👤 Guang-Quan Feng

The constitutive activity of melanocortin receptors (MCRs) is integral to several physiological processes. The unliganded cryo-electron microscopy structures of MC1R, MC2R, MC3R, MC4R, and MC5R in complex with G Show less

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with increasing evidence implicating the oral microbiome and tumor microenvironment in its progression. However, the mechanistic impact of OSCC patient-derived saliva on tumor development remains poorly understood. We established an orthotopic OSCC mouse model and topically applied saliva collected from OSCC patients to assess its effects on tumor progression. Multi-omics analyses, including 16 S rRNA sequencing, tumor transcriptomics (RNA-seq), and metabolomics (LC-MS), were performed to explore changes in the oral microbiota, gene expression profiles, and metabolic pathways. Treatment with OSCC patient saliva significantly accelerated tumor growth compared to controls. Saliva application altered the oral microbiota, most notably causing a significant enrichment of the genus Staphylococcus. Tumor transcriptomics revealed upregulation of genes associated with chronic neutrophilic inflammation (Mpo), cancer-associated fibroblast (CAF) activation, and extracellular matrix (ECM) remodeling (Angptl4, Col2a1). Metabolomic analysis demonstrated profound metabolic reprogramming within the tumors, including enhanced amino acid metabolism (tryptophan, glutamate), fatty acid oxidation, and accumulation of the oncometabolite succinate. Integrated analysis showed that Staphylococcus abundance was strongly correlated with these inflammatory and metabolic signatures. This study demonstrates that saliva from OSCC patients promotes tumor progression in vivo through a multifactorial mechanism involving inflammation, stromal remodeling, and metabolic rewiring. These findings highlight the tumor-promoting potential of salivary and microbial components, suggesting new avenues for diagnostic and therapeutic strategies targeting the oral microenvironment in OSCC. Show less

In retinopathy of prematurity (ROP), preventing avascular dysplasia may be more critical than inhibiting abnormal neovascularization. While hypoxia-inducible factors (HIFs) are implicated in angiogenesis, their role in preventing ROP remains unclear. Oxygen-induced retinopathy (OIR) model and hyperoxic cell model were used in this study. Immunofluorescence, western blot, ELISA, cell counting kit-8 (CCK-8), and flow cytometry were applied to assess the effects of hyperoxia on the astrocytes. Co-culture of astrocytes with retinal microvascular endothelial cells (RMECs) was used to observe the effects of astrocyte inactivation on the RMECs. Overexpression of HIFs in astrocytes was used to investigate the mechanism. The OIR model revealed a decreased number of retinal astrocytes and the expression of dystrophin and R-cadherin in hyperoxic environments (P12), which was reversed after room air rearing (P17-P21), with an upward trend in RMECs (P21). In vitro hyperoxia induced significant apoptosis in astrocytes at 24 h. Moreover, the expression of angiogenesis-related factors (VEGF and ANGPTL4), vascular stabilization, and development-related factors (Laminin-β2, Dystrophin, R-cadherin) was decreased. Co-culture of astrocytes and RMECs yielded similar conclusions, with astrocyte inactivation decreasing the tube-forming capacity of RMECs. Overexpression of HIFs in astrocytes promoted the expression of VEGF, ANGPTL4, and Laminin-β2 under hyperoxic conditions. Emphatically, HIF-1α was more effective than HIF-2α in promoting the expression of integrin β1, dystrophin, and R-cadherin. Overexpression of HIFs in astrocytes reverses hyperoxia-induced retinal astrocyte inactivation and retinal vascular structural disruption and dysplasia. Strikingly, HIF-1α is a more suitable therapeutic target for ROP prevention than HIF-2α. Show less

NDRG1, a cell differentiation-associated factor, has recently emerged as a regulator ferroptosis. Nevertheless, its role in modulating ferroptosis within hepatocellular carcinoma (HCC) remains uncharacterized. The differential expression of NDRG1 and its prognostic value were analyzed in HCC using data from TCGA and GEO. Ferroptosis in HepG2 and Huh7 cells was assessed using flow cytometry, transmission electron microscopy, and propidium iodide staining following NDRG1 knockdown using shRNA. RNA-seq was performed to characterize the mRNA expression profiles in HepG2 cells, identifying differentially expressed mRNAs (DE-mRNAs) and NDRG1-related hub genes. NDRG1 was overexpressed in multiple malignant tumors, including HCC, and was associated with a significantly poor prognosis in HCC patients. A nomogram model integrating NDRG1 expression and clinical parameters demonstrated robust prognostic accuracy. NDRG1 knockdown potentiated erastin-induced alterations in Fe NDRG1 exhibits strong predictive value for HCC, and accelerates tumor progression by suppressing ferroptosis. Show less

Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still unclear. This study integrated proteomics and lactylation profiles from the longissimus thoracis (LT) muscles of pigs with extremely high (IMF_H) and extremely low (IMF_L) IMF content to clarify the association between lactylation and porcine fat deposition. Furthermore, an intramuscular preadipocyte induction and differentiation model was conducted to elucidate the changes in lactylation during adipocyte differentiation. Finally, the regulatory role of lactylation in adipocyte differentiation was explored by modulating lactate production during the induction and differentiation of preadipocytes. Proteomic analysis revealed significantly increased expression of key lipid metabolism related proteins (FASN, APOA4, FABP4, ACLY, PLIN1) in IMF_H pig muscle tissues compared with IMF_L tissues, along with substantial activation of lipid metabolism pathways. Lactylation profiling identified 95 differential lysine sites across 56 proteins, with most showing lower lactylation levels in the IMF_H group. The integrative omics analysis revealed differences in lactylation profiles in porcine LT tissues with varying efficiencies of IMF deposition, highlighted PGK1, PKM, and PYGM as central lactylation-modified proteins in porcine fat deposition regulation. Further in vitro study proved that lactate-mediated lactylation inhibited adipogenic differentiation of porcine intramuscular preadipocytes through PPARγ signaling pathway. This study clarified the changes in the lactylation profile in porcine LT tissues with varying efficiencies of IMF deposition, and demonstrated that lactate-mediated lactylation inhibits the PPARγ signaling pathway and the adipogenic differentiation of porcine intramuscular preadipocyte. This study provided a new insight to understanding the epigenetic regulation mechanisms of lipid deposition in pigs. Show less

The lack of standardized objective approaches hinders the accurate diagnosis and treatment of depression. Herein, a novel electrochemical platform was created utilizing cost-effective and rapid 3D printing technology to overcome the constraints of conventional diagnostic methods. This method allows for highly sensitive detection of Apolipoprotein A4 (Apo-A4), an important biomarker for depression, using dual-signal outputs. The electrode material utilized in this setup consisted of a combination of carbon black/polylactic acid (CB/PLA) and ferrocene-chitosan-gold nanoparticles (Fc-CS-AuNPs). On the other hand, the signal label was composed of gold nanoparticles-thionine-secondary antibody (AuNPs-Thi-Ab Show less

Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known for minimally invasive biomarkers are scarce. Here, we analyzed 1,345 human plasma proteins using proteome-wide association studies, identifying 78 proteins significantly associated with PC risk. Of these, four proteins (ROR1, FN1, APOA5, and ABO) showed the most substantial causal link to PC, confirmed through Mendelian randomization and colocalization analyses. Data from two clinical cohorts further demonstrated that FN1 and ABO were notably overexpressed in both blood and tumor samples from PC patients, compared to healthy controls or para-tumor tissues. Additionally, elevated FN1 and ABO levels correlated with shorter median survival in patients. Multiple drugs targeting FN1 or ROR1 are available or in clinical trials. These findings suggest that plasma protein FN1 associated with PC holds potential as both prognostic biomarkers and therapeutic targets. Show less

Cardiovascular disease (CVD) remains the leading cause of death worldwide, according to global statistics from the WHO and GBD, with the incidence of acute coronary syndromes (ACS) continuing to rise annually. This study aims to develop a nomogram model to predict the risk in ACS patients with hypertension, providing clinicians with a tool for early diagnosis, personalized treatment, and prognostic evaluation. Data were collected from ACS patients at Huangshi Aikang Hospital between 2018 and 2023. Patient characteristics, including age, sex, hypertension history, initial blood test results, and cardiac doppler ultrasonography findings, were recorded. ACS diagnosis followed the 2019 revised Guidelines for the Diagnosis and Treatment of Acute ST-Segment Elevation Myocardial Infarction (STEMI) by the Chinese Society of Cardiology. The 2024 Revised Guidelines for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes from the Chinese Journal of Cardiovascular Diseases were used for NSTEMI and unstable angina (UA) diagnoses. Statistical analyses were performed using SPSS (version 27.0.1) and R software (version 4.3.2), with statistical significance at P < 0.05. A total of 980 ACS patients were included in the study. Among the three clinical subtypes, 592 patients (60.4%) had UA, which was the most prevalent. The hypertensive group comprised 682 ACS patients (69.59%), with a mean age of 64.93 ± 9.51 years. Significant differences between hypertensive and non-hypertensive groups were found in sex (P = 0.001), age (P < 0.001), clinical subtype (P < 0.001), and several clinical and laboratory parameters, including creatinine (Cr) (P < 0.001), left ventricular ejection fraction (LVEF) (P = 0.049), left ventricular posterior wall thickness (LVPW) (P = 0.003), CK-MB (P = 0.019), AST (P = 0.028), total cholesterol (TC) (P = 0.035), LDL-C (P = 0.007), and APOB (P = 0.005). Using LASSO regression, nine variables were selected for multivariate logistic regression analysis, leading to the construction of the nomogram model. The calibration curve, Hosmer-Lemeshow test, ROC curve, decision curve, and clinical impact curve all demonstrated the model's high quality. A high-quality predictive nomogram model for assessing the risk of ACS in patients with hypertension has been developed. This model can assist clinicians in early diagnosis, personalized treatment, and prognostic evaluation. Show less

To construct a nomogram for predicting metabolic syndrome (MetS) in women with polycystic ovary syndrome. In this retrospective study, we analyzed clinical and biochemical data from 859 Chinese women diagnosed with PCOS. Univariable logistic regression and forward stepwise logistic regression were employed to identify independent predictors of MetS. A predictive nomogram was developed that integrates age, acne status, body mass index (BMI), fasting insulin levels (FINS), and the ApoB/ApoA ratio. The model's discriminative performance, calibration accuracy, and clinical utility were assessed using the area under the receiver operating characteristic curve (AUC), calibration curves accompanied by Brier scores, Hosmer - Lemeshow tests, decision curve analysis (DCA), and clinical impact curves (CIC). Internal validation was conducted through bootstrap resampling over 1,000 iterations. The nomogram exhibited strong discriminative capability with an AUC of 0.874 (95% CI: 0.850-0.899), surpassing BMI alone which had an AUC of 0.824 ( The proposed nomogram accurately predicts MetS risk in PCOS patients, supporting early identification and individualized management. Show less

The incidence of silent myocardial infarction (SMI) is increasing. Meanwhile, due to the atypical clinical symptoms and signs associated with SMI, the prognosis for patients is often poor. This prediction model used the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analyses to screen variables. Predictive accuracy was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). The clinical decision curve analysis (DCA), alongside the calibration curve and clinical impact curve (CIC) analyses, were used to assess model validity. This study included 174 patients, 64 (36.8%) of whom experienced SMI; logistic regression analysis identified six variables: gender, age, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B/apolipoprotein A1 (ApoB/A1), uric acid (UA), and triglyceride glucose-body mass index (TyG-BMI). The results identified the TyG-BMI as a predictor of SMI (odds ratios (OR) = 1.02, 95% CI: 1.01-1.03; The TyG-BMI is an independent predictor of SMI. A prediction model based on the TyG-BMI showed good predictive ability for SMI. Show less

This study aimed to (1) evaluate small dense low-density lipoprotein cholesterol (sdLDL-C) dynamics from prediabetes to type 2 diabetes mellitus (T2DM) with complications, (2) validate existing sdLDL-C estimation formulas (Sampson’s, Srisawasdi’s, Han’s) in Chinese populations, and (3) develop a population-specific formula for enhanced accuracy. A multicenter study recruited 1,944 participants (216 controls, 70 with prediabetes, 212 with newly diagnosed T2DM, 164 with treated T2DM, and 1,286 in validation cohorts). Lipid profiles, including sdLDL-C (measured via enzymatic assays), were analyzed. Formula performance was assessed using spearman correlation, intraclass correlation coefficients (ICC), and multivariable linear regression. A novel formula was derived via multivariable regression. Atherogenic lipid triad manifestations emerged early: sdLDL-C was significantly elevated in participants with prediabetes (1.07 [0.73, 1.40] vs. 0.57 [0.44, 0.72] mmol/L in controls, P < 0.05) and further increased in those with T2DM, correlating strongly with triglycerides (TG; sdLDL-C elevation begins in prediabetes, highlighting its value for early atherosclerotic cardiovascular disease (ASCVD) risk assessment. Current formulas show population-specific limitations, whereas the new model provides improved accuracy for Chinese T2DM patients, enabling cost-effective sdLDL-C estimation and personalized lipid management. The online version contains supplementary material available at 10.1186/s12944-025-02636-0. Show less

This study aimed to investigate the role of Apolipoprotein B (Apo B) in diabetic nephropathy (DN) from epidemiological and genetic perspectives. We employed weighted multivariable-adjusted logistic regression to assess the relationship between ApoB and DN risk, utilizing data from the National Health and Nutrition Examination Survey spanning 2007-2016. Then, we used restricted cubic splines (RCS) to flexibly model and visualize the relation of predicted ApoB levels with DN risk. Subsequently, a bidirectional two-sample Mendelian randomization study using genome-wide association study summary statistics was performed. The primary Inverse Variance Weighted method, along with supplementary MR approaches, was employed to verify the causal link between ApoB and DN. Sensitivity analyses were conducted to confirm the robustness of the results. Our observational study enrolled 2242 participants with diabetes mellitus from NHANES. The multivariable logistic regression model indicated that elevated ApoB levels (>1.2 g/L), compared to low levels (<0.8 g/L), were significantly associated with DN risk (P < 0.05). The RCS model revealed a positive linear association with the risk of DN when ApoB levels exceeded 1.12 g/L (OR = 1.29, 95% CI: 1.07-1.57, P = 0.008). However, the MR IVW method did not reveal a direct causal effect of DN on ApoB (OR: 0.976; 95% CI: 0.950-1.004; P = 0.095), nor a direct causal effect of ApoB on DN (OR: 0.837; 95% CI: 0.950-1.078; P = 0.428). The evidence from observational studies indicates a positive correlation between ApoB levels exceeding 1.12 g/L and the onset of DN. However, the causal effects of ApoB on DN and vice versa were not supported by the MR analysis. Show less

We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete tolerogenic adjuvant that acts systemically to form an active vaccine in situ with endogenous pathogenic autoantigens. This active vaccine suppresses autoimmunity by expanding antigen-specific Treg cells in affected tissues. In a mouse model of atherosclerosis, 8206 successfully targeted all three analyzed pathogenic autoantigens (ApoB, HSP60, and HMGB1) and inhibited disease progression. These findings suggest that 8206 can potentially serve as a universal treatment vaccine for autoimmune diseases by eliminating the need for exogenous immunogens, with implications for broad applications in immunotherapy. Show less

Exosomes play important role in biological functions, including both normal and disease process. Multiple cell types can secret exosomes, which act as message carriers. Increased evidences reveal that exosomes are promising diagnosis biomarkers in malignant tumors. In this study, we enrolled 78 participants, including 20 lung adenocarcinoma (LUAD), 18 lung squamous carcinoma (LUSC), 20 lung benign diseases (LUBN) and 20 healthy controls (NL) and we performed parallel reaction-monitoring (PRM)-mass spectrometry to screening the proteomic variation by label free analysis in exosomes from all groups, which has been widely used to quantify and detect target proteins. Total 14 protein were identified as candidate biomarkers, complement components C9, apolipoprotein B (APOB), filamin A (FLNA), guanine nucleotide binding protein G subunit 2 (GNB2), fermitin family homolog 3 (FERMT3) showed significantly differentiation in total lung cancer (LUAD and LUSC together), we then obtained combination analysis of 5 proteins and the area under the curve (AUC), sensitivity (SN) and specificity (SP) were 63.0%, 65.0%, and 75.0%, respectively, in comparison to NL group. And the LUAD combination panel, peroxiredoxin 6 (PRDX6), integrin alpha-IIb (ITGA2B) and hemoglobin subunit delta (HBD) revealed AUC was 95.0%, SN was 90.0% and SP was 95.0% in comparison to NL controls. In LUSC analysis, combination analysis of fibronectin 1 (FN1), pregnancy zone protein (PZP) and complement C1q tumor necrosis factor related protein 3 (C1QTNF3) showed that AUC was 88.1%, SN was 75.0%, SP was 100% in paralleled with NL group. Finally C9, FLNA, PZP were overexpressed in lung cancer H1299 and A549 cell lines and the results indicated that C9 acted as oncogenic role by increasing proliferation, migration and invasion of lung cancer cells, while FLNA and PZP played tumor-suppression by inhibition biological functions of lung cancer cells. Taken together, our study revealed multiple exosomal proteins which could be applied as candidate biomarkers in diagnosis of lung cancer. Show less

To investigate the impact of the Panax notoginseng saponin extract on hyperlipidaemic mice. We developed a hyperlipidemia model in mouse through the administration of a high-fat diet. We conducted weekly measurements of body weight, serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and highdensity lipoprotein cholesterol (HDL-C). Additionally, serum levels of Apolipoprotein A (APOA) and Apolipoprotein B (APOB) were determined post-feeding. We assessed pathological liver tissue damage in mice, as well as examined malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity in liver tissue. Immunohistochemical analysis was conducted to detect the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) proteins within liver tissues. Administration of Panax notoginseng saponin extract led to a reduction in body weight, liver index, and histopathological scores among mice. Additionally, there was a significant reduction in TC, TG and LDL-C levels, accompanied by an increase in HDL-C levels. Additionally, an increase in hepatic SOD activity and a decrease in MDA content were observed in the liver homogenates of mice. Furthermore, the expression levels of HO-1 and Nrf2 proteins were upregulated in liver tissue. These findings suggest that Panax notoginseng saponin extracts may ameliorate high-fat diet-induced hyperlipidemia. Show less

Lipoprotein subclasses and high-density lipoprotein (HDL) functions are associated with atherosclerotic cardiovascular disease (ASCVD), but researches on them in patients with nephrotic syndrome (NS) are limited. The aims of this study were (1) to analyze the changes in quantity and quality of lipoprotein in patients with idiopathic nephrotic syndrome (INS) and patients in remission from NS, and (2) to evaluate the lipid-related atherosclerotic risk in these patients. 51 patients with idiopathic nephrotic syndrome (NS group), 72 NS patients with complete remission (NS remission group), and 80 healthy controls (control group) were recruited. The levels of conventional lipids, lipoprotein subclasses, including VLDL, IDL (C, B, A), LDL (LDL1-7), HDL (large, intermediate, small) and HDL cholesterol efflux capacity (CEC), were measured and compared across the three groups. Conventional lipid parameters [TG, TC, LDL-C, apo-B and Lp(a)] and lipoprotein subclasses (VLDL, IDL-C, IDL-B, LDL-2 and sdLDL) were higher in NS group when compared to NS remission group and control group (P < 0.05). CEC in NS group was significantly lower than that in control group [21.0 (18.3-27.2) % vs 25.7 (23.3-28.9) %] (P < 0.001) and improved to 22.8 (20.6-23.7) % in NS remission group with the disease recovery. Proatherogenic changes in conventional lipid parameters, lipoprotein subclasses and HDL-CEC were observed in patients with NS, suggesting that more rigorous lipid regulation strategies may help reduce cardiovascular disease risk in patients with NS. Show less

Molecular QTL studies quantify whether genetic variants affect molecular traits, but non-linear effects including distributional patterns, variance, and interactions provide mechanistic insights beyond mean-level associations. Methods for detecting distributional effects have been developed for eQTL analysis, yet applications have focused on method demonstrations rather than large-scale biological discovery. We comprehensively mapped quantile, variance, and interaction QTLs across 34 data-set from 22 molecular contexts in >2,300 human brain donors, revealing that 48.7% of quantile QTLs (qQTLs) exhibit context-dependent regulation invisible to linear models, with enrichment at phenotypic extremes and in cell-type-specific regulatory elements, chromatin accessibility regions, and long-range chromosomal contacts. qQTL variants explained additional trait heritability beyond linear QTLs for brain-related traits. At Alzheimer's disease (AD) risk loci, qQTL analysis revealed complex regulatory architecture including variance effects at Show less

Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing. Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia-astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair. Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation. Show less

The uptake of modified lipoproteins by macrophages to form foam cells is a crucial step in atherosclerosis (AS) development. N7-methylguanosine (m7G) is frequently methylated internally in eukaryotic RNA transcripts and plays a crucial role in various processes. This study aimed to investigate the m7G RNA methylation profile in AS. We employed high-throughput sequencing to analyze the m7G methylome in foam cells induced by ox-LDL, using an in vitro AS model. Then, m7G-seq, RNA-seq, bioinformatic analysis, cell biological analyses, followed by qRT-PCR were performed. Additionally, the roles of SCARB2 and RASSF8 were investigated in an in vivo AS mouse model, and cells with SCARB2/RASSF8 overexpression/knockdown. In vitro and in vivo oil red O staining confirmed the successful establishment of the atherosclerotic foam cell and mouse models. We identified 1197 m7G peaks and 430 differentially expressed mRNAs during foam cell formation. Bioinformatics analyses revealed different m7G peaks associated with the gonadotropin-releasing hormone (GnRH) signaling pathway, cytoskeleton-dependent intracellular transport, and mitochondrial organization, regulating the processes of macrophage foaminess. Moreover, 28 key differentially expressed methylated genes were identified. m7G methyltransferases (WDR4, METTL1, WBSCR22) were upregulated in the AS cell model, and m7G modification genes (SCARB2 and RASSF8) associated with pathological processes were confirmed. Immunofluorescence staining showed that RASSF8 and SCARB2 were both expressed in AS mice plaque tissues. Finally, RASSF8/SCARB2 overexpression could promote apoptosis and lipid accumulation of ox-LDL-induced RAW264.7 cells. An m7G transcriptome-wide map of AS in vitro was created, and the differentially m7G methylated genes SCARB2 and RASSF8 may be crucial in macrophage foaminess. Our findings offer novel insights into the underlying mechanisms and potential treatments for AS. Show less

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

Amyloid-β (Aβ) deposition was an important pathomechanisms of Alzheimer's disease (AD). Aβ generation was highly regulated by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is a prime drug target for AD therapy. The silence of BACE1 function to slow down Aβ production was accepted as an effective strategy for combating AD. Herein, BACE1 interfering RNA, metallothionein (MT) and ruthenium complexes ([Ru(bpy) Show less

Alzheimer's disease (AD) represents a neurodegenerative condition characterized by steadily increasing prevalence and incidence, arising significant challenge to both patients and social insurance. However, the etiology of AD remains controversial so far, and pathogenesis is far more complicated. Presently, no definitive therapeutic methodologies were available for AD, and only partial symptomatic relief can be achieved. Consequently, early diagnosis and intervention are emergently needed for AD patients. The diagnostic criteria for AD are continuously evolving, and biomarker testing is becoming increasingly critical for diagnosis. Currently, the diagnosis of AD primarily relies on the detection of pathological proteins through cerebrospinal fluid (CSF) testing and positron emission tomography (PET). However, factors such as high costs, operational contraindications, and invasiveness limited the application of these technologies, making them particularly challenging to implement in large-scale clinical trials and screenings. Core fluid biomarkers for AD including β-amyloid (Aβ), phosphorylated tau protein (p-tau), total tau protein (t-tau), and their combinations were found in CSF. Although these biomarkers were demonstrated with significant specificity and sensitivity, challenges remain high concerning the collection of CSF. Blood-derived biomarkers for Aβ and tau proteins are essential for preliminary screening, diagnosis, and monitoring of AD. Additionally, other bodily fluids such as saliva, urine, and tears have been investigated for their potential as biomarkers, offering unique characteristics and applications. Emerging biomarkers, including neurofilament light chain (NfL), neurogranin (Ng), Beta-site APP cleaving enzyme 1 (BACE1), synaptosome associated protein 25 (SNAP-25), as well as inflammation-related and gene-related factors, provided valuable insights into the diagnosis and pathogenesis of AD from diverse perspectives. Despite the substantial progress made in AD biomarker research, there are still baskets of limitations concerning the complication of the disease. The current review focused on the reported literature to summarize the biomarkers associated with AD. By critically analyzing studies published over the past decade, we aimed to strengthen the recent research progress, theoretical frameworks, and unresolved challenges related to AD biomarkers. Show less

Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD model mice and negatively correlated with amyloid-beta (Aβ) load in patients with AD. Enhancing GLP-1 signaling through GLP-1RAs increased CaMKK2-AMPK signaling, which subsequently reduced BACE1-mediated cleavage of amyloid precursor protein (APP) and Aβ generation. GLP-1RAs also increased AMPK activity in microglia, inhibiting neuroinflammation and promoting Aβ phagocytosis. Consequently, GLP-1RAs inhibited plaque formation and improved memory deficits in AD model mice. Our findings indicate that AMPK activation mediates the effects of GLP-1RAs on AD, highlighting the therapeutic potential of GLP-1RAs for the treatment of AD. Show less

Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals. Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group). EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs accounted for the majority and were mainly accompanied by downregulated mRNAs, which was consistent with the downregulated expression of the m6A writer methyltransferase-like 4 (METTL4). 27-OHC and 24S-OHC combined with various gut metabolites significantly distinguished between MCI subgroups from healthy controls (EMCI/Control: AUC = 0.877; LMCI/Control: AUC = 0.952). Heatmap revealed the correlation between Phorbol myristate and differentially m6A-methylated mRNAs. Differentially expressed gut metabolites and methylated mRNAs were commonly enriched in 34 KEGG metabolic pathways, including cholesterol metabolism and neurodegenerative disease-related pathways. Our study explored the altered oxysterols, gut metabolites, and m6A methylation and their associations in different stages of MCI. The potential function of aberrant gut metabolites in oxysterols and m6A methylation driving MCI progression warrants further mechanistic investigation. Show less

Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (Aβ) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) plays a critical role in the production of Aβ, making it a key therapeutic target. In the current work, a CNS library of ChemDiv database containing 44085 compounds was screened against the BACE1 protein. Initially, a structure-based pharmacophore hypothesis was constructed, followed by virtual screening, with the screened hits docked to the BACE1 protein to determine the optimal binding modes. The docking results were examined using the glide gscore and chemical interactions of the docked molecules. The cutoff value of -5 kcal/mol was used to select hits with high binding affinities. A total of seven hits were chosen based on the glide g score. Furthermore, the possible binding mechanisms of the docked ligands were investigated, and it was discovered that all seven selected ligands occupied the same site in the predicted binding pocket of protein. The bioactivity scores of the compounds demonstrated that the chosen compounds possess the features of lead compounds. The toxicity risks and ADMET features of the selected hits were anticipated, and four compounds, J032-0080, SC13-0774, V030-0915, and V006-5608 were chosen for stability analysis. The selected hits were extremely stable and strongly bound to the BACE1 pocket, and conformational changes caused by RMSD, RMSF, and protein-ligand interactions were assessed using MD modeling. Similarly, principal component analysis revealed a large static number of hydrogen bonds. The MM/GBSA binding free energies maps revealed a significant energy contribution in the binding of selected hits to BACE1. The binding free energy landscapes indicated that the hits were bound with a high binding affinity. Thus, the hits could serve as lead compounds in biophysical investigations to limit the biological activity of the BACE1 protein. Show less

Alzheimer's disease (AD) is a neurodegeneration driven by beta-amyloid (Aβ) deposits in the brain involving autophagy dysfunction. Ginsenoside Rg1, a pharmacologically active compound found in ginseng, has possible therapeutic effects for AD. This study discovered that FGR proto-oncogene (FGR) was a therapeutic target of Rg1 in AD and it was possibly involved in autophagy. C57BL/6 J mice were injected with 5 μL (1 μg/mL) Aβ Show less

Interferon-induced transmembrane protein 3 (IFITM3) modulates γ-secretase in Alzheimer's Disease (AD). Although IFITM3 knockout reduces amyloid β protein (Aβ) production, its cell-specific effect on AD remains unclear. Single nucleus RNA sequencing (snRNA-seq) was used to assess IFITM3 expression. Adeno-associated virus-BI30 (AAV-BI30) was injected to reduce IFITM3 expression in the cerebrovascular endothelial cells (CVECs). The effects on AD phenotypes in cells and AD mice were examined through behavioral tests, two-photon imaging, flow cytometry, Western blot, immunohistochemistry, and quantitative polymerase chain reaction assay (qPCR). IFITM3 expression was increased in the CVECs of patients with AD. Overexpression of IFITM3 in primary endothelial cells enhanced Aβ generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ further increased IFITM3 expression, creating a vicious cycle. Knockdown of IFITM3 in CVECs decreased Aβ accumulation within cerebrovascular walls, reduced Alzheimer's-related pathology, and improved cognitive performance in AD transgenic mice. Knockdown of IFITM3 in CVECs alleviates AD pathology and cognitive impairment. Targeting cerebrovascular endothelial IFITM3 holds promise for AD treatment. Interferon-induced transmembrane protein 3 (IFITM3) expression was increased in the cerebrovascular endothelial cells (CVECs) of patients with Alzheimer's Disease (AD). Cerebrovascular endothelial IFITM3 regulates amyloid β protein (Aβ) generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Knockdown of IFITM3 in CVECs reduces Aβ deposits and improves cognitive impairments in AD transgenic mice. Cerebrovascular endothelial IFITM3 could be a potential target for the treatment of AD. Show less

By integrating single-cell and bulk RNA-sequencing data for esophageal cancer (ESCA), we developed and validated a seven-macrophage-gene prognostic signature (FCN1, SCARB2, ATF5, PHLDA2, GLIPR1, CHORDC1, and BCKDK). This signature effectively stratified patients into high- and low-risk groups with significantly different overall survival, achieving area under the curve (AUC) values greater than 0.7 for 1-, 2-, and 3-year survival prediction. A high-risk status correlated with an immunosuppressive tumor microenvironment, characterized by lower infiltration of B cells and CD8 + T cells, and was associated with reduced sensitivity to multiple chemotherapeutic agents, including Cisplatin and 5-Fluorouracil. Conversely, a low-risk status was linked to greater immune cell infiltration and higher predicted chemosensitivity. At the single-cell level, pseudotime analysis revealed that macrophage maturation significantly correlated with a decreasing risk score, suggesting that mature macrophages may contribute to a favorable prognosis. Furthermore, cell communication analysis identified high-risk macrophages as dominant drivers of a pro-tumorigenic microenvironment via signaling pathways, such as SPP1 and complement. In conclusion, this seven-gene signature is a robust prognostic biomarker that offers a new strategy for personalized risk assessment and treatment selection in ESCA. The online version contains supplementary material available at 10.1007/s13205-025-04452-w. Show less

Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune-based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched-chain α-keto-acid dehydrogenase kinase (BCKDK) has been implicated in promoting RCC metastasis, but its specific substrates and the mechanisms underlying its regulation of RCC progression remain poorly understood. This study uncovers a novel mechanism whereby BCKDK-mediated AKT phosphorylation drives RCC tumorigenesis and drug resistance. Elevated BCKDK expression correlates with poor prognosis in RCC clinical samples. BCKDK deficiency inhibits RCC cell proliferation and tumorigenesis both in vitro and in vivo. Mechanistic investigations reveal that BCKDK directly binds to and regulates the phosphorylation of AKT. BCKDK-mediated phosphorylation of AKT decreases ubiquitin-mediated AKT protein degradation, and promotes tumorigenesis via activation of the AKT/mTOR signaling pathway. RNA sequencing identifies BCKDK's involvement in the drug metabolism network and apoptotic signaling pathways. The BCKDK/AKT/ABCB1 axis mediates doxorubicin resistance. Targeting BCKDK/AKT inhibits the growth of RCC patient-derived organoids (PDOs), enhances doxorubicin-induced apoptosis in RCC cells, and suppresses tumor growth in vivo. These findings identify a previously unrecognized phosphorylation substrate of BCKDK and highlight the critical role of the BCKDK/AKT signaling axis in RCC progression, offering a promising target for therapeutic intervention. Show less