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ABSTRACT Background Depressive disorder is a common and serious public health challenge globally. Fructus arctii is a traditional medicinal plant ingredient with diverse pharmacological effects. This study aimed to investigate the therapeutic potential of Fructus arctii in alleviating depressive‐like behaviors. Materials and Methods We established a chronic unpredictable mild stress (CUMS)‐induced depression mouse model to assess the antidepressant effects of Fructus arctii. BV2 cells treated with lipopolysaccharide (LPS) were used to mimic neuronal damage. Behavioral tests, including the sucrose preference test, tail‐suspension test, and forced swim test, were conducted to evaluate the impact of Fructus arctii on depressive‐like behaviors. Let‐7e expression was detected by RT‐qPCR, and TLR4 signaling pathway activation was evaluated by western blot analysis, which also assessed the inflammatory response by measuring levels of IL‐6, IL‐1β, MCP‐1, TNF‐α, and iNOS. Immunohistological analysis was conducted to detect the expression of microglia markers. Luciferase reporter assays verified the interaction between let‐7e and TLR4. Results Fructus arctii administration effectively alleviated depressive‐like behaviors induced by CUMS in mice, as evidenced by improved sucrose preference and reduced immobility time in behavioral tests. Mechanistically, Fructus arctii reversed the CUMS‐induced downregulation of let‐7e and upregulation of TLR4 and MyD88 protein levels in mice hippocampus tissues. In addition, Fructus arctii suppressed microglial activation and reduced the levels of inflammatory factors by upregulating let‐7e. Let‐7e was verified to bind to TLR4, thereby negatively regulating its expression. TLR4 overexpression reversed the suppressive effect of let‐7e upregulation on inflammatory reactions and microglial activation. Furthermore, intracerebroventricular injection of let‐7e agomiR alleviated depressive‐like behavior and inhibited microglial activation in vivo. Conclusion In summary, Fructus arctii mitigates depression by regulating the let‐7e/TLR4/MyD88 pathway, offering new insights into potential depression therapies.

Glioblastoma (GBM) is a highly invasive neurological malignancy with poor prognosis. LncRNA-GAS5 (growth arrest-specific transcript 5) is a tumor suppressor involved in multiple cancers. In this study, we explored the clinical significance, biological function, and underlying mechanisms of GAS5 in GBM. We showed that lncRNA-GAS5 expression decreased in high-grade glioma tissues and cells, which might be associated with poor prognosis. GAS5 overexpression lowered cell viability, suppressed GBM cell migration and invasion, and impaired the stemness and proliferation of glioma stem cells (GSCs). We further discovered that GAS5 inhibited the viability of glioma cells through miR-let-7e and miR-125a by protecting SPACA6 from degradation. Moreover, GAS5 played an anti-oncogenic role in GBM through the combined involvement of let-7e and miR-125a in vivo and in vitro. Notably, these two miRNAs block the IL-6/STAT3 pathway in tumor tissues extracted from a xenograft model. Taken together, our study provides evidence for an important role of GAS5 in GBM by affecting the proliferation and migration of GSCs, thus providing a new potential prognostic biomarker and treatment strategy for GBM.

MicroRNAs (miRNA) are major regulators of intercellular communication and key players in the pathophysiology of cardiovascular disease. This study aimed to determine the miRNA fingerprint in a cohort of 53 patients with acute myocardial infarction (AMI) with non-ST-segment elevation (NSTEMI) relative to miRNA expression in healthy controls (n = 51). miRNA expression was initially profiled by miRNA array in the serum of patients undergoing cardiac catheterization during NSTEMI (n = 8) and 1 year past the event (follow-up, n = 8) and validated in the entire cohort. In total, 58 miRNAs were differentially expressed during AMI (p < 0.05), while 36 were modified at follow-up (Fisher’s exact test: p = 0.0138). Enrichment analyses revealed differential regulation of biological processes by miRNA at each specific time point (AMI vs. follow-up). During AMI, the miRNA profile was associated mainly with processes involved in vascular development. However, 1 year after AMI, changes in miRNA expression were partially related to the regulation of cardiac tissue morphogenesis. Linear correlation analysis of miRNA with serum levels of cytokines and chemokines revealed that let-7g-5p, let-7e-5p, and miR-26a-5p expression was inversely associated with serum levels of pro-inflammatory cytokines TNF-α, and the chemokines MCP-3 and MDC. Transient transfection of human endothelial cells (HUVEC) with let-7e-5p inhibitor or mimic demonstrated a key role for this miRNA in endothelial function regulation in terms of cell adhesion and angiogenesis capacity. HUVEC transfected with let-7e-5p mimic showed a 20% increase in adhesion capacity, whereas transfection with let-7e-5p inhibitor increased the number of tube-like structures. This study pinpoints circulating miRNA expression fingerprint in NSTEMI patients, specific to the acute event and changes at 1-year follow-up. Additionally, given its involvement in modulating endothelial cell function and vascularization, altered let-7e-5p expression may constitute a therapeutic biomarker and target for ischemic heart disease.

Abstract Background Resistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment. The human let-7 family contains 13 members located on nine different chromosomes, and most members have been implicated in the modulation of drug sensitivity in cancers. Our previous study showed that deregulation of let-7e in epithelial ovarian cancer (EOC) promoted the development of resistance to cisplatin. In the present study, we aimed to investigate the underlying mechanism and further evaluate the clinical value of let-7e in predicting chemo-response and prognosis in EOC. Results In situ hybridization assays revealed a significantly decreased expression of let-7e in chemo-resistant EOC tissues compared with chemo-sensitive cases. Transfection with let-7e agomir sensitized EOC cells to cisplatin, down-regulated BRCA1 and Rad51 expression, and repressed the repair of cisplatin-induced DNA double strand break, while let-7e inhibitor exerted the opposite effects. In human EOC tissues, BRCA1 and Rad51 levels were increased in the chemo-resistant group compared with the sensitive group and were negatively correlated with let-7e. Low let-7e and high Rad51 were significantly associated with poor progression-free survival and overall survival and multivariate regression analyses showed that let-7e was an independent predictor for overall survival and chemotherapy response in EOC. Receiver operating characteristic analysis indicated that let-7e level was highly predictive of resistance to platinum-taxane chemotherapy with an area under the curve of 0.826. Conclusions In EOC, low let-7e leads to activation of BRCA1 and Rad51 expression and subsequent enhancement of DSB repair, which in turn results in cisplatin-resistance. Let-7e is a potential predictor for survival and chemo-response in EOC and re-expression of let-7e might be an effective strategy for overcoming chemo-resistance.

Chronic inflammation and abnormalities in Toll-like receptor (TLR) signaling pathways are associated with major depressive disorder (MDD). Our previous work reported that impaired negative regulators for the TLR pathways are associated with MDD. This study aimed to assess the association between the severity of depression and the intracellular microRNAs that regulate TLR4 signaling in both peripheral blood mononuclear cells (PBMCs) and monocytes from MDD patients. The severity of MDD before and after antidepressant treatment was determined by the 17-item Hamilton Depression Rating Scale, and quantitative RT-PCR was used to measure the levels of intracellular regulatory microRNAs, including let-7e, miR-21-5p miR-145, miR-223, miR-146a, and miR-155, in PBMCs and monocytes isolated from 43 healthy controls and 84 patients with MDD before and after treatment with antidepressants. Assays of PBMCs showed that the levels of let-7e, miR-146a, and miR-155 were lower in MDD patients than in healthy controls and were significantly higher after than before treatment in the 69 patients who completed treatment with antidepressants for four weeks. Levels of miR-146a and miR-155 in monocytes were lower in MDD patients than in controls and were increased in the former after antidepressant treatment. Multiple linear regression analyses found that let-7e and miR-146a expression before treatment was inversely correlated with severity of depression, whereas miR-155 before treatment was directly correlated with severity of depression. These findings suggest that intracellular regulatory microRNAs which regulate TLR4 signaling are aberrantly expressed in patients with MDD and that these levels are ameliorated by antidepressant treatment.