Translational research : the journal of laboratory and clinical medicine
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Tumor angiogenesis and the immune microenvironment are 2 essential aspects of the tumor microenvironment (TME). The combination of receptor tyrosine kinase (RTK) inhibitor (TKI)-mediated antiangiogenic therapy and CD8 T-lymphocyte-mediated immunotherapy has become an important focus of cancer treatment, with good results for many tumor types. However, the complex regulatory interactions between these 2 treatment strategies have not been elucidated. ⋯ Then, 4 co-expression patterns were identified, with different patterns reflecting different prognoses and immune microenvironments. The RTKlowCD8Thigh group was associated with the best prognosis and immune-activated microenvironment. In summary, the present study indicates co-expression of RTKs and CD8Ts, which supports the potential application of the combination of inhibiting RTKs activity via TKI-targeted therapy and increasing CD8 T cell activity via immunotherapy in the treatment of cancer.
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The molecular mechanism of miR-96-5p in the pathogenesis and treatment of polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS), characterized by the androgen excess and arrest of antral follicles, is a common endocrine disorder among women lacking specific diagnostic biomarkers and therapeutic targets. Herein, we studied the molecular mechanism of miR-96-5p in the process of PCOS and its potential applications in PCOS. Clinically, we found that miR-96-5p significantly decreased in serum, follicular fluid and primary human granulosa cells (hGCs) of PCOS patients (n = 70) vs non-PCOS women (n = 60), as well as in the ovaries of 3-types of induced PCOS-like mice. ⋯ Inversely, inhibition of FOXO1 abrogated the effect of miR-96-5p on estrogen synthesis and proliferation index. Of note, ovarian intra-bursal injection of miR-96-5p agomir rescued the phenotypes of dehydroepiandrosterone-induced PCOS like mice. In conclusion, our results clarified a vital role of miR-96-5p in the pathogenesis of PCOS and might serve as a novel diagnostic biomarker and therapeutic target for PCOS.
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Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the elderly population. Neovascular AMD is the late stage, characterized by choroidal neovascularization (CNV). Non-coding RNAs have been implicated in CNV; however, the role of circular RNAs (circRNAs) has not yet been elucidated. ⋯ By subretinal injections of adeno-associated virus (AAV), we demonstrated the anti-angiogenic function of circRNA Uxs1 knockdown in vivo. In conclusion, circRNA Uxs1 promoted CNV by sponging miR-335-5p, which stimulated PGF expression and subsequently activated the mTOR/p70 S6k pathway. Therefore, circRNA Uxs1 may serve as a promising therapeutic target for CNV.
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Age is the most important risk factor for cardiovascular disease and appears to be more than a marker of cumulative exposure to other risk factors such as dyslipidemia and hypertension. With aging, genetic mutations occur that are not present in our germline DNA, observed as somatic mosaicism. Hematopoietic stem cells have an increased chance of developing mosaicism because they are highly proliferative, and mutations with survival benefits can establish clonal populations. ⋯ The subset of clonal hematopoiesis in which a driver mutation with variant allele frequency of at least 2% occurs in a gene implicated in hematologic malignancies but in the absence of known hematologic malignancy or other clonal disorder is termed clonal hematopoiesis of indeterminate potential (CHIP). Large-scale exome-sequencing projects have recently enabled the study of CHIP frequency, gene-specific analyses, and longitudinal clinical consequences of CHIP, including an observed increased risk for cardiovascular disease. Animal models provide insight into the mechanisms by which CHIP increases cardiovascular disease risk, and combined animal, clinical, and epidemiological data suggest therapeutic implications for CHIP in cardiovascular disease prevention.
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Takayasu arteritis (TAK) is a chronic large vessel disease characterized by aortic fibrotic thickening, which was mainly mediated by activation of aorta adventitial fibroblasts (AAFs). Our previous genetic study demonstrated that TAK-associated locus IL6 rs2069837 regulated glycoprotein non-metastatic melanoma protein B (GPNMB) expression. Thus, this study aimed to investigate the pathogenic role of GPNMB in TAK. ⋯ Furthermore, we showed that leflunomide treatment inhibited GPNMB-mediated fibrosis in AAFs, as well as GPNMB expression in macrophages, which were also partially validated in leflunomide-treated patients. Taken together, these data indicated that macrophage-derived GPNMB promotes AAFs ECM expression via the integrin αVβ1 receptor and Akt/Erk signaling pathway and leflunomide might play an anti-fibrotic role in TAK by interfering with the macrophage-derived GPNMB/AAFs axis. This study provides evidence that targeting GPNMB is a potential therapeutic strategy for treating vascular fibrosis in TAK.