Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Case report: Gitelman syndrome with diabetes: Confirmed by both hydrochlorothiazide test and genetic testing.

RATIONALE: Gitelman syndrome (GS) is an autosomal recessive tubulopathy caused by mutations of the SLC12A3 gene. It is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Hypokalemia, hypomagnesemia, and increased renin-angiotensin-aldosterone system (RAAS) activity can cause glucose metabolism dysfunction. The diagnosis of GS includes clinical diagnosis, genetic diagnosis and functional diagnosis. The gene diagnosis is the golden criterion while as functional diagnosis is of great value in differential diagnosis. The hydrochlorothiazide (HCT) test is helpful to distinguish GS from batter syndrome, but few cases have been reported to have HCT testing. PATIENT CONCERNS: A 51-year-old Chinese woman presented to emergency department because of intermittent fatigue for more than 10 years. DIAGNOSES: Laboratory test results showed hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis. The HCT test showed no response. Using next-generation and Sanger sequencing, we identified 2 heterozygous missense variants (c.533C > T:p.S178L and c.2582G > A:p.R861H) in the SLC12A3 gene. In addition, the patient was diagnosed with type 2 diabetes mellitus 7 years ago. Based on these findings, the patient was diagnosed with GS with type 2 diabetic mellitus (T2DM). INTERVENTIONS: She was given potassium and magnesium supplements, and dapagliflozin was used to control her blood glucose. OUTCOMES: After treatments, her fatigue symptoms were reduced, blood potassium and magnesium levels were increased, and blood glucose levels were well controlled. LESSONS: When GS is considered in patients with unexplained hypokalemia, the HCT test can be used for differential diagnosis, and genetic testing can be continued to confirm the diagnosis when conditions are available. GS patients often have abnormal glucose metabolism, which is mainly caused by hypokalemia, hypomagnesemia, and secondary activation of RAAS. When a patient is diagnosed with GS and type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) can be used to control the blood glucose level and assist in raising blood magnesium.

Sex hormone-like Effects of Icariin on T-cells immune modulation in spontaneously hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium brevicornu Maxim as a Chinese herb, is recommended for the treatment of menopausal women with hypertension for 50 years. Icariin, as the main hydrophilic ingredient of Epimedium brevicornu Maxim, has been proven to be a plant sex hormone and lower blood pressure down. Here, we hypothesized that Icariin can regulate T cells differentiation which leads to the blood pressure decrease in castrated SHR rats. AIM OF THE STUDY: The present study aimed to investigate the effects of the exogenous estrogen, androgen and Icariin on T-cell modulation in hypertension. MATERIALS AND METHODS: Two weeks after castration, both male and female SHR rats were given estradiol, testosterone, and Icariin intervention respectively. Body weight, blood pressure, and heart rate were tested weekly. After six weeks, proportion of T helper cells (Th), cytotoxic T cells (Tc), and regulatory T cells (Tregs) in both peripheral blood mononuclear cells (PBMCs) and splenocytes were tested by flowcytometry. Serum levels of estrogen, testosterone, AngII, TNF-α, IL-17 were tested by Elisa. Aortic arches were isolated for HE and Masson staining. The expressions of ERß and AR in aorta were tested by Western-blot. RESULTS: In both male and female SHR rats, we found that Icariin and estradiol lower blood pressure, but testosterone elevates blood pressure. Similar as testosterone, Icariin can attenuate Tc and Th proportions and elevate Tregs proportion in both peripheral blood and splenocyte in male SHR, which can be blunt by flutamide. Besides, Icariin performs similar function as estradiol that attenuates Tc proportions and elevates Tregs proportion in both peripheral blood and splenocytes in female SHR, which leads to the lower blood pressure and can be partly blunt by fulvestrant. Testosterone increases AngII and TNF-α levels in serum, leading to the higher blood pressure in both male and female SHR rats. CONCLUSION: These results verified that Icariin, as a plant sex hormone, can regulate T cells differentiation related to blood pressure decrease in SHR rats.

Computational screen and experimental validation of anti-influenza effects of quercetin and chlorogenic acid from traditional Chinese medicine.

The Influenza A virus is a great threat for human health, while various subtypes of the virus made it difficult to develop drugs. With the development of state-of-art computational chemistry, computational molecular docking could serve as a virtual screen of potential leading compound. In this study, we performed molecular docking for influenza A H1N1 (A/PR/8/34) with small molecules such as quercetin and chlorogenic acid, which were derived from traditional Chinese medicine. The results showed that these small molecules have strong binding abilities with neuraminidase from H1N1 (A/PR/8/34). Further details showed that the structural features of the molecules might be helpful for further drug design and development. The experiments in vitro, in vivo have validated the anti-influenza effect of quercetin and chlorogenic acid, which indicating comparable protection effects as zanamivir. Taken together, it was proposed that chlorogenic acid and quercetin could be employed as the effective lead compounds for anti-influenza A H1N1.