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Volume 25
Issue 18
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Int. J. Mol. Sci., Volume 25, Issue 18 (September-2 2024) – 474 articles

Cover Story (view full-size image): The coordination of ICI therapy and the gut microbiota triggers a synergistic anti-tumour immune response. The inflammation induced by ICI promotes the uptake of gut microbiota by the intestinal dendritic cells (DCs), leading to the upregulation of MHC, CD86, and CCR7, which facilitates the transport of microbiota-loaded DCs into the MLNs. Additionally, ICI therapy induces lymphangiogenesis and the dilation of high endothelial venules in the MLNs, enhancing the translocation of bacteria to the TDLNs and the tumour itself. In the TME, the microbiota modifies the intrinsic tumour factors and influences the anti-tumour immune response, resulting in increased leukocyte infiltration and enhanced secretion of Granzyme B and perforin by the effector immune cells, such as CD8 killer T cells and NKT cells, ultimately driving tumour elimination. View this paper
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14 pages, 2865 KiB  
Review
Lectin-Based Approaches to Analyze the Role of Glycans and Their Clinical Application in Disease
by Hiroko Ideo, Akiko Tsuchida and Yoshio Takada
Int. J. Mol. Sci. 2024, 25(18), 10231; https://doi.org/10.3390/ijms251810231 - 23 Sep 2024
Viewed by 1283
Abstract
Lectin-based approaches remain a valuable tool for analyzing glycosylation, especially when detecting cancer-related changes. Certain glycans function as platforms for cell communication, signal transduction, and adhesion. Therefore, the functions of glycans are important considerations for clinical aspects, such as cancer, infection, and immunity. [...] Read more.
Lectin-based approaches remain a valuable tool for analyzing glycosylation, especially when detecting cancer-related changes. Certain glycans function as platforms for cell communication, signal transduction, and adhesion. Therefore, the functions of glycans are important considerations for clinical aspects, such as cancer, infection, and immunity. Considering that the three-dimensional structure and multivalency of glycans are important factors for their function, their binding characteristics toward lectins provide vital information. Glycans and lectins are inextricably linked, and studies on lectins have also led to research on the roles of glycans. The applications of lectins are not limited to analysis but can also be used as drug delivery tools. Moreover, mammalian lectins are potential therapeutic targets because certain lectins change their expression in cancer, and lectin regulation subsequently regulates several molecules with glycans. Herein, we review lectin-based approaches for analyzing the role of glycans and their clinical applications in diseases, as well as our recent results. Full article
(This article belongs to the Special Issue Glycobiology of Health and Diseases)
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18 pages, 3870 KiB  
Article
A Machine Learning Algorithm Suggests Repurposing Opportunities for Targeting Selected GPCRs
by Shayma El-Atawneh and Amiram Goldblum
Int. J. Mol. Sci. 2024, 25(18), 10230; https://doi.org/10.3390/ijms251810230 - 23 Sep 2024
Viewed by 955
Abstract
Repurposing utilizes existing drugs with known safety profiles and discovers new uses by combining experimental and computational approaches. The integration of computational methods has greatly advanced drug repurposing, offering a rational approach and reducing the risk of failure in these efforts. Recognizing the [...] Read more.
Repurposing utilizes existing drugs with known safety profiles and discovers new uses by combining experimental and computational approaches. The integration of computational methods has greatly advanced drug repurposing, offering a rational approach and reducing the risk of failure in these efforts. Recognizing the potential for drug repurposing, we employed our Iterative Stochastic Elimination (ISE) algorithm to screen known drugs from the DrugBank database. Repurposing in our hands is based on computer models of the actions of ligands: the ISE algorithm is a machine learning tool that creates ligand-based models by distinguishing between the physicochemical properties of known drugs and those of decoys. The models are large sets of “filters” made out, each, of molecular properties. We screen and score external sets of molecules (in our case- the DrugBank molecules) by our agonism and antagonism models based on published data (i.e., IC50, Ki, or EC50) and pick the top-scoring molecules as candidates for experiments. Such agonist and antagonist models for six G-protein coupled receptors (GPCRs) families facilitated the identification of repurposing opportunities. Our screening revealed 5982 new potential molecular actions (agonists, antagonists), which suggest repurposing candidates for the cannabinoid 2 (CB2), histamine (H1, H3, and H4), and dopamine 3 (D3) receptors, which may be useful to treat conditions such as neuroinflammation, obesity, allergic dermatitis, and drug abuse. These sets of best candidates should now be examined by experimentalists: based on previous such experiments, there is a very high chance of discovering novel highly bioactive molecules. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)
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13 pages, 4324 KiB  
Article
Glial-Cell-Line-Derived Neurotrophic Factor Promotes Glioblastoma Cell Migration and Invasion via the SMAD2/3-SERPINE1-Signaling Axis
by Xiaoxiao Guo, Han Zhou, Yifang Liu, Wei Xu, Kouminin Kanwore and Lin Zhang
Int. J. Mol. Sci. 2024, 25(18), 10229; https://doi.org/10.3390/ijms251810229 - 23 Sep 2024
Viewed by 964
Abstract
Glial-cell-line-derived neurotrophic factor (GDNF) is highly expressed and is involved in the malignant phenotype in glioblastomas (GBMs). However, uncovering its underlying mechanism for promoting GBM progression is still a challenging work. In this study, we found that serine protease inhibitor family E member [...] Read more.
Glial-cell-line-derived neurotrophic factor (GDNF) is highly expressed and is involved in the malignant phenotype in glioblastomas (GBMs). However, uncovering its underlying mechanism for promoting GBM progression is still a challenging work. In this study, we found that serine protease inhibitor family E member 1 (SERPINE1) was a potential downstream gene of GDNF. Further experiments confirmed that SERPINE1 was highly expressed in GBM tissues and cells, and its levels of expression and secretion were enhanced by exogenous GDNF. SERPINE1 knockdown inhibited the migration and invasion of GBM cells promoted by GDNF. Mechanistically, GDNF increased SERPINE1 by promoting the phosphorylation of SMAD2/3. In vivo experiments demonstrated that GDNF facilitated GBM growth and the expressions of proteins related to migration and invasion via SERPINE1. Collectively, our findings revealed that GDNF upregulated SERPINE1 via the SMAD2/3-signaling pathway, thereby accelerating GBM cell migration and invasion. The present work presents a new mechanism of GDNF, supporting GBM development. Full article
(This article belongs to the Section Biochemistry)
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20 pages, 2200 KiB  
Article
Synergistic Effect between the APOE ε4 Allele with Genetic Variants of GSK3B and MAPT: Differential Profile between Refractory Epilepsy and Alzheimer Disease
by Danira Toral-Rios, Pavel Pichardo-Rojas, Elizabeth Ruiz-Sánchez, Óscar Rosas-Carrasco, Rosa Carvajal-García, Dey Carol Gálvez-Coutiño, Nancy Lucero Martínez-Rodríguez, Ana Daniela Rubio-Chávez, Myr Alcántara-Flores, Arely López-Ramírez, Alma Rosa Martínez-Rosas, Ángel Alberto Ruiz-Chow, Mario Alonso-Vanegas and Victoria Campos-Peña
Int. J. Mol. Sci. 2024, 25(18), 10228; https://doi.org/10.3390/ijms251810228 - 23 Sep 2024
Viewed by 1494
Abstract
Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is [...] Read more.
Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is complex and multifactorial. Increasing evidence indicates that Alzheimer’s disease (AD) and drug-resistant TLE present common pathological features that may induce hyperexcitability, especially aberrant hyperphosphorylation of tau protein. Genetic polymorphic variants located in genes of the microtubule-associated protein tau (MAPT) and glycogen synthase kinase-3β (GSK3B) have been associated with the risk of developing AD. The APOE ε4 allele is a major genetic risk factor for AD. Likewise, a gene-dose-dependent effect of ε4 seems to influence TLE. The present study aimed to investigate whether the APOE ɛ4 allele and genetic variants located in the MAPT and GSK3B genes are associated with the risk of developing AD and drug-resistant TLE in a cohort of the Mexican population. A significant association with the APOE ε4 allele was observed in patients with AD and TLE. Additional genetic interactions were identified between this allele and variants of the MAPT and GSK3B genes. Full article
(This article belongs to the Special Issue Neurogenetics of Diseases)
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10 pages, 603 KiB  
Article
Influence of Intraocular Pressure on the Expression and Activity of Sodium–Potassium Pumps in the Corneal Endothelium
by Princia Anney, Pascale Charpentier and Stéphanie Proulx
Int. J. Mol. Sci. 2024, 25(18), 10227; https://doi.org/10.3390/ijms251810227 - 23 Sep 2024
Viewed by 813
Abstract
The corneal endothelium is responsible for pumping fluid out of the stroma in order to maintain corneal transparency, which depends in part on the expression and activity of sodium–potassium pumps. In this study, we evaluated how physiologic pressure and flow influence transcription, protein [...] Read more.
The corneal endothelium is responsible for pumping fluid out of the stroma in order to maintain corneal transparency, which depends in part on the expression and activity of sodium–potassium pumps. In this study, we evaluated how physiologic pressure and flow influence transcription, protein expression, and activity of Na+/K+-ATPase. Native and engineered corneal endothelia were cultured in a bioreactor in the presence of pressure and flow (hydrodynamic culture condition) or in a Petri dish (static culture condition). Transcription of ATP1A1 was assessed using qPCR, the expression of the α1 subunit of Na+/K+-ATPase was measured using Western blots and ELISA assays, and Na+/K+-ATPase activity was evaluated using an ATPase assay in the presence of ouabain. Results show that physiologic pressure and flow increase the transcription and the protein expression of Na+/K+-ATPase α1 in engineered corneal endothelia, while they remain stable in native corneal endothelia. Interestingly, the activity of Na+/K+-ATPase was increased in the presence of physiologic pressure and flow in both native and engineered corneal endothelia. These findings highlight the role of the in vivo environment on the functionality of the corneal endothelium. Full article
(This article belongs to the Special Issue Functional Roles of Epithelial and Endothelial Cells)
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15 pages, 3493 KiB  
Article
Ascochlorin Attenuates the Early Stage of Adipogenesis via the Wnt/β-Catenin Pathway and Inhibits High-Fat-Diet-Induced Obesity in Mice
by Mi-Hee Yu, Yun-Jeong Jeong, Sung Wook Son, So Yoon Kwon, Kwon-Ho Song, Ho-Sang Son, Eon-Ju Jeon and Young-Chae Chang
Int. J. Mol. Sci. 2024, 25(18), 10226; https://doi.org/10.3390/ijms251810226 - 23 Sep 2024
Viewed by 696
Abstract
This study investigated the effects of ascochlorin (ASC), a natural compound derived from the fungus Ascochyta viciae, on adipogenesis and obesity. We determined the effects of ASC on 3T3-L1 preadipocytes and whether it ameliorated to mitigate high-fat diet (HFD)-induced obesity in C57BL/6J mice. [...] Read more.
This study investigated the effects of ascochlorin (ASC), a natural compound derived from the fungus Ascochyta viciae, on adipogenesis and obesity. We determined the effects of ASC on 3T3-L1 preadipocytes and whether it ameliorated to mitigate high-fat diet (HFD)-induced obesity in C57BL/6J mice. We found that ASC significantly inhibited the differentiation of preadipocytes by modulating the Wnt/β-catenin signaling pathway, a key regulator of adipogenic processes. Treatment with ASC not only reduced the mRNA and protein expression of key adipogenic transcription factors such as C/EBPα and PPARγ, but also reduced lipid accumulation both in vitro and in vivo. In addition, treatment HFD-fed mice with ASC significantly reduced their weight gain and adiposity vs. control mice. These results suggest that ASC has considerable potential as a therapeutic agent for obesity, owing to its dual action of inhibiting adipocyte differentiation and reducing lipid accumulation. Thus, ASC represents a promising candidate as a natural anti-obesity agent. Full article
(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)
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12 pages, 971 KiB  
Review
Current Understanding of Cardiovascular Calcification in Patients with Chronic Kidney Disease
by Sijie Chen, Rining Tang and Bicheng Liu
Int. J. Mol. Sci. 2024, 25(18), 10225; https://doi.org/10.3390/ijms251810225 - 23 Sep 2024
Viewed by 924
Abstract
The burden of chronic kidney disease (CKD) is increasing, posing a serious threat to human health. Cardiovascular calcification (CVC) is one of the most common manifestations of CKD, which significantly influences the morbidity and mortality of patients. The manifestation of CVC is an [...] Read more.
The burden of chronic kidney disease (CKD) is increasing, posing a serious threat to human health. Cardiovascular calcification (CVC) is one of the most common manifestations of CKD, which significantly influences the morbidity and mortality of patients. The manifestation of CVC is an unusual accumulation of mineral substances containing calcium and phosphate. The main component is hydroxyapatite. Many cells are involved in this process, such as smooth muscle cells (SMCs) and endothelial cells. CVC is an osteogenic process initiated by complex mechanisms such as metabolic disorders of calcium and phosphorus minerals, inflammation, extracellular vesicles, autophagy, and micro-RNAs with a variety of signaling pathways like Notch, STAT, and JAK. Although drug therapy and dialysis technology continue to advance, the survival time and quality of life of CVC patients still face challenges. Therefore, early diagnosis and prevention of CKD-related CVC, reducing its mortality rate, and improving patients’ quality of life have become urgent issues in the field of public health. In this review, we try to summarize the state-of-the-art understanding of the progression of CVC and hope that it will help in the prevention and treatment of CVC in CKD. Full article
(This article belongs to the Special Issue Signaling Pathways and Novel Therapies in Heart Disease)
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12 pages, 3820 KiB  
Article
Rapid Diagnostic PCR Assay Method for Species Identification of Mantidis Ootheca (Sangpiaoxiao) Based on Cytochrom C Oxidase I (COI) Barcode Analysis
by Sumin Noh, Wook Jin Kim, Ji-Min Cha, Goya Choi, Sungyu Yang, Jun-Ho Song and Byeong Cheol Moon
Int. J. Mol. Sci. 2024, 25(18), 10224; https://doi.org/10.3390/ijms251810224 - 23 Sep 2024
Viewed by 709
Abstract
Mantidis Ootheca (sangpiaoxiao), the egg case of the mantis, is a type of insect-derived traditional medicine widely used in East Asia. However, species identification based on egg morphology is challenging, leading to the distribution of counterfeit and adulterated products. The use of inauthentic [...] Read more.
Mantidis Ootheca (sangpiaoxiao), the egg case of the mantis, is a type of insect-derived traditional medicine widely used in East Asia. However, species identification based on egg morphology is challenging, leading to the distribution of counterfeit and adulterated products. The use of inauthentic ingredients can pose serious health risks to consumers. This study aimed to develop PCR markers that can rapidly and accurately differentiate between authentic and counterfeit Mantidis Ootheca. The mitochondrial cytochrome c oxidase I (COI) region was sequenced in thirteen samples from four mantis species: Tenodera angustipennis, Statilia maculata, Hierodula patellifera, and T. sinensis. Four sets of SCAR primers were designed based on species-specific nucleotide polymorphisms, and a multiplex SCAR assay was developed by combining all sets of the primers. The sequence-characterized amplified region (SCAR) primers successfully produced amplicons for each target species, even with low-DNA templates or templates containing DNA from multiple samples. No amplification was observed for nontarget species. This study presents a novel approach for identifying authentic Mantidis Ootheca species using DNA-based diagnostic marker assays, which enable rapid and precise species identification. The SCAR assays developed in this study will aid in maintaining quality control and promoting the standardization of commercial Mantidis Ootheca products. Full article
(This article belongs to the Special Issue Advances in Diagnostics: Applications of Nucleic Acids and Their Analogs)
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14 pages, 3482 KiB  
Article
Exosomal miRNAs Differentiate Chronic Total Occlusion from Acute Myocardial Infarction
by Ji-Hye Son, Jeong Kyu Park, Ji-Hong Bang, Dongeon Kim, Inki Moon, Min Gyu Kong, Hyun-Woo Park, Hyung-Oh Choi, Hye-Sun Seo, Yoon Haeng Cho, Hun Soo Chang and Jon Suh
Int. J. Mol. Sci. 2024, 25(18), 10223; https://doi.org/10.3390/ijms251810223 - 23 Sep 2024
Viewed by 761
Abstract
Although coronary artery occlusion can have a negative effect on the myocardium, chronic total occlusion (CTO) exhibits different clinical features from those of acute myocardial infarction (AMI). In this study, we identify the differential associations of exosomal miRNAs with CTO and AMI. Exosomes [...] Read more.
Although coronary artery occlusion can have a negative effect on the myocardium, chronic total occlusion (CTO) exhibits different clinical features from those of acute myocardial infarction (AMI). In this study, we identify the differential associations of exosomal miRNAs with CTO and AMI. Exosomes were isolated from the plasma obtained from coronary arteries of patients undergoing percutaneous coronary intervention to treat CTO (n = 29) and AMI (n = 24), followed by small RNA sequencing, target gene predictions, and functional enrichment analyses. Promising miRNA markers were validated using real-time PCR in 35 CTO, 35 AMI, and 10 normal subjects. A total of 205 miRNAs were detected in all subjects, and 20 and 12 miRNAs were upregulated and downregulated in CTO compared to AMI patients, respectively (|fold change| > 4, FDR q < 0.05). The target genes of miRNAs that were higher in CTO patients were associated with “regulation of cell cycle phase transition”, “cell growth”, and “apoptosis”. The target genes of miRNAs that were lower in CTO patients were enriched in terms such as “muscle cell differentiation”, “response to oxygen levels”, and “artery morphogenesis”. On qRT-PCR analysis, the expression levels of miR-9-5p and miR-127-3p were significantly different between CTO and AMI patients. The miRNA expression levels accurately distinguished CTO from AMI patients with 79% specificity and 97% sensitivity. The miRNA contents of plasma exosomes were significantly different between CTO and AMI patients. The miRNAs may play important roles in CTO and AMI. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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24 pages, 969 KiB  
Review
Novel Insights into Diabetic Kidney Disease
by Ewelina Młynarska, Dominika Buławska, Witold Czarnik, Joanna Hajdys, Gabriela Majchrowicz, Filip Prusinowski, Magdalena Stabrawa, Jacek Rysz and Beata Franczyk
Int. J. Mol. Sci. 2024, 25(18), 10222; https://doi.org/10.3390/ijms251810222 - 23 Sep 2024
Viewed by 2579
Abstract
Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM), affecting over one-third of type 1 and nearly half of type 2 diabetes patients. As the leading cause of end-stage renal disease (ESRD) globally, DKD develops through a complex interplay of [...] Read more.
Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM), affecting over one-third of type 1 and nearly half of type 2 diabetes patients. As the leading cause of end-stage renal disease (ESRD) globally, DKD develops through a complex interplay of chronic hyperglycemia, oxidative stress, and inflammation. Early detection is crucial, with diagnosis based on persistent albuminuria and reduced estimated glomerular filtration rate (eGFR). Treatment strategies emphasize comprehensive management, including glycemic control, blood pressure regulation, and the use of nephroprotective agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Ongoing research explores novel therapies targeting molecular pathways and non-coding RNAs. Preventive measures focus on rigorous control of hyperglycemia and hypertension, aiming to mitigate disease progression. Despite therapeutic advances, DKD remains a leading cause of ESRD, highlighting the need for continued research to identify new biomarkers and innovative treatments. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease: Second Edition)
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22 pages, 6569 KiB  
Article
Bioinformatics Identification and Expression Analysis of Acetyl-CoA Carboxylase Reveal Its Role in Isoflavone Accumulation during Soybean Seed Development
by Xu Wu, Zhenhong Yang, Yina Zhu, Yuhang Zhan, Yongguang Li, Weili Teng, Yingpeng Han and Xue Zhao
Int. J. Mol. Sci. 2024, 25(18), 10221; https://doi.org/10.3390/ijms251810221 - 23 Sep 2024
Cited by 1 | Viewed by 802
Abstract
Isoflavones belong to the class of flavonoid compounds, which are important secondary metabolites that play a crucial role in plant development and defense. Acetyl-CoA carboxylase (ACCase) is a biotin-dependent enzyme that catalyzes the conversion of Acetyl-CoA into Malonyl-CoA in plants. It is a [...] Read more.
Isoflavones belong to the class of flavonoid compounds, which are important secondary metabolites that play a crucial role in plant development and defense. Acetyl-CoA carboxylase (ACCase) is a biotin-dependent enzyme that catalyzes the conversion of Acetyl-CoA into Malonyl-CoA in plants. It is a key enzyme in fatty acid synthesis and also catalyzes the production of various secondary metabolites. However, information on the ACC gene family in the soybean (Glycine max L. Merr.) genome and the specific members involved in isoflavone biosynthesis is still lacking. In this study, we identified 20 ACC family genes (GmACCs) from the soybean genome and further characterized their evolutionary relationships and expression patterns. Phylogenetic analysis showed that the GmACCs could be divided into five groups, and the gene structures within the same groups were highly conserved, indicating that they had similar functions. The GmACCs were randomly distributed across 12 chromosomes, and collinearity analysis suggested that many GmACCs originated from tandem and segmental duplications, with these genes being under purifying selection. In addition, gene expression pattern analysis indicated that there was functional divergence among GmACCs in different tissues. The GmACCs reached their peak expression levels during the early or middle stages of seed development. Based on the transcriptome and isoflavone content data, a weighted gene co-expression network was constructed, and three candidate genes (Glyma.06G105900, Glyma.13G363500, and Glyma.13G057400) that may positively regulate isoflavone content were identified. These results provide valuable information for the further functional characterization and application of GmACCs in isoflavone biosynthesis in soybean. Full article
(This article belongs to the Special Issue Genetics- and Genomics-Based Crop Improvement and Breeding: 3rd Edition)
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21 pages, 1564 KiB  
Review
NMDARs in Alzheimer’s Disease: Between Synaptic and Extrasynaptic Membranes
by Sergio Escamilla, Javier Sáez-Valero and Inmaculada Cuchillo-Ibáñez
Int. J. Mol. Sci. 2024, 25(18), 10220; https://doi.org/10.3390/ijms251810220 - 23 Sep 2024
Viewed by 1261
Abstract
N-methyl-D-aspartate receptors (NMDARs) are glutamate receptors with key roles in synaptic communication and plasticity. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs can promote cell death underlying a potential mechanism of neurodegeneration occurring [...] Read more.
N-methyl-D-aspartate receptors (NMDARs) are glutamate receptors with key roles in synaptic communication and plasticity. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs can promote cell death underlying a potential mechanism of neurodegeneration occurring in Alzheimer’s disease (AD). The distribution of synaptic versus extrasynaptic NMDARs has emerged as an important parameter contributing to neuronal dysfunction in neurodegenerative diseases including AD. Here, we review the concept of extrasynaptic NMDARs, as this population is present in numerous neuronal cell membranes but also in the membranes of various non-neuronal cells. Previous evidence regarding the membranal distribution of synaptic versus extrasynaptic NMDRs in relation to AD mice models and in the brains of AD patients will also be reviewed. Full article
(This article belongs to the Collection Feature Papers in Molecular Neurobiology)
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16 pages, 2333 KiB  
Article
Discovery and Prediction Study of the Dominant Pharmacological Action Organ of Aconitum carmichaeli Debeaux Using Multiple Bioinformatic Analyses
by Musun Park, Eun-Hye Seo, Jin-Mu Yi and Seongwon Cha
Int. J. Mol. Sci. 2024, 25(18), 10219; https://doi.org/10.3390/ijms251810219 - 23 Sep 2024
Viewed by 812
Abstract
Herbs, such as Aconitum carmichaeli Debeaux (ACD), have long been used as therapies, but it is difficult to identify which organs of the human body are affected by the various compounds. In this study, we predicted the organ where the drug predominantly acts [...] Read more.
Herbs, such as Aconitum carmichaeli Debeaux (ACD), have long been used as therapies, but it is difficult to identify which organs of the human body are affected by the various compounds. In this study, we predicted the organ where the drug predominantly acts using bioinformatics and verified it using transcriptomics. We constructed a computer-aided brain system network (BSN) and intestinal system network (ISN). We predicted the action points of ACD using network pharmacology (NP) analysis and predicted the dockable proteins acting in the BSN and ISN using statistical-based docking analysis. The predicted results were verified using ACD-induced transcriptome analysis. The predicted results showed that both the NP and docking analyses predominantly acted on the BSN and showed better hit rates in the hub nodes. In addition, we confirmed through verification experiments that the SW1783 cell line had more than 10 times more differentially expressed genes than the HT29 cell line and that the dominant acting organ is the brain, using network dimension spanning analysis. In conclusion, we found that ACD preferentially acts in the brain rather than in the intestine, and this multi-bioinformatics-based approach is expected to be used in future studies of drug efficacy and side effects. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Action of Adaptogens—in Search of Natural Methods of Restoring Homeostasis)
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88 pages, 16393 KiB  
Review
Structural Features, Chemical Diversity, and Physical Properties of Microporous Sodalite-Type Materials: A Review
by Nikita V. Chukanov and Sergey M. Aksenov
Int. J. Mol. Sci. 2024, 25(18), 10218; https://doi.org/10.3390/ijms251810218 - 23 Sep 2024
Viewed by 766
Abstract
This review contains data on a wide class of microporous materials with frameworks belonging to the sodalite topological type. Various methods for the synthesis of these materials, their structural and crystal chemical features, as well as physical and chemical properties are discussed. Specific [...] Read more.
This review contains data on a wide class of microporous materials with frameworks belonging to the sodalite topological type. Various methods for the synthesis of these materials, their structural and crystal chemical features, as well as physical and chemical properties are discussed. Specific properties of sodalite-related materials make it possible to consider they as thermally stable ionic conductors, catalysts and catalyst carriers, sorbents, ion exchangers for water purification, matrices for the immobilization of radionuclides and heavy metals, hydrogen and methane storage, and stabilization of chromophores and phosphors. It has been shown that the diversity of properties of sodalite-type materials is associated with the chemical diversity of their frameworks and extra-framework components, as well as with the high elasticity of the framework. Full article
(This article belongs to the Special Issue Women’s Special Issue Series: Recent Advances in Molecular Crystal Materials)
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12 pages, 861 KiB  
Article
Zinc and Ferritin Levels and Their Associations with Functional Disorders and/or Thyroid Autoimmunity: A Population-Based Case–Control Study
by Hernando Vargas-Uricoechea, Karen Urrego-Noguera, Hernando Vargas-Sierra and María Pinzón-Fernández
Int. J. Mol. Sci. 2024, 25(18), 10217; https://doi.org/10.3390/ijms251810217 - 23 Sep 2024
Viewed by 792
Abstract
Population zinc and iron status appear to be associated with an increased risk of thyroid function abnormalities and thyroid autoimmunity (AITD). In the present study, we aimed to determine whether zinc and/or iron levels (assessed by ferritin levels) were associated with the presence [...] Read more.
Population zinc and iron status appear to be associated with an increased risk of thyroid function abnormalities and thyroid autoimmunity (AITD). In the present study, we aimed to determine whether zinc and/or iron levels (assessed by ferritin levels) were associated with the presence of AITD and with alterations in thyroid function. A population-based case–control study (n = 1048) was conducted (cases: n = 524; controls: n = 524). Participants were measured for blood concentrations of zinc and ferritin, TSH, FT4, FT3, and thyroid autoantibodies. No significant differences were found in relation to ferritin levels between cases and controls. Among cases, the prevalence of low zinc levels in those with hypothyroidism (both subclinical and overt) was 49.1% [odds ratio (OR) of low zinc levels: 5.926; 95% CI: 3.756–9.351]. The prevalence of low zinc levels in participants with hyperthyroidism (both subclinical and overt) was 37.5% [OR of low zinc levels: 3.683; 95% CI: 1.628–8.33]. The zinc value that best discriminated the highest frequency of AITD was 70.4 µg/dL [sensitivity: 0.947, 1–specificity: 0.655, specificity: 0.345]. The highest frequency of AITD was calculated based on a zinc value <70 µg/dL (relative to a normal value), with this frequency being significantly higher in cases than in controls [OR: 9.3; 95% CI: 6.1–14.3 (p = 0.001)]. In conclusion, the results of our study suggest that zinc deficiency is associated with an increased frequency of functional thyroid disorders and thyroid autoimmunity. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Health and Diseases)
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16 pages, 6730 KiB  
Article
Hypoxia-Induced Adaptations of N-Glycomes and Proteomes in Breast Cancer Cells and Their Secreted Extracellular Vesicles
by Bojia Peng, Kai Bartkowiak, Feizhi Song, Paula Nissen, Hartmut Schlüter and Bente Siebels
Int. J. Mol. Sci. 2024, 25(18), 10216; https://doi.org/10.3390/ijms251810216 - 23 Sep 2024
Viewed by 972
Abstract
The hypoxic tumor microenvironment significantly impacts cellular behavior and intercellular communication, with extracellular vesicles (EVs) playing a crucial role in promoting angiogenesis, metastasis, and host immunosuppression, and presumed cancer progression and metastasis are closely associated with the aberrant surface N-glycan expression in EVs. [...] Read more.
The hypoxic tumor microenvironment significantly impacts cellular behavior and intercellular communication, with extracellular vesicles (EVs) playing a crucial role in promoting angiogenesis, metastasis, and host immunosuppression, and presumed cancer progression and metastasis are closely associated with the aberrant surface N-glycan expression in EVs. We hypothesize that hypoxic tumors synthesize specific hypoxia-induced N-glycans in response to or as a consequence of hypoxia. This study utilized nano-LC–MS/MS to integrate quantitative proteomic and N-glycomic analyses of both cells and EVs derived from the MDA-MB-231 breast cancer cell line cultured under normoxic and hypoxic conditions. Whole N-glycome and proteome profiling revealed that hypoxia has an impact on the asparagine N-linked glycosylation patterns and on the glycolysis/gluconeogenesis proteins in cells in terms of altered N-glycosylation for their adaptation to low-oxygen conditions. Distinct N-glycan types, high-mannose glycans like Man3 and Man9, were highly abundant in the hypoxic cells. On the other hand, alterations in the sialylation and fucosylation patterns were observed in the hypoxic cells. Furthermore, hypoxia-induced EVs exhibit a signature consisting of mono-antennary structures and specific N-glycans (H4N3F1S2, H3N3F1S0, and H7N4F3S2; H8N4F1S0 and H8N6F1S2), which are significantly associated with poor prognoses for breast tumors, presumably altering the interactions within the tumor microenvironment to promote tumorigenesis and metastasis. Our findings provide an overview of the N-glycan profiles, particularly under hypoxic conditions, and offer insights into the potential biomarkers for tracking tumor microenvironment dynamics and for developing precision medicine approaches in oncology. Full article
(This article belongs to the Section Molecular Oncology)
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16 pages, 2437 KiB  
Article
Polymer Physics Models Reveal Structural Folding Features of Single-Molecule Gene Chromatin Conformations
by Mattia Conte, Alex Abraham, Andrea Esposito, Liyan Yang, Johan H. Gibcus, Krishna M. Parsi, Francesca Vercellone, Andrea Fontana, Florinda Di Pierno, Job Dekker and Mario Nicodemi
Int. J. Mol. Sci. 2024, 25(18), 10215; https://doi.org/10.3390/ijms251810215 - 23 Sep 2024
Viewed by 820
Abstract
Here, we employ polymer physics models of chromatin to investigate the 3D folding of a 2 Mb wide genomic region encompassing the human LTN1 gene, a crucial DNA locus involved in key cellular functions. Through extensive Molecular Dynamics simulations, we reconstruct in silico [...] Read more.
Here, we employ polymer physics models of chromatin to investigate the 3D folding of a 2 Mb wide genomic region encompassing the human LTN1 gene, a crucial DNA locus involved in key cellular functions. Through extensive Molecular Dynamics simulations, we reconstruct in silico the ensemble of single-molecule LTN1 3D structures, which we benchmark against recent in situ Hi-C 2.0 data. The model-derived single molecules are then used to predict structural folding features at the single-cell level, providing testable predictions for super-resolution microscopy experiments. Full article
(This article belongs to the Special Issue Computational Modelling and Molecular Dynamics Simulations of Biological Systems)
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12 pages, 2159 KiB  
Article
Genomic Landscape of Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Central Study
by Fei Fei, Amar Jariwala, Sheeja Pullarkat, Eric Loo, Yan Liu, Parastou Tizro, Haris Ali, Salman Otoukesh, Idoroenyi Amanam, Andrew Artz, Feras Ally, Milhan Telatar, Ryotaro Nakamura, Guido Marcucci and Michelle Afkhami
Int. J. Mol. Sci. 2024, 25(18), 10214; https://doi.org/10.3390/ijms251810214 - 23 Sep 2024
Viewed by 901
Abstract
The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = [...] Read more.
The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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16 pages, 2874 KiB  
Article
Age-Dependent Differences in Radiation-Induced DNA Damage Responses in Intestinal Stem Cells
by Guanyu Zhou, Tsutomu Shimura, Taiki Yoneima, Akiko Nagamachi, Akinori Kanai, Kazutaka Doi and Megumi Sasatani
Int. J. Mol. Sci. 2024, 25(18), 10213; https://doi.org/10.3390/ijms251810213 - 23 Sep 2024
Viewed by 968
Abstract
Age at exposure is a critical modifier of the risk of radiation-induced cancer. However, the effects of age on radiation-induced carcinogenesis remain poorly understood. In this study, we focused on tissue stem cells using Lgr5-eGFP-ires-CreERT2 mice to compare radiation-induced DNA damage responses [...] Read more.
Age at exposure is a critical modifier of the risk of radiation-induced cancer. However, the effects of age on radiation-induced carcinogenesis remain poorly understood. In this study, we focused on tissue stem cells using Lgr5-eGFP-ires-CreERT2 mice to compare radiation-induced DNA damage responses between Lgr5+ and Lgr5- intestinal stem cells. Three-dimensional immunostaining analyses demonstrated that radiation induced apoptosis and the mitotic index more efficiently in adult Lgr5- stem cells than in adult Lgr5+ stem cells but not in infants, regardless of Lgr5 expression. Supporting this evidence, rapid and transient p53 activation occurred after irradiation in adult intestinal crypts but not in infants. RNA sequencing revealed greater variability in gene expression in adult Lgr5+ stem cells than in infant Lgr5+ stem cells after irradiation. Notably, the cell cycle and DNA repair pathways were more enriched in adult stem cells than in infant stem cells after irradiation. Our findings suggest that radiation-induced DNA damage responses in mouse intestinal crypts differ between infants and adults, potentially contributing to the age-dependent susceptibility to radiation carcinogenesis. Full article
(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)
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14 pages, 4597 KiB  
Article
Needle and Branch Trait Variation Analysis and Associated SNP Loci Mining in Larix olgensis
by Ying Cui, Jiawei Yan, Luping Jiang, Junhui Wang, Manman Huang, Xiyang Zhao and Shengqing Shi
Int. J. Mol. Sci. 2024, 25(18), 10212; https://doi.org/10.3390/ijms251810212 - 23 Sep 2024
Viewed by 648
Abstract
Needles play key roles in photosynthesis and branch growth in Larix olgensis. However, genetic variation and SNP marker mining associated with needle and branch-related traits have not been reported yet. In this study, we examined 131 samples of unrelated genotypes from L. [...] Read more.
Needles play key roles in photosynthesis and branch growth in Larix olgensis. However, genetic variation and SNP marker mining associated with needle and branch-related traits have not been reported yet. In this study, we examined 131 samples of unrelated genotypes from L. olgensis provenance trails. We investigated phenotypic data for seven needle and one branch-related traits before whole genome resequencing (WGRS) was employed to perform a genome-wide association study (GWAS). Subsequently, the results were used to screen single nucleotide polymorphism (SNP) loci that were significantly correlated with the studied traits. We identified a total of 243,090,868 SNP loci, and among them, we discovered a total of 161 SNP loci that were significantly associated with these traits using a general linear model (GLM). Based on the GWAS results, Kompetitive Allele-Specific PCR (KASP), designed based on the DNA of population samples, were used to validate the loci associated with L. olgensis phenotypes. In total, 20 KASP markers were selected from the 161 SNPs loci, and BSBM01000635.1_4693780, BSBM01000114.1_5114757, and BSBM01000114.1_5128586 were successfully amplified, were polymorphic, and were associated with the phenotypic variation. These developed KASP markers could be used for the genetic improvement of needle and branch-related traits in L. olgensis. Full article
(This article belongs to the Section Molecular Plant Sciences)
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26 pages, 2109 KiB  
Review
Bioavailability as Proof to Authorize the Clinical Testing of Neurodegenerative Drugs—Protocols and Advice for the FDA to Meet the ALS Act Vision
by Sarfaraz K. Niazi
Int. J. Mol. Sci. 2024, 25(18), 10211; https://doi.org/10.3390/ijms251810211 - 23 Sep 2024
Viewed by 846
Abstract
Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved [...] Read more.
Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood–brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs. Full article
(This article belongs to the Section Molecular Pharmacology)
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16 pages, 9353 KiB  
Article
Discovery of Novel Biomarkers with Extended Non-Coding RNA Interactor Networks from Genetic and Protein Biomarkers
by Gregor Jezernik, Damjan Glavač, Pavel Skok, Martina Krušič, Uroš Potočnik and Mario Gorenjak
Int. J. Mol. Sci. 2024, 25(18), 10210; https://doi.org/10.3390/ijms251810210 - 23 Sep 2024
Viewed by 694
Abstract
Curated online interaction databases and gene ontology tools have streamlined the analysis of highly complex gene/protein networks. However, understanding of disease pathogenesis has gradually shifted from a protein-based core to complex interactive networks where non-coding RNA (ncRNA) is thought to play an essential [...] Read more.
Curated online interaction databases and gene ontology tools have streamlined the analysis of highly complex gene/protein networks. However, understanding of disease pathogenesis has gradually shifted from a protein-based core to complex interactive networks where non-coding RNA (ncRNA) is thought to play an essential role. As current gene ontology is based predominantly on protein-level information, there is a growing need to analyze networks with ncRNA. In this study, we propose a gene ontology workflow integrating ncRNA using the NPInter V5.0 database. To validate the proposed workflow, we analyzed our previously published curated biomarker datasets for hidden disease susceptibility processes and pharmacogenomics. Our results show a novel involvement of melanogenesis in psoriasis response to biological drugs in general. Hyperpigmentation has been previously observed in psoriasis following treatment with currently indicated biological drugs, thus calling attention to melanogenesis research as a response biomarker in psoriasis. Moreover, our proposed workflow highlights the need to critically evaluate computed ncRNA interactions within databases and a demand for gene ontology analysis of large miRNA blocks. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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24 pages, 7372 KiB  
Article
Insights into the Detoxification of Spruce Monoterpenes by the Eurasian Spruce Bark Beetle
by Aisha Naseer, Vivek Vikram Singh, Gothandapani Sellamuthu, Jiří Synek, Kanakachari Mogilicherla, Ladislav Kokoska and Amit Roy
Int. J. Mol. Sci. 2024, 25(18), 10209; https://doi.org/10.3390/ijms251810209 - 23 Sep 2024
Viewed by 740
Abstract
Plant defence mechanisms, including physical barriers like toughened bark and chemical defences like allelochemicals, are essential for protecting them against pests. Trees allocate non-structural carbohydrates (NSCs) to produce secondary metabolites like monoterpenes, which increase during biotic stress to fend off pests like the [...] Read more.
Plant defence mechanisms, including physical barriers like toughened bark and chemical defences like allelochemicals, are essential for protecting them against pests. Trees allocate non-structural carbohydrates (NSCs) to produce secondary metabolites like monoterpenes, which increase during biotic stress to fend off pests like the Eurasian spruce bark beetle, ESBB (Ips typographus). Despite these defences, the ESBB infests Norway spruce, causing significant ecological damage by exploiting weakened trees and using pheromones for aggregation. However, the mechanism of sensing and resistance towards host allelochemicals in ESBB is poorly understood. We hypothesised that the exposure of ESBB to spruce allelochemicals, especially monoterpenes, leads to an upsurge in the important detoxification genes like P450s, GSTs, UGTs, and transporters, and at the same time, genes responsible for development must be compromised. The current study demonstrates that exposure to monoterpenes like R-limonene and sabiene effectively elevated detoxification enzyme activities. The differential gene expression (DGE) analysis revealed 294 differentially expressed (DE) detoxification genes in response to R-limonene and 426 DE detoxification genes in response to sabiene treatments, with 209 common genes between the treatments. Amongst these, genes from the cytochrome P450 family 4 and 6 genes (CP4 and CP6), esterases, glutathione S-transferases family 1 (GSTT1), UDP-glucuronosyltransferase 2B genes (UDB), and glucose synthesis-related dehydrogenases were highly upregulated. We further validated 19 genes using RT-qPCR. Additionally, we observed similar high expression levels of detoxification genes across different monoterpene treatments, including myrcene and α-pinene, suggesting a conserved detoxification mechanism in ESBB, which demands further investigation. These findings highlight the potential for molecular target-based beetle management strategies targeting these key detoxification genes. Full article
(This article belongs to the Special Issue Molecular Signalling in Multitrophic Systems Involving Arthropods)
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27 pages, 2288 KiB  
Review
Role of Gut Microbial Metabolites in Cardiovascular Diseases—Current Insights and the Road Ahead
by Sayantap Datta, Sindhura Pasham, Sriram Inavolu, Krishna M. Boini and Saisudha Koka
Int. J. Mol. Sci. 2024, 25(18), 10208; https://doi.org/10.3390/ijms251810208 - 23 Sep 2024
Cited by 2 | Viewed by 1674
Abstract
Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood [...] Read more.
Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come. Full article
(This article belongs to the Special Issue Endothelial Dysfunction and Cardiovascular Diseases)
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15 pages, 2800 KiB  
Article
bZIP Transcription Factor PavbZIP6 Regulates Anthocyanin Accumulation by Increasing Abscisic Acid in Sweet Cherry
by Shilin Gai, Bingyang Du, Yuqin Xiao, Xiang Zhang, Maihemuti Turupu, Qisheng Yao, Xinyu Wang, Yongzhen Yan and Tianhong Li
Int. J. Mol. Sci. 2024, 25(18), 10207; https://doi.org/10.3390/ijms251810207 - 23 Sep 2024
Viewed by 694
Abstract
Basic leucine zipper (bZIP) transcription factors (TFs) play a crucial role in anthocyanin accumulation in plants. In addition to bZIP TFs, abscisic acid (ABA) increases anthocyanin biosynthesis. Therefore, this study aimed to investigate whether bZIP TFs are involved in ABA-induced anthocyanin accumulation in [...] Read more.
Basic leucine zipper (bZIP) transcription factors (TFs) play a crucial role in anthocyanin accumulation in plants. In addition to bZIP TFs, abscisic acid (ABA) increases anthocyanin biosynthesis. Therefore, this study aimed to investigate whether bZIP TFs are involved in ABA-induced anthocyanin accumulation in sweet cherry and elucidate the underlying molecular mechanisms. Specifically, the BLAST method was used to identify bZIP genes in sweet cherry. Additionally, we examined the expression of ABA- and anthocyanin-related genes in sweet cherry following the overexpression or knockdown of a bZIP candidate gene. In total, we identified 54 bZIP-encoding genes in the sweet cherry genome. Basic leucine zipper 6 (bZIP6) showed significantly increased expression, along with increased anthocyanin accumulation in sweet cherry. Additionally, yeast one-hybrid and dual-luciferase assays indicated that PavbZIP6 enhanced the expression of anthocyanin biosynthetic genes (PavDFR, PavANS, and PavUFGT), thereby increasing anthocyanin accumulation. Moreover, PavbZIP6 interacted directly with the PavBBX6 promoter, thereby regulating PavNCED1 to promote abscisic acid (ABA) synthesis and enhance anthocyanin accumulation in sweet cherry fruit. Conclusively, this study reveals a novel mechanism by which PavbZIP6 mediates anthocyanin biosynthesis in response to ABA and contributes to our understanding of the mechanism of bZIP genes in the regulation of anthocyanin biosynthesis in sweet cherry. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 2300 KiB  
Article
Vitexin Mitigates Haloperidol-Induced Orofacial Dyskinesia in Rats through Activation of the Nrf2 Pathway
by Shu-Mei Chen, Mao-Hsien Wang, Kuo-Chi Chang, Chih-Hsiang Fang, Yi-Wen Lin and Hsiang-Chien Tseng
Int. J. Mol. Sci. 2024, 25(18), 10206; https://doi.org/10.3390/ijms251810206 - 23 Sep 2024
Viewed by 626
Abstract
Vitexin (VTX), a C-glycosylated flavone found in various medicinal herbs, is known for its antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the protective effects of VTX against orofacial dyskinesia (OD) in rats, induced by haloperidol (HPD), along with the neuroprotective mechanisms underlying [...] Read more.
Vitexin (VTX), a C-glycosylated flavone found in various medicinal herbs, is known for its antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the protective effects of VTX against orofacial dyskinesia (OD) in rats, induced by haloperidol (HPD), along with the neuroprotective mechanisms underlying these effects. OD was induced by administering HPD (1 mg/kg i.p.) to rats for 21 days, which led to an increase in the frequency of vacuous chewing movements (VCMs) and tongue protrusion (TP). VTX (10 and 30 mg/kg) was given intraperitoneally 60 min after each HPD injection during the same period. On the 21st day, following assessments of OD, the rats were sacrificed, and nitrosative and oxidative stress, antioxidant capacity, mitochondrial function, neuroinflammation, and apoptosis markers in the striatum were measured. HPD effectively induced OD, while VTX significantly reduced HPD-induced OD, decreased oxidative stress, enhanced antioxidant capacity, prevented mitochondrial dysfunction, and reduced neuroinflammatory and apoptotic markers in the striatum, and the protective effects of VTX on both behavioral and biochemical aspects of HPD-induced OD were significantly reduced when trigonelline (TGN), an inhibitor of the nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated pathway, was administered. These findings suggest that VTX provides neuroprotection against HPD-induced OD, potentially through the Nrf2 pathway, indicating its potential as a therapeutic candidate for the prevention or treatment of tardive dyskinesia (TD) in clinical settings. However, further detailed research is required to confirm these preclinical findings and fully elucidate VTX’s therapeutic potential in human studies. Full article
(This article belongs to the Special Issue The Impact of Natural Bioactive Compounds on Human Health and Disease)
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19 pages, 2334 KiB  
Article
Accumulation of Cerebrospinal Fluid, Ventricular Enlargement, and Cerebral Folate Metabolic Errors Unify a Diverse Group of Neuropsychiatric Conditions Affecting Adult Neocortical Functions
by Lena Ikeda, Adrià Vilaseca Capel, Dhruti Doddaballapur and Jaleel Miyan
Int. J. Mol. Sci. 2024, 25(18), 10205; https://doi.org/10.3390/ijms251810205 - 23 Sep 2024
Viewed by 1091
Abstract
Cerebrospinal fluid (CSF) is a fluid critical to brain development, function, and health. It is actively secreted by the choroid plexus, and it emanates from brain tissue due to osmolar exchange and the constant contribution of brain metabolism and astroglial fluid output to [...] Read more.
Cerebrospinal fluid (CSF) is a fluid critical to brain development, function, and health. It is actively secreted by the choroid plexus, and it emanates from brain tissue due to osmolar exchange and the constant contribution of brain metabolism and astroglial fluid output to interstitial fluid into the ventricles of the brain. CSF acts as a growth medium for the developing cerebral cortex and a source of nutrients and signalling throughout life. Together with perivascular glymphatic and interstitial fluid movement through the brain and into CSF, it also acts to remove toxins and maintain metabolic balance. In this study, we focused on cerebral folate status, measuring CSF concentrations of folate receptor alpha (FOLR1); aldehyde dehydrogenase 1L1, also known as 10-formyl tetrahydrofolate dehydrogenase (ALDH1L1 and FDH); and total folate. These demonstrate the transport of folate from blood across the blood–CSF barrier and into CSF (FOLR1 + folate), and the transport of folate through the primary FDH pathway from CSF into brain FDH + ve astrocytes. Based on our hypothesis that CSF flow, drainage issues, or osmotic forces, resulting in fluid accumulation, would have an associated cerebral folate imbalance, we investigated folate status in CSF from neurological conditions that have a severity association with enlarged ventricles. We found that all the conditions we examined had a folate imbalance, but these folate imbalances were not all the same. Given that folate is essential for key cellular processes, including DNA/RNA synthesis, methylation, nitric oxide, and neurotransmitter synthesis, we conclude that ageing or some form of trauma in life can lead to CSF accumulation and ventricular enlargement and result in a specific folate imbalance/deficiency associated with the specific neurological condition. We believe that addressing cerebral folate imbalance may therefore alleviate many of the underlying deficits and symptoms in these conditions. Full article
(This article belongs to the Special Issue Multiplicity of Cerebrospinal Fluid Functions in Health and Disease)
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22 pages, 1101 KiB  
Review
Mathematical Modeling and Inference of Epidermal Growth Factor-Induced Mitogen-Activated Protein Kinase Cell Signaling Pathways
by Jinping Feng, Xinan Zhang and Tianhai Tian
Int. J. Mol. Sci. 2024, 25(18), 10204; https://doi.org/10.3390/ijms251810204 - 23 Sep 2024
Viewed by 1015
Abstract
The mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling cascade that plays a key role in various cellular processes. Understanding the regulatory mechanisms of this pathway is essential for developing effective interventions and targeted therapies for related diseases. Recent advances in [...] Read more.
The mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling cascade that plays a key role in various cellular processes. Understanding the regulatory mechanisms of this pathway is essential for developing effective interventions and targeted therapies for related diseases. Recent advances in single-cell proteomic technologies have provided unprecedented opportunities to investigate the heterogeneity and noise within complex, multi-signaling networks across diverse cells and cell types. Mathematical modeling has become a powerful interdisciplinary tool that bridges mathematics and experimental biology, providing valuable insights into these intricate cellular processes. In addition, statistical methods have been developed to infer pathway topologies and estimate unknown parameters within dynamic models. This review presents a comprehensive analysis of how mathematical modeling of the MAPK pathway deepens our understanding of its regulatory mechanisms, enhances the prediction of system behavior, and informs experimental research, with a particular focus on recent advances in modeling and inference using single-cell proteomic data. Full article
(This article belongs to the Special Issue Computational Modelling and Molecular Dynamics Simulations of Biological Systems)
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10 pages, 716 KiB  
Review
Follicular Skin Disorders, Inflammatory Bowel Disease, and the Microbiome: A Systematic Review
by Lauren Fleshner, Katie Roster, Banu Farabi, Rahim Hirani, Katharine Tepper, Capecomorin S Pitchumoni, Bijan Safai and Shoshana Marmon
Int. J. Mol. Sci. 2024, 25(18), 10203; https://doi.org/10.3390/ijms251810203 - 23 Sep 2024
Viewed by 1021
Abstract
Follicular skin disorders, including hidradenitis suppurativa (HS), frequently coexist with systemic autoinflammatory diseases, such as inflammatory bowel disease (IBD) and its subtypes, Crohn’s disease and ulcerative colitis. Previous studies suggest that dysbiosis of the human gut microbiome may serve as a pathogenic link [...] Read more.
Follicular skin disorders, including hidradenitis suppurativa (HS), frequently coexist with systemic autoinflammatory diseases, such as inflammatory bowel disease (IBD) and its subtypes, Crohn’s disease and ulcerative colitis. Previous studies suggest that dysbiosis of the human gut microbiome may serve as a pathogenic link between HS and IBD. However, the role of the microbiome (gut, skin, and blood) in the context of IBD and various follicular disorders remains underexplored. Here, we performed a systematic review to investigate the relationship between follicular skin disorders, IBD, and the microbiome. Of the sixteen included studies, four evaluated the impact of diet on the microbiome in HS patients, highlighting a possible link between gut dysbiosis and yeast-exclusion diets. Ten studies explored bacterial colonization and HS severity with specific gut and skin microbiota, including Enterococcus and Veillonella. Two studies reported on immunological or serological biomarkers in HS patients with autoinflammatory disease, including IBD, and identified common markers including elevated cytokines and T-lymphocytes. Six studies investigated HS and IBD patients concurrently. Our systematic literature review highlights the complex interplay between the human microbiome, IBD, and follicular disorders with a particular focus on HS. The results indicate that dietary modifications hold promise as a therapeutic intervention to mitigate the burden of HS and IBD. Microbiota analyses and the identification of key serological biomarkers are crucial for a deeper understanding of the impact of dysbiosis in these conditions. Future research is needed to more thoroughly delineate the causal versus associative roles of dysbiosis in patients with both follicular disorders and IBD. Full article
(This article belongs to the Special Issue Interactions of Microbiome in Skin, Gastrointestinal, and Mucocutaneous Diseases)
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17 pages, 10727 KiB  
Article
Supraphysiological Dose of Testosterone Impairs the Expression and Distribution of Sex Steroid Receptors during Endometrial Receptivity Development in Female Sprague–Dawley Rats
by Allia Najmie Muhammad Yusuf, Mohd Fariz Amri, Azizah Ugusman, Adila A Hamid and Mohd Helmy Mokhtar
Int. J. Mol. Sci. 2024, 25(18), 10202; https://doi.org/10.3390/ijms251810202 - 23 Sep 2024
Viewed by 582
Abstract
This study aims to investigate the effect of a supraphysiological dose of testosterone on the levels of sex steroid hormones and the expression and distribution of sex steroid receptors in the uterus during the endometrial receptivity development period. In this study, adult female [...] Read more.
This study aims to investigate the effect of a supraphysiological dose of testosterone on the levels of sex steroid hormones and the expression and distribution of sex steroid receptors in the uterus during the endometrial receptivity development period. In this study, adult female Sprague–Dawley rats (n = 24) were subcutaneously administered 1 mg/kg/day of testosterone alone or in combination with the inhibitors (finasteride or anastrozole or both) from day 1 to day 3 post-coitus, while a group of six untreated rats served as a control group. The rats were sacrificed on the evening of post-coital day 4 of to measure sex steroid hormone levels by ELISA. Meanwhile, gene expression and protein distribution of sex steroid receptors were analysed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), respectively. In this study, treatment with a supraphysiological dose of testosterone led to a significant reduction in oestrogen and progesterone levels compared to the control. The mRNA expression of the androgen receptor increased significantly in all treatment groups, while the mRNA expression of both the progesterone receptor and the oestrogen receptor-α decreased significantly in all treatment groups. The IHC findings of all sex steroid receptors were coherent with all mRNAs involved. This study shows that a supraphysiological dose of testosterone was able to interrupt the short period of the implantation window. This finding could serve as a basis for understanding the role of testosterone in endometrial receptivity in order to develop further therapeutic approaches targeting androgen-mediated disorders of endometrial receptivity. Full article
(This article belongs to the Special Issue Molecular Research on Embryo Developmental Potential)
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