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At least 19 recordsLinked to original sources
PubMed2026

Elevated phthalate exposure and metabolic susceptibility increased breast cancer risk: A 20-y follow-up study in Taiwan.

Widely used phthalates, especially di-(2-ethylhexyl) phthalate (DEHP), increase breast cancer risk in experimental animals and humans, but long-term follow-up evidence of its human breast carcinogenicity remains inconclusive. This nested case-control study included 119 invasive breast cancer cases and 245 matched controls from a longitudinal cohort of 11,923 women recruited in 1991-1992 and followed to 2010 in Taiwan. Urine samples at baseline and follow-up visit were tested for 11 metabolites of seven phthalates using LC-ESI-MS/MS. DEHP metabolism susceptibility was evaluated by the percentage of mono-2-ethylhexyl phthalate (MEHP%) in the sum of five DEHP metabolites (∑DEHP). Odds ratios (ORs) with 95% CI from conditional logistic regression were used to examine risk predictors. DEHP was the only phthalate significantly associated with breast cancer risk. Risk increased significantly with elevated urinary levels of ∑DEHP (> 0.381 μmol/g creatinine, OR = 1.71, 95% CI = 1.02 to 2.43), MEHP (> 0.022 μmol/g creatinine, OR = 1.87, 95% CI = 1.07 to 3.25), and MEHP% (> 6.7%, OR = 1.65, 95% CI = 0.96 to 2.82). Elevated ∑DEHP and MEHP% combined with early menarche (≤ 14 years) was associated with further increased risk (OR = 7.52, 95% CI = 2.68 to 21.05). The intraclass correlation coefficient between paired baseline and follow-up samples of 152 women was 0.06 for ∑DEHP and 0.31 for MEHP%. High DEHP exposure, high MEHP%, and early menarche were associated with increased breast cancer risk. MEHP% was a better biomarker for DEHP metabolism.

Humans↗
PubMed2025

Assessing individual genetic susceptibility to metabolic syndrome: interpretable machine learning method.

BACKGROUND: Genome-wide association studies have provided profound insights into the genetic aetiology of metabolic syndrome (MetS). However, there is a lack of machine-learning (ML)-based predictive models to assess individual genetic susceptibility to MetS. This study utilized single-nucleotide polymorphisms (SNPs) as variables and employed ML-based genetic risk score (GRS) models to predict the occurrence of MetS, bringing it closer to clinical application. METHODS: Feature selection was performed using Least Absolute Shrinkage and Selection Operator. Six ML algorithms were employed to construct GRS models. A fivefold cross-validation was utilized to aid in the internal validation of models. The receiver operating characteristic (ROC) curve was used to select the better-performing GRS model. The SHapley Additive exPlanations (SHAP) was then applied to interpret the model. After extracting GRS, stratified analysis of BMI, age and gender was performed. Finally, these conventional risk factors and GRS were integrated through multivariate logistic regression to establish a combined model. RESULTS: A total of 17 SNPs were selected for analysis. Among the GRS models, the extreme gradient boosting (XGBoost) model demonstrated superior discriminative performance (AUC = 0.837). The XGBoost's optimal robustness was also validated through five-fold cross-validation (mean ROC-AUC = 0.706). The XGBoost-based SHAP algorithm not only elucidated the global effects of 17 SNPs across all samples, but also described the interaction between SNPs, providing a visual representation of how SNPs impact the prediction of MetS in an individual. There was a strong correlation between GRS and MetS risk, particularly observed among young individuals, males and overweight individuals. Furthermore, the model combining conventional risk factors and GRS exhibited excellent discriminative performance (AUC = 0.962) and outstanding robustness (mean ROC-AUC = 0.959). CONCLUSION: This study established a reliable XGBoost-based GRS model and a GRS prediction platform (https://metabolicsyndromeapps.shinyapps.io/geneticriskscore/) to assess individual genetic susceptibility to MetS. This model has high interpretability and can provide personalized reference for determining the necessity of primary prevention measures for MetS. Additionally, there may be interactions between traditional risk factors and GRS, and the integration of both in a comprehensive model is useful in the prediction of MetS occurrence.

Humans↗
PubMed2026

SNP-derived CpG variation and DNA methylation linking genetic susceptibility to metabolic disease.

DNA methylation at CpG dinucleotides represents a key epigenetic mechanism linking genetic variation to gene regulation in complex human diseases. Single-nucleotide polymorphisms (SNPs) that create or disrupt CpG sites can alter local DNA methylation and transcriptional activity, thereby influencing disease susceptibility. These CpG-modifying variants provide a functional interface between inherited genetic variation and epigenetic regulation in complex metabolic disorders. This review summarizes current evidence on SNP-derived CpG variation and its role in allele-specific DNA methylation and gene regulation in metabolically relevant tissues. By integrating findings from genome-wide association studies, epigenome-wide association studies, and multi-omics research, this review provides a mechanistic framework explaining how CpG-modifying polymorphisms influence adipogenesis, pancreatic β-cell function, inflammation, and glucose metabolism. Special emphasis is placed on South Asian populations, who exhibit early β-cell dysfunction and increased visceral adiposity. Many CpG-modifying variants act as methylation quantitative trait loci (meQTLs), influencing allele-specific methylation and gene expression. Understanding SNP-CpG-methylation interactions may improve functional interpretation of disease-associated genetic variants, enhance biomarker discovery, and support precision medicine strategies for metabolic disease.

Humans↗
PubMed1979

Divergent toxicity of parathion in two freshwater invertebrates, orconectes rusticus and viviparus malleatus.

The toxicity of parathion and its metabolite paraoxon was examined in the crayfish Orconectes rusticus and the snail Viviparus malleatus and attempts were made to relate this to parathion uptake and metabolism. The crayfish was found to be very susceptible with all animals tested dying at 0.1 ppb of parathion in 48 hours. The snail was resistant to exposure to 1000 ppm. The absence of lethality even to injected (50 mg/kg) parathion and paraoxon suggests an innate lack of susceptibility. Metabolism of the compounds could not be detected in vitro or in vivo in either species.

Animals↗
PubMed1976

Amidated carboxyl groups in elastin.

Dicarboxylic amino acids constitute the most numerous residues of insoluble elastin in which are potentially ionizable in the physiological range of pH. These residues are essential in facilitating productive electrostatic interaction between elastase and elastin. The present study has investigated the possibility that the glutamic and aspartic acid residues of elastin are amidated. Acid-labile amide-bound ammonia of elastin was quantitated after hydrolysis of the insoluble protein with 2 M HC1 by incubating aliquots of microdistilled hydrolysates with glutamate dehydrogenase, excess alpha-ketoglutarate, and reduced nicotinamide adenine dinucleotide and measuring the resultant decrease in A340 due to oxidation of the dinucleotide cofactor. It was found that ligament elastin purified by repeated autoclaving contains approximately 2.29 mumol of acid-labile amide nitrogen per 10 mg of protein, a value equivalent to approximately 70% of the total number of dicarboxylic amino acid residues. Independent analysis of the amide content was obtained by amino acid analysis of an esterified and reduced elastin sample in which the free dicarboxylic amino acid residues had been converted to the corresponding alcohol derivatives. This analysis indicated that autoclaved ligament elastin contains approximately 18 glutamine, 3 asparagine, 4 glutamic acid and 5 aspartic acid residues per 1000 residues, in good agreement with the analysis of total acid-labile ammonia. The esterified and reduced elastin derivative was nearly inert as an elastase substrate, consistent with a lack of free dicarboxylic amino acid residues. However, addition of sodium dodecyl sulfate to this elastin derivative restores enzyme-substrate charge complementarity, and the elastin-ligand complex was readily hydrolyzed by elastase at the fully stimulated rate, emphasizing the control such ligands can exert in elastolysis. The amide bonds of elastin were found to be significantly more resistant to hydrolysis by 0.1 M NaOH at 98 degrees C than were those of lysozyme or free amidated amino acids. The finding that most of dicarboxylic amino acid residues of elastin exist at neutral amides further emphasizes the apolar character of elastin and has bearing upon the metabolic susceptibility, ligand-binding ability and structural aspects of this connective tissue protein.

Amides↗
PubMed1978

Stereoselectivity and affinity in molecular pharmacology. IV. A search for eudismic-affinity correlations among angiotension II analogues.

In order to establish the applicability of eudismic analysis (correlation between potency and the ratio of isomer potencies), the extensive data reported on the biological activities of angiotensin II analogues were examined. For a series of 13 heptapeptides epimeric at the N-terminal residue, apparent correlations were found for pressor activity in vivo, but not for 10 of them on the basis of their myotropic activity under in vitro conditions. The analogues belongning to sub-groups displaying correlations have side chains of sufficiently different nature so that their grouping is questionable. 3 octapeptides epimeric at the second residue displayed an excellent correlation for their pressor activity. The demonstrated differential metabolic susceptibility of these epimers, however, casts further doubt on the usefulness of the data as a measure of their potency. The lack of a correlation under in vitro conditions would indicate that eudismic-affinity correlations (EAC) may be limited to epimers which differ less in their properties than these angiotensin analogues. Nevertheless, until better receptor affinity estimates become available, the observed correlations may be useful in advancing our knowledge of the angiotensin II receptor in particular, and of stereoselective molecular recognition in general.

Angiotensin II↗
PubMed1979

A possible role for elastin ligands in the proteolytic degradation of arterial elastic lamellae in the rabbit.

Thoracic aortae of normal rabbits were perfused with pancreatic elastase in vitro at 37 degrees C and 70 mm Hg pressure in the presence or absence of elastin ligands previously shown to stimulate or inhibit the enzymatic degradation of elastin. Perfusion with elastase results in an average of 3.6 lamellae degraded, whereas addition of sodium linoleate before and during the perfusion with elastase increases this value to 7.9 (P less than 0.001). Conversely, perfusion with the cationic detergent, dodecyltrimethylammonium chloride, completely prevents the degradation of elastic lamellae by elastase. These effects do not reflect alterations of the intrinsic catalytic activity of elastase, but apparently indicate the formation of complexes between the elastin ligands and arterial elastic lamellae, as is consistent with prior studies indicating such interactions between fatty acids or detergents and purified elastin. These studies suggest that agents such as fatty acids may significantly alter the metabolic susceptibility of elastin in vivo and possibly contribute to the degradation of elastic lamellae seen in arteries with advanced atherosclerosis.

Animals↗
PubMed1976

Central pontine myelinolysis. Two cases with associated electrolyte disturbance.

Two patients with central pontine myelinolysis are described. Both were middle aged women presenting with a history of protracted vomiting and drowsiness. Hyponatraemia (serum sodium 96 to 100 mmol/L) was a feature in both patients. No underlying malignancy, alcoholism, malnutrition or other serious disease was identified. Correction of electrolyte abnormalities was accompanied by deterioration in level of consciousness and development of a neurological syndrome characterized by quadriparesis, dysphasia and mutism. Death followed and histopathological examination confirmed classical myelinolysis in the central pons and extensive similar, though not identical, lesions in the cerebral hemispheres in both cases. The pathophysiological basis of the lesions is likely to be a special metabolic susceptibility of oligodendroglial cells in areas where neurones, glial cells and myelin sheaths lie in close proximity to one another.

Brain Diseases↗
PubMed1976

Penetration and comparative metabolism of leptophos in susceptible and resistant houseflies.

The metabolism and rate of penetration of leptophos (O-methyl O-4-bromo-2,5-dichlorophenyl phenylphosphonothioate) was determined in a susceptible strain and a strain of housefies which was 50-fold resistant to leptophos. Penetration of leptophos into resistant flies was substantially slower than into susceptible flies but large differences in metabolism, both quantitatively and qualitatively, were not observed. No difference was observed in the sensitivity of flyhead and thorax acetylcholinesterase to leptophos-oxon in vitro, and tolerance to leptophos by the resistant strain is explained in terms of decreased rates or penetration and minor differences in metabolism.

Animals↗
PubMed2025

Amino acid profiles, aging, and sex hormone interactions in the elderly Iranian population: a metabolomics study.

BACKGROUND: Aging and sex hormones significantly influences on metabolic profiles, particularly in individuals aged 50 year and older. This study aimed to investigate the associations between serum metabolites, aging, and sex hormone levels among elderly individuals in Bushehr, Iran - a coastal region characterized by a unique lifestyle, dietary patterns, and environmental conditions, such as high seafood consumption and exposure to marine climate, which may collectively influence metabolic profiles and hormone levels in the aging population. METHODS: This cross-sectional study analyzed data from the Bushehr Elderly Health Program, which included 2001 participants (1143 women and 858 men) aged over 50 years old from Bushehr, Iran. Serum levels of 20 amino acids were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the results were analyzed based on gender, age, menopause status, menopause age, and serum levels of sex hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and estradiol (E2). Statistical analyses were performed using SPSS version 25.0 and R version 4.0.3, with a focus on gender differences and the correlation between aging, sex hormones, and metabolite profiles. RESULTS: Among the 2001 participants, mean ages were 61.57 ± 7.6 years for women and 62.92 ± 8.4 years for men. Men had higher serum levels of glutamic acid, leucine, methionine, phenylalanine, tyrosine, valine, citrulline, ornithine, proline, threonine, histidine, lysine, tryptophan, asparagine, and glutamine, while women had higher levels of glycine and serine. Aging was associated with notable changes in amino acid levels, such as increased citrulline and decreased threonine in women, and similar trends in men with a pronounced decrease in alanine. In men, low testosterone levels were linked to reduced concentration of alanine, methionine, phenylalanine, tyrosine, citrulline, glycine ornithine, serine, lysine, asparagine, and glutamine. Postmenopausal women showed a significant decrease in threonine levels. DISCUSSION: The findings highlight the complex interplay between aging, sex hormones, and metabolic changes. Gender-specific differences in amino acid profiles suggest that sex hormones play a pivotal role in modulating metabolism, which may influence susceptibility to metabolic disorders. These insights could inform the development of targeted interventions tailored to the specific needs of aging populations. Future research should investigate the underlying mechanisms linking sex hormones to metabolic pathways and assess their potential for improving health outcomes in older adults.

Aging↗
PubMed2022

Expansive and Diverse Phenotypic Landscape of Field Aedes aegypti (Diptera: Culicidae) Larvae with Differential Susceptibility to Temephos: Beyond Metabolic Detoxification.

Arboviruses including dengue, Zika, and chikungunya are amongst the most significant public health concerns worldwide. Arbovirus control relies on the use of insecticides to control the vector mosquito Aedes aegypti (Linnaeus), the success of which is threatened by widespread insecticide resistance. The work presented here profiled the gene expression of Ae. aegypti larvae from field populations of Ae. aegypti with differential susceptibility to temephos originating from two Colombian urban locations, Bello and Cúcuta, previously reported to have distinctive disease incidence, socioeconomics, and climate. We demonstrated that an exclusive field-to-lab (Ae. aegypti strain New Orleans) comparison generates an over estimation of differential gene expression (DGE) and that the inclusion of a geographically relevant field control yields a more discrete, and likely, more specific set of genes. The composition of the obtained DGE profiles is varied, with commonly reported resistance associated genes including detoxifying enzymes having only a small representation. We identify cuticle biosynthesis, ion exchange homeostasis, an extensive number of long noncoding RNAs, and chromatin modelling among the differentially expressed genes in field resistant Ae. aegypti larvae. It was also shown that temephos resistant larvae undertake further gene expression responses when temporarily exposed to temephos. The results from the sampling triangulation approach here contribute a discrete DGE profiling with reduced noise that permitted the observation of a greater gene diversity, increasing the number of potential targets for the control of insecticide resistant mosquitoes and widening our knowledge base on the complex phenotypic network of the Ae. aegypti response to insecticides.

Aedes↗
PubMed2026

Distinct cochlear cell types associated with genetic susceptibility to sensory and metabolic hearing loss in older adults.

Hearing loss is a heterogeneous condition that can be classified into different subtypes with diverse genetic and cellular components. To investigate the cochlear cell types underlying the genetic basis of sensory and metabolic components of age-related hearing loss (ARHL), we integrated human genome-wide association study data with mouse cochlear single-cell RNA sequencing data using the single-cell disease relevance score tool. These analyses revealed that genes associated with the sensory component of ARHL were most highly expressed in hair cells, while genes associated with the metabolic component of ARHL were most highly expressed in spiral ganglion neurons. We also investigated whether ARHL-associated gene expression patterns differed across subpopulations of the same cell type. Sensory hearing loss-associated genes showed differential expression across supporting cell subpopulations in younger mice, whereas metabolic hearing loss-associated genes exhibited differences across intermediate cell subpopulations of the stria vascularis in older mice. These findings provide evidence for the role of distinct genetic and cellular risk profiles for different ARHL subtypes, suggesting that prevention and therapeutic strategies may require targeting specific cell populations at different life stages.

ARHL↗
PubMed1978

Indian childhood cirrhosis: an inherited disorder of tryptophan metabolism?

Urine samples from members of 29 families of patients with Indian childhood cirrhosis (ICC) and nine families with related disorders gave positive reactions when tested with ferric chloride. Column chromatography showed that this was due to the presence of abnormally large amounts of tryptophan metabolites, notably 3-hydroxyanthranilic acid. Affected pedigrees had a significantly greater prevalence of peptic ulcer, adult cirrhosis, diabetes mellitus, migraine, and Parkinsonism than a control population. ICC may result from an inborn error of tryptophan metabolism in susceptible ethnic groups.

Adult↗
PubMed1975

Alteration of cell-surface antigenicity of the mouse plasmacytoma. I. Immunologic characterization of surface antigens masked during successive transplantations.

Alterations of membrane antigenicity of IgA-synthesizing plasmacytoma cells (58-8) induced in a BALB/c mouse were investigated with rabbit antisera against 58-8 transplanted from 7-8 generations (anti-58-8) and mouse antisera against H-2d (anti-H-2d). The 58-8 cells transplanted (TP) for 8 generations (TP8), showed moderate susceptibilities to anti-58-8 [cytotoxicity index (CI) = 72%] and to anti-H-2d (Cl = 30-40%). At TP12, the susceptibility to anti-58-8 remained (tCl approximately 50%) but there was none to anti-H-2d (Cl = 0-10%). After TP13, 58-8 cells had detectable reactivity neither with anti-58-8 nor with anti-H-2d before proteolysis. However, antigenicity was demonstrated after treatment of cells with proteases: Anti-58-8 and anti-H-2d became cytotoxic to pronase-treated 58-8 (P-58-8) and these cytotoxic reactivities of antisera could be completely absorbed with P-58-8- but not with "intact" 58-8. Anti-H-2d absorbed with P-58-8 had no cytotoxicity to BALB/c spleen cells. Absorption of anti-H-2d with BALB/c spleen cells did not show any measurable cytotoxicity to P-58-8. Appearance of antigenicity after proteolysis was transient and reversible. When P-58-8 was incubated in vitro, susceptibilities to antisera were decreased. Actinomycin D and puromycin inhibited the loss of susceptibility; these metabolic inhibitors suppressed the "masking" of antigenic determinants with protein-like material(s). In early generations (TP8), 58-8 cells were susceptible to antiserum to bone marrow-derived lymphocytes (anti-B) and complement. The cells completely absorbed the cytotoxicity of anti-B against spleen cells. After additional transplantations (TP14, TP30), susceptibilities to anti-B were no longer detectable and no removal of the cytotoxicity was shown, though the cells were pretreated with pronase. Anti-B failed to kill MOPC-31C.

Animals↗
PubMed2025

Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.

Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.

Blood-Brain Barrier↗