Altered calcium regulation by thermosensitive transient receptor potential channels in etoposide-resistant WERI-Rb1 retinoblastoma cells

Differences in transient receptor potential (TRP) and cannabinoid receptor type 1 (CB1) expression levels can serve as prognostic factors for retinoblastoma (RB) tumor progression. We hypothesized in RB tissue that such differences are also indicators of whether or not they are sensitive to etoposide. Accordingly, we compared in malignant etoposide-sensitive and etoposide-resistant WERI-Rb1 cells TRPV1, TRPM8 and TRPA1 subtype and CB1 gene expression pattern levels and accompanying functional activity using quantitative real-time RT-PCR, immunohistochemistry, immunofluorescence microscopy, calcium imaging as well as patch-clamp technology. Gene expression patterns were evaluated in enucleated human RB tissues (n?=?4). Both etoposide-resistant and etoposide-sensitive WERI-Rb1 cells expressed all of the aforementioned channels based on responses to known activators and thermal challenges. However, TRPA1 was absent in the etoposide-resistant counterpart. Even though both types of RB cells express TRPV1 as well as TRPM8 and CB1, the capsaicin (50?μM) (CAP)-induced Ca(2+) rise caused by TRPV1 activation was prompt and transient only in etoposide-resistant RB cells (n?=?8). In this cell type, the inability of CB1 activation (10?μM WIN) to suppress Ca(2+) responses to CAP (50?μM; n?=?4) may be attributable to the absence of TRPA1 gene expression. Therefore, using genetic approaches to upregulate TRPA1 expression could provide a means to induce etoposide sensitivity and suppress RB cell tumorigenesis.     

Neuroendocrine and immunotoxicity of polyaromatic hydrocarbon,chrysene in crustacean post larvae

Ecotoxicology - Polyaromatic hydrocarbons are a group of chemical pollutants which cause a significant threat to the living organisms in estuaries and marine ecosystems. We report the effect of...     

Protective effects of α-tocopherol against oxidative stress related to nephrotoxicity by monosodium glutamate in rats

Context: Chronic oral intake of high doses of monosodium glutamate (MSG) could be harmful to tissues and organs. Oxidative stress enhances membrane damage by lipid peroxidation and alterations of antioxidant enzymes, which affects the functional activity of organs. Antioxidant vitamins have the capacity to regulate the oxidative stress related functional and pathological processes. Objective: In this study, the protective role of α-tocopherol against MSG-induced nephrotoxicity was analyzed. Materials and methods: MSG (4?g/kg) was given orally to female wistar rats for a period of 180 days. Renal function parameters (urea, uric acid, and creatinine), lipid peroxidation markers (malondialdehyde and conjugated dienes), antioxidant system (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, and reduced glutathione), and histopathology were investigated. All tests were done in rats treated with MSG and at two different doses of α-tocopherol (100 and 200?mg/kg). Results: Oral exposure of MSG significantly increased renal function markers, lipid peroxidation byproducts, and altered antioxidant system. Moreover, the kidney showed congested glomeruli, tubular swelling, capillary congestion and microhemorrhages in stromal areas of the tubules. Co-administration of MSG and α-tocopherol (200?mg/kg) significantly reduced the oxidative damage compared with MSG-treated group and also restored the normal renal function. Discussion: The results indicated that oxidative stress was involved in MSG-induced functional and pathological changes in the kidney. α-tocopherol modulates the functional disorder and maintains the normal architecture of renal tissue by reducing oxidative stress. Conclusion: The α-tocopherol may be a potent protective agent in combating MSG-induced renal toxicity.     

Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4 g/kg b.wt for 90 days. After 90 days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250 mg/kg b.wt) and AA (250 mg/kg b.wt) supplemented groups and maintained for 30 days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β₁ and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α₁ (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis.     

Sarcopenia in hepatocellular carcinoma: Current knowledge and future directions

Liver cancer is the second most occurring cancer worldwide and is one of the leading causes of cancer-related deaths.Hepatocellular carcinoma(HCC)is the most common(80%-90%)type among malignant liver cancers.Sarcopenia occurs very early in HCC and can predict and provide an opportunity to improve muscle health before engaging in the treatment options such as loco-regional,systemic,and transplant management.Multiple prognostic stating systems have been developed in HCC,such as Barcelona Clinic Liver Cancer,Child-Pugh score and Albumin-Bilirubin grade.However,the evaluation of patients’performance status is a major limitation of these scoring systems.In this review,we aim to summarize the current knowledge and recent advances about the role of sarcopenia in cirrhosis in general,while focusing specifically on HCC.Additionally,the role of sarcopenia in predicting clinical outcomes and prognostication in HCC patients undergoing loco-regional therapies,liver resection,liver transplantation and systematic therapy has been discussed.A literature review was performed using databases PubMed/MEDLINE,EMBASE,Cochrane,Web of Science,and CINAHL on April 1,2021,to identify published reports on sarcopenia in HCC.Sarcopenia can independently predict HCC-related mortality especially in patients undergoing treatments such as loco-regional,surgical liver transplantation and systemic therapies.Basic research is focused on evaluating a balance of anabolic and catabolic pathways responsible for muscle health.Early clinical studies have shown promising results in methods to improve sarcopenia in HCC which can potentially increase prognosis in these patients.As sarcopenia occurs very early in HCC,it can predict and provide an opportunity to improve muscle health before engaging in the treatment options such as loco-regional,systemic,and transplant management.Further,sarcopenia measurement can obviate the confounding caused by the abdominal ascites in these patients.The use of sarcopenia can add to the existing scoring systems to better prognosticate the HCC.     

Application of mass spectrometry-based proteomics for biomarker discovery in neurological disorders

Mass spectrometry-based quantitative proteomics has emerged as a powerful approach that has the potential to accelerate biomarker discovery, both for diagnostic as well as therapeutic purposes. Proteomics has traditionally been synonymous with 2D gels but is increasingly shifting to the use of gel-free systems and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Quantitative proteomic approaches have already been applied to investigate various neurological disorders, especially in the context of identifying biomarkers from cerebrospinal fluid and serum. This review highlights the scope of different applications of quantitative proteomics in understanding neurological disorders with special emphasis on biomarker discovery.