Current Issues in Molecular Biology

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)

► Show Figures

Figure 1

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)

► Show Figures

Figure 1

31 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)

► Show Figures

Figure 1

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)

► Show Figures

Figure 1

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)

► Show Figures

Figure 1

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)

► Show Figures

Figure 1

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)

► Show Figures

Figure 1

11 pages, 2422 KiB

Open AccessArticle

Cross-Activity Analysis of CRISPR/Cas9 Editing in Gene Families of Solanum lycopersicum Detected by Long-Read Sequencing

by Ofri Kutchinsky, Dongqi Li, Guy Assa, Asaph Aharoni and Zohar Yakhini

Curr. Issues Mol. Biol. 2025, 47(7), 507; https://doi.org/10.3390/cimb47070507 - 2 Jul 2025

Abstract

CRISPR/Cas9 genome editing holds promise for precise genetic modifications, yet off-target effects remain a concern—particularly in gene families with high sequence similarity. In this study, we present a computational framework for analyzing editing specificity and cross-reactivity in gene families using long-read sequencing data. [...] Read more.

CRISPR/Cas9 genome editing holds promise for precise genetic modifications, yet off-target effects remain a concern—particularly in gene families with high sequence similarity. In this study, we present a computational framework for analyzing editing specificity and cross-reactivity in gene families using long-read sequencing data. The pipeline integrates multiplex PCR, NGS, and CRISPECTOR-based analysis to detect and quantify on- and off-target events with high sensitivity. As a use case, we applied this framework to Solanum lycopersicum, evaluating on-target editing in thirteen gene families and analyzing off-target cross-reactivity in five representative families. While the biological results are illustrative, the primary contribution lies in the generalizable analysis approach, which can support genome editing studies in complex plant genomes and beyond. Full article

(This article belongs to the Section Molecular Plant Sciences)

► Show Figures

Figure 1

21 pages, 2880 KiB

Open AccessArticle

Valorization of a Natural Compound Library in Exploring Potential Marburg Virus VP35 Cofactor Inhibitors via an In Silico Drug Discovery Strategy

by Mohamed Mouadh Messaoui, Mebarka Ouassaf, Nada Anede, Kannan R. R. Rengasamy, Shafi Ullah Khan and Bader Y. Alhatlani

Curr. Issues Mol. Biol. 2025, 47(7), 506; https://doi.org/10.3390/cimb47070506 - 2 Jul 2025

Abstract

This study focuses on exploring potential inhibitors of the Marburg virus interferon inhibitory domain protein (MARV-VP35), which is responsible for immune evasion and immunosuppression during viral manifestation. A combination of in silico techniques was applied, including structure-based pharmacophore virtual screening, molecular docking, absorption, [...] Read more.

This study focuses on exploring potential inhibitors of the Marburg virus interferon inhibitory domain protein (MARV-VP35), which is responsible for immune evasion and immunosuppression during viral manifestation. A combination of in silico techniques was applied, including structure-based pharmacophore virtual screening, molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, molecular dynamics (MD), and molecular stability assessment of the identified hits. The docking scores of the 14 selected ligands ranged between −6.88 kcal/mol and −5.28 kcal/mol, the latter being comparable to the control ligand. ADMET and drug likeness evaluation identified Mol_01 and Mol_09 as the most promising candidates, both demonstrating good predicted antiviral activity against viral targets. Density functional theory (DFT) calculations, along with relevant quantum chemical descriptors, correlated well with the docking score hierarchy, and molecular electrostatic potential (MEP) mapping confirmed favorable electronic distributions supporting the docking orientation. Molecular dynamics simulations further validated complex stability, with consistent root mean square deviation (RMSD), root mean square fluctuation (RMSF), and secondary structure element (SSE) profiles. These findings support Mol_01 and Mol_09 as viable candidates for experimental validation. Full article

(This article belongs to the Special Issue Molecular Research in Bioactivity of Natural Products, 2nd Edition)

► Show Figures

Figure 1

14 pages, 311 KiB

Open AccessReview

Systematic Review on the Importance of Gut Microbiota in the Regulation of Type 2 Diabetes Through Physical Activity and Exercise

by Luis Muguerza-Rodríguez, Alba Mier, Jesus G. Ponce-González, Cristina Casals and Juan Corral-Pérez

Curr. Issues Mol. Biol. 2025, 47(7), 505; https://doi.org/10.3390/cimb47070505 - 1 Jul 2025

Abstract

Type 2 diabetes (T2D) is a major global health issue, influenced by sedentary behavior and obesity. Emerging evidence implicates the gut microbiota in T2D pathophysiology through effects on glucose metabolism, inflammation, and insulin sensitivity. This systematic review included eleven studies, six observational and [...] Read more.

Type 2 diabetes (T2D) is a major global health issue, influenced by sedentary behavior and obesity. Emerging evidence implicates the gut microbiota in T2D pathophysiology through effects on glucose metabolism, inflammation, and insulin sensitivity. This systematic review included eleven studies, six observational and five interventional, examining the relationship between physical activity, exercise, and gut microbiota in individuals with or at risk of T2D. Observational studies associated low physical activity and high sedentary time with reduced α-diversity and increased abundance of potentially harmful bacteria. Interventional studies showed that structured exercise, including moderate-intensity and sprint interval training, increased beneficial bacteria such as Faecalibacterium, Veillonella, Lachnospira, and Bifidobacterium, linked to anti-inflammatory effects and improved metabolic profiles. However, overall microbial diversity often remained unchanged unless combined with dietary modifications. Exercise also reduced levels of trimethylamine N-oxide, a metabolite linked to cardiovascular risk. Despite increases in butyrate-producing taxa, most studies did not report significant short-term changes in short-chain fatty acid levels, highlighting the complex interaction between microbiota and host metabolism. These findings support physical activity and exercise as modifiable factors that can influence gut microbiota composition, potentially contributing to improved metabolic regulation and better management of T2D. Full article

(This article belongs to the Special Issue Molecular Insights into Multifactorial Causes of Insulin Resistance in Obesity)

► Show Figures

Figure 1

20 pages, 581 KiB

Open AccessReview

Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence

by Anna Makridou, Evangelie Sintou, Sofia Chatzianagnosti, Iasonas Dermitzakis, Sofia Gargani, Maria Eleni Manthou and Paschalis Theotokis

Curr. Issues Mol. Biol. 2025, 47(7), 504; https://doi.org/10.3390/cimb47070504 - 1 Jul 2025

Abstract

Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from [...] Read more.

Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)

► Show Figures

Figure 1

19 pages, 9845 KiB

Open AccessArticle

Extract of Allium Chinense G. Don, a Medicinal Plant, Ameliorates Myocardial Ischemia–Reperfusion Injury by Inhibiting Platelet Activation

by Siyuan Liu, Huaxiang Wang, Min Wang, Zhihui Wang, Na Li, Jianyong Si and Jingxue Ye

Curr. Issues Mol. Biol. 2025, 47(7), 503; https://doi.org/10.3390/cimb47070503 - 1 Jul 2025

Abstract

Allium chinense G. Don is valued for its edible and medicinal qualities. It has been reported that Allium chinense has the potential to inhibit platelet activation, but its mechanism of action is unknown, which needs to be further explored. This study investigates the [...] Read more.

Allium chinense G. Don is valued for its edible and medicinal qualities. It has been reported that Allium chinense has the potential to inhibit platelet activation, but its mechanism of action is unknown, which needs to be further explored. This study investigates the anti-myocardial ischemia–reperfusion (I/R) injury potential of Allium chinense from the perspective of platelet activation, focusing on its chemical composition and underlying mechanisms of action. A combination of transcriptome sequencing, molecular docking, and experimental validation was employed in our study. The antiplatelet active fraction MT-95ET of Allium chinense was screened by the ADP-induced platelet aggregation model in vitro. In vivo experiments demonstrated that MT-95ET can reduce the myocardial injury of I/R rats and inhibit I/R-induced platelet activation, adhesion, and aggregation. UHPLC-Q-Orbitrap-MS/MS was used to identify 13 compounds from MT-95ET. Transcriptome sequencing and molecular docking identified aerobic glycolysis key checkpoints PDK1 and PKM2 as key targets, with Sarsasapogenin and Hecogenin exhibiting strong binding affinities to these proteins. Western blot analysis further validated that MT-95ET downregulated PKM2 and PDK1, indicating a possible mechanism for its antiplatelet effects and anti-myocardial I/R injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

► Show Figures

Figure 1

12 pages, 652 KiB

Open AccessReview

Unraveling the Contribution of Estrobolome Alterations to Endometriosis Pathogenesis

by Giulia Nannini, Francesco Cei and Amedeo Amedei

Curr. Issues Mol. Biol. 2025, 47(7), 502; https://doi.org/10.3390/cimb47070502 - 1 Jul 2025

Abstract

Endometriosis (EMS) is a long-term inflammatory disease. It represents one of the most prevalent gynecological conditions, impacting an estimated 5% of reproductive women. Therefore, endometriosis contributes to substantial worldwide health challenges and healthcare costs. In EMS disease, endometrial glandular and stromal tissues are [...] Read more.

Endometriosis (EMS) is a long-term inflammatory disease. It represents one of the most prevalent gynecological conditions, impacting an estimated 5% of reproductive women. Therefore, endometriosis contributes to substantial worldwide health challenges and healthcare costs. In EMS disease, endometrial glandular and stromal tissues are abnormally located outside the uterus. Similarly to the natural endometrium, these tissues grow and proliferate in response to estrogen-dependent signals. The pain and limited effectiveness of treatments are often linked to the inflammatory reaction triggered by EMS-associated ectopic tissue. This is especially amplified during the peaks of estrogen release that occur as the menstrual cycle transitions from the proliferative phase to ovulation. Maintaining the integrity of the mucosal lining, defending against pathogenic insults, and controlling physiological processes are all made possible by a healthy, balanced state of gut biomass. Additionally, numerous intestinal bacteria have been discovered to possess estrogen-metabolizing enzymes, which affect the estrobolome and, consequently, influence estrogen-related disorders. Therefore, there is increasing interest in understanding the role of microbiota and the estrobolome in endometriosis pathogenesis. This review will focus on the role of microbiota and the impact of estrobolome alterations in endometriosis pathogenesis. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

15 pages, 2783 KiB

Open AccessReview

Angiotensin II and Cardiovascular Disease: Balancing Pathogenic and Protective Pathways

by Ulvi Bayraktutan

Curr. Issues Mol. Biol. 2025, 47(7), 501; https://doi.org/10.3390/cimb47070501 - 1 Jul 2025

Abstract

The renin-angiotensin-aldosterone system (RAAS) is a hormone system that controls blood pressure and fluid and electrolyte balance. Angiotensin II, a key effector, is produced from angiotensin I by angiotensin-converting enzyme (ACE) and exerts its effects through binding to its type 1 (AT1R) or [...] Read more.

The renin-angiotensin-aldosterone system (RAAS) is a hormone system that controls blood pressure and fluid and electrolyte balance. Angiotensin II, a key effector, is produced from angiotensin I by angiotensin-converting enzyme (ACE) and exerts its effects through binding to its type 1 (AT1R) or type 2 (AT2R) receptors. AT1R activation promotes vasoconstriction, oxidative stress, endothelial dysfunction, peripheral vascular resistance, and atherosclerosis, all of which substantially contribute to cellular senescence and organismal ageing. Conversely, AT2R activation counteracts these effects by inducing vascular relaxation and attenuating vascular cell proliferation and migration, offering protection against occlusive vascular disease. Additionally, conversion of angiotensin II to angiotensin (1-7) or angiotensin I to angiotensin (1-9) by ACE2 provides further cardiovascular protection by lowering oxidative stress, inflammation, and abnormal cell growth. Bearing these in mind, measures to control angiotensin II synthesis or receptor activity have been at the forefront of antihypertensive treatment. This paper briefly reviews the RAAS and explores the dual role of angiotensin II in promoting disease and mediating vascular protection, with a focus on its impact on ageing and cardiovascular pathology. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Therapeutic Innovations)

► Show Figures

Figure 1

43 pages, 2497 KiB

Open AccessReview

The Role of Vitamin D and Vitamin D Receptor in Sepsis

by Shenglan Shang, Dongxin Chen, Yuqi Wei, Shuo Zou, Qiuyue Chang, Hong Zhou and Airong Yu

Curr. Issues Mol. Biol. 2025, 47(7), 500; https://doi.org/10.3390/cimb47070500 - 1 Jul 2025

Abstract

Sepsis acts as the leading cause of mortality in intensive care units, characterized by life-threatening organ dysfunction due to a dysregulated host response to infection. Vitamin D (VD) pleiotropic functions were demonstrated in different biological processes, including inflammation and immunity. VD receptor (VDR) [...] Read more.

Sepsis acts as the leading cause of mortality in intensive care units, characterized by life-threatening organ dysfunction due to a dysregulated host response to infection. Vitamin D (VD) pleiotropic functions were demonstrated in different biological processes, including inflammation and immunity. VD receptor (VDR) is a member of the nuclear receptor superfamily, involved in immunoregulation and resistance to infections. Previous studies have demonstrated that VD deficiency is a potential risk factor for sepsis development, which may be regulated by VDR-related physiological processes. In this review, we present a comprehensive overview of the roles of VD and VDR in sepsis, focusing on immune modulation, anti-inflammatory and anti-infective responses, oxidative stress regulation, gut microbiome enhancement, vascular endothelial cell modulation, and antiplatelet activity. We also discuss recent advances in clinical research on VD/VDR in sepsis, considering the clinical implications and potential interventions of VD analogs and VDR ligands in treatment. Despite its challenges, VD holds potential for personalized sepsis interventions. Additionally, VD/VDR may serve as a promising bidirectional immunomodulator, capable of addressing both hyperinflammatory and immunosuppressive phases of sepsis, yet require systematic investigations into its dynamic states and functions across different sepsis phases. Ongoing study and evidence-based guidelines are crucial to maximize its therapeutic benefits and improve clinical outcomes. Full article

(This article belongs to the Special Issue Human and Animal Infectious Diseases: Prevention, Diagnosis and Treatment, 2nd Edition)

► Show Figures

Figure 1

24 pages, 6571 KiB

Open AccessArticle

Leech Extract Enhances the Pro-Angiogenic Effects of Endothelial Cell-Derived Exosomes in a Mouse Model of Ischemic Stroke

by Yushuang Cao, Jin Sun, Lichen Guo, Meng Wang, Linlin Su, Tong Zhang, Shaoxia Wang, Lijuan Chai, Qing Yuan and Limin Hu

Curr. Issues Mol. Biol. 2025, 47(7), 499; https://doi.org/10.3390/cimb47070499 - 1 Jul 2025

Abstract

Background: Intercellular communication, facilitated by exosomes (Exos) derived from endothelial cells (ECs), significantly influences the regulation of angiogenesis. Leech extract significantly reduces ischemia–reperfusion injury, promotes angiogenesis, and improves neurological function in mice with stroke. However, further investigation is required to determine whether leech [...] Read more.

Background: Intercellular communication, facilitated by exosomes (Exos) derived from endothelial cells (ECs), significantly influences the regulation of angiogenesis. Leech extract significantly reduces ischemia–reperfusion injury, promotes angiogenesis, and improves neurological function in mice with stroke. However, further investigation is required to determine whether leech promotes angiogenesis through EC-Exo. Objective: This study aims to further explore whether leech regulates Exos to promote the establishment of collateral circulation in mice with ischemic stroke (IS) and the specific mechanisms involved. Methods: Here, we utilized an in vitro co-culture system comprising ECs and pericytes to investigate the impact of Leech-EC-Exo on enhancing the proliferation and migration of mouse brain microvascular pericytes (MBVPs). We further established an in vivo mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) to investigate the effects and underlying mechanisms of leech on collateral circulation establishment. Results: The findings demonstrated that leech significantly enhanced the in vitro cell migration number and migration number of pericytes. Therefore, it can also enhance the effect of EC-Exo on improving the infarct area and gait of mice, as well as modulating the HIFα-VEGF-DLL4-Notch1 signaling pathway to promote cerebral angiogenesis and facilitating the stable maturation of neovascularization in vivo. Conclusions: These results suggest that leech has the potential to enhance collateral circulation establishment, and its mechanism may involve the modulation of miRNA content in Exos and the promotion of signaling pathways associated with angiogenesis and vascular maturation. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

53 pages, 2742 KiB

Open AccessReview

The Role of Plant-Derived Natural Products as a Regulator of the Tyrosine Kinase Pathway in the Management of Lung Cancer

by Faris Alrumaihi, Arshad Husain Rahmani, Sitrarasu Vijaya Prabhu, Vikalp Kumar and Shehwaz Anwar

Curr. Issues Mol. Biol. 2025, 47(7), 498; https://doi.org/10.3390/cimb47070498 - 30 Jun 2025

Abstract

One of the most common malignant tumors worldwide is lung cancer, and it is associated with the highest death rate among all cancers. Traditional treatment options for lung cancer include radiation, chemotherapy, targeted therapy, and surgical resection. However, the survival rate is low, [...] Read more.

One of the most common malignant tumors worldwide is lung cancer, and it is associated with the highest death rate among all cancers. Traditional treatment options for lung cancer include radiation, chemotherapy, targeted therapy, and surgical resection. However, the survival rate is low, and the outlook is still dreadfully dire. The pursuit of a paradigm change in treatment approaches is, therefore, imperative. Tyrosine kinases (TKs), a subclass of protein kinases, regulate vital cellular function by phosphorylating tyrosine residues in proteins. Mutations, overexpression, and autocrine paracrine stimulation can transform TKs into oncogenic drivers, causing cancer pathogenesis. Tyrosine kinase inhibitors (TKIs) have emerged as an attractive targeted therapy option, especially for non-small cell lung cancer (NSCLC). However, resistance to TKIs, and adverse cardiovascular effects such as heart failure, atrial fibrillation, hypertension, and sudden death, are among the most common adverse effects of TKIs. There is increasing interest in plant-derived natural products in the hunt for powerful chemosensitizer and pathway modulators for enhancing TKI activity and/or overcoming resistance mechanisms. This highlights the mechanism of TKs’ activation in cancer, the role of TKIs in NSCLC mechanisms, and the challenges posed by TKI-acquired resistance. Additionally, we explored various plant-derived natural products’ bioactive compounds with the chemosensitizer and pathway-modulating potential with TKs’ inhibitory and anticancer effects. Our review suggests that a combination of natural products with TKIs may provide a novel and promising strategy for overcoming resistance in lung cancer. In future, further preclinical and clinical studies are advised. Full article

(This article belongs to the Special Issue Natural Compounds: An Adjuvant Strategy in Cancer Management)

► Show Figures

Figure 1

19 pages, 5478 KiB

Open AccessArticle

The Interaction of DMRTA2 with HSP90β Inhibits p53 Ubiquitination and Activates the p53 Pathway to Suppress the Malignant Progression of Non-Small-Cell Lung Cancer

by Shiyang Deng, Ling Li and Jiang Du

Curr. Issues Mol. Biol. 2025, 47(7), 497; https://doi.org/10.3390/cimb47070497 - 28 Jun 2025

Abstract

Background: Lung cancer, predominantly NSCLC (80%), has a poor prognosis due to late diagnosis and limited treatment efficacy. DMRTA2 (DMRT5), a transcription factor linked to neural/germ cell development, is overexpressed in NSCLC per TCGA data, indicating its potential role in tumorigenesis and [...] Read more.

Background: Lung cancer, predominantly NSCLC (80%), has a poor prognosis due to late diagnosis and limited treatment efficacy. DMRTA2 (DMRT5), a transcription factor linked to neural/germ cell development, is overexpressed in NSCLC per TCGA data, indicating its potential role in tumorigenesis and as a therapeutic target. Methods: Conduct a comprehensive search of the relevant theoretical foundations. Based on this, differential expression analysis will be performed using the DESeq2 package in R on RNA-seq data from lung adenocarcinoma and lung squamous cell carcinoma in the TCGA database. The research will then employ various methods, including CRISPR genome editing, MTS assay, flow cytometry, Western blot, co-immunoprecipitation, immunofluorescence, and qRT-PCR. Results: Through experimental validation, we found that DMRTA2 mRNA is highly expressed in non-small-cell lung cancer (NSCLC) tissues and is negatively correlated with poor prognosis. DMRTA2 binds to HSP90β, inhibiting the interaction between HSP90β and p53, thereby suppressing p53 ubiquitination and nuclear export. This activates the p53 pathway, inhibiting the proliferation and invasion of lung cancer cells. Conclusions: In NSCLC, DMRTA2 acts as a context-dependent regulator, stabilizing wild-type p53 through competitive HSP90β binding to suppress tumors, while in p53-compromised cells, potentially engaging HSP90β or alternative pathways to promote malignancy. Its dual localization and transport interactions reveal multifunctional, stress-responsive roles beyond transcription. Full article

(This article belongs to the Special Issue Autophagy and the Ubiquitin–Proteasome System: Regulators of Protein Homeostasis, Cell Death, and Disease Pathogenesis)

► Show Figures

Figure 1

24 pages, 4447 KiB

Open AccessArticle

The Construction of ceRNA Regulatory Network Unraveled Prognostic Biomarkers and Repositioned Drug Candidates for the Management of Pancreatic Ductal Adenocarcinoma

by Busra Aydin, Keziban Okutan, Ozge Onluturk Aydogan, Raghu Sinha and Beste Turanli

Curr. Issues Mol. Biol. 2025, 47(7), 496; https://doi.org/10.3390/cimb47070496 - 27 Jun 2025

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types due to its late diagnosis, low survival rates, and high frequency of metastasis. Considering the molecular mechanism of PDAC development has not been fully elucidated, this study aimed to shed more [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types due to its late diagnosis, low survival rates, and high frequency of metastasis. Considering the molecular mechanism of PDAC development has not been fully elucidated, this study aimed to shed more light on the molecular regulatory signatures of circular RNAs (circRNAs) in PDAC progression and provide a different perspective to identify potential biomarkers as well as discover candidate repositioned drug molecules for the prevention or treatment of PDAC with network-based integrative analysis. The mRNA, miRNA, and circRNA expression profiles of PDAC were obtained from nine microarray datasets. Differentially expressed genes (DEGs), microRNAs (DEmiRNAs), and circular RNAs (DEcircRNAs) were identified. The competing endogenous RNA (ceRNA; DEG–DEmiRNA–DEcircRNA) regulatory network was constructed, which included 12 DEcircRNAs, 64 DEGs, and 6 miRNAs specific to PDAC. The ADAM12, MET, QKI, SEC23A, and ZEB2 were identified as hub genes and demonstrated significant survival probability for PDAC. In addition to providing novel biomarkers for diagnosis that can be detected non-invasively, the secretion levels of hub genes-associated proteins were found in plasma, serum, and oral epithelium. The drug repositioning analysis revealed vorinostat, meclocycline sulfosalicylate, and trichostatin A, which exhibited significant binding affinities to the hub genes compared to their inhibitors via molecular docking analysis. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development, 2nd Edition)

► Show Figures

Figure 1

Journal Description

Current Issues in Molecular Biology

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI