Pulmonary histopathology in fatal paraquat poisoning

Paraquat is a potent herbicide widely used in the Indian agriculture industry. Human fatality due to paraquat poisoning is not uncommon in this country. The primary effect of paraquat is on the lungs, and the resultant pulmonary damage leads to the patient’s demise. There is a high mortality rate in paraquat poisoning as the treatment is usually supportive with no known antidote. There are limited human studies that have observed the histopathological changes in lungs in paraquat poisoning. The authors have discussed the time-related histopathological changes in lungs in paraquat poisoning on autopsy subjects. The role of anticoagulants and fibrinolytic agents in the treatment of this poisoning has also been discussed

SelSA-1, a novel HDAC inhibitor demonstrates enhanced chemotherapeutic potential by redox modulation

Abstract Colorectal cancer (CRC) is a multistep disorder resulting from genetic and epigenetic genome changes. It is the third most common malignancy in developed nations accounting for roughly 600,000 deaths annually. Persistent gut inflammation, as observed in inflammatory bowel disease (IBD), is a key risk factor for CRC development. From an epigenetic viewpoint, the pharmacological inhibition of HDACs using HDAC inhibitors such as SAHA has emerged as a suitable anticancer strategy in the recent past. However, the clinical success of these strategies is limited and has risk factors associated with their uses. Thus, considering the critical involvement of epigenetic regulation of key molecular mechanisms in carcinogenesis as well as HDAC inhibitory and anti-tumorigenic properties of Selenium (Se), we aimed to explore the potentially safer and enhanced chemotherapeutic potential of a Se derivative of SAHA namely SelSA-1, in an experimental model of colitis-associated experimental cancer (CAC) model and mechanism involved therein. The in vitro study indicated improved efficiency, specificity, and better safety margin in terms of lower IC50 value of SelSA-1 than SAHA in both NIH3T3 (9.44 and 10.87 µM) and HCT 115 (5.70 and 7.49 µM) cell lines as well on primary colonocytes (5.61 and 6.30 µM) respectively. In an in vivo experimental model, SelSA-1 efficiently demonstrated amelioration of the multiple plaque lesions (MPLs), tumor burden/incidence, and modulation of various histological and morphological parameters. Further, redox-mediated alterations in apoptotic mediators suggested induction of cancer cell apoptosis by SelSA-1. These findings indicate the enhanced chemotherapeutic and pro-resolution effects of SelSA-1 in part mediated through redox modulation of multiple epigenetic and apoptotic pathways

Resolution of Cox mediated inflammation by Se supplementation in mouse experimental model of colitis

<div><p>UC a form of IBD is a chronic inflammatory disorder of large intestine, with unknown etiology. Reports suggest a critical role of COX-2 dependent prostaglandins (PGs) mediated inflammatory pathway in pathophysiology of UC. However, COX inhibition using NSAIDs exacerbate IBD and thus is not a viable solution. Currently, in DSS induced experimental colitis in mice, we have demonstrated that dietary Se supplementation (0.5ppm as sodium selenite) symptomatically resolves the signs of inflammation in a redox sensitive manner as compared to Se deficient (0.01ppm) conditions, as seen by modulation in oxidative stress markers, morphological changes, histopathological examinations, biochemical studies such as MPO activity, activity of intestinal markers enzymes as well as mRNA and expressions of various pro and anti-inflammatory factors such as, mPGES, hPGDS, TXAS, 15-PGDH, GPX-1 and GPX-2. These findings were validated and correlated with changes in the biophysical parameters such as membrane fluidity, electrical parameters (impedance), transport across the colonic tissue and FTIR. Current study not only concluded that Se at supranutritional concentrations by modulating the redox status relieves the signs of colitis by regulating COX dependent PG biosynthetic pathway, but also sheds light on the biophysical characterization of these inflammatory/resolution pathways involved in UC.</p></div

Biophysical characterization of protective effects of Se.

<p>(a) Demonstrates significant decrease in membrane fluidity in Se-D group in comparison with Se-Ade and Se-Sup groups (b) shows changes in the Histidine transport levels across the epithelial membrane (c, d) shows significant decrease in impedance at 1KHz and 100Hz in Se-Def group in comparison with Se-Ade and Se-Sup groups in series and parallel respectively. Data is represented as mean ± SEM of atleast 4 independent observations and ***, **, * represent p<0.001, p<0.01 & p<0.05.</p

Redox mediated resolution of inflammation by Se.

<p>(a) and (b) shows histopathology images and scoring of colonic tissues in Se-Def, Se-Ade and Se-Sup groups. (c) Increased myeloperoxidase activity in Se-Ade and Se-Sup groups compared to Se Def groups. (d, e) Alteration in MDA levels and catalase activity after DSS treatment in colons of mice fed on diets containing different Se concentration. Data is represented as mean ± SEM of atleast4 independent observations and ***, **, * represent p<0.001, p<0.01& p<0.05 respectively.</p

Protective effects of Se are mediated through modulation of Cox pathway.

<p>(a) and (b) represents the specific activity of intestinal marker disaccharidases in BBM and colon homogenates of Se-Def, Se-Ade and Se-Sup groups. (c) and (d) shows Se concentration dependent significant alterations in the mRNA and protein expressions of pro and anti-inflammatory markers. Data is represented as mean ± SEM of atleast4 independent observations and ***, **, * represent p<0.001, p<0.01& p<0.05 respectively.</p

List of primers used.

<p>List of primers used.</p

Se relives sign of inflammation in DSS colitis model.

<p>(a) Differential GPx activity in Se-Def, Se-Ade and Se-Sup. (b) Shows significant decrease in body weights in Se-Def group when compared with Se-Ade and Se-Sup group. (c, d) shortening of colons of Se-Def mice compared to Se-Ade and Se-Sup groups (e) Percent survival curves of three groups with Se-Def with poor survival when compared to Se-Ade and Se-Sup groups. (f) Disease activity index (DAI). Data is represented as mean ± SEM of atleast4 independent observations and ***, **, * represent p<0.001, p<0.01& p<0.05 respectively).</p