Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome.

BACKGROUND: Rapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. We investigated the therapeutic effects of rapamycin-metformin combination therapy in obese mice with collagen-induced arthritis (CIA). METHODS: Mouse embryonic fibroblasts were treated with rapamycin, metformin, or rapamycin-metformin, and their respiratory level and mitochondrial gene expression were assayed. Mice were fed a high-fat diet, immunized with type II collagen, and subsequently treated with rapamycin-metformin daily for 10 weeks. RESULTS: Rapamycin-treated cells exhibited dysfunction of mitochondrial respiration and decreased mitochondrial gene expression compared with rapamycin-metformin-treated cells. Moreover, rapamycin-metformin reduced the clinical arthritis score and the extent of histological inflammation and improved the metabolic profile in obese mice with CIA. Rapamycin-metformin enhanced the balance between T helper 17 and regulatory T cells in vitro and in vivo. CONCLUSIONS: These results suggest that rapamycin-metformin is a potential therapeutic option for autoimmune arthritis.

IL-17 Induced Stromal Cell-Derived Factor-1 and Profibrotic Factor in Keloid-Derived Skin Fibroblasts via the STAT3 Pathway.

The pathogenesis of keloids has not been elucidated, and the disease is thought to be caused by abnormal secretion of proinflammatory mediators and irregular responses to other inflammatory signals mediated by keloid fibroblasts (KFs). In this study, we investigated whether a local increase in interleukin IL-17 in keloid tissues stimulates the production of stromal cell-derived factor-1 (SDF-1) in KFs causing further recruitment of IL-17-producing T helper 17 (Th17) cells, which subsequently creates a positive feedback loop. Histological assessment was performed and the change in the expression of IL-17, IL-1ß, IL-6, and TNF-α which of fibrosis and inflammation associated markers was examined. In addition, fibroblasts were treated with IL-17 in the presence or absence of STAT3 inhibitor STA-21; SDF-1 levels and fibrosis genes were measured. Our results showed that fibrotic reaction and expression of proinflammatory cytokines including IL-17 were most prominent in the growing margin (perilesional area) of keloid tissue and Th17 cells significantly infiltrated the perilesional area. In addition, IL-17 upregulated the expression of SDF-1, collagen, and α-SMA in KFs. Finally, STA-21 decreased SDF-1α expression and the expression of fibrosis genes in KFs even after IL-17 stimulation. Our study demonstrated that a local increase in IL-17 in keloid tissues stimulates the production of SDF-1 in KFs causing further recruitment of IL-17-producing T helper 17 (Th17) cells, which subsequently creates a positive feedback loop. These findings suggest that STAT3 inhibition can be used to treat keloid scars by reversing the vicious cycle between Th17 cells and KFs.

Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb.

BACKGROUND/AIMS: Complementary medicines, including herbal preparations and nutritional supplements, are widely used without prescriptions. As a result, there has been growing interest in the risk of hepatotoxicity with these agents. It is difficult to determine causal relationships between these herbal preparations and hepatotoxicity. We report on 25 patients diagnosed with toxic hepatitis following ingestion of Polygonum multiflorum Thunb. METHODS: Twenty-five patients (median age, 48 years [24 to 65 years]; M:F=18:7) with suspected P. multiflorum Thunb-induced liver injury were admitted to our hospital between 2007 and 2009. We analyzed clinical and histological data, including the types and the duration of P. multiflorum Thunb intake and the duration of hospital care. We also determined the type of liver injury using the R ratio (serum activity of ALT/serum activity of ALP). RESULTS: The types of complementary medicine used included tea (n=16), liquor (n=5), tea and liquor (n=2), powder (n=1), and honeyed pudding (n=1). The most common presenting sign was jaundice (76%), and 18 patients (72%) had evidence of hepatocellular liver injury. Histological findings were consistent with acute hepatitis in all cases (n=10) for which liver biopsy was performed. Twenty-three patients (91.6%) recovered with conservative management, 1 patient (4%) had a liver transplant, and 1 patient (4%) died of hepatic failure. CONCLUSIONS: In our cases, we found that P. multiflorum Thunb could be hepatotoxic and could lead to severe drug-induced liver injury, and even death.

Effect of mechanical strain on human limbal epithelial cells in vitro.

PURPOSE: To investigate the effects of the mechanical cyclic strain on the extracellular matrix (ECM) production by cultivated human limbal epithelial cells (HLECs) in vitro. METHODS: HLECs were repetitively stretched and relaxed by 20% of their original length. Morphology of HLECs was observed, and concentrations of fibronectin and laminin V were measured. RESULTS: The strained HLECs were elongated and aligned perpendicular to the direction of force. Fibronectin and laminin V were highly expressed in the strain group compared with the control. CONCLUSIONS: Cyclic strain induces the synthesis of fibronectin and laminin V in cultivated HLECs.

A case of hyperglycemic hyperosmolar state associated with Graves' hyperthyroidism: a case report.

Hyperglycemic hyperosmolar state (HHS) is an acute complication mostly occurring in elderly type 2 diabetes mellitus (DM). Thyrotoxicosis causes dramatic increase of glycogen degradation and/or gluconeogenesis and enhances breakdown of triglycerides. Thus, in general, it augments glucose intolerance in diabetic patients. A 23-yr-old female patient with Graves' disease and type 2 DM, complying with methimazole and insulin injection, had symptoms of nausea, polyuria and generalized weakness. Her serum glucose and osmolarity were 32.7 mM/L, and 321 mosm/kg, respectively. Thyroid function tests revealed that she had more aggravated hyperthyroid status; 0.01 mU/L TSH and 2.78 pM/L free T3 (reference range, 0.17-4.05, 0.31-0.62, respectively) than when she was discharged two weeks before (0.12 mU/L TSH and 1.41 pM/L free T3). Being diagnosed as HHS and refractory Graves' hyperthyroidism, she was treated successfully with intravenous fluids, insulin and high doses of methimazole (90 mg daily). Here, we described the case of a woman with Graves' disease and type 2 DM developing to HHS.