Current molecular medicine最新文献

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.

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.

Introduction: Endometriosis is a chronic disorder characterized by abnormal endometrial tissue growth. This study evaluates a novel combination immunomodulatory treatment involving etanercept (ETN) and exosomes derived from human Wharton's jelly mesenchymal stem cells (hWJMSC-Exo) as a promising alternative to conventional therapies for modulating inflammation in endometriosis.

Methods: Endometrial stromal cells were isolated by enzymatic digestion of eutopic (EuESCs, N = 6) and ectopic (EESCs, N = 6) tissues of endometriosis patients and non-endometriotic controls (CESCs, N = 6). hWJMSC-Exo were confirmed by flow cytometry, SEM, and DLS tests. Cells were treated with varying concentrations of ETN (0-40 μg/ml), hWJMSC-Exo (0-15 μg/ml), and their combination (E+E). IC50 values were determined using the MTT assay at 24, 48, and 72 hours. Protein levels of TNF- α, VEGF-A, and IL-10, and gene expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 were measured using ELISA and RT-PCR, respectively.

Results: The combination of ETN (10 μg/ml) and hWJMSC-Exo (10 μg/ml) at 24 and 48 hours, respectively, reduced protein expression of TNF-α, VEGF-A, and IL-10 in EESCs, EuESCs, and CESCs compared with untreated groups (P < 0.001). Additionally, E+E treatment significantly reduced mRNA expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 in all three groups compared to untreated groups.

Discussion: This combination therapy improves inflammation, angiogenesis, tissue remodeling, and immune regulation in endometriosis. However, clinical validation and long-term safety require further in vivo studies with larger sample sizes.

Conclusion: E+E treatment synergistically reduced key cytokines and enzymes in endometriosis. This approach is a promising means of regulating inflammation.

Endometriosis is a typical disorder affecting the female reproductive system and is characterized by the presence of tissue resembling the endometrium both within and beyond the pelvic cavity. Unfortunately, the etiology of endometriosis is not well understood. The purpose of this document is to create a summary of the factors contributing to endometriosis, especially the dysregulation of cellular and molecular pathways. Key biological processes implicated include enzyme dysregulation, exosome dysfunction, hormonal imbalances, apoptosis, angiogenesis, oxidative stress, epigenetic dysregulation, and the involvement of cytokines and chemokines. Many of these factors have overlapping pathways that can enhance the survival of endometrial debris and facilitate the implantation of endometrial tissue in extrauterine sites. This knowledge can provide a broader perspective on the onset and progression of endometriosis. Additionally, this study paves the way for the discovery of new therapeutic targets to improve the efficacy of endometriosis treatments and reduce the side effects associated with current treatments. Further research is needed to better understand the underlying mechanisms that lead to the dysregulation of diseaserelated pathways, which could ultimately be useful in early diagnosis and disease staging.

Introduction: Studies have stated that there has been a close association between the telomere length (TL) and the incidence of non-alcoholic fatty liver disease (NAFLD). The goal of this report is to explore the possible association between TL and NAFLD.

Methods: This study adhered to the PRISMA guidelines for systematic reviews. An extensive literature search was conducted in the Cochrane Library, CINAHL, Scopus, PubMed, and Web of Science. The "meta" package in the R programming language, version 4.3.1, was used for statistical analysis.

Results: The meta-analysis of the included studies showed a pooled standard mean difference (SMD) of -0.25 (95% CI: -0.39 to -0.10), indicating shorter TL in NAFLD patients. Subgroup analyses revealed significant TL shortening in NAFLD patients with body mass index (BMI) <28 (SMD = -0.68, 95% CI: -0.96 to -0.39) and in case-control (-0.35, 95% CI: -0.51 to -0.20) and cohort studies (-0.68, 95% CI: -1.19 to -0.17). An odds ratio (OR) meta-analysis of six studies found that individuals with short TL had 1.72 times higher odds of NAFLD, which was statistically significant (95% CI: 1.23- 2.42, I2 = 85%). Excluding one study reduced heterogeneity (I2 = 37%) and increased the OR to 1.93 (95% CI: 1.45-2.56), confirming a strong association between short TL and NAFLD risk.

Discussion: The findings suggest a potential link between shorter TL and NAFLD. The odds ratio analyses further emphasized the increased risk of NAFLD in individuals with short TL. Nevertheless, the residual heterogeneity highlights the need for further high-quality, standardized research.

Conclusion: Our findings supported the connection between reduced TL and NAFLD. Regardless of significant between-study diversity, the results remained consistent even after repeated sensitivity evaluations. Despite these findings, the high heterogeneity highlights the need for further well-designed studies to confirm TL as a reliable biomarker for NAFLD risk and progression.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and severe complications, including cardiovascular diseases, neuropathy, retinopathy, and nephropathy. This article examines the role of gut microbiota in modulating inflammation and insulin resistance in type 2 diabetes mellitus (T2DM), as well as its implications for managing complications associated with the disease. We analyzed published literature to elucidate mechanisms linking microbial dysbiosis, impaired gut barrier function, and chronic inflammation to glycemic control and T2DM complications. Key findings suggest that gut microbiota dysbiosis contributes to systemic inflammation and insulin resistance, thereby exacerbating the complications of type 2 diabetes mellitus (T2DM). Therapeutic strategies, such as probiotics, prebiotics, and fecal microbiota transplantation, promise to improve glycemic control and mitigate complications by restoring microbial balance. This review provides a comprehensive framework for understanding the role of the gut microbiota in type 2 diabetes mellitus (T2DM) and highlights potential therapeutic interventions to enhance the management of complications.

Introduction: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis, primarily due to therapy resistance mediated by CD133+ glioblastoma stem cells (GSCs). The BCL3 gene contributes to this resistance and is potentially regulated by Carbonic Anhydrase II (CA II). Additionally, BCL3 enhances β-catenin-mediated transcription, promoting tumor growth. Since CA II may modulate both BCL3 expression and Wnt/β-catenin signaling, its inhibition represents a promising therapeutic strategy. Therefore, this study investigated the antiglioblastoma potential of the CA II inhibitor Dorzolamide, alone and in combination with Temozolomide (TMZ), in U87 cells and CD133+ GSCs.

Methods: U87 cells were treated with Dorzolamide, TMZ, or both. MTT, migration, invasion, TUNEL, and cell cycle assays assessed proliferation, motility, apoptosis, and cell cycle arrest. CD133+ GSCs were isolated by MACS and characterized by flow cytometry. Neurosphere assays and RT-qPCR analyzed neurosphere formation and mRNA expression of CA II, BCL3, β- catenin, and Twist, respectively. β-catenin protein expression was evaluated by immunocytochemistry.

Results: Dorzolamide and TMZ significantly inhibited proliferation, migration, and invasion while promoting apoptosis in U87 cells; the combination had the strongest effect (P<0.001). Cell cycle arrest occurred in G0/G1. Neurosphere formation by CD133+ GSCs was markedly reduced (P<0.001). Expression of CA II, BCL3, β-catenin, and Twist was significantly downregulated in all treatment groups (P<0.001).

Discussion: This study highlights FDA-approved CA II inhibitor Dorzolamide as a promising adjunct to TMZ therapy, effectively targeting GBM cells and therapy-resistant CD133+ GSCs. Its ability to inhibit CAII, BCL3, β-catenin, and Twist indicates its disruption of critical survival pathways in GSCs. However, further in vivo studies are required to confirm its therapeutic potential against GBM.

Conclusion: Dorzolamide inhibits GSC proliferation, promotes apoptosis in U87 cells, affects the cell cycle, and enhances TMZ activity, suggesting potential in GBM treatment.

Interest in fungal research has increased in recent years due to its relevance in producing bioactive compounds, which serve as promising sources of bacteriostatic and fungistatic agents. Their use represents a significant alternative to traditional antibiotics, minimizing the risks associated with microbial resistance. In this context, the present work aimed to: assess the volume of annual publications on the subject and identify key players, analyze the collaboration network among researchers, and check the patents filed on this topic For this purpose, the Bibliometrix R-package, as well as scientific metadata from the Web of Science and Scopus databases, were used (n=506). In total, 256 sources, authors (n=2,526), keywords (n=1,812), and references (n=19,315), from 1989 to 2023, were analyzed. The academic debate on the subject has been promoted by India (29%), the United Kingdom (UK) (7%), China (6%), and the United States of America (USA) (6%). The authors identified as the most cited were Liu J (n = 142), followed by Jesu Arockiaraj (n = 106). A knowledge predominance of publications focusing on the life science disciplines. The most prolific institutions were the National Research Center (n=20) and the University of Pittsburgh (n=13). The most cited journals were the World Journal of Microbiology & Biotechnology (n=719) and Applied Microbiology and Biotechnology (n=661). Finally, the United States Patent and Trademark Office represented 85% of the patents filed on the subject (n=28,303). Collectively, the findings herein can guide researchers and biotechnology industries in identifying the most relevant sources for antimicrobial biotechnology.

Introduction: Pregnancy-induced hypertension (PIH) is a severe pregnancy complication characterized by placental insufficiency, abnormal vascular remodeling, and immune dysregulation, but personalized therapeutic markers remain unclear. This study aimed to identify key genes and explore immune mechanisms in PIH using transcriptome analysis, machine learning, and experimental validation.

Methods: We analyzed the GSE204835 transcriptomic dataset to screen differentially expressed genes (DEGs) and performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Set Enrichment Analysis (GSEA) for functional annotation. Immune infiltration analysis was also performed to examine the immune landscape in PIH. Least Absolute Shrinkage and Selection Operator (LASSO) regression identified key genes, which were validated in a PIH cell model. Flow cytometry and immunofluorescence assays assessed the effect of CDK7 knockdown on macrophage polarization.

Results: A total of 1,598 DEGs (1,123 upregulated, 475 downregulated) were identified. Enrichment analyses highlighted associations with embryonic organ development, oxidative phosphorylation, angiogenesis, and oxidative stress. Immune infiltration analysis revealed altered eosinophil and macrophage polarization in PIH. LASSO regression selected 12 key genes, with CDK7 showing the most significant upregulation in the PIH model. CDK7 knockdown promoted macrophage polarization toward the anti-inflammatory M2 phenotype.

Discussion: These findings link CDK7 to immune dysregulation in PIH by modulating macrophage polarization, expanding our understanding of PIH's molecular mechanisms. The study's limitations include reliance on public datasets and in vitro models, warranting in vivo validation.

Conclusion: CDK7 emerges as a potential therapeutic target for PIH, offering new insights into immunoregulatory interventions for this complication.

Tuberculosis (TB) poses a serious public health risk and is a hot topic in the international health forums. Global health organizations emphasize the importance of effectively managing and eradicating TB. The emergence of drug-resistant TB and the elevated risk of hepatotoxicity associated with anti-TB medications have highlighted the need for reevaluation of existing TB drugs. These challenges have led to prolonged dosing schedules and increased dosages to combat resistance and effectively eliminate the disease. In India, the government revised the National Tuberculosis Control Program to address this growing concern. India is home to six well-established traditional medical systems: Ayurveda, Siddha, Unani, Yoga, Naturopathy, and Homoeopathy (collectively known as AYUSH). This review compares the effectiveness of traditional medicinal regimens with conventional TB treatment. Herbal extracts used in Ayurveda, Siddha, and Unani offer promising alternatives for TB treatment, potentially reducing hepatotoxicity and liver damage while combating antibiotic resistance. These natural remedies are generally safe for consumption in larger quantities, cost-effective to produce, and free from harmful toxins. The findings in this article provide scientific support for the anti-TB potential of the diverse medical systems recognized by India's Ministry of AYUSH.