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PubMed2025

Uncovering parental exposure risks of TCPP: Impaired development and metabolic homeostasis in zebrafish offspring.

As brominated flame retardants are phased out, tris (1‑chloro-2-propyl) phosphate (TCPP), a phosphorus-based flame retardant, has emerged as a prominent detectable flame retardant in the environment. However, TCPP has been found to exhibit endocrine-disrupting effects on organisms, raising significant safety concerns. In our study, we utilized the zebrafish model to explore the toxic effects of parental TCPP exposure on offspring and uncover its regulatory mechanisms through metabolomics analysis. Moreover, the impact on the nervous system and lipid metabolism was examined through behavioral analysis and specific staining. Our findings demonstrated that both embryonic and parental TCPP exposure induced developmental disorders in larvae, along with decreased locomotor activity and disordered lipid metabolism homeostasis. Parental exposure to TCPP, exhibiting stronger developmental toxicity than direct embryonic exposure, notably led to reductions in crucial energy substrates such as amino acids and carbohydrates. Meanwhile, embryonic TCPP exposure primarily affected the endogenous lipid-related metabolites including phospholipids, lipid-soluble vitamins, steroids and fatty acids, promoting lipid accumulation in larval liver and subcutaneous tissue. What's more, continuously parental and embryonic exposure showed the most pronounced effects on zebrafish development and metabolic regulation. Our study highlights the risk posed by parental exposure to TCPP on offspring zebrafish, underscoring the need for comprehensive consideration of the impact from parental exposure in pollutants regulation.

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PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

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PubMed2026

PGR expression as a pharmacogenomic companion biomarker to GENE70-derived genomic risk in ER-positive/HER2-negative breast cancer.

BACKGROUND: The biology of the estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancers is heterogeneous even when they are categorized by their risk via genomics. Transcriptomic PGR expression reflects endocrine pathway activity and may provide complementary biological information within established GENE70-derived genomic-risk categories. Whether this molecular marker improves the biological interpretation of genomic-risk stratification beyond conventional clinicopathological assessment remains uncertain. OBJECTIVES: The aim of this study was to determine whether transcriptomic PGR expression provides complementary biological and prognostic information within reconstructed GENE70-derived genomic-risk categories and refines the characterization of endocrine-related tumour biology in ER-positive/HER2-negative breast cancer. METHODS: This study analysed publicly available transcriptomic and clinical data from three cohorts: METABRIC (discovery cohort), GSE96058/SCAN-B cohort (validation cohort) and TCGA-BRCA cohort (molecular validation cohort). The GENE70-derived genomic-risk score was reconstructed for each cohort using matched genes. Cox regression, Kaplan-Meier analysis and subgroup comparisons were used to assess relationships between PGR expression, clinicopathologic variables, molecular features and survival outcomes. RESULTS: Across the three independent cohorts, low transcriptomic PGR expression was consistently associated with higher GENE70-derived genomic risk, increased MKI67 expression, reduced ESR1 expression and enrichment of the Luminal B subtype. Survival findings differed between cohorts. In the discovery METABRIC cohort, transcriptomic PGR expression showed heterogeneous associations with survival, particularly within GENE70-derived high-risk subgroups, whereas the external GSE96058/SCAN-B validation cohort demonstrated consistent associations between low PGR expression and poorer overall survival in both the overall ER-positive/HER2-negative population and GENE70-derived high-risk subgroups. CONCLUSION: These findings suggest that transcriptomic PGR provides complementary biological and prognostic information within GENE70-derived genomic-risk categories. However, because treatment response was not evaluated in the present study, the findings should not be interpreted as evidence of predictive or pharmacogenomic utility and prospective studies incorporating treatment-response analyses are required before such applications can be established.

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PubMed2025

Systematic meta-analysis of the toxicities and side effects of the targeted drug lenvatinib.

BACKGROUND: Lenvatinib, an effective targeted drug for various cancers, has clinical medication safety concerns due to its toxicities and side effects. OBJECTIVE: This study evaluated lenvatinib-induced any adverse events (any AEs) and nine aspects: vascular toxicities related to the circulatory system (vascular toxicities, blood system, and heart), toxicities of the skin and its appendages (skin/subcutaneous tissue and taste system), toxicities of the respiratory system (respiratory, thoracic, and mediastinal and respiratory tract), toxicities of the nervous system (nervous system and general), toxicities of the digestive system (gastrointestinal and liver), toxicities of the urinary system, toxicities of the endocrine and metabolic system (endocrine and metabolism/nutrition), toxicities of the musculoskeletal system, and other severe toxicities. Toxicities and side effects were stratified by severity into any and ≥3 grades for analysis. PATIENTS/MATERIALS AND METHODS: Multiple databases were searched for lenvatinib cancer clinical studies (cohort studies and randomized controlled trials) from inception to December 31, 2024; toxicity and side effect data were extracted and analyzed. RESULTS: Nine high-quality studies were included, showing that lenvatinib is effective in cancers but has notable toxicities. Taking hypertension as an example, for any grade, the risk ratio (RR) was 2.34 with a 95% confidence interval (CI) of [2.09, 2.62], a Z-value of 14.74, and a P-value <0.00001; for grade ≥3, the RR was 2.60 with a 95% CI of [2.21, 3.06], a Z-value of 11.44, and a P-value <0.00001. CONCLUSION: Lenvatinib is effective for cancer but toxic, and this study supports its rational clinical use.

Humans↗

PubMed2026

Role of omentin-1 in the global proteome of porcine pituitary cells: insights into proliferation- and apoptosis-related processes.

The anterior pituitary integrates endocrine regulation, cellular growth, and adaptive responses. Adipokines, secreted mainly by adipose tissue, act as hormonal signals linking metabolism, inflammation, appetite, and reproduction. They regulate hypothalamic-pituitary-ovarian axis by modulating hormone secretion and intracellular signaling. The presence of adipokine receptors in anterior pituitary suggests local metabolic-endocrine interactions. Omentin-1, predominantly expressed in visceral adipose tissue, participates in glucose metabolism and ovarian steroid regulation. Recent findings indicate that omentin-1 modulates tropic hormones, their receptors, and adipokine balance in anterior pituitary cells. We hypothesized that omentin-1 affects protein expression and signaling pathways involved in pituitary cell proliferation and apoptosis. This study examined its effects in anterior pituitary cells from Large White and Meishan pigs. Proteomic analysis identified 230 candidate differentially abundant proteins after omentin-1 treatment: 30 downregulated and 3 upregulated in Large White pigs, and 107 downregulated and 90 upregulated in Meishan pigs, associated with enriched 116 Gene Ontology terms. Key proteins were associated with cell cycle, DNA replication, gene expression, and posttranscriptional/posttranslational regulation. Responses differed between breeds. CDK5RAP2 and SIX1 were linked to proliferative control in Large White pigs, whereas AKT1S1 and RHOA were among the proteins associated with the broader proteomic response observed in Meishan pigs. Meishan pigs showed dynamic apoptotic protein regulation, including HTRA2, PARP2, and DFFA. Complementary in vitro experiments demonstrated that omentin-1 downregulated cyclins and caspase-3, upregulated BCL2, increased BCL2/BAX ratio, and modulated ERK1/2, AKT, AMPKα, and STAT3 phosphorylation. Together, these findings suggest that omentin-1 modulates proteomic networks and intracellular signaling associated with anterior pituitary cell function during the mid-luteal phase of the estrous cycle.

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PubMed2026

Environmentally relevant concentrations of DCOIT impaired lifespan and healthspan in Caenorhabditis elegans.

DCOIT (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one) is an antifouling biocide widely used as an alternative to organotin compounds. While previous studies had focused on its effects on energy production, endocrine disruption, and lipid metabolism, its impact on aging and underlying mechanisms remained unclear. Here, we demonstrated that environmentally relevant concentrations of DCOIT (37, 370 and 3700 ng/L) significantly impaired both lifespan and healthspan in Caenorhabditis elegans. RNA-seq and validation assays revealed that DCOIT upregulated comt-4, a key gene in dopamine metabolism, leading to dopamine depletion and subsequent induction of oxidative stress. This redox imbalance critically contributed to accelerated aging phenotypes. Importantly, both genetic (comt-4 RNAi) and pharmacological (opicapone) interventions restored dopamine levels, alleviated oxidative stress, and reversed DCOIT-induced aging deficits. Our study established the comt-4/dopamine/oxidative stress axis as a central mechanism in DCOIT toxicity, suggesting dopamine modulation as a potential countermeasure against environmental toxicant-induced aging.

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PubMed2026

Integrated multi-omics analyses identify an RAS-SLC11A2-associated molecular framework linking iron metabolism with PCOS-related cardiometabolic risk.

INTRODUCTION: PCOS is a common endocrine disorder with elevated cardiometabolic risk, yet the role of the renin-angiotensin system (RAS)-iron metabolism axis in this comorbidity remains unclear. We explored its underlying mechanisms and evaluated the therapeutic potential of gentiopicroside. METHODS: Integrated multi-omics analyses combining transcriptomics, single-cell RNA sequencing, Mendelian randomization, machine learning, molecular docking, and in vitro functional assays were performed to identify shared molecular pathways and therapeutic targets across PCOS, hypertension, NAFLD, and T2DM. RESULTS: SLC11A2 was consistently dysregulated in PCOS transcriptomic datasets, and associated with iron metabolism, inflammatory response and oxidative stress pathways. Genetic analyses validated RAS-related regulation in hypertension susceptibility and revealed shared genetic architecture between PCOS and cardiometabolic traits. Network and single-cell analyses characterized SLC11A2-associated molecular patterns in disease-relevant cell types; machine learning identified disease-classifying molecular signatures. Gentiopicroside alleviated inflammatory and oxidative stress phenotypes, including reduced IL-6 expression and reactive oxygen species accumulation. CONCLUSION: This study defines an RAS-SLC11A2 molecular framework linking iron metabolism dysregulation to PCOS-related cardiometabolic risk, elucidating the mechanisms connecting ovarian dysfunction, inflammation, oxidative stress and hypertension, and supports gentiopicroside as a promising therapeutic candidate.

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PubMed2026

Protein sorting and proteostasis mechanisms in CFTR-related exocrine pancreas dysfunction: A systematic narrative review.

The pancreas consists of exocrine and endocrine compartments. In the exocrine pancreas, cystic fibrosis transmembrane conductance regulator (CFTR) functions mainly in ductal epithelial cells as a chloride and bicarbonate channel. Its activity depends on proper protein folding, trafficking, and localization to the apical membrane. This systematic narrative review aims to synthesize the available evidence on the role of protein sorting machinery in CFTR channelopathies and its contribution to exocrine pancreatic dysfunction. A thorough search was conducted using PRISMA criteria on PubMed, Wiley Online Library, and Scopus for studies published in English between January 2000 and November 2025. Twenty studies that met the inclusion criteria were included in this review. Pathogenic CFTR variants impair protein folding, endoplasmic reticulum (ER) exit, and endosomal recycling, resulting in reduced apical membrane expression and stability. These defects disrupt the localization of associated transporters and secretory proteins, impair ductal bicarbonate secretion, alter zymogen handling, and promote acinar injury, although these claims are supported mainly by indirect experimental models and therefore require clinical confirmation. CFTR channelopathies in the exocrine pancreas encompass both ion transport defects and broader disruptions of protein sorting machinery. CFTR may contribute to the assembly, stabilization, or localization of selected apical transport complexes, and its loss can secondarily alter epithelial organization. Therapeutic approaches targeting both channel correction and intracellular trafficking may improve pancreatic function and mitigate disease progression.

Humans↗

PubMed2026

Molecular mechanisms of neuroendocrine regulation of molting in the Chinese mitten crab (Eriocheir sinensis): A transcriptomic analysis based on eyestalk ablation model.

Molting disability severely restricts the sustainable aquaculture of the Chinese mitten crab, yet the neuroendocrine mechanisms coordinating physiological responses remain poorly understood. Using unilateral eyestalk ablation to remove the primary source of molt-inhibiting hormone (MIH), we performed time-resolved transcriptomic profiling of the thoracic ganglion at 24 h (early premolt) and 48 h (ecdysis) post-ablation. We identified 2825 differentially expressed genes and uncovered a biphasic molecular response. At 24 h, the thoracic ganglion activates pathways associated with neuromuscular adaptation, oxidative stress, and cardiac muscle contraction. Notably, the arachidonic acid metabolism pathway is selectively rewired: cytochrome P450 ω-hydroxylases (CYP2J2, CYP4V2) are upregulated, while competing branches (epoxide hydrolase, cyclooxygenase) are suppressed, promoting local synthesis of the potent vasoconstrictor 20-HETE within the thoracic ganglion. This enzymatic switch provides a mechanistic link between MIH withdrawal and the local generation of elevated hemolymph pressure required for molting. By 48 h, the transcriptional program shifts toward chitin-based extracellular matrix remodeling, glycosphingolipid biosynthesis, and synaptic reorganization. Collectively, our findings redefine the thoracic ganglion as an active neuroendocrine integrator that translates reduced MIH signaling into phased physiological outputs, revealing a "neuro-endocrine-hemolymph pressure" regulatory axis. This study provides novel molecular targets (e.g., CYP2J2, CHS1, UGCG) for mitigating molting disability in E. sinensis aquaculture.

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PubMed2026

Protective association of the ELMO1 rs741301 variant against diabetes mellitus and diabetic nephropathy: a systematic meta-analysis of case-control studies.

CONTEXT: Diabetes mellitus (DM), an endocrine disorder, is characterised by persistently elevated blood glucose levels due to inadequate insulin production. Diabetic nephropathy (DN), is a critical complication associated with DM, often leading to end-stage renal failure and increased mortality. OBJECTIVE: This meta-analysis aimed to evaluate the association between the ELMO1 rs741301 polymorphism and susceptibility to DN among individuals with diabetes. METHOD: A systematic literature search was conducted for studies published between 2014 and 2024 using Embase, Google Scholar, and PubMed. Eligible case-control studies investigating the association between ELMO1 rs741301 and DN among individuals with DM were selected according to predefined inclusion criteria. Nine case-control studies comprising 880 individuals with DM and 1008 individuals with DN were included in the meta-analysis. RESULTS: The pooled analysis demonstrated a significant protective association between the ELMO1 rs741301 polymorphism and DN under the allelic model (OR = 0.77, 95% CI: 0.67-0.88), recessive model (OR = 0.74, 95% CI: 0.61-0.90), and dominant model (OR = 0.68, 95% CI: 0.53-0.88). In contrast, no statistically significant association was observed under the over-dominant model. CONCLUSION: The findings suggest that the ELMO1 rs741301 polymorphism may be associated with a reduced susceptibility to DN among individuals with DM. These findings provide evidence for a potential genetic contribution of ELMO1 to DN susceptibility and may help improve understanding of the genetic factors underlying diabetic complications. Further well-designed studies in diverse populations are warranted to validate this association.

Humans↗

PubMed2026

Glucocorticoid receptor antagonism in major depressive disorder with childhood trauma: a randomized controlled trial.

Childhood trauma (CT) is a key risk factor for major depressive disorder (MDD) onset and persistence. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie this link, and preclinical studies suggest glucocorticoid receptor (GR) antagonism can reverse early life stress effects. This study tested whether the GR antagonist mifepristone reduces depressive symptoms in adults with MDD and CT. The RESET-medication study was a randomized, double-blind, placebo-controlled trial evaluating a 7-day course of mifepristone (1200 mg/day) or placebo in 158 adults with MDD and CT, assessed at baseline, 1 week, 6 weeks (primary endpoint), 3 months, and 6 months. The primary outcome was depressive symptom severity (IDS-SR) at week 6; secondary outcomes included symptom severity at other timepoints, clinical response, remission, anxiety, sleep, stress, disability, and salivary cortisol. At week 6, depressive symptoms declined in both groups, with no significant difference between mifepristone and placebo (b=-0.25, d=-0.03, 95% CI [-0.42, 0.36], pnom=0.887), and no group differences were found for secondary outcomes. Morning and evening cortisol were significantly higher with mifepristone at week 1, consistent with GR antagonism, but not at week 6. Adverse events were more frequent with mifepristone; mild and severe events occurred significantly more often, while the proportion reporting at least one adverse event was numerically higher but not statistically significant (93.6%vs. 82.5%, χ²(1)=3.60, p=0.058). Mifepristone produced the expected endocrine response but did not lead to clinical improvements in individuals with MDD and CT compared to placebo.

Humans↗

PubMed2026

Opposite metabolic and gut responses to oral glutamine in male and female mice with diet-induced obesity.

Obesity is often associated with sex-dependent metabolic complications, to which altered intestinal barrier function and gut microbiota contribute. Glutamine supplementation has previously shown beneficial effects on gut barrier function and glycemic control. We thus aimed to characterize, in male and female mice, the effects of oral glutamine supplementation during high-fat-diet-induced obesity. Male and female C57BL/6 mice received a standard (SD) or high-fat diet (HFD; 60 % kcal from fat) for 14 weeks (W14). From W12 onward, mice received glutamine in drinking water (2 g/kg/day) or no supplementation. Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic inflammatory response, cecal microbiota and inflammatory/endocrine adipose response were assessed. In both male and female mice, glutamine supplementation failed to improve body weight and body composition. However, glutamine reduced glucose intolerance in HFD-fed males (AUC reduced by 14.57 %) that was associated with a partial restoration of plasma resistin and insulin and a trend toward limiting adipose inflammatory response. In males, glutamine did not affect gut microbiota composition and colonic response. Conversely, in HFD-fed females, glutamine supplementation led to gut microbiota changes (increase in Bacteroidota and Pseudomonadota phyla; increase in Muribaculaceae and Tannerellaceae families), increased colonic inflammatory markers (Il1b, Tlr4, Myd88, Irf3), increased inflammatory response in subcutaneous adipose tissue and increased HOMA-IR. Finally, HFD-fed mice exhibited sex-specific responses to glutamine supplementation with protective effects in males and harmful effects in females that need to be further deeply explored.

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PubMed2026

Spermidine and melatonin ameliorate heat stress-induced decline in sheep semen quality.

Heat stress impairs reproductive performance in sheep through endocrine disruption and oxidative stress. This study evaluated the protective effects of spermidine (SPD) and melatonin (MT) supplementation on semen quality in Dorper rams during summer. Twenty-four rams were randomly assigned to a control group, an SPD group (5 mg/kg, dietary supplementation), or an MT group (60 mg, subcutaneous implantation) and treated for 60 days. The temperature-humidity index (THI) was monitored throughout the experimental period. Compared with the control group, MT significantly reduced serum cortisol concentration on day 30 (P < 0.05), whereas no significant differences were observed at the other sampling time points. Serum testosterone, spermidine, and melatonin concentrations remained unchanged throughout the study (P > 0.05). SPD supplementation significantly increased ejaculate volume on day 35 and sperm motility on day 42 (P < 0.05), whereas MT did not significantly affect these parameters. Neither treatment reduced the overall sperm abnormality rate. However, both SPD and MT significantly decreased the proportion of acephalic and decaudated sperm on day 56 (P < 0.05). Neither treatment significantly affected pregnancy rate, delivery rate, or the expression of PMFBP1 and SUN5 proteins in semen (P > 0.05). Regarding oxidative stress, MT significantly downregulated CAT protein expression (P < 0.05), whereas SPD significantly reduced MDA content and SOD1 protein expression (P < 0.05); MT showed similar but non-significant trends for these two markers (P > 0.05). Collectively, these findings demonstrate that SPD and MT exert distinct protective effects against heat stress, with SPD improving selected semen quality traits and both treatments reducing sperm head-tail separation, although these benefits did not translate into improved reproductive performance.

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