ABSTRACT
Metabolic syndrome is recognized as a proinflammatory condition leading to hepatic steatosis and nonalcoholic steatohepatitis (NASH). We tested the effects of a succulent species Hoodia parviflora N.E. Br., of the genus Hoodia sweetex Dence, on animal models of NASH and insulin resistance (ob/ob mouse and the sand rat Psammomys obesus). IL6 secretion was evaluated by ELISA and hepatic signal transducer and activator of transcription 3 by Western blot. We followed liver enzymes, weight, glucose, hepatic histology, hepatic triglycerides (TGs), and total fat and serum insulin. Oral administration of extracts derived from H. parviflora alleviated the insulin resistance manifested by improved glucose tolerance tests. Treatment alleviated the liver injury noted by a decrease in liver enzyme levels, improved intrahepatic TG content, total hepatic fat, and improved hepatic histology. Similarly, treatment with H. parviflora reduced hepatic inflammation in mice with Concanavalin A-induced hepatitis. These effects were independent of food consumption and weight. H. parviflora was associated with alleviated insulin resistance, hepatic steatosis, and liver injury. The data support its use as a liver protector.
Subject(s)
Hoodia/chemistry , Insulin Resistance , Non-alcoholic Fatty Liver Disease/drug therapy , Plant Extracts/pharmacology , Administration, Oral , Animals , Blood Glucose , Chemical and Drug Induced Liver Injury/drug therapy , Diabetes Mellitus, Type 2 , Disease Models, Animal , Fatty Liver/drug therapy , Glucose Tolerance Test , Hepatitis , Insulin/blood , Interleukin-6/metabolism , Liver/injuries , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Rats , Triglycerides/bloodABSTRACT
Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiation-induced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (γH2AX and 53BP1) and the expression of senescence-associated markers (SA-ßgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy.
