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IScience Jun 2024The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited...
The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 inhibitor . We initially isolated bioactive from cockroach () extracts and then developed the synthesis of this compound Further investigation revealed that impaired SIRT7 enzymatic activities through occupation of the NAD binding pocket. attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal cancer cells and exhibited a synergistic anticancer effect when used in combination with etoposide. Overall, our study not only identified as a selective SIRT7 inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.
PubMed: 38947512
DOI: 10.1016/j.isci.2024.110014 -
Research Square Jun 2024is an obligate intracellular 𝛼-proteobacterium which commonly infects arthropods and filarial nematodes. Different strains of are capable of a wide range of...
is an obligate intracellular 𝛼-proteobacterium which commonly infects arthropods and filarial nematodes. Different strains of are capable of a wide range of regulatory manipulations in many hosts and modulate host cellular differentiation to influence host reproduction. The genetic basis for the majority of these phenotypes is unknown. The Wil strain from the neotropical fruit fly, , exhibits a remarkably high affinity for host germline-derived cells relative to the soma. This trait could be leveraged for understanding how influences the host germline and for controlling host populations in the field. To further the use of this strain in biological and biomedical research, we sequenced the genome of the Wil strain isolated from host cell culture cells. Here, we present the first high quality nanopore assembly of Wil, the endosymbiont of . Our assembly resulted in a circular genome of 1.27 Mb with a BUSCO completeness score of 99.7%. Consistent with other insect-associated strains, comparative genomic analysis revealed that wWil has a highly mosaic genome relative to the closely related wMel strain from .
PubMed: 38946980
DOI: 10.21203/rs.3.rs-4510571/v1 -
Journal of Nutritional Science and... 2024Niacin is a cofactor in many biological reactions related to energy metabolism, redox reactions, DNA repair and longevity. Although it has been considered that...
Niacin is a cofactor in many biological reactions related to energy metabolism, redox reactions, DNA repair and longevity. Although it has been considered that increasing energy expenditure increases NAD consumption, little study has directly demonstrated the effect of exercise on niacin nutritional status. We have recently established the niacin insufficient model mice using kynurenine 3-monooxygenase knock out (KMO) mice with niacin-limited diet, which lack the de novo NAD synthesis pathway from tryptophan. To evaluate the effects of chronic endurance exercise on niacin nutritional status, 4 wk old KMO mice were fed 4 or 30 mg/kg nicotinic acid containing diets, and forced to swim in a running water pool every other day for 35 d. The swim-exercised mice fed 4 mg/kg nicotinic acid diet showed lower body weight gain and niacin nutritional markers such as liver and blood NAD, and urine nicotinamide metabolites than the sedentary mice. These animals did not show any difference in the NAD synthesis, NAD salvage and nicotinamide catabolic pathways. Chronic endurance exercise failed to affect any indices in the mice fed the 30 mg/kg nicotinic acid diet. When the diet was exchanged the 4 mg/kg for 30 mg/kg nicotinic acid diet to the mice showed chronic endurance exercise-induced growth retardation, their body weight rapidly increased. These results show that chronic endurance exercise impairs niacin nutritional status in the niacin insufficient mice, and enough niacin intake can prevent this impairment. Our findings also suggest that chronic endurance exercise increases niacin requirement by increase of NAD consumption.
Topics: Animals; Niacin; Nutritional Status; Physical Conditioning, Animal; Male; Mice; Mice, Knockout; Physical Endurance; Liver; NAD; Swimming; Weight Gain; Diet; Body Weight; Mice, Inbred C57BL; Niacinamide
PubMed: 38945883
DOI: 10.3177/jnsv.70.185 -
Experimental Gerontology Jun 2024Ames dwarf mice (df/df) display delayed aging relative to their normal (N) siblings, living approximately 40-60 % longer. As such, investigating the mechanisms that...
Ames dwarf mice (df/df) display delayed aging relative to their normal (N) siblings, living approximately 40-60 % longer. As such, investigating the mechanisms that enable these organisms to have extended lifespan is useful for the development of interventions to slow aging and deter age-related disease. Nonalcoholic fatty liver disease (NAFLD) is a condition that is characterized by the accumulation of excess adipose tissue in the liver. Previous studies highlight the potential of calorie restriction (CR) in promoting longevity, but little is known about its effects on the biomolecular processes that govern NAFLD. In this study, we examined the role of 6-month CR on genes regulating lipid metabolism in the livers of long-living df/df mice and their N littermates. Importantly, our findings showed significant downregulation of miR-34a-5p in N-CR mice and df/df mice regardless of dietary regimen. Alongside, our RT-PCR results indicated that downregulation of miR-34a-5p is correlated with the expression of metabolism-associated mRNAs involved in modulating the processes of de novo lipogenesis (DNL), fatty acid oxidation (FAO), very-low density lipoprotein transport (VLDL-T), and reverse cholesterol transport (RCT). To further verify the role of miR-34a-5p in regulating metabolic processes, we transfected the human liver cancer (HepG2) cell line with miR-34a mimic, and studied its effect on direct targets Sirt1, Ampk, and Ppara as well as downstream lipid transport regulating genes. Our findings suggest that CR and df/df life extending mutation are robust drivers of the miR-34a-5p signaling pathway and prevent the pathogenesis of age-related diseases by improving overall lipid homeostasis.
PubMed: 38945410
DOI: 10.1016/j.exger.2024.112506 -
Plant Physiology and Biochemistry : PPB Jun 2024The phytohormones cytokinins are essential mediators of developmental and environmental signaling, primarily during cell division and endophytic interactions, among...
The phytohormones cytokinins are essential mediators of developmental and environmental signaling, primarily during cell division and endophytic interactions, among other processes. Considering the limited understanding of the regulatory mechanisms that affect the growth and bioactivity of the medicinal plant Nepeta nuda (Lamiaceae), our study aimed to explore how cytokinins influence the plant's metabolic status. Exogenous administration of active cytokinin forms on in vitro N. nuda internodes stimulated intensive callus formation and de novo shoot regeneration, leading to a marked increase in biomass. This process involved an accumulation of oxidants, which were scavenged by peroxidases using phenolics as substrates. The callus tissue formed upon the addition of the cytokinin 6-benzylaminopurine (BAP) acted as a sink for sugars and phenolics during the allocation of nutrients between the culture medium and regenerated plants. In accordance, the cytokinin significantly enhanced the content of polar metabolites and their respective in vitro biological activities compared to untreated in vitro and wild-grown plants. The BAP-mediated accumulation of major phenolic metabolites, rosmarinic acid (RA) and caffeic acid (CA), corresponded with variations in the expression levels of genes involved in their biosynthesis. In contrast, the accumulation of iridoids and the expression of corresponding biosynthetic genes were not significantly affected. In conclusion, our study elucidated the mechanism of cytokinin action in N. nuda in vitro culture and demonstrated its potential in stimulating the production of bioactive compounds. This knowledge could serve as a basis for further investigations of the environmental impact on plant productivity.
PubMed: 38945096
DOI: 10.1016/j.plaphy.2024.108884 -
Water Research Jun 2024Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by abnormal lipid deposition, with oxidative stress being a risk factor in its onset and...
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by abnormal lipid deposition, with oxidative stress being a risk factor in its onset and progression. Haloacetamides (HAcAms), as unregulated disinfection by-products in drinking water, may alter the incidence and severity of NAFLD through the production of oxidative stress. We explored whether HAcAms at 1, 10, and 100-fold concentrations in Shanghai drinking water perturbed lipid metabolism in normal human liver LO-2 cells. CRISPR/Cas9 was used to construct a LO-2 line with stable NRF2 knock-down (NRF2-KD) to investigate the mechanism underlying abnormal lipid accumulation and hepatocyte damage caused by mixed exposure to HAcAms. At 100-fold real-world concentration, HAcAms caused lipid deposition and increased triglyceride accumulation in LO-2 cells, consistent with altered de novo lipogenesis. Differences in responses to HAcAms in normal and NRF2-KD LO-2 cells indicated that HAcAms caused hepatocyte lipid deposition and triglyceride accumulation by activation of the NRF2/PPARγ pathway and aggravated liver cell toxicity by inducing ferroptosis. These results indicate that HAcAms are important risk factors for NAFLD. Further observations and verifications of the effect of HAcAms on NAFLD in the population are warranted in the future.
PubMed: 38944971
DOI: 10.1016/j.watres.2024.122008 -
Mymensingh Medical Journal : MMJ Jul 2024Metabolic Syndrome (METS) plays a pivotal role in the development of diabetes mellitus, coronary artery diseases and stroke. Due to the scarcity of data in this issue,...
Metabolic Syndrome (METS) plays a pivotal role in the development of diabetes mellitus, coronary artery diseases and stroke. Due to the scarcity of data in this issue, this study aims to assess the frequency and risk factors association of METS among the hypertensive patients. This cross-sectional study recruited 667 eligible hypertensive patients aged between 20 and 70 years using non-probability purposive sampling method conducted from 1st January 2019 to 30th June 2019. Hypertensive patients with the known history of diabetes, thyroid, renal, cardiac, or hepatic disease, Cushing syndrome or malignancy and secondary causes of obesity, confirmed pregnancy, bed ridden, taking lipid lowering drugs or drugs that affect lipid and glucose metabolism were excluded from the study. METS among the hypertensive patients (DE novo or established hypertensive patients) of this study was demonstrated by NCEP-ATPIII (National Cholesterol Education Program-Adult Treatment Panel III) criteria having two or more of the following points [a) increased waist circumference ≥102cm in men and ≥88cm in women, b) hypertriglyceridemia: ≥150mg/dl, c) reduced High density lipoprotein cholesterol (HDL-C) <40mg/dL (1.04mmol/L) in men and <50mg/dL (1.29mmol/L) in women, d) high fasting blood glucose: 110mg/dl]. Significantly high frequency (69.9%, p<0.001) of METS was found with a significant female preponderance (52.5%, p<0.001) where the mean age of the study population was 48±11 years. Sex (p<0.001), education (p=0.041), occupation (p<0.001), Body mass index (BMI) (p<0.001) and hypertensive status (p=0.002) showed a highly significant role in the development of METS. Following binary logistic regression analysis after adjusting for confounders, the female sex was 17 times higher than the male [Adjusted odd ratio (AOR) =16.96, 95% CI=4.91-58.66, p<0.001)], obesity 4 times higher than non-obese [BMI (obese AOR=4.24, 95% CI=2.55-7.98, p<0.001)], hypertensive status [established hypertension two times higher than de novo (de-novo AOR=0.60, 95% CI=0.037-0.97, p=0.037)] were significant and independent predictors of METS. Significantly high BMI (27.7±4.2 and p<0.001), high waist circumference (60.4%, p<0.001) and hyper tri-glyceridaemia and reduced HDL (46.0%, p<0.001 and 51.3%, p<0.001) were found in the subjects with METS. In conclusion, high frequency of METS among the hypertensive patients was found in Jashore, Bangladesh with significant risk factors related to female sex, education, occupation, BMI and hypertensive status. So, a holistic evaluation of metabolic components among the hypertensive patients may reduce premature cardiovascular morbidity and mortality.
Topics: Humans; Female; Male; Middle Aged; Metabolic Syndrome; Hypertension; Cross-Sectional Studies; Adult; Bangladesh; Risk Factors; Aged; Waist Circumference
PubMed: 38944728
DOI: No ID Found -
Journal of Molecular Biology Jun 2024Autophagy is a cellular degradation pathway where double-membrane autophagosomes form de novo to engulf cytoplasmic material destined for lysosomal degradation. This... (Review)
Review
Autophagy is a cellular degradation pathway where double-membrane autophagosomes form de novo to engulf cytoplasmic material destined for lysosomal degradation. This process requires regulated membrane remodeling, beginning with the initial autophagosomal precursor and progressing to its elongation and maturation into a fully enclosed, fusion-capable vesicle. While the core protein machinery involved in autophagosome formation has been extensively studied over the past two decades, the role of phospholipids in this process has only recently been studied. This review focuses on the phospholipid composition of the phagophore membrane and the mechanisms that supply lipids to expand this unique organelle.
PubMed: 38944336
DOI: 10.1016/j.jmb.2024.168691 -
Biomedicine & Pharmacotherapy =... Jun 2024Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only...
BACKGROUND AND AIMS
Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only efficacy, but also a high safety profile. Repurposing of drugs in clinical use, such as pemafibrate and mirabegron, could facilitate the finding of an effective and safe drug-treatment for SLD.
APPROACH AND RESULTS
The SLD High Fat High Fructose (HFHFr) rat model develops steatosis without the influence of other metabolic disturbances, such as obesity, inflammation, or type 2 diabetes. Further, liver fatty acids are provided, as in human pathology, both from dietary origin and de novo lipid synthesis. We used the HFHFr model to evaluate the efficacy of pemafibrate and mirabegron, alone or in combination, in the resolution of SLD, analyzing zoometric, biochemical, histological, transcriptomic, fecal metabolomic and microbiome data. We provide evidence showing that pemafibrate, but not mirabegron, completely reverted liver steatosis, due to a direct effect on liver PPARα-driven fatty acid catabolism, without changes in total energy consumption, subcutaneous, perigonadal and brown fat, blood lipids and body weight. Moreover, pemafibrate treatment showed a neutral effect on whole-body glucose metabolism, but deeply modified fecal bile acid composition and microbiota.
CONCLUSIONS
Pemafibrate administration reverts liver steatosis in the HFHFr dietary rat SLD model without altering parameters related to metabolic or organ toxicity. Our results strongly support further clinical research to reposition pemafibrate for the treatment of SLD/MASLD.
PubMed: 38943989
DOI: 10.1016/j.biopha.2024.117067 -
Journal of Agricultural and Food... Jun 2024Omega-3 long-chain polyunsaturated fatty acids (LCPUFA) play critical roles in human development and health. Their intake is often effectively estimated solely based on...
Omega-3 Long-Chain Polyunsaturated Fatty Acids in Nonseafood and Estimated Intake in the USA: Quantitative Analysis by Covalent Adduct Chemical Ionization Mass Spectrometry.
Omega-3 long-chain polyunsaturated fatty acids (LCPUFA) play critical roles in human development and health. Their intake is often effectively estimated solely based on seafood consumption, though the high intake of terrestrial animal-based foods with minor amounts of LCPUFA may be significant. Covalent adduct chemical ionization (CACI) tandem mass spectrometry is one approach for structural and quantitative analysis of minor unsaturated fatty acids (FA), for which standards are unavailable. Here, CACI-MS and MS/MS are used to identify and quantify minor omega-3 LCPUFA of terrestrial animal foods based on the application of measured response factors (RFs) to various FA. American mean intakes of pork, beef, chicken, and eggs contribute 20, 27, 45, and 71 mg/day of docosahexaenoic acid (DHA), respectively. The estimated intake of omega-3 DHA, eicosapentaenoic acid, and docosapentaenoic acid from nonseafood sources is significant, at 164, 103, and 330 mg/day, greater than most existing estimates of omega-3 LCPUFA intake.
PubMed: 38943596
DOI: 10.1021/acs.jafc.4c03546