GX-G03

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype. NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.

Neutropenia is a condition of an abnormally low number of neutrophils which render patients more susceptible to infections, especially to bacterial infections, as the condition may become life threatening and deadly without prompt medical attention. Various factors such as, anticancer drugs, radiotherapy, infectious diseases, congenital defects, or vitamin B12/B9 deficiency can trigger neutropenia. GX‐G3, a human hybrid (hy) Fc‐fused granulocyte colony stimulating factor (G‐CSF), was developed as next‐generation G‐CSF for the treatment of cancer therapy‐induced neutropenia. In this study, with the aim of investigating this promising potential next‐generation G‐CSF, comparative pharmacokinetic and pharmacodynamic studies were conducted in healthy and neutropenia‐induced rats. It was found that t1/2 of GX‐G3 is longer than same mass injection of filgrastim and pegfilgrastim and AUEClast (area under theeffect‐time curve from time zero to the last measurable ANC level) of absolute neutrophil count showed a significant increase after GX‐G3 injection compared with filgrastim and pegfilgrastim in healthy rats. Besides, in duration of neutropenia after the same mass injection GX‐G3 showed about 3.3 days of reduction effect compared with that of filgrastim, and 1.3 days of reduction effect compared with that of pegfilgrastim in neutropenia‐induced rats. These results demonstrate that the half‐life of GX‐G3 is longer than pegfilgrastim and GX‐G3 is more effective than filgrastim and pegfilgrastim in neutropenia‐induced rats.