Current Molecular Medicine[JOURNAL]
Sun
200 papers
Exposure to Stress or an Enriched Environment in Youth Modulates Prenatal Inflammation-Induced Cognitive Deficits in Mice and Is Associated with Hippocampal SNAP-25 Expression Levels.
Wu YF, Cao L, Zeng LP … +2 more , Zhang YX, Chen GH
Curr Mol Med · 2025 Nov · PMID 41261834 · Publisher ↗
INTRODUCTION: Brain aging can promote neuronal damage, contributing to aging-associated memory impairments (AAMI), a phenomenon characteristic of normal aging. However, it remains unclear whether and how exposure to stre...
INTRODUCTION: Brain aging can promote neuronal damage, contributing to aging-associated memory impairments (AAMI), a phenomenon characteristic of normal aging. However, it remains unclear whether and how exposure to stress or an enriched environment (S/E) during youth influences AAMI induced by prenatal inflammation. Therefore, SNAP-25, a key presynaptic membrane protein closely related to cognitive function, was selected as the primary molecular target. This project aimed to investigate the effects and underlying mechanisms of youth stress (S) and enriched environment (E) on the AAMI induced by prenatal inflammation. METHODS: Lipopolysaccharide (LPS) injection was used to establish an animal model of prenatal inflammation. Two experimental techniques, including S and E, were applied. The male offspring mice were randomly divided into four groups: LPS+S, LPS+E, LPS, and NS. Cognitive function was assessed using the Morris water maze test, while hippocampal synaptosomal-associated protein 25 (SNAP-25) expression was examined using Western blot and RNA in situ hybridization (RNAscope) techniques. RESULTS: Young mice (3 months old) exhibited better cognitive function and lower SNAP-25 expression compared with middle-aged mice (15 months old), indicating that the middle-aged mice displayed the expected impairment in spatial cognitive ability. Furthermore, LPS significantly impaired memory performance and increased SNAP-25 expression, whereas exposure to stress or an enriched environment (S/E) alleviated AAMI. In addition, a significant correlation was observed between SNAP-25 expression and cognitive performance. CONCLUSION: Youth exposure to stress or an enriched environment (S/E) at 2 months of age modulated the expression level of hippocampal SNAP-25 induced by prenatal inflammation. Moreover, increased SNAP-25 expression was associated with memory impairment.
Therapeutic Potential of Vericiguat in Myocardial Ischemia/ Reperfusion Injury: Crosstalk between Heat Shock Protein 90 and Complement Activation.
Chen J, Pan S, Wang D … +4 more , Meng J, Wang M, Zhong G, Tu R
Curr Mol Med · 2025 Nov · PMID 41261832 · Publisher ↗
INTRODUCTION: The present study aimed to examine the functions of heat shock protein 90 (HSP90), NF-κB, C3, and C5a in cardioprotective effects induced by vericiguat in mice. METHODS: Male mice were randomly assigned to...
INTRODUCTION: The present study aimed to examine the functions of heat shock protein 90 (HSP90), NF-κB, C3, and C5a in cardioprotective effects induced by vericiguat in mice. METHODS: Male mice were randomly assigned to six groups: sham, ischemia/ reperfusion (I/R), vericiguat preconditioning (VPre), VPre + HSP90 inhibitor geldanamycin (GA), vericiguat postconditioning (VPost), and VPost + GA. An experimental mouse model of I/R was established in mice through surgery and treatments with vericiguat and GA. The following parameters were assessed: myocardial infarct size; cardiomyocyte apoptosis; cTnI, CK-MB, and LDH serum levels, protein expression levels of Bcl-2, Bax, HSP90, NF-κB, and complement components C3 and C5a, and mRNA expression levels of IL-1β, TNF-α, and ICAM-1. RESULTS: Vericiguat significantly attenuated the myocardial infarct size induced by I/R injury; suppressed cardiomyocyte apoptosis; reduced serum levels of myocardial markers (CK-MB, LDH, and cTnI); decreased C5a, and C3 levels, NF-κB signaling, and expression of inflammatory cytokine （ICAM-1,TNF-α, and IL-1β); and enhanced HSP90 and Bcl-2 expression levels. However, GA reversed these effects. DISCUSSION: The study contributes to the investigation of the crosstalk between HSP90 and complement in the protective effects of vericiguat on myocardial I/R injury. However, further in-depth research is needed to explore the underlying mechanisms of vericiguat's cardioprotective effects against myocardial I/R injury. CONCLUSION: HSP90 plays a crucial role in the cardioprotective effects of vericiguat, providing new insights into its mechanisms of action.
Causal Relationship Between Plasma Protein-to-Protein Ratios and Rheumatoid Arthritis: A Proteome-wide Mendelian Randomization Study.
Yan M, Hou K, Wang T … +1 more , Zhang Y
Curr Mol Med · 2025 Nov · PMID 41239930 · Publisher ↗
INTRODUCTION: The causal relevance of circulating plasma protein-to-protein ratios (PPRs) in Rheumatoid Arthritis (RA) remains unclear. We employed Mendelian Randomization (MR) to investigate this relationship. METHODS:...
INTRODUCTION: The causal relevance of circulating plasma protein-to-protein ratios (PPRs) in Rheumatoid Arthritis (RA) remains unclear. We employed Mendelian Randomization (MR) to investigate this relationship. METHODS: This study utilized summary data of ratio quantitative trait loci (rQTLs) for 2,821 circulating PPRs from the GWAS Catalog and two RA-related GWAS datasets (FinnGen and GWAS Catalog). Causal estimates were obtained using various Mendelian randomization (MR) methods, including IVW and MR-Egger regression. Significant PPRs were further analyzed via protein-protein interaction (PPI), functional enrichment, and druggability assessments. Key genes were validated using qPCR. RESULTS: Fifteen candidate PPRs with consistent directional effects, and nine core PPRs, achieved statistical significance in both datasets. Protein-protein interaction (PPI) network analysis revealed involvement of these proteins in various biological processes. Gene Ontology (GO) analysis indicated roles in immune response and protein binding, while KEGG pathway analysis showed enrichment in Toll-like receptor signaling pathways. Friends analysis identified UBAC1 as a key gene, and seven PPR-associated proteins were found to be druggable. qPCR validation confirmed differential expression of UBAC1, CD40, ITGB5, and GLOD4. DISCUSSION: Our findings establish a robust genetic causal link between specific PPRs and RA, moving beyond association to suggest potential etiology. Integrated analyses prioritize UBAC1, CD40, ITGB5, and GLOD4 as key contributors to RA pathogenesis, with functional enrichment indicating their involvement in immune and inflammatory pathways. The druggability of several implicated proteins underscores the translational potential of these results. CONCLUSIONS: This study used MR to establish a causal relationship between plasma PPRs and RA risk. UBAC1, CD40, ITGB5, and GLOD4 may play key roles in the pathogenesis of RA.
Effects of the Total Flavonoids from Drynaria on Methyltransferase METTL3 and the Coupling of Osteogenesis and Angiogenesis in a Bone Defect Rat Model.
Wu J, Zeng J, Wu R … +7 more , Jin H, Ma H, Xu H, Li Y, Tan L, Sun S, Wang F
Curr Mol Med · 2025 Nov · PMID 41239929 · Publisher ↗
INTRODUCTION: This study aimed to investigate the effects of the Total Flavonoids from Rhizoma Drynaria (TFRD) on METTL3-mediated m6A methylation and osteogenic-angiogenic coupling during the repair of large bone defects...
INTRODUCTION: This study aimed to investigate the effects of the Total Flavonoids from Rhizoma Drynaria (TFRD) on METTL3-mediated m6A methylation and osteogenic-angiogenic coupling during the repair of large bone defects and to elucidate its role in bone remodeling under the Masquelet technique. METHODS: A large femoral bone defect rat model was established in Sprague Dawley (SD) rats using the Masquelet technique. Postoperatively, a total of 24 rats were randomly divided into four groups, namely the model group (MOD), low-dose group (0.11 g/kg/day), mid-dose group (0.22 g/kg/day), and high-dose group (TFRD) (0.44 g/kg/day). These groups were established using the corresponding TFRD dosages or saline interventions. The neobone tissue quality was assessed using X-rays (Lane-Sandhu score), and the bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) were quantified using micro-computed tomography (micro-CT). The localization and expression of type H vessel markers (CD31, EMCN) and measurement of the total RNA m6A methylation levels in the neobone tissues were performed using Immunohistochemistry (IHC). The osteogenic-angiogenic coupling factors (BMP-2, PDGF-BB, S1P) and m6A methylation regulators (METTL3, IGF2BP2) were analyzed using a western blot and qRT-PCR. RESULTS: The micro-CT and X-ray techniques revealed that TFRD significantly enhanced the neobone tissue quality, increased the BV/TV, and thickened Tb.Th compared to the MOD group. IHC showed a dose-dependent upregulation of the CD31 and EMCN expression areas and intensity in the neobone tissues, in addition to elevated m6A methylation levels with increasing TFRD doses. The western blot showed that the osteogenic-angiogenic coupling proteins (PDGFBB, S1P, BMP-2) and m6A regulators (METTL3, IGF2BP2) were upregulated in a dosedependent manner. Notably, while qRT-PCR indicated that TFRD suppressed PDGF-BB mRNA expression, the protein level was elevated, suggesting potential post-transcriptional regulation. The mRNA levels of BMP-2, S1P, METTL3, and IGF2BP2 were enhanced. CONCLUSION: TFRD facilitated bone regeneration by modulating METTL3-mediated m6A methylation, upregulating osteogenic-angiogenic coupling factors, and stimulating type H vessel formation. These findings support the potential of TFRD as a promising therapeutic agent for bone defect repair. TFRD acted through mechanisms that involve RNA methylation and enhanced the interaction between osteogenesis and angiogenesis. Targeting the epitranscriptomic regulation of bone-vascular interaction may open new avenues for orthopedic rehabilitation.
Exosome-Based Regulation and Therapy in Osteoporosis: Mechanistic Insights and Translational Advances.
Luo Y, Li S, Jin X
Curr Mol Med · 2025 Oct · PMID 41178764 · Publisher ↗
Osteoporosis is a chronic and progressive skeletal disease characterized by decreased bone mass and microarchitectural deterioration, leading to increased fracture susceptibility. Emerging evidence suggests that extracel...
Osteoporosis is a chronic and progressive skeletal disease characterized by decreased bone mass and microarchitectural deterioration, leading to increased fracture susceptibility. Emerging evidence suggests that extracellular vesicles, particularly exosomes, play a pivotal role as mediators of intercellular communication within the bone microenvironment. This review focuses on the functional roles of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) and other bone-resident cells in modulating bone remodeling. We detail the mechanisms by which exosome-encapsulated non-coding RNAs influence osteoblast and osteoclast activity through key regulatory pathways. Furthermore, we examine how pathological conditions, such as chronic inflammation and diabetes, reshape exosomal cargo, contributing to dysregulated bone homeostasis through mechanisms involving ferroptosis and oxidative stress. Advances in therapeutic applications are discussed, including engineered exosomes, bone-targeting delivery strategies, and hydrogelbased scaffolds. We also highlight the diagnostic potential of exosome-derived RNAs as biomarkers for disease progression and treatment response. Although exosomebased approaches represent a promising frontier in osteoporosis therapy and diagnosis, challenges, such as cargo heterogeneity, targeting specificity, and scalable manufacturing, remain to be addressed before clinical implementation.
CDK12 as a Potential Biomarker for Characterization of Circulating Tumor Cells in Epithelial Ovarian Tumors.
Jabbar S, Ahmed N, Hasan JA … +2 more , Haque Z, Farooqui WA
Curr Mol Med · 2025 Oct · PMID 41177788 · Publisher ↗
INTRODUCTION: The utility of epithelial markers is limited for the detection of circulatory tumor cells in patients with epithelial ovarian tumors, as these markers do not relate to clinicopathological characteristics no...
INTRODUCTION: The utility of epithelial markers is limited for the detection of circulatory tumor cells in patients with epithelial ovarian tumors, as these markers do not relate to clinicopathological characteristics nor assist in decision making for chemotherapeutic strategies. Cyclin-dependent kinase 12 (CDK12) has been implicated in the pathogenesis of ovarian cancer and holds potential as a valuable biomarker for diagnosis, prognosis, and the development of personalized therapeutic approaches. AIM: The study is aimed at assessing EPCAM+CDK12+ circulating tumor cells (CTCs) of patients diagnosed with epithelial ovarian tumors. METHOD: A total of 46 cases were included in the study, with 35 cases of epithelial ovarian neoplasms diagnosed as benign, borderline, and malignant tumors, and 11 cases in the control group. The percentage of EPCAM+CDK12+ CTCs in negatively selected CD45 (leukocyte common antigen) cells in all cases was assessed by flow cytometry. RESULT: Data analysis was performed by SPSS version 27.0. We found a significant difference in EPCAM+CDK12+ CTCs count between benign and malignant tumors (p < 0.03) and control and malignant (p < 0.004). A cut-off value of 0.35 percent cell count was calculated to differentiate benign from malignant ovarian tumors. Flow cytometry detected CTCs with a sensitivity of 68.4% and specificity of 83.3% respectively, with an area under the curve of 0.820 (P < 0.003). CONCLUSION: Hence, the study demonstrated the potential of CDK12 as a biomarker for future blood-based diagnosis and personalized treatment in epithelial ovarian tumor patients.
Artificial Intelligence in the Management of One Health: An Update.
Pandey SK, Kulshreshtha A, Mishra A
Curr Mol Med · 2025 Oct · PMID 41163283 · Publisher ↗
The One Health concept emphasizes the complex connection between environmental, animal, and human health and calls for cross-sectoral cooperation to improve ecological integrity and advance world health. The need for coo...
The One Health concept emphasizes the complex connection between environmental, animal, and human health and calls for cross-sectoral cooperation to improve ecological integrity and advance world health. The need for coordinated, preventative measures has grown more pressing as the frequency and complexity of new health risks caused by urbanization, globalization, and climate change increase. In this regard, current developments in machine learning (ML) and artificial intelligence (AI) are revolutionizing the One Health paradigm by greatly enhancing our ability to monitor, diagnose, and predict diseases. Predictive analytics, deep learning models, and decision support systems are examples of AI-driven technologies that help identify outbreaks early, allocate resources optimally, and reduce the cognitive load on medical staff. Predicting the spread of zoonotic illnesses, tracking antimicrobial resistance (AMR) trends, improving diagnostic precision, and guiding coordinated public health interventions are some of the main uses. Additionally, these technologies are being utilized to forecast health risks associated with pollution and habitat alteration, as well as to enhance environmental monitoring. In addition to highlighting the vital significance of international collaboration, moral leadership, and inclusive policymaking, this review broadens our knowledge of how AI and ML are transforming the One Health paradigm.
Regulatory Mechanisms of CHD7 and PAX4 Gene Mutations on Proliferation and Apoptosis in Chondrocytes.
Xu F, Li Y, Li D … +3 more , Dai Y, Wang B, Zhang R
Curr Mol Med · 2025 Oct · PMID 41088997 · Publisher ↗
INTRODUCTION: Mutations in Chromodomain Helicase DNA Binding Protein 7 (CHD7) and Paired Box Gene 4 (PAX4) are critical for normal cartilage development and are implicated through their impact on chondrocyte functions. T...
INTRODUCTION: Mutations in Chromodomain Helicase DNA Binding Protein 7 (CHD7) and Paired Box Gene 4 (PAX4) are critical for normal cartilage development and are implicated through their impact on chondrocyte functions. This study examines how these genetic alterations specifically modulate Tumor protein p53 (p53) expression to affect cellular proliferation and apoptosis, shedding light on potential therapeutic targets for mitigating developmental anomalies in cartilage. METHOD: Using Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- associated protein 9 (Cas9), specific mutations were introduced into CHD7 and PAX4 in chondrocytes. Subsequent analyses included 5-ethynyl-2'-deoxyuridine (EdU) assay for proliferation, Terminal deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining for apoptosis, quantitative real-time polymerase chain reaction (qRTPCR), and Western blot alongside co-immunoprecipitation (Co-IP) to evaluate expression levels and protein interactions. RESULT: Mutations in CHD7 and PAX4 resulted in decreased proliferation and increased apoptosis in chondrocytes. Notably, these mutations disrupted the interaction between the mutant proteins and p53, leading to altered expression of apoptotic regulators such as Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), indicating activation of p53-dependent apoptotic pathways. DISCUSSION: This study elucidates the core molecular mechanism by which mutations in the CHD7 and PAX4 genes disrupt their interaction with p53, leading to aberrant activation of the p53-dependent apoptotic pathway. These findings provide a new theoretical basis and potential intervention strategies for developing p53 pathwaytargeted therapies to treat related cartilage developmental disorders. Future research should focus on in vivo validation and mechanistic refinement. CONCLUSION: The study reveals that CHD7 and PAX4 mutations exacerbate the apoptotic pathways in chondrocytes by enhancing the activity of p53, leading to decreased cell proliferation and increased apoptosis. These findings underscore the mutations' profound impact on cartilage cell dynamics and highlight the therapeutic potential of targeting p53 to correct the cellular imbalances caused by these genetic changes in cartilage-related developmental disorders.
Roles of Exosomes in Cancer Pathogenesis, Progression, and Therapy Resistance.
Moni ZA, Kamal T, Auwal A … +4 more , Hossain MM, Bulbul MIA, Roy N, Islam F
Curr Mol Med · 2025 Oct · PMID 41088996 · Publisher ↗
Cancer is a major health concern worldwide, and there have been numerous efforts to fully understand the mechanism of cancer pathogenesis and develop effective treatments. In this context, exosomes play a crucial role in...
Cancer is a major health concern worldwide, and there have been numerous efforts to fully understand the mechanism of cancer pathogenesis and develop effective treatments. In this context, exosomes play a crucial role in the detection and management of cancer. Exosomes are extracellular vesicles that share components with their parent cells and mediate intercellular communication, especially in cancer patients. Exosomal cargo, which includes proteins, lipids, and RNAs, has been extensively investigated due to its potential significance in cancer. Exosomes play a crucial role in cancer biology, as they have been demonstrated to alter the tumor microenvironment and facilitate communication between the tumor and its host. Exosomal composition is influenced by packaging and secretion processes, which can affect the function, distribution, and uptake of cargo in target cells. Exosome-mediated communication within the tumor microenvironment suggests that variations in endocytosis and plasma membrane remodeling, which are specific to cancer, are partly responsible for the abnormal exosomal process in cancer. Numerous processes, including the modification of the tumor microenvironment, the promotion of angiogenesis, metastasis, and invasion, as well as the regulation of tumor cells' immune escape, are thought to be facilitated by exosomes in the development and progression of cancers originating from various tissues. Exosomal components have the ability to mediate immune responses against cancer and aid in the development of cancer cell resistance to treatments and medications. This study aims to provide a concise review of exosome composition, the processes involved in their synthesis, their roles in cancer development, progression, and metastasis, as well as their ability to evade immune surveillance and contribute to resistance against cancer-related drugs and therapies. Therefore, we conducted an extensive search across numerous academic databases, including Scopus, PubMed, ScienceDirect, Crossref, and Google Scholar, using the keywords "cancer," "exosomes," "progression," "metastasis," "therapy resistance," etc. The retrieved literature was critically analyzed. This knowledge may contribute to more effective cancer treatment in the future by informing potential therapeutic applications.
The Impact of Anaerobic & Aerobic Exercise on Oxidative Stress and Cellular Fitness in Healthy Trained Young Men: A Randomized Trial.
Hardiany NS, Purnomo E, Dewi S … +1 more , Yustisia I
Curr Mol Med · 2025 Oct · PMID 41088995 · Publisher ↗
INTRODUCTION: Anaerobic and aerobic exercise are known to increase reactive oxygen species (ROS) and cytokines, which may lead to oxidative stress when ROS accumulate. However, the findings are still inconsistent, with m...
INTRODUCTION: Anaerobic and aerobic exercise are known to increase reactive oxygen species (ROS) and cytokines, which may lead to oxidative stress when ROS accumulate. However, the findings are still inconsistent, with most studies focusing on short exercise durations. This study aimed to compare the effects of anaerobic and aerobic exercise on oxidative stress and cellular fitness in healthy trained young men. METHODS: A randomized trial was conducted involving 18 young male subjects, divided into two groups: anaerobic (short-distance running) and aerobic (long-distance running), with each group exercising three times per week for one month. Blood samples were collected before and after the intervention. Malondialdehyde (MDA) reflected oxidative stress, ROS (H2O2), and antioxidant levels (total antioxidant capacity, superoxide dismutase/SOD, glutathione peroxidase/GPX) were detected using spectrophotometry, while Interleukin-6 (IL-6) and ATPase Inhibitory Factor 1 (ATPIF1) reflected cellular fitness, were measured using ELISA. RESULTS: Both anaerobic and aerobic exercise significantly reduced MDA levels. Aerobic exercise significantly increased SOD and total antioxidant capacity, while anaerobic exercise resulted in decreased GPX levels. No significant changes were observed in HⁿOⁿ, IL-6, or ATPIF1 levels in either group. DISCUSSION: The findings suggest that aerobic exercise enhances the body's antioxidant defense system more effectively than anaerobic exercise, contributing to reduced oxidative stress. The participants' trained status may have influenced the SOD response. Limitations include a lack of control over lifestyle variables and limited generalizability due to the homogenous sample. CONCLUSION: One month of exercise reduces oxidative stress in trained young men, with aerobic exercise showing greater benefits in boosting endogenous antioxidants.
SIRT6 Relieves Acute Lung Injury by Enhancing PGC-1α Expression and Improving Mitochondrial Function.
Li X, Mo Y, Shi J … +5 more , Liu S, Bu S, Liu H, Li W, Yu J
Curr Mol Med · 2025 Oct · PMID 41088931 · Publisher ↗
INTRODUCTION: Sepsis-induced acute lung injury (ALI) is closely related to the dysfunction of mitochondria. Sirtuin 6 (SIRT6), as a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylase, is involved in sev...
INTRODUCTION: Sepsis-induced acute lung injury (ALI) is closely related to the dysfunction of mitochondria. Sirtuin 6 (SIRT6), as a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylase, is involved in several cellular processes. However, research has shown that the interaction of SIRT6 and mitochondrial function plays a role in acute lung injury. The objective of this research study was to explore the effect of SIRT6 on mitochondrial function during septic lung injury. METHODS: Lipopolysaccharide (LPS) was used to establish ALI models in C57BL/6J, SIRT6fl/fl/CAG-CreERT2 mice and in MLE12 cells. Hematoxylin and eosin staining, cell counting kit-8 (CCK-8), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate lung injury, cell viability, and inflammation. Western blot (WB) was used to measure the protein expression of SIRT6 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). The function and integrity of mitochondria were detected by transmission electron microscopy (TEM), etc. Results: In this study, LPS stimulation reduced the protein expression levels of SIRT6 and PGC-1α. Furthermore, it inhibited mitochondrial DNA (mtDNA), mitochondrial membrane potential, and mitochondrial oxygen consumption rate, while promoting mitochondrial swelling in vivo in a model of acute lung injury. Adenovirus-mediated SIRT6 overexpression alleviated acute lung injury, simultaneously enhancing the protein levels of PGC-1α, mtDNA content, mitochondrial membrane potential, and mitochondrial oxygen consumption rate, and inhibiting mitochondrial swelling in vivo. Conversely, the deletion or knockout of SIRT6 diminished PGC-1α protein expression levels, enhanced mitochondrial dysfunction, and further aggravated acute lung injury. CONCLUSION: SIRT6 protected against LPS-induced acute lung injury by promoting PGC-1α expression and improving mitochondrial function both in vivo and in vitro.
Molecular Pathways and Recent Therapeutic Strategies for Polyglutamine Diseases.
Roy SK, Barman A, Richard SA … +1 more , Lacmane BA
Curr Mol Med · 2025 Oct · PMID 41088930 · Publisher ↗
The abnormal expansion of trinucleotide cytosine-adenine-guanine [CAG] repeats within disease-associated genes is the primary cause of polyglutamine [polyQ] diseases. This study aims to evaluate the pathological threshol...
The abnormal expansion of trinucleotide cytosine-adenine-guanine [CAG] repeats within disease-associated genes is the primary cause of polyglutamine [polyQ] diseases. This study aims to evaluate the pathological threshold at which the polyglutamine [polyQ] tract, following mutation, leads to neurotoxic effects and to explore emerging therapeutic strategies targeting these mechanisms. The formation of protein aggregates comprising pathogenic polyQ proteins, which induce cellular cytotoxicity, is a key hallmark of polyQ diseases. Despite extensive research, the molecular pathways responsible for the cellular toxicity caused by mutant polyQ proteins remain untreatable. However, strategies to reduce the abnormal expansion of CAG repeats, inhibit the accumulation and aggregation of toxic polyQ-expanded proteins, and promote protein refolding, degradation, or prevention of proteolytic cleavage have shown promise. Additionally, therapeutic approaches such as induced autophagy and stem cell therapies represent promising avenues for intervention. Current treatment modalities for polyQ diseases primarily focus on temporarily alleviating symptoms and slowing disease progression. Continued research into targeted therapeutic strategies is essential to address the underlying pathophysiology of these disorders effectively.
SCH79797, an Antiplatelet Agent, Alleviates Restenosis by Inducing Apoptosis via p53-Mediated Mitochondrial Depolarization and Inhibiting Thrombus Formation after Angioplasty.
Yen TL, Hong KJ, Jan JS … +4 more , Chen YL, Chou PC, Chen CY, Ko WC
Curr Mol Med · 2025 Oct · PMID 41036752 · Publisher ↗
INTRODUCTION: In the field of interventional cardiology, coronary in-stent restenosis (ISR) continues to present a clinical hurdle, even with the progress made in stent design and pharmacological interventions. While dru...
INTRODUCTION: In the field of interventional cardiology, coronary in-stent restenosis (ISR) continues to present a clinical hurdle, even with the progress made in stent design and pharmacological interventions. While drug-eluting stents (DESs) and drug-eluting balloons (DEBs) have markedly decreased the occurrence of ISR when compared to bare-metal stents, the condition persists as a complication in revascularization, contributing to increased patient morbidity and challenging long-term treatment outcomes. Thus, a deeper understanding of ISR mechanisms and the development of novel therapeutic approaches are crucial for improving patient outcomes. METHODS: In this study, we utilized the A10 cell as an in vitro model and induced common carotid artery balloon dilation injury in Sprague-Dawley rats as an animal model to explore the potential clinical applications of SCH79797, particularly in the treatment of ISR. RESULTS: SCH79797, a protease-activated receptor-1 antagonist, induced apoptosis of smooth muscle cells through various pathways. SCH79797 promoted apoptosis via JNK/c-Jun and p53 upregulation in the cytosol. We also observed an increased Bax/Bcl-2 ratio in mitochondria, p53 translocation to mitochondria, and changes in the mitochondrial membrane potential to mitochondrial membrane permeabilization. Our comparative analysis with vorapaxar revealed the apoptotic effects of SCH79797 to be independent of its PAR-1 antagonist activity. Furthermore, SCH79797 administration significantly reduced common carotid artery restenosis and thrombosis following balloon injury in vivo. DISCUSSION: Our study has been the first to demonstrate SCH79797 to directly induce VSMC apoptosis via the p53-mediated mitochondrial pathway, providing a novel mechanistic insight into ISR treatment. Unlike traditional anti-proliferative agents used in DESs, SCH79797 uniquely combines apoptotic induction with antithrombotic effects, making it a dual-action therapeutic candidate. This research study has laid the groundwork for localized drug-eluting strategies that can leverage SCH79797's properties to prevent ISR more effectively while minimizing systemic side effects. CONCLUSION: Our findings have established SCH79797 as a promising candidate for reducing ISR through apoptosis modulation. By leveraging the p53-mediated mitochondrial apoptotic pathway, SCH79797 may provide a groundbreaking approach to reducing restenosis. These findings could offer significant implications for the future development of targeted drug-eluting strategies by locally delivering SCH79797 in a controlled manner using DES or DEB, presenting SCH79797 as a transformative candidate in interventional cardiology.
ELOVL4 is a Prognostic Biomarker with Implications for Immune Modulation and Therapeutic Response in Gastric Cancer.
Chu Y, Yao Y, Song Q
Curr Mol Med · 2026 · PMID 41036751 · Publisher ↗
BACKGROUND: Gastric cancer (GC) remains a major health burden with poor prognosis, highlighting the need for reliable prognostic biomarkers and therapeutic targets. ELOVL4 (Elongation of Very Long Chain Fatty Acids Prote...
BACKGROUND: Gastric cancer (GC) remains a major health burden with poor prognosis, highlighting the need for reliable prognostic biomarkers and therapeutic targets. ELOVL4 (Elongation of Very Long Chain Fatty Acids Protein 4) is an enzyme involved in lipid metabolism, which has been implicated in various cancers, but its role in GC remains largely unexplored. METHODS: We evaluated the prognostic value of ELOVL4 expression in GC based on samples from The Cancer Genome Atlas (TCGA) database. Subsequently, we investigated the associations between ELOVL4 expression and tumor immune microenvironment features, including tumor microenvironment (TME) scores, immune cell infiltration, and immune checkpoint gene expression. Moreover, we assessed the correlation between ELOVL4 expression and tumor mutational burden (TMB) as well as drug sensitivity profiles. Functional and pathway enrichment analyses were performed to gain mechanistic insights. RESULTS AND DISCUSSION: High ELOVL4 expression was significantly associated with adverse clinical outcomes. A nomogram incorporating ELOVL4 expression was developed for individualized prognosis evaluation. Patients with high ELOVL4 expression exhibited an activated TME, with distinct immune cell infiltration patterns and correlations with immune checkpoint gene expression. Additionally, ELOVL4 expression was negatively correlated with TMB. Differential drug sensitivity profiles were identified between the high and low ELOVL4 expression groups. Enrichment analyses revealed the involvement of ELOVL4 in various biological processes and signaling pathways. CONCLUSION: Our findings establish ELOVL4 as a biomarker for poor prognosis and therapeutic target in GC, with implications for prognosis evaluation, immune microenvironment modulation, and chemotherapeutic response.
Astragalus Mongholicus for Idiopathic Pulmonary Fibrosis Treatment: From Molecules to Systems.
Yang Y, Guo J, Ye G … +1 more , Li N
Curr Mol Med · 2025 Sep · PMID 41031494 · Publisher ↗
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Astragalus mongholicus (AM), a cornerstone herb in traditional Chinese medicine (TCM), demonstrates...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Astragalus mongholicus (AM), a cornerstone herb in traditional Chinese medicine (TCM), demonstrates significant therapeutic potential for IPF due to its multi-target mechanisms. This review synthesizes evidence on AM and its bioactive components; astragalus polysaccharide (APS), astragaloside IV (AS IV), and calycosin (CAL) in targeting key IPF pathological processes. These include suppression of inflammatory responses (via TLR4/NF-κB inhibition), inhibition of extracellular matrix deposition (via MMP/TIMP modulation), attenuation of oxidative stress, regulation of autophagy, and blockade of epithelial-mesenchymal transition (via lncRNA-ATB/miR-200c/ZEB1 axis). We further highlight the integration of molecularlevel mechanisms with systems pharmacology to elucidate AM's holistic actions. Clinical studies support AM-containing TCM prescriptions in improving lung function with fewer adverse effects. This synthesis underscores AM's promise as a multi-target therapeutic agent and advocates for systematic pharmacology approaches in future IPF drug development.
The Epigenetic Landscape of Hemophilia.
Pandey SK, Kulshreshtha A, Mishra A
Curr Mol Med · 2025 Sep · PMID 41031493 · Publisher ↗
Hemophilia, a rare inherited bleeding illness that needs to be managed throughout one's life to stop bleeding episodes and lessen complications. Although the genetic foundation of hemophilia is well documented, recent re...
Hemophilia, a rare inherited bleeding illness that needs to be managed throughout one's life to stop bleeding episodes and lessen complications. Although the genetic foundation of hemophilia is well documented, recent research has demonstrated that epigenetic pathways can influence the severity of the disease, the effectiveness of treatment, and the occurrence of complications. Advances in epigenetic research have made it possible to better understand the complexities of hemophilia and design suitable and targeted treatments. Emerging advancements as well as challenges are explored within many countries around the globe. Several epigenetic factors influence how the disorder manifests and its severity. Therapeutic interventions are the cornerstone for treating the disorder. The epigenetic regulation of the principal hemophilia genes (F8/F9) is still not fully understood. With the right treatment, preventative strategies, and better healthcare protocols, hemophilia cases in a confined area can be decreased. We explore the intricate blood clotting processes, inheritance patterns, and genetic changes that contribute to hemophilia's pathophysiology. The current understanding of epigenetics in hemophilia is examined in this review, with particular attention paid to non-coding RNAs, histone changes, and DNA methylation.
The Role of Rho-Associated Kinase in the Cognitive Benefits of the ACE Inhibitory Peptide LAP for Hypertension.
Huang J, Wang H, Liu Y … +3 more , Luo B, Fang H, Luo M
Curr Mol Med · 2025 Sep · PMID 41029923 · Publisher ↗
INTRODUCTION: This study assessed the effects of the synthesized ACE inhibitory peptide LAP (Leu-Arg-Pro-Val-Ala-Ala) on cognitive impairment in hypertensive rats. METHODS: Rho-associated coiled-coil containing protein k...
INTRODUCTION: This study assessed the effects of the synthesized ACE inhibitory peptide LAP (Leu-Arg-Pro-Val-Ala-Ala) on cognitive impairment in hypertensive rats. METHODS: Rho-associated coiled-coil containing protein kinase (ROCK) activity in peripheral blood mononuclear cells (PBMCs) was initially measured in elderly patients with hypertension and cognitive impairment using western blot analysis. The effect of LAP on the ROCK pathway was studied in a human cell line with ROCK1. Fifteenweek- old male spontaneously hypertensive rats (SHR) received intragastric LAP (500 μg/week) for eight weeks. Cognitive function was assessed using the Morris water maze test, and thoracic aorta remodeling was evaluated by determining the media/lumen ratio through immunohistochemistry. Amyloid beta (Aβ), phosphorylated tau (p-tau), and apoptotic neurons in the hippocampus were examined by western blot analysis and immunohistochemistry. Protein expression and activation related to the ROCK pathway, including moesin, myosin light chain (MLC), and myosin phosphatase target subunit (MYPT), were analyzed in the aorta and hippocampus using western blot and immunohistochemistry. RESULTS: Hypertensive patients with cognitive impairment showed increased phosphorylated/total myosin-binding subunit ratios in PBMCs, indicating higher ROCK pathway activity. In vitro, LAP reduced p-moesin levels, confirming ROCK inhibition. In vivo, oral LAP lowered blood pressure and heart rate in SHR models and improved cognitive function. LAP also reduced aortic remodeling, decreased hippocampal Aβ and p-tau deposition, reduced neuronal apoptosis, and increased neuronal survival. Mechanistically, LAP inhibited ROCK pathway activation in the aorta and hippocampus, similar to the ROCK inhibitor fasudil. DISCUSSION: Hypertension contributes to neurodegenerative changes through the activation of the ROCK signaling pathway. The study found that the ACE inhibitory peptide LAP not only sustainably lowered blood pressure, but also inhibited the ROCK pathway, reducing hippocampal Aβ and p-tau deposition, thereby offering a dual therapeutic approach for hypertension-related cognitive impairment. CONCLUSION: LAP alleviated hypertension-related cognitive impairment in SHR by inhibiting the hippocampal ROCK pathway, showing therapeutic potential.
Effect of Sema3F on VEGF in Primary Rat Hippocampal Neurons In vitro.
Li CX, Rihemuqiqige E, Lv T … +4 more , Fu JX, Liu XY, Tang R, Yang GL
Curr Mol Med · 2025 Sep · PMID 41029010 · Publisher ↗
INTRODUCTION: This study aimed to explore the mechanism of semaphorin 3F- (Sema3F) induced hippocampal axonal growth cone collapse by studying the effect of Sema3F on vascular endothelial growth factor (VEGF) in vitro pr...
INTRODUCTION: This study aimed to explore the mechanism of semaphorin 3F- (Sema3F) induced hippocampal axonal growth cone collapse by studying the effect of Sema3F on vascular endothelial growth factor (VEGF) in vitro primary rat hippocampal neuron culture system. METHODS: Hippocampal neurons were taken from Wistar rats within 24 hours after birth for primary culture in vitro. On the third day, Sema3F was added to the experimental group, and fetal bovine serum at the same concentration was added to the control group. The cells were collected at 0, 5, 15, and 30 min. The expression of VEGF messenger ribonucleic acid (mRNA) in the hippocampal neurons was detected by real-time polymerase chain reaction (PCR), while VEGF expression was detected by Western blot. The level of VEGF expression in the hippocampal neuron culture medium was detected by enzyme-linked immunosorbent assay. RESULTS: The expression of both VEGF mRNA and VEGF protein in the rats' hippocampal neurons decreased at different times. The VEGF concentration in the culture medium initially increased before decreasing over time. DISCUSSION: Sema3F is known to induce growth cone collapse in hippocampal neurons, and this study provides evidence that this effect may be mediated by downregulating VEGF expression and secretion. The initial increase in VEGF concentration in the culture medium could be a compensatory response to the collapse of growth cones, while the subsequent decrease suggests a sustained effect of Sema3F on VEGF regulation. The findings highlight the complex interplay between Sema3F and VEGF in neuronal development and repair. Future research should explore the underlying signaling pathways and potential therapeutic applications of these interactions. CONCLUSION: Sema3F inhibited the synthesis of VEGF in hippocampal neurons at transcription and translation levels in a time-dependent manner. Sema3F may also affect the secretion level of VEGF, initially increasing its extracellular expression before decreasing it over time.
Dynamin-Related Protein 1 and the NLRP3 Inflammasome in Parkinson's Disease: Mechanistic Insights and Therapeutic Opportunities.
Someshwar CK, Krishna KL
Curr Mol Med · 2025 Sep · PMID 41029009 · Publisher ↗
INTRODUCTION: Parkinson's disease (PD) is characterized by the progressive destruction of the dopaminergic cells in the substantia nigra region. The incidence of PD continues to rise, with over 8.5 million people affecte...
INTRODUCTION: Parkinson's disease (PD) is characterized by the progressive destruction of the dopaminergic cells in the substantia nigra region. The incidence of PD continues to rise, with over 8.5 million people affected in 2019 and projections indicating it could reach over 17 million by 2040 compared with levels observed since 1980. This review examines the mechanistic role of Dynamin-Related Protein 1 (Drp1) and Nod-Like Receptor Family Pyrin Domain-Containing 3 (NLRP3) inflammasome in the development and pathogenesis of PD. METHODS: The information was collected from databases such as PubMed, Embase, Google Scholar, Web of Science, and Elsevier database. RESULTS: There is a potential for Drp1 and NLRP3 pathways to serve as therapeutic targets in PD. Drp1 inhibitors, such as Mdivi-1, aid in mediating mitochondrial homeostasis, and NLRP3 inhibitors prevent inflammation. Natural compounds that modulate such pathways include resveratrol and curcumin, and preclinical models demonstrate multi-target neuroprotection via direct antioxidant and anti-inflammatory properties. DISCUSSION: The intricate relationship among oxidative stress, mitochondrial dynamics and inflammation indicates that a combination drug therapy approach is more likely to be effective compared to a single-agent strategy. In a subsequent phase, there is a need for improved formulation and enhancement of natural compounds to maximize their bioavailability and efficacy, particularly in terms of selective Drp1 and NLRP3 inhibitors. CONCLUSION: The Drp1-NLRP3 axis is one of the essential mechanistic connections between mitochondrial dynamics and neuroinflammation in PD. Focusing on this axis could offer novel therapeutic options, and advancing these approaches could pave the way for therapies that not only alleviate symptoms but also slow or halt the progression of the disease.
The Tumor Microenvironment: Impact on Tumor Growth, Metastasis, and Therapeutic Resistance: A Systematic Review.
Yan J, Tu S
Curr Mol Med · 2025 Sep · PMID 41029008 · Publisher ↗
INTRODUCTION: This systematic review assesses the role of the tumor microenvironment (TME) in cancer progression and therapy resistance by defining drug-microenvironment interactions and determining the molecular determi...
INTRODUCTION: This systematic review assesses the role of the tumor microenvironment (TME) in cancer progression and therapy resistance by defining drug-microenvironment interactions and determining the molecular determinants in the TME that could help improve the efficacy of administered treatments and alleviate existing adverse effects. METHODS: This systematic review follows the PRISMA protocol and the PICOS selection framework to retrieve studies from PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane Library. Only original human-related research published in English between 2008 and 2023 was used to explore the reciprocal relation between tumor cells and TME components. The ROBINS-I tool assessed the risk of bias. RESULTS: Out of 258 articles initially identified, 15 met the inclusion criteria for this review. The results showed that TMEs significantly influence treatment outcomes in cancer progression, metastasis, and drug resistance. Focusing on TMEs like CAFs, immune cells, and ECM enhances drug efficacy. The study highlighted potential strategies to improve drug delivery, suppress metastatic processes, and restore immune function, ultimately leading to better outcomes for cancer patients. DISCUSSION: Original evidence suggests that Cancer-Associated Fibroblasts (CAFs), immune cells, and Extracellular Matrix (ECM) contribute to therapeutic resistance and metastasis within the TME. They also promote metastasis by inducing Epithelial- Mesenchymal Transition (EMT) and affecting Cancer Stem Cell (CSC) populations. Moreover, the immunosuppressive TME consists of regulatory T cells and myeloidderived suppressor cells that allow tumors to evade the immune system, a concern for immunotherapy. CONCLUSION: The TME plays a vital role in cancer development, metastasis formation, and therapy failure. The perspectives for innovative ECM-modulating treatments and interventions targeting the direct interactions between TME and cancer cells can be revolutionary and suggest better outcomes for treatment-naïve and refractory cancers. Future research should use these results as inputs to apply clinical and therapy studies to enhance cancer management outcomes.
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