[Tofacitinib inhibits the transformation of lung fibroblasts into myofibroblasts through JAK/STAT3 pathway].

OBJECTIVE: To investigate the effect of tofacitinib, a pan-Janus kinase (JAK) inhibitor, on transforming growth factor-beta 1 (TGF-ß1)-induced fibroblast to myofibroblast transition (FMT) and to explore its mechanism. To provide a theoretical basis for the clinical treatment of connective tissue disease-related interstitial lung disease (CTD-ILD). METHODS: (1) Human fetal lung fibroblast 1 (HFL-1) were cultured in vitro, and 6 groups were established: DMSO blank control group, TGF-ß1 induction group, and TGF-ß1 with different concentrations of tofacitinib (0.5, 1.0, 2.0, 5.0 µmol/L) drug intervention experimental groups. CCK-8 was used to measure the cell viability, and wound-healing assay was performed to measure cell migration ability. After 48 h of combined treatment, quantitative real-time PCR (RT-PCR) and Western blotting were used to detect the gene and protein expression levels of α-smooth muscle actin (α-SMA), fibronectin (FN), and collagen type Ⅰ (COL1). (2) RT-PCR and enzyme-linked immunosorbnent assay (ELISA) were used to detect the interleukin-6 (IL-6) gene and protein expression changes, respectively. (3) DMSO carrier controls, 1.0 µmol/L and 5.0 µmol/L tofacitinib were added to the cell culture media of different groups for pre-incubation for 30 min, and then TGF-ß1 was added to treat for 1 h, 6 h and 24 h. The phosphorylation levels of Smad2/3 and signal transducer and activator of transcription 3 (STAT3) protein were detected by Western blotting. RESULTS: (1) Tofacitinib inhibited the viability and migration ability of HFL-1 cells after TGF-ß1 induction. (2) The expression of α-SMA, COL1A1 and FN1 genes of HFL-1 in the TGF-ß1-induced groups was significantly up-regulated compared with the blank control group (P < 0.05). Compared with the TGF-ß1 induction group, α-SMA expression in the 5.0 µmol/L tofacitinib intervention group was significantly inhi-bited (P < 0.05). Compared with the TGF-ß1-induced group, FN1 gene was significantly inhibited in each intervention group at a concentration of 0.5-5.0 µmol/L (P < 0.05). Compared with the TGF-ß1-induced group, the COL1A1 gene expression in each intervention group did not change significantly. (3) Western blotting results showed that the protein levels of α-SMA and FN1 in the TGF-ß1-induced group were significantly higher than those in the control group (P < 0.05), and there was no significant difference in the expression of COL1A1. Compared with the TGF-ß1-induced group, the α-SMA protein level in the intervention groups with different concentrations decreased. And the differences between the TGF-ß1-induced group and 2.0 µmol/L or 5.0 µmol/L intervention groups were statistically significant (P < 0.05). Compared with the TGF-ß1-induced group, the FN1 protein levels in the intervention groups with different concentrations showed a downward trend, but the difference was not statistically significant. There was no difference in COL1A1 protein expression between the intervention groups compared with the TGF-ß1-induced group. (4) After TGF-ß1 acted on HFL-1 cells for 48 h, the gene expression of the IL-6 was up-regulated and IL-6 in culture supernatant was increased, the intervention with tofacitinib partly inhibited the TGF-ß1-induced IL-6 gene expression and IL-6 in culture supernatant. TGF-ß1 induced the increase of Smad2/3 protein phosphorylation in HFL-1 cells for 1 h and 6 h, STAT3 protein phosphorylation increased at 1 h, 6 h and 24 h, the pre-intervention with tofacitinib inhibited the TGF-ß1-induced Smad2/3 phosphorylation at 6 h and inhibited TGF-ß1-induced STAT3 phosphorylation at 1 h, 6 h and 24 h. CONCLUSION: Tofacitinib can inhibit the transformation of HFL-1 cells into myofibroblasts induced by TGF-ß1, and the mechanism may be through inhibiting the classic Smad2/3 pathway as well as the phosphorylation of STAT3 induced by TGF-ß1, thereby protecting the disease progression of pulmonary fibrosis.

Dietary anthocyanin is associated with a lower prevalence of hyperuricemia independently of metabolic syndrome among females: Results from NHANES 2007-2010 and 2017-2018.

OBJECTIVE: Known for anti-inflammatory and antioxidant properties, flavonoid has phytoestrogenic effects, but it is unclear whether its role in hyperuricemia and metabolic syndrome (MetS) differs by gender. Moreover, given the strong association between hyperuricemia and MetS, we aimed to explore whether flavonoid is a protective factor for hyperuricemia, independently of MetS, in different genders. METHODS: Data for 2007-2010 and 2017-2018 were obtained from the National Health and Nutrition Examination Survey (NHANES) and the Food and Nutrient Database for Dietary Studies (FNDDS). To assess the association among flavonoid, hyperuricemia, and MetS, multivariate logistic regression and subgroup analyses were conducted. Besides, to investigate whether the association between flavonoid and hyperuricemia was independent of MetS, multivariate logistic regression models were further conducted to explore the association between flavonoid and MetS among females with hyperuricemia and to investigate the association between flavonoid and hyperuricemia among females after excluding MetS. RESULT: Among 5356 females, anthocyanin intake was inversely associated with the prevalence of hyperuricemia (Q4 vs. Q1: OR 0.49, 95% CI 0.31 to 0.76), and MetS (Q4 vs. Q1: OR 0.68, 95% CI 0.50 to 0.93). Furthermore, subgroup analyses showed the beneficial association between anthocyanin and hyperuricemia among females aged 40 to 59 years and menopausal. However, among 5104 males, no significant association was observed after adjustment for covariates (Q4 vs. Q1: OR 0.81, 95% CI 0.56 to 1.18). While in 372 females with hyperuricemia, no significant association was found between MetS and anthocyanin (Q4 vs. Q1: OR 0.88, 95% CI 0.31 to 2.49). Meanwhile, among 3335 females after excluding MetS, there was still a significant association between anthocyanin and a lower prevalence of hyperuricemia (Q4 vs. Q1: OR 0.38, 95% CI 0.17 to 0.85). CONCLUSION: Dietary anthocyanin is associated with a lower prevalence of hyperuricemia independently of MetS among females. Foods rich in anthocyanin should be emphasized for females, especially those aged 40 to 59 years and menopausal, which may be of potential significance in the prevention of hyperuricemia.

The role of gut microbiota in gout: Is gut microbiota a potential target for gout treatment.

Numerous studies have demonstrated that gut microbiota is essential for the host's health because it regulates the host's metabolism, endocrine, and immune systems. In recent years, increasing evidence has shown that gut microbiota plays a role in the onset and progression of gout. Changes in the composition and metabolism of the gut microbiota, result in abnormalities of uric acid degradation, increasing uric acid generation, releasing pro-inflammatory mediators, and intestinal barrier damage in developing gout. As a result, gout therapy that targets gut microbiota has drawn significant interest. This review summarized how the gut microbiota contributes to the pathophysiology of gout and how gout affects the gut microbiota. Additionally, this study explained how gut microbiota might serve as a unique index for the diagnosis of gout and how conventional gout treatment medicines interact with it. Finally, prospective therapeutic approaches focusing on gut microbiota for the prevention and treatment of gout were highlighted, which may represent a future avenue in gout treatment.