Khalid Majid Fazili

Ameliorated effects of green tea extract on lead induced liver toxicity in rats.

In the present study, the effect of green tea extract (GTE) on lead induced toxicity was studied in Sprague-Dawley rats. Four groups of rats were used in the study. Lead and GTE was given orally to the rats with drinking water for 8 weeks. Lead concentration in the digested tissues of liver was detected using atomic absorption spectroscopy. The activities of glutathione-S-transferase (GST) and superoxide dismutase (SOD) were used as markers to evaluate the anti oxidant status of tissues. Lead exposure was found to attenuate the antioxidant potential of liver, which was however augmented when supplemented with green tea extract. Liver enzymes ALT, AST and ALP and serum protein determinations indicated the protective effects of green tea extract. Histopathological studies of liver revealed that supplementation of green tea extract resulted in mild degeneration and congestion of the blood vessels and an enhanced regenerative capacity.

Emerging tale of UPR and cancer: an essentiality for malignancy.

A set of cellular response to counter any alteration in homeostasis of a cell originating at endoplasmic reticulum is collectively termed as unfolded protein response (UPR). It initially is adaptive in nature as to restore cellular normalcy failing in course often activates pro-apoptotic signaling pathway resulting in cell death. UPR has emerged as an essential adaptation mechanism that cross talk with various cellular processes for cancer pathogenesis. Interestingly, it plays diverse role in plethora of signaling pathways instrumental in transformation, cell invasion, cell migration, metastasis, neovascularization, proliferation, and maintenance of energy metabolism of cancerous cells. In cancerous cells, it is triggered by change in microenvironment of a cell usually driven by hypoxia, acidosis, and nutrient deprivation, which often leads to positive selection pressure involving the reprogramming of energy metabolism which promotes channelization of limited metabolites into the hexosamine biosynthetic pathway (HBP). Substantial evidences suggest the role of UPR in oncogene (Myc, mTOR, RAS, HER2) driven cancer transformation and progression. In this review, we have comprehensively underlined the role played by UPR in adaptation, transformation, proliferation, invasion, and metastasis of cancerous cells.

Fusobacterium nucleatum, inflammation, and immunity: the fire within human gut

Fusobacterium nucleatum is an identified proinflammatory autochthonous bacterium implicated in human colorectal cancer. It is also abundantly found in patients suffering from chronic gut inflammation (inflammatory bowel disease), consequently contributing to the pathogenesis of colorectal cancer. Majority of the studies have reported that colorectal tumors/colorectal adenocarcinomas are highly enriched with F. nucleatum compared to noninvolved adjacent colonic tissue. During the course of multistep development of colorectal cancer, tumors have evolved many mechanisms to resist the antitumor immune response. One of such favorite ploy is providing access to pathogenic bacteria, especially F. nucleatum in the colorectal tumor microenvironment, wherein both (colorectal tumors and F. nucleatum) exert profound effect on each other, consequently attracting tumor-permissive myeloid-derived suppressor cells, suppressing cytotoxic CD8+ T cells and inhibiting NK cell-mediated cancer cell killing. In this review, we have primarily focused on how this bug modulates the immune response, consequently rendering the antitumor immune cells inactive.

Tertiary Butanol Induced Amyloidogenesis of Hen Egg White Lysozyme (HEWL) Is Facilitated by Aggregation-Prone Alkali-Induced Molten Globule Like Conformational State

Proteins may form undesirable aggregates during the process of folding. Increasing evidence suggests that amyloid fibrils may arise from partially folded precursor molecules. We have previously demonstrated that hen egg white lysozyme [HEWL] exists as molten globule at pH 12.7. Here, we report that lysozyme at pH 7.0 and 11.0 are nearly stable to the addition of up to 45% t-butanol, but treatment of the alkali-induced molten globule form of HEWL [AMGL] with 20% t-butanol caused the formation of amyloid-like fibrils as evidenced by enhanced Thioflavin T binding and DLS measurements.

Fusobacterium nucleatum: an emerging bug in colorectal tumorigenesis.

The human intestinal microbiota is a plethora of diverse microbial species, wherein certain bacteria considered as driver bacteria with procarcinogenic features contribute directly toward colonic epithelium cell damage to initiate colorectal carcinogenesis. However, some bacteria, in particular Fusobacterium nucleatum, which is otherwise a normal resident of the oral microflora and a relatively poor colonizer of the healthy gut, have also been considered to play a role in the development of colorectal cancer. Many studies have reported that F. nucleatum is associated with colorectal adenomas and advanced-stage colorectal cancer, but its precise role in the early stages of colorectal tumorigenesis is poorly understood. Here, we review some of the important features of F. nucleatum, its association with inflammatory bowel disease, modulation of the tumor-immune microenvironment, and E-cadherin/&bgr;-catenin signaling.

Novel variants of SERPIN1A gene: Interplay between alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease

Alpha1-antitrypsin (AAT) is one of the major circulating anti-protease whose levels in circulation are raised during excessive amount of proteases, especially neutrophil elastase (NE) released during the course of inflammation. Proteolytic attack of NE on peripheral organs, more exclusively on lung parenchyma has severe consequence that may precipitate pulmonary emphysema. Normally, human body has its own molecular and physiological mechanisms to synthesize and regulate the production of anti-protease like AAT to mitigate the extent of inflammatory damage. AAT coded by serine-protease inhibitor (SERPINA1) is predominantly expressed in hepatocytes and to some extent by macrophages, monocytes, lung tissue etc. The observation that persons with AAT deficiency developed chronic obstructive pulmonary disease (COPD) and early-onset of emphysema proposed a role for pathways connecting AAT in pathogenesis. Extensive studies have been done till now to bridge a connection between numerous genetic polymorphisms of SERPINA1 gene and the early onset of COPD. Here in this review, we have comprehensively discussed some of the variants of SERPINA1 gene discovered till date and their association with the exacerbation of obstructive pulmonary disease.

Natural osmolytes alleviate GRP78 and ATF-4 levels: Corroboration for potential modulators of unfolded protein response.

AIMS Osmolytes are small organic molecules which play a significant role in maintaining functional homeostasis of proteins under extreme hostile stresses. Any imbalance to cell homeostasis leads to Endoplasmic Reticulum stress (ER-stress) to which a set of cellular responses both at transcriptional and translational level are initialed for restoration of cellular homeostasis called Unfolded Protein Response (UPR). In the present study we evaluated the role of Sarcosine, Betaine, Hydroxyectoine and Ectoine as potential modulators of UPR. ER-stress was induced by Tunicamycin, a prototypic experimental ER-stress inducer. MAIN METHODS The endogenous cellular levels of UPR markers Glucose-Regulated Protein 78 (GRP78) and Activating Transcription Factor-4 (ATF-4) were evaluated in presence and absence of these osmolytes after inducing UPR with tunicamycin. As a prelude to this, IC50 values of these osmolytes were determined by using cell viability assays like MTT and Trypan Blue exclusion assay. KEY FINDINGS We found that these osmolytes in a dose-dependent manner increased the rate of restoration of homeostasis as was evident by the decreased endogenous levels of GRP78 and ATF-4. SIGNIFICANCE These natural osmolytes can thus be useful in therapeutic intervention to mitigate the pathophysiological state resulting from ER-stress.

Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents

HIGHLIGHTSA series of triazole derivatives of diosgenin was prepared.Their cytotoxic activity was evaluated using MTT assay.Dgn‐1 was identified as the most potent analogue against A549 cells. ABSTRACT Diosgenin, a promising anticancer steroidal sapogenin, was isolated from Dioscorea deltoidea. Keeping its stereochemistry rich architecture intact, a scheme for the synthesis of novel diosgenin analogues was designed using Cu (I)‐catalysed alkyne‐azide cycloaddition in order to study their structure‐activity relationship. Both diosgenin and its analogues exhibited interesting anti‐proliferative effect against four human cancer cell lines viz. HBL‐100 (breast), A549 (lung), HT‐29 (colon) and HCT‐116 (colon) using [3‐(4,5‐dimethylthiazolyl‐2)‐2,5‐diphenyltetrazoliumbromide] (MTT) assay. Among the synthesized analogues, Dgn‐1 bearing a simple phenyl R moiety attached via triazole to the parent molecule was identified as the most potent analogue against A549 cancer cell line having IC50 of 5.54 &mgr;M, better than the positive control (BEZ‐235). Dgn‐2 and Dgn‐5 bearing o‐nitrophenyl and o‐cyanophenyl R moieties respectively, displayed impressive anti‐proliferative activity against all the tested human cancer cell lines with IC50 values ranging from 5.77 to 9.44 &mgr;M. The structure‐activity relationship (SAR) revealed that the analogues with simple phenyl R moiety or electron withdrawing ortho substituted R moieties seem to have beneficial impact on the anti‐proliferative activity.

Actin depolymerization mediated loss of SNTA1 phosphorylation and Rac1 activity has implications on ROS production, cell migration and apoptosis.

Alpha-1-syntrophin (SNTA1) and Rac1 are part of a signaling pathway via the dystrophin glycoprotein complex (DGC). Both SNTA1 and Rac1 proteins are over-expressed in various carcinomas. It is through the DGC signaling pathway that SNTA1 has been shown to act as a link between the extra cellular matrix, the internal cell signaling apparatus and the actin cytoskeleton. SNTA1 is involved in the modulation of the actin cytoskeleton and actin reorganization. Rac1 also controls actin cytoskeletal organization in the cell. In this study, we present the interplay between f-actin, SNTA1 and Rac1. We analyzed the effect of actin depolymerization on SNTA1 tyrosine phosphorylation and Rac1 activity using actin depolymerizing drugs, cytochalasin D and latrunculin A. Our results indicate a marked decrease in the tyrosine phosphorylation of SNTA1 upon actin depolymerization. Results suggest that actin depolymerization mediated loss of SNTA1 phosphorylation leads to loss of interaction between SNTA1 and Rac1, with a concomitant loss of Rac1 activation. The loss of SNTA1tyrosine phosphorylation and Rac1 activity by actin depolymerization results in increased apoptosis, decreased cell migration and decreased reactive oxygen species (ROS) levels in breast carcinoma cells. Collectively, our results present a possible role of f-actin in the SNTA1-Rac1 signaling pathway and implications of actin depolymerization on cell migration, ROS production and apoptosis.

Morphological and Molecular Characterization of Diplozoon kashmirensis;D. aegyptensis and D. guptai Collected from Fishes of Kashmir Valley-India

The study reports the results of molecular characterization of the Internal Transcribed Spacer (ITS) of ribosomal DNA of 3 Monogenean species using polymerase chain reaction (PCR), nucleotide sequencing and construction of phylogenetic trees from different fish hosts of Kashmir. The present study shows that the size of the amplified product is 873bp long for D. kashmirensis, 1120bp long in D. aegyptensis and 687bp long in D. guptai revealing that there are intraspecific differences in their base pair lengths. Guanine and Cytocine (G+C) content of three Diplozoon species was found nearly constant for three species i.e., 47% (D. kashmirensis); 47% (D. aegyptensis) and 48% (D. guptai), this GC richness contributes to physical attributes of RNA structures, as there is correlation between GC content and optimal growth temperature. An important observation during the present study has been noticed that Schizothorax niger is infected by all the three species of Diplozoidae; D. kashmirensis; D. aegyptensis and D. guptai, but when all six fishes were collected simultaneously, parasitism by all the parasite species was never observed. Phylogenetic trees Maximum Parsimony (MP), Maximum Likelihood (ML) and Neighbor Joining (NJ) showed that D. kashmirensis and D. aegyptensis share a common host Carassius carassius and S. niger.