i) the structure and advantages of nanobodies compared to conventional monoclonal antibodies, (ii) methods used to generate and produce antigen-specific nanobodies, (iii) applications for diagnostics, and (iv) ongoing clinical trials for nanobody therapeutics as well as promising candidates for clinical development. Full article
(This article belongs to the Special Issue Advances in Single Domain-Based Antibodies)
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20 pages, 5718 KiB  
Article
GSK2801 Reverses Paclitaxel Resistance in Anaplastic Thyroid Cancer Cell Lines through MYCN Downregulation
by Elisabetta Molteni, Federica Baldan, Giuseppe Damante and Lorenzo Allegri
Int. J. Mol. Sci. 2023, 24(6), 5993; https://doi.org/10.3390/ijms24065993 - 22 Mar 2023
Cited by 1 | Viewed by 1703
Abstract
Anaplastic thyroid cancer (ATC) is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. Treatment with taxanes (such as paclitaxel) is an important approach in counteracting ATC or slowing its progression in [...] Read more.
Anaplastic thyroid cancer (ATC) is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. Treatment with taxanes (such as paclitaxel) is an important approach in counteracting ATC or slowing its progression in tumors without known genetic aberrations or those which are unresponsive to other treatments. Unfortunately, resistance often develops and, for this reason, new therapies that overcome taxane resistance are needed. In this study, effects of inhibition of several bromodomain proteins in paclitaxel-resistant ATC cell lines were investigated. GSK2801, a specific inhibitor of BAZ2A, BAZ2B and BRD9, was effective in resensitizing cells to paclitaxel. In fact, when used in combination with paclitaxel, it was able to reduce cell viability, block the ability to form colonies in an anchor-independent manner, and strongly decrease cell motility. After RNA-seq following treatment with GSK2801, we focused our attention on MYCN. Based on the hypothesis that MYCN was a major downstream player in the biological effects of GSK2801, we tested a specific inhibitor, VPC-70619, which showed effective biological effects when used in association with paclitaxel. This suggests that the functional deficiency of MYCN determines a partial resensitization of the cells examined and, ultimately, that a substantial part of the effect of GSK2801 results from inhibition of MYCN expression. Full article
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23 pages, 4270 KiB  
Article
TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1
by Shiraz Dib, Rodrigo Azevedo Loiola, Emmanuel Sevin, Julien Saint-Pol, Fumitaka Shimizu, Takashi Kanda, Jens Pahnke and Fabien Gosselet
Int. J. Mol. Sci. 2023, 24(6), 5992; https://doi.org/10.3390/ijms24065992 - 22 Mar 2023
Cited by 3 | Viewed by 2450
Abstract
Neuroinflammation and brain lipid imbalances are observed in Alzheimer’s disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes [...] Read more.
Neuroinflammation and brain lipid imbalances are observed in Alzheimer’s disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes (HBP) of the neurovascular unit. In cultivated HBP, TNFα activates the LXR pathway and increases the expression of one of its target genes, the transporter ATP-binding cassette family A member 1 (ABCA1), while ABCG1 is not expressed. Apolipoprotein E (APOE) synthesis and release are diminished. The cholesterol efflux is promoted, but is not inhibited, when ABCA1 or LXR are blocked. Moreover, as for TNFα, direct LXR activation by the agonist (T0901317) increases ABCA1 expression and the associated cholesterol efflux. However, this process is abolished when LXR/ABCA1 are both inhibited. Neither the other ABC transporters nor the SR-BI are involved in this TNFα-mediated lipid efflux regulation. We also report that inflammation increases ABCB1 expression and function. In conclusion, our data suggest that inflammation increases HBP protection against xenobiotics and triggers an LXR/ABCA1 independent cholesterol release. Understanding the molecular mechanisms regulating this efflux at the level of the neurovascular unit remains fundamental to the characterization of links between neuroinflammation, cholesterol and HBP function in neurodegenerative disorders. Full article
(This article belongs to the Collection Feature Paper Collection in Biochemistry)
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12 pages, 2016 KiB  
Article
The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation
by Andrius Sakalauskas, Mantas Ziaunys, Ruta Snieckute, Agne Janoniene, Dominykas Veiveris, Mantas Zvirblis, Virginija Dudutiene and Vytautas Smirnovas
Int. J. Mol. Sci. 2023, 24(6), 5991; https://doi.org/10.3390/ijms24065991 - 22 Mar 2023
Viewed by 1634
Abstract
The main pathological hallmark of Alzheimer’s disease (AD) is the aggregation of amyloid-β into amyloid fibrils, leading to a neurodegeneration cascade. The current medications are far from sufficient to prevent the onset of the disease, hence requiring more research to find new alternative [...] Read more.
The main pathological hallmark of Alzheimer’s disease (AD) is the aggregation of amyloid-β into amyloid fibrils, leading to a neurodegeneration cascade. The current medications are far from sufficient to prevent the onset of the disease, hence requiring more research to find new alternative drugs for curing AD. In vitro inhibition experiments are one of the primary tools in testing whether a molecule may be potent to impede the aggregation of amyloid-beta peptide (Aβ42). However, kinetic experiments in vitro do not match the mechanism found when aggregating Aβ42 in cerebrospinal fluid. The different aggregation mechanisms and the composition of the reaction mixtures may also impact the characteristics of the inhibitor molecules. For this reason, altering the reaction mixture to resemble components found in cerebrospinal fluid (CSF) is critical to partially compensate for the mismatch between the inhibition experiments in vivo and in vitro. In this study, we used an artificial cerebrospinal fluid that contained the major components found in CSF and performed Aβ42 aggregation inhibition studies using oxidized epigallocatechin-3-gallate (EGCG) and fluorinated benzenesulfonamide VR16-09. This led to a discovery of a complete turnaround of their inhibitory characteristics, rendering EGCG ineffective while significantly improving the efficacy of VR16-09. HSA was the main contributor in the mixture that significantly increased the anti-amyloid characteristics of VR16-09. Full article
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29 pages, 2793 KiB  
Review
Ethylene and Jasmonates Signaling Network Mediating Secondary Metabolites under Abiotic Stress
by Marina Pérez-Llorca, Stephan Pollmann and Maren Müller
Int. J. Mol. Sci. 2023, 24(6), 5990; https://doi.org/10.3390/ijms24065990 - 22 Mar 2023
Cited by 15 | Viewed by 3385
Abstract
Plants are sessile organisms that face environmental threats throughout their life cycle, but increasing global warming poses an even more existential threat. Despite these unfavorable circumstances, plants try to adapt by developing a variety of strategies coordinated by plant hormones, resulting in a [...] Read more.
Plants are sessile organisms that face environmental threats throughout their life cycle, but increasing global warming poses an even more existential threat. Despite these unfavorable circumstances, plants try to adapt by developing a variety of strategies coordinated by plant hormones, resulting in a stress-specific phenotype. In this context, ethylene and jasmonates (JAs) present a fascinating case of synergism and antagonism. Here, Ethylene Insensitive 3/Ethylene Insensitive-Like Protein1 (EIN3/EIL1) and Jasmonate-Zim Domain (JAZs)-MYC2 of the ethylene and JAs signaling pathways, respectively, appear to act as nodes connecting multiple networks to regulate stress responses, including secondary metabolites. Secondary metabolites are multifunctional organic compounds that play crucial roles in stress acclimation of plants. Plants that exhibit high plasticity in their secondary metabolism, which allows them to generate near-infinite chemical diversity through structural and chemical modifications, are likely to have a selective and adaptive advantage, especially in the face of climate change challenges. In contrast, domestication of crop plants has resulted in change or even loss in diversity of phytochemicals, making them significantly more vulnerable to environmental stresses over time. For this reason, there is a need to advance our understanding of the underlying mechanisms by which plant hormones and secondary metabolites respond to abiotic stress. This knowledge may help to improve the adaptability and resilience of plants to changing climatic conditions without compromising yield and productivity. Our aim in this review was to provide a detailed overview of abiotic stress responses mediated by ethylene and JAs and their impact on secondary metabolites. Full article
(This article belongs to the Special Issue Phytohormones and the Regulation of Stress Tolerance in Plants)
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16 pages, 11720 KiB  
Article
Heterologous VvDREB2c Expression Improves Heat Tolerance in Arabidopsis by Inducing Photoprotective Responses
by Qian Zha, Xiangjing Yin, Xiaojun Xi and Aili Jiang
Int. J. Mol. Sci. 2023, 24(6), 5989; https://doi.org/10.3390/ijms24065989 - 22 Mar 2023
Cited by 1 | Viewed by 1436
Abstract
Extreme temperatures limit grape production and sustainability. Dehydration-responsive element-binding (DREB) transcription factors affect plant responses to temperature related stresses. Therefore, we investigated the role of VvDREB2c, a DREB-coding gene, found in grapes (Vitis vinifera L.). Protein characterization revealed that VvDREB2c is localized [...] Read more.
Extreme temperatures limit grape production and sustainability. Dehydration-responsive element-binding (DREB) transcription factors affect plant responses to temperature related stresses. Therefore, we investigated the role of VvDREB2c, a DREB-coding gene, found in grapes (Vitis vinifera L.). Protein characterization revealed that VvDREB2c is localized to the nucleus and that its AP2/ERF domain contains three β-sheets and one α-helix sheet. Analysis of the VvDREB2c promoter region revealed the presence of light-, hormone-, and stress-related cis-acting elements. Furthermore, we observed that the heterologous expression of VvDREB2c in Arabidopsis improved growth, drought tolerance, and heat tolerance. Furthermore, it improved the leaf quantum yield of regulated energy dissipation [Y(NPQ)], elevated the activities of RuBisCO, and phosphoenolpyruvate carboxylase and reduced the quantum yield of non-regulated energy dissipation [Y(NO)] in plants exposed to high temperatures. VvDREB2c-overexpressing lines also specifically upregulated several photosynthesis-related genes (CSD2, HSP21, and MYB102). In addition, VvDREB2c-overexpressing lines reduced light damage and enhanced photoprotective ability by dissipating excess light energy and converting it into heat, which eventually improves tolerance to high temperature. The contents of abscisic acid, jasmonic acid, and salicylic acid and differentially expressed genes (DEGs) in the mitogen-activated protein kinase (MAPK) signaling pathway were affected by heat stress in VvDREB2c-overexpressing lines, which indicated that VvDREB2c positively regulates heat tolerance via a hormonal pathway in Arabidopsis. VvDREB2c promotes heat tolerance in Arabidopsis by exerting effects on photosynthesis, hormones, and growth conditions. This study may provide useful insights into the enrichment of the heat-tolerance pathways in plants. Full article
(This article belongs to the Special Issue Recent Advances in Plant Molecular Science in China 2023)
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16 pages, 7743 KiB  
Article
Variation in Lipid Species Profiles among Leukemic Cells Significantly Impacts Their Sensitivity to the Drug Targeting of Lipid Metabolism and the Prognosis of AML Patients
by Caroline Lo Presti, Yoshiki Yamaryo-Botté, Julie Mondet, Sylvie Berthier, Denisa Nutiu, Cyrille Botté and Pascal Mossuz
Int. J. Mol. Sci. 2023, 24(6), 5988; https://doi.org/10.3390/ijms24065988 - 22 Mar 2023
Cited by 5 | Viewed by 1549
Abstract
Several studies have linked bad prognoses of acute myeloid leukemia (AML) to the ability of leukemic cells to reprogram their metabolism and, in particular, their lipid metabolism. In this context, we performed “in-depth” characterization of fatty acids (FAs) and lipid species in leukemic [...] Read more.
Several studies have linked bad prognoses of acute myeloid leukemia (AML) to the ability of leukemic cells to reprogram their metabolism and, in particular, their lipid metabolism. In this context, we performed “in-depth” characterization of fatty acids (FAs) and lipid species in leukemic cell lines and in plasma from AML patients. We firstly showed that leukemic cell lines harbored significant differences in their lipid profiles at steady state, and that under nutrient stress, they developed common mechanisms of protection that led to variation in the same lipid species; this highlights that the remodeling of lipid species is a major and shared mechanism of adaptation to stress in leukemic cells. We also showed that sensitivity to etomoxir, which blocks fatty acid oxidation (FAO), was dependent on the initial lipid profile of cell lines, suggesting that only a particular “lipidic phenotype” is sensitive to the drug targeting of FAO. We then showed that the lipid profiles of plasma samples from AML patients were significantly correlated with the prognosis of patients. In particular, we highlighted the impact of phosphocholine and phosphatidyl-choline metabolism on patients’ survival. In conclusion, our data show that balance between lipid species is a phenotypic marker of the diversity of leukemic cells that significantly influences their proliferation and resistance to stress, and thereby, the prognosis of AML patients. Full article
(This article belongs to the Special Issue Translational Research on Leukemia)
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21 pages, 3638 KiB  
Article
Structure and Dynamics of Three Escherichia coli NfsB Nitro-Reductase Mutants Selected for Enhanced Activity with the Cancer Prodrug CB1954
by Martin A. Day, Andrew J. Christofferson, J. L. Ross Anderson, Simon O. Vass, Adam Evans, Peter F. Searle, Scott A. White and Eva I. Hyde
Int. J. Mol. Sci. 2023, 24(6), 5987; https://doi.org/10.3390/ijms24065987 - 22 Mar 2023
Viewed by 1432
Abstract
Escherichia coli NfsB has been studied extensively for its potential for cancer gene therapy by reducing the prodrug CB1954 to a cytotoxic derivative. We have previously made several mutants with enhanced activity for the prodrug and characterised their activity in vitro and in [...] Read more.
Escherichia coli NfsB has been studied extensively for its potential for cancer gene therapy by reducing the prodrug CB1954 to a cytotoxic derivative. We have previously made several mutants with enhanced activity for the prodrug and characterised their activity in vitro and in vivo. Here, we determine the X-ray structure of our most active triple and double mutants to date, T41Q/N71S/F124T and T41L/N71S. The two mutant proteins have lower redox potentials than wild-type NfsB, and the mutations have lowered activity with NADH so that, in contrast to the wild-type enzyme, the reduction of the enzyme by NADH, rather than the reaction with CB1954, has a slower maximum rate. The structure of the triple mutant shows the interaction between Q41 and T124, explaining the synergy between these two mutations. Based on these structures, we selected mutants with even higher activity. The most active one contains T41Q/N71S/F124T/M127V, in which the additional M127V mutation enlarges a small channel to the active site. Molecular dynamics simulations show that the mutations or reduction of the FMN cofactors of the protein has little effect on its dynamics and that the largest backbone fluctuations occur at residues that flank the active site, contributing towards its broad substrate range. Full article
(This article belongs to the Special Issue Nitroreductases and Nitro-Reduction)
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17 pages, 4029 KiB  
Article
Neuronal Prosurvival Role of Ceramide Synthase 2 by Olidogendrocyte-to-Neuron Extracellular Vesicle Transfer
by Álvaro Casadomé-Perales, Sara Naya, Elisa Fernández-Martínez, Bea G. Mille, Marta Guerrero-Valero, Héctor Peinado, Francesc X. Guix, Carlos G. Dotti and Ernest Palomer
Int. J. Mol. Sci. 2023, 24(6), 5986; https://doi.org/10.3390/ijms24065986 - 22 Mar 2023
Cited by 1 | Viewed by 1799
Abstract
Ageing is associated with notorious alterations in neurons, i.e., in gene expression, mitochondrial function, membrane degradation or intercellular communication. However, neurons live for the entire lifespan of the individual. One of the reasons why neurons remain functional in elderly people is survival mechanisms [...] Read more.
Ageing is associated with notorious alterations in neurons, i.e., in gene expression, mitochondrial function, membrane degradation or intercellular communication. However, neurons live for the entire lifespan of the individual. One of the reasons why neurons remain functional in elderly people is survival mechanisms prevail over death mechanisms. While many signals are either pro-survival or pro-death, others can play both roles. Extracellular vesicles (EVs) can signal both pro-toxicity and survival. We used young and old animals, primary neuronal and oligodendrocyte cultures and neuroblastoma and oligodendrocytic lines. We analysed our samples using a combination of proteomics and artificial neural networks, biochemistry and immunofluorescence approaches. We found an age-dependent increase in ceramide synthase 2 (CerS2) in cortical EVs, expressed by oligodendrocytes. In addition, we show that CerS2 is present in neurons via the uptake of oligodendrocyte-derived EVs. Finally, we show that age-associated inflammation and metabolic stress favour CerS2 expression and that oligodendrocyte-derived EVs loaded with CerS2 lead to the expression of the antiapoptotic factor Bcl2 in inflammatory conditions. Our study shows that intercellular communication is altered in the ageing brain, which favours neuronal survival through the transfer of oligodendrocyte-derived EVs containing CerS2. Full article
(This article belongs to the Special Issue The Role of Glial Cells in Health and Disease)
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16 pages, 5605 KiB  
Article
Macrophage Migration Inhibitory Factor in Psoroptes ovis: Molecular Characterization and Potential Role in Eosinophil Accumulation of Skin in Rabbit and Its Implication in the Host–Parasite Interaction
by Xiaobin Gu, You Ge, Ya Wang, Cuirui Huang, Guangyou Yang, Yue Xie, Jing Xu, Ran He, Zhijun Zhong, Deying Yang, Zhi He and Xuerong Peng
Int. J. Mol. Sci. 2023, 24(6), 5985; https://doi.org/10.3390/ijms24065985 - 22 Mar 2023
Viewed by 1536
Abstract
Psoroptes ovis, a common surface-living mite of domestic and wild animals worldwide, results in huge economic losses and serious welfare issues in the animal industry. P. ovis infestation rapidly causes massive eosinophil infiltration in skin lesions, and increasing research revealed that eosinophils might play [...] Read more.
Psoroptes ovis, a common surface-living mite of domestic and wild animals worldwide, results in huge economic losses and serious welfare issues in the animal industry. P. ovis infestation rapidly causes massive eosinophil infiltration in skin lesions, and increasing research revealed that eosinophils might play an important role in the pathogenesis of P. ovis infestation. Intradermal injection of P. ovis antigen invoked massive eosinophil infiltration, suggesting that this mite should contain some relative molecules involved in eosinophil accumulation in the skin. However, these active molecules have not yet been identified. Herein, we identified macrophage migration inhibitor factor (MIF) in P. ovis (PsoMIF) using bioinformatics and molecular biology methods. Sequence analyses revealed that PsoMIF appeared with high similarity to the topology of monomer and trimer formation with host MIF (RMSD = 0.28 angstroms and 2.826 angstroms, respectively) but with differences in tautomerase and thiol-protein oxidoreductase active sites. Reverse transcription PCR analysis (qRT-PCR) results showed that PsoMIF was expressed throughout all the developmental stages of P. ovis, particularly with the highest expression in female mites. Immunolocalization revealed that MIF protein located in the ovary and oviduct of female mites and also localized throughout the stratum spinosum, stratum granulosum, and even basal layers of the epidermis in skin lesions caused by P. ovis. rPsoMIF significantly upregulated eosinophil-related gene expression both in vitro (PBMC: CCL5, CCL11; HaCaT: IL-3, IL-4, IL-5, CCL5, CCL11) and in vivo (rabbit: IL-5, CCL5, CCL11, P-selectin, ICAM-1). Moreover, rPsoMIF could induce cutaneous eosinophil accumulation in a rabbit model and increased the vascular permeability in a mouse model. Our findings indicated that PsoMIF served as one of the key molecules contributing to skin eosinophil accumulation in P. ovis infection of rabbits. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)
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19 pages, 3624 KiB  
Article
Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation
by Nadia Papini, Roberta Todisco, Paola Giussani, Michele Dei Cas, Rita Paroni, Chiara Giallanza and Cristina Tringali
Int. J. Mol. Sci. 2023, 24(6), 5984; https://doi.org/10.3390/ijms24065984 - 22 Mar 2023
Cited by 6 | Viewed by 1474
Abstract
Autophagic impairment was identified in many lysosomal storage diseases and adult neurodegenerative diseases. It seems that this defect could be directly related to the appearance of a neurodegenerative phenotype and could contribute to worsen metabolite accumulation and lysosomal distress. Thus, autophagy is becoming [...] Read more.
Autophagic impairment was identified in many lysosomal storage diseases and adult neurodegenerative diseases. It seems that this defect could be directly related to the appearance of a neurodegenerative phenotype and could contribute to worsen metabolite accumulation and lysosomal distress. Thus, autophagy is becoming a promising target for supportive therapies. Autophagy alterations were recently identified also in Krabbe disease. Krabbe disease is characterized by extensive demyelination and dysmyelination and it is due to the genetic loss of function of the lysosomal enzyme galactocerebrosidase (GALC). This enzyme leads to the accumulation of galactosylceramide, psychosine, and secondary substrates such as lactosylceramide. In this paper, we induced autophagy through starvation and examined the cellular response occurring in fibroblasts isolated from patients. We demonstrated that the inhibitory AKT-mediated phosphorylation of beclin-1 and the BCL2-beclin-1 complex concur to reduce autophagosomes formation in response to starvation. These events were not dependent on the accumulation of psychosine, which was previously identified as a possible player in autophagic impairment in Krabbe disease. We believe that these data could better elucidate the capability of response to autophagic stimuli in Krabbe disease, in order to identify possible molecules able to stimulate the process. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)
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15 pages, 1390 KiB  
Review
A Role of Sodium-Glucose Co-Transporter 2 in Cardiorenal Anemia Iron Deficiency Syndrome
by Motoaki Sano
Int. J. Mol. Sci. 2023, 24(6), 5983; https://doi.org/10.3390/ijms24065983 - 22 Mar 2023
Cited by 2 | Viewed by 4708
Abstract
Heart failure, renal dysfunction, anemia, and iron deficiency affect each other and form a vicious cycle, a condition referred to as cardiorenal anemia iron deficiency syndrome. The presence of diabetes further accelerates this vicious cycle. Surprisingly, simply inhibiting sodium-glucose co-transporter 2 (SGLT2), which [...] Read more.
Heart failure, renal dysfunction, anemia, and iron deficiency affect each other and form a vicious cycle, a condition referred to as cardiorenal anemia iron deficiency syndrome. The presence of diabetes further accelerates this vicious cycle. Surprisingly, simply inhibiting sodium-glucose co-transporter 2 (SGLT2), which is expressed almost exclusively in the proximal tubular epithelial cells of the kidney, not only increases glucose excretion into the urine and effectively controls blood glucose levels in diabetes but can also correct the vicious cycle of cardiorenal anemia iron deficiency syndrome. This review describes how SGLT2 is involved in energy metabolism regulation, hemodynamics (i.e., circulating blood volume and sympathetic nervous system activity), erythropoiesis, iron bioavailability, and inflammatory set points in diabetes, heart failure, and renal dysfunction. Full article
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