Comparative study of wound healing effect of topical Acacia catechu extract and silver sulfadiazine on excisional wound model in guinea pigs

Background: Impaired and aberrant wound healing imposes a huge financial burden and places an enormous drain in health care resources in the developed world and an insurmountable problem in the developing countries too. In this study, authors have compared the wound healing effect of topical application of Acacia catechu extract with silver sulfadiazine in excisional wound model in guinea pigs.Methods: Twelve guinea pigs were randomly divided into two groups (n=6). The wound healing was observed in excision model. The standard group is treated with silver sulfadiazine (group 1) and the test group with Acacia catechu extract (group 2). The mean wound size expressed in mm2 and the mean percentage of the wound healed was measured on day 0, 4, 8, 12, 16 and 19. Biopsy was done on day 21 for histopathological examination (HPE).Results: Statistical analysis was done by using unpaired t test for between the groups comparison and by using paired t test for within the group comparison. The mean percentage of the wound healed with-in the groups was found to be statistically highly significant (p value 0.05). A comparable increase in collagen content and granulation tissue was found on HPE in both the groups on day 21.Conclusions: Wound healing effect of the Acacia catechu extract is equal to and comparable with that of silver sulfadiazine

The Effect of Two Novel Anti-Inflammatory Drugs on Sensorimotor Gating and Microglial Activation in the Poly I:C Rodent Model of Schizophrenia

Antipsychotic medications remain the first line of treatment for individuals diagnosed with schizophrenia (SCZ). However, antipsychotic treatment is often not compliant due to dysregulation of both the central (CNS) and autonomic (ANS) nervous systems, resulting in debilitating dose-dependent side effects. Recent work suggests a new approach for treatment of SCZ that could potentially lower treatment doses and reduce side effects. Increased neuroinflammation has been shown in patients diagnosed with SCZ, particularly within the prefrontal cortex (PFC) and hippocampal (HPC) regions of the brain. Tumor necrosis factor-alpha (TNFa) is one of the key pro-inflammatory cytokines observed to be secreted during the inflammatory response. When TNFa is chronically secreted, resident CNS microglia become pro-inflammatory and toxic to the local environment. Microglial activation alongside of dopamine dysregulation thereby results in both the behavioral and neuroinflammatory aspects of SCZ. In this study, we hypothesized dietary administration of two different novel TNFamodulators (PD2024 – Experiment 1 and PD340 – Experiment 2) developed by our collaborators from P2D Bioscience, Inc. (Cincinnati, OH) would alleviate auditory sensorimotor gating deficits and reduce microglial cell activation caused by neonatal polyinosinic:polycytidylic acid (Poly I:C) treatment in rats, which is a validated rodent model of SCZ. Four groups (Experiment 1: Poly IC/PD2024, Poly IC/Control, Saline/PD2024, Saline/Control and Experiment 2: Poly IC/PD340, Poly IC/Control, Saline/PD340, Saline/Control) were intraperitoneally administered either Poly I:C (2 mg/kg) or saline (0.9% NaCl) from postnatal days 5-7. From P30-67, animals were placed on the experimental diet containing either low (10 mg/kg) or high (30 mg/kg) doses of either PD2024 or PD340, whereas the control animals remained on a normal diet. Prepulse inhibition (PPI) was used to test for auditory sensorimotor gating (behavioral abnormalities) in both adolescence (P44-46) and in adulthood (P60-66). At P67, immunohistochemistry (IHC) and confocal microscopy were used to evaluate and examine microglial cell activation using the Iba1-GFP antibody (neuroinflammatory abnormalities) in the PFC and HPC. Results revealed auditory sensorimotor gating deficits in Poly IC/Controls were alleviated in both adolescence and adulthood with either PD2024 or PD340. It was also found that both TNFa modulators significantly reduced microglial activation in the HPC, but not the PFC. The data supports our hypothesis that dietary administration of PD2024 or PD340 alleviates behavioral deficits and decreases neuroinflammation generated from the Poly I:C rodent model of SCZ. Therefore, an approach with a TNFa modulator alongside of current antipsychotic medications could treat both the behavioral and neuroinflammatory aspects of SCZ

Evaluation of adverse drug reactions of first line antiretroviral drugs in a tertiary care centre of Telangana, India

Background: The introduction of highly active anti-retroviral therapy (HAART) has led to a significant reduction in AIDS related morbidity and mortality. Most of the adverse drug reactions are preventable. So continuous evaluation will benefit Antiretroviral treatment that helped to achieve ultimate goal of making treatment safer and more effective to patients. The present study was designed to monitor and analyse the incidence, type and nature of adverse events to first line Antiretroviral drugs.Methods: A cross sectional observational study was conducted at Antiretroviral treatment center of Gandhi Hospital, Secunderabd, Telangana. The study was conducted over a period of 6 months involving all HIV patients. After initiation of 1st line regimen- tenofovir 300mg + lamivudine 300mg + efavirenz 600mg (TLE), patients were followed for any adverse event. Descriptive statistics was used for analysis of data.Results: Out of 453 studied, 47 patients developed adverse events. A total of 79 adverse events were reported. The assessment of total adverse drug reaction profile revealed cutaneous 44.30%, hematological 40.50%, renal 11.39%, gastrointestinal 3.79%. WHO-UMC causality assessment scale showed 76.5% and 23.4% Adverse events as probable and possible respectively. Hartwig and Siegel severity scale revealed 93.6%, 2.1% and 4.3% as mild, moderate and severe cases respectively.Conclusions: The TLE regimen found with lower adverse events in this study. The study focuses the importance of active adverse event monitoring to detect early toxicities and to support safe use of anti-retroviral treatment

Structural and kinetic analysis of an MsrA–MsrB fusion protein from Streptococcus pneumoniae

Methionine sulphoxide reductases (Msr) catalyse the reduction of oxidized methionine to methionine. These enzymes are divided into two classes, MsrA and MsrB, according to substrate specificity. Although most MsrA and MsrB exist as separate enzymes, in some bacteria these two enzymes are fused to form a single polypeptide (MsrAB). Here, we report the first crystal structure of MsrAB from Streptococcus pneumoniae (SpMsrAB) at 2.4 Å resolution. SpMsrAB consists of an N-terminal MsrA domain, a C-terminal MsrB domain and a linker. The linker is composed of 13 residues and contains one 310-helix and several hydrogen bonds interacting with both MsrA and MsrB domains. Interestingly, our structure includes the MsrB domain complexed with an SHMAEI hexa-peptide that is the N-terminal region of neighbouring MsrA domain. A kinetic analysis showed that the apparent Km of SpMsrAB for the R-form-substrate was 20-fold lower than that for the S-form substrate, indicating that the MsrB domain had a much higher affinity for the substrate than the MsrA domain. Our study reveals the first structure of the MsrAB by providing insights into the formation of a disulphide bridge in the MsrB, the structure of the linker region, and the distinct structural nature of active site of each MsrA and MsrB domain

Intersection between metabolic dysfunction, high fat diet consumption, and brain aging

Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high‐fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high‐fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age‐related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.Fil: Uranga, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bruce Keller, Annadora J.. State University of Louisiana; Estados UnidosFil: Morrison, Christopher D.. State University of Louisiana; Estados UnidosFil: Fernandez Kim, Sun Ok. State University of Louisiana; Estados UnidosFil: Ebenezer, Philip J.. State University of Louisiana; Estados UnidosFil: Zhang, Le. State University of Louisiana; Estados UnidosFil: Dasuri, Kalavathi. State University of Louisiana; Estados UnidosFil: Keller, Jeffrey N.. State University of Louisiana; Estados Unido

Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells

<p>Abstract</p> <p>Background</p> <p>The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood.</p> <p>Methods</p> <p>Proteasome activity, intracellular glutathione (GSH) and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR.</p> <p>Results</p> <p>At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH) and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death.</p> <p>Conclusion</p> <p>GSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis.</p

Loss of Caveolin-1 Accelerates Neurodegeneration and Aging

The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease.We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression.Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease

Location and Level of Etk Expression in Neurons Are Associated with Varied Severity of Traumatic Brain Injury

Much recent research effort in traumatic brain injury (TBI) has been devoted to the discovery of a reliable biomarker correlating with severity of injury. Currently, no consensus has been reached regarding a representative marker for traumatic brain injury. In this study, we explored the potential of epithelial/endothelial tyrosine kinase (Etk) as a novel marker for TBI.TBI was induced in Sprague Dawley (SD) rats by controlled cortical impact. Brain tissue samples were analyzed by Western blot, Q-PCR, and immunofluorescence staining using various markers including glial fibrillary acidic protein, and epithelial/endothelial tyrosine kinase (Etk). Results show increased Etk expression with increased number and severity of impacts. Expression increased 2.36 to 7-fold relative to trauma severity. Significant upregulation of Etk appeared at 1 hour after injury. The expression level of Etk was inversely correlated with distance from injury site. Etk and trauma/inflammation related markers increased post-TBI, while other tyrosine kinases did not.The observed correlation between Etk level and the number of impacts, the severity of impact, and the time course after impact, as well as its inverse correlation with distance away from injury site, support the potential of Etk as a possible indicator of trauma severity

Mitochondrial Superoxide Contributes to Blood Flow and Axonal Transport Deficits in the Tg2576 Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive decline in cognitive functions and the deposition of aggregated amyloid beta (Abeta) into senile plaques and the protein tau into tangles. In addition, a general state of oxidation has long been known to be a major hallmark of the disease. What is not known however, are the mechanisms by which oxidative stress contributes to the pathology of AD.In the current study, we used a mouse model of AD and genetically boosted its ability to quench free radicals of specific mitochondrial origin. We found that such manipulation conferred to the AD mice protection against vascular as well as neuronal deficits that typically affect them. We also found that the vascular deficits are improved via antioxidant modulation of the endothelial nitric oxide synthase, an enzyme primarily responsible for the production of nitric oxide, while neuronal deficits are improved via modulation of the phosphorylation status of the protein tau, which is a neuronal cytoskeletal stabilizer.These findings directly link free radicals of specific mitochondrial origin to AD-associated vascular and neuronal pathology