Beneficial Effects of a Curcumin Derivative and Transforming Growth Factor-β Receptor I Inhibitor Combination on Nonalcoholic Steatohepatitis

Background@#Curcumin 2005-8 (Cur5-8), a derivative of curcumin, improves fatty liver disease via AMP-activated protein kinase activation and autophagy regulation. EW-7197 (vactosertib) is a small molecule inhibitor of transforming growth factor β (TGF-β) receptor I and may scavenge reactive oxygen species and ameliorate fibrosis through the SMAD2/3 canonical pathway. This study aimed to determine whether co-administering these two drugs having different mechanisms is beneficial. @*Methods@#Hepatocellular fibrosis was induced in mouse hepatocytes (alpha mouse liver 12 [AML12]) and human hepatic stellate cells (LX-2) using TGF-β (2 ng/mL). The cells were then treated with Cur5-8 (1 μM), EW-7197 (0.5 μM), or both. In animal experiments were also conducted during which, methionine-choline deficient diet, Cur5-8 (100 mg/kg), and EW-7197 (20 mg/kg) were administered orally to 8-week-old C57BL/6J mice for 6 weeks. @*Results@#TGF-β-induced cell morphological changes were improved by EW-7197, and lipid accumulation was restored on the administration of EW-7197 in combination with Cur5-8. In a nonalcoholic steatohepatitis (NASH)-induced mouse model, 6 weeks of EW-7197 and Cur5-8 co-administration alleviated liver fibrosis and improved the nonalcoholic fatty liver disease (NAFLD) activity score. @*Conclusion@#Co-administering Cur5-8 and EW-7197 to NASH-induced mice and fibrotic hepatocytes reduced liver fibrosis and steatohepatitis while maintaining the advantages of both drugs. This is the first study to show the effect of the drug combination against NASH and NAFLD. Similar effects in other animal models will confirm its potential as a new therapeutic agent.

EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation

Background@#Diabetic nephropathy (DN) is characterized by albuminuria and accumulation of extracellular matrix (ECM) in kidney. Transforming growth factor-β (TGF-β) plays a central role in promoting ECM accumulation. We aimed to examine the effects of EW-7197, an inhibitor of TGF-β type 1 receptor kinase (ALK5), in retarding the progression of DN, both in vivo, using a diabetic mouse model (db/db mice), and in vitro, in podocytes and mesangial cells. @*Methods@#In vivo study: 8-week-old db/db mice were orally administered EW-7197 at a dose of 5 or 20 mg/kg/day for 10 weeks. Metabolic parameters and renal function were monitored. Glomerular histomorphology and renal protein expression were evaluated by histochemical staining and Western blot analyses, respectively. In vitro study: DN was induced by high glucose (30 mM) in podocytes and TGF-β (2 ng/mL) in mesangial cells. Cells were treated with EW-7197 (500 nM) for 24 hours and the mechanism associated with the attenuation of DN was investigated. @*Results@#Enhanced albuminuria and glomerular morphohistological changes were observed in db/db compared to that of the nondiabetic (db/m) mice. These alterations were associated with the activation of the TGF-β signaling pathway. Treatment with EW-7197 significantly inhibited TGF-β signaling, inflammation, apoptosis, reactive oxygen species, and endoplasmic reticulum stress in diabetic mice and renal cells. @*Conclusion@#EW-7197 exhibits renoprotective effect in DN. EW-7197 alleviates renal fibrosis and inflammation in diabetes by inhibiting downstream TGF-β signaling, thereby retarding the progression of DN. Our study supports EW-7197 as a therapeutically beneficial compound to treat DN.

A Case of Pulmonary Capillary Hemangiomatosis-Like Lesion Followed for Seven Years / 결핵및호흡기질환

Pulmonary capillary hemangiomatosis (PCH) is a rare disease of unknown etiology that is characterized by nodules composed of infiltrating capillary blood vessels. Herein, we describe a case of a PCH-like lesion that was detected by chest computed tomography. Transthoracic needle aspiration resulted in life-threatening hemorrhage. The patient was followed for seven years. He remained in good health and a follow up image showed little interval change.

Thyrotoxic Vomiting: A Case Report and Possible Mechanisms

The symptoms related to gastrointestinal (GI) tract are sometimes chief complaints in patients with endocrine disease. Thyrotoxicosis is a rare, but notable cause for unexplained and repeated vomiting. Here, we report an adolescent patient with thyrotoxicosis who was initially presented with repeated vomiting and epigastric pain. A 13-year-old female was referred to a GI outpatient department for evaluation of vomiting and abdominal pain from a pediatric clinic. Esophagogastroduodenoscopy revealed acute gastritis with duodenogastric reflux and suspicious reflux esophagitis of minimal change, but there was no significant improvement after treatment and as a result she was admitted to the emergency room. She was subsequently diagnosed as Graves' disease because an initial laboratory test at the GI outpatient department revealed thyroid stimulating hormone < 0.01 microIU/mL and additional blood tests showed elevated thyroid hormones and positive thyroid stimulating hormone receptor antibody. The vomiting and epigastric pain improved remarkably after treatment with antithyroid drugs. Clinicians should consider the possibility of thyrotoxicosis in patient with unexplained and repeated vomiting.