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Targeting the glucose dependent insulinotropic polypeptide receptor (GIPR) is of growing interest for treating type 2 diabetes and obesity, though the optimal approach remains unclear. Both GIPR agonism and antagonism, respectively, incorporated into drugs like tirzepatide and maridebart cafraglutide, have paradoxically both shown significant weight loss effects in humans. In this study, the metabolic impacts of a GIPR agonist (GIP108) and antagonist (NN-GIPR-Ant) were evaluated in lean and high-fat diet (HFD)-induced obese male mice. We assessed the impacts on food intake, body weight, glucose and insulin tolerance, liver triglyceride levels, bone markers and adipose tissue lipolytic gene expression. In lean mice, neither peptide affected food intake or body weight, but GIP108 improved glucose tolerance. In obese mice, both agents reduced food intake and body weight, with NN-GIPR-Ant producing more sustained appetite suppression. Energy expenditure remained unchanged, as weight loss matched that of pair-fed controls. GIP108 improved glucose tolerance independently of weight loss, whereas NN-GIPR-Ant reduced insulin sensitivity compared to pair-fed controls. Both treatments slightly increased liver triglyceride content compared to their pair-fed controls, and no treatment significantly affected plasma bone marker levels. Finally, NN-GIPR-Ant reduced the expression of adipose tissue lipolytic genes. Our data highlights the distinct metabolic effects of GIPR agonism and antagonism, offering insights for their future application in personalised metabolic disease treatments. Further human studies are needed to understand the long-term metabolic impacts of these therapies. Show less

Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) have strong triglyceride-lowering and anti-inflammatory properties, and high levels of these fatty acids have been associated with reduced risk of cardiovascular disease. The synthesis of n3-LCPUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and n6-LCPUFA, arachidonic acid, share a common pathway mediated by fatty acid desaturase genes, FADS1 and FADS2. LCPUFA synthesis is regulated by both modifiable and non-modifiable factors. Of particular interest is the role of genetic variants in the FADS gene cluster, which are associated with altered FADS1 and FADS2 expression, as well as LCPUFA levels. However, the specific functional variants and the precise molecular mechanisms by which these variants regulate FADS gene expression remain to be elucidated. Variation in the FADS gene cluster is thought to have arisen through natural selection and changing dietary patterns. Available evidence suggests these variants, either individually or as a haplotype, may alter FADS gene expression by modifying DNA methylation in regulatory regions, as well as microRNA and transcription factor binding sites. This review explores the current state of knowledge regarding the functional roles of these variants on LCPUFA synthesis and how these new insights will help support precision nutrition strategies aimed at improving an individual's n3-LCPUFA status and health. Identifying specific functional variants in or near the FADS gene cluster and elucidating the mechanisms by which these variants impact LCPUFA synthesis requires further investigation. However, hypothesis generating in vitro studies have revealed roles for epigenetics, non-coding RNAs, and modification of transcription factor binding sites. This knowledge will generate new insights that will help improve our understanding of the genetic basis underlying LCPUFA synthesis and how this may differ across populations. Show less

We examined whether wake-time movement composition was associated with weight loss maintenance among individuals who experienced clinically meaningful weight loss (> 5% of initial weight) using compositional data analysis. This was a secondary analysis from a behavioral weight loss maintenance intervention on weight regain over 12 months following clinically meaningful 3-month weight loss. Body weight was assessed at baseline, after weight loss (3 months), and at end of intervention (15 months). Wake-time behaviors (sedentary time [ST], light physical activity [LPA], and moderate-to-vigorous PA [MVPA]) were assessed at two time points during the maintenance intervention using accelerometry. Compositional data analysis was used to examine associations between wake-time movement composition and weight regain (kg). Among 153 individuals (80.4% female, 69.9% White), wake-time movement composition was related to weight regain (p = 0.001). MVPA was negatively associated with weight regain (p's < 0.05). Reallocating 10 min/day from ST or LPA to MVPA was associated with less weight regain (ST: -0.32 kg [-0.53, -0.12]; LPA: -0.37 kg [-0.59, -0.15]). Individuals who maintained clinically meaningful weight loss and those who did not differed in wake-time movement composition, driven by MVPA (36.1 vs. 24.3 min/day). The composition of wake-time behaviors, specifically MVPA, reduces weight regain after clinically meaningful weight loss in a behavioral weight loss maintenance intervention. ClinicalTrials.gov identifier: NCT01664715. Show less

Dysregulated extracellular matrix (ECM) deposition and epithelial-mesenchymal transition (EMT) in the trabecular meshwork (TM) contribute to glaucoma-associated fibrotic remodeling, and lysophosphatidic acid (LPA) potently induces these profibrotic responses in human trabecular meshwork (HTM) cells. We investigated whether an ethanolic extract of Show less

The dysregulated immune system, which drives chronic vascular inflammation and remodeling, plays a critical role in the pathogenesis of abdominal aortic aneurysm (AAA). CCR4 (C-C chemokine receptor 4), which is predominantly expressed on T cells and mediates their responses, has been shown to protect against inflammatory diseases including atherosclerosis. However, its role in AAA remains unknown. By analyzing hypercholesterolemic CCR4-deficient ( Genetic deletion of CCR4 on an CCR4 may serve as a potential therapeutic target for AAA. Show less

To determine whether genetic ancestry modulates Cross-sectional analysis of community-dwelling older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort (N = 2733). Participants spanning the cognitive spectrum underwent cognitive assessment, neuroimaging, plasma biomarker collection, and genome-wide genotyping from 2018 to 2023. Cognitive performance (global cognition, memory, executive function, verbal ability), brain morphometry (cortical thickness, hippocampal volume), and plasma biomarkers (Aβ In the full cohort, Genetic ancestry modifies the effect of Show less

Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4 Show less

Anoikis resistance and epithelial-mesenchymal transition (EMT) are crucial factors in tumor invasiveness and metastasis in lung adenocarcinoma (LUAD). Identifying anoikis-EMT-related genes could be beneficial for predicting prognosis and immunotherapeutic efficacy in patients with LUAD. This study aims to establish and validate a novel prognostic signature based on anoikis-EMT-related genes for LUAD and to identify the potential biomarkers encapsulated within it. Anoikis-related genes and EMT-related genes were retrieved from the GeneCards and dbEMT 2.0 databases. Univariate Cox regression analysis and principal component analysis (PCA) were conducted to define anoikis and EMT levels. Gene expression and clinical information of patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Univariate Cox regression and multivariate Cox regression analyses were conducted to construct a risk score model. Immune correlation and drug sensitivity analyses were performed to investigate the association of the risk score with the immune profile and antitumor treatment. Three essential genes in the model were examined for messenger RNA (mRNA) expression by reverse transcription-polymerase chain reaction (RT-PCR) and for protein levels via the Human Protein Atlas (HPA) database. LUAD patients demonstrating low Anoikis Potential Index (API) combined with high EMT Potential Index (EPI) exhibited the poorest overall survival (OS). We further constructed a nine-gene prognostic risk model that combines anoikis and EMT. High-risk patients demonstrated significantly shorter survival duration. The clinical-prognostic nomogram accurately predicted outcomes at 1, 3, and 5 years. In addition, patients in low-risk group demonstrated superior immune responses to treatment and were more sensitive to commonly used chemotherapy drugs. Our validation studies confirmed upregulated expression of ANGPTL4, SLC2A1, and BIRC5 in LUAD, observed at both transcriptional and translational levels. The anoikis-EMT-based risk model effectively forecasts both OS and immunotherapy response in LUAD patients, accelerating the identification of groundbreaking molecular biomarkers and prospective molecular targets. Show less

Rising global temperatures lead to a continuous increase in the frequency and intensity of extreme weather events, such as droughts and floods, posing serious threats to terrestrial homeotherms. However, adaptive changes in respiratory metabolism and molecular mechanisms in lung tissues of small mammals under extreme water shortage conditions remain unclear. This study hypothesized that small desert mammals can adapt to extreme water shortage environments by regulating the plasticity of lung tissue gene expression and respiratory metabolism. Using 29 wild-caught Siberian jerboas ( Show less

Cardiac fibrosis is characterized by an excessive accumulation of extracellular matrix proteins and occurs in a variety of cardiac diseases, such as the highly prevalent syndrome heart failure with preserved ejection fraction (HFpEF) and other cardiac disorders. Interstitial fibrosis has been identified as a central pathophysiological factor induced and maintained by metabolic stress and chronic inflammation. Considering the limited treatment options for cardiac fibrosis, new therapeutic targets are urgently needed. Mounting evidence for the cardioprotective effects of the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) provides a rationale to elucidate its role and that of its receptor PAC1 in metabolic stress-mediated cardiac fibrosis. Metabolic stress was induced by feeding a cholesterol-enriched diet (CED) to PACAP Show less

Tc17 cells (IL-17 The percentage of Tc17 cells, monocytes and IL-1β Higher populations of Tc17 cells, IL-1β The present results show that suppressing IL-1β expression by preventing CD80 [Figure: see text] The online version contains supplementary material available at 10.1186/s12964-026-02785-4. Show less

The comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in abdominal aortic aneurysm (AAA) pathogenesis are unclear. To evaluate the putative causal role of TRLs in AAA, quantify the relative effect on AAA risk ("aneurysmogenicity") of TRL vs LDL particles, and prioritize lipid-lowering drug targets for AAA prevention and treatment. We performed summary-level and individual-level Mendelian randomization (MR) analyses. Genetic variants were selected from 383,983 UK Biobank participants and ranked into 10 sets of variants where set 1 predominantly affected LDL cholesterol (LDL-C) and set 10 predominantly affected TRL cholesterol (TRL-C; and with mixed effects for intermediate variant sets). AAA outcome data were obtained from AAAgen (37,214 cases), FinnGen (4,439 cases), and the VA Million Veteran Program (MVP; 23,848 cases). Multivariable MR was used to assess the independent roles of LDL-C and TRL-C in AAA. For each set of variants, MR or logistic regression was used to estimate AAA odds ratios (ORs) per 10 mg/dL higher apolipoprotein B (apoB). Interaction analyses were conducted between a statin-like LDL-C-lowering variant set (set 3) and a TRL-C-lowering variant set (set 10). Drug-target MR was performed to evaluate lipid-lowering targets relevant to LDL-C- and TRL-C-lowering. Genetically predicted LDL-C and TRL-C concentrations were each associated independently with genetic liability for AAA after mutual adjustment, with 3.0 to 5.5 times stronger associations for TRL-C compared to LDL-C on a per-cholesterol basis. In AAAgen, the AAA OR per 10 mg/dL increased apoB concentrations were 1.10 (95% CI, 1.05-1.14) for variant set 1 (LDL-C-predominant) and 1.89 (95% CI, 1.69-2.11) for variant set 10 (TRL-C-predominant). Using the ratio of log(OR) per 10 mg/dL apoB for set 10 versus set 1 as a conservative estimate of relative aneurysmogenicity, TRLs were approximately 3.2 to 6.9 times more aneurysmogenic than LDLs across the three studies. No evidence of interaction was observed between LDLs and TRLs, indicating additive contribution to AAA risk. Drug-target MR supported strong protective associations for genetically proxied inhibition of TRL-pathway targets, particularly TRLs are at least threefold more aneurysmogenic than LDLs on a per-particle basis. Therapeutic strategies targeting TRL-C -especially via Show less

Low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL are generally considered normal. We tested the controversial hypothesis that a subset of individuals with 'normal' LDL-C levels may have a non-negligible risk of coronary artery disease (CAD) due to inherited factors, including monogenic variants and polygenic risk scores (PGS). A retrospective analysis of a prospective cohort from the Genomic Health Initiative at Endeavor Health, including 7880 participants without a prior diagnosis of CAD and not on statins at recruitment. Participants were stratified by baseline LDL-C levels and followed for incident CAD. The association of CAD risk with carrier status for pathogenic/likely pathogenic (P/LP) variants in Among participants, 31.2 % had LDL-C <100 mg/dL (normal), 39.5 % had LDL-C 100-129 mg/dL, and 29.3 % had LDL-C ≥130 mg/dL. Over a median follow-up of 8 years, CAD was diagnosed in 5.3 %, 6.9 %, and 7.6 % of participants in these LDL-C groups, respectively. Among those with normal LDL-C, CAD incidence rose to 9.5 % in individuals with high genetic risk (P/LP variants and/or high PGS). Genetic risk was significantly associated with CAD in multivariable models ( Individuals with 'normal' LDL-C levels can have substantial CAD risk if they carry high genetic risk. These findings underscore the importance of incorporating genetic information into CAD risk assessment, even among those with traditionally normal lipid profiles. Show less

Establishing early physical activity (PA) habits is vital for long-term health, with parents considered as key influencers on children's PA. Yet, most previous parent-offspring dyads examining PA associations were cross-sectional, rarely used device-based measures, and often overlooked movement composition. The aim of this study was to determine whether mother's and father's waking movement composition is cross-sectionally or longitudinally associated with those of their children. The SOPHYA cohort recruited families from a nation-wide population-based random sample stratified by child's sex, birth year, and language. All youth aged 6-16 years and their parents officially residing in Switzerland, were eligible. Baseline and follow-up assessment occurred in 2013-2015 and 2019-2020, respectively. Questionnaire information and accelerometer measurements were collected remotely. The main predictor was parental movement composition at baseline. The associations between parental and child movement compositions were examined using Dirichlet regression models, adjusting for child's age and sex, parental education, and language region. The endpoints were children's movement composition at baseline (cross-sectional) and follow-up (longitudinal), respectively. Baseline assessment provided accelerometer and self-reported covariate data for the same measurement week in 686 mother-child and 373 father-child pairs. Follow-up assessment provided accelerometer data for 263 children with maternal and 149 with paternal baseline data. Cross-sectionally, replacing parental sedentary behaviour (SB) with moderate-to-vigorous activity (MVPA) (mothers: 0.10, p < 0.001; fathers: 0.09, p = 0.002) or replacing SB with light physical activity (LPA) (mothers: 0.13; < 0.001; fathers: 0.09; p < 0.005) was associated with similar, but smaller shifts in children. Longitudinally, replacing parental SB with LPA was associated with similar, but smaller shifts in children five years later (mothers: coefficient: 0.12, p = 0.021; fathers: coefficient: 0.10, p = 0.108). The cross-sectional change in children's LPA/SB ratio predicted from a parent's 20% decrease in SB and corresponding 20% increase in LPA was about 18-fold smaller than the observed maternal shift and about 29-fold smaller than the paternal shift from which it was predicted. Dirichlet regression results suggest that parental movement composition may predict children's movement composition, highlighting parental movement patterns, particularly SB, as potentially effective targets for short- and long-term interventions to increase PA in both parents and children. Show less

Dietary bile acids (BAs) have been shown to affect food intake in chicks; however, the underlying central mechanisms remain unclear. This study investigated the effects of taurochenodeoxycholic acid (TCDCA), sodium taurocholate (STC), chenodeoxycholic acid (CDCA), taurocholic acid (TCA), hyodeoxycholic acid (HDCA), allocholic acid (ACA), and a mixed BA (MBA; 4.6% hyodicolate, 72.6% hyodeoxycholate, and 18.3% chenodeoxycholate) on feed intake and hypothalamic mRNA expression of appetite-related neuropeptides in chicks. To determine the effects, intracerebroventricular (ICV) injections of three doses (0.25, 0.5, and 1 μg) of each BA were administered to 5-day-old layer-type chicks, and feed intake was recorded at 30, 60, and 120 minutes post-injection. Quantitative PCR was used to determine the hypothalamic mRNA expression of neuropeptide Y (NPY) and its receptors, agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), and melanocortin receptors. Results showed that feed intake decreased after ICV administration of CDCA, CA, HDCA, MBA, and STC, whereas ACA and TCDCA increased intake (P < 0.05). TCDCA upregulated NPY5R, while CDCA downregulated NPY4R (P < 0.05). STC and CA increased POMC and MC4R expression and reduced AgRP (P < 0.05), whereas HDCA decreased AgRP (P < 0.05). ACA reduced MC4R expression, and MBA downregulated both NPY4R and NPY5R (P < 0.05). The result suggests that both orexigenic and anorexigenic neuropeptide genes are involved in the effects of BAs. The effect of BAs acts in a dose-dependent manner in the hypothalamus to influence feed intake. Show less

Hippocampal neuroinflammation (HNF) is a key pathological feature in neurodegenerative disorders. Milk-derived exosomes, as bioactive extracellular vesicles, have underexplored potential in regulating brain neuroinflammatory responses. This study aimed to characterize desert milk exosomes (D-Exo) and investigate their neuroprotective and anti-neuroinflammatory effects in LPS-induced HNF mice model and an LPS-stimulated BV2 microglia. Exosomes were isolated from desert and non-desert milk (ND-Exo) for proteomic analysis. After pretreating BV2 cells with exosomes and stimulating with LPS, their inflammatory responses and polarization were assessed by RT-PCR. Balb/c mice were orally gavaged with D-Exo or 0.9% NaCl for 28 days before LPS injection. Cognitive function was assessed via behavioral tests, with microglial/astrocyte activation analyzed by immunofluorescence. D-Exo exhibited superior stability and a unique proteomic profile enriched with proteins linked to neuroinflammation and blood-brain barrier (BBB) integrity, notably within the AMPK signaling pathway. In vitro, D-Exo shifted LPS-stimulated microglia from the M1 to the M2 phenotype. In vivo, it alleviated HNF and cognitive decline, reduced Aβ D-Exo is enriched with specific proteins, attenuates neuroinflammation and cognitive decline by regulating microglial M1/M2 polarization and AMPK pathway, highlighting its preventive potential. Show less

Exosomes are crucial mediators of intercellular communication. As a key component of milk, milk-derived exosomes are abundant in genetic cargo, particularly microRNAs (miRNAs), indicating their potential role in regulating mammary gland physiology. Therefore, this study aimed to investigate the specificity of miRNAs in milk-derived exosomes and their regulatory roles in lipid synthesis in bovine mammary epithelial cells (BMECs). Based on 17,838 DHI records showing a significantly higher milk fat percentage (MFP) in late lactation (4.24% ± 1.07%), 10 high- (5.96% ± 0.26%, HMF) and 10 low-MFP (1.68% ± 0.23%, LMF) cows were selected during this stage for milk-derived exosome isolation and miRNA profiling. Exosomes isolated via differential ultracentrifugation were verified as 50-150 nm vesicles expressing CD9, CD81, and TSG101. miRNA sequencing identified 1,320 differentially expressed miRNAs (496 upregulated and 824 downregulated) between the HMF_EXO and LMF_EXO groups. Uptake assays confirmed that BMECs internalized these exosomes, and qRT-PCR validation showed that miR-423-5p and miR-125b were significantly upregulated and downregulated in HMF_EXO- and LMF_EXO-treated BMECs, respectively. Functionally, exosomal miR-423-5p promoted intracellular lipid accumulation and TG synthesis in BMECs by targeting APOA5, whereas miR-125b inhibited lipolysis and fatty acid oxidation by repressing SLC27A1. This study demonstrates that milk-derived exosomal miRNAs represent a novel mechanism for regulating milk fat synthesis. Specifically, miR-423-5p and miR-125b directly modulated lipid metabolism in BMECs via the miR-423-5p/APOA5 and miR-125b/SLC27A1 pathways. These findings provide new insights into the molecular regulation of milk fat synthesis and highlight the importance of exosome-mediated intercellular communication in the lactating mammary gland. Show less

A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody-based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease. Show less

The Hedgehog (Hh) signaling pathway is a key regulator of adipogenesis and lipid metabolism. However, the specific role of its receptor, Patched2 (Ptch2), in these processes remains unclear. Here, using a CRISPR/Cas9-mediated Show less

Familial hypercholesterolemia (FH) is a heritable condition that disrupts the body's ability to clear low-density lipoprotein cholesterol (LDL-C), commonly known as "bad cholesterol" from the bloodstream. This leads to persistently elevated LDL levels from birth, significantly increasing the risk of premature atherosclerosis and cardiovascular events, such as heart attack and stroke. This occurs due to variations in genes such as low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). The treatments that are available for FH include pharmacological interventions, microbiome-based treatments, molecular approaches, nanotechnology methods, surgical procedures, nutraceuticals, herbal therapy, yoga and physical fitness methods, along with lifestyle management. This review discusses the adverse effects associated with various conventional treatment methods for hypercholesterolemia and the need for a safe and effective approach for the treatment of this genetic condition. An integrated approach combining pharmacological, molecular, and lifestyle interventions has emerged as a pragmatic solution. Yoga and fitness-based therapies positively impact lipid profiles, offering non-pharmacological and holistic adjunctive options. This comprehensive approach addresses the multifaceted aspects of FH management, considering genetic factors, socioeconomic considerations, and individualized patient needs. Show less

Familial dysbetalipoproteinemia (FDB) is a lipid disorder characterized by defective clearance of triglyceride-rich lipoprotein remnants. Definitive diagnosis has relied on genetic markers, lipid profiles, and specialized lipid assays including gel electrophoresis that demonstrates the characteristic beta-band consistent with enriched small VLDL and IDL. We present a case of a 51-year-old female with progressive hyperlipidemia despite a stable plant-based diet and regular exercise. Her lipid profile met many of the diagnostic criteria for FDB (ApoB < 120 mgd/L, TG > 133 mg/dL [1.5 mmol/L], and TG/ApoB ratio < 8.8). However, advanced lipid testing failed to demonstrate hallmark lipid remnant accumulation, likely due to statin therapy initiation prior to the time of testing. Genetic testing revealed heterozygosity for the ApoE2 variant (Arg176Cys) and another novel variant of unknown significance (VUS), 593 G > A (Arg198His), on the same allele (herein termed ApoE2-Wolverine). The ApoE2-Wolverine variant may be contributing to the patient's dyslipidemia; however, further investigation into its functional significance and cardiovascular implications is needed. Her treatment with rosuvastatin 10 mg, 2 g of daily eicosapentaenoic acid (EPA), and lifestyle modifications contributed to improvements in her lipid levels. This case highlights the diagnostic challenges in FDB, especially when novel genetic variants are involved. While many criteria for FDB were met, confirmatory gel electrophoresis and genetic testing were inconclusive. This case underscores the need for multimodal assessment in FDB diagnosis, incorporating genetic analysis, lipid profiles, and therapeutic response. Show less

G protein-coupled receptors (GPCRs) rapidly transmit extracellular signals by activating effector proteins, thereby producing well-characterized second messenger molecules. Free, unanchored polyubiquitin chains have been proposed as secondary messengers in immune and inflammatory pathways that regulate cellular responses to invading pathogens and the inflammatory cytokine Interleukin-1 beta (IL-1β). It remains unknown whether these molecules play a role in GPCR signaling. The present study used primary, immortalized, and transformed cellular models, together with loss-of-function approaches, to demonstrate the presence and functions of unanchored polyubiquitin chains in inflammatory signaling pathways that activate the activator protein 1 (AP-1) and nuclear factor-kappa B (NF-κB) transcription factors. In response to inflammatory GPCR agonists Angiotensin II (Ang II), lysophosphatidic acid (LPA), and thrombin (Thr), the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) controls early signaling events that lead to T-loop phosphorylation of Transforming Growth Factor β-activated kinase 1 (TAK1), IκB kinase beta (IKKβ), c-Jun N-terminal kinases (JNK1/2), and p38 mitogen-activated protein kinases (p38). In parallel, we document the rapid, transient TRAF6-dependent production of unanchored lysine (K)63-linked polyubiquitin chains that accumulate in TAK1 and IKKβ immunocomplexes. Pull-down assays specifically designed to capture unanchored polyubiquitin chains in cellular extracts from stimulated cells further support their transient nature. Lastly, stable expression of a zinc finger ubiquitin-binding protein (ZnF-UBP) domain, which specifically binds unanchored polyubiquitin chains in immortalized keratinocytes exposed to LPA and Thr, shows that this production occurs in the proximity to the plasma membrane and diminishes the T-loop phosphorylation of TAK1, IKKβ, JNK1/2, and p38, thereby affecting the induction of early transcriptional events. Our results support a novel paradigm in GPCR signal transduction, identifying unanchored K63-linked polyubiquitin chains as second messenger molecules. The online version contains supplementary material available at 10.1186/s12964-025-02646-6. Show less

Clutch length is a key determinant of reproductive efficiency in geese and strongly positively correlates with egg production. We recorded daily egg production in 280 individually housed Zi geese, calculated clutch-related indices, and selected 12 geese to form long-clutch (LC) and short-clutch (SC) groups for ovarian transcriptomic, proteomic, and metabolomic analyses. The results showed that egg number, large clutch length, large clutch number, average clutch length, and average clutch number were significantly higher in LC than in SC groups (P < 0.0001). Transcriptomic analysis identified 885 differentially expressed genes enriched in oocyte development and ovarian steroidogenesis, with APOB, PLA2G4C, MMP2, MMP9, and NOBOX as key genes; proteomic analysis identified 437 differentially abundant proteins enriched in arachidonic acid metabolism and mitophagy, with CXCL12, RARB, and MAD2L1 as key proteins; and metabolomic analysis identified 35 differentially abundant metabolites enriched in glycolysis/gluconeogenesis, with lactic acid, guanidinoacetic acid, and 3-hydroxybutyrylcarnitine as key metabolites. Integration of multi-omics datasets highlighted a lactate-associated cross-omics signature supported by YWHAZ at the protein level and by the lactate transporter SLC16A3. Collectively, these findings deepen our understanding of the molecular basis underlying clutch-length variation in goose ovaries and highlight candidate genes, proteins, and metabolites for future functional validation. Show less

Breast cancer (BC) progression is intricately linked to the dysregulation of transfer RNA-derived fragments (tRFs). Through comprehensive analysis of The Cancer Genome Atlas (TCGA) data, it is demonstrated that 5'tRF-GlyGCC is overexpressed in BC tissues and negatively associated with patients' survival. Mechanistically, 5'tRF-GlyGCC binds to lactate dehydrogenase A (LDHA), enhancing its enzymatic activity and promoting glycolysis, which drives BC cell malignancy. This binding is mediated by the phosphorylation of LDHA at tyrosine 10, and facilitated by fibroblast growth factor receptor 1 (FGFR1), through the formation of a ternary complex that amplifies oncogenic signaling. Furthermore, 5'tRF-GlyGCC/LDHA axis induces macrophage infiltration and polarization toward an M2 phenotype, mediated by the chemokine CCL7, thereby reshaping the tumor microenvironment. Additionally, it is uncovered that the biogenesis of 5'tRF-GlyGCC is regulated by ALKBH3 and ANG, which also modulate LDHA activity. In vivo, targeting 5'tRF-GlyGCC/LDHA signaling significantly suppresses tumor growth and enhances the efficacy of immunotherapy. Collectively, these findings elucidate the pivotal role of 5'tRF-GlyGCC in BC progression, highlighting its potential as therapeutic target for BC treatment. Show less