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BACKGROUND: Exosomes and exosomal microRNAs have been implicated in tumor occurrence and metastasis. Our previous study showed that microRNA-761 (miR-761) is overexpressed in hepatocellular carcinoma (HCC) tissues and that its inhibition affects mitochondrial function and inhibits HCC metastasis. The mechanism by which exosomal miR-761 modulates the tumor microenvironment has not been elucidated. METHODS: Exosomal miR-761 was detected in six cell lines. Cell counting kit-8 (CCK-8) and transwell migration assays were performed to determine the function of exosomal miR-761 in HCC cells. The luciferase reporter assay was used to analyze miR-761 target genes in normal fibroblasts (NFs). The inhibitors AZD1480 and C188-9 were employed to determine the role of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the transformation of cancer-associated fibroblasts (CAFs). RESULTS: In this study, we characterized the mechanism by which miR-761 reprogrammed the tumor microenvironment. We found that HCC-derived exosomal miR-761 was taken up by NFs. Moreover, HCC exosomes affected the tumor microenvironment by activating NFs via suppressor of cytokine signaling 2 (SOCS2) and the JAK2/STAT3 signaling pathway. CONCLUSIONS: These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs. Our findings may inspire new strategies for HCC prevention and therapy.
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BACKGROUND: Since the initial recognition of coronavirus disease 2019 (COVID-19) in Wuhan, this infectious disease has spread to most areas of the world. The pathogenesis of COVID-19 is yet unclear. Hepatitis B virus (HBV) reactivation occurring in COVID-19 patients has not yet been reported. CASE SUMMARY: A 45-year-old hepatitis B man with long-term use of adefovir dipivoxil and entecavir for antiviral therapy had HBV reactivation after being treated with methylprednisolone for COVID-19 for 6 d. CONCLUSION: COVID-19 or treatment associated immunosuppression may trigger HBV reactivation.
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Bone marrow mesenchymal stem cells (BMMSCs) regulate the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells. However, the role of different factors on BMMSCsmediated regulation of the Treg/Th17 balance is unknown. BMMSCs and CD4+ T lymphocytes were cocultured with various treatments. The ratio of Treg/Th17 cells was calculated and the expression of different cytokines was measured. BMMSCs were found to have a proliferative effect on Th17 cells at a basal concentration and at a 2fold increase in the number of BMMSCs. However, when the number of BMMSCs used was increased 4fold, they had an inhibitory effect on the Th17 cells. The effect of BMMSCs on Tregs was inhibited by the addition of tacrolimus but not rapamycin. The effect of BMMSCs on Th17 cells was inhibited by rapamycin. Additionally, the effect of BMMSCs on Tregs were inhibited by the addition of a transforming growth factorß (TGFß) blocker, whereas these TGFßblockers had no effect on Th17 cells. Addition of an interleukin (IL)2 blocker reduced the proportion of Th17 cells when cocultured with a high number of MSCs compared with the low concentration group and the proportion of Treg cells was significantly decreased when cells were treated with an IL2 blocker compared with the control group. Together, these results showed the varying effects of MSCs on the ratio of Treg/Th17, its dependence on the number of MSCs and the effects of cytokines in inducing these changes in the balance.
Assuntos
Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células-Tronco Mesenquimais/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Técnicas de Cocultura , Citocinas/metabolismo , Masculino , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/metabolismoRESUMO
Hypoxia upregulates hypothalamic corticotrophin releasing hormone (CRH) and its receptor type-1 (CRHR1) expression and activates the HPA axis and induces hypoxic sickness and behavioral change. The transcriptional mechanism by which hypoxia differently regulates CRHR1 expression remains unclear. Here we report hypoxia time-dependently induced biphasic expression of CRHR1mRNA in rat pituitary during different physiological status. Short exposure of gestational dams to hypoxia reduced CRHR1mRNA in the pituitary of P1-P14 male rat offspring. A short- and prolonged-hypoxia evoked biphasic response of CRHR1mRNA characterized initially by decreases and subsequently by persistent increases, mediated by a rapid negative feedback via CRHR1 signaling and positive transcriptional control via NF-κB, respectively. Further analysis of CRHR1 promoter in cultured primary anterior pituitary and AtT20 cells showed that c-Jun/AP-1 delivered negative while HIF-1α and NF-κB delivered positive control of transcription at CRHR1 promoter. The negative and positive inputs are integrated by hypoxic initiation and duration in CRHR1 transcription.