Induced alteration of rat erythrocyte membrane with effect of pyrethroid based compounds

The effects of tetramethrin and prallethrin exposure on plasma total proteins, free amino acids, albumins, urea, urea nitrogen, uric acid, creatinine were tested. Serum SGOT, SGPT and lipid profile, antioxidants super oxide dismutase (SOD), catalase, GSH, G-Px, phospholipids, cholesterol, C/P ratio in membranes of erythrocyte and membrane fluidity were analyzed. The reason of the study were analyzed to examine the possessions of mosquito repellent pyrethroid (MRP) based compounds tetramethrin and prallethrin exposure on plasma profile, antioxidant status of erythrocyte membrane, membrane fluidity in male Wistar rats. We tested chronically for three months exposure every day (continuously for 8–10 h per day by inhalation) of tetramethrin and prallethrin markedly available (MRP) repellents treated on male Wistar rats. Our results confirmed that tetrarmethrin and prallethrin treatment effect of plasma profile alterations, and lipid homeostasis mechanism in Red Blood cells (RBCs). Tetramethrin and prallethrin treatment significantly increased in erythrocyte membrane phospholipids and decreased levels of cholesterol with no change of protein content, increased C/P ration levels. Inhalation of tetramethrin and prallethrin stimulate plasma biophysical and biochemical modify SGOT, SGPT, erythrocyte membrane cholesterol and phospholipid levels, individual phospholipids and membrane fluidity of exposure rats compared to controls.     

Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

Background

The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive.

Methods

30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch.

Results

66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model.

Conclusions

Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.     

Expression and inducibility of endosulfan metabolizing gene in Rhodococcus strain isolated from earthworm gut microflora for its application in bioremediation

The metabolizing potential of a bacterial strain Rhodococcus MTCC 6716, isolated from the gut of an Indian earthworm (Metaphire posthuma) was studied for endosulfan bioremediation. In the present work, the optimum conditions for the maximum growth, kinetic of endosulfan degradation, regression equation, half life and correlation coefficient were studied. Endosulfan induced alterations in the expression of mRNA and protein of specific endosulfan metabolizing marker gene (Esd) was studied. Maximum growth of bacteria was observed at pH 7.0, 30°C and 0.085 M sodium chloride concentration in a liquid culture medium. Endosulfan was degraded by Rhodococcus strain up to 97.23% within 15 days without producing toxic metabolite and with strong correlation coefficient (-0.728) and half life 5.99 days. Endosulfan degradation was mediated through gene(s) present in genomic DNA. Expression of marker gene was found endosulfan concentration dependent. The results suggest that this novel strain (Rhodococcus) may be utilized for bioremediation of endosulfan.     

Characterization of the Kallikrein-Kinin System Post Chemical Neuronal Injury: An In Vitro Biochemical and Neuroproteomics Assessment

Traumatic Brain Injury (TBI) is the result of a mechanical impact on the brain provoking mild, moderate or severe symptoms. It is acknowledged that TBI leads to apoptotic and necrotic cell death; however, the exact mechanism by which brain trauma leads to neural injury is not fully elucidated. Some studies have highlighted the pivotal role of the Kallikrein-Kinin System (KKS) in brain trauma but the results are still controversial and inconclusive. In this study, we investigated both the expression and the role of Bradykinin 1 and 2 receptors (B1R and B2R), in mediating neuronal injury under chemical neurotoxicity paradigm in PC12 cell lines. The neuronal cell line PC12 was treated with the apoptotic drug Staurosporine (STS) to induce cell death. Intracellular calcium release was evaluated by Fluo 4-AM staining and showed that inhibition of the B2R prevented calcium release following STS treatment. Differential analyses utilizing immunofluorescence, Western blot and Real-time Polymerase Chain Reaction revealed an upregulation of both bradykinin receptors occurring at 3h and 12h post-STS treatment, but with a higher induction of B2R compared to B1R. This implies that STS-mediated apoptosis in PC12 cells is mainly conducted through B2R and partly via B1R. Finally, a neuroproteomics approach was conducted to find relevant proteins associated to STS and KKS in PC12 cells. Neuroproteomics results confirmed the presence of an inflammatory response leading to cell death during apoptosis-mediated STS treatment; however, a “survival” capacity was shown following inhibition of B2R coupled with STS treatment. Our data suggest that B2R is a key player in the inflammatory pathway following STS-mediated apoptosis in PC12 cells and its inhibition may represent a potential therapeutic tool in TBI.     

Larvicidal activity of novel anthraquinone analogues and their molecular docking studies

To investigate the larvicidal activities of novel anthraquinones (1a-1k) against Culex quinquefasciatus mosquito larvae. Novel anthraquinones (1a-1k) derivatives were synthesis via condensation method. The compounds were confirmed through FT-IR spectroscopy, ¹H & ¹³C NMR spectrum, and mass spectral studies. The larvicidal activity of compound 1c was highly active LD₅₀ 20.92 µg/mL against Culex quinquefasciatus compared standard permethrin with LD₅₀ 25.49 µg/mL. Molecular docking studies were carried out for compound 1c against Odorant-binding protein of Culex quinquefasciatus. The compound 1c (−9.8 Kcal/mol) was a potent larvicide with more binding energy than control permethrin (−9.7 Kcal/mol). Therefore, compound (1c) may be more significant inhibitors of mosquito larvicidal.     

De Novo Mutations in Moderate or Severe Intellectual Disability

Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.     

Analysis of maslinic acid and gallic acid compounds as xanthine oxidase inhibitors in isoprenaline administered myocardial necrotic rats

ObjectiveThis research designed to analyze the in vivo and in silico ameliorative action of maslinic acid (MA) and gallic acid (GA) on reactive oxygen species generating enzyme xanthine oxidase (XO) in isoprenaline or isoproterenol (ISO) induced myocardial infarcted rats.MethodsAlbino Wistar rats were categorized into four groups with eight rats in each group. A dose of 15 mg/kg of MA and GA were pretreated to each MA and GA groups for seven days. A dose of 85 mg/kg of ISO administered to the ISO group along with MA and GA groups except normal group on two consecutive days of pretreatment. All animals sacrificed and the heart tissues were collected for the analysis of XO. The in silico molecular docking analysis of the compounds MA and GA with XO was analyzed by using Gold 3.0.1 software.ResultsXO enzyme levels were significantly increased in the heart homogenate of ISO administered rats when compared to normal rats. Pretreatment of MA and GA to ISO treated rats significantly brought XO enzyme to the near normal levels which indicate the protective action of MA and GA against myocardial necrosis. The in vivo results were further supported by the in silico molecular docking study which revealed the inhibition of XO enzyme by the formation of enzyme and ligand complex with the compounds MA and GA.ConclusionMA and GA compounds manifested the ameliorative effect against ISO administrated myocardial necrosis by inhibiting the free radical generating enzyme XO which is evidenced by both in vivo and in silico studies.     

Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors

There is an urgent need for more efficient therapies for people infected with hepatitis C virus (HCV). HCV NS3 protease inhibitors have shown proof-of-concept in clinical trials, which make the virally encoded NS3 protease an attractive drug target. Product-based NS3 protease inhibitors comprising a P1 C-terminal carboxylic acid have shown to be effective and we were interested in finding alternatives to this crucial carboxylic acid group. Thus, a series of diverse P1 functional groups with different acidity and with possibilities to form a similar, or an even more powerful, hydrogen bond network as compared to the carboxylic acid were synthesized and incorporated into potential inhibitors of the NS3 protease. Biochemical evaluation of the inhibitors was performed in both enzyme and cell-based assays. Several non-acidic C-terminal groups, such as amides and hydrazides, were evaluated but failed to produce inhibitors more potent than the corresponding carboxylic acid inhibitor. The tetrazole moiety, although of similar acidity to a carboxylic acid, provided an inhibitor with mediocre potencies in both assays. However, the acyl cyanamide and the acyl sulfinamide groups rendered compounds with low nanomolar inhibitory potencies and were more potent than the corresponding carboxylic acid inhibitor in the enzymatic assay. Additionally, results from a pH-study suggest that the P(1) C-terminal of the inhibitors comprising a carboxylic acid, an acyl sulfonamide or an acyl cyanamide group binds in a similar mode in the active site of the NS3 protease.     

Reactive Oxygen Species-Mediated DNA Damage and Apoptosis in Human Skin Epidermal Cells After Exposure to Nickel Nanoparticles

Nickel nanoparticles (NiNPs) are increasingly used in various applications due to their unique properties. However, there is little information concerning the toxicity of NiNPs in the human skin cell (A431). The present study was designed to investigate the cytotoxicity, apoptosis, and DNA damage due to NiNPs in A431 cells. A cellular proliferative capacity test showed that NiNPs induce significant cytotoxicity in a dose- and time-dependent manner. NiNPs were also found to induce oxidative stress evidenced by the generation of reactive oxygen species (ROS) and depletion of glutathione (GSH). Further, co-treatment with the antioxidant N-acetylcysteine (NAC) mitigated the ROS generation due to NiNPs, suggesting the potential mechanism of oxidative stress. NiNPs also induced significant elevation of lipid peroxidation, catalase, and superoxide dismutase and caspase-3 activity in A431 cells. In addition, NAC suppressed NiNP-induced caspase-3 activity. DNA fragmentation analysis using the comet assay showed that the NiNPs cause genotoxicity in a dose- and time-dependent manner. Therefore, the study points out the capability of the NiNPs to induce oxidative stress resulting in apoptosis and genotoxicity. This study warrants more careful assessment of NiNPs before their industrial applications.