Current molecular medicine最新文献

Introduction: Intrauterine Adhesions (IUA), a common gynecological condition often caused by infection or endometrial injury, significantly impact women's reproductive and mental health. Its unclear pathogenesis hinders the development of effective treatments. Adiponectin, a bioactive protein with anti-inflammatory and antifibrotic properties, may offer therapeutic potential. This study investigates adiponectin's effects and mechanisms in IUA to inform new clinical strategies..

Methods: Endometrial tissues from IUA patients and controls were analyzed via immunohistochemistry to assess NLRP3, IL-1β, TGF-β1, and adiponectin expression. A human IUA cell model was established by stimulating human endometrial stromal cells (HESCs) with TGF-β1 (10 ng/ml, 48 hours). Interventions using the NLRP3 inhibitor MCC950, activator nigericin sodium salt, and adiponectin were applied. Protein and mRNA expression levels of NLRP3, IL-1β, TGF-β1, α-SMA, and COL1A1 were evaluated via Western blot and RT-qPCR. In vivo, IUA model rats were treated with adiponectin, and uterine morphology, gland count, collagen deposition, and inflammatory/fibrotic markers were analyzed.

Results: NLRP3, IL-1β, and TGF-β1 expression were significantly upregulated in IUA patient tissues, while adiponectin was downregulated (P<0.05). In the TGF-β1-induced IUA cell model, NLRP3 inhibition with MCC950 reduced IL-1β and TGF-β1 levels, whereas NLRP3 activation with nigericin increased them. Adiponectin intervention significantly decreased NLRP3, IL-1β, TGF-β1, α-SMA, and COL1A1 expression in vitro (P<0.05). In IUA rats, adiponectin improved uterine morphology, increased endometrial glands, reduced collagen fiber deposition, and downregulated NLRP3, IL- 1β, and TGF-β1 expression (P<0.05).

Discussion: Adiponectin alleviates endometrial inflammation and fibrosis in IUA, potentially by modulating the NLRP3/IL-1β/TGF-β1 signaling pathway. These findings highlight adiponectin's role in mitigating IUA progression and provide a theoretical basis for its clinical applications.

Conclusion: Adiponectin reduces inflammation and fibrosis in IUA by suppressing the NLRP3/IL-1β/TGF-β1 axis, offering new insights for IUA treatment strategies.

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.

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.

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.

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.

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.

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.

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.

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.