A prospective open-label randomized comparative study in Alzheimer’s disease between two commonly used drugs in coastal Indian population

Background: Currently, therapy for Alzheimer’s disease (AD) is only symptomatic. Only two classes of drugs are approved by the United States Food and Drug Administration. Our study aimed at comparing efficacy and safety of memantine and donepezil in moderate to severe AD patients.Methods: Totally, 22 patients with moderate to severe AD were randomized into the 2 arms of the study. The study was divided into an initial 4 weeks for determination of onset of efficacy and subsequent 28 weeks of the treatment phase. Onset of efficacy and response was defined as >20% and >50% reduction in the mean total score of functional dementia scale (FDS) and clinical global impression scale (CGIS) from baseline to the study end, respectively.Results: Onset of efficacy on FDS and CGIS was 16.7% (mean-time 61.25 days) and 80% (mean-time 36 days) with memantine and donepezil, respectively. Response was 89.3% and 40% with memantine and Donepezil, respectively. Total reduction in FDS and CGIS score of from baseline to the study end was 39.50, 40.00, and 25.60, 27.20 with memantine and donepezil, respectively. Tolerability was 86.33% and 20% with memantine and donepezil, respectively. Anorexia, muscle cramps, constipation, headache, and insomnia, were the common side-effects and self-limiting. Safety was 100% in both groups.Conclusions: Onset of efficacy was faster with donepezil seen at 2 weeks. Response, improvement in CGIS, FDS, and tolerability were better seen with memantine at 40 weeks. Thus, in similar clinical settings, memantine can be preferred

Angiopoietin-like protein 3, an emerging cardiometabolic therapy target with systemic and cell-autonomous functions

Angiopoietin like protein 3 (ANGPTL3) is best known for its function as an inhibitor of lipoprotein and endothelial lipases. Due to the capacity of genetic or pharmacologic ANGPTL3 suppression to markedly reduce circulating lipoproteins, and the documented cardioprotection upon such suppression, ANGPTL3 has become an emerging therapy target for which both antibody and antisense oligonucleotide (ASO) therapeutics are being clinically tested. While the antibody is relatively selective for circulating ANGPTL3, the ASO also depletes the intra-hepatocellular protein, and there is emerging evidence for cell-autonomous functions of ANGPTL3 in the liver. These include regulation of hepatocyte glucose and fatty acid uptake, insulin sensitivity, LDL/VLDL remnant uptake, VLDL assembly/secretion, polyunsaturated fatty acid (PUFA) and PUFA-derived lipid mediator content, and gene expression. In this review we elaborate on (i) why ANGPTL3 is considered one of the most promising new cardiometabolic therapy targets, and (ii) the present evidences for its intra-hepatocellular or cell-autonomous functions.Peer reviewe

Angiopoietin-like 8 (Angptl8) controls adipocyte lipolysis and phospholipid composition

Angiopoietin-like 8 (Angptl8) inhibits lipolysis in the circulation together with Angplt3 and controls post-prandial fat storage in white adipose tissue (WAT). It is strongly induced by insulin in vivo in WAT and in vitro in adipocytes. In this study we addressed the function of Angptl8 in adipocytes by its stable lentivirus-mediated knock-down in 3T3-L1 cells, followed by analyses of triglyceride (TG) storage, lipid droplet (LD) morphology, the cellular lipidome, lipolysis, and gene expression. Depletion of Angptl8 did not drastically affect the adipocyte differentiation of 3T3-L1 cells but resulted in a moderate (18-19%) reduction of stored TGs. The lipidome analysis revealed a reduction of alkyl-phosphatidylcholines (PCs) and phosphatidylethanolamine (PE) plasmalogens, as well as saturated PCs and PEs. Importantly, the Angptl8 depleted cells displayed enhanced lipolysis as measured by release of non-esterified fatty acids (NEFA5). Consistently, mRNAs encoding Angptl4 and Leptin, which facilitate lipolysis, as well as Cpt1a, Cpt1b, and Pgc-1 alpha involved in FA oxidation, were elevated. The Angptl8 mRNA itself was suppressed by pharmacologic treatments inducing lipolysis: stimulation with the beta-adrenergic agonist isoproterenol or with the adenylate cyclase activator forskolin. To conclude, knock-down of Angptl8 in adipocytes suggests that the protein acts to inhibit intracellular lipolysis, analogous to its activity in the circulation. Depletion of Angptl8 results in an altered cellular phospholipid composition. The findings identify Angptl8 as a central insulin-regulated controller of adipocyte lipid metabolism. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Comparative study of quality of life in breast cancer patients receiving two different chemotherapy regimens using European Organization for Research and Treatment of Cancer Quality of Questionnaire-Core 30 questionnaire module; for tolerability and safety

Background: Breast cancer is one of the most frequent occurring cancers in women and burgeoning worldwide. It is the second most common malignancy in India after carcinoma of the uterine cervix. In clinical trials, quality of life (QOL) outcome measurements is an important as endpoints with improving subjects physical, emotional, and social well-being.Methods: In this study, we were evaluated the comparison of the QOL in breast cancer patients on anthracycline-based regimen (six cycles of 5-fluorouracil, adriamycin, and cyclophosphamide [FAC] for a period of 18 weeks) and taxane-containing regimen (four cycles of adriamycin and cyclophosphamide [AC] followed by four cycles of paclitaxel [PTX] for a period of 24 weeks) using European Organization for Research and Treatment of Cancer Quality of Questionnaire-Core 30.Results: During first 3 months of therapy, both treatment groups exhibited a reduction in health-related QOL (HRQOL) with no clinically significant difference between them. The effect on HRQOL was less evident 3 weeks after completing chemotherapy with HRQOL of both groups returning to near baseline scores.Conclusions: Both treatment regimens (FAC and AC → PTX [AC followed by PTX]) were equally tolerated in patients

Phyllosticta citricarpa and sister species of global importance to Citrus.

Several Phyllosticta species are known as pathogens of Citrus spp., and are responsible for various disease symptoms including leaf and fruit spots. One of the most important species is P. citricarpa, which causes a foliar and fruit disease called citrus black spot. The Phyllosticta species occurring on citrus can most effectively be distinguished from P. citricarpa by means of multilocus DNA sequence data. Recent studies also demonstrated P. citricarpa to be heterothallic, and reported successful mating in the laboratory. Since the domestication of citrus, different clones of P. citricarpa have escaped Asia to other continents via trade routes, with obvious disease management consequences. This pathogen profile represents a comprehensive literature review of this pathogen and allied taxa associated with citrus, focusing on identification, distribution, genomics, epidemiology and disease management. This review also considers the knowledge emerging from seven genomes of Phyllosticta spp., demonstrating unknown aspects of these species, including their mating behaviour.TaxonomyPhyllosticta citricarpa (McAlpine) Aa, 1973. Kingdom Fungi, Phylum Ascomycota, Class Dothideomycetes, Order Botryosphaeriales, Family Phyllostictaceae, Genus Phyllosticta, Species citricarpa.Host rangeConfirmed on more than 12 Citrus species, Phyllosticta citricarpa has only been found on plant species in the Rutaceae.Disease symptomsP. citricarpa causes diverse symptoms such as hard spot, virulent spot, false melanose and freckle spot on fruit, and necrotic lesions on leaves and twigs.Useful websitesDOE Joint Genome Institute MycoCosm portals for the Phyllosticta capitalensis (https://genome.jgi.doe.gov/Phycap1), P. citriasiana (https://genome.jgi.doe.gov/Phycit1), P. citribraziliensis (https://genome.jgi.doe.gov/Phcit1), P. citrichinaensis (https://genome.jgi.doe.gov/Phcitr1), P. citricarpa (https://genome.jgi.doe.gov/Phycitr1, https://genome.jgi.doe.gov/Phycpc1), P. paracitricarpa (https://genome.jgi.doe.gov/Phy27169) genomes. All available Phyllosticta genomes on MycoCosm can be viewed at https://genome.jgi.doe.gov/Phyllosticta

The Anticancer Plant Triterpenoid, Avicin D, Regulates Glucocorticoid Receptor Signaling: Implications for Cellular Metabolism

Avicins, a family of apoptotic triterpene electrophiles, are known to regulate cellular metabolism and energy homeostasis, by targeting the mitochondria. Having evolved from “ancient hopanoids,” avicins bear a structural resemblance with glucocorticoids (GCs), which are the endogenous regulators of metabolism and energy balance. These structural and functional similarities prompted us to compare the mode of action of avicin D with dexamethasone (Dex), a prototypical GC. Using cold competition assay, we show that Avicin D competes with Dex for binding to the GC receptor (GR), leading to its nuclear translocation. In contrast to Dex, avicin-induced nuclear translocation of GR does not result in transcriptional activation of GC-dependent genes. Instead we observe a decrease in the expression of GC-dependent metabolic proteins such as PEPCK and FASN. However, like Dex, avicin D treatment does induce a transrepressive effect on the pro-inflammatory transcription factor NF-κB. While avicin's ability to inhibit NF-κB and its downstream targets appear to be GR-dependent, its pro-apoptotic effects were independent of GR expression. Using various deletion mutants of GR, we demonstrate the requirement of both the DNA and ligand binding domains of GR in mediating avicin D's transrepressive effects. Modeling of avicin-GR interaction revealed that avicin molecule binds only to the antagonist confirmation of GR. These findings suggest that avicin D has properties of being a selective GR modulator that separates transactivation from transrepression. Since the gene-activating properties of GR are mainly linked to its metabolic effects, and the negative interference with the activity of transcription factors to its anti-inflammatory and immune suppressive effects, the identification of such a dissociated GR ligand could have great potential for therapeutic use

Depletion of TM6SF2 disturbs membrane lipid composition and dynamics in HuH7 hepatoma cells.

A polymorphism of TM6SF2 associates with hepatic lipid accumulation and reduction of triacylglycerol (TAG) secretion, but the function of the encoded protein has remained enigmatic. We studied the effect of stable TM6SF2 knock-down on the lipid content and composition, mitochondrial fatty acid oxidation and organelle structure of HuH7 hepatoma cells. Knock-down of TM6SF2 resulted in intracellular accumulation of TAGs, cholesterol esters, phosphatidylcholine (PC) and phosphatidylethanolamine. In all of these lipid classes, polyunsaturated lipid species were significantly reduced while saturated and monounsaturated species increased their proportions. The PCs encountered relative and absolute arachidonic acid (AA, 20:4n-6) depletion, and AA was also reduced in the total cellular fatty acid pool. Synthesis and turnover of the hepatocellular glycerolipids was enhanced. The TM6SF2 knock-down cells secreted lipoprotein-like particles with a smaller diameter than in the controls, and more lysosome/endosome structures appeared in the knock-down cells. The mitochondrial capacity for palmitate oxidation was significantly reduced. These observations provide novel clues to TM6SF2 function and raise altered mebrane lipid composition and dynamics among the mechanism(s) by which the protein deficiency disturbs hepatic TAG secretion.Peer reviewe

Mathematical Modelling of the Relationship between Two Different Temperament Classifications: During the Covid-19 Pandemic

In medicine, it is well known that healthy individuals have different physical and mental characteristics. Ancient Indian medicine, Ayurveda and the Persian-Arabic traditional Unani medicine has two distinct approaches for the classification of human subjects according to their temperaments. The individual temperament is an important foundation for personalized medicine, which can help in the prevention and treatment of many diseases including COVID-19. This paper attempts to explore the relationship of the utmost important concepts of these systems called individual temperament named as Prakruti in Ayurveda and Mizaj in Unani practice using mathematical modelling. The results of mathematical modelling can be adopted expediently for the development of algorithms that can be applied in medical informatics. For this, a significant literature review has been carried out. Based on the previous researchers' reviews the essential parameters have been identified for making the relationship and hypothesis were framed. The mathematical modelling was adopted to propose the existence of the relationship between the parameters of such an ancient and rich medicine systems. The hypotheses are validated through the mathematic driven model. Doi: 10.28991/esj-2021-01258 Full Text: PD

Avicin D, a Plant Triterpenoid, Induces Cell Apoptosis by Recruitment of Fas and Downstream Signaling Molecules into Lipid Rafts

Avicins, a family of triterpene electrophiles originally identified as potent inhibitors of tumor cell growth, have been shown to be pleiotropic compounds that also possess antioxidant, anti-mutagenic, and anti-inflammatory activities. We previously showed that Jurkat cells, which express a high level of Fas, are very sensitive to treatment with avicins. Thus, we hypothesized that avicins may induce cell apoptosis by activation of the Fas pathway. By using a series of cell lines deficient in cell death receptors, we demonstrated that upon avicin D treatment, Fas translocates to the cholesterol- and sphingolipid-enriched membrane microdomains known as lipid rafts. In the lipid rafts, Fas interacts with Fas-associated death domain (FADD) and Caspase-8 to form death-inducing signaling complex (DISC) and thus mediates cell apoptosis. Interfering with lipid raft organization by using a cholesterol-depleting compound, methyl-β-cyclodextrin, not only prevents the clustering of Fas and its DISC complex but also reduces the sensitivity of the cells to avicin D. Avicin D activates Fas pathways independent of the association between extracellular Fas ligands and Fas receptors. A deficiency in Fas and its downstream signaling molecules leads to the resistance of the cells to avicin D treatment. Taken together, our results demonstrate that avicin D triggers the redistribution of Fas in the membrane lipid rafts, where Fas activates receptor-mediated cell death

MiR-107 inhibits CDK6 expression, differentiation, and lipid storage in human adipocytes

MicroRNA-107 (miR-107) plays a regulatory role in obesity and insulin resistance, but the mechanisms of its function in adipocytes have not been elucidated in detail. Here we show that overexpression of miR-107 in pre- and mature human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes attenuates differentiation and lipid accumulation. Our results suggest that miR-107 controls adipocyte differentiation via CDK6 and Notch signaling. CDK6 is a validated target of miR-107 and was downregulated upon miR-107 overexpression. Notch3, a signaling receptor involved in adipocyte differentiation, has been shown to decrease upon CDK6 depletion; Here Notch3 and its target Hes1 were downregulated by miR-107 overexpression. In mature adipocytes, miR-107 induces a triglyceride storage defect by impairing glucose uptake and triglyceride synthesis. To conclude, our data suggests that miR-107 has distinct functional roles in preadipocytes and mature adipocytes; Its elevated expression at these different stages of adipocytes may on one hand dampen adipogenesis, and on the other, promote ectopic fatty acid accumulation and reduced glucose tolerance.Peer reviewe