SUMMARY The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor, α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2−/−) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced bodyweight gain, insulin resistance, inflammation and fatty liver. NE inhibitor GW311616A reversed insulin resistance and bodyweight gain in HFD-fed mice. Compared with wild-type mice, Ela2−/− mice augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK) and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT), and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance and liver steatosis.

The role of curcumin (diferuloylmethane), a proapoptotic compound, for the treatment of cancer has been an area of growing interest. Curcumin in its free form is poorly absorbed in the gastrointestinal tract and therefore may be limited in its clinical efficacy. Liposome encapsulation of this compound would allow systemic administration. The current study evaluated the preclinical antitumor activity of liposomal curcumin in colorectal cancer. We also compared the efficacy of liposomal curcumin with oxaliplatin, a standard chemotherapy for this malignancy. In vitro treatment with liposomal curcumin induced a dose-dependent growth inhibition [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt] and apoptosis [poly(ADP-ribose) polymerase] in the two human colorectal cancer cell lines tested (LoVo and Colo205 cells). There was also synergism between liposomal curcumin and oxaliplatin at a ratio of 4:1 in LoVo cells in vitro. In vivo, significant tumor growth inhibition was observed in Colo205 and LoVo xenografts, and the growth inhibition by liposomal curcumin was greater than that for oxaliplatin (P < 0.05) in Colo205 cells. Tumors from animals treated with liposomal curcumin showed an antiangiogenic effect, including attenuation of CD31 (an endothelial marker), vascular endothelial growth factor, and interleukin-8 expression by immunohistochemistry. This study establishes the comparable or greater growth-inhibitory and apoptotic effects of liposomal curcumin with oxaliplatin both in vitro and in vivo in colorectal cancer. We are currently developing liposomal curcumin for introduction into the clinical setting.

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Objectives Dyslipidemia is a major risk issue for the development of cardiovascular disease. The aim of our study was to observe the pattern and prevalence of dyslipidemia in Pakistani population. Methodology This is a sub analysis of a population based second National Diabetes Survey of Pakistan (NDSP) 2016-2017 in adults aged 20 years or above, carried out from February 2016 to August 2017 across Pakistan. Multi stage sampling technique was used for the stratification of population, based on rural and urban domains. District wise clusters and sub clusters were selected i.e. 27 and 46 in number. Subjects, consented to participate were requested to come after an overnight fast for anthropometric measurements, oral glucose tolerance test and fasting lipid profile (except for subjects with self-reported diabetes). Dyslipidemia was identified using Adult Treatment Panel III guidelines. Results A total of 10,834 subjects (43.8% male and 56.2% female) having mean age of 43.8 ± 14.0 years, participated in the survey. Of the subjects studied, 39.3% had hypercholesterolemia, 48.9% had hypertriglyceridemia, 39.7% had high LDL-C levels while 83.9% men and 90% women had low HDL levels. High cholesterol and triglyceride levels were highest in 50-59 years age group, while high LDL and low HDL was most common in 40-49 years age group. Diabetes, obesity and hypertension were found to be the significant determinants for dyslipidemia. Conclusion Prevalence of dyslipidemia seems to be very high in Pakistan, necessitating an urgent call for early screening and effective management through lifestyle intervention and appropriate lipid lowering drugs to prevent this important cardiovascular risk factor.