👤 Ruolan Miao

Endoplasmic reticulum (ER) stress plays a significant role in chronic pain, but its potential involvement in chronic itch remains largely unexplored and poorly understood. In the current study, we investigated whether ER stress signaling in keratinocytes contributes to the pathogenesis of chronic itch. Our behavioral tests showed that the ER stress inhibitor 4-PBA attenuated itch-related behaviors in both acute and chronic itching mouse models, and reduced compound 48/80 and serotonin-induced activity of dorsal root ganglion (DRG) neurons. qPCR and western blotting revealed that the ER stress-related proteins and Lipocalin-2 (LCN2) were significantly elevated in the affected skin under chronic itch conditions and in cultured keratinocyte HaCaT cells and mice skin keratinocytes. The ELISA test showed that the level of LCN2 increased significantly in plasma but not in DRG tissue, from both acetone-ether-water (AEW) induced dry skin and imiquimod (IMQ) induced psoriasis model mice. Current clamp recording demonstrated that LCN2 induced hyperexcitability in dorsal root ganglia neurons, which could be abolished by HS024, the inhibitor of melanocortin receptor 4 (MC4R). In addition, pharmacological inhibition of transient receptor potential vanilloid 1 (TRPV1) or TRPV1 knockout blocked LCN2-induced hyperexcitability in DRG neurons. In conclusion, this study demonstrated that keratinocyte ER stress is involved in chronic itch genesis by releasing LCN2, which sensitized primary sensory neurons via TRPV1. These findings suggested that inhibition of ER stress in keratinocytes could be a promising therapeutic strategy for treating chronic itch. Show less

Geriatric depression affects 12.95-28.4% of adults aged ≥ 60, yet treatment rates remain critically low globally. Lifestyle factors, particularly exercise and sleep demonstrate therapeutic potential, integrated interventions may exert synergistic effects on geriatric depression, though such interventions remain scarce. The Geriatric Exercise-Sleep Optimization (GESO) project aims to evaluate the clinical efficacy and cost-effectiveness of a combined exercise and sleep health intervention in alleviating depressive symptoms among community-dwelling older adults with depression, and exploring the potential underlying mechanisms. This is a stepped-wedge cluster-randomized trial (SW-CRT). A 12-week integrated exercise and sleep intervention will be implemented to all eligible participants during the study period. The primary aim is to evaluate the clinical efficacy in alleviating depressive symptoms. Secondary aims are to evaluate the additional health outcomes (i.e., quality of life, physical activity level, daily step count, sleep quality, and anxiety symptom), cost-effectiveness, and potential mechanisms. Costs will be aggregated and analyzed for economic evaluation. Costs will be aggregated and analyzed for economic evaluation. Salivary measured BDNF and irisin levels, and EEG-based brain function connectivity will be collected to assess potential intervention mechanisms. Mixed-effect linear regression models will be used to evaluate the effects of the integrated exercise-sleep intervention on primary and secondary outcomes. This study is expected to provide an effective and practical mode for an integrated exercise and sleep intervention among community-dwelling older adults with depression. Intended outcomes of the trial will facilitate changes in best practice to improve outcomes for this population.Trial registration Chinese Clinical Trail Registry ChiCTR2500107641, Registration date: 15 August 2025. Show less

The gastrointestinal system is of particular importance in radiation biodosimetry because of its constant cell renewal and sensitivity to radiation-induced injury. It has been reported that total abdominal irradiation causes distant cognitive defects in a mouse model. In this study, we demonstrated that metformin alleviated the cognitive dysfunction caused by total abdominal irradiation. No neuropathological changes were observed in hippocampal tissues in control, irradiated, and irradiated plus metformin-treated groups. However, we found that metformin treatment improved the expression of brain-derived neurotrophic factor and the phosphorylation level of cAMP response element-binding in the hippocampus from irradiated mice. Furthermore, our results revealed that metformin treatment reduced the expression of miR-34a-5p, which targets the brain-derived neurotrophic factor mRNA, in the small intestine, peripheral blood, and hippocampus. More importantly, injection of miR-34a-5p agomir inhibited the enhancement effects of metformin on the cognitive defects induced by total abdominal irradiation, as well as the enhanced expression of BNDF and the phosphorylation level of cAMP response element-binding in the hippocampus. Thus, our results provide alternative strategies for the treatment of total abdominal irradiation-induced distant cognitive impairment using metformin and further confirmed that miR-34a-5p is a potential drug target to reduce the cognitive defects caused by total abdominal irradiation. Show less

Alcohol use disorder (AUD) is a chronic condition marked by compulsive drinking and withdrawal-related negative affect. Histamine (HA) signaling, particularly via the histamine H3 receptor (H3R), may modulate alcohol-related behaviors. We investigated the effects of pitolisant, an FDA-approved H3R antagonist, on ethanol (EtOH)-related behaviors in mice. Adult male C57BL/6J mice underwent acute or chronic (2 or > 8 weeks) intermittent alcohol exposure. Pitolisant pretreatment was administered, and then pharmacological behavior, histologic, and molecular assays were conducted. Pitolisant administration reduced acute EtOH-induced locomotor activation, conditioned place preference, and sedative effects, and also curtailed EtOH intake. It alleviated anxiety and depression-like behavior during 24-h withdrawal (Post-EtOH). Mechanistically, the Post-EtOH condition was featured by complicated brain cFos expression mapping, including elevated cFos, [HA] and [glutamine]/[glutamate] ratio in the lateral habenula (LHb). However, systemic pitolisant treatment significantly increased [norepinephrine]/[normetanephrine] ratio, and restored the diminished phosphorylated CREB and BDNF levels in the LHb. Intra-LHb H2R antagonist cimetidine infusion partly blocked the pitolisant therapeutic effect on alcohol-related behavior. These findings highlight the HAergic system as a critical regulator of alcohol-related behaviors. The LHb HA signaling and norepinephrine neurotransmission might underlie pitolisant's potential novel therapeutic strategy for AUD. 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

The mechanisms by which Polycyclic Aromatic Hydrocarbons (PAHs) induce lipid metabolic disorder and inflammation in marine invertebrates remain poorly understood. This study utilized the clam Ruditapes philippinarum during its reproductive stage as a model organism, integrating high-throughput omics, computational simulation, and confocal microscopy to elucidate the accumulation characteristics and toxicological pathways of PAHs. The results demonstrated that PAHs significantly accumulated in the digestive gland and gonads, primarily sequestered within lipid droplets. This tissue distribution was found to be dependent on a lipid-dependent transport mechanism mediated by ApoB, FATP, and FABP4. Mechanistically, PAHs activated SREBP1 and PPARα, β nuclear receptors by interfering with the neuroendocrine system and endoplasmic reticulum stress pathways. This activation resulted in dysregulated lipid metabolism (favoring synthesis over degradation) and subsequent abnormal lipid (TG, PL) deposition. Furthermore, PAHs induced low-grade inflammation by synergistically activating the NF-κB and AP-1 pathways, a response driven by both lipotoxicity and cellular organelle stress. This finding provides important scientific evidence for contaminant risk assessment in aquatic organisms. Show less

Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36 (cluster of differentiation 36). The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health. Show less

Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated with the incidence of ischemic heart disease (IHD). However, the causal association between ApoC3 and IHD development is unclear. ApoC3 expression changes were assessed in plasma from IHF patients/healthy donors and cardiac tissue from rodent models. 10-week-old male human ApoC3 transgenic (ApoC3 Overexpression of human ApoC3 in ApoC3 ApoC3 overexpression could activate cardiac TLR2/NF-κB to trigger the inflammation, oxidation, and apoptosis pathways, finally aggravating IHF in mice. Inactivation of ApoC3 could significantly alleviate IHF in hamsters. Show less

Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive. We analysed the expression of deubiquitinating enzymes in human atherosclerotic lesions and found that USP25 was significantly downregulated. The role of USP25 in atherosclerosis was validated in mouse models with an ApoE USP25 was predominantly expressed in macrophages in atherosclerotic lesions, and ablation of macrophagic USP25 significantly exacerbated atherosclerosis in ApoE This study elucidated the function and molecular mechanism of USP25 in atherosclerosis, identifying USP25 as a beneficial regulator for this disease. This work was supported by the Natural Science Foundation of Zhejiang Province (LZ24H090003 to X.W. and LTGY23H090001 to W.W.), the National Natural Science Foundation of China (82150710557 and 82293642 to W.S.; 81971143 to X.W., and 82271347 to G.W.), and Wenzhou Municipal Science and Technology Bureau (Y2021094 to J.H.). Show less

We tested whether inflammation indexed by soluble tumor necrosis factor receptor-1 (sTNFR1) is related to cognitive decline. We examined serum sTNFR1 with cognition in the Health and Retirement Study (HRS) and cerebrospinal fluid (CSF) sTNFR1 with tau pathology and magnetic resonance imaging (MRI)-based atrophy in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Finally, we used Mendelian randomization (MR) to assess associations between genetically proxied sTNFR1 and regional brain volumes. Data were from HRS (2016-2020; N = 6028) and ADNI (N = 287). In HRS, serum sTNFR1 was log-transformed (quartiles); in ADNI, CSF sTNFR1 was analyzed. Global cognition included word recall, serial 7 s, and counting backwards. In ADNI, cognition was measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB); CSF total tau/phosphorylated tau and longitudinal MRI regional volumes were analyzed. Associations were estimated with linear and linear mixed-effects models adjusted for demographic, clinical, and genetic covariates including apolipoprotein E ε4 (APOE ε4). Incident mild cognitive impairment (MCI)/dementia was modeled with cause-specific Cox and Fine-Gray models. Incremental prediction used optimism-corrected change in area under the curve (AUC; ΔAUC), net reclassification improvement (NRI)/integrated discrimination improvement (IDI), calibration, and decision curve analysis. MR used genome-wide association study (GWAS) statistics to test effects of genetically proxied sTNFR1 on MRI-derived regional volumes. In HRS (follow-up 4 years), higher serum sTNFR1 was associated with lower baseline cognition and faster decline in global cognition (β = - 0.16/year). Higher sTNFR1 predicted MCI/dementia (Cox HR ≈ 1.17; Fine-Gray sHR ≈ 1.14); among cognitively normal individuals, risk was elevated (OR = 1.30; 95% CI, 1.03-1.63). Adding sTNFR1 to 2- and 4-year prediction models conferred small discrimination gains after internal validation (ΔAUC ≤ 0.003) and minimal or inconsistent net clinical benefit. In ADNI, higher CSF sTNFR1 was associated with greater CSF total tau and phosphorylated tau, and predicted accelerated caudate atrophy. Exploratory MR suggested a nominal association with reduced right inferior temporal volume, limited by instruments. sTNFR1 is associated with cognitive decline and tau-related selective neurodegeneration, but provides limited incremental predictive value beyond established risk factors; external validation and replication are warranted. Show less

We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an in vivo apolipoprotein E-deficient (ApoE Show less

The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2 Show less

Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain. We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs-Fgf/Fgfr axis in regulating ventricular compaction. Show less

Enzyme immobilization is critical for enhancing enzyme stability and reusability. Catalytically active inclusion bodies (CatIBs) have emerged as a promising immobilization strategy due to their straightforward production, ease of separation, and high purity. Unlike traditional cross-linked enzyme aggregates (CLEAs) that require a precipitation step, CatIBs form through carrier-free self-aggregation during expression. To overcome the limitations of conventional methods, a novel technique has been developed in this study, focusing on L-phenylserine aldolase (LPA) as the model enzyme. A hybrid tag (HLHLHL) was fused to the N-terminus of LPA to generate 3HL-LPA, which promotes the formation of active inclusion bodies. Based on structural prediction and surface properties, the active aggregation process of 3HL tags through electrostatic interactions and hydrophobic interactions was analyzed. Innovatively, we combined CatIBs and CLEAs technologies to develop novel CatIBs-CLEAs. For comparison, a control was prepared by fusing a hexahistidine tag (HHHHHH) to LPA's N-terminus (6H-LPA) to enhance soluble expression, followed by conventional CLEAs preparation. Results showed that CatIBs-CLEAs achieved an activity recovery of 69.87% after glutaraldehyde crosslinking, significantly higher than the 48.1% for conventional CLEAs. CatIBs-CLEAs also exhibited superior thermal stability across temperatures, high stability between pH 5-9, and retained over 70% activity after seven batch cycles. The integrated CatIBs-CLEAs technology combines the production advantages of CatIBs with the stability benefits of CLEAs, offering a promising strategy for designing efficient, robust industrial biocatalysts with broad application potential. Show less

To identify latent profiles of proactive health behaviors in patients with hypertension, examine the category-specific influencing factors. Proactive health behavior, as an emerging concept, refers to a self-motivated approach to systematically managing health-related factors in order to actively maintain and promote one's health status. However, existing studies have largely focused on describing the overall level of such behaviors among patients with hypertension, with insufficient exploration of behavioral heterogeneity within this population. Moreover, there has been a lack of systematic integration of established behavioral theories to explain the multifactorial mechanisms underlying different behavioral patterns, which limits the development of precise nursing interventions. A cross-sectional study was performed, involving 352 patients with hypertension from 8 communities in Anhui Province from September to December 2025. The survey tools included self-designed demographic and clinical instrument, the Proactive Health Behavior Scale for Hypertensive Patients, the Self-Efficacy Scale for Hypertensive Patients, the Health Literacy Management Scale (HeLMS). Latent profile analysis (LPA) was used to identify subtypes of proactive health behavior among hypertension patients. Multinomial logistic regression analysis was applied to determine the factors associated with the identified subtypes. A total of 352 questionnaires were distributed, yielding 321 valid responses (a response rate of 91.2%). The total score of proactive health behavior was 89.57 ± 22.99 points. The LPA revealed four profiles of proactive health behavior: the positive proactive health behavior profile (Class 1, The proactive health behavior among hypertension patients was at a moderate level, revealing four distinct behavioral categories with significant differences. Guided by the Health Belief Model, profile-specific influencing factors were analyzed, which informed the development of tailored intervention strategies. Show less

Acetyl-CoA synthetase 2 (ACSS2) is the obligatory gatekeeper for converting rumen-derived acetate into acetyl-CoA in ruminants. However, whether ACSS2 actively regulates the transcriptional networks governing lactation, beyond its catalytic role, remains unclear. This study aimed to elucidate the molecular characteristics of buffalo ACSS2 and investigate its function as a central node in the metabolic-transcriptional circuitry of buffalo mammary epithelial cells (BuMECs). The complete coding sequence of buffalo ACSS2 was characterized, and its expression was analyzed across lactation stages. Subcellular localization was determined via high-resolution confocal microscopy. We utilized siRNA-mediated knockdown in BuMECs to assess cell viability, triglyceride (TAG) content, and the expression of core metabolic and regulatory genes to dissect the underlying molecular mechanisms. ACSS2 expression was highly enriched in lactating mammary tissue, and the protein exhibited a dual nucleocytoplasmic distribution. ACSS2 knockdown induced a "dual collapse" of cellular function: it severely impaired lipogenesis (significantly reducing intracellular TAG and downregulating FASN, ACACA, SCD, CD36, LPL, FABP3, DGAT1, DGAT2 and AGPAT6) and arrested cell proliferation (downregulating the G1/S phase regulators CCND1, CCNE1, CDK2 and CDK4). Mechanistically, ACSS2 depletion dismantled the transcriptional machinery itself, suppressing the mRNA levels of master regulators SREBF1 and PPARG. Crucially, this collapse was accompanied by the paradoxical upregulation of the SREBP1-inhibitor INSIG1, suggesting that metabolic stress triggers an INSIG1-mediated blockade of the feedback loop. This study establishes ACSS2 as a critical metabolic checkpoint in the buffalo mammary gland, rather than a passive enzyme. We propose a model where ACSS2 maintains a reciprocal positive feedback loop with SREBP1 and PPARG. By ensuring sufficient acetyl-CoA to suppress INSIG1 and support histone acetylation (implied by nuclear localization), ACSS2 couples substrate availability to the stability of the lipogenic program and cell cycle progression. These findings reveal an evolutionarily conserved metabolic-epigenetic axis essential for high-efficiency lactation in ruminants. Show less

Increased fasting and postprandial triglyceride levels are risk factors for cardiovascular disease (CVD). Partially metabolized triglyceride-rich lipoproteins (TRLs) termed remnants are created when intestinally-derived chylomicrons and liver secreted very low density lipoproteins (VLDLs) interact with lipoprotein lipase (LpL) situated on the luminal surface of capillary endothelial cells. Higher circulating remnant levels have been implicated as the reason for the relationship between TRL levels and CVD. We hypothesized that nascent lipoproteins not only remnants are atherogenic. To test this, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl Show less

Tight junctions (TJs) between pulmonary vascular endothelial cells (ECs) constitute the physical barrier that impedes the metastasis of tumor cells. We previously reported that circulating microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive extracellular vesicles (LC3 Show less

Defects in mitochondrial energy metabolism in injured tubular epithelial cells (TECs) are a well-recognized hallmark of kidney injury pathogenesis; however, the key target leading to this defect during the acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition remains elusive. Here, we found that during the AKI-to-CKD transition, the increased WW domain containing E3 ubiquitin protein ligase 2 (WWP2) was shuttled to the mitochondria and disabled TEC mitochondrial energy metabolism by ubiquitinating and degrading complex II subunit succinate dehydrogenase complex subunit C (SDHC), leading to oxidative phosphorylation (OXPHOS) disability and aggravated TEC maladaptive repair. Preemptive and late depletion of Wwp2 both ameliorated unilateral ischemia-reperfusion (UIR) injury-induced AKI-to-CKD transition, and tubular-specific Wwp2 depletion resulted in the same protective phenotype. Furthermore, Sdhc knockdown abolished the protective effects of Wwp2 deletion in UIR mice. Conversely, SDHC overexpression attenuated OXPHOS impairment and TEC injury following WWP2 overexpression. Finally, we leveraged high-throughput virtual screening, enzyme activity assays, and binding affinity assays to identify two candidate WWP2 inhibitors. Both inhibitors significantly improved TEC maladaptive repair and deferred the AKI-to-CKD transition. Overall, we identified WWP2 as a critical regulator of mitochondrial OXPHOS integrity in maladaptive repairing TECs and identified two WWP2 inhibitors as potential drug candidates for interrupting the AKI-to-CKD transition. Show less

This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis. The triple-transgenic (PNPLA3 The TG2 pigs presented mild metaflammation and insulin resistance (IR) which was similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as ETNPPL, GABBR2, and BMP8B might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury. ETNPPL, GABBR2, and BMP8B might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases. Show less

Lung cancer (LC) is the most prevalent form of malignant neoplasm globally, as well as the major cause of cancer-related death. Identifying effective pharmaceutical targets is paramount in advancing the development of treatment modalities for LC. Protein-wide Mendelian randomization (MR) was used in this study. The present study collated data on plasma proteins from a protein quantitative trait loci (pQTL) study with a total of 4907 individuals. Genetic associations with LC were obtained from GWAS, including 3791 cases and 489012 controls. Integration of pQTL and LC genome-wide association study (GWAS) data was employed to identify candidate proteins. MR used single nucleotide polymorphisms (SNPs) as a genetic tool to estimate the causal effect of exposure on the outcome, while reverse Mendelian randomization was performed to assess the presence of false positives. The present study utilized these approaches to evaluate the causal relationship between plasma proteins and LC. Finally, protein-protein interaction (PPI) and functional enrichment analyses were performed to illustrate potential links between proteins and current LC drugs. Finally, drug prediction and molecular docking were performed to predict drugs and explored the expression distribution of key genes by single-cell sequencing. We identified 46 plasma proteins that are strongly associated with LC Fifteen of these proteins have protective effects. Among them, MMP8(OR = 0.87, 95%CI:0.78-0.97, p = 0.013) had the most significant protective effect. In contrast, 31 proteins increased the risk of LC. IL36A༈OR = 1.20, 95%CI:1.041-1.38, p = 0.012) exhibited the most significant MR result. Notably, COL2A1, MMP19 showed reverse causality. This was further verified by enrichment analysis, which confirmed the causal effect of these proteins. Additionally, the researchers utilized the DSigDB database to predict potentially effective intervening drugs, identifying nine possible candidates. Molecular docking showed that the drugs bind very much to the proteins. KDR and ANGPTL4 are abundantly expressed in lung tissue and are differentially expressed between cells. The present study has revealed six potential drug targets for the treatment of LC. Drugs designed to target these proteins will be more likely to attain success in clinical trials and are expected to assist in the development of LC drugs and reduce drug development costs. Show less

In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less

Diabetes mellitus and dyslipidemia are major risk factors for atherosclerosis. Hypoechoic plaques, which indicate vulnerable or unstable plaques, may rupture and lead to ischemic stroke, cognitive impairment, increased adverse cardiac events, and even death. This study aimed to investigate the correlation between plasma lipid levels and the characteristics of atherosclerotic plaques in adult patients with type 2 diabetes mellitus. A retrospective analysis was conducted on adult patients with type 2 mellitus who were hospitalized in the Department of Endocrinology at Affiliated Hospital of Hebei University between January 2017 and December 2021.Patients were categorized into two groups based on arterial ultrasound results. Statistical analyses were performed to compare plasma lipid levels and plaque characteristics across the groups. 1) Statistically significant differences were observed among the two groups in terms of gender, hypertension, age, duration of diabetes mellitus, plaque location, triglycerides (TG),total cholesterol (TC), Apolipoprotein A1 (Apo A1),very-low-density lipoprotein (VLDL), VLDL/apolipoprotein B(ApoB), high-density lipoprotein cholesterol (HDL)/ApoA1 ( In clinical practice, the characteristics of atherosclerotic plaques and lipid profiles should be jointly evaluated to guide targeted treatment and effectively reduce the risk of atherosclerotic cardiovascular disease. Show less

Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell (EC) barrier. This process allows the heart to obtain fatty acids, its chief source of energy, and apoB-containing lipoproteins to cross the arterial endothelial barrier, leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial TRLs (triglyceride-rich lipoproteins) as an independent risk factor for cardiovascular disease. We explored how chylomicrons affect ECs and transfer their fatty acids across the EC barrier. We had reported that media from chylomicron-treated ECs lead to lipid droplet formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid, and microRNA content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of SR-BI (scavenger receptor-BI) altered these responses. In addition, using chylomicrons labeled with [ Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage lipid droplet accumulation. The EVs contained little free fatty acids and triglycerides, but abundant phospholipids and diacylglycerols. In concert with this, [ EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. Fatty acids within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition. Show less

Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell barrier. This process allows the heart to obtain fatty acids (FAs), its chief source of energy and apolipoprotein B (apoB)-containing lipoproteins to cross the arterial endothelial barrier leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial triglyceride-rich lipoproteins (TRLs) as an independent risk factor for cardiovascular disease (CVD). We explored how chylomicrons affect ECs and transfer their FAs across the EC barrier. We had reported that media from chylomicron-treated ECs leads to lipid droplet (LD) formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid and microRNA (miR) content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of scavenger receptor-BI (SR-BI) altered these responses. In addition, using chylomicrons labeled with [ Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage LD accumulation. The EVs contained little free fatty acids and triglyceride, but abundant phospholipids and diacylglycerols. In concert with this, [ EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. FAs within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition. Show less

This study aimed to explore the effects of chili meal (CM), a by-product of chili pepper oil extraction, on the productive performance, intestinal health, and lipid metabolism of laying hens fed low-protein (LP) diets. A total of 384 Hy-Line brown laying hens (32 weeks old) were divided into six groups: control (CON) diet with 16.5 % crude protein (CP), LP diet with 15 % CP, and LP diets supplemented with 3 %, 5 %, 7 %, and 9 % CM. Results showed that dietary CM supplementation of up to 5 % did not negatively affect the productive performance of laying hens fed LP diets. However, the groups receiving 7 % and 9 % CM exhibited a significant increase in the feed-to-egg ratio (P < 0.05). Additionally, dietary CM supplementation effectively enhanced egg yolk color in a dose-dependent manner (P < 0.05). Intestinal morphology analysis indicated that the 5 % CM group had a higher villus height-to-crypt depth ratio than the LP and 9 % CM groups (P < 0.05), with no significant differences among the other groups. Dietary supplementation with 3 %-7 % CM did not significantly affect serum and jejunal antioxidant capacity, and the 9 % CM group exhibited the highest levels of serum and jejunal malondialdehyde among the groups (P < 0.05). Dietary CM supplementation significantly increased anti-inflammatory cytokines (IL-4 and IL-10) and decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum and jejunal tissue of laying hens (P < 0.05). Moreover, CM supplementation significantly altered the cecal microbiota composition in laying hens, increasing the abundance of beneficial bacteria, such as Desulfovibrio and Megamonas. Furthermore, dietary CM supplementation significantly decreased serum triglyceride levels; downregulated liver mRNA levels of ACC, FAS, and SREBP-1C/2; and upregulated the mRNA levels of ACOX1, PPAR-α, Apob, and CPT in laying hens fed LP diets. In conclusion, CM supplementation should not exceed 5 % to avoid negative impacts on performance while supporting intestinal health and lipid metabolism. Show less

Pre-eclampsia (PE) is a common complication of pregnancy and there is an urgent need for new drug targets. We performed whole proteome-wide Mendelian randomisation (MR) and colocalisation analyses to identify potential therapeutic targets for PE. A two-sample MR study was conducted using summary-level statistics of 734 plasma proteins retrieved from large genome-proteome-wide association studies. The summary statistics of PE or eclampsia were obtained from the FinnGen consortium. Wald ratio and Inverse variance weighted (IVW) were used to assess the causal association between proteins and PE. Colocalisation analyses were conducted to examine whether the identified proteins and PE shared incidental variants. Genetically predicted circulating levels of 42 proteins were associated with PE risk after Benjamini-Hochberg correction. Nineteen of the gene-predicted proteins showed evidence of increased PE risk (CRELD1, CPA4, AHSG, NFASC, QDPR, NTM, PZP, FAM171B, RTN4R, FLRT2, ADH4, ADM, SPINK5, LGALS4, CKM, SPON2, UROS, CXCL10 and APOBEC3G); 23 proteins reduced the risk of PE (CLIC5, NEO1, SWAP70, KLK8, VWA2, FSTL1, CXCL11, APOB, NPPB, CNTN4, IL12B, ACHE, TCN1, GFRA2, GNMT, HPGDS, DPT, MANBA, SPARCL1, ACE, FUT8, BST1 and ACP1). Bayesian colocalisation indicated that six proteins (VWA2, ACHE, CXCL10, PZP, AHSG and UROS) and PE, which were identified as high evidence of colocalisation with PE. This study provides evidence of the causal association between genetically predicted 42 proteins associated with PE risk, which might be promising drug targets for PE. Show less

As a highly heterogeneous cancer, hepatocellular carcinoma (HCC) shows different response rates to the multi-kinase inhibitor lenvatinib. Thus, it is important to explore genetic biomarkers for precision lenvatinib therapy in HCC. The effect and mechanism of AXIN1 mutation on HCC were revealed by cell proliferation assay, long-term clone formation assay, sphere formation assay and small molecule inhibitor library screening. A new therapeutic strategy targeting HCC with AXIN1 mutation was evaluated in humanized models (patient-derived xenograft [PDX] and patient-derived organoid [PDO]). Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo. AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC. Show less