👤 Huimin Xiong

Perioperative neurocognitive disorder (PND) is one of the most prevalent neurological complications in elderly surgical patients. Dysregulated lipid metabolism is a hallmark of aging and is strongly associated with cognitive dysfunction. This study aimed to investigate whether ω-6 polyunsaturated fatty acid (PUFA) metabolism contribute to PND and examined whether fatty acid desaturase 1 (FADS1) represents a key regulatory link between fatty acid metabolism and PND in aged mice. An anesthesia/surgery-induced cognitive dysfunction model was established Anesthesia/surgery significantly upregulated hippocampal FADS1 expression (1.91-fold [0.37] vs. 1.00-fold [0.43]; These findings highlight anesthesia/surgery could disrupt ω-6 PUFA metabolism, notably activating the PGD The online version contains supplementary material available at 10.1186/s12974-025-03678-y. Show less

High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). Show less

Acute respiratory distress syndrome (ARDS) induced by sepsis is a clinical syndrome characterized by high morbidity and mortality rates. This study aims to clarify the effects of recombinant mouse IL-27 protein on macrophage ferritinophagy, macrophage polarization, and its interventional role in sepsis-induced ARDS. This study utilized wild-type (WT) and IL-27 receptor knockout (IL-27R This study investigates the role of IL-27 in exacerbating ferritinophagy and ferroptosis in macrophages and septic lung injury, and explores the therapeutic potential of the NCOA4 degrader CV3. We found that IL-27 synergizes with LPS to enhance NCOA4-mediated ferritinophagy, leading to increased degradation of FTH1, upregulation of LC3A/B, and promotion of ferroptosis. Ferritinophagy amplification drove M1 macrophage polarization and inflammatory cytokine release. CV3, a PROTAC-based NCOA4 degrader, effectively disrupted the NCOA4-FTH1 interaction, inhibited ferritinophagy, and mitigated ferroptosis and inflammation. In murine models of sepsis-induced ARDS, CV3 alleviated lung injury, restored antioxidant defenses, and reduced ferroptosis. Notably, IL-27R These findings reveal a potential mechanistic link between NCOA4-mediated ferritinophagy and sepsis-associated ARDS pathogenesis. Targeting this pathway with CV3 may offer a novel therapeutic strategy, which warrants further investigation. Show less

Phytate (phytic acid, or InsP6), the primary phosphorus storage compound in plants, plays essential roles in nutrient homeostasis and cellular signaling. However, its strong metal-chelating properties make cytosolic accumulation cytotoxic, necessitating its sequestration into vacuoles for safe storage. Here, we present the cryo-EM structures of the rice vacuolar phytate transporter, OsMRP5, captured in distinct functional states. These structures reveal the molecular basis of OsMRP5 function as an ATP-binding cassette (ABC) transporter. OsMRP5 employs a specialized substrate-recognition mechanism, uniquely adapted to bind the fully hydrophilic InsP6 through extensive electrostatic and hydrogen-bonding interactions within two distinct, highly polar binding sites in its central cavity. A distinctive electropositive tunnel, positioned above the central cavity, forms a continuous pathway connecting the InsP6-binding pocket to the vacuolar export site. This tunnel likely generates an electrostatic attraction that facilitates the movement of the highly anionic InsP6 through the transporter. By mapping mutations from low-phytic acid (lpa) crop variants onto the OsMRP5 structures, we pinpoint their conserved locations critical for transporter function and validate their impact experimentally. These results reveal how OsMRP5 recognizes and transports the highly charged InsP6 molecules into vacuoles, providing a molecular framework for targeted manipulation of this agriculturally important transporter. Show less

Nursing interns often face maladjustment during the early stages of clinical practice, which not only directly affects their physical and mental health as well as work efficiency but also significantly inhibits their proactive feedback-seeking behavior (FSB). As an active self-regulation strategy, FSB can enhance interns' work initiative and promote role transition. However, existing research has yet to thoroughly investigate the potential heterogeneity and categorical characteristics of FSB within this population, and the role of psychological resources such as career adaptability in shaping these patterns requires further investigation. To investigate the status of FSB in early-stage nursing interns, identify latent subgroups via latent profile analysis (LPA), and analyze associated factors, thereby providing evidence for targeted clinical educational interventions. Multicenter cross-sectional research. This study employed a multistage stratified cluster sampling to survey 1,308 early-stage nursing interns from nine universities in Hubei, China, between June and September 2024. Data were collected using a demographic questionnaire, Feedback-Seeking Behavior Scale, and Career Adapt-Abilities Scale. LPA was employed to delineate FSB profiles and multivariate logistic regression analysis to examine the associated predictors. A total of 1,370 questionnaires were distributed, with 1,308 valid responses, yielding an effective response rate of 95.47%. The mean score on the feedback-seeking behavior scale was 5.06 ± 1.08. LPA identified three distinct feedback-seeking profiles: low (20.87%), moderate (38.3%), and high (40.83%). Education level, student cadre experience, internship hospital type, and career adaptability were significant predictors of profile membership ( FSB among early-stage nursing interns exhibited heterogeneity. Nursing educators and managers should implement tiered interventions: for the low and moderate feedback-seeking groups, career guidance and feedback awareness cultivation should be strengthened; for the high feedback-seeking group, peer modeling should be encouraged. This strategy can enhance proactive FSB, supports role transition and professional identity, and promotes long-term nursing workforce stability. Show less

Fear of progression (FoP) is a prevalent psychological issue among stroke patients. Previous studies failing to distinguish characteristics of patient groups with varying FoP levels. Latent profile analysis (LPA) classifies individuals into distinct subgroups via continuous FoP indicators, boosting classification accuracy by accounting for variable uncertainty. Given FoP's heterogeneity, investigating FoP profiles and their influencing factors in stroke patients is clinically significant for personalized psychological care and improved patient quality of life. A total of 366 stroke patients were selected as study subjects through convenience sampling, and a cross-sectional survey was conducted. FoP was assessed using the Fear of Progression Questionnaire-Short Form (FoP-Q-SF, 2 dimensions, 12 items). Independent variables included demographic characteristics, clinical indicators, the Recurrence Risk Perception Scale for Stroke patients (RRPSS), and the Medical Coping Modes Questionnaire (MCMQ). LPA was performed on the FoP-Q-SF items to identify subgroups. The R3STEP method was used to analyze influencing factors of subgroup membership, and the BCH method was applied to compare differences in distal outcomes across subgroups. Statistical significance was set at The study sample had a mean age of 63.93 ± 10.58 years, with 70.5% males and 65.0% first-ever stroke patients. Two latent profiles were identified: Low-FoP Adaptive Type (C1, 48.6%) and High-FoP Sustained Type (C2, 51.4%). The R3STEP showed that age 18-59 years (OR = 0.476, 95%CI = 0.245-0.924, This study revealed significant heterogeneity in FoP among stroke patients. Age, hypertension comorbidity, excessive recurrence risk perception, MCMQ-confrontation, and MCMQ-avoidance were associated with high FoP. Healthcare providers should prioritize identifying high-risk individuals and develop tailored interventions to reduce FoP and improve rehabilitation outcomes. Show less

Using latent profile analysis (LPA) based on Self-Determination Theory (SDT), this study aimed to explore the profiles of health behavior motivation among Chinese patients with prediabetes and examine the relationship between these profiles and self-management ability. A cross-sectional study was conducted involving 335 patients with prediabetes. The questionnaires were used to assess health behavior motivation, self-management ability, satisfaction of basic psychological needs and disease knowledge level. Latent profile analysis was performed based on five subscale scores of the health behavior motivation measure. Three distinct latent profiles were identified: a "Self-Determined" profile (C1,29.55%, n=99), a "Non Self-Determined" profile (C2, 55.82%, n=187), and a "Conflicted" profile (C3, 14.63%, n=49). Patients in the C1 profile demonstrated higher levels of autonomy and competence. Patients in the C2 profile were characterized by better disease knowledge and lower relatedness. Compared to patients in the C3 profile, patients in both the C1 and C2 profiles exhibited significantly lower self-management ability. The heterogeneity in health behavior motivation profiles must be considered in the design and clinical practice of personalized interventions for prediabetes. Profile-specific strategies serve as the foundation for enhancing patients' self-management ability and sustaining healthy behaviors. Show less

This study aims to identify the latent profiles of sense of coherence (SOC) in patients with advanced cancer and explore its influencing factors encompassing sociodemographic and clinical characteristics, and generalized resistance resources (GRRs). A cross-sectional study of 262 patients with advanced cancer was conducted by convenience sampling in Guangzhou, China, from September 2023 to July 2024. Data were collected including sociodemographic and clinical characteristics, SOC-13, Revised Life Orientation Test (LOT-R), Rosenberg Self-Esteem Scale (RSES), Inner Peace State Scale (IPSS), Gratitude Questionnaire-6 (GQ-6), and Social Support Rating Scale (SSRS). Statistical analysis was performed using latent profile analysis (LPA) and multivariate logistic regression analysis. Three latent profiles of SOC were identified: low SOC and low comprehensibility group (29.01%), moderate SOC and high meaningfulness group (40.08%), and high SOC and high manageability group (30.91%). This study found that SOC was impacted by self-perceived severity of the disease and GRRs including optimism, self-esteem, and inner peace ( SOC in patients with advanced cancer exhibited different characteristics. Enhancing positive disease perception and GRRs including optimism, self-esteem, and inner peace may be effective strategies for improving their SOC. Healthcare professionals can formulate strategies such as tailored health education, symptom management, and positive psychological interventions to enhance SOC in patients with advanced cancer. Show less

Social isolation has emerged as an increasingly critical public health issue among adolescents with depression. This study aimed to identify latent subgroups of social isolation based on its manifestations among adolescent patients with depression and to explore the associated influencing factors. A cross-sectional study was conducted from August 2024 to March 2025 at a specialized psychiatric hospital in Nanjing, China. Data were collected using paper-based questionnaires, which included demographic characteristics, the General Social Alienation Scale (GSAS), the Patient Health Questionnaire for Adolescents (PHQ-A), and the Resilience Scale for Chinese Adolescents (RSCA). Latent profile analysis (LPA) was used to classify patterns of social isolation. Chi-square tests, analysis of variance (ANOVA), lasso regression, and multinomial logistic regression were used to analyze profile characteristics and their influencing factors. A total of 412 adolescent patients with depression were included. This study identified three distinct profiles of social isolation: "Low isolation - Fluctuating group" (24.7 %, n = 102), "Moderate isolation - Skeptical group" (39.6 %, n = 163), and "High isolation - Avoidant group" (35.7 %, n = 147). Patients were significantly more likely to be classified into the "High isolation - Avoidant group" if they had siblings, a longer duration of mental illness, more severe depressive symptoms, or lower psychological resilience (all p < 0.05). This study revealed the heterogeneity of social isolation among adolescents with depression through LPA and identified key influencing factors. These findings provide a theoretical foundation for the development of tailored intervention strategies. Show less

Accumulating research has demonstrated a significant association between early-life inflammation and behavioral disorders later in life. However, the effects of early-life inflammation on aggressive behavior in adulthood remain poorly understood. Here, we show that early-life inflammation induced by lipopolysaccharide (LPS) upregulated neuronal dynamin-related protein 1 (DRP1) and impaired mitochondrial function in medial prefrontal cortex (mPFC) of adult mice, thereby increasing aggressive behavior in adulthood. We further identify that CCAAT/enhancer binding protein β (C/EBPβ) is the transcription factor of Dnm1l, which was activated by an increased release of lysophosphatidic acid (LPA) induced by early-life inflammation. Moreover, the overproduction of LPA was due to a specific increase in astrocyte-secreted autotaxin (ATX). Specific knockdown of astrocytic ATX reduced early-life inflammation-induced aggression in wild-type mice, but not in Thy1-C/EBPβ transgenic mice. Remarkably, coenzyme Q10 decreased early-life inflammation-induced aggressive behavior in adult mice. Altogether, these findings provide new insights into the molecular mechanisms by which early inflammation promotes aggressive behavior in adulthood. Show less

Male infertility affects approximately one in seven couples worldwide. Prenatal cadmium (Cd) exposure has been shown to affect offspring phenotypes and increase susceptibility to diseases later in life. However, the effects of prenatal Cd exposure on multi-generational offspring fertility and the mechanisms remain unknown. A novel murine multi-generational (F1-F3 offspring) male subfertility model induced by prenatal Cd exposure was developed. The levels of testosterone and steroidogenic enzymes were also lower in these offspring's testes. The ubiquitin-dependent degradation of NR4A1, the upstream transcription factor regulating steroidogenic enzymes, was enhanced across generations upon prenatal Cd exposure. After treatment with MG132, an inhibitor of the ubiquitin-proteasome system, the levels of NR4A1 and steroidogenic enzymes were higher in offspring testes with prenatal Cd exposure. Based on the analysis of the UbiBrowser database and testicular global transcriptome, RAPSN was identified as a novel ubiquitin E3 ligase containing the RING-H2_Rapsyn domain that mediates multi-generational testicular NR4A1 ubiquitination. m Show less

Incretin mimetics, especially dual/triple agonists, are effective for type 2 diabetes and obesity, though mechanisms remain unclear. This study applied PET using [ In vitro binding assays on frozen HEK293 cell sections overexpressing human GLP-1R, GIPR, or GCGR assessed [ [ PET imaging in pigs demonstrated in vivo GLP-1R engagement by SAR441255 and tirzepatide, and GIPR engagement by SAR441255 in the pancreas. SAR441255 exhibited dose-dependent GLP-1R occupancy in the pancreas and brain regions linked to appetite regulation. The study was funded by Uppsala Diabetes Center, Diabetesfonden, ExoDiab, Diabetes Wellness Sweden, Barndiabetesfonden, Science for Life Laboratory, and the Swedish Research Council. Show less

Unimolecular multireceptor coagonists have emerged as a promising approach in the development of next-generation GLP-1 therapeutics. Herein, we describe the development of a long-acting and stapled GLP-1R/GIPR/GCGR triple agonist that exhibits balanced bioactivities comparable with those of their native ligands along with improved pharmacokinetic parameters. A robust and straightforward solid-phase Ugi macrocyclization strategy enables the facile synthesis of targeted peptides with a side-chain protractor attached on the exocyclic lactam bridge. In obese mice, the lead candidate UTG-4 demonstrates enhanced efficacy in promoting weight loss, suppressing food intake, and improving glucose tolerance and liver health compared to the clinically approved GLP-1R monoagonist semaglutide and GLP-1R/GIPR dual agonist tirzepatide. UTG-4 also exhibits remarkable antiatherosclerotic effects in the Show less

This study established a polymerase chain reaction-lateral flow dipstick (PCR-LFD) method for the visual detection of SNP genotypes. Targeting the MC4R gene SNP g.732 C > G, highly specific primers were designed for the mutation site, incorporating a Locked Nucleic Acid (LNA) modification at the 3' terminal nucleotide of the SNP, a BIOTIN modification at the 5' end of the upstream primer, and a fluorescein isothiocyanate (FITC) modification at the 5' end of the downstream primer. The detection primers were used for PCR amplification with the sample, and the reaction system was optimized. The amplification products were subsequently detected using LFD. The results demonstrated that the optimized reaction system and modified primers effectively distinguished among CC, CG, and GG genotypes at the g.732 C > G. Blood samples from 24 Hu sheep were analyzed using the PCR-LFD assay specific to this SNP. The genotyping results from PCR-LFD were completely consistent with those obtained from the mutation analysis of the same blood samples. The PCR-LFD method established in this study did not require genomic DNA extraction; whole blood could be directly used as a template for PCR amplification combined with LFD, enabling on-site visual detection. This positions PCR-LFD as a rapid, simple, and visually interpretable tool for on-site SNP genotyping. Show less

Weight loss medications are emerging candidates for pharmacotherapy of sleep-disordered breathing (SDB). A melanocortin 4 receptor (MC4R) agonist, setmelanotide (Set), is used to treat obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that Set can treat SDB in mice with diet-induced obesity. We performed a proof-of-concept randomized crossover trial of a single dose of Set versus vehicle and a 2-week daily Set versus vehicle trial, examined colocalization of Mc4r mRNAs with the markers of CO2-sensing neurons Phox2b and neuromedin B in the brainstem, and expressed Cre-dependent designer receptors exclusively activated by designer drugs (DREADDs) or caspase in obese Mc4r-Cre mice. Set increased minute ventilation across sleep/wake states, enhanced the hypercapnic ventilatory response (HCVR), and abolished apneas during sleep. Phox2b+ neurons in the nucleus of the solitary tract (NTS) and the parafacial region expressed Mc4r. Chemogenetic stimulation of the MC4R+ neurons in the parafacial region, but not in the NTS, augmented HCVR without any changes in metabolism. Caspase elimination of the parafacial MC4R+ neurons abolished effects of Set on HCVR. Parafacial MC4R+ neurons projected to the respiratory premotor neurons retrogradely labeled from C3-C4. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R+ neurons. Show less

Increasing epidemiological studies suggested that maternal exposure to fine particulate matter (PM This study aimed to investigate PM In the present study, we first identified that angiopoietin-like 4 (ANGPTL4), sirtuin 3 (SIRT3), and D2-hydroxyglutarate (D2-HG) may be potential biomarkers for PM These findings suggested that PM Show less

Triglyceride-rich lipoproteins carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multilayered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure. Show less

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies. The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance. We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6'-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells. We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy. This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice. Show less

To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships between TCM constitutions, uric acid levels, and various cardiovascular risk factors. A cross-sectional study involving 683 patients diagnosed with HUA was conducted. Patients' TCM constitutions were classified using the standardise "Classification and Determination of TCM Constitution" questionnaire. Serum uric acid (UA), lipid profiles, ApoB, and homocysteine (Hcy) levels were measured. Among 683 HUA patients, phlegm-dampness (22.99% ) and damp-heat constitution (20.06% ) were the most common TCM constitution types. UA, ApoB, and Hcy levels in patients with phlegm-damp constitution were significantly higher than those in other constitutions (P< 0.05). UA levels were negatively correlated with HDL-C (r=-0.472, P= 0.027) and positively correlated with ApoB (r= 0.618, P= 0.012) and Hcy (r= 0.492, P= 0.018). Phlegm-damp and damp-heat constitutions are the most common TCM constitution types in HUA patients and are associated with higher levels of UA, ApoB, and Hcy. These constitutional types are independently associated with increased cardiovascular risk. Show less

Elevated lipoprotein(a) (Lp[a]) and apolipoprotein B (apoB) are individually associated with the risk of atherosclerotic cardiovascular disease (ASCVD). Moreover, previous basic research has implicated the potential interaction between apoB and Lp(a) in the atherogenic process. We aimed to determine whether apoB levels significantly modulate ASCVD risk associated with Lp(a) in a large community-based population without baseline cardiovascular disease. Plasma Lp(a) and apoB were measured in the Atherosclerosis Risk in Communities (ARIC) study. Elevated Lp(a) was defined as the highest race-specific quintile, and elevated apoB was defined as ≥89 mg/dl (median value). The modifying effect of apoB on the Lp(a)-related risk of ASCVD and coronary heart disease (CHD) was determined using Cox regression models adjusted for cardiovascular risk factors. Among 12,988 ARIC participants, 3,888 ASCVD events and 1754 CHD events were observed. Elevated apoB (≥89 mg/dl) and elevated Lp(a) (race-specific quintile 5) were independently associated with ASCVD (hazard ratio [HR]: 1.19; 95% CI: 1.08-1.30; P <0.001; HR: 1.27; 95% CI: 1.16-1.40; P < .001, respectively). Lp(a)-by-apoB interaction was noted [Lp(a) (quintile 1-4 or quintile 5) * apoB (<89 or ≥89 mg/dl) = 0.002]. Compared to the concordantly low Lp(a) group, the individuals with high Lp(a) had a greater ASCVD risk only when apoB was elevated (HR: 1.48; 95% CI: 1.34-1.63; P < .001). In the context of primary prevention, ASCVD risk associated with Lp(a) was observed only when apoB was elevated. The measurement of apoB can further refine and contextualize the ASCVD risk associated with Lp(a). Show less

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options, thus necessitating novel strategies targeting upstream fibrogenic drivers; the exact impact of apolipoprotein E (apoE) on IPF and its therapeutic potential remain unexplored. This study aims to identify novel therapeutic targets for pulmonary fibrosis and elucidate the mechanism by which plasma apoE alleviates this condition. We conducted an integrated meta-analysis of seven plasma cohorts and two-sample Mendelian randomization to assess apoE's association with IPF risk. CRISPR-engineered APOE-deficient canines and Apoe Plasma apoE was identified as a robust protective factor against IPF, with genetically elevated levels correlating with improved pulmonary function, and its deficiency in plasma showed potential diagnostic value for IPF. APOE-deficient canines developed spontaneous pulmonary fibrosis, and Apoe Plasma apoE is a causal guardian against pulmonary fibrogenesis, inhibiting TGF-β/Smad signaling through dual receptor (LRP1/PLAU) engagement. Cross-species validation and mechanistic elucidation position RGX-104, a small-molecule LXR agonist, as a potential therapeutic candidate for clinical translation in IPF. Show less

This study assessed the role of nucleotide-binding domain and leucine-rich repeat containing receptor, caspase recruitment domain containing 5 (NLRC5) in macrophages in atherosclerotic plaque formation in acute coronary syndromes (ACS) by modulating the nuclear factor-kappaB (NF-κB) cascade. Peripheral blood was obtained from ACS patients and matched controls, and NLRC5 expression and DNA methylation were analyzed. In vitro, peripheral blood mononuclear cells from donors were induced into macrophage-derived foam cells and transfected with small interfering RNA negative control (si-NC) or si-NLRC5 plasmids to assess foam cell formation and cytokine release. In vivo, ApoE Show less

Recent research has emphasized the significance of testis-specific serine proteases in regulating various aspects of sperm maturation and function. Among them, serine protease 55 (PRS55) plays an important role in the energy metabolism of sperm and is essential for male fertility in mice. A recent case study further suggests its potential importance to human fertility. However, the underlying molecular mechanism by which PRS55 influences sperm function are still not well understood. The present study aims to investigate these mechanisms further. In this study, we found impaired mitochondrial function in Prss55 Our study demonstrates that PRSS55 interacts with BCKDK and BCKDHA, and regulates BCAA metabolism and energy homeostasis, thereby facilitating sperm migration. Our study provides a biological rationale for PRSS55 as a potential therapeutic target for the treatment of male infertility in clinical. Show less

Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were approximately 20 million new cancer cases and 10 million cancer deaths worldwide. Amidst this global health concern, branched chain amino acids have emerged as key players, playing an important role in the occurrence and development of cancer. In certain malignancies like colorectal cancer, the average level of BCAA in tumor tissues is twice that in normal tissues. BCAA metabolism is intricately associated with the progression of multiple tumors and is modulated by diverse enzymes, including BCAT, BCKDH, and BCKDK. The metabolism of BCAA involves multiple enzymes and biochemical processes via signaling pathways such as PI3K/AKT/mTOR and AMPK/mTOR, etc. In addition, mTOR inhibitors show potential value in cancer treatment by regulating the metabolism and signaling pathways of tumor cells, which provides a new direction for anticancer efforts. Simultaneously, BCAAs are closely associated with tumor immunity, including NK cells, CD4 Show less

Atherosclerosis (AS) is a serious threat to human health. Although glucose balance, lipid metabolism, inflammation and hypertension are closely related to AS, whether methyltransferase-like (METTL) family members are involved in the occurrence and development of AS remains elusive. Differentially expressed genes of METTLs in AS and normal blood vessels in GSE43292 and GSE100927 databases were analyzed. Random forest screening was used to screen marker genes, and the intersection genes in the two databases were selected. GSE28829/GSE41571 and clinical tissue samples were used for verification. The databases were further used to analyze marker genes' tissue and cellular localization and their correlation with lipid metabolism and efferocytosis. 7 and 17 differentially expressed METTL genes were obtained from GSE43292 and GSE100927 databases, respectively. METTL7B and METTL5 were verified as the intersection marker genes. Compared with the control group, the expression of METTL7B was significantly increased in advanced AS, AS ruptured plaque and clinical heavy-load plaque tissues. ROC curve analysis showed that the AUC of METTL7B in GSE28829 and GSE41571 was greater than 0.9. In addition, it was found that METTL7B was significantly correlated with lipid metabolism-related genes and promoted the formation of lipid droplets. METTL7B was positively correlated with atherosclerosis and macrophage-mediated efferocytosis. RNA-seq and targeted lipidomics results also confirmed that METTL7B is closely related to lipid metabolism and atherosclerosis. And further analysis also indicated that METTL7B could regulate 104 kinds of lipids, such as Lipid-n-0041, Lipid-n-0056, Lipid-n-0057, Lipid-n-0098, Lipid-n-0099 and Lipid-n-0169, mediated by AKR1C1, CETP and RORA. This study reveals a new mechanism for the occurrence and development of AS, thereby providing a potential target for the treatment of AS. In conclusion, METTL7B can be used as a predictor and therapeutic target for AS. Show less

Ankylosing spondylitis (AS) is a chronic and progressive inflammatory arthritis involving disorders of both the immune and skeletal systems. Multiple osteochondromas (MO) is a rare skeletal disorder with a variety of clinical manifestations characterized by multiple benign exostoses. Here, we investigate a Chinese family with HLA-B27-negative AS complicated with MO. Whole-exome sequencing (WES) and Sanger sequencing were used to screen and identify the pathogenic gene. In vitro functional analysis was performed, and a pathogenesis-associated interleukin (IL)-17 receptor C (IL17RC) mutation was analyzed to investigate its effect on phenotypes. WES was used to identify a known missense mutation, NM₀₀₀₁₂₇.3:c.1019 G > A(p.Arg340His), in the pathogenic gene EXT1 that is causal for MO. Moreover, a missense mutation, NM₁₅₃₄₆₁.3:c.1067 C > T(p.Thr356Met), in the IL17RC gene was identified as potentially responsible for AS or spondyloarthritis symptoms in this family. In vitro over-expression of mutant IL17RC decreased its expression and increased the expression of IL17RA, consistent with the expression of these two genes in patients. Mechanistically, mutant IL17RC enhanced the activation of the NF-κB pathway. This study increases our understanding of the pathogenesis and progression of these diseases. Our findings broaden the risk factors in non-HLA-B genes associated with the NF-κB pathway in AS. Show less