Wei-Wen Hung

Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet

BackgroundPioglitazone was reported to improve hepatic steatosis and necroinflammation in human studies. To investigate whether the hepato-protective effect of pioglitazone was associated with an improvement of antioxidant defense mechanism, oxidative DNA damage and repair activity were determined in a high fat diet model. Male C57BL/6 mice were respectively fed with a 30% fat diet, the same diet with pioglitazone 100 mg/kg/day, or a chow diet as control for 8 weeks. Tissue oxidative stress was indicated by malondialdehyde concentration. Oxidative DNA damage was detected by immunohistochemical 8-oxoG staining. Enzymatic antioxidant defense was detected by the real-time PCR of superoxide dismutase (Sod1, Sod2) and DNA glycosylase (Ogg1, MutY). Oxidative DNA repair was detected by immunohistochemical staining and western blotting of OGG1 expression.ResultsOur results show that hepatic steatosis was induced by a high-fat diet and improved by adding pioglitazone. Malondialdehyde concentration and 8-oxoG staining were strongly increased in the high-fat diet group, but attenuated by pioglitazone. Gene expressions of antioxidant defense mechanism: Sod1, Sod2, Ogg1 and MutY significantly decreased in the high-fat diet group but reversed by pioglitazone co-administration.ConclusionThe attenuation of hepatic oxidative DNA damage by pioglitazone in a high-fat diet may be mediated by up-regulation of the antioxidant defense mechanism and oxidative DNA repair activity. The diminution of oxidative damage may explain the clinical benefit of pioglitazone treatment in patients with non-alcoholic fatty liver disease.

Increased Unbound Retinol-binding Protein 4 Concentration Induces Apoptosis through Receptor-mediated Signaling

Background: An increase of apo- to holo-RBP4 concentration in plasma is observed in subjects with renal dysfunction and is supposed to induce cell damage. Results: Increased apo-/holo-RBP4 ratio affects STRA6 signaling, which activates JAK2/STAT5 and then induces apoptosis. Conclusion: Increased apo-RBP4 concentration can affect vitamin A signaling, leading to cell death. Significance: This study establishes a direct relationship between increased apo-RBP4 concentration and apoptosis. The increase of apo-/holo-retinol-binding protein 4 (RBP4) concentrations has been found in subjects with renal dysfunction and even in diabetic patients with microalbuminuria. Holo-RBP4 is recognized to possess cytoprotective function. Therefore, we supposed that the relative increase in apo-RBP4 might induce cell damage. In this study, we investigated the signal transduction that activated apoptosis in response to the increase of apo-/holo-RBP4 concentration. We found that increase of apo-/holo-RBP4 concentration ratio delayed the displacement of RBP4 with “stimulated by retinoic acid 6” (STRA6), enhanced Janus kinase 2 (JAK2)/STAT5 cascade, up-regulated adenylate cyclase 6 (AC6), increased cAMP, enhanced JNK1/p38 cascade, suppressed CRBP-I/RARα (cellular retinol-binding protein/retinoic acid receptor α) expression, and led to apoptosis in HK-2 and human umbilical vein endothelial cells. Furthermore, STRA6, JAK2, STAT5, JNK1, or p38 siRNA and cAMP-PKA inhibitor reversed the repression of CRBP-I/RARα and apoptosis in apo-RBP4 stimulation. In conclusion, this study indicates that the increase of apo-/holo-RBP4 concentration may influence STRA6 signaling, finally causing apoptosis.

Risk interaction of obesity, insulin resistance and hormone-sensitive lipase promoter polymorphisms (LIPE-60 C > G) in the development of fatty liver

BackgroundHormone sensitive lipase (HSL) promoter (LIPE-60 C > G) polymorphism has been found to be involved in hepatic steatosis, obesity, diabetes and dyslipidemia. The precise interactions between these risk factors and genetic susceptibility that may affect non-alcoholic fatty liver disease (NAFLD) are still not fully determined.MethodsA cross-sectional study was conducted in 1056 men. To avoid the confounding effect of plasma glucose, the study population was classified into normal glucose tolerance (NGT, n = 729) and glucose intolerance (GI, n = 299) groups. NAFLD was diagnosed by abdominal ultrasound after ruling out any history of alcohol abuse. A multivariate regression model was used to estimate the impact of these factors on NAFLD.ResultsIn the NGT group, subjects with NAFLD often have complicated metabolic abnormalities. The coexistence of NAFLD and GI has been demonstrated to have a synergistic effect raising BMI, serum insulin and HOMA-insulin resistance (HOMA-IR). BMI and adipose-insulin resistance (Adipo-IR), but not HOMA-IR, significantly contributed to a greater risk of developing NAFLD. Serum triglyceride was significantly up-regulated in men with the (CG + GG) genotype of HSL promoter polymorphism, NAFLD and Adiopo-IR in sequence.ConclusionAdipo-IR, rather than HOMA-IR, appears to be a consistent insulin resistance index in the study of NAFLD. G allele of the HSL promoter polymorphism may contribute the greatest impact raising serum triglyceride in a state of glucose intolerance.

A case of acromegaly complicated with diabetic ketoacidosis, pituitary apoplexy, and lymphoma.

Acromegaly is always complicated with comorbidities and increased mortality. The disease activity and mortality outcomes are highly correlated to the level of growth hormone and insulin‐like growth factor 1. A variety of clinical manifestations of acromegaly have been reported. We present a unique case where a 49‐year‐old male was diagnosed with acromegaly with a first manifestation as an episode of diabetic ketoacidosis. Because he refused any suggestion of treatment, a recurrent episode of diabetic ketoacidosis with pituitary apoplexy occurred. A huge B‐cell lymphoma displaying as a huge facial mass followed within 1 year of the diagnosis of acromegaly. Death from advanced cancer ensued 3 years later. This clinical experience strongly reinforces the urgency of controlling growth hormone and insulin‐like growth factor 1 as soon as possible once acromegaly is diagnosed.

Acute Brachial Artery Thrombosis: A Rare Complication of Diabetic Ketoacidosis

Diabetes mellitus is a worldwide disease that leads to several acute complications including diabetic ketoacidosis, hyperosmolar hyperglycemia, and hypoglycemia. In addition, diabetes causes many chronic complications that lead to debilitation and diminished quality of life. Diabetic ketoacidosis is one of the serious acute complications; however, it is usually preceded by infection, acute myocardial infarction, stroke, or other dire events. Rarely does it accompany acute arterial thrombosis. Here, we report on a female patient who suffered from diabetic ketoacidosis combined with acute brachial artery thrombosis. After emergency treatment, including insulin therapy and surgical thrombectomy, the brachial artery was rescued and her prognosis was good.

Calcitonin Expression in the Metastatic Tissue of Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is an uncommon primary thyroid carcinoma accounting for as much as 10% of all thyroid malignancies and as much as 14% of thyroid cancer-related deaths.[1] It is a neuroendocrine malignancy arising from the C cell or parafollicular cell of the thyroid.[2] The sporadic and hereditary forms of MTC account for 80% and 20% of all cases, respectively.[3] The hereditary form is part of the multiple endocrine neoplasia (MEN) syndromes including MEN 2A (MTC, pheochromocytoma, and hyperparathyroidism), MEN 2B (MTC, pheochromocytoma, mucosal neuroma, and marfanoid habitus), and familial MTC (FMTC).[4] About 40% to 50% of sporadic MTC cases present with distant metastasis involving cervical lymph nodes, lungs, liver, and/or bones at initial diagnosis.[5] The literature reports other rare metastatic sites including pituitary metastasis, [6] choroidal and optic disc metastasis, [7,8] breast metastasis, [9] and skin metastasis. [10]