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Int. J. Mol. Sci., Volume 25, Issue 8 (April-2 2024) – 443 articles

Cover Story (view full-size image): Iron is an essential element in human brain physiology but is detrimental upon abnormal accumulation, which is observed in the brains of patients with neurodegenerative proteinopathies, including Alzheimer’s disease, progressive supranuclear palsy, Parkinson’s disease, and multiple system atrophy. The comprehensive involvement of iron in multiple disease pathomechanisms challenges the current understanding of its functions in disease pathogenesis. Relevant disease-specific observations are deconstructed and summarized under four distinct hypotheses: 1) iron deposition is a consequence of protein pathology, 2) iron promotes protein pathology, 3) iron protects from or hinders protein pathology, and 4) the deposition of iron and protein pathology contribute parallelly to the pathogenesis. View this paper
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13 pages, 2335 KiB  
Review
The Role of the Placental Enzyme Indoleamine 2,3-Dioxygenase in Normal and Abnormal Human Pregnancy
by Yoshiki Kudo and Jun Sugimoto
Int. J. Mol. Sci. 2024, 25(8), 4577; https://doi.org/10.3390/ijms25084577 - 22 Apr 2024
Viewed by 790
Abstract
The biologically significant phenomenon that the fetus can survive immune attacks from the mother has been demonstrated in mammals. The survival mechanism depends on the fetus and placenta actively defending themselves against attacks by maternal T cells, achieved through the localized depletion of [...] Read more.
The biologically significant phenomenon that the fetus can survive immune attacks from the mother has been demonstrated in mammals. The survival mechanism depends on the fetus and placenta actively defending themselves against attacks by maternal T cells, achieved through the localized depletion of the amino acid L-tryptophan by an enzyme called indoleamine 2,3-dioxygenase. These findings were entirely unexpected and pose important questions regarding diseases related to human pregnancy and their prevention during human pregnancy. Specifically, the role of this mechanism, as discovered in mice, in humans remains unknown, as does the extent to which impaired activation of this process contributes to major clinical diseases in humans. We have, thus, elucidated several key aspects of this enzyme expressed in the human placenta both in normal and abnormal human pregnancy. The questions addressed in this brief review are as follows: (1) localization and characteristics of human placental indoleamine 2,3-dioxygenas; (2) overall tryptophan catabolism in human pregnancy and a comparison of indoleamine 2,3-dioxygenase expression levels between normal and pre-eclamptic pregnancy; (3) controlling trophoblast invasion by indoleamine 2,3-dioxygenase and its relation to the pathogenesis of placenta accrete spectrum. Full article
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18 pages, 674 KiB  
Review
Coenzyme Q10 and Autoimmune Disorders: An Overview
by David Mantle and Iain P. Hargreaves
Int. J. Mol. Sci. 2024, 25(8), 4576; https://doi.org/10.3390/ijms25084576 - 22 Apr 2024
Viewed by 1371
Abstract
Some 90 autoimmune disorders have been described in medical literature, affecting most of the tissues within the body. Autoimmune disorders may be difficult to treat, and there is a need to develop novel therapeutic strategies for these disorders. Autoimmune disorders are characterised by [...] Read more.
Some 90 autoimmune disorders have been described in medical literature, affecting most of the tissues within the body. Autoimmune disorders may be difficult to treat, and there is a need to develop novel therapeutic strategies for these disorders. Autoimmune disorders are characterised by mitochondrial dysfunction, oxidative stress, and inflammation; there is therefore a rationale for a role for coenzyme Q10 in the management of these disorders, on the basis of its key role in normal mitochondrial function, as an antioxidant, and as an anti-inflammatory agent. In this article, we have therefore reviewed the potential role of CoQ10, in terms of both deficiency and/or supplementation, in a range of autoimmune disorders. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Autoimmune Diseases)
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13 pages, 3820 KiB  
Article
K+-Driven Cl/HCO3 Exchange Mediated by Slc4a8 and Slc4a10
by Gaspar Peña-Münzenmayer, Alvin T. George, Nuria Llontop, Yuliet Mazola, Natalia Apablaza, Carlos Spichiger, Sebastián Brauchi, José Sarmiento, Leandro Zúñiga, Wendy González and Marcelo A. Catalán
Int. J. Mol. Sci. 2024, 25(8), 4575; https://doi.org/10.3390/ijms25084575 - 22 Apr 2024
Viewed by 515
Abstract
Slc4a genes encode various types of transporters, including Na+-HCO3 cotransporters, Cl/HCO3 exchangers, or Na+-driven Cl/HCO3 exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl/HCO [...] Read more.
Slc4a genes encode various types of transporters, including Na+-HCO3 cotransporters, Cl/HCO3 exchangers, or Na+-driven Cl/HCO3 exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl/HCO3 exchanger, which can be driven by either Na+ or K+, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na+ or K+ drive Cl/HCO3 exchanger activity in cells overexpressing Slc4a8 or Slc4a10. Further characterization of cation-driven Cl/HCO3 exchange demonstrated that Slc4a8 and Slc4a10 also mediate Cl and HCO3-dependent K+ transport. Full-atom molecular dynamics simulation on the recently solved structure of Slc4a8 supports the coordination of K+ at the Na+ binding site in S1. Sequence analysis shows that the critical residues coordinating monovalent cations are conserved among mouse Slc4a8 and Slc4a10 proteins. Together, our results suggest that Slc4a8 and Slc4a10 might transport K+ in the same direction as HCO3 ions in a similar fashion to that described for Na+ transport in the rat Slc4a8 structure. Full article
(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)
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14 pages, 3160 KiB  
Article
Free Radical–Associated Gene Signature Predicts Survival in Sepsis Patients
by Anlin Feng, Marissa D. Pokharel, Ying Liang, Wenli Ma, Saurabh Aggarwal, Stephen M. Black and Ting Wang
Int. J. Mol. Sci. 2024, 25(8), 4574; https://doi.org/10.3390/ijms25084574 - 22 Apr 2024
Viewed by 501
Abstract
Sepsis continues to overwhelm hospital systems with its high mortality rate and prevalence. A strategy to reduce the strain of sepsis on hospital systems is to develop a diagnostic/prognostic measure that identifies patients who are more susceptible to septic death. Current biomarkers fail [...] Read more.
Sepsis continues to overwhelm hospital systems with its high mortality rate and prevalence. A strategy to reduce the strain of sepsis on hospital systems is to develop a diagnostic/prognostic measure that identifies patients who are more susceptible to septic death. Current biomarkers fail to achieve this outcome, as they only have moderate diagnostic power and limited prognostic capabilities. Sepsis disrupts a multitude of pathways in many different organ systems, making the identification of a single powerful biomarker difficult to achieve. However, a common feature of many of these perturbed pathways is the increased generation of reactive oxygen species (ROS), which can alter gene expression, changes in which may precede the clinical manifestation of severe sepsis. Therefore, the aim of this study was to evaluate whether ROS-related circulating molecular signature can be used as a tool to predict sepsis survival. Here we created a ROS-related gene signature and used two Gene Expression Omnibus datasets from whole blood samples of septic patients to generate a 37-gene molecular signature that can predict survival of sepsis patients. Our results indicate that peripheral blood gene expression data can be used to predict the survival of sepsis patients by assessing the gene expression pattern of free radical–associated -related genes in patients, warranting further exploration. Full article
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14 pages, 3481 KiB  
Article
Comparative Analysis of Gut Bacterial Community Composition in Two Tropical Economic Sea Cucumbers under Different Seasons of Artificial Environment
by Chenghao Jia, Yuanhang Wang, Bojun Zheng, Yanan Wang, Linwen He, Qiang Xu and Fei Gao
Int. J. Mol. Sci. 2024, 25(8), 4573; https://doi.org/10.3390/ijms25084573 - 22 Apr 2024
Viewed by 513
Abstract
With the continuous rise of the sea cucumber aquaculture industry in China, the tropical sea cucumber aquaculture industry is also improving. However, research on the gut microorganisms of tropical sea cucumbers in captivity is scarce. In this study, high-throughput sequencing methods were used [...] Read more.
With the continuous rise of the sea cucumber aquaculture industry in China, the tropical sea cucumber aquaculture industry is also improving. However, research on the gut microorganisms of tropical sea cucumbers in captivity is scarce. In this study, high-throughput sequencing methods were used to analyze the gut microbial composition of Stichopus monotuberculatus and Holothuria scabra in the dry season and wet season of artificial environments. The results showed that 66 phyla were obtained in all samples, of which 59 phyla were obtained in the dry season, and 45 phyla were obtained in the wet season. The Tax4Fun analysis showed that certain gut bacterial communities affect the daily metabolism of two sea cucumber species and are involved in maintaining gut microecological balance in the gut of two sea cucumber species. In addition, compared with differences between species, PCoA and UPGMA clustering analysis showed the gut prokaryotes of the same sea cucumber species varied more in different seasons, indicating that the influence of environment was higher than the feeding choices of sea cucumbers under relatively closed conditions. These results revealed the gut bacterial community composition of S. monotuberculatus and H. scabra and the differences in gut bacterial structure between two sea cucumber species in different seasons were compared, which would provide the foundation for tropical sea cucumber aquaculture in the future. Full article
(This article belongs to the Section Molecular Microbiology)
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22 pages, 3829 KiB  
Article
Role of Protein Tyrosine Phosphatase Receptor Type E (PTPRE) in Chemoresistant Retinoblastoma
by Lars Mohren, Annika Doege, Natalia Miroschnikov, Oliver Dräger, Maike Anna Busch and Nicole Dünker
Int. J. Mol. Sci. 2024, 25(8), 4572; https://doi.org/10.3390/ijms25084572 - 22 Apr 2024
Viewed by 593
Abstract
Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different [...] Read more.
Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide-resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage-independent growth of etoposide-resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide-resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide-resistant RB cells. These impacts mirror PTPRE KD effects, indicating a regulation of PTPRE via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and—dependent on the cell line—AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma. Full article
(This article belongs to the Section Molecular Oncology)
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13 pages, 1399 KiB  
Article
APOE ε2-Carriers Are Associated with an Increased Risk of Primary Angle-Closure Glaucoma in Patients of Saudi Origin
by Altaf A. Kondkar, Taif A. Azad, Tahira Sultan, Tanvir Khatlani, Abdulaziz A. Alshehri, Rakesh Radhakrishnan, Glenn P. Lobo, Ehab Alsirhy, Faisal A. Almobarak, Essam A. Osman and Saleh A. Al-Obeidan
Int. J. Mol. Sci. 2024, 25(8), 4571; https://doi.org/10.3390/ijms25084571 - 22 Apr 2024
Viewed by 496
Abstract
This study investigated the association between apolipoprotein E (APOE) gene polymorphisms (rs429358 and rs7412) and primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG) in a Saudi cohort. Genotyping of 437 DNA samples (251 controls, 92 PACG, 94 PXG) was conducted using [...] Read more.
This study investigated the association between apolipoprotein E (APOE) gene polymorphisms (rs429358 and rs7412) and primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG) in a Saudi cohort. Genotyping of 437 DNA samples (251 controls, 92 PACG, 94 PXG) was conducted using PCR-based Sanger sequencing. The results showed no significant differences in the allele and genotype frequencies of rs429358 and rs7412 between the PACG/PXG cases and controls. Haplotype analysis revealed ε3 as predominant, followed by ε4 and ε2 alleles, with no significant variance in PACG/PXG. However, APOE genotype analysis indicated a significant association between ε2-carriers and PACG (odds ratio = 4.82, 95% CI 1.52–15.26, p = 0.007), whereas no notable association was observed with PXG. Logistic regression confirmed ε2-carriers as a significant predictor for PACG (p = 0.008), while age emerged as significant for PXG (p < 0.001). These findings suggest a potential role of ε2-carriers in PACG risk within the Saudi cohort. Further validation and larger-scale investigations are essential to elucidate the precise role of APOE in PACG pathogenesis and progression. Full article
(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)
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17 pages, 3694 KiB  
Article
EspP2 Regulates the Adhesion of Glaesserella parasuis via Rap1 Signaling Pathway
by Xinwei Tang, Shiyu Xu, Zhen Yang, Kang Wang, Ke Dai, Yiwen Zhang, Bangdi Hu, Yu Wang, Sanjie Cao, Xiaobo Huang, Qigui Yan, Rui Wu, Qin Zhao, Senyan Du, Xintian Wen and Yiping Wen
Int. J. Mol. Sci. 2024, 25(8), 4570; https://doi.org/10.3390/ijms25084570 - 22 Apr 2024
Viewed by 547
Abstract
Different levels of EspP2 expression are seen in strains of Glaesserella parasuis with high and low pathogenicity. As a potential virulence factor for G. parasuis, the pathogenic mechanism of EspP2 in infection of host cells is not clear. To begin to elucidate [...] Read more.
Different levels of EspP2 expression are seen in strains of Glaesserella parasuis with high and low pathogenicity. As a potential virulence factor for G. parasuis, the pathogenic mechanism of EspP2 in infection of host cells is not clear. To begin to elucidate the effect of EspP2 on virulence, we used G. parasuis SC1401 in its wild-type form and SC1401, which was made EspP2-deficient. We demonstrated that EspP2 causes up-regulation of claudin-1 and occludin expression, thereby promoting the adhesion of G. parasuis to host cells; EspP2-deficiency resulted in significantly reduced adhesion of G. parasuis to cells. Transcriptome sequencing analysis of EspP2-treated PK15 cells revealed that the Rap1 signaling pathway is stimulated by EspP2. Blocking this pathway diminished occludin expression and adhesion. These results indicated that EspP2 regulates the adhesion of Glaesserella parasuis via Rap1 signaling pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Infection for Pathogenic Bacteria 2.0)
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17 pages, 7098 KiB  
Article
Transcription Factor McHB7 Improves Ice Plant Drought Tolerance through ABA Signaling Pathway
by Xuemei Zhang, Zihan Cheng, Gaofeng Fan, Dan Zhu, Bowen Tan, Tingbo Jiang and Sixue Chen
Int. J. Mol. Sci. 2024, 25(8), 4569; https://doi.org/10.3390/ijms25084569 - 22 Apr 2024
Viewed by 603
Abstract
As global climate change continues, drought episodes have become increasingly frequent. Studying plant stress tolerance is urgently needed to ensure food security. The common ice plant is one of the model halophyte plants for plant stress biology research. This study aimed to investigate [...] Read more.
As global climate change continues, drought episodes have become increasingly frequent. Studying plant stress tolerance is urgently needed to ensure food security. The common ice plant is one of the model halophyte plants for plant stress biology research. This study aimed to investigate the functions of a newly discovered transcription factor, Homeobox 7 (HB7), from the ice plant in response to drought stress. An efficient Agrobacterium-mediated transformation method was established in the ice plant, where ectopic McHB7 expression may be sustained for four weeks. The McHB7 overexpression (OE) plants displayed drought tolerance, and the activities of redox enzymes and chlorophyll content in the OE plants were higher than the wild type. Quantitative proteomics revealed 1910 and 495 proteins significantly changed in the OE leaves compared to the wild type under the control and drought conditions, respectively. Most increased proteins were involved in the tricarboxylic acid cycle, photosynthesis, glycolysis, pyruvate metabolism, and oxidative phosphorylation pathways. Some were found to participate in abscisic acid signaling or response. Furthermore, the abscisic acid levels increased in the OE compared with the wild type. McHB7 was revealed to bind to the promoter motifs of Early Responsive to Dehydration genes and abscisic acid-responsive genes, and protein–protein interaction analysis revealed candidate proteins responsive to stresses and hormones (e.g., abscisic acid). To conclude, McHB7 may contribute to enhance plant drought tolerance through abscisic acid signaling. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Plant Defense against Abiotic Stress 2.0)
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19 pages, 4666 KiB  
Article
Effect of Trichomonacide 6-Nitro-1H-benzimidazole Derivative Compounds on Expression Level of Metabolic Genes in Trichomonas vaginalis
by Jocelyn Yamin Gutiérrez-Cardona, Ernesto Calderón-Jaimes, Daniel Ortega-Cuellar, Adrián Sánchez-Carrillo, Rosa Angélica Castillo-Rodríguez, Luis Miguel Canseco-Ávila, Luz María Rocha-Ramírez, Víctor Martínez-Rosas, Saúl Gómez-Manzo and Beatriz Hernández-Ochoa
Int. J. Mol. Sci. 2024, 25(8), 4568; https://doi.org/10.3390/ijms25084568 - 22 Apr 2024
Viewed by 524
Abstract
The parasite Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease worldwide. This infection often remains asymptomatic and is related to several health complications. The traditional treatment for trichomoniasis is the use of drugs of the 5-nitroimidazole [...] Read more.
The parasite Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease worldwide. This infection often remains asymptomatic and is related to several health complications. The traditional treatment for trichomoniasis is the use of drugs of the 5-nitroimidazole family, such as metronidazole; however, scientific reports indicate an increasing number of drug-resistant strains. Benzimidazole derivatives could offer an alternative in the search for new anti-trichomonas drugs. In this sense, two attractive candidates are the compounds O2N-BZM7 and O2N-BZM9 (1H-benzimidazole derivatives), since, through in vitro tests, they have shown a higher trichomonacide activity. In this study, we determined the effect on the expression level of metabolic genes in T. vaginalis. The results show that genes involved in redox balance (NADHOX, G6PD::6PGL) are overexpressed, as well as the gene that participates in the first reaction of glycolysis (CK); on the other hand, structural genes such as ACT and TUB are decreased in expression in trophozoites treated with the compound O2N-BZM9, which would probably affect its morphology, motility and virulence. These results align with the trichomonacidal activity of the compounds, with benzimidazole O2N-BZM9 being the most potent, with an IC50 value of 4.8 μM. These results are promising for potential future therapeutic applications. Full article
(This article belongs to the Special Issue Recent Advances: Heterocycles in Drugs and Drug Discovery 2.0)
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20 pages, 4317 KiB  
Article
The Long-Acting Serine Protease Inhibitor mPEG-SPA-MDSPI16 Alleviates LPS-Induced Acute Lung Injury
by Jingrui Chen, Xinjun Zhou, Nan Dai, Xiaoyu Liu, Shihan Liu, Haipeng Zhang, Lingcong Kong and Hongxia Ma
Int. J. Mol. Sci. 2024, 25(8), 4567; https://doi.org/10.3390/ijms25084567 - 22 Apr 2024
Viewed by 537
Abstract
Anti-inflammatory drugs have become the second-largest class of common drugs after anti-infective drugs in animal clinical care worldwide and are often combined with other drugs to treat fever and viral diseases caused by various factors. In our previous study, a novel serine protease [...] Read more.
Anti-inflammatory drugs have become the second-largest class of common drugs after anti-infective drugs in animal clinical care worldwide and are often combined with other drugs to treat fever and viral diseases caused by various factors. In our previous study, a novel serine protease inhibitor-encoding gene (MDSPI16) with improved anti-inflammatory activity was selected from a constructed suppressive subducted hybridization library of housefly larvae. This protein could easily induce an immune response in animals and had a short half-life, which limited its wide application in the clinic. Thus, in this study, mPEG-succinimidyl propionate (mPEG-SPA, Mw = 5 kDa) was used to molecularly modify the MDSPI16 protein, and the modified product mPEG-SPA-MDSPI16, which strongly inhibited elastase production, was purified. It had good stability and safety, low immunogenicity, and a long half-life, and the IC50 for elastase was 86 nM. mPEG-SPA-MDSPI16 effectively inhibited the expression of neutrophil elastase and decreased ROS levels. Moreover, mPEG-SPA-MDSPI16 exerted anti-inflammatory effects by inhibiting activation of the NF-κB signaling pathway and the MAPK signaling pathway in neutrophils. It also exerted therapeutic effects on a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. In summary, mPEG-SPA-MDSPI16 is a novel anti-inflammatory protein modified with PEG that has the advantages of safety, nontoxicity, improved stability, and strong anti-inflammatory activity in vivo and in vitro and is expected to become an effective anti-inflammatory drug. Full article
(This article belongs to the Section Molecular Pharmacology)
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13 pages, 726 KiB  
Review
OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses
by Robert Gilkerson, Harpreet Kaur, Omar Carrillo and Isaiah Ramos
Int. J. Mol. Sci. 2024, 25(8), 4566; https://doi.org/10.3390/ijms25084566 - 22 Apr 2024
Viewed by 562
Abstract
In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide [...] Read more.
In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψm) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities. Full article
(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders 2.0)
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13 pages, 576 KiB  
Review
Dual Drug Repurposing: The Example of Saracatinib
by Raquel Ramos and Nuno Vale
Int. J. Mol. Sci. 2024, 25(8), 4565; https://doi.org/10.3390/ijms25084565 - 22 Apr 2024
Viewed by 774
Abstract
Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising [...] Read more.
Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer’s disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer’s disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases. Full article
(This article belongs to the Special Issue Drug Metabolism in Cancer Therapy)
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18 pages, 5943 KiB  
Review
Contributions of Non-Neuronal Cholinergic Systems to the Regulation of Immune Cell Function, Highlighting the Role of α7 Nicotinic Acetylcholine Receptors
by Koichiro Kawashima, Masato Mashimo, Atsuo Nomura and Takeshi Fujii
Int. J. Mol. Sci. 2024, 25(8), 4564; https://doi.org/10.3390/ijms25084564 - 22 Apr 2024
Viewed by 544
Abstract
Loewi’s discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, [...] Read more.
Loewi’s discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, advances in the techniques for ACh detection have led to its discovery in many lifeforms lacking a nervous system, including eubacteria, archaea, fungi, and plants. Notably, mRNAs encoding choline acetyltransferase and muscarinic and nicotinic ACh receptors (nAChRs) have been found in uninnervated mammalian cells, including immune cells, keratinocytes, vascular endothelial cells, cardiac myocytes, respiratory, and digestive epithelial cells. It thus appears that non-neuronal cholinergic systems are expressed in a variety of mammalian cells, and that ACh should now be recognized not only as a neurotransmitter, but also as a local regulator of non-neuronal cholinergic systems. Here, we discuss the role of non-neuronal cholinergic systems, with a focus on immune cells. A current focus of much research on non-neuronal cholinergic systems in immune cells is α7 nAChRs, as these receptors expressed on macrophages and T cells are involved in regulating inflammatory and immune responses. This makes α7 nAChRs an attractive potential therapeutic target. Full article
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2 pages, 149 KiB  
Editorial
Advances in the Pathogenesis of Diabetic Kidney Disease
by Christodoula Kourtidou and Konstantinos Tziomalos
Int. J. Mol. Sci. 2024, 25(8), 4563; https://doi.org/10.3390/ijms25084563 - 22 Apr 2024
Viewed by 487
Abstract
Diabetic kidney disease (DKD) is both a frequent complication of diabetes mellitus (DM) [...] Full article
(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)
16 pages, 6382 KiB  
Article
Change in Tissue Microbiome and Related Human Beta Defensin Levels Induced by Antibiotic Use in Bladder Carcinoma
by Ádám Monyók, Bassel Mansour, István Vadnay, Nóra Makra, Zsuzsanna A. Dunai, Éva Nemes-Nikodém, Balázs Stercz, Dóra Szabó and Eszter Ostorházi
Int. J. Mol. Sci. 2024, 25(8), 4562; https://doi.org/10.3390/ijms25084562 - 22 Apr 2024
Viewed by 481
Abstract
It is now generally accepted that the success of antitumor therapy can be impaired by concurrent antibiotic therapy, the presence of certain bacteria, and elevated defensin levels around the tumor tissue. The aim of our current investigation was to identify the underlying changes [...] Read more.
It is now generally accepted that the success of antitumor therapy can be impaired by concurrent antibiotic therapy, the presence of certain bacteria, and elevated defensin levels around the tumor tissue. The aim of our current investigation was to identify the underlying changes in microbiome and defensin levels in the tumor tissue induced by different antibiotics, as well as the duration of this modification. The microbiome of the tumor tissues was significantly different from that of healthy volunteers. Comparing only the tumor samples, no significant difference was confirmed between the untreated group and the group treated with antibiotics more than 3 months earlier. However, antibiotic treatment within 3 months of analysis resulted in a significantly modified microbiome composition. Irrespective of whether Fosfomycin, Fluoroquinolone or Beta-lactam treatment was used, the abundance of Bacteroides decreased, and Staphylococcus abundance increased. Large amounts of the genus Acinetobacter were observed in the Fluoroquinolone-treated group. Regardless of the antibiotic treatment, hBD1 expression of the tumor cells consistently doubled. The increase in hBD2 and hBD3 expression was the highest in the Beta-lactam treated group. Apparently, antibiotic treatment within 3 months of sample analysis induced microbiome changes and defensin expression levels, depending on the identity of the applied antibiotic. Full article
(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Target in Bladder Cancer)
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25 pages, 1049 KiB  
Article
Interferon-Gamma Secretion Is Significantly Decreased in Stage III Breast Cancer Patients
by Jung Im Yi, Jean Schneider, Seung Taek Lim, Byeongkwan Park and Young Jin Suh
Int. J. Mol. Sci. 2024, 25(8), 4561; https://doi.org/10.3390/ijms25084561 - 22 Apr 2024
Viewed by 559
Abstract
Even though some studies have shown possible clinical relationship between molecular subtypes and tumor infiltrating natural killer (NK) cells around tumors, there are few studies showing the clinical relevance of peripheral NK cell activity at diagnosis in female patients with invasive breast cancer. [...] Read more.
Even though some studies have shown possible clinical relationship between molecular subtypes and tumor infiltrating natural killer (NK) cells around tumors, there are few studies showing the clinical relevance of peripheral NK cell activity at diagnosis in female patients with invasive breast cancer. A total of 396 female invasive breast cancer patients who received curative surgical treatment from March 2017 to July 2021 were retrospectively analyzed. NK cell activation-induced interferon-gamma (IFN-γ) secretion measured by enzyme-linked immunosorbent assay was used to measure the activity of peripheral NK cells. Statistical analyses were performed to determine clinical relationships with major clinicopathologic parameters. Quadripartite NK cell activity measured by induced interferon-gamma showed significant relevance with staging and body mass index, and some of the inflammatory serological markers, namely N/L (neutrophil/lymphocyte), P/N (platelet/neutrophil), and P/L (platelet/lymphocyte), showed significantly different NK activity in each interval by univariate analysis. A binary subgroup analysis, setting the IFN-γ secretion cut-off at 100 pg/mL, showed that stage III was significantly increased and axillary lymph node metastasis positivity was increased in the group of IFN-γ < 100 pg/mL, and IFN-γ secretion decreased with an increasing N stage, increased BMI (body mass index), and decreased production of IFN-γ. Following this, the same binary analysis, but with the IFN-γ secretion cut-off at 250 pg/mL, also showed that secretion in stage III was increased in those concentrations with <250 pg/mL, axillary lymph node positivity appeared to be correlated, and BMI ≥ 30 increased in prevalence. Additional ANOVA post hoc tests (Bonferroni) were performed on some serological markers that tended to be somewhat inconsistent. By subgroup analysis with Bonferroni adjustment between the IFN-γ secretion and TNM stage, no significant difference in IFN-γ secretion could be identified at stages I, II, and IV, but at stage III, the IFN-γ secretion < 100 pg/mL was significantly higher than 250 ≤ IFN-γ secretion < 500 pg/mL or IFN-γ secretion ≥ 500 pg/mL. According to this study, stage III was significantly associated with the lowest IFN-γ secretion. Compared to a higher level of IFN-γ secretion, a lower level of IFN-γ secretion seemed to be associated with increased body mass index. Unlike when IFN-γ secretion was analyzed in quartiles, as the IFN-γ secretion fell below 100 pg/mL, the correlation between axillary lymph node positivity and increased N stage, increased BMI, and increased N/L and P/L, which are suggested poor prognostic factors, became more pronounced. We think a peripheral IFN-γ secretion test might be convenient and useful tool for pretreatment risk assessment and selecting probable candidates for further treatment such as immunotherapy in some curable but high-risk invasive breast cancer patients, compared to other costly assaying of tissue NK cell activity at diagnosis. Full article
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14 pages, 964 KiB  
Review
Role of Dermal Factors Involved in Regulating the Melanin and Melanogenesis of Mammalian Melanocytes in Normal and Abnormal Skin
by Tomohisa Hirobe
Int. J. Mol. Sci. 2024, 25(8), 4560; https://doi.org/10.3390/ijms25084560 - 22 Apr 2024
Viewed by 451
Abstract
Mammalian melanin is produced in melanocytes and accumulated in melanosomes. Melanogenesis is supported by many factors derived from the surrounding tissue environment, such as the epidermis, dermis, and subcutaneous tissue, in addition to numerous melanogenesis-related genes. The roles of these genes have been [...] Read more.
Mammalian melanin is produced in melanocytes and accumulated in melanosomes. Melanogenesis is supported by many factors derived from the surrounding tissue environment, such as the epidermis, dermis, and subcutaneous tissue, in addition to numerous melanogenesis-related genes. The roles of these genes have been fully investigated and the molecular analysis has been performed. Moreover, the role of paracrine factors derived from epidermis has also been studied. However, the role of dermis has not been fully studied. Thus, in this review, dermis-derived factors including soluble and insoluble components were overviewed and discussed in normal and abnormal circumstances. Dermal factors play an important role in the regulation of melanogenesis in the normal and abnormal mammalian skin. Full article
(This article belongs to the Special Issue Melanins and Melanogenesis 4.0: From Nature to Applications)
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29 pages, 1205 KiB  
Review
Lipid Peroxidation-Related Redox Signaling in Osteosarcoma
by Suzana Borović Šunjić, Morana Jaganjac, Josipa Vlainić, Mirna Halasz and Neven Žarković
Int. J. Mol. Sci. 2024, 25(8), 4559; https://doi.org/10.3390/ijms25084559 - 22 Apr 2024
Viewed by 663
Abstract
Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including [...] Read more.
Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies. Full article
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23 pages, 8710 KiB  
Case Report
Enterotype-Dependent Probiotic-Mediated Changes in the Male Rat Intestinal Microbiome In Vivo and In Vitro
by Nikolay Kolzhetsov, Natalia Markelova, Maria Frolova, Olga Alikina, Olga Glazunova, Lubov Safonova, Irina Kalashnikova, Vladimir Yudin, Valentin Makarov, Anton Keskinov, Sergey Yudin, Daria Troshina, Viktoria Rechkina, Viktoria Shcherbakova, Konstantin Shavkunov and Olga Ozoline
Int. J. Mol. Sci. 2024, 25(8), 4558; https://doi.org/10.3390/ijms25084558 - 22 Apr 2024
Viewed by 612
Abstract
Beneficial properties of lactic acid bacteria have been known long ago, but particular interest in probiotics has arisen in the last two decades due to the understanding of the important role of intestinal microflora in human life. Thus, the ability of probiotics to [...] Read more.
Beneficial properties of lactic acid bacteria have been known long ago, but particular interest in probiotics has arisen in the last two decades due to the understanding of the important role of intestinal microflora in human life. Thus, the ability of probiotics to support healthy homeostasis of gut microbiomes has received particular attention. Here, we evaluated the effect of a probiotic consisting of Bifidobacterium longum and Lacticaseibacillus paracasei on the gut microbiome of male rats, assessed their persistence in the fecal biota, and compared probiotic-mediated changes in vitro and in vivo. As expected, microbiomes of two enterotypes were identified in the feces of 21 animals, and it turned out that even a single dose of the probiotic altered the microbial composition. Upon repeated administration, the E1 biota temporarily acquired properties of the E2 type. Being highly sensitive to the intervention of probiotic bacteria at the phylum and genus levels, the fecal microbiomes retained the identity of their enterotypes when transferred to a medium optimized for gut bacteria. For the E2 biota, even similarities between probiotic-mediated reactions in vitro and in vivo were detected. Therefore, fecal-derived microbial communities are proposed as model consortia to optimize the response of resident bacteria to various agents. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)
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19 pages, 25378 KiB  
Article
Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis
by Matko Rošin, Nela Kelam, Ivana Jurić, Anita Racetin, Marin Ogorevc, Brieuc Corre, Davor Čarić, Natalija Filipović and Katarina Vukojević
Int. J. Mol. Sci. 2024, 25(8), 4557; https://doi.org/10.3390/ijms25084557 - 22 Apr 2024
Viewed by 448
Abstract
The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in [...] Read more.
The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans’ heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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15 pages, 1397 KiB  
Article
Multiple Sclerosis Onset before and after COVID-19 Vaccination: Can HLA Haplotype Be Determinant?
by Assunta Bianco, Gabriele Di Sante, Francesca Colò, Valeria De Arcangelis, Alessandra Cicia, Paola Del Giacomo, Maria De Bonis, Tommaso Giuseppe Morganti, Vincenzo Carlomagno, Matteo Lucchini, Angelo Minucci, Paolo Calabresi and Massimiliano Mirabella
Int. J. Mol. Sci. 2024, 25(8), 4556; https://doi.org/10.3390/ijms25084556 - 22 Apr 2024
Viewed by 1021
Abstract
A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing–remitting MS before and after the outbreak of the [...] Read more.
A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing–remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing–remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing–remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients’ characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients’ characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing–remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options. Full article
(This article belongs to the Special Issue New Advances of Proteins in Neuroinflammation)
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16 pages, 9922 KiB  
Article
RNA Interference-Mediated Suppression of Ecdysone Signaling Inhibits Choriogenesis in Two Coleoptera Species
by Xiao-Qing Zhang, Lin Jin, Wen-Chao Guo, Kai-Yun Fu and Guo-Qing Li
Int. J. Mol. Sci. 2024, 25(8), 4555; https://doi.org/10.3390/ijms25084555 - 22 Apr 2024
Viewed by 426
Abstract
During choriogenesis in insects, chorion (eggshell) is formed by surrounding follicular epithelial cells in ovarioles. However, the regulatory endocrine factor(s) activating choriogenesis and the effect of chemical components on eggshell deserve further exploration. In two representative coleopterans, a coccinellid Henosepilachna vigintioctopunctata and a [...] Read more.
During choriogenesis in insects, chorion (eggshell) is formed by surrounding follicular epithelial cells in ovarioles. However, the regulatory endocrine factor(s) activating choriogenesis and the effect of chemical components on eggshell deserve further exploration. In two representative coleopterans, a coccinellid Henosepilachna vigintioctopunctata and a chrysomelid Leptinotarsa decemlineata, genes encoding the 20-hydroxyecdysone (20E) receptor heterodimer, ecdysone receptor (EcR) and ultraspiracle (USP), and two chitin biosynthesis enzymes UDP-N-acetylglucosamine pyrophosphorylase (UAP) and chitin synthase (ChS1), were highly expressed in ovaries of the young females. RNA interference (RNAi)-aided knockdown of either HvEcR or Hvusp in H. vigintioctopunctata inhibited oviposition, suppressed the expression of HvChS1, and lessened the positive signal of Calcofluor staining on the chorions, which suggests the reduction of a chitin-like substance (CLS) deposited on eggshells. Similarly, RNAi of LdEcR or Ldusp in L. decemlineata constrained oviposition, decreased the expression of LdUAP1 and LdChS1, and reduced CLS contents in the resultant ovaries. Knockdown of LdUAP1 or LdChS1 caused similar defective phenotypes, i.e., reduced oviposition and CLS contents in the L. decemlineata ovaries. These results, for the first time, indicate that 20E signaling activates choriogenesis in two coleopteran species. Moreover, our findings suggest the deposition of a CLS on the chorions. Full article
(This article belongs to the Special Issue Ovary and Testis: Molecular Biological Insights)
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13 pages, 1271 KiB  
Article
Batimastat Induces Cytotoxic and Cytostatic Effects in In Vitro Models of Hematological Tumors
by Raquel Alves, Ana Pires, Joana Jorge, Joana Balça-Silva, Ana Cristina Gonçalves and Ana Bela Sarmento-Ribeiro
Int. J. Mol. Sci. 2024, 25(8), 4554; https://doi.org/10.3390/ijms25084554 - 22 Apr 2024
Viewed by 490
Abstract
The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an [...] Read more.
The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat’s therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects. Full article
(This article belongs to the Special Issue 23rd Anniversary of IJMS: Advances in Biochemistry)
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17 pages, 12124 KiB  
Article
The Neurotranscriptome of Monochamus alternatus
by Xiaohong Han, Mingqing Weng, Wenchao Shi, Yingxin Wen, Yirong Long, Xinran Hu, Guoxi Ji, Yukun Zhu, Xuanye Wen, Feiping Zhang and Songqing Wu
Int. J. Mol. Sci. 2024, 25(8), 4553; https://doi.org/10.3390/ijms25084553 - 22 Apr 2024
Viewed by 461
Abstract
The Japanese pine sawyer Monochamus alternatus serves as the primary vector for pine wilt disease, a devastating pine disease that poses a significant threat to the sustainable development of forestry in the Eurasian region. Currently, trap devices based on informational compounds have played [...] Read more.
The Japanese pine sawyer Monochamus alternatus serves as the primary vector for pine wilt disease, a devastating pine disease that poses a significant threat to the sustainable development of forestry in the Eurasian region. Currently, trap devices based on informational compounds have played a crucial role in monitoring and controlling the M. alternatus population. However, the specific proteins within M. alternatus involved in recognizing the aforementioned informational compounds remain largely unclear. To elucidate the spatiotemporal distribution of M. alternatus chemosensory-related genes, this study conducted neural transcriptome analyses to investigate gene expression patterns in different body parts during the feeding and mating stages of both male and female beetles. The results revealed that 15 genes in the gustatory receptor (GR) gene family exhibited high expression in the mouthparts, most genes in the odorant binding protein (OBP) gene family exhibited high expression across all body parts, 22 genes in the odorant receptor (OR) gene family exhibited high expression in the antennae, a significant number of genes in the chemosensory protein (CSP) and sensory neuron membrane protein (SNMP) gene families exhibited high expression in both the mouthparts and antennae, and 30 genes in the ionotropic receptors (IR) gene family were expressed in the antennae. Through co-expression analyses, it was observed that 34 genes in the IR gene family were co-expressed across the four developmental stages. The Antenna IR subfamily and IR8a/Ir25a subfamily exhibited relatively high expression levels in the antennae, while the Kainate subfamily, NMDA subfamily, and Divergent subfamily exhibited predominantly high expression in the facial region. MalIR33 is expressed only during the feeding stage of M. alternatus, the MalIR37 gene exhibits specific expression in male beetles, the MalIR34 gene exhibits specific expression during the feeding stage in male beetles, the MalIR8 and MalIR39 genes exhibit specific expression during the feeding stage in female beetles, and MalIR8 is expressed only during two developmental stages in male beetles and during the mating stage in female beetles. The IR gene family exhibits gene-specific expression in different spatiotemporal contexts, laying the foundation for the subsequent selection of functional genes and facilitating the full utilization of host plant volatiles and insect sex pheromones, thereby enabling the development of more efficient attractants. Full article
(This article belongs to the Section Molecular Plant Sciences)
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7 pages, 525 KiB  
Case Report
The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy
by Ioannis Petrakis, Maria Sfakiotaki, Maria Bitsori, Eleni Drosataki, Kleio Dermitzaki, Christos Pleros, Ariadni Androvitsanea, Dimitrios Samonakis, Amalia Sertedaki, Paraskevi Xekouki, Emmanouil Galanakis and Kostas Stylianou
Int. J. Mol. Sci. 2024, 25(8), 4552; https://doi.org/10.3390/ijms25084552 - 22 Apr 2024
Viewed by 454
Abstract
The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing [...] Read more.
The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient’s electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged −2.22 ± 0.7 mL/min/1.73 m2. Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools. Full article
(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Kidney Disease)
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21 pages, 6131 KiB  
Review
Melatonin-Mediated Molecular Responses in Plants: Enhancing Stress Tolerance and Mitigating Environmental Challenges in Cereal Crop Production
by Ihsan Muhammad, Shakeel Ahmad and Weijun Shen
Int. J. Mol. Sci. 2024, 25(8), 4551; https://doi.org/10.3390/ijms25084551 - 21 Apr 2024
Viewed by 898
Abstract
Cereal crops are crucial for global food security; however, they are susceptible to various environmental stresses that significantly hamper their productivity. In response, melatonin has emerged as a promising regulator, offering potential benefits for stress tolerance and crop growth. This review explores the [...] Read more.
Cereal crops are crucial for global food security; however, they are susceptible to various environmental stresses that significantly hamper their productivity. In response, melatonin has emerged as a promising regulator, offering potential benefits for stress tolerance and crop growth. This review explores the effects of melatonin on maize, sorghum, millet, rice, barley, and wheat, aiming to enhance their resilience to stress. The application of melatonin has shown promising outcomes, improving water use efficiency and reducing transpiration rates in millet under drought stress conditions. Furthermore, it enhances the salinity and heavy metal tolerance of millet by regulating the activity of stress-responsive genes. Similarly, melatonin application in sorghum enhances its resistance to high temperatures, low humidity, and nutrient deficiency, potentially involving the modulation of antioxidant defense and aspects related to photosynthetic genes. Melatonin also exerts protective effects against drought, salinity, heavy metal, extreme temperatures, and waterlogging stresses in maize, wheat, rice, and barley crops by decreasing reactive oxygen species (ROS) production through regulating the antioxidant defense system. The molecular reactions of melatonin upregulated photosynthesis, antioxidant defense mechanisms, the metabolic pathway, and genes and downregulated stress susceptibility genes. In conclusion, melatonin serves as a versatile tool in cereal crops, bolstering stress resistance and promoting sustainable development. Further investigations are warranted to elucidate the underlying molecular mechanisms and refine application techniques to fully harness the potential role of melatonin in cereal crop production systems. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Plant Abiotic Stress Tolerance)
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16 pages, 20385 KiB  
Article
Molecular Dynamics Simulations of Different Nanoparticles at Substrates
by Małgorzata Borówko and Tomasz Staszewski
Int. J. Mol. Sci. 2024, 25(8), 4550; https://doi.org/10.3390/ijms25084550 - 21 Apr 2024
Viewed by 508
Abstract
We report the results of large-scale molecular dynamics simulations of adsorption nanoparticles on solid surfaces. The particles were modeled as stiff aggregates of spherical segments. Three types of particles were studied: rods, rectangles, and triangles built of the same number of segments. We [...] Read more.
We report the results of large-scale molecular dynamics simulations of adsorption nanoparticles on solid surfaces. The particles were modeled as stiff aggregates of spherical segments. Three types of particles were studied: rods, rectangles, and triangles built of the same number of segments. We show how the particle shape affects the adsorption, the structure of the surface layer, and the degree of the removal of particles from the solvent. The systems with different segment–segment and segment–surface interactions and different concentrations of particles were investigated. The ordered structures formed in adsorption monolayers were also analyzed. The results are consistent with experimental observations. Full article
(This article belongs to the Special Issue Molecular Simulation and Modeling)
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15 pages, 3460 KiB  
Article
Bulked Segregant RNA-Seq Reveals Different Gene Expression Patterns and Mutant Genes Associated with the Zigzag Pattern of Tea Plants (Camellia sinensis)
by Yuan-Yuan Ye, Ding-Ding Liu, Rong-Jin Tang, Yang Gong, Chen-Yu Zhang, Piao Mei, Chun-Lei Ma and Jie-Dan Chen
Int. J. Mol. Sci. 2024, 25(8), 4549; https://doi.org/10.3390/ijms25084549 - 21 Apr 2024
Viewed by 544
Abstract
The unique zigzag-patterned tea plant is a rare germplasm resource. However, the molecular mechanism behind the formation of zigzag stems remains unclear. To address this, a BC1 genetic population of tea plants with zigzag stems was studied using histological observation and bulked segregant [...] Read more.
The unique zigzag-patterned tea plant is a rare germplasm resource. However, the molecular mechanism behind the formation of zigzag stems remains unclear. To address this, a BC1 genetic population of tea plants with zigzag stems was studied using histological observation and bulked segregant RNA-seq. The analysis revealed 1494 differentially expressed genes (DEGs) between the upright and zigzag stem groups. These DEGs may regulate the transduction and biosynthesis of plant hormones, and the effects on the phenylpropane biosynthesis pathways may cause the accumulation of lignin. Tissue sections further supported this finding, showing differences in cell wall thickness between upright and curved stems, potentially due to lignin accumulation. Additionally, 262 single-nucleotide polymorphisms (SNPs) across 38 genes were identified as key SNPs, and 5 genes related to zigzag stems were identified through homologous gene function annotation. Mutations in these genes may impact auxin distribution and content, resulting in the asymmetric development of vascular bundles in curved stems. In summary, we identified the key genes associated with the tortuous phenotype by using BSR-seq on a BC1 population to minimize genetic background noise. Full article
(This article belongs to the Special Issue Advances in Tea Tree Genetics and Breeding)
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29 pages, 2026 KiB  
Review
Exploring the Key Signaling Pathways and ncRNAs in Colorectal Cancer
by Yun Ju Lee, Woo Ryung Kim, Eun Gyung Park, Du Hyeong Lee, Jung-min Kim, Hae Jin Shin, Hyeon-su Jeong, Hyun-Young Roh and Heui-Soo Kim
Int. J. Mol. Sci. 2024, 25(8), 4548; https://doi.org/10.3390/ijms25084548 - 21 Apr 2024
Viewed by 812
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer to be diagnosed, and it has a substantial mortality rate. Despite numerous studies being conducted on CRC, it remains a significant health concern. The disease-free survival rates notably decrease as CRC progresses, emphasizing the [...] Read more.
Colorectal cancer (CRC) is the third most prevalent cancer to be diagnosed, and it has a substantial mortality rate. Despite numerous studies being conducted on CRC, it remains a significant health concern. The disease-free survival rates notably decrease as CRC progresses, emphasizing the urgency for effective diagnostic and therapeutic approaches. CRC development is caused by environmental factors, which mostly lead to the disruption of signaling pathways. Among these pathways, the Wingless/Integrated (Wnt) signaling pathway, Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, Mitogen-Activated Protein Kinase (MAPK) signaling pathway, Transforming Growth Factor-β (TGF-β) signaling pathway, and p53 signaling pathway are considered to be important. These signaling pathways are also regulated by non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). They have emerged as crucial regulators of gene expression in CRC by changing their expression levels. The altered expression patterns of these ncRNAs have been implicated in CRC progression and development, suggesting their potential as diagnostic and therapeutic targets. This review provides an overview of the five key signaling pathways and regulation of ncRNAs involved in CRC pathogenesis that are studied to identify promising avenues for diagnosis and treatment strategies. Full article
(This article belongs to the Special Issue Functional Molecules in Tracing and Cancer Therapeutics)
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