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Fibroblast Growth Factor (FGF) ligands and their receptor have been identified as the potent target in non-small cell lung cancer (NSCLC). However, the clinicopathological and microenvironmental characteristics of FGF/FGFR in NSCLC remain poorly elucidated. Here, we summarize 4656 NSCLCs and analyze clinicopathological features in 478 FGF/FGFR altered cases. AI analysis and multiplex immunofluorescence staining are used to reveal microenvironment features. First, around 10.27% NSCLC carry FGF/FGFR variant. Squamous cell carcinoma (41.95%) is much more than adenocarcinoma (8.32%). In 118 pathogenic variant (PV) cases, the most frequent variant is FGF/FGFR copy number increase (83.05%), the second is FGFR gene fusion (11.86%). Surprisingly, CCND1 always co-amplifies with FGF19 (100.00%). Furthermore, FGF PV is an independent risk factor for poor outcomes (overall survival: HR = 3.781, disease-free survival: HR = 3.340). And one-third of FGFR3-TACC3 fusion cases show clear cytoplasm in histology. Either CCND1/FGF19 co-amplification or KRAS co-mutation is closely related to cigarette exposure, and KRAS co-mutation acts as an independent factor of poor prognosis. Finally, the FGF/FGFR1/NOTCH1 within RB1 variant group has a remarkably high ratio of inner-tumor CD8+ T cell infiltration, non-exhausted T cells, exhausted T Show less

Elaidic Acid (EA) is a major trans-fatty acid that has garnered significant attention due to its potential role in inducing systemic toxicity. The current investigation was conducted to assess the toxic effects of EA (50 mg/kg, 100 mg/kg, and 150 mg/kg) on testicular tissues of Sprague Dawley rats. EA intoxication disrupted Wnt/β-catenin via downregulating the expression of WNT3A and TCF7L2 while upregulating the expression of AXIN1 and GSK-3β. The activities of antioxidant enzymes were reduced while the levels of cellular oxidative stress were escalated following the EA exposure. EA administration disrupted the process of steroidogenesis as well as spermatogenesis through the downregulation of CYP11A1, 5α-reductase, 3β-HSD, CYP17A1, and StAR while elevating spermatogenic abnormalities in head, tail and neck of sperm cells. The levels of LH, androgen binding protein, FSH, inhibin B, plasma testosterone and estradiol were lowered after EA administration. Testicular tissues showed inflammatory responses after EA exposure that is evident by elevated levels of TNF-α, IL-1β, COX-2, IL-6 and NF-κB. The expressions of Bax and Caspase-3 were upsurged while expression of Bcl-2 was reduced following the EA intoxication. These findings showed EA exerted toxic effects on testicular tissues via elevating oxidative stress, inflammation and apoptosis. Show less

Alzheimer's disease (AD) pathology is complex and involves mitochondrial dysfunction. There are emerging therapies targeting mitochondrial function in clinical trials for AD. This highlights the need for biomarkers that measure mitochondrial function. We determined the utility of a novel blood-based mitochondrial biomarker, the mitochondrial functional index (MFI), in the context of AD in a pilot study. In vitro and in vivo models of AD had a reduced MFI. MFI was lower in human AD subjects and APOE 𝜀4 carriers. Receiver operating characteristic analysis showed MFI had a higher area under the curve than other plasma biomarkers. The MFI biomarker correlated with the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. This study highlights the potential utility of MFI as a functional blood-based mitochondrial biomarker to interrogate energy metabolism. Ongoing studies are examining the relationship of MFI with brain energy metabolism outcomes. The MFI biomarker is reduced in cell and animal models of AD. The MFI biomarker is reduced in human AD subjects and APOE ε4 carriers. The MFI biomarker can discriminate between subjects with normal cognition and AD with better performance than other plasma biomarkers. The MFI biomarker correlates with cognitive scores. Show less

To examine cross-sectional and longitudinal associations between vascular risk factors, APOE genotype, and perivascular spaces (PVS), with attention to sex- and region-specific patterns in older adults. Population-based observational study using automated PVS quantification and multivariable regression models. UK Biobank, a large prospective cohort study of community-dwelling adults across the United Kingdom. A total of 38,121 participants (aged 47-90) were included cross-sectionally, and 4,225 longitudinally (mean follow-up 2.61 ± 1.0 years). A deep learning model was applied to brain MRI to quantify PVS in the basal ganglia (BG) and centrum semiovale (CSO). Vascular risk factors included hypertension, hypercholesterolemia, obesity, diabetes, smoking, and alcohol consumption. Models were adjusted for age, sex, scanner, and APOE-ɛ4 carrier status. Cross-sectionally, hypertension (b = 0.089, 95% CI = 0.069-0.108), hypercholesterolemia (b = 0.043, 95% CI = 0.017-0.064), obesity (b = 0.040, 95% CI = 0.016-0.064), and smoking (b = 0.056, 95% CI = 0.037-0.074) were associated with more BG-PVS. APOE-ɛ4 carriers (b = 0.039, 95% CI = 0.0015-0.076) and hypertension (b = 0.093, 95% CI = 0.056-0.130) were linked to more CSO-PVS. Moderate alcohol intake was associated with fewer BG-PVS in males but was associated with higher BG-PVS in females. Longitudinally, risk factor associations with PVS were limited. These findings support the utility of PVS as a biologically meaningful indicator of vascular brain health, with potential relevance for early identification of neurodegenerative risk in older adults. Show less

Lipoprotein (a) [Lp(a)] is a highly heterogeneous lipoprotein particle promoting panvascular disease. Structurally, it consists of an LDL-like core covalently bound to apolipoprotein (a) [apo(a)]. Molecular determinants linking various genetic variants of apo(a) constituent of Lp(a) to vascular pathology remain incompletely defined. We have built a model allowing dissection which variations in LPA gene are functional, and which are mere associates of these functional variations. Copy number changes in kringle IV type 2 (KIV-2), together with a spectrum of single nucleotide polymorphisms (SNPs), regulate apo(a) size, expression, and function. These variants can be broadly categorized into Lp(a)-increasing, Lp(a)-lowering, and null alleles, with distinct prevalence across populations. Notably, risk alleles such as rs10455872 and rs3798220 account for substantial variance in circulating Lp(a) and confer elevated susceptibility to coronary artery disease, whereas splice-altering and nonsense alleles markedly reduce Lp(a) concentrations. The therapeutic implications of modifying circulating Lp(a) levels are profound. While conventional lipid-lowering therapies exert little influence on Lp(a), antisense oligonucleotides (pelacarsen) and small interfering RNA agents (olpasiran, SLN360) achieve robust Lp(a) reductions. Integrating genetic insights with structural modeling provides a framework to disentangle functional from proxy associations within LPA and neutralize the cardiovascular hazard conferred by elevated levels of Lp(a). Show less

Apolipoprotein E (ApoE) and monocyte chemoattractant protein-1 (MCP-1) are inflammatory markers associated with premature atherosclerosis, which leads to increased cardiovascular disease risk among people with HIV (PWH). We aimed to evaluate the association between the plasma levels of these inflammatory markers and ischemic stroke in young PWH. We conducted a prospective case-control study at the University Teaching Hospital in Lusaka, Zambia, between March 2022 and October 2024, comparing young PWH with non-cardioembolic ischemic stroke (cases) to age- and sex-matched PWH without a history of stroke (controls). Standardized data collection instruments were used to collect information on other known risk factors for stroke, including demographic, clinical, laboratory, and imaging parameters. ELISA was done to measure ApoE and MCP-1 levels in the plasma of individuals in both the case and control groups. We analyzed results for 50 cases and 50 controls. Compared to controls, cases were more likely to have (1) traditional stroke risk factors such as hypertension (42 vs. 2%, The results suggest that lower plasma ApoE levels are independently associated with non-cardioembolic ischemic stroke in young PWH. Additional studies with larger sample sizes are needed to further explore the contribution of these inflammatory markers in young-onset HIV-associated stroke. Show less

Disruptive eating behaviors can negatively impact psychological well-being and increase the risk of metabolic diseases such as obesity, type 2 diabetes, and cardiovascular disease. While behavioral strategies remain central to dietary interventions, emerging research highlights genetic factors, particularly single nucleotide polymorphisms (SNPs), as contributors to individual differences in eating behaviors. This scoping review maps existing research on genetic modifiers of adult eating behaviors, identifying key variants and genetic predispositions. An extensive systematic search was conducted across 12 electronic databases, including PubMed, MEDLINE, and EMBASE, alongside relevant grey literature. Sixty-five studies published from 2014 to April 2024 met inclusion criteria. Data were synthesized using Covidence and NVivo for thematic mapping. Studies were eligible if they utilized genotyping to examine genetic markers, variations, or SNPs in relation to adult eating behaviors using validated questionnaires and/or dietary interventions. Six key themes emerged: taste perception; appetite and satiety; emotional eating; disinhibition; food timing and eating habits; and snacking, craving and binge eating. Frequently studied genes included CD36, MC4R, FTO, TAS1R, TAS2R, SLC4A5, SLC6A2, SLC6A4, DRD2, CLOCK, ADIPOQ and CA6, with some studies incorporating genetic risk scores. Across reviewed studies, there was a female predominance (female-to-male ratio of 1.6:1), while older adults were underrepresented (mean age: 35.2 ± 8.4 years). Cross-sectional study designs (58 %), highlighted a methodological gap, underscoring the need for longitudinal research to explore causality. This review provides valuable insights into the genetic underpinnings of eating behaviors and emphasizes the need for future research in more diverse populations to support precision nutrition strategies. Show less

Obesity is a complex, multifactorial disease influenced by genetic, hormonal, and metabolic factors. The fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes have been implicated in body weight regulation through gut–brain signaling and their interactions with adipokines and enteroendocrine hormones. This study investigated the association between gastric expression of FTO and MC4R genes and circulating levels of leptin, adiponectin, and ghrelin in individuals with and without obesity. We conducted a case–control study including 50 patients with obesity undergoing sleeve gastrectomy and 50 controls undergoing diagnostic endoscopy. Gastric tissue gene expression was assessed by qRT-PCR, and serum hormone levels were quantified using ELISA. Inverse propensity score weighting was used to adjust for age and sex. FTO expression was significantly upregulated in patients with obesity (fold-change: 5.8 vs. 1.0, Show less

Given that lipoprotein lipase (LPL) activity assays are not standardized for clinical use, we aimed to define reference values applicable to our clinical setting and identify a cut-off point to help distinguish Familial Chylomicronemia Syndrome from Multifactorial Chylomicronemia Syndrome, particularly in patients with inconclusive genetic findings. We evaluated 28 patients with a history of TG levels above 880 mg/dL (10 mmol/L), and assessed their likelihood of FCS using the Moulin score. LPL activity was measured in post-heparin plasma using a radiometric assay. Thirty normotriglyceridemic controls were used to define reference values. Genetic testing for FCS canonical genes and lipid profile was performed in all sHTG patients. The reference value for LPL activity was 33.3 (18.7-70.3) mIU, with a cut-off of 8.42 mIU (25 % of the median of NTG) to distinguish FCS from MCS. Eighteen patients without genetic variants in canonical genes, a Moulin score <9 and LPL activity >25 % of NTG, were classified as MCS. Five genetic diagnosed FCS patients, with a Moulin score>10 presented LPL activity <25 % of NTG. Four patients with inconclusive genetic results and a Moulin score>10 were classified as FCS according to LPL activity. LPL activity in patients with sHTG could be useful for differentiating FCS and MCS, particularly in patients with ambiguous or negative genetic findings, highlighting the need for specialized laboratory support in diagnostics. Show less

Ischemic stroke is frequently associated with symptomatic intracranial atherosclerotic stenosis (sICAS), is a leading cause of global disability and mortality. Current guidelines recommend dual antiplatelet and intensive statin therapies. Proprotein convertase subtilisin 9/kexin type 9 (PCSK9) inhibitors have emerged as a potent lipid-lowering therapy, potentially influenced by genetic variations, particularly in the CYP2C19 gene. This study at Xuzhou Central Hospital from January 2021 to December 2023 included 151 patients divided into a statin group (n = 73) and a PCSK9 inhibitor (PCSK9i) group (n = 78). It evaluated lipid profiles, inflammatory markers, neurological function, and clinical outcomes over a 180-day follow-up period, with additional analysis stratified by CYP2C19 genotype. The PCSK9i group demonstrated significant improvements in lipid parameters compared to the statin group, including greater reductions in low-density lipoprotein cholesterol (LDL-C) (p = 0.008), total cholesterol (TC) (p < 0.001), and triacylglycerols (TAG) (p = 0.041), along with apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) (both p < 0.001). Inflammatory markers, particularly interleukin-6 (IL-6), significantly reduced in the PCSK9i group (p < 0.001). In the PCSK9i group, CYP2C19 rapid metabolizers achieved greater reductions in LDL-C (p = 0.021), ApoB (p = 0.003), and IL-6 levels (p = 0.041) compared to slow metabolizers. Post-treatment modified Rankin Scale (mRS) scores were significantly lower in rapid metabolizers compared to slow metabolizers (p = 0.018), though clinical events occurred infrequently in both subgroups. This study demonstrates that PCSK9 inhibitor therapy combined with statins provides enhanced lipid-lowering and anti-inflammatory effects compared to statin monotherapy in sICAS patients. While the CYP2C19 genotype may influence specific treatment responses, particularly lipid parameters, its impact on clinical outcomes requires further investigation. Show less

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders. Show less

An 88-year-old man was referred with peripheral edema, pleural effusion and nephrotic syndrome that had developed 3 months prior. Based on a kidney biopsy, the majority of glomeruli exhibited capillary wall thickening and the slight area of glomeruli exhibited spike formations and bubbly appearances. Fluorescent immunostaining showed global deposition of neural epidermal growth factor-like 1 (NELL-1), immunoglobulin (Ig) G1 and complement (C) 3c within the glomerular capillary wall. Electron microscopy showed the presence of unique subepithelial electron-dense deposits distributed in a ribbon-like manner along more than 75% of glomerular capillary walls. Fluorescent immunostaining showed no positivity for other recently identified antigens associated with membranous nephropathy, including M-type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), and exostosin 1 (EXT1). A comprehensive medical examination for malignant diseases yielded negative results, and there was no discernible change in κ/λ staining. Additionally, serum complement levels were within the normal range. The patient was therefore diagnosed with NELL-1-positive membranous nephropathy and has been refractory to the treatment with prednisolone, cyclosporine (CyA) and rituximab for 10 months. According to previous reports, segmental or incomplete IgG capillary loop staining have been observed in 93.4% of cases of NELL-1-positive membranous nephropathy. Diffuse and global ribbon-like deposits, as observed in this case, are exceedingly rare. Show less

Trazodone, an antidepressant, may play a potential role in enhancing long-term memory by combining anxious behavior deficits induced by scopolamine. The current study proposes the potential novel mechanistic insights between oxidative stress and memory biomarkers, including BNDF and CREB pathways, to modulate the pathogenesis of AD-like symptoms. Behavioral deficits were studied in terms of biochemical determination of lipid peroxidation and acetylcholinesterase activities. In addition, the study looked at the immunohistochemistry of BDNF and CREB against scopolamine-induced AD-like symptoms. Moreover, histopathological alterations were also performed against an AD-like model. Aβ The present study findings showed that administration of TRAZ considerably improved cognitive impairments as validated by NOR and display of anti-anxiety behavior, as verified by EPM. In addition, biochemical findings confirmed that TRAZ lowered oxidative stress through LPO, reduced Aβ deposition, and decreased the AChE. Furthermore, there was a notable upregulation of BDNF and CREB signaling expression, as confirmed by the IHC. Overall, the study findings confirmed that TRAZ could be useful in mitigating the negative effects of scopolamine-induced cognitive impairment and lowering oxidative stress by enhancing memory indicators. Show less

Primary hepatocellular carcinoma (HCC) is a common malignancy with high morbidity and mortality. Despite progress in systemic therapies, survival in advanced HCC remains poor due to patient heterogeneity and individual differences, necessitating a personalized approach rather than relying solely on guidelines. Here, we present an exceptional case study in which a systematic regimen without immune checkpoint inhibitors was chosen based on the patient's specific genetic test results. Remarkably effective with long-term survival benefits were observed as a result. This case underscores the importance of incorporating tumor profiling and personalized treatment plans, in addition to adhering to guidelines and standards, for delivering more efficacious and well-tolerated therapeutic options to patients with liver cancer. Show less

ASD is a neurodevelopmental disorder with specific core symptoms. Physical activity has been demonstrated to positively influence the pathological mechanisms underlying autism and to alleviate associated symptoms. A comprehensive synthesis was conducted by reviewing and integrating relevant literature. Literature review revealed that the mechanism of physical activity intervention in autism primarily involves modulation through neuronal factors, glial cells, and gut microbiota. Neuronal factors include brain-derived neurotrophic factor, axonal protein families, and neurotransmitters. Additionally, physical activity helps alleviate stereotypical behaviors and internal anxiety in individuals with ASD, reduce obesity and cardiovascular diseases in some patients, and enhance social communication skills. Show less

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. This study aims to elucidate the role and mechanisms of fatty acid desaturase 1 (FADS1) in ferroptosis as well as AMD progression. An integrated bioinformatics analysis based on the array of data from the GEO database was conducted to identify candidates involved in ferroptosis during AMD. Subsequently, cellular and mouse models of AMD were developed using sodium iodate (NaIO FADS1 expression was upregulated in AMD patients and in vitro and in vivo models of AMD. Its pharmacological inhibition had decreased mitochondrial ROS formation, lipid peroxidation, and ferroptosis as well as increased RPE cell function in ARPE-19 cells and C57BL/6J mouse models of AMD. Mechanistically, Sp1 was identified as a key transcription factor of FADS1. Moreover, Sp1 inhibition downregulated FADS1 expression consequently attenuating FADS1-mediated ferroptosis as well as AMD phenotypes. For the first time, we demonstrated that Sp1 regulates FADS1-mediated ferroptosis in RPE cells. Our findings provide novel insights into the progression and treatment of AMD. Show less

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) triggered by a shift in peripheral inflammation. A main mechanism by which peripheral alterations are transmitted to the brain is the infiltration of extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduces cognitive impairment. Injection of EV from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats to normal rats induces neuroinflammation, alterations in neurotransmission, and cognitive impairment. PBMC contain different cell types. The aims were 1) to identify which cell type produces the pathological EV in hyperammonemic rats; 2) to identify the mechanisms by which hyperammonemia increases EV release from monocytes and induces the formation of pathological EV; and 3) to analyze the role of TNFα and PKA in these mechanisms. EV were isolated from primary cultures of CD4 In hyperammonemic rats, monocytes but not CD4 These data unveil that monocytes produce the pathological EV in hyperammonemia and the underlying mechanisms and provide the bases for new treatments to improve cognitive and motor function in hyperammonemia and MHE. Show less

To explore latent profiles of social isolation in maintenance haemodialysis (MHD) patients and to analyse the factors influencing different latent profiles. Multicentre cross-sectional study. Between November 2024 to March 2025, 305 MHD patients from the haemodialysis centres of three hospitals in Henan Province, China, were recruited using a convenience sampling method. All participants completed the general information questionnaire, Lubben Social Network Scale 6 (LSNS-6), UCLA Loneliness Scale-6 (ULS-6) and Personal Mastery Scale. Latent Profile Analysis (LPA) was used to classify the participants into potential subgroups with different types of social isolation. The influencing factors of profiles were explored by univariate analysis and multiple logistic regression analysis. Social isolation of 305 patients can be divided into three profiles: the family-friend dual isolation group (14.10%), friend isolation-only group (47.54%), and social network well-being group (38.36%). Multivariable logistic regression analysis revealed that monthly personal income, living arrangement, social participation, dialysis time, post-dialysis fatigue, number of comorbidities, loneliness and personal mastery were identified as factors influencing the profiles. There is heterogeneity in social isolation among MHD patients. It is therefore necessary to implement targeted intervention measures based on the distinct characteristics of each subgroup to facilitate their social reintegration. Nurses should identify differences in social isolation among MHD patients. It is necessary to establish tripartite connections between families, hospitals and communities, and develop personalised psychosocial interventions to alleviate social isolation. The study identified distinct subgroups of social isolation among MHD patients, while emphasising the impact of psychological resources such as loneliness and personal mastery on social isolation. This may offer critical insights for nurses to develop targeted interventions for patients' social health. The study followed the STROBE guidelines for cross-sectional studies. No patient or public involvement. Show less

Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Bronchial biopsy specimens were obtained from healthy subjects and patients with severe asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). A selective CDH11 antagonist SD133 (100 mg/kg) was given to allergen-exposed mice after airway challenge. The effects of recombinant CDH11 were also tested in vivo, and FGFR1 inhibition was used to explore a possible mechanism for CDH11-induced inflammatory responses in the lung. We detected upregulated expression of CDH11 in the airway mucosa of severe asthma patients when compared with the healthy control. In the OVA/CFA-induced model, though CDH11 expression in the lung remained unchanged, pharmacological antagonism of CDH11 with SD133 dramatically decreased airway neutrophil accumulation, as well as IL-6 production, but had no effect on eosinophilic infiltration, type 2 inflammation (IL-4 and IL-5) nor airway hyperresponsiveness. In the TDI model, pulmonary CDH11 expression was upregulated. Treatment with SD133 inhibited TDI-induced airway hyperresponsiveness and neutrophilic inflammation, decreased IL-6 and TNF-α production, with no effect on airway eosinophil counts and type 2 inflammatory cytokines. In addition, intratracheal instillation of recombinant CDH11 led to neutrophil recruitment in the lungs of mice, which could be attenuated by inhibition of FGFR1 signaling. CDH11 contributes to airway neutrophilic inflammation in severe asthma through the FGFR1 pathway. Show less

Microplastics intrigue kidney toxicity such as mitochondrial dysfunction and inflammation promotion. However, as an organ relying heavily on fatty acid oxidation, how microplastics influence kidney lipidomes remain unclear. Hence, we performed Raman spectra and multidimensional mass spectrometry-based shotgun lipidomics to decode kidney lipidomics landscape under polypropylene microplastics exposure. Kidney functions and cellular redox homeostasis were remarkably disturbed as revealed by levels of biochemical renal function markers, malonaldehyde, hydrogen peroxide and antioxidants. Ultrastructure alterations including the foot process fusion implied the kidney injury associated with lipidomic changes. Raman spectra successfully further confirmed the cellular change of reactive oxygen species and lipid disorders. Lipidomics showed that polypropylene microplastics caused abnormal lipidome and irregular exchange by remodeling triglycerides and phospholipids. Genes involved in lipid metabolism such as Fads1 and Elovl5 exhibited highly diversified expression profiles responding to polypropylene microplastics stress and possessed significant correlations with ROS indicators. These results explained ultrastructure alterations and aggravation of kidney injuries. Our work revealed polypropylene microplastics inducing lipidomic detriment in mouse kidney by Raman spectra and lipidomics firstly, elucidating the significances of lipidomic remodeling coupled with ROS stress in the kidney damages. The findings provided reliable evidence on the health risks of polypropylene microplastics in kidney. Show less

Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and long-term ASCVD risk is not known. We characterised the plasma metabolomic profile (1228 metabolites) of 1852 participants (58.1 ± 7.5 years old, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Logistic regression was used to assess the impact of metabolite levels on ASCVD risk (nonfatal MI, revascularisation, and cardiac mortality). We additionally explored the effect of genetic variants neighbouring ASCVD-related genes on the levels of metabolites predictive of ASCVD events. The Atherosclerosis Risk in Communities (ARIC) study (n = 4790; 75.5 ± 5.1 years old, 57.4% female, 19.5% self-identified as Black) was used as an independent validation cohort. In fully adjusted models, alpha-ketobutyrate [AKB] (OR 0.62 [95% CI, 0.49-0.80]; p < 0.001), and 1-palmitoyl-2-linoleoyl-GPI [OR, 0.62, 95% CI, 0.47-0.83; p < 0.001], two metabolites in amino acid and phosphatidylinositol lipid pathways, respectively, showed a significant protective association with incident ASCVD risk in both Heart SCORE and ARIC cohorts. Three plasmalogens and a bilirubin derivative, whose levels were regulated by genetic variants neighbouring FADS1 and UGT1A1, respectively, exhibited a significant protective association with ASCVD risk in the Heart SCORE only. Higher mid-life levels of AKB and 1-palmitoyl-2-linoleoyl-GPI metabolites may be associated with lower risk late-life ASCVD events. Further research can determine the causality and therapeutic potential of these metabolites in ASCVD. This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health (NIH) grant R01HL089292 and UL1 TR001857 (Steven Reis). Further, NIH funded R01HL141824 and R01HL168683 were used for the ARIC study validation (Bing Yu). Show less

Psychosomatic disorders are conditions in which physical (somatic) symptoms are triggered or aggravated by psychological distress. These disorders result from complex interactions among the endocrine, central nervous, and immune systems. Emerging evidence indicates that gut microbiota (GM) dysbiosis, epigenetic alterations, and immune system dysregulation play pivotal roles in the pathogenesis of psychosomatic disorders and may serve as potential biomarkers for disease states and therapeutic outcomes. This review first outlines how epigenetic dysregulation contributes to psychosomatic disorders through altered expression of genes such as GRM2, TRPA1, SLC6A4, NR3C1, leptin, BDNF, NAT15, HDAC4, PRKCA, RTN1, PRKG1, and HDAC7. We then examine current evidence linking psychosomatic disorders with changes in GM composition and GM-derived epigenetic metabolites, which influence immune function and neurobiological pathways. The core focus of this review is on therapeutic interventions-including probiotics, prebiotics, postbiotics, fecal microbiota transplantation, and targeted dietary approaches-that modulate the gut-brain axis through epigenetic mechanisms for the management of psychosomatic disorders. Finally, we highlight the current challenges and future directions in elucidating the interplay between epigenetics, the GM, and psychosomatic disease mechanisms. In this context, human iPSC-derived multicellular organoids may serve as powerful platforms to unravel mechanistic pathways underlying inter-organ interactions. Show less

Poor feather growth not only affects the appearance of the organism but also decreases the feed efficiency. Methionine (Met) is an essential amino acid required for feather follicle development; yet the exact mechanism involved remains insufficiently understood. A total of 180 1-day-old broilers were selected and randomly divided into 3 treatments: control group (0.45% Met), Met-deficiency group (0.25% Met), and Met-rescue group (0.45% Met in the pre-trial period and 0.25% Met in the post-trial period). The experimental period lasted for 56 d, with a pre-trial period of 1-28 d and a post-trial period of 29-56 d. In addition, Met-deficiency and Met-rescue models were constructed in feather follicle epidermal stem cell by controlling the supply of Met in the culture medium. Dietary Met-deficiency significantly (P < 0.05) reduced the ADG, ADFI and F/G, and inhibited feather follicle development. Met supplementation significantly (P < 0.05) improved growth performance and the feather growth in broilers. Met-rescue may promote feather growth in broilers by activating the Wnt/β-catenin signaling pathway (GSK-3β, CK1, Axin1, β-catenin, Active β-catenin, TCF4, and Cyclin D1). Compared with Met-deficiency group, Met-rescue significantly (P < 0.05) increased the activity of feather follicle epidermal stem cell and mitochondrial membrane potential, activated Wnt/β-catenin signaling pathway, and decreased the content of reactive oxygen species (P < 0.05). CO-IP confirmed that mitochondrial protein PGAM5 interacted with Axin1, the scaffold protein of the disruption complex of the Wnt/β-catenin signaling pathway, and directly mediated Met regulation of Wnt/β-catenin signaling pathway and feather follicle development. PGAM5 binding to Axin1 mediates the regulation of Wnt/β-catenin signaling pathway, and promotes feather follicle development and feather growth of broiler chickens through Met supplementation. These results provide theoretical support for the improvement of economic value and production efficiency of broiler chickens. Show less

Fibroblast growth factor receptors (FGFRs) play a critical role in the regulation of cancer cell proliferation, differentiation, and migration. However, the development of acquired resistance to FGFR inhibitors remains a major challenge in treating non-small cell lung cancer (NSCLC), particularly due to mutations at the gatekeeper residue. In this study, we report the discovery of a series of irreversible FGFR inhibitors targeting gatekeeper mutations in FGFR1-3, utilizing a 2,4,5-trisubstituted pyrimidine scaffold. Through rational design, structure-activity relationship optimization, and pharmacokinetic evaluation, compound ng Show less