Individual-level preventive measures during the first wave of COVID-19 pandemic among Bangladeshi residents

COVID-19 causes mild to severe respiratory illness in humans. Government and non-government authorities along with telecommunication, print and electronic media undertook extensive advertising campaign regarding protective measures against COVID-19 to raise the public awareness. Therefore, this web-based cross-sectional study was conducted to evaluate peoples' responses towards COVID-19 during the first wave of COVID-19 in Bangladesh. We performed univariate and multivariate analyses to estimate the association between demographic characteristics, awareness, and individual preventive measures. The overall awareness level of the majority of the respondents (89%, n=920) was good, but the overall score for individual-level preventive measures during lockdown was poor to moderate. The relation between a good level of awareness and a higher level of educational status was found statistically significant (aOR 5.87, 95% CI: 1.58-21.86). Service holders were two times more likely to follow COVID-19 prevention practices than students (aOR 2.08, 95% CI: 1.24-3.51). Despite having adequate knowledge on awareness, many respondents were reluctant to follow preventive measures during the lockdown. The outcomes of this study highlight the requirement for stringent execution of preventative measures by law enforcement agencies to stop the transmission of the COVID-19 virus

Rev1 contributes to proper mitochondrial function via the PARP-NAD(+)-SIRT1-PGC1 alpha axis

Abstract Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress. Here, we show that Rev1-deficiency in mouse embryo fibroblasts or mouse liver tissue is associated with replicative stress and mitochondrial dysfunction. In addition, Rev1-deficiency is associated with high poly(ADP) ribose polymerase 1 (PARP1) activity, low endogenous NAD+, low expression of SIRT1 and PGC1α and low adenosine monophosphate (AMP)-activated kinase (AMPK) activity. We conclude that replication stress via Rev1-deficiency contributes to metabolic stress caused by compromized mitochondrial function via the PARP-NAD+-SIRT1-PGC1α axis

Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide

Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14–15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome‐wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late‐stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy‐lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.</p

Down syndrome is an oxidative phosphorylation disorder

Down syndrome is the most common genomic disorder of intellectual disability and is caused by trisomy of chromosome 21. Several genes in this chromosome repress mitochondrial biogenesis. The goal of this study was to evaluate whether early overexpression of these genes may cause a prenatal impairment of oxidative phosphorylation negatively affecting neurogenesis. Reduction in the mitochondrial energy production and a lower mitochondrial function have been reported in diverse tissues or cell types, and also at any age, including early fetuses, suggesting that a defect in oxidative phosphorylation is an early and general event in Down syndrome individuals. Moreover, many of the medical conditions associated with Down syndrome are also frequently found in patients with oxidative phosphorylation disease. Several drugs that enhance mitochondrial biogenesis are nowadays available and some of them have been already tested in mouse models of Down syndrome restoring neurogenesis and cognitive defects. Because neurogenesis relies on a correct mitochondrial function and critical periods of brain development occur mainly in the prenatal and early neonatal stages, therapeutic approaches intended to improve oxidative phosphorylation should be provided in these periods.Funding sources: This work was supported by grants from Instituto de Salud Carlos III [FIS-PI17/00021, FIS-PI17/00166]; Fundación Mutua Madrileña [MMA17/01]; Precipita-FECYT crowdfunding program [PR194]; Gobierno de Aragón [LMP135_18, Grupos Consolidados B33_17R] and FEDER 2014–2020 “Construyendo Europa desde Aragón”. CIBERER is an initiative of the ISCIII

ARIA 2016 : Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.Peer reviewe

Synthesis and bio-molecular study of (+)-N-Acetyl-α-amino acid dehydroabietylamine derivative for the selective therapy of hepatocellular carcinoma

BACKGROUND: The purpose of present work is to synthesize novel (+)-Dehydroabietylamine derivatives (DAAD) using N-acetyl-α-amino acid conjugates and determine its cytotoxic effects on hepatocellular carcinoma cells. METHODS: An analytical study was conducted to explore cytotoxic activity of DAAD on hepatocellular carcinoma cell lines. The cytotoxicity effect was recorded using sulforhodamine B technique. Cell cycle analysis was performed using Propidium Iodide (PI) staining. Based on cell morphology, anti growth activity and microarray findings of DAAD2 treatment, Comet assay, Annexin V/PI staining, Immunoperoxidase assay and western blots were performed accoringly. RESULTS: Hep3B cells were found to be the most sensitive with IC(50) of 2.00 ± 0.4 μM against (+)-N-(N-Acetyl-L-Cysteine)-dehydroabietylamine as DAAD2. In compliance to time dependent morphological changes of low cellular confluence, detachment and rounding of DAAD2 treated cells; noticeable changes in G(2)/M phase were recorded may be leading to cell cycle cessation. Up-regulation (5folds) of TUBA1A gene in Hep3B cells was determined in microarray experiments. Apoptotic mode of cell death was evaluated using standardized staining procedures including comet assay and annexin V/PI staining, Immuno-peroxidase assay. Using western blotting technique, caspase dependant apoptotic mode of cell death was recorded against Hep3B cell line. CONCLUSION: It is concluded that a novel DAAD2 with IC(50) values less than 8 μM can induce massive cell attenuation following caspase dependent apoptotic cell death in Hep3B cells. Moreover, the corelation study indicated that DAAD2 may have vital influence on cell prolifration properties. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2942-5) contains supplementary material, which is available to authorized users

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients

Background A growing body of evidence suggests that the accumulation of amyloid-β and tau (HPτ) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated with delayed extravascular clearance of metabolic waste. Whether also clearance of intracellular debris is affected in these patients needs to be examined. Hypothetically, defective extra- and intra-cellular clearance of metabolites may be instrumental in the neurodegeneration and dementia characterizing iNPH. This study explores whether iNPH is associated with altered mitochondria phenotype in neurons and astrocytes. Methods Cortical brain biopsies of 9 reference (REF) individuals and 30 iNPH patients were analyzed for subcellular distribution and morphology of mitochondria using transmission electron microscopy. In neuronal soma of REF and iNPH patients, we identified normal, pathological and clustered mitochondria, mitochondria-endoplasmic reticulum contact sites and autophagic vacuoles. We also differentiated normal and pathological mitochondria in pre- and post-synaptic nerve terminals, as well as in astrocytic endfoot processes towards vessels. Results We found a high prevalence of pathological mitochondria in neuronal soma and pre- and post-synaptic terminals, as well as increased mitochondrial clustering, and altered number of mitochondria-endoplasmic reticulum contact sites in iNPH. Non-fused autophagic vacuoles were more abundant in neuronal soma of iNPH patients, suggestive of cellular clearance failure. Moreover, the length of postsynaptic densities was reduced in iNPH, potentially related to reduced synaptic activity. In astrocytic endfoot processes, we also found increased number, area and area fraction of pathological mitochondria in iNPH patients. The proportion of pathological mitochondria correlated significantly with increasing degree of astrogliosis and reduced perivascular expression of aquaporin-4 (AQP4), assessed by light microscopy immunohistochemistry. Conclusion Our results provide evidence of mitochondrial pathology and signs of impaired cellular clearance in iNPH patients. The results indicate that iNPH is a neurodegenerative disease with close similarity to Alzheimer’s disease