Labdane diterpenes protect against anoxia/reperfusion injury in cardiomyocytes: involvement of AKT activation

Several labdane diterpenes exert anti-inflammatory and cytoprotective actions; therefore, we have investigated whether these molecules protect cardiomyocytes in an anoxia/reperfusion (A/R) model, establishing the molecular mechanisms involved in the process. The cardioprotective activity of three diterpenes (T1, T2 and T3) was studied in the H9c2 cell line and in isolated rat cardiomyocyte subjected to A/R injury. In both cases, treatment with diterpenes T1 and T2 protected from A/R-induced apoptosis, as deduced by a decrease in the percentage of apoptotic and caspase-3 active positive cells, a decrease in the Bcl-2/Bax ratio and an increase in the expression of antiapoptotic proteins. Analysis of cell survival signaling pathways showed that diterpenes T1 and T2 added after A/R increased phospho-AKT and phospho-ERK 1/2 levels. These cardioprotective effects were lost when AKT activity was pharmacologically inhibited. Moreover, the labdane-induced cardioprotection involves activation of AMPK, suggesting a role for energy homeostasis in their mechanism of action. Labdane diterpenes (T1 and T2) also exerted cardioprotective effects against A/R-induced injury in isolated cardiomyocytes and the mechanisms involved activation of specific survival signals (PI3K/AKT pathways, ERK1/2 and AMPK) and inhibition of apoptosis

Parental breeding age effects on descendants' longevity interact over 2 generations in matrilines and patrilines

Individuals within populations vary enormously in mortality risk and longevity, but the causes of this variation remain poorly understood. A potentially important and phylogenetically widespread source of such variation is maternal age at breeding, which typically has negative effects on offspring longevity. Here, we show that paternal age can affect offspring longevity as strongly as maternal age does and that breeding age effects can interact over 2 generations in both matrilines and patrilines. We manipulated maternal and paternal ages at breeding over 2 generations in the neriid fly Telostylinus angusticollis. To determine whether breeding age effects can be modulated by the environment, we also manipulated larval diet and male competitive environment in the first generation. We found separate and interactive effects of parental and grand-parental ages at breeding on descendants' mortality rate and life span in both matrilines and patrilines. These breeding age effects were not modulated by grand-parental larval diet quality or competitive environment. Our findings suggest that variation in maternal and paternal ages at breeding could contribute substantially to intrapopulation variation in mortality and longevity

Multi-center feasibility study evaluating recruitment, variability in risk factors and biomarkers for a diet and cancer cohort in India

<p>Abstract</p> <p>Background</p> <p>India's population exhibits diverse dietary habits and chronic disease patterns. Nutritional epidemiologic studies in India are primarily of cross-sectional or case-control design and subject to biases, including differential recall of past diet. The aim of this feasibility study was to evaluate whether a diet-focused cohort study of cancer could be established in India, providing insight into potentially unique diet and lifestyle exposures.</p> <p>Methods</p> <p>Field staff contacted 7,064 households within three regions of India (New Delhi, Mumbai, and Trivandrum) and found 4,671 eligible adults aged 35-69 years. Participants completed interviewer-administered questionnaires (demographic, diet history, physical activity, medical/reproductive history, tobacco/alcohol use, and occupational history), and staff collected biological samples (blood, urine, and toenail clippings), anthropometric measurements (weight, standing and sitting height; waist, hip, and thigh circumference; triceps, sub-scapula and supra-patella skin fold), and blood pressure measurements.</p> <p>Results</p> <p>Eighty-eight percent of eligible subjects completed all questionnaires and 67% provided biological samples. Unique protein sources by region were fish in Trivandrum, dairy in New Delhi, and pulses (legumes) in Mumbai. Consumption of meat, alcohol, fast food, and soft drinks was scarce in all three regions. A large percentage of the participants were centrally obese and had elevated blood glucose levels. New Delhi participants were also the least physically active and had elevated lipids levels, suggesting a high prevalence of metabolic syndrome.</p> <p>Conclusions</p> <p>A high percentage of participants complied with study procedures including biological sample collection. Epidemiologic expertise and sufficient infrastructure exists at these three sites in India to successfully carry out a modest sized population-based study; however, we identified some potential problems in conducting a cohort study, such as limited number of facilities to handle biological samples.</p

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

GENCODE: reference annotation for the human and mouse genomes in 2023

Data availability: No new data were generated or analysed in support of this research.Copyright © The Author(s) 2022. GENCODE produces high quality gene and transcript annotation for the human and mouse genomes. All GENCODE annotation is supported by experimental data and serves as a reference for genome biology and clinical genomics. The GENCODE consortium generates targeted experimental data, develops bioinformatic tools and carries out analyses that, along with externally produced data and methods, support the identification and annotation of transcript structures and the determination of their function. Here, we present an update on the annotation of human and mouse genes, including developments in the tools, data, analyses and major collaborations which underpin this progress. For example, we report the creation of a set of non-canonical ORFs identified in GENCODE transcripts, the LRGASP collaboration to assess the use of long transcriptomic data to build transcript models, the progress in collaborations with RefSeq and UniProt to increase convergence in the annotation of human and mouse protein-coding genes, the propagation of GENCODE across the human pan-genome and the development of new tools to support annotation of regulatory features by GENCODE. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.National Human Genome Research Institute of the National Institutes of Health [U41HG007234, R01HG004037]; Wellcome Trust [WT222155/Z/20/Z]; European Molecular Biology Laboratory. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding for open access charge: National Institutes of Health

(188)Rhenium-induced cell death and apoptosis in a panel of tumor cell lines

Assessment of "in vitro" tumor growth inhibition and radiobiological effects, such as apoptosis, have been evaluated in human neoplastic cells of different histotypes (H460 lung cancer cells, U87 glioblastoma, LnCaP prostate tumor cells) treated using solutions of (188)Rhenium-perrhenate. The MTT assay, which measures mitochondrial metabolism in the entire cell culture is a recognized test for cytotoxicity and was used in cells exposed 48-72 It to specific activities ranged from 37 to 148 GBq/1. Whereas H460 and LnCaP were particularly sensitive to treatment, U87 glioblastoma cells behaved as radioresistant ones. However, evaluation of Re-188-induced apoptosis indicated that this kind of cell death contributed only marginally to the reduction in cell viability of H460 and LNCaP lines, suggesting the existence of protective mechanisms against apoptosis. In this respect, the membrane receptor, CD44, whose expression is dysregulated in most malignant cell types has proven to alter the response of cancer cells to apoptotic stimuli, including ionizing radiation. Cell samples decorated with a FITC-labelled CD44 antibody indicated, that in H460 and U87 cells the CD44(+) correlated well with an apoptosis-resistant response. Conversely, LnCap cells proven as CD44(-) did not display however sensitivity to radio-induced apoptosis. (c) 2006 Published by Elsevier B.V