The mitochondrial coenzyme Q junction and complex III : biochemistry and pathophysiology

Coenzyme Q (CoQ, ubiquinone) is the electron-carrying lipid in the mitochondrial electron transport system (ETS). In mammals, it serves as the electron acceptor for nine mitochondrial inner membrane dehydrogenases. These include the NADH dehydrogenase (complex I, CI) and succinate dehydrogenase (complex II, CII) but also several others that are often omitted in the context of respiratory enzymes: dihydroorotate dehydrogenase, choline dehydrogenase, electron-transferring flavoprotein dehydrogenase, mitochondrial glycerol-3-phosphate dehydrogenase, proline dehydrogenases 1 and 2, and sulfide:quinone oxidoreductase. The metabolic pathways these enzymes are involved in range from amino acid and fatty acid oxidation to nucleotide biosynthesis, methylation, and hydrogen sulfide detoxification, among many others. The CoQ-linked metabolism depends on CoQ reoxidation by the mitochondrial complex III (cytochrome bc(1) complex, CIII). However, the literature is surprisingly limited as for the role of the CoQ-linked metabolism in the pathogenesis of human diseases of oxidative phosphorylation (OXPHOS), in which the CoQ homeostasis is directly or indirectly affected. In this review, we give an introduction to CIII function, and an overview of the pathological consequences of CIII dysfunction in humans and mice and of the CoQ-dependent metabolic processes potentially affected in these pathological states. Finally, we discuss some experimental tools to dissect the various aspects of compromised CoQ oxidation.Peer reviewe

Pharmacological activities of pyrazolone derivatives

Pyrazoline is a five member heterocyclic ring which is a versatile lead compound for designing potent bioactive agents. The review of the literature shows that the pyrazoline derivatives are quite stable and has inspired the chemists to synthesize the new pyrazoline derivatives. The past studies of pyrazoline derivative revealed that they are useful in pharmaceutical and agrochemical research. Pyrazoline derivatives display various pharmacological activities such as antitumor, antitubercular, antimicrobial, antibacterial, anti-inflammatory and antioxidant etc. and the pharmacological activities of different synthesized compound are reviewed in the present article

A short glimpse on promising pharmacological effects of Begenia ciliata

Bergenia ciliata is a potent indigenous folk medicine that has been proved fruitful in the treatment of various adverse conditions of the body. The major chemical constituents of plant include tannic acid, gallic acid, glucose, metarbin, albumen, bergenin, (+)-catechin, gallicin. Bergenia ciliata was subjected to bioactivity analysis. The plant has antitussive, antiulcer, antioxidant, antibacterial, hypoglycemic, toxicological activity. It was observed that root and leaves extract were promising as antifungal agent. The root and leaves extract were effective against Microsporum canis, Pleuroetus oustreatus and Candida albicans.   All the extracts except chloroform extract of root and leaves of Bergenia ciliata were found to possess hypoglycemic activity in Streptozotocin (STZ) treated rats. The methanolic extract exhibited significant anti-tussive activity in a dose-dependent manner. B. ciliata bear potent anti-neoplastic activities that may have prospective clinical use as precursor for preventive medicine. Methanolic and aqueous B. ciliata rhizome extracts were found to possess antioxidant activity, including reducing power, free radical scavenging activity and lipid peroxidation inhibition potential. Bergenia ciliata extracts exhibit a narrow spectrum antibacterial activity. The results obtained thus suggest that extracts of B. ciliata have promising therapeutic potential and could be considered as potential source for drug development by pharmaceutical industries

A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye and inhibitor-resistant high-fidelity DNA polymerase

Deoxyribonucleoside triphosphates (dNTPs) are vital for the biosynthesis and repair of DNA. Their cellular concentration peaks during the S phase of the cell cycle. In non-proliferating cells, dNTP concentrations are low, making their reliable quantification from tissue samples of heterogeneous cellular composition challenging. Partly because of this, the current knowledge related to the regulation of and disturbances in cellular dNTP concentrations derive mostly from cell culture experiments with little corroboration at the tissue or organismal level. Here, we fill the methodological gap by presenting a simple non-radioactive microplate assay for the quantification of dNTPs with a minimum requirement of 4-12 mg of biopsy material. In contrast to published assays, this assay is based on long synthetic single-stranded DNA templates (50-200 nucleotides), an inhibitor-resistant high-fidelity DNA polymerase, and the double-stranded-DNA-binding EvaGreen dye. The assay quantified reliably less than 50 fmol of each of the four dNTPs and discriminated well against ribonucleotides. Additionally, thermostable RNAse HII-mediated nicking of the reaction products and a subsequent shift in their melting temperature allowed near-complete elimination of the interfering ribonucleotide signal, if present. Importantly, the assay allowed measurement of minute dNTP concentrations in mouse liver, heart and skeletal muscle.Peer reviewe

Nanotechnology platforms in Parkinson’s Disease

Parkinson’s disease (PD) remains a serious concern due to its effects on the quality of life of patients and its socioeconomic burden to society. Present day management of PD has limitations in both diagnosis and treatment. Nanotechnology may provide smart solutions to this problem. The present review highlights the recent advancements in the development of nanotechnology platforms for PD. The review focuses on the use of such platforms in diagnostics, treatments, deep brain stimulation, neurosurgery and other modalities of management and the role of nanotechnology in each of these fields. The review also sheds light on the translation of technologies from labs to clinics and the essential advantages as well as concerns that accompany the translation

Who funded the research behind the Oxford-AstraZeneca COVID-19 vaccine?

Objectives The Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1 nCoV-19, Vaxzevira or Covishield) builds on two decades of research and development (R&D) into chimpanzee adenovirus-vectored vaccine (ChAdOx) technology at the University of Oxford. This study aimed to approximate the funding for the R&D of ChAdOx and the Oxford-AstraZeneca vaccine and to assess the transparency of funding reporting mechanisms. Methods We conducted a scoping review and publication history analysis of the principal investigators to reconstruct R&D funding the ChAdOx technology. We matched award numbers with publicly accessible grant databases. We filed freedom of information (FOI) requests to the University of Oxford for the disclosure of all grants for ChAdOx R&D. Results We identified 100 peer-reviewed articles relevant to ChAdOx technology published between January 2002 and October 2020, extracting 577 mentions of funding bodies from acknowledgements. Government funders from overseas (including the European Union) were mentioned 158 times (27.4%), the UK government 147 (25.5%) and charitable funders 138 (23.9%). Grant award numbers were identified for 215 (37.3%) mentions; amounts were publicly available for 121 (21.0%). Based on the FOIs, until December 2019, the biggest funders of ChAdOx R&D were the European Commission (34.0%), Wellcome Trust (20.4%) and Coalition for Epidemic Preparedness Innovations (17.5%). Since January 2020, the UK government contributed 95.5% of funding identified. The total identified R&D funding was £104 226 076 reported in the FOIs and £228 466 771 reconstructed from the literature search. Conclusion Our study approximates that public and charitable financing accounted for 97%-99% of identifiable funding for the ChAdOx vaccine technology research at the University of Oxford underlying the Oxford-AstraZeneca vaccine until autumn 2020. We encountered a lack of transparency in research funding reporting

Hospital mortality and resource implications of hospitalisation with COVID-19 in London, UK: a prospective cohort study

Background. Coronavirus disease 2019 (COVID-19) had a significant impact on the National Health Service in the United Kingdom (UK), with over 35 000 cases reported in London by July 30, 2020. Detailed hospital-level information on patient characteristics, outcomes, and capacity strain is currently scarce but would guide clinical decision-making and inform prioritisation and planning. Methods. We aimed to determine factors associated with hospital mortality and describe hospital and ICU strain by conducting a prospective cohort study at a tertiary academic centre in London, UK. We included adult patients admitted to the hospital with laboratory-confirmed COVID-19 and followed them up until hospital discharge or 30 days. Baseline factors that are associated with hospital mortality were identified via semiparametric and parametric survival analyses. Results. Our study included 429 patients: 18% of them were admitted to the ICU, 52% met criteria for ICU outreach team activation, and 61% had treatment limitations placed during their admission. Hospital mortality was 26% and ICU mortality was 34%. Hospital mortality was independently associated with increasing age, male sex, history of chronic kidney disease, increasing baseline C-reactive protein level, and dyspnoea at presentation. COVID-19 resulted in substantial ICU and hospital strain, with up to 9 daily ICU admissions and 41 daily hospital admissions, to a peak census of 80 infected patients admitted in the ICU and 250 in the hospital. Management of such a surge required extensive reorganisation of critical care services with expansion of ICU capacity from 69 to 129 beds, redeployment of staff from other hospital areas, and coordinated hospital-level effort. Conclusions. COVID-19 is associated with a high burden of mortality for patients treated on the ward and the ICU and required substantial reconfiguration of critical care services. This has significant implications for planning and resource utilisation

Ethnicity-specific BMI cutoffs for obesity based on type 2 diabetes risk in England: a population-based cohort study.

BACKGROUND: National and global recommendations for BMI cutoffs to trigger action to prevent obesity-related complications like type 2 diabetes among non-White populations are questionable. We aimed to prospectively identify ethnicity-specific BMI cutoffs for obesity based on the risk of type 2 diabetes that are risk-equivalent to the BMI cutoff for obesity among White populations (≥30 kg/m2). METHODS: In this population-based cohort study, we used electronic health records across primary care (Clinical Practice Research Datalink) linked to secondary care records (Hospital Episodes Statistics) from a network of general practitioner practices in England. Eligible participants were aged 18 years or older, without any past or current diagnosis of type 2 diabetes, had a BMI of 15·0-50·0 kg/m2 and complete ethnicity data, were registered with a general practitioner practice in England at any point between Sept 1, 1990, and Dec 1, 2018, and had at least 1 year of follow-up data. Patients with type 2 diabetes were identified by use of a CALIBER phenotyping algorithm. Self-reported ethnicity was collapsed into five main categories. Age-adjusted and sex-adjusted negative binomial regression models, with fractional polynomials for BMI, were fitted with incident type 2 diabetes and ethnicity data. FINDINGS: 1 472 819 people were included in our study, of whom 1 333 816 (90·6%) were White, 75 956 (5·2%) were south Asian, 49 349 (3·4%) were Black, 10 934 (0·7%) were Chinese, and 2764 (0·2%) were Arab. After a median follow-up of 6·5 years (IQR 3·2-11·2), 97 823 (6·6%) of 1 472 819 individuals were diagnosed with type 2 diabetes. For the equivalent age-adjusted and sex-adjusted incidence of type 2 diabetes at a BMI of 30·0 kg/m2 in White populations, the BMI cutoffs were 23·9 kg/m2 (95% CI 23·6-24·0) in south Asian populations, 28·1 kg/m2 (28·0-28·4) in Black populations, 26·9 kg/m2 (26·7-27·2) in Chinese populations, and 26·6 kg/m2 (26·5-27·0) in Arab populations. INTERPRETATION: Revisions of ethnicity-specific BMI cutoffs are needed to ensure that minority ethnic populations are provided with appropriate clinical surveillance to optimise the prevention, early diagnosis, and timely management of type 2 diabetes. FUNDING: National Institute for Health Research