Zinc Deficiency and Oxidative Stress Involved in Valproic Acid Induced Hepatotoxicity: Protection by Zinc and Selenium Supplementation

Valproic acid (VPA) is an antiepileptic drug, which its usage is limited due to its hepatotoxicity. The present study was conducted to investigate the efficacy of zinc (Zn) and selenium (Se), necessary trace elements, against VPA-induced hepatotoxicity in Wistar rats. The animals were divided into five groups: control, VPA 200 mg/kg, VPA + Zn (100 mg/kg), VPA + Se (100 mg/kg), and VPA + Zn + Se. The administration of VPA for four consecutive weeks resulted in decrease in serum level of Zn in rats. Also, an increase in liver marker enzymes (ALT and AST) and also histological changes in liver tissue were shown after VPA administration. Oxidative stress was evident in VPA group by increased lipid peroxidation (LPO), protein carbonyl (PCO), glutathione (GSH) oxidation, and reducing total antioxidant capacity. Zn and Se (100 mg/kg) administration was able to protect against deterioration in liver enzyme, abrogated the histological change in liver tissue, and suppressed the increase in oxidative stress markers. Zn and combination of Zn plus Se treatment showed more protective effects than Se alone. These results imply that Zn and Se should be suggested as effective supplement products for the prevention of VPA-induced hepatotoxicity.     

Molecular taxonomy of Hyrcanian Alnus using nuclear ribosomal ITS and chloroplast trnH-psbA DNA barcode markers

The taxonomy and phylogeny of Hyrcanian Alnus (eight taxa) were investigated using sequence data from the nuclear ribosomal ITS and the chloroplast trnH-psbA intergenic spacer. The mean nucleotide compositions of the ITS region were completely equal for two main Hyrcanian taxa, and the ITS1 region had fewer variable sites than the ITS2 region. Two relatively distinct types of ITS2 were identified for two main clades of Hyrcanian Alnus, the A. subcoradata complex and A. glutinosa. Two recently described species, A. dolichocarpa and A. djavanshirii, did not show any diagnostic sites and had a similar pattern with A. subcordata. Three recognized subspecies of A. glutinosa were distributed in the A. incana complex. In the analysis of trnH-psbA sequence data, the three subgenera of Alnus were poorly resolved relative to one another. Alnus glutinosa had minimal sequence divergence from A. incana and A. tenuifolia, and A. subcordata had a minimum distance from A. cordata and A. orientalis. A maximum pairwise distance also was observed between Hyrcanian species (A. glutinosa and A. subcordata) with A. pendula and A. sieboldiana, respectively. Ultimately, the molecular phylogeny of Alnus based on two DNA barcode markers was not congruent with recent morphological classifications, so additional DNA markers should be explored for identifying Alder taxa in the Hyrcanian forest.     

Discontinuous Schedule of Bevacizumab in Colorectal Cancer Induces Accelerated Tumor Growth and Phenotypic Changes

Antiangiogenics administration in colorectal cancer patients seemed promising therapeutic approach. Inspite of early encouraging results, it however gave only modest clinical benefits. When AAG was administered with discontinuous schedule, the disease showed acceleration in certain cases. Though resistance to AAG has been extensively studied, it is not documented for discontinuous schedules. To simulate clinical situations, we subjected a patient-derived CRC subcutaneous xenograft in mice to three different protocols: 1) AAG (bevacizumab) treatment for 30 days (group A) (group B was the control), 2) bevacizumab treatment for 50 days (group C) and bevacizumab for 30 days and 20 without treatment (group D), and 3) bevacizumab treatment for 70 days (group E) and 70 days treatment with a drug-break period between day 30 and 50 (group F). The tumor growth was monitored, and at sacrifice, the vascularity of tumors was measured and the proangiogenic factors quantified. Tumor phenotype was studied by quantifying cancer stem cells. Interrupting bevacizumab during treatment accelerated tumor growth and revascularization. A significant increase of proangiogenic factors was observed when therapy was stopped. On withdrawal of bevacizumab, as also after the drug-break period, the plasmatic VEGF increased significantly. Similarly, a notable increase of CSCs after the withdrawal and drug-break period of bevacizumab was observed (P<.01). The present study indicates that bevacizumab treatment needs to be maintained because discontinuous schedules tend to trigger tumor regrowth, and increase tumor resistance and CSC heterogeneity.     

Benefit of nicorandil using an immunologic murine model of experimental colitis

Inflammatory bowel disease (IBD) is a chronic inflammatory condition with an unknown etiology. Nicorandil, a potassium channel opener, has been used for many years for the treatment of angina. Recently, it has been shown that nicorandil possesses some novel traits such as anti-apoptotic, gastroprotective, free radical scavenging, and anti-inflammatory properties. Therefore, we set out to examine the possible beneficial effect of nicorandil in a rat model of IBD. Colitis was induced by rectal administration of 2,4,6-trintrobenzene sulphonic acid (TNBS) into rats. Groups of animals used in this study were sham, control, and exposure to dexamethasone, nicorandil, glibenclamid (a pure adenosine triphosphate sensitive potassium channel (KATP) blocker), or nicorandil plus glibenclamid. Drugs were administered by gavage and animals were sacrificed after 7 days. Biochemical markers, including TNF-α and IL-1β, ferric reducing/antioxidant power (FRAP), myeloperoxidase (MPO) activity and thiobarbitoric acid-reactive substance (TBARS), were measured in the homogenate of colonic tissue. Results indicate that nicorandil significantly reduces macroscopic and histological damage induced by TNBS. Nicorandil diminishes MPO activity and levels of TBARS, TNF-∢, and IL-1β in damaged colonic tissue with a concomitant increase in FRAP value (P<0.01). These effects were not reversed by coadministration of glibenclamide. In conclusion, nicorandil is able to ameliorate experimental IBD with a dose in which it does not show any anti-hypertensive effect, and the mechanism of which is partially or totally independent from KATP channels. It is hypothesized that nitric oxide donation and free-radical scavenging properties of nicorandil upregulate endothelial nitric oxide synthase may be responsible for this phenomenon. These findings suggest that nicorandil can be useful in treatment of IBD, although further investigations are needed to elucidate the mechanisms involved.     

Promising insights into the kosmotropic effect of magnetic nanoparticles on proteins: The pivotal role of protein corona formation

Increasing concerns about biosafety of nanoparticles (NPs) has raised the need for detailed knowledge of NP interactions with biological molecules especially proteins. Herein, the concentration-dependent effect of magnetic NPs (MNPs) on bovine serum albumin and hen egg white lysozyme was explored. The X-ray diffraction patterns, zeta potential, and dynamic light scattering measurements together with scanning electron microscopy images were employed to characterize MNPs synthesized through coprecipitation method. Then, we studied the behavior of two model proteins with different surface charges and structural properties on interaction with Fe₃O₄. A thorough investigation of protein–MNP interaction by the help of intrinsic fluorescence at different experimental conditions revealed that affinity of proteins for MNPs is strongly affected by the similarity of protein and MNP surface charges. MNPs exerted structure-making kosmotropic effect on both proteins under a concentration threshold; however, binding strength was found to determine the extent of stabilizing effect as well as magnitude of the concentration threshold. Circular dichroism spectra showed that proteins with less resistance to conformational deformations are more prone to secondary structure changes upon adsorption on MNPs. By screening thermal aggregation of proteins in the presence of Fe₃O₄, it was also found that like chemical stability, thermal stability is influenced to a higher extent in more strongly bound proteins. Overall, this report not only provides an integrated picture of protein–MNP interaction but also sheds light on the molecular mechanism underling this process.     

Aerobic exercise modulates noncoding RNA network upstream of FNDC5 in the Gastrocnemius muscle of high-fat-diet-induced obese mice

Journal of Physiology and Biochemistry - The purpose of the study was to determine the influence of aerobic exercise with a fat-rich diet on ncRNAs expression associated with FNDC5 in the...     

The Antimicrobial Peptide,Nisin, Synergistically Enhances the Cytotoxic and Apoptotic Effects of Rituximab Treatment on Human Burkitt’s Lymphoma Cell Lines

Background:Non-Hodgkin''s lymphomas comprise the most common hematological cancers worldwide and consist of a heterogenous group of malignancies affecting the lymphoid system. Treatment of non-Hodgkin’s lymphoma has been significantly enhanced with the addition of Rituximab to the standard chemotherapy regimen. However, even with the advancement of treatment patients continue to relapse and develop resistance to Rituximab, rendering subsequent treatments unsuccessful. The use of novel drugs with unique antitumor mechanisms has gained considerable attention. In this study, we explored the in vitro anti-cancer effects of the combined therapy of Rituximab and Nisin on human Burkitt’s lymphoma cells.Methods:The human Burkitt’s lymphoma cells lines, Raji and Daudi, were treated with Nisin, Rituximab, or a combination of the two agents at various concentrations. Cytotoxicity following treatment was determined using cell viability assay. The degree of apoptosis was verified via flow cytometric analysis using FITC annexin V/PI staining.Results:Our findings show that the combined treatment of Rituximab and Nisin results in a more significant reduction in the survival of Raji and Daudi Burkitt’s lymphoma cells, compared to Nisin or Rituximab treatment alone. Additionally, our results indicate that Nisin can induce a significant degree of apoptosis in the Burkitt’s lymphoma cells compared to the negative controls. However, the addition of Nisin to the Rituximab treatment synergistically enhances the apoptotic antitumor effect.Conclusion:This study demonstrates the synergistic antitumor effect of Nisin treatment in vitro to enhance tumor cell apoptosis and the potential value of Nisin as an adjunct therapy in the treatment of lymphoma.Key Words: Apoptosis, Burkitt’s lymphoma, Cell viability, Combination, Nisin, Rituximab