Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their anti-tumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding miRNA (miR) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRs that were reactivated by DZNep to directly target TGFβ1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFβ1 synthesis and secretion in PDAC cells and partially phenocopied DZNep’s EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRs by synthetic histone methylation reversal agents as a viable approach to attenuate TGFβ1-induced EMT features in human PDAC and uncover putative miR targets involved in the process.

In previous studies, it has been reported that rosiglitazone has opposing effects on nonalcoholic fatty liver disease. The purpose of the current study is to test the hypothesis that such opposing effects are related to different levels of peroxisome proliferator-activated receptor gamma (PPAR-γ) in the liver. Using a gene transfer approach and mice fed a high-fat diet (HFD) as an animal model, we demonstrate that mice with low levels of PPAR-γ expression in the liver are resistant to HFD-induced development of fatty liver when treated with rosiglitazone. Conversely, rosiglitazone treatment actually exacerbates liver steatosis in obese mice that have a higher level of PPAR-γ. Mechanistic studies show that an elevated hepatic PPAR-γ level is associated with an increased expression of genes responsible for lipid metabolism in the liver, particularly Cd36, Fabp4, and Mgat1. The concurrent transfer of these three genes into the mouse liver fully recapitulates the phenotypic change induced by the overexpression of PPAR-γ. These results provide evidence in support of the importance of PPAR-γ in the liver when rosiglitazone is considered for the treatment of fatty liver disease. Clinically, our results suggest the necessity of verifying PPAR-γ levels in the liver when rosiglitazone is considered as a treatment option, and indicate that the direct use of rosiglitazone for treatment of nonalcoholic fatty liver may not be desirable when the patient's PPAR-γ level in the liver is significantly elevated.

The worldwide prevalence of obesity is increasing, raising health concerns regarding obesity-related complications. Chronic inflammation has been characterized as a major contributor to the development of obesity and obesity-associated metabolic disorders. The purpose of the current study is to assess whether overexpression of interferon beta (IFNβ1), an immune-modulating cytokine, will attenuate high fat diet-induced adipose inflammation and protect animals against obesity development. Using hydrodynamic gene transfer to elevate and sustain blood concentration of IFNβ1 in mice fed a high fat diet, we showed that overexpression of Ifnβ1 gene markedly suppressed immune cell infiltration into adipose tissue, and attenuated production of pro-inflammatory cytokines. Systemically, IFNβ1 blocked adipose tissue expansion and body weight gain, independent of food intake. Possible browning of white adipose tissue might also contribute to blockade of weight gain. More importantly, IFNβ1 improved insulin sensitivity and glucose homeostasis. These results suggest that targeting inflammation represents a practical strategy to block the development of obesity and its related pathologies. In addition, IFNβ1-based therapies have promising potential for clinical applications for the prevention and treatment of various inflammation-driven pathologies.

Background: Obesity is a multifactorial chronic disease that comprises several pathological events, such as adipose hypertrophy, fatty liver and insulin resistance. Inflammation is a key contributer to development of these events, and therefore, targeting inflammation is increasingly considered for management of obesity and its complications. The aim of the current study was to investigate therapeutic outcomes of anti-inflammatory activities of the natural compound Silibinin in reversing obesity and its complication in mice. Methods: C57BL/6 male mice were fed high-fat diet for 8 weeks until development of obesity, and then injected with 50 mg/kg silibinin intraperitoneally twice per week, or vehicle for 8 weeks. Throughout the experiment, mice were continuously checked for body weight and food intake, and glucose tolerance test was performed toward the end of the experiment. Animals were sacrificed and serum and tissues were collected for biochemical, histological, and gene expression analysis to assess silibinin effects on adipose inflammation, fat accumulation, liver adipogenesis and glucose homeostasis. Results: Silibinin treatment reversed adipose tissue inflammation and adipocyte hypertrophy, and blocked progression in weight gain and obesity development with no significant effects on rates of food intake. Silibinin also reversed fatty liver disease and restored glucose homeostasis in treated animals, and reversed hyperglycemia, hyperinsulinemia and hypertriglyceridemia. Conclusion: In this study, we demonstrated that silibinin as an anti-inflammatory therapy is a potential alternative to manage obesity, as well as its related complications. Moreover, silibinin-based therapies could further evolve as a novel treatment to manage various inflammation-driven disorders.

The phenomenal advances in pharmaceutical sciences over the last few decades have led to the development of new therapeutics like peptides, proteins, RNAs, DNAs and highly potent small molecules. Fruitful applications of these therapeutics have been challenged by several anatomical and physiological barriers that limit adequate drug disposition at the site-of-action and by off-target drug distribution to undesired tissues, which together result in the reduced effectiveness and increased side effects of therapeutic agents. As such, the development of drug delivery and targeting systems has been recognised as a cornerstone for future drug development. Research in pharmaceutical sciences is now devoted to tackling delivery challenges through engineering delivery systems that move beyond conventional dosage forms and regimens into state-of-the-art targeted drug delivery tailored toward specific therapeutic needs. Modern drug delivery systems comprise passive and active targeting approaches. While passive targeting relies on the natural course of distribution of drugs or drug carriers in the body, as governed by their physicochemical properties, active targeting often exploits targeting moieties that home preferentially into target tissues. Here, we provide an overview of theories of and approaches to passive and active drug delivery. As the design of drug delivery is dependent on the unique structure of target tissues and organs, we present our discussion in an organ-specific manner with the aim to inspire the development of new strategies for curing disease with high accuracy and efficiency.