Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian ...systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional ...perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify ...associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose FG, HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.
We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h).
Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.
NaV1.9 regulates normal colonic afferent mechanosensation and is required for hypersensitivity to noxious inflammatory mediators and those derived from inflammatory bowel disease tissues.
Chronic ...visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9−/− mice. Deletion of NaV1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE2, and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9, and there was a rightward shift in stimulus–response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in NaV1.9−/− afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9−/− mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics.
The Arctic Andersen, J. K.; Andreassen, Liss M.; Baker, Emily H. ...
Bulletin of the American Meteorological Society,
08/2020, Letnik:
101, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown
to be highly efficient for discovery of genetic associations
. Despite the ...advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group
. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting ...the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear.
Using an
mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation.
FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of
and
family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes.
The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.
We introduce a new method for the purification of recombinant proteins expressed in Escherichia coli using self-cleaving elastin-like polypeptide (ELP) fusion tags without the need for affinity ...chromatography or proteolytic tag removal. Using this method we obtained high purity, activity and reasonable yields for ten diverse target proteins.
COPD in Never-Smokers: BOLD Australia Study Ivey, Marsha A; Smith, Sheree M; Benke, Geza ...
International journal of chronic obstructive pulmonary disease,
01/2024, Letnik:
19
Journal Article
Recenzirano
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Tobacco smoking is the major risk factor for COPD, and it is common for other risk factors in never-smokers to be overlooked. We examined the prevalence of COPD among never-smokers in Australia and ...identified associated risk factors.
We used data from the Australia Burden of Obstructive Lung Disease (BOLD) study, a cross-section of people aged ≥40 years from six sites. Participants completed interviews and post-bronchodilator spirometry. COPD was primarily defined as an FEV
/FVC ratio <0.70 and secondarily as the ratio less than the lower limit of normal (LLN).
The prevalence of COPD in the 1656 never-smokers who completed the study was 10.5% (95% CI: 9.1-12.1%) ratio<LLN 4.6%. The likelihood of having COPD increased with advancing age odds ratio (OR) 4.11 in those 60-69 years and OR 8.73 in those 70 years and older, having attained up to 12 years of education (OR 1.75) compared to those with more than 12 years, having a history of asthma (OR 2.30), childhood hospitalization due to breathing problems before age 10 years (OR 2.50), or having a family history of respiratory diseases (OR 2.70). Being overweight or obese was associated with reduced prevalence of COPD compared with being normal weight. In males and females, advanced age, a history of asthma, and childhood breathing problems before age 10 were factors that elevated the likelihood of COPD. However, in males, additional factors such as a higher body mass index and a family history of respiratory diseases also contributed to increased odds of COPD.
COPD was prevalent in this population of never-smokers aged 40 years and over. This finding highlights the significance of risk factors other than smoking in the development of COPD.
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