Self Nano-Emulsifying Curcumin (SNEC30) attenuates arsenic-induced cell death in mice.

Several precedents have confirmed numerous infirmities caused by arsenic poisoning, including immune suppression and cancer. Exposure to arsenic leads to alterations of the cellular machinery and eventually cell death, depending on the dose and duration of exposure. Oxidative stress induced by arsenic is the major mechanism by which it inflicts cellular toxicity, challenging the survival-support - autophagy and culminating in apoptosis in the thymus and spleen of mice. Curcumin, a potent dietary anti-oxidant with known anti-apoptotic and anti-inflammatory properties, was assessed for therapeutic benefits. However, the major caveat of this polyphenol is its low water solubility and limited bioavailability. Therefore, Self Nano-Emulsifying Curcumin (SNEC30) was used to treat mice exposed to arsenic. When administered, SNEC30 effectively ameliorated the adverse effects of arsenic in mice, by restoring structural alterations and reducing ROS-mediated cell death, thereby endorsing the importance of nutraceuticals in counteracting heavy metal-induced cellular toxicity.

Reciprocal interplay between asporin and decorin: Implications in gastric cancer prognosis.

Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing TCGA-gastric adenocarcinoma dataset. Small leucine-rich proteoglycans, asporin (ASPN) and decorin (DCN), play overlapping roles in development and diseases; however, the mechanisms underlying their interplay remain elusive. Here, we investigated the complex interplay of asporin, decorin and their interaction with TGFß in GC tumor and corresponding normal tissues. The mRNA levels, protein expressions and cellular localizations of ASPN and DCN were analyzed using real-time PCR, western blot and immunohistochemistry, respectively. The protein-protein interaction was predicted by in-silico interaction analysis and validated by co-immunoprecipitation assay. The correlations between ASPN and EMT proteins, VEGF and collagen were achieved using western blot analysis. A significant increase in expression of ASPN in tumor tissue vs. normal tissue was observed in both TCGA and our patient cohort. DCN, an effective inhibitor of the TGFß pathway, was negatively correlated with stages of GC. Co-immunoprecipitation demonstrated that DCN binds with TGFß, in normal gastric epithelium, whereas in GC, ASPN preferentially binds TGFß. Possible activation of the canonical TGFß pathway by phosphorylation of SMAD2 in tumor tissues suggests its role as an intracellular tumor promoter. Furthermore, tissues expressing ASPN showed unregulated EMT signalling. Our study uncovers ASPN as a GC-promoting gene and DCN as tumor suppressor, suggesting that ASPN can act as a prognostic marker in GC. For the first time, we describe the physical interaction of TGFß with ASPN in GC and DCN with TGFß in GC and normal gastric epithelium respectively. This study suggests that prevention of ASPN-TGFß interaction or overexpression of DCN could serve as promising therapeutic strategies for GC patients.

Arsenic-induced immunomodulatory effects disorient the survival-death interface by stabilizing the Hsp90/Beclin1 interaction.

Ground water arsenic contamination is a global menace. Since arsenic may affect the immune system, leading to immunesuppression, we investigated the effects of acute arsenic exposure on the thymus and spleen using Swiss albino mice, exposed to 5 ppm, 15 ppm and 300 ppm of sodium arsenite for 7 d. Effects on cytokine balance and cell survivability were subsequently analyzed. Our data showed that arsenic treatment induced debilitating alterations in the tissue architecture of thymus and spleen. A dose-dependent decrease in the ratio of CD4+-CD8+ T-cells was observed along with a pro-inflammatory response and redox imbalance. In addition, pioneering evidences established the ability of arsenic to induce an up regulation of Hsp90, eventually resulting in stabilization of its client protein Beclin-1, an important autophagy-initiating factor. This association initiated the autophagic process, confirmed by co-immunoprecipitation assay, acridine orange staining and Western blot, indicating the effort of cells trying to survive at lower doses. However, increased arsenic assault led to apoptotic cell death in the lymphoid organs, possibly by increased ROS generation. There are several instances of autophagy and apoptosis taking place either simultaneously or sequentially due to oxidative stress. Since arsenic is a potent environmental stress factor, exposure to arsenic led to a dose-dependent increase in both autophagy and apoptosis in the thymus and spleen, and cell death could therefore possibly be induced by autophagy. Therefore, exposure to arsenic leads to serious effects on the immune physiology in mice, which may further have dire consequences on the health of exposed animals.

Enhancing Chemosensitivity of Breast Cancer Stem Cells by Downregulating SOX2 and ABCG2 Using Wedelolactone-encapsulated Nanoparticles.

A major caveat in the treatment of breast cancer is disease recurrence after therapeutic regime at both local and distal sites. Tumor relapse is attributed to the persistence of chemoresistant cancer stem cells (CSC), which need to be obliterated along with conventional chemotherapy. Wedelolactone, a naturally occurring coumestan, demonstrates anticancer effects in different cancer cells, although with several limitations, and is mostly ineffective against CSCs. To enhance its biological activity in cancer cells and additionally target the CSCs, wedelolactone-encapsulated PLGA nanoparticles (nWdl) were formulated. Initial results indicated that nanoformulation of wedelolactone not only increased its uptake in breast cancer cells and the CSC population, it enhanced drug retention and sustained release within the cells. Enhanced drug retention was achieved by downregulation of SOX2 and ABCG2, both of which contribute to drug resistance of the CSCs. In addition, nWdl prevented epithelial-to-mesenchymal transition, suppressed cell migration and invasion, and reduced the percentage of breast cancer stem cells (BCSC) in MDA-MB-231 cells. When administered in combination with paclitaxel, which is known to be ineffective against BCSCs, nWdl sensitized the cells to the effects of paclitaxel and reduced the percentage of ALDH+ BCSCs and mammospheres. Furthermore, nWdl suppressed growth of solid tumors in mice and also reduced CD44+/CD24-/low population. Taken together, our data imply that nWdl decreased metastatic potential of BCSCs, enhanced chemosensitivity through coordinated regulation of pluripotent and efflux genes, and thereby provides an insight into effective drug delivery specifically for obliterating BCSCs.