Current Issues in Molecular Biology

20 pages, 7063 KiB

Open AccessArticle

Toxicity Responses from Tributyltin Chloride on Haarder (Planiliza haematocheila) Livers: Oxidative Stress, Energy Metabolism Dysfunction, and Apoptosis

by Changsheng Zhao, Anning Suo, Dewen Ding and Wencheng Song

Curr. Issues Mol. Biol. 2025, 47(7), 526; https://doi.org/10.3390/cimb47070526 - 8 Jul 2025

Abstract

In coastal waters, tributyltin chloride (TBTC), a persistent organic pollutant, is extensively present. It is uncertain, therefore, if exposure to TBTC can harm haarders and how. This study exposed the fish for 60 days in order to investigate the molecular mechanism of haarder [...] Read more.

In coastal waters, tributyltin chloride (TBTC), a persistent organic pollutant, is extensively present. It is uncertain, therefore, if exposure to TBTC can harm haarders and how. This study exposed the fish for 60 days in order to investigate the molecular mechanism of haarder following TBTC poisoning. Our findings demonstrated that growth indices dropped, liver tissue was damaged, and the liver’s total tin concentration rose following TBTC exposure. Furthermore, we discovered that blood reactive oxygen species rose while total blood cell count decreased. As malondialdehyde levels rose, total antioxidant capacity and antioxidant enzyme activity (superoxide dismutase, catalase, and glutathione peroxidase) were markedly reduced. After being exposed to TBTC, liver cells displayed clear signs of apoptosis. Differentially expressed genes were primarily linked to oxidative stress, energy metabolism, and apoptosis, according to the transcriptome study of livers. Overall, the long-term stress of TBTC resulted in the antioxidant system being harmed, as well as serious malfunction of the energy metabolism and apoptotic response. Full article

(This article belongs to the Special Issue Advances in Molecular Biology Methods in Hepatology Research)

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15 pages, 2011 KiB

Open AccessReview

Targeting Exosomal PD-L1 as a New Frontier in Cancer Immunotherapy

by Laura Denisa Dragu, Mihaela Chivu-Economescu, Ioana Madalina Pitica, Lilia Matei, Coralia Bleotu, Carmen Cristina Diaconu and Laura Georgiana Necula

Curr. Issues Mol. Biol. 2025, 47(7), 525; https://doi.org/10.3390/cimb47070525 - 8 Jul 2025

Abstract

This manuscript assesses the critical role of exosomal PD-L1 (ExoPD-L1) in immune suppression, tumor progression, and resistance to therapy. ExoPD-L1 has been identified as a key mediator of tumor immune evasion, contributing to systemic immunosuppression beyond the tumor microenvironment (TME) due to its [...] Read more.

This manuscript assesses the critical role of exosomal PD-L1 (ExoPD-L1) in immune suppression, tumor progression, and resistance to therapy. ExoPD-L1 has been identified as a key mediator of tumor immune evasion, contributing to systemic immunosuppression beyond the tumor microenvironment (TME) due to its capacity to travel to distant anatomical sites. In this context, the review aims to elaborate on the mechanisms by which exosomal PD-L1 interacts with T cell receptors and modulates both the tumor microenvironment and immune responses, impacting patient outcomes. We further explore emerging therapeutic strategies that target ExoPD-L1 to enhance the effectiveness of immunotherapy. Blocking ExoPD-L1 offers a novel approach to counteracting immune escape in cancer. Promising strategies include inhibiting exosome biogenesis with GW4869 or Rab inhibitors, neutralizing ExoPD-L1 with targeted antibodies, and silencing PD-L1 expression through RNA interference (RNAi) or CRISPR-based methods. While each approach presents certain limitations, their integration into combination therapies holds significant potential to improve the efficacy of immune checkpoint inhibitors. Future research should focus on optimizing these strategies for clinical application, with particular attention to improving delivery specificity and minimizing off-target effects. Full article

(This article belongs to the Special Issue Molecular Insights into Cancer Biomarkers: Identification and Practical Applications)

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9 pages, 825 KiB

Open AccessArticle

Tamarixetin: A Promising Bioflavonoid Against Acetaminophen-Induced Liver Injury

by Mehmet Ali Telafarlı, Ejder Saylav Bora, Firdes Topal and Oytun Erbaş

Curr. Issues Mol. Biol. 2025, 47(7), 524; https://doi.org/10.3390/cimb47070524 - 8 Jul 2025

Abstract

Oxidative stress, mitochondrial dysfunction, and inflammatory responses cause acute liver failure in most cases of acetaminophen (APAP) overdose. Tamarixetin (Trx), an antioxidant and anti-inflammatory flavonoid, has not yet been studied in models of APAP-induced hepatotoxicity. Trx was tested for its protective effects on [...] Read more.

Oxidative stress, mitochondrial dysfunction, and inflammatory responses cause acute liver failure in most cases of acetaminophen (APAP) overdose. Tamarixetin (Trx), an antioxidant and anti-inflammatory flavonoid, has not yet been studied in models of APAP-induced hepatotoxicity. Trx was tested for its protective effects on APAP-induced liver injury in rats using biochemical, histopathological, and oxidative stress parameters. Three groups of 30 male Wistar rats were randomly assigned to the following groups: control, APAP + Saline, and APAP + Trx (3 mg/kg/day, intraperitoneally for 3 days). A single 300 mg/kg intraperitoneal APAP dose caused hepatotoxicity. ALT, MDA, GSH, HSP-70, and thioredoxin were measured in blood and liver tissues. Liver sections were histopathologically examined. APAP depleted hepatic GSH and Trx and increased serum ALT and MDA. Trx treatment significantly reduced ALT (201.2 → 105.1 U/L), MDA (5.5 → 3.4 nmol/mg), and the percentage of histologically damaged hepatocytes (58.5% → 9.5%), while restoring GSH and thioredoxin levels. Notably, HSP-70 expression exceeded that of APAP and control levels, suggesting the modulation of the stress response. The Trx group showed significant hepatoprotection histologically. Trx reduces APAP-induced hepatic damage, likely through antioxidant and anti-inflammatory mechanisms. These findings suggest that Trx may be a natural hepatoprotectant, warranting clinical trials. Full article

(This article belongs to the Special Issue Novel Drugs and Natural Products Discovery)

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18 pages, 4262 KiB

Open AccessArticle

Transcriptomic Analysis Reveals C-C Motif Chemokine Receptor 1 as a Critical Pathogenic Hub Linking Sjögren’s Syndrome and Periodontitis

by Yanjun Lin, Jingjing Su, Shupin Tang, Jun Jiang, Wenwei Wei, Jiang Chen and Dong Wu

Curr. Issues Mol. Biol. 2025, 47(7), 523; https://doi.org/10.3390/cimb47070523 - 7 Jul 2025

Abstract

Compelling evidence has demonstrated a bidirectional relationship between Sjögren’s syndrome (SS) and periodontitis (PD). Nevertheless, the underlying mechanisms driving their co-occurrence remain unclear, highlighting the need for finding the hub gene. This study sought to examine the common genes and any connections between [...] Read more.

Compelling evidence has demonstrated a bidirectional relationship between Sjögren’s syndrome (SS) and periodontitis (PD). Nevertheless, the underlying mechanisms driving their co-occurrence remain unclear, highlighting the need for finding the hub gene. This study sought to examine the common genes and any connections between SS and PD. Differently expressed genes (DEGs) were analyzed by means of gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO) methods. The test and validation sets were used to depict the receiver operating characteristic (ROC) curves. The immune cell infiltration was performed via the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) methodology. The relationships between immune infiltrating cells and the common gene were examined. Ninety-five common genes with similar expression trends were obtained after DEGs analysis, which were enriched in cytokine—cytokine receptor interaction, chemokine signaling pathway, proteasome, intestinal immune network for IgA production, and cytosolic DNA sensing pathway. Thirty-nine common genes were obtained after WGCNA. Sixteen shared genes of DEGs analysis and WGCNA were incorporated into the LASSO model to obtain the unique shared gene, C-C motif chemokine receptor 1 (CCR1), which overexpressed and owned predictable ROC curves in test and validation sets. The examination of immune cell infiltration underscored its crucial roles in the disturbance of immune homeostasis and the emergence of pathogenic circumstances with the simultaneous occurrence of SS and PD. CCR1 overexpresses and serves as a critical pathogenic hub linking SS and PD, which may play a role through immune cell infiltration. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Innovative Therapeutic Approaches in Inflammatory Diseases, Pioneering Precision Medicine Solutions)

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17 pages, 2055 KiB

Open AccessArticle

Genome-Wide Identification and Characterization of TaCRY Gene Family and Its Expression in Seed Aging Process of Wheat

by Guoqing Cui, Xiuyan Cui, Junjie Wang, Menglin Lei, Xia Liu, Yanzhen Wang, Haigang Wang, Longlong Liu, Zhixin Mu and Xia Xin

Curr. Issues Mol. Biol. 2025, 47(7), 522; https://doi.org/10.3390/cimb47070522 - 6 Jul 2025

Abstract

Cryptochromes (CRYs), as essential blue-light photoreceptors, play pivotal roles in modulating plant growth, development, and stress responses. Although CRY-mediated light signaling has been extensively studied in model species, their functions remain limited in wheat. In this work, a comprehensive analysis of the [...] Read more.

Cryptochromes (CRYs), as essential blue-light photoreceptors, play pivotal roles in modulating plant growth, development, and stress responses. Although CRY-mediated light signaling has been extensively studied in model species, their functions remain limited in wheat. In this work, a comprehensive analysis of the TaCRY gene family was performed in wheat, identifying 12 TaCRY members localized to distinct chromosomes 2, 6, and 7. TaCRYs contain the conserved PHR and CCT domains and diverse gene structures. Collinearity relationships indicated their dynamic evolution patterns during polyploidization. Cis-acting elements of TaCRY members associated with light responsiveness, phytohormone signaling, and abiotic stress were also identified. Transcriptome analysis revealed that the differential expression patterns of TaCRY members under seed vigor process. This study expands our understanding of TaCRY diversity and provides valuable molecular information for marker-assisted selection in wheat improvement. Full article

(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants, 3rd Edition)

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16 pages, 2421 KiB

Open AccessArticle

Characterization and Analysis of the Complete Mitochondrial Genome of Platycrater arguta

by Xule Zhang, Lei Feng, Xiaohua Ma, Qingdi Hu, Yaping Hu and Jian Zheng

Curr. Issues Mol. Biol. 2025, 47(7), 521; https://doi.org/10.3390/cimb47070521 - 5 Jul 2025

Abstract

Platycrater arguta (Hydrangeaceae), a rare and endangered Tertiary relict shrub endemic to East Asia, holds significant ecological and evolutionary value. However, the P. arguta mitochondrial (mt) genome remains unexplored, limiting insights into its cytoplasmic evolution and phylogenetic relationships. In this study, a complete [...] Read more.

Platycrater arguta (Hydrangeaceae), a rare and endangered Tertiary relict shrub endemic to East Asia, holds significant ecological and evolutionary value. However, the P. arguta mitochondrial (mt) genome remains unexplored, limiting insights into its cytoplasmic evolution and phylogenetic relationships. In this study, a complete mt genome of P. arguta was sequenced, and we assembled the mt genome into two linear contigs for description, due to the complexity of its chromosome structure. The mt genome encodes 37 protein-coding genes, 27 tRNA genes, and three rRNA genes. A total of 687 RNA editing sites were predicted, and the most RNA editing sites were found in the nad4 gene. Repeat sequences with different sizes were detected in the mt genome, including 160 simple sequence repeats, 26 tandem repeats, and 320 dispersed repeats. Phylogenetic analysis grouped P. arguta with Hydrangea macrophylla (Hydrangeaceae), which is closely related to Eucommiaceae and Ericaceae. This study provides the first assembled and annotated mt genome of P. arguta, which enhances our understanding of the genome of this relict plant in Hydrangeaceae. Taken together, this study offered foundational data for conservation strategies, molecular breeding, and evolutionary studies of this endangered relict species. Full article

(This article belongs to the Special Issue Advances in Multi-Omics for Functional Genomics Studies and Molecular Breeding)

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15 pages, 1003 KiB

Open AccessArticle

Restoration of Autophagy and Apoptosis in Myelodysplastic Syndromes: The Effect of Azacitidine in Disease Pathogenesis

by Georgia Tsekoura, Andreas Agathangelidis, Christina-Nefeli Kontandreopoulou, Eirini Sofia Fasouli, Eleni Katsantoni, Vaia Pliaka, Leonidas Alexopoulos, Eleni Katana, Myrto Papaioannou, Georgia Taktikou, Maria Eleftheria Strataki, Angeliki Taliouraki, Marina Mantzourani, Nora-Athina Viniou, Panagiotis T. Diamantopoulos and Panagoula Kollia

Curr. Issues Mol. Biol. 2025, 47(7), 520; https://doi.org/10.3390/cimb47070520 - 4 Jul 2025

Abstract

Myelodysplastic syndromes (MDSs) comprise a diverse group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cytopenia in the peripheral blood, and an increased risk of transformation into acute myeloid leukemia (AML). Despite extensive research, the mechanisms underlying MDS pathogenesis remain unclear. [...] Read more.

Myelodysplastic syndromes (MDSs) comprise a diverse group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cytopenia in the peripheral blood, and an increased risk of transformation into acute myeloid leukemia (AML). Despite extensive research, the mechanisms underlying MDS pathogenesis remain unclear. In the present study, we explored the role of autophagy and apoptosis in the development of MDS and assessed the impact of azacitidine on these processes in vitro. First, we assessed the expression of proteins involved in both autophagic and apoptotic pathways in MDS patients with different prognoses. Furthermore, using the MDS-L cell line as a model, we investigated the in vitro effects of azacitidine treatment on these processes. We report that MDS, irrespective of risk classification, is associated with the dysregulation of autophagy and apoptosis. Notably, azacitidine treatment restored these cellular processes, accompanied by modulation of key signaling phosphoproteins. Overall, these findings provide evidence that impaired autophagy and apoptosis contribute to MDS pathogenesis and that azacitidine helps restore cellular homeostasis by activating both processes. Furthermore, our study highlights the potential therapeutic benefits of targeting these mechanisms and suggests that combining azacitidine with agents that modulate autophagy and apoptosis could enhance the treatment efficacy for MDS patients. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 14919 KiB

Open AccessArticle

Characterization of an mRNA-Encoded Antibody Against Henipavirus

by Zixuan Liu, Bingjie Sun, Ting Fang, Xiaofan Zhao, Yi Ren, Zhenwei Song, Sijun He, Jianmin Li, Pengfei Fan and Changming Yu

Curr. Issues Mol. Biol. 2025, 47(7), 519; https://doi.org/10.3390/cimb47070519 - 4 Jul 2025

Abstract

Nipah and Hendra viruses are lethal zoonotic pathogens with no approved vaccines or therapeutics. mRNA produced via in vitro transcription enables endogenous protein expression and cost reduction. Here, we systematically screened natural and artificial untranslated regions (UTRs) and identified an optimal combination for [...] Read more.

Nipah and Hendra viruses are lethal zoonotic pathogens with no approved vaccines or therapeutics. mRNA produced via in vitro transcription enables endogenous protein expression and cost reduction. Here, we systematically screened natural and artificial untranslated regions (UTRs) and identified an optimal combination for expressing henipavirus-neutralizing antibody 1E5. We generated mRNA-1E5 encapsulated in lipid nanoparticles (mRNA-1E5-LNPs). In vitro, mRNA-1E5-LNPs achieved functional antibody expression levels of >1500 ng/mL. In BALB/c mice, intravenous administration of mRNA-1E5-LNPs induced rapid antibody elevation (peak at day 3), without hepatic toxicity or tissue inflammation. We established two Hendra pseudovirus models in biosafety level 2 facilities to evaluate the efficacy of mRNA-1E5-LNPs. Low-dose prophylactic administration effectively blocked entry of the Hendra pseudovirus. Notably, a single 0.5 mg/kg dose of mRNA-1E5-LNPs, stored at 4 °C for two months and administered 7 days prior, provided good protection. Our findings provide a therapeutic strategy for henipaviral infections and a blueprint for the development of mRNA-based antibodies against emerging viruses. Full article

(This article belongs to the Special Issue Molecular Research in Vaccinology and Vaccine Development)

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16 pages, 2795 KiB

Open AccessArticle

Therapeutic Potential of 7,8-Dimethoxycoumarin in Tumor Necrosis Factor-Alpha-Induced Trigeminal Neuralgia in a Rat Model

by Nallupillai Paramakrishnan, Kanthiraj Raadhika, Sumitha Elayaperumal, Yuvaraj Sivamani, Yamunna Paramaswaran, Lim Joe Siang, Thiagharajan Venkata Rathina Kumar, Khian Giap Lim, Muthusamy Ramesh and Arunachalam Muthuraman

Curr. Issues Mol. Biol. 2025, 47(7), 518; https://doi.org/10.3390/cimb47070518 - 4 Jul 2025

Abstract

Trigeminal neuralgia is a chronic pain disorder due to neuronal damage. The present study was designed to investigate the effect of 7,8-dimethoxy coumarin (DMC) in a rat model of trigeminal neuralgia. The neuropathic pain was induced by the single endoneural injection of tumor [...] Read more.

Trigeminal neuralgia is a chronic pain disorder due to neuronal damage. The present study was designed to investigate the effect of 7,8-dimethoxy coumarin (DMC) in a rat model of trigeminal neuralgia. The neuropathic pain was induced by the single endoneural injection of tumor necrosis factor-alpha (TNF-α; 0.1 μL: stock 10 pg/mL) in the rat trigeminal nerve. The DMC (100 and 200 mg/kg) and carbamazepine (100 mg/kg) were administered orally for 10 consecutive days from the 5th day of TNF-α injection. The battery of behavioral tests, i.e., acetone drop and Von Frey filament test, was performed to assess the degree of thermal and mechanical allodynia on 0, 1st, 7th, and 14th days. In addition, the biochemical tests, i.e., total protein, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and TNF-α, were also performed in trigeminal nerve tissue. Furthermore, TNF-α-induced neuronal histopathological changes were also evaluated by the eosin and hematoxylin staining method. The administration of DMC was shown to demonstrate the significant (p < 0.05) reversal of TNF-α-induced percentage reduction of thermal and mechanical sensitivity, along with a rise in TBARS and TNF-α and a decrease in GSH levels. Further, DMC also attenuates the histopathological changes. It may be concluded that DMC may be a potential therapeutic agent for the management of trigeminal neuralgia disorders. Full article

(This article belongs to the Section Molecular Pharmacology)

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14 pages, 2756 KiB

Open AccessArticle

Mechanistic Insights into the Bornyl Diphosphate Synthase from Lavandula angustifolia

by Dafeng Liu, Na Li, Feng Yu, Yanyan Du, Hongjun Song and Wenshuang Yao

Curr. Issues Mol. Biol. 2025, 47(7), 517; https://doi.org/10.3390/cimb47070517 - 4 Jul 2025

Abstract

Lavender species hold substantial economic importance due to their widespread cultivation for essential oils (EOs). Lavender EOs contain terpenes essential for industries such as cosmetics, personal care, and pharmaceuticals. In the biosynthetic pathway of EOs, Lavandula angustifolia bornyl diphosphate synthase (LaBPPS) catalyzes the [...] Read more.

Lavender species hold substantial economic importance due to their widespread cultivation for essential oils (EOs). Lavender EOs contain terpenes essential for industries such as cosmetics, personal care, and pharmaceuticals. In the biosynthetic pathway of EOs, Lavandula angustifolia bornyl diphosphate synthase (LaBPPS) catalyzes the conversion of geranyl diphosphate (GPP) to bornyl diphosphate (BPP). However, the functional mechanisms of LaBPPS remain poorly understood. Here, we conducted mutational experiments based on the molecular docking results, and found that mutations at positions D356A, D360A, R497A, D501A, or E508A led to a 50- to 100-fold reduction in the activity. Deletion of region 1–58 (∆1–58) did not affect activity compared to the wild-type (WT) protein, while deletions of regions 1–74 or 59–74 (∆1–74 or ∆59–74) significantly decreased the activity. Conversely, deletion of residues 578–602 (∆578–602) dramatically increased the activity. The LaBPPS gene showed dramatically higher expression levels in flowers compared to other tissues (stems, leaves and roots), peaking at 8:00. Our results provide valuable insights into EO biosynthesis in lavender and suggest potential strategies for genetic engineering aimed at improving EO quality. Full article

(This article belongs to the Section Molecular Plant Sciences)

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12 pages, 2964 KiB

Open AccessArticle

Inhibiting the Interaction Between Phospholipase A2 and Phospholipid Serine as a Potential Therapeutic Method for Pneumonia

by Jianyu Wang, Huanchun Xing, Lin Wang, Zhongxing Xu, Xin Sui, Yuan Luo, Jun Yang and Yongan Wang

Curr. Issues Mol. Biol. 2025, 47(7), 516; https://doi.org/10.3390/cimb47070516 - 4 Jul 2025

Abstract

Pneumonia is a severe lower respiratory tract infection. This study demonstrates that phospholipase A2 (PLA2), a potential biomarker for pneumonia, contributes to alveoli damage by hydrolyzing pulmonary surfactant phospholipids. This process impairs gas exchange and generates hemolytic phospholipids that disrupt cellular membranes, exacerbating [...] Read more.

Pneumonia is a severe lower respiratory tract infection. This study demonstrates that phospholipase A2 (PLA2), a potential biomarker for pneumonia, contributes to alveoli damage by hydrolyzing pulmonary surfactant phospholipids. This process impairs gas exchange and generates hemolytic phospholipids that disrupt cellular membranes, exacerbating pulmonary injury. Experimental evidence demonstrates that PLA2 inhibitors significantly alleviate cellular damage in lipopolysaccharide (LPS)-induced pulmonary inflammation. These findings reveal a key mechanistic role of PLA2 in pneumonia pathogenesis and suggest novel therapeutic strategies. The results may provide more effective clinical interventions and guide further research in related fields. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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21 pages, 10334 KiB

Open AccessArticle

Gypenosides Alleviate Hyperglycemia by Regulating Gut Microbiota Metabolites and Intestinal Permeability

by Rong Wang, Xue-Feng Liu, Kuan Yang, Li-Li Yu, Shao-Jing Liu, Na-Na Wang, Yun-Mei Chen, Ya-Qi Hu and Bei Qin

Curr. Issues Mol. Biol. 2025, 47(7), 515; https://doi.org/10.3390/cimb47070515 - 3 Jul 2025

Abstract

Background/Objectives: Gypenosides (Gps) are the main active compounds of Gynostemma and show promise in managing diabetes; nevertheless, the mechanism by which Gps exert anti-diabetic effects is still not fully understood. The aim of this study is to clarify the molecular mechanisms of [...] Read more.

Background/Objectives: Gypenosides (Gps) are the main active compounds of Gynostemma and show promise in managing diabetes; nevertheless, the mechanism by which Gps exert anti-diabetic effects is still not fully understood. The aim of this study is to clarify the molecular mechanisms of Gps in ameliorating glucose dysregulation. Methods: Qualitative and quantitative analyses on the chemical components of Gps were performed, respectively. Type 2 diabetes mellitus mouse models were established, and the mice were subsequently treated with Gps at doses of 200, 100, or 50 mg/kg for 4 weeks. Biochemical markers were measured. Histopathological assessments of hepatic and colonic tissues were conducted. The compositions of the intestinal microbiota, short-chain fatty acids (SCFAs), and bile acids (BAs) in fecal samples were analyzed. Western blotting was applied to examine the activation of relevant signaling pathways. Results: Gps have potent regulatory effects on metabolic homeostasis by improving glucose and lipid profiles and alleviating hepatic tissue damage. Treatment with Gps significantly reduced serum levels of lipopolysaccharides and key pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α). Moreover, Gps enhanced the integrity of the gut barrier by upregulating the level of tight junction proteins (ZO-1 and occludin). Microbiota profiling revealed that Gps markedly increased microbial diversity and richness, decreased the ratio of Firmicutes/Bacteroidetes, and elevated Bacteroidia abundance from the phylum to the genus level. Targeted metabolomics further demonstrated that Gps modulated gut microbial metabolites by promoting SCFA production and reshaping BA profiles. Specifically, Gps elevated the primary-to-secondary BA ratio while reducing the 12α-hydroxylated to non-12α-hydroxylated BA ratio. Mechanistically, Western blotting demonstrated that Gps triggered the hepatic PI3K/AKT pathway and the intestinal BA/FXR/FGF15 axis, suggesting the coordinated regulation of metabolic and gut–liver axis signaling pathways. Conclusions: Gps significantly ameliorate hyperglycemia and hyperlipidemia through a multifaceted mechanism involving gut microbiota modulation, the restoration of intestinal barrier function, and the regulation of microbial metabolites such as SCFAs and BAs. These findings offer novel insights into their mechanism of action via the gut–liver axis. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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16 pages, 8324 KiB

Open AccessArticle

Transcriptomic Differences Between Human Trabecular Meshwork Stem Cells and Trabecular Meshwork Cells Reveal Specific Biomarker Profiles

by Rong Du, Ajay Kumar, Enzhi Yang, Jingxue Zhang, Ningli Wang and Yiqin Du

Curr. Issues Mol. Biol. 2025, 47(7), 514; https://doi.org/10.3390/cimb47070514 - 3 Jul 2025

Abstract

Glaucoma is a leading cause of irreversible blindness, normally associated with dysfunction and degeneration of the trabecular meshwork (TM) as the primary cause. Trabecular meshwork stem cells (TMSCs) have emerged as promising candidates for TM regeneration toward glaucoma therapies, yet their molecular characteristics [...] Read more.

Glaucoma is a leading cause of irreversible blindness, normally associated with dysfunction and degeneration of the trabecular meshwork (TM) as the primary cause. Trabecular meshwork stem cells (TMSCs) have emerged as promising candidates for TM regeneration toward glaucoma therapies, yet their molecular characteristics remain poorly defined. In this study, we performed a comprehensive transcriptomic comparison of human TMSCs and human TM cells (TMCs) using RNA sequencing and microarray analyses, followed by qPCR validation. A total of 465 differentially expressed genes were identified, with 254 upregulated in TMSCs and 211 in TMCs. A functional enrichment analysis revealed that TMSCs are associated with development, immune signaling, and extracellular matrix remodeling pathways, while TMCs are enriched in structural, contractile, and adhesion-related functions. A network topology analysis identified CXCL3, CXCL6, and BMP2 as robust TMSC-specific hub genes, and LMOD1 and BGN as TMC-specific markers, with expression patterns confirmed by qPCR. These findings define distinct molecular signatures of TMSCs and TMCs, providing reliable biomarkers for cell identity and a foundation for future stem cell-based therapies targeting TM dysfunction in glaucoma. Full article

(This article belongs to the Section Molecular Medicine)

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25 pages, 12149 KiB

Open AccessArticle

Total Flavones of Rhododendron Protect Against Ischemic Cerebral Injury by Regulating the Phosphorylation of the RhoA-ROCK₂ Pathway via Endothelial-Derived H₂S

by Xiaoqing Sun, Xingyu Zhang, Yuwen Li, Jiyue Wen, Zhiwu Chen and Shuo Chen

Curr. Issues Mol. Biol. 2025, 47(7), 513; https://doi.org/10.3390/cimb47070513 - 3 Jul 2025

Abstract

This study aims to investigate the mechanism by which the total flavones of Rhododendron (TFR) protect against cerebral ischemic injury through the endothelial-derived H₂S-mediated regulation of RhoA phosphorylation at the Ser188 and Rho kinase 2 (ROCK₂) phosphorylation at Thr436. [...] Read more.

This study aims to investigate the mechanism by which the total flavones of Rhododendron (TFR) protect against cerebral ischemic injury through the endothelial-derived H₂S-mediated regulation of RhoA phosphorylation at the Ser188 and Rho kinase 2 (ROCK₂) phosphorylation at Thr436. For experimental design, mouse or rat cerebrovascular endothelial cells (ECs) were cultured with or without neurons and subjected to hypoxia/reoxygenation (H/R) injury. The vasodilation of the cerebral basilar artery was assessed. Cerebral ischemia/reperfusion (I/R) injury was induced in mice by bilateral carotid artery ligation, followed by Morris water maze and open field behavioral assessments. The protein levels of cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST), RhoA, ROCK₂, p-RhoA (RhoA phosphorylated at Ser188), and p-ROCK₂ (ROCK₂ phosphorylated at Thr436) were quantified. Additionally, the activities of RhoA and ROCK₂ were measured. Notably, TFR significantly inhibited H/R-induced H₂S reduction and suppressed the increased expression and activity of RhoA and ROCK₂ in ECs, effects attenuated by CSE or 3-MST knockout. Moreover, TFR-mediated cerebrovascular dilation was reduced by RhoA or ROCK₂ inhibitors, while the protective effect of TFR against cerebral I/R injury in mice was markedly attenuated by the heterozygous knockout of ROCK₂. In the ECs-co-cultured neurons, the inhibition of TFR on H/R-induced neuronal injury and decrease in H₂S level in the co-culture was attenuated by the knockout of CSE or 3-MST in the ECs. TFR notably inhibited the H/R-induced upregulation of neuronal RhoA, ROCK₂, and p-ROCK₂ protein levels, as well as the activities of RhoA and ROCK₂, while reversing the decrease in p-RhoA. However, the knockout of CSE or 3-MST in the ECs significantly attenuated the inhibition of TFR on these increases. Furthermore, 3-MST knockout in ECs attenuated the TFR-mediated suppression of p-RhoA reduction. Additionally, CSE or 3-MST knockout in ECs exacerbated H/R-induced neuronal injury, reduced H₂S level in the co-culture system, and increased RhoA activity and ROCK₂ expression in neurons. In summary, TFR protected against ischemic cerebral injury by endothelial-derived H₂S promoting the phosphorylation of RhoA at Ser188 but inhibited the phosphorylation of ROCK₂ at Thr436 to inhibit the RhoA-ROCK₂ pathway in neurons. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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30 pages, 4520 KiB

Open AccessArticle

Optimization of Eugenol, Camphor, and Terpineol Mixture Using Simplex-Centroid Design for Targeted Inhibition of Key Antidiabetic Enzymes

by Amine Elbouzidi, Mohamed Jeddi, Abdellah Baraich, Mohamed Taibi, Mounir Haddou, Naoufal El Hachlafi, Meryem Idrissi Yahyaoui, Reda Bellaouchi, Bouchra El Guerrouj, Khalid Chaabane and Mohamed Addi

Curr. Issues Mol. Biol. 2025, 47(7), 512; https://doi.org/10.3390/cimb47070512 - 2 Jul 2025

Abstract

The optimization of bioactive compound mixtures is critical for enhancing pharmacological efficacy. This study investigates, for the first time, the combined effects of eugenol, camphor, and terpineol, focusing on their half-maximal inhibitory concentrations (IC₅₀) across multiple biological responses related to diabetes [...] Read more.

The optimization of bioactive compound mixtures is critical for enhancing pharmacological efficacy. This study investigates, for the first time, the combined effects of eugenol, camphor, and terpineol, focusing on their half-maximal inhibitory concentrations (IC₅₀) across multiple biological responses related to diabetes management. Using a mixture design approach, the objective was to determine the optimal formulation that maximizes bioactivity and validate the findings experimentally. A simplex-centroid design was applied to evaluate the combined effects of eugenol, camphor, and terpineol on AAI _IC50, AGI _IC50, LIP _IC50, and ALR _IC50 responses. The desirability function was used to determine the ideal composition. The optimized formulation was experimentally validated using in vitro assays, and IC50 values were measured for each response using standard protocols. Results: The optimal formulation identified was 44% eugenol, 0.19% camphor, and 37% terpineol, yielding IC₅₀ values of 10.38 µg/mL (AAI), 62.22 µg/mL (AGI), 3.42 µg/mL (LIP), and 49.58 µg/mL (ALR). The desirability score (0.99) confirmed the effectiveness of the optimized blend. Experimental validation of the optimal mixture resulted in IC₅₀ values of 11.02 µg/mL (AAI), 60.85 µg/mL (AGI), 3.75 µg/mL (LIP), and 50.12 µg/mL (ALR), showing less than 10% deviation from predicted values, indicating high model accuracy. This study confirms the combined potential of eugenol, camphor, and terpineol, with eugenol and terpineol significantly enhancing bioactivity. The validated formulation demonstrates potential for pharmaceutical and cosmeceutical applications. Future research should explore mechanistic interactions, bioavailability, and in vivo efficacy to support the development of optimized natural compound-based therapies. Full article

(This article belongs to the Special Issue Molecular Insights into Phytochemicals: Therapeutic Potential in Metabolic Disorders and Cancer)

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12 pages, 1583 KiB

Open AccessArticle

Characterization of Netrin-1 and Its Receptors UNC5B and Neogenin-1 in a Rat Rotator Cuff Tear Model: Associations with Inflammatory Mediators and Neurite Extension

by Kosuke Inoue, Kentaro Uchida, Mitsuyoshi Matsumoto, Ryo Tazawa, Etsuro Ohta, Akito Hattori, Tomonori Kenmoku, Yuka Ito, Yui Uekusa, Gen Inoue and Masashi Takaso

Curr. Issues Mol. Biol. 2025, 47(7), 511; https://doi.org/10.3390/cimb47070511 - 2 Jul 2025

Abstract

Rotator cuff tears are a leading cause of shoulder pain and dysfunction, yet the molecular mechanisms that link tendon injury to inflammation and nociceptive signaling remain poorly understood. Netrin-1, a classical axon guidance cue signaling through dependence receptors UNC5B and Neogenin-1, has been [...] Read more.

Rotator cuff tears are a leading cause of shoulder pain and dysfunction, yet the molecular mechanisms that link tendon injury to inflammation and nociceptive signaling remain poorly understood. Netrin-1, a classical axon guidance cue signaling through dependence receptors UNC5B and Neogenin-1, has been implicated in both neuronal plasticity and inflammatory processes, but its role in tendon pathology has not been explored. A rat supraspinatus tear model was employed to assess, in vivo, the expression of genes encoding netrin-1 (Ntn1) and its receptors (Unc5b and Neo1) at 0, 7, 14, 28, and 56 days post-injury (n = 10 per time point). Primary rat tenocytes isolated from rotator cuff tissue were treated in vitro with recombinant netrin-1, and transcriptional changes in genes encoding TNF-α (Tnfa), IL-6 (Il6), MMP-1 (Mmp1), and MMP-3 (Mmp3) were quantified by qRT-PCR. Separately, human iPSC-derived sensory neurons were exposed to netrin-1, and dose- and time-dependent effects on neurite outgrowth were measured at 4 and 14 days in culture. In injured tendons, Ntn1 mRNA increased significantly at day 14 (p = 0.010) and 28 (p = 0.042), Unc5b at day 7 (p = 0.002) and 14 (p < 0.001), and Neo1 at day 14 (p < 0.001) versus intact controls. Tenocyte exposure to 500 ng/mL netrin-1 induced transient upregulation of Tnfa (3 h, p = 0.023; 6 h, p = 0.009) and Il6 (3 h–24 h, all p < 0.013), as well as Mmp3 (3–24 h, p < 0.043) and Mmp1 (6 h–24 h, p < 0.024); no induction was observed at 50 ng/mL. In sensory neurons, 50 ng/mL of netrin-1 enhanced neurite extension at day 4 (p = 0.006) but not at 500 ng/mL or at day 14 for either dose. Netrin-1 and its receptors are upregulated in a rat rotator cuff tear model, and netrin-1 elicits distinct pro-inflammatory and matrix-remodeling responses in tenocytes while promoting early neurite growth in sensory neurons. These findings suggest netrin-1 as a key modulator of tendon inflammation, matrix turnover, and peripheral nerve plasticity following injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Innovative Therapeutic Approaches in Inflammatory Diseases, Pioneering Precision Medicine Solutions)

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15 pages, 496 KiB

Open AccessArticle

CD63 Immunological Activation Versus Hemostatic Function: Platelet Alterations After Polytrauma

by Gregor Roemmermann, Olivia Bohe, Laura Heimann, Franziska Wirth, Franziska Drumm, Peter Biberthaler, Philipp Moog, Christina Schwenk, Nadja Muehlhaupt, Li Wan and Marc Hanschen

Curr. Issues Mol. Biol. 2025, 47(7), 510; https://doi.org/10.3390/cimb47070510 - 2 Jul 2025

Abstract

Platelets are attributed an increasing role in the post-traumatic immune response. The exact mechanisms, particularly the link between immune response and hemostasis, have not been conclusively established. This study aimed to investigate the activity marker CD63 on platelets after polytrauma and its significance [...] Read more.

Platelets are attributed an increasing role in the post-traumatic immune response. The exact mechanisms, particularly the link between immune response and hemostasis, have not been conclusively established. This study aimed to investigate the activity marker CD63 on platelets after polytrauma and its significance for hemostasis. A non-interventional, prospective clinical study was conducted, in which the blood of 20 polytraumatized patients was analyzed at nine time points within 10 days following trauma. Peripheral blood platelets were analyzed using flow cytometry to determine CD63 expression and rotational thromboelastometry (ROTEM^®) for hemostatic platelet function. Additionally, the clinical parameters of age, gender, and injury severity were correlated to the experimental outcomes. During the observation period, an increase in platelet count and CD63 expression was observed. Simultaneously, a hemostasiological dysfunction with reduced platelet maximum clot firmness (MCF) was observed. The factors of age, gender, and injury severity showed no significant influence on immunological activation or coagulation function. These results suggest that polytrauma induces a platelet response and CD63 activation while simultaneously impairing hemostasis. This reveals a novel perspective on post-traumatic coagulation disorders, indicating that immunologically active platelets may lose their ability to contribute effectively to blood clotting. Consequently, these findings emphasize the critical role of platelet immunology in hemostatic regulation. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 937 KiB

Open AccessReview

Tissue Repair Mechanisms of Dental Pulp Stem Cells: A Comprehensive Review from Cutaneous Regeneration to Mucosal Healing

by Jihui He, Jiao Fu, Ruoxuan Wang, Xiaojing Liu, Juming Yao, Wenbo Xing, Xinxin Wang and Yan He

Curr. Issues Mol. Biol. 2025, 47(7), 509; https://doi.org/10.3390/cimb47070509 - 2 Jul 2025

Abstract

Repairing and regenerating tissue barriers is a key challenge in regenerative medicine. Stem cells play a crucial role in restoring the structural and functional integrity of key epithelial barrier surfaces, including the skin and mucosa. This review analyzes the role of dental pulp [...] Read more.

Repairing and regenerating tissue barriers is a key challenge in regenerative medicine. Stem cells play a crucial role in restoring the structural and functional integrity of key epithelial barrier surfaces, including the skin and mucosa. This review analyzes the role of dental pulp stem cells (DPSCs) and their derivatives, including extracellular vesicles, conditioned medium, and intracellular factors, in accelerating skin wound healing. The key mechanisms include: (1) DPSCs regulating inflammatory microenvironments by promoting anti-inflammatory M2 macrophage polarization; (2) DPSCs activating vascular endothelial growth factor (VEGF) to drive angiogenesis; (3) DPSCs optimizing extracellular matrix (ECM) spatial structure through matrix metalloproteinase/tissue inhibitor of metalloproteinase (MMP/TIMP) balance; and (4) DPSCs enhancing transforming growth factor-β (TGF-β) secretion to accelerate granulation tissue formation. Collectively, these processes promote wound healing. In addition, we explored potential factors that accelerate wound healing in DPSCs, such as oxidative stress, mechanical stimulation, hypertension, electrical stimulation, and organoid modeling. In addition to demonstrating the great potential of DPSCs for skin repair, this review explores their translational prospects in mucosal regenerative medicine. It covers the oral cavity, esophagus, colon, and fallopian tube. Some studies have found that combining DPSCs and their derivatives with drugs can significantly enhance their biological effects. By integrating insights from skin and mucosal models, this review offers novel ideas and strategies for treating chronic wounds, inflammatory bowel disease, and mucosal injuries. It also lays the foundation for connecting basic research results with clinical practice. This represents a significant step forward in tackling these complex medical challenges and lays a solid scientific foundation for developing more targeted and efficient regenerative therapies. Full article

(This article belongs to the Section Molecular Medicine)

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14 pages, 1841 KiB

Open AccessArticle

Validation of Prognostic Circulating Cell-Free RNA Biomarkers HPGD, PACS1, and TDP2 in Colorectal Cancer Through TaqMan qPCR and Correlation Analysis

by Chau Ming Kan, Xiao Meng Pei, Simon Siu Man Ng, Wing Wa Leung, Yee Ni Wong, Hennie Yuk-Lin Cheng, William Chi Shing Cho, Hin Fung Tsang and Sze Chuen Cesar Wong

Curr. Issues Mol. Biol. 2025, 47(7), 508; https://doi.org/10.3390/cimb47070508 - 2 Jul 2025

Abstract

Circulating cell-free RNAs (cfRNAs) have emerged as promising non-invasive biomarkers for colorectal cancer (CRC), offering insights into the disease’s prognosis. This study investigates the prognostic significance of the specific cfRNA biomarkers HPGD, PACS1, and TDP2 by employing the Taqman quantitative PCR [...] Read more.

Circulating cell-free RNAs (cfRNAs) have emerged as promising non-invasive biomarkers for colorectal cancer (CRC), offering insights into the disease’s prognosis. This study investigates the prognostic significance of the specific cfRNA biomarkers HPGD, PACS1, and TDP2 by employing the Taqman quantitative PCR (qPCR) to evaluate their expression levels in a cohort of 52 CRC patients. The methodology involved a robust statistical analysis to assess correlations between cfRNA levels and clinical parameters, including survival rates and recurrence incidences. Findings revealed a significant upregulation in the expression of HPGD and PACS1, while TDP2 displayed varying results, indicating a complex role in disease dynamics. Notably, lower expression levels of HPGD were associated with reduced survival, suggesting its potential as a negative prognostic indicator. Conversely, TDP2 levels correlated strongly with increased risks of recurrence, highlighting its clinical relevance in monitoring disease progression. Overall, this study elucidates the intricate interplay between these cfRNAs in the CRC prognosis. The results advocate for further exploratory studies to validate PACS1’s potential as a prognostic marker and reinforce the clinical significance of HPGD and TDP2 in the context of CRC management, positioning them as vital elements in the landscape of molecular oncology. Full article

(This article belongs to the Special Issue Early Molecular Diagnosis and Comprehensive Treatment of Tumors)

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