Current molecular medicine最新文献

Introduction: Genistein is an isoflavone primarily extracted from soybeans and the Dyer's broom (Genista tinctora L.). It has been extensively studied using various extraction methods and characterized via NMR for structural elucidation. Its pharmacological potential, mediated through interactions with multiple receptors and signalling pathways, has been validated through numerous preclinical studies globally.

Methods: To analyze the pharmaceutical profile of genistein using PASS software, we correlated it with existing literature, and evaluated its efficacy against various diseases. The study aims to explore the broad-spectrum potential of genistein as a lead compound against the various diseases such as cancer, cardiovascular disease (CVD), neurodegenerative and viral diseases.

Results: It is a broad-spectrum drug that is effective against - cancer, heart associated diseases, neurodegenerative diseases and viral diseases. It is a potential anticancer drug that modulates apoptosis, cell cycle, metastasis, and regulates the cancer signalling pathways. Based on the compilation of reports from the literature reviews, it is effective against breast cancer (23%), neuroblastoma (12.77%), prostate and lung cancer (10.64%). Secondly, it has cardio protectant properties and supports cardiovascular health by improving endothelial function and lowering cholesterol. It is reported to be effective against cardiac dysfunction (38.46%), atherosclerosis (26.92%), and cardiotoxicity (15.39%). Thirdly, it offers various neuroprotective benefits in neurodegenerative diseases like Alzheimer's (69.84%) and Parkinson's (19.05%). Lastly, it was also reported to be effective against HSV (23.08%), HIV (23.08%) and HPV (15.39%) viral infections.

Discussion: Genistein exhibits a wide range of therapeutic properties, including anticancer, cardioprotective, neuroprotective, and antiviral effects. It has shown notable efficacy in treating cancers such as breast, prostate, and lung, as well as neurodegenerative conditions like Alzheimer's and Parkinson's. Additionally, its benefits in improving cardiovascular health and combating viral infections further support its potential as a multifunctional therapeutic agent. Although genistein has a broad pharmacological spectrum, its clinical relevance is hampered by a suboptimal pharmacokinetic profile, such as poor bioavailability, rapid systemic clearance, extensive first-pass metabolism, and low aqueous solubility, which limit its therapeutic efficacy.

Conclusions: This systematic review highlights genistein's pharmacological profile, demonstrating its efficacy against various diseases and its potential as a lead candidate for drug development in oncology, cardiovascular health, and neurodegenerative therapies. Thus, underscoring its potential, Genistein can be considered a versatile therapeutic agent.

Introduction: Hemifacial Microsomia (HFM) is the second most common congenital deformity, yet its etiology and pathogenesis remain unclear. Therefore, this study aimed to identify differentially expressed microRNAs (miRNAs) between healthy and affected bone marrow mesenchymal stem cells (BMSCs) from HFM patients, focusing on the functional roles of miR-148a in osteogenesis and osteoclastogenesis.

Methods: The specific expression of microRNAs was screened by sequencing and verified by PCR. Through the use of mimics, inhibitors, and knockout technology, we controlled the expression of miR-148a in vivo and in vitro. Osteogenesis and osteoclastogenesis induction, PCR, western blot, ALP staining, alizarin red staining, TRAP staining, micro-CT, and tissue sections were performed to explore the effects of miR-148 on osteogenesis and osteoclastogenesis.

Results: MiR-148a was identified and confirmed through our research as a differentially expressed miRNA in HFM. Overexpression of miR-148a increased osteogenesis-related gene and protein expression and mineralized calcium nodule formation while decreasing osteoclast-related gene and protein levels. Silencing or knockout of miR-148a produced opposite effects. miR-148a knockout mice were smaller than wild-type, with reduced osteogenesis, fewer trabeculae, increased trabecular bone separation in the mandible, and decreased ramus length. Additionally, local overexpression of miR-148a in knockout mice increased local bone mass.

Discussions: The current study findings demonstrate that miR-148a can influence the bone volume, and its role in chondrogenesis deserves further research. Additionally, further studies on the changes upstream of miR-148a that lead to differences in miR-148a expression between the healthy and affected sides of HFM patients and the differences in bone size are warranted to better understand HFM pathogenesis.

Conclusion: Our findings suggest that the opposing effects of miR-148a on osteogenesis and osteoclastogenesis lead to decreased bone mass in HFM. Local overexpression can reverse bone defects caused by miR-148a, suggesting its promising role in future treatments. We anticipate that further investigations will enhance our understanding and ultimately pave the way for the application of these insights in clinical settings for disease treatment.

Introduction: Obesity is a major risk factor for metabolic and cardiovascular disorders. Recently, emerging biomarkers, such as the Visceral Adiposity Index (VAI) and Lipid Accumulation Product (LAP), have garnered attention for their utility in assessing visceral obesity. Bilirubin, a potent endogenous antioxidant, has been associated with protective effects against various diseases. This study aims to investigate the relationship between serum total bilirubin (STB) levels and VAI/LAP in adults.

Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 2003 and 2020. The calculation of VAI and LAP was performed computationally. Weighted multivariate regression models were used to explore the potential correlation between STB levels and VAI or LAP. RCS curves were used to identify the potential non-linear relationship. Moreover, subgroup analyses were conducted to examine heterogeneity across different populations.

Results: The analysis included a cohort of 10,625 individuals aged 20 to 85 years. Both unadjusted and adjusted statistical models revealed a significant negative association between STB levels and VAI or LAP (all P< 0.001). RCS indicates that these relationships are linear. Subgroup analyses identified particularly strong associations in non-smokers aged 20-59 without hypertension/diabetes (P < 0.05).

Discussion: Our study's strengths include the use of nationally representative data with appropriate weighting, comprehensive adjustment for confounding variables, and pioneering research on the link between serum bilirubin levels and visceral fat indices, which may indicate early metabolic risk markers. This finding highlights the significant role of bilirubin in body fat distribution and lipid metabolism.

Conclusion: This study revealed that STB was associated with VAI or LAP among the specific general American population aged 20-59 without hypertension/diabetes. Further prospective investigations are warranted to clarify the temporal relationship between STB and novel obesity indices.

Background: Hypothetically, fetal anemic hypoxia causes cellular damage with an increase in oxidative stress levels. This study, using hemoglobin (Hb) Bart’s disease as a study model, aims to compare the levels of oxidative stress and inflammatory markers as well as fetal hemodynamics in anemic fetuses with those of non-anemic fetuses.

Materials and methods: Forty pregnancies at risk of fetal Hb Bart’s disease scheduled for cordocentesis at 18 to 22 weeks were recruited into the study. Fetal blood was collected to measure the levels of 8-Isoprostane (8-Isop), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and hemoglobin as well as for hemoglobin typing.

Results: There was no significant difference in cord blood 8-Isop, TNF-α, and IL-10 levels between the Hb Bart’s disease group and the unaffected group, whereas several hemodynamic parameters, such as cardiac output, cardiac size, cardiac performance, middle cerebral artery – peak systolic velocity, etc., were significantly changed in the fetal Hb Bart’s group. In the subgroup analysis, the level of serum 8-Isop in the severe anemia group tended to increase, though not significantly, compared with the nonanemic group (275.3±141.8 vs. 203.9±49.2 pg/mL; p=0.079).

Conclusion: In response to anemia, fetuses might have a high capacity of hemodynamic adaptation without significant cellular damage, though a trend of an increase in oxidative stress marker was found in severe fetal anemia. Theoretically, intrauterine blood transfusion for fetal anemia during adaptive compensation may result in no residual insults.

Background: Observational studies suggest the potential association between sleep traits and vertigo; however, causal evidence remains limited.

Objective: This study aimed to explore the relationship between genetically predicted sleep traits and vertigo with the Mendelian randomization (MR) method.

Methods: Instrumental variables for sleep traits (snoring, sleep duration, insomnia, daytime sleepiness, daytime napping, and chronotype) were adopted from genomewide association studies (GWAS) data of European ancestry from UK Biobank. The summary-level datasets of vertigo were retrieved from the GWAS of FinnGen. Inversevariance weighted (IVW) method was adopted as the main analysis.

Results: IVW analysis revealed a significant association between genetically predicted daytime napping (OR = 1.51, 95% CI =1.08-2.12, P = 0.016) and chronotype (OR = 1.13, 95% CI =1.01-1.26, P = 0.033), both of which were associated with an increased risk of vertigo. However, we did not find evidence for a causal effect of snoring, overall sleep duration, long sleep duration, short sleep duration, insomnia, and excessive daytime sleepiness on vertigo. No reverse causality was detected.

Conclusion: Our findings suggest that abnormal sleep patterns may serve as risk factors for vertigo disorders and offer opportunities for the prevention and management of vertigo disorders.

Objective: ARHGAP40 is a Rho GTPase-activating protein (RhoGAP). The expression and biological roles of ARHGAP40 in breast cancer are unknown. We aimed to investigate the expression of ARHGAP40 and its epigenetic mechanism in breast cancer.

Methods: The expression level of ARHGAP40 was examined in breast cancer cell lines and tissues. The methylation status of ARHGAP40 was analyzed using a bisulfite sequencing PCR (BSP). The biological roles of ARHGAP40 in breast cancer were investigated.

Results: ARHGAP40 mRNA was significantly expressed in MCF-7 and weakly in MDA-MB-231, whereas methylated ARHGAP40 was detected in MDA-MB-231 and partly in MCF-7. ARHGAP40 protein was positively expressed in normal breast epithelial cells in all paracancerous tissues. The expression level of ARHGAP40 was significantly associated with age, TNM stage, lymph node metastasis, molecular subtypes, proliferative marker Ki67, and HER2 expression. The overall survival (OS) of patients with high expression of ARHGAP40 was longer than those with low expression. Overexpression of ARHGAP40 in MCF-7 and MDA-MB-231 cells induced apoptosis and suppressed cell proliferation. The opposite outcomes were observed in the ARHGAP40 knockdown experiment.

Conclusion: Our data suggested ARHGAP40 to be downregulated in breast cancer due to hypermethylation. ARHGAP40 was found to act as a tumor suppressor in breast cancer and could be a potential therapeutic target for breast cancer.

Introduction: Vasopressin receptors can have different effects on tumorigenesis. The in vitro usage of agonists and antagonists of these receptors can also have a potential impact on developing adjuvant treatment options. Therefore, we aimed to demonstrate the expression and function of vasopressin receptors in the HT- 29 cell line, which is one of the cell lines frequently used in colorectal cancer studies. Colorectal cancer is one of the most prevalent cancer types worldwide. There are many risk factors for colorectal cancer, including unhealthy lifestyle and social environment, and early diagnosis can enhance the survival of patients. Main treatment strategies aim to slow down the progression of cancer, increase survival, and enhance the quality of life. Investigating the relationship between colorectal cancer and vasopressin receptors has been an interesting research area in terms of developing new treatment strategies lately.

Methods: For receptor expression and functional analysis, RT-PCR experiments and cAMP accumulation assay were performed.

Results: The expression of V2R and V1aR was observed in HT-29 cells, and V2Rs demonstrated their function as cAMP responders after treatment with agonists and antagonists.

Discussion: This is the first study to report that V2R and V1aR expressions were detected by RT-PCR, and the functionality of V2R was analyzed by cAMP accumulation assay after treating HT-29 cells with agonists and antagonists.

Conclusion: We hope that these results may contribute to colorectal cancer research and the development of novel therapeutic strategies targeting vasopressin receptor signaling pathways.

Background: Lung cancer remains the leading cause of cancer-related mortality. Determining the T790M resistance variants and epidermal growth factor receptor (EGFR) mutations is crucial for personalized treatment, especially when using targeted therapies.

Objective: This review article aims to comprehensively compare some of the various diagnostic techniques associated with liquid biopsies, such as cell-free DNA (cfDNA) for T790M and EGFR mutant identification. It also aims to evaluate their pertinence in clinical settings, as well as their sensitivity and specificity to determine how effectively they monitor treatment response and resistance.

Methods: A literature search was conducted using databases including PubMed, Scopus, and Web of Science. The keyword list included "EGFR mutations," "T790M resistance," "liquid biopsy," "COLD PCR," "NGS," "ddPCR," "BEAMing," and other methods. The effect of these studies on diagnostic technologies for identifying EGFR mutations was assessed in terms of clinical practice, methodological accuracy, and significance. Sensitivity, specificity, clinical applicability, cost analysis, turnaround times, and ease of integration into clinical workflows were used as parameters for evaluation based on the literature.

Results: There are advantages and disadvantages to cfDNA monitoring strategies for treatment response and resistance, as well as to the assessment of sensitivity, specificity, and clinical applicability for identifying EGFR mutations.

Conclusion: Advanced techniques such as COLD-PCR, LC-MS, qPCR, NGS sequencing, Sanger sequencing, PNA microarrays, the Allele-Specific Competitive Extension (ASCE) real-time PCR assay, and nanopore technology are necessary for personalized lung cancer management. However, depending on the objective of the work, the suitable method should be selected based on its benefits and drawbacks.

Introduction: Obliterative bronchiolitis (OB) is a severe and progressive complication characterized by the fibrotic obliteration of small airways, leading to significant morbidity and mortality, particularly in lung transplant recipients. The pathogenesis of OB involves complex cellular processes, among which epithelial-tomesenchymal transition (EMT) plays a crucial role. This study investigates the role of mechanosensitive ion channel Piezo1 in promoting OB through Yes-associated protein (YAP)-dependent EMT.

Method: Piezo1-induced signal pathway alterations, fibrosis, and EMT-related features were examined in the mouse OB model and BEAS-2B cells. The efficacy of Piezo1 in EMT and OB was explored and validated both in vitro and in vivo.

Results: Piezo1 was found to be upregulated in OB, and pharmacological inhibition of Piezo1 effectively alleviated EMT and fibrotic deposition. Piezo1 activation stimulated the Ca2+ influx and nuclear translocation of YAP that triggered the transition of epithelial cells into a mesenchymal phenotype, which contributed to airway fibrosis and obstruction. Furthermore, inhibition of YAP or calcium chelation significantly attenuated Piezo1 activation-induced EMT and OB, indicating that YAP and Ca2+ are critical mediators in this process.

Discussion: Piezo1 expression was found to be upregulated in OB, and its activation induced the epithelial-to-mesenchymal transition (EMT) process via a YAP-dependent pathway. Piezo1 could accelerate EMT and the occlusion rate of grafts via Ca2+ influx-dependent YAP activation in OB, suggesting a direct role in facilitating EMT and subsequent fibrotic remodeling in OB.

Conclusion: The present results highlight that Piezo1 promotes OB through a YAPdependent EMT pathway, suggesting Piezo1 as a novel therapeutic strategy for treating OB and potentially improving outcomes of lung transplant recipients.