A Review On Omaveloxolone

Omaveloxolone is a semisynthetic triterpenoid used to treat friedreich’s ataxia. It is the second generation oleananetriterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties. It is currently used to test in medical trials for freidreich’s ataxia, a genetic, multi –organ disease involving mitochondrial dysfunction. It is a nuclear factor erythroid 2 related factor 2 (Nrf2) activator. It is reviewed under Food and Drug Administration and it has the potential to first approved treatment for friedreich’s ataxia. Omaveloxolone is not the cure for friedreich’s ataxia, it is the first agent targeting to reach NDA submission. It is the rational and potent therapy that is probably disease modifying in the treatment of friedreich’s ataxia. Omaveloxolone (RTA-408) is an Nrf2 activator, which decreases the susceptibility of cells through oxidative stress and it leads to cell death and tissue degradation. It is good tolerated not having any significant long term adverse effects. Treatment with RTA-408 remarkably improved in the neurological function, it is measured by modified Freidreich’s Ataxia Rating Scale

A prospective study of efficacy of ultrasound guided transversus abdominis plane block for postcesarean analgesia

Background: The ultrasound guided transversus abdominis plane (TAP) block which provides effective analgesia after lower abdominal surgeries including caesarean section. It is a simple and reliable technique. In this prospective, randomized double-blind study, we determined the efficacy of TAP block using 0.25% Bupivacaine and 0.9N Saline with respect to VAS for pain, postoperative Tramadol consumption and post-operative ondansetron usage.Methods: This study was conducted on 100 adult patients of ASA physical status I and II in the   age group of 18 to 40 years undergoing elective lower segment cesarean section under spinal anaesthesia. Study group received TAP block with 0.25% Bupivacaine and control group received 10 ml of 0.9N saline on each side. Patients were analyzed for postoperative pain by pain score (at rest, on movement, on cough) using VAS was recorded at 0, ½, 1, 2, 4, 6, 12 and 24 hours postoperatively. Need for rescue analgesia was assessed by time to first dose of Tramadol requirement and total dose of Tramadol over 24 hours of postoperative period. Ondansetron (4 mg i.v.) was administered whenever nausea score was more than 2 or the patient vomited. All the data was noted using uniform performs.Results: Patients received TAP block with 0.25% Bupivacaine had better pain scores at first hour of postoperative period during rest, cough and movement which was statistically significant (p0.001).Conclusions: TAP block using ultrasound provides substantial reduction in Tramadol consumption, time to first dose of rescue tramadol when compared with control group. This study reinforces the recommendation for TAP as a part of multimodal post-operative analgesic regimen

Mathematical approach to analysis of therapeutic properties of four important flowers mentioned in Siribhoovalaya- An ancient Indian multilingual manuscript

804-812Pushpayurveda is considered to be a unique branch of ayurvedic medicine which was first conceived by Jain monks as early as 9th century. Various ancient Indian manuscripts contain notes about the use of flowers for medicinal applications. The petals of flowers could be directly administered orally or can be made into the form of juice, decoction and or by mixing with other active ingredients. ‘Siribhoovalaya’, a multilingual literature written by Jain monk Kumudendu muni mentions the application of eight important flowers for the purification of mercury. In the present study, the antibacterial and antioxidant analysis of extracts of four of the eight mentioned flowers- Panasa, Padari, Kedige, Krishnapushpa was carried out. The results of antioxidant analysis were studied in detail with the help of modern mathematical software MATHEMATICA. Combination of all four flowers was found to be effective against B. cereus, S. aureus and S. marcescenes. The antioxidant activity was found reduced when a combination of the four flowers were used. The extract of Ketaki showed significantly higher antioxidant activity compared to all the other extracts. The whole study is carried out based on the standard tests of hypotheses, using ANOVA and the correlation effect is studied using regression models

Platelet-type 12-lipoxygenase deletion provokes a compensatory 12/15-lipoxygenase increase that exacerbates oxidative stress in mouse islet β cells

In type 1 diabetes, an autoimmune event increases oxidative stress in islet β cells, giving rise to cellular dysfunction and apoptosis. Lipoxygenases are enzymes that catalyze the oxygenation of polyunsaturated fatty acids that can form lipid metabolites involved in several biological functions, including oxidative stress. 12-Lipoxygenase and 12/15-lipoxygenase are related but distinct enzymes that are expressed in pancreatic islets, but their relative contributions to oxidative stress in these regions are still being elucidated. In this study, we used mice with global genetic deletion of the genes encoding 12-lipoxygenase (arachidonate 12-lipoxygenase, 12S type [Alox12]) or 12/15-lipoxygenase (Alox15) to compare the influence of each gene deletion on β cell function and survival in response to the β cell toxin streptozotocin. Alox12−/− mice exhibited greater impairment in glucose tolerance following streptozotocin exposure than WT mice, whereas Alox15−/− mice were protected against dysglycemia. These changes were accompanied by evidence of islet oxidative stress in Alox12−/− mice and reduced oxidative stress in Alox15−/− mice, consistent with alterations in the expression of the antioxidant response enzymes in islets from these mice. Additionally, islets from Alox12−/− mice displayed a compensatory increase in Alox15 gene expression, and treatment of these mice with the 12/15-lipoxygenase inhibitor ML-351 rescued the dysglycemic phenotype. Collectively, these results indicate that Alox12 loss activates a compensatory increase in Alox15 that sensitizes mouse β cells to oxidative stress

Mathematical approach to analysis of therapeutic properties of four important flowers mentioned in Siribhoovalaya- An ancient Indian multilingual manuscript

Pushpayurveda is considered to be a unique branch of ayurvedic medicine which was first conceived by Jain monks as early as 9th century. Various ancient Indian manuscripts contain notes about the use of flowers for medicinal applications. The petals of flowers could be directly administered orally or can be made into the form of juice, decoction and or by mixing with other active ingredients. ‘Siribhoovalaya’, a multilingual literature written by Jain monk Kumudendu muni mentions the application of eight important flowers for the purification of mercury. In the present study, the antibacterial and antioxidant analysis of extracts of four of the eight mentioned flowers- Panasa, Padari, Kedige, Krishnapushpa was carried out. The results of antioxidant analysis were studied in detail with the help of modern mathematical software MATHEMATICA. Combination of all four flowers was found to be effective against B. cereus, S. aureus and S. marcescenes. The antioxidant activity was found reduced when a combination of the four flowers were used. The extract of Ketaki showed significantly higher antioxidant activity compared to all the other extracts. The whole study is carried out based on the standard tests of hypotheses, using ANOVA and the correlation effect is studied using regression models

Higher cardiorespiratory fitness predicts long-term survival in patients with heart failure and preserved ejection fraction: the Henry Ford Exercise Testing (FIT) Project

Introduction: Higher cardiorespiratory fitness (CRF) is associated with improved exercise capacity and quality of life in heart failure with preserved ejection fraction (HFpEF), but there are no large studies evaluating the association of HFpEF, CRF, and long-term survival. We therefore aimed to determine the association between CRF and all-cause mortality, in patients with HFpEF. Material and methods: In the Henry Ford Exercise Testing (FIT) Project, 167 patients had baseline HFpEF, defined as a clinical diagnosis of heart failure with ejection fraction ≥ 50% on echocardiogram. The CRF was estimated from the peak workload (in METs) from a clinician-referred treadmill stress test and categorized as poor (1-4 METs), intermediate (5-6 METs), and moderate-high (≥ 7 METs). Additional analyses assessing the effect of HFpEF and CRF on mortality were also conducted, matching HFpEF patients to non-HFpEF patients using propensity scores. Results: Mean age was 64 ±13 years, with 55% women, and 46% Black. Over a median follow-up of 9.7 (5.2-18.9) years, there were 103 deaths. In fully adjusted models, moderate-high CRF was associated with 63% lower mortality risk (HR = 0.37, 95% CI: 0.18-0.73) compared to the poor-CRF group. In the propensity-matched cohort, HFpEF was associated with a HR of 2.3 (95% CI: 1.7-3.2) for mortality compared to non-HFpEF patients, which was attenuated to 1.8 (95% CI: 1.3-2.5) after adjusting for CRF. Conclusions: Moderate-high CRF in patients with HFpEF is associated with improved survival, and differences in CRF partly explain the intrinsic risk of HFpEF. Randomized trials of interventions aimed at improving CRF in HFpEF are needed

Phenylalanine-Rich Peptides Potently Bind ESAT6, a Virulence Determinant of Mycobacterium tuberculosis, and Concurrently Affect the Pathogen's Growth

BACKGROUND:The secretory proteins of Mycobacterium tuberculosis (M. tuberculosis) have been known to be involved in the virulence, pathogenesis as well as proliferation of the pathogen. Among this set, many proteins have been hypothesized to play a critical role at the genesis of the onset of infection, the primary site of which is invariably the human lung. METHODOLOGY/PRINCIPAL FINDINGS:During our efforts to isolate potential binding partners of key secretory proteins of M. tuberculosis from a human lung protein library, we isolated peptides that strongly bound the virulence determinant protein Esat6. All peptides were less than fifty amino acids in length and the binding was confirmed by in vivo as well as in vitro studies. Curiously, we found all three binders to be unusually rich in phenylalanine, with one of the three peptides a short fragment of the human cytochrome c oxidase-3 (Cox-3). The most accessible of the three binders, named Hcl1, was shown also to bind to the Mycobacterium smegmatis (M. smegmatis) Esat6 homologue. Expression of hcl1 in M. tuberculosis H37Rv led to considerable reduction in growth. Microarray analysis showed that Hcl1 affects a host of key cellular pathways in M. tuberculosis. In a macrophage infection model, the sets expressing hcl1 were shown to clear off M. tuberculosis in much greater numbers than those infected macrophages wherein the M. tuberculosis was not expressing the peptide. Transmission electron microscopy studies of hcl1 expressing M. tuberculosis showed prominent expulsion of cellular material into the matrix, hinting at cell wall damage. CONCLUSIONS/SIGNIFICANCE:While the debilitating effects of Hcl1 on M. tuberculosis are unrelated and not because of the peptide's binding to Esat6-as the latter is not an essential protein of M. tuberculosis-nonetheless, further studies with this peptide, as well as a closer inspection of the microarray data may shed important light on the suitability of such small phenylalanine-rich peptides as potential drug-like molecules against this pathogen

Dedifferentiation of Foetal CNS Stem Cells to Mesendoderm-Like Cells through an EMT Process

Tissue-specific stem cells are considered to have a limited differentiation potential. Recently, this notion was challenged by reports that showed a broader differentiation potential of neural stem cells, in vitro and in vivo, although the molecular mechanisms that regulate plasticity of neural stem cells are unknown. Here, we report that neural stem cells derived from mouse embryonic cortex respond to Lif and serum in vitro and undergo epithelial to mesenchymal transition (EMT)-mediated dedifferentiation process within 48 h, together with transient upregulation of pluripotency markers and, more notably, upregulation of mesendoderm genes, Brachyury (T) and Sox17. These induced putative mesendoderm cells were injected into early gastrulating chick embryos, which revealed that they integrated more efficiently into mesoderm and endoderm lineages compared to non-induced cells. We also found that TGFβ and Jak/Stat pathways are necessary but not sufficient for the induction of mesendodermal phenotype in neural stem cells. These results provide insights into the regulation of plasticity of neural stem cells through EMT. Dissecting the regulatory pathways involved in these processes may help to gain control over cell fate decisions

abd-A Regulation by the iab-8 Noncoding RNA

The homeotic genes in Drosophila melanogaster are aligned on the chromosome in the order of the body segments that they affect. The genes affecting the more posterior segments repress the more anterior genes. This posterior dominance rule must be qualified in the case of abdominal-A (abd-A) repression by Abdominal-B (Abd-B). Animals lacking Abd-B show ectopic expression of abd-A in the epidermis of the eighth abdominal segment, but not in the central nervous system. Repression in these neuronal cells is accomplished by a 92 kb noncoding RNA. This “iab-8 RNA” produces a micro RNA to repress abd-A, but also has a second, redundant repression mechanism that acts only “in cis.” Transcriptional interference with the abd-A promoter is the most likely mechanism

Analysis of Endocytic Pathways in Drosophila Cells Reveals a Conserved Role for GBF1 in Internalization via GEECs

In mammalian cells, endocytosis of the fluid phase and glycosylphosphatidylinositol-anchored proteins (GPI-APs) forms GEECs (GPI-AP enriched early endosomal compartments) via an Arf1- and Cdc42-mediated, dynamin independent mechanism. Here we use four different fluorescently labeled probes and several markers in combination with quantitative kinetic assays, RNA interference and high resolution imaging to delineate major endocytic routes in Drosophila cultured cells. We find that the hallmarks of the pinocytic GEEC pathway are conserved in Drosophila and identify garz, the fly ortholog of the GTP exchange factor GBF1, as a novel component of this pathway. Live confocal and TIRF imaging reveals that a fraction of GBF1 GFP dynamically associates with ABD RFP (a sensor for activated Arf1 present on nascent pinosomes). Correspondingly, a GTP exchange mutant of GBF1 has altered ABD RFP localization in the evanescent field and is impaired in fluid phase uptake. Furthermore, GBF1 activation is required for the GEEC pathway even in the presence of Brefeldin A, implying that, like Arf1, it has a role in endocytosis that is separable from its role in secretion