Binding of ANGPTL (angiopoietin-like protein)-3 to ANGPTL8 generates a protein complex (ANGPTL3/8) that strongly inhibits LPL (lipoprotein lipase) activity, as compared with ANGPTL3 alone, suggesting Show more
Binding of ANGPTL (angiopoietin-like protein)-3 to ANGPTL8 generates a protein complex (ANGPTL3/8) that strongly inhibits LPL (lipoprotein lipase) activity, as compared with ANGPTL3 alone, suggesting that ANGPTL3/8 concentrations are critical for the regulation of circulation lipoprotein concentrations and subsequent increased coronary heart disease (CHD) risk. To test this hypothesis in humans, we evaluated the associations of circulating free ANGPTL3 and ANGPTL3/8 complex concentrations with lipoprotein concentrations and CHD risk in 2 prospective cohort studies. Fasting blood samples were obtained in conjunction with the baseline evaluation of 9479 subjects from 2 population-based Swedish cohorts of middle-aged men and women. Standard biochemical blood analyses, including all lipid/lipoprotein measurements, were performed in these samples at baseline. Additional serum samples were stored at -80 °C and used at a later stage for ANGPTL3 and ANGPTL3/8 concentration measurements. Information about incident CHD was obtained for both cohorts by matching to the Swedish National Patient Register and the Cause of Death Register. ANGPTL3 concentrations showed modest, positive associations with all lipoprotein concentrations but were not associated with CHD risk. In contrast, ANGPTL3/8 concentrations were associated in both cohorts with an atherogenic lipoprotein profile (characterized by increased triglyceride and LDL [low-density lipoprotein] concentrations and reduced HDL [high-density lipoprotein] concentrations). In the combined cohort, ANGPTL3/8 was associated with increased CHD risk. Hazard ratio per 1 SD increase was 1.10 (95% CI, 1.03-1.17) after adjustment for age, sex, cohort, smoking, and hypertension. Elevated concentrations of ANGPTL3/8, but not ANGPTL3, are associated with an atherogenic lipoprotein profile and increased CHD risk in humans. Show less
Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- T Show more
Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- TNBC mechanisms of UA by network pharmacology and experimental validation. TNBC cell lines MDA-MB-231 and BT-549 cells were treated with UA. A CCK-8 assay was performed to detect cell growth, while flow cytometry assessed cell cycle arrest and apoptosis. The underlying mechanism and potential targets of UA for TNBC treatment were investigated by network pharmacology, including PharmMapper database, GO, KEGG enrichment, and PPI analysis. The protein expressions and phosphorylation levels of FGFR1, AKT, and ERK were measured by western blot. Pull-down assay, cellular thermal shift assay (CETSA), and molecular docking were used to analyze the interaction between UA and FGFR1. Xenograft models were established to examine the effect of UA on TNBC tumor growth. UA effectively reduced cell viability, induced apoptosis, and arrested cell cycle in TNBC cells. Moreover, UA significantly regulated the expression of Bcl-2 and Bax to induce apoptosis. The results of network pharmacology and western blot suggested that UA reduced FGFR1/AKT/ERK pathway. Furthermore, pull-down, CETSA, and molecular docking results revealed that UA directly bound to FGFR1. In the xenograft model, UA inhibited the growth by suppressing FGFR1. In this study, we employed network pharmacology and experimental approaches to elucidate the mechanism of UA on TNBC. The results demonstrated that UA targeted FGFR1 to inhibit TNBC via mediating FGFR1/AKT/ERK pathway. Our findings demonstrate that UA inhibits the FGFR1/AKT/ERK pathway by directly targeting FGFR1, thereby suppressing TNBC progression and supporting its potential as a therapeutic agent for TNBC treatment. Show less
Human papillomavirus (HPV) infection is a global public health issue, and HPV-related stigma can affect cervical cancer prevention. But no validated tools exist to assess HPV stigma in Chinese adult w Show more
Human papillomavirus (HPV) infection is a global public health issue, and HPV-related stigma can affect cervical cancer prevention. But no validated tools exist to assess HPV stigma in Chinese adult women infected with HPV. This study aimed to adapt and validate the HPVsStigma scale (HPV-SS) in the Chinese context. A cross-sectional study was conducted from December 2024 to February 2025 among 501 HPV-infected women in Shenzhen, China. The HPV-SS was adapted from a 12-item HIV stigma scale. Demographic characteristics, HPV-related variables, and data on mental health were collected. Factor analyses (FA) were used to assess the scale's factorial structure, reliability, and validity. The bi-factor model was used to determine the score-reporting method of the scale. Item response theory (IRT) was employed to assess the relationship between participants' stigma levels and scale scores. Latent profile analysis (LPA) was conducted to classify the participants with different HPV stigma characteristics and determine the optimal cut-off value for HPV-SS. FA showed that the 3-factor model (personalized stigma, public-disclosure concerns, and negative self-image) had the best fit among the nested models, with good reliability and validity. The bi-factor model analysis indicated that the total scale score was more meaningful than dimension scores. IRT analysis confirmed that higher HPV-SS scores represented higher stigma levels. LPA identified a 2-class model as optimal, and the optimal cut-off value of the scale for high HPV stigma was 35. This study validated the 12-item HPV-SS for Chinese women infected with HPV, with good reliability and validity. The scale can be used to evaluate HPV stigma levels, facilitating targeted interventions to improve cervical cancer prevention and the psychological well-being of affected women. Show less
Haixiong Tang, Lin Fu, Changyun Yang+9 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Br Show more
Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Bronchial biopsy specimens were obtained from healthy subjects and patients with severe asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). A selective CDH11 antagonist SD133 (100 mg/kg) was given to allergen-exposed mice after airway challenge. The effects of recombinant CDH11 were also tested in vivo, and FGFR1 inhibition was used to explore a possible mechanism for CDH11-induced inflammatory responses in the lung. We detected upregulated expression of CDH11 in the airway mucosa of severe asthma patients when compared with the healthy control. In the OVA/CFA-induced model, though CDH11 expression in the lung remained unchanged, pharmacological antagonism of CDH11 with SD133 dramatically decreased airway neutrophil accumulation, as well as IL-6 production, but had no effect on eosinophilic infiltration, type 2 inflammation (IL-4 and IL-5) nor airway hyperresponsiveness. In the TDI model, pulmonary CDH11 expression was upregulated. Treatment with SD133 inhibited TDI-induced airway hyperresponsiveness and neutrophilic inflammation, decreased IL-6 and TNF-α production, with no effect on airway eosinophil counts and type 2 inflammatory cytokines. In addition, intratracheal instillation of recombinant CDH11 led to neutrophil recruitment in the lungs of mice, which could be attenuated by inhibition of FGFR1 signaling. CDH11 contributes to airway neutrophilic inflammation in severe asthma through the FGFR1 pathway. Show less
Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi- Show more
Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi-component activity. The effectiveness of these botanical extracts is thought to involve complex interactions among diverse constituents; however, the molecular basis of such interactions remains insufficiently understood. In this study, we explored the anti-inflammatory properties of the ethanol extract of Polygonum multiflorum (PME) through a combination of chemical profiling and computational analysis. PME was found to reduce the production of nitric oxide, inducible nitric oxide synthase, and interleukin-6 in LPS-stimulated RAW 264.7 macrophages. Using HS-SPME-GC-MS in conjunction with network pharmacology, we identified 32 volatile constituents, among which five core compounds were predicted to be associated with three inflammation-related targets: ESR1, FASN, and NR1H3. Dual-ligand molecular docking and molecular dynamics simulations suggested that the sequence of ligand binding may influence the stability and interaction patterns of protein-ligand complexes, offering insights into possible mechanisms of synergy and antagonism mediated by key residues such as ARG394 in ESR1. Overall, these findings contribute to a better understanding of how binding order and structural context may shape constituent-target interactions, providing a basis for the further development of multi-component natural product strategies against inflammation. This study underscores the relevance of incorporating multi-ligand dynamics into natural product research and presents an integrated experimental-computational framework to investigate the cooperative or competitive behaviors of functional food constituents, thereby supporting the rational design of optimized multi-target formulations. Show less
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical Show more
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the microRNAs arising from the lack of the antioxidant transcription factor Nrf2 lead to cancer metastasis. However, much less is known about the regulation of microRNAs by Nrf1, even though it acts as an essential determinon of cell homoeostasis by governing the transcriptional expression of those driver genes contributing to the EMT involved in its metastasis. In this study, distinct EMT phenotypes resulted from specific knockouts of Nrf1 and Nrf2 in HepG2 cells, as accompanied by their differential migratory and invasive capabilities. The Show less
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute Show more
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute lung injury (ALI) and their relationship to injury remain unclear. Transcriptomic and lipidomic analyses revealed downregulation of PUFA synthesis pathways, particularly omega-3 PUFAs, in pulmonary ECs during LPS-induced ALI. Activation of the PUFA metabolic pathway, through FADS1/2 overexpression or omega-3 fatty acid supplementation, protected ECs from ferroptosis and restored barrier function. In vivo, pulmonary EC-specific overexpression of FADS1/2 contributed to the alleviation of ALI. Overexpression of whole lung FADS1/2, combined with alpha-linolenic acid (ALA) supplementation, also significantly mitigated ALI. PARK7 is identified as an endogenous regulator of FADS1/2, acting through the BMP-BMPR-SMAD1/5/9 signaling. Driven by histone H3K14 lactylation, which is also promoted by the downregulation of FADS1/2, PARK7 upregulation restored FADS1/2 expression and counteracted ferroptosis, thereby forming a protective feedback loop. This study elucidates a novel regulatory axis involving the two major metabolic changes-downregulation of PUFA synthesis and upregulation of histone lactylation-in ALI pathogenesis, which are interconnected through the PARK7-BMP signaling pathway. Targeting this axis offers potential therapeutic strategies for mitigating endothelial dysfunction and ferroptosis in ARDS/ALI. 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-ac Show more
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
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevale Show more
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non-coding regions. However, the role of non-coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome-wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib-lenalidomide-dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd-resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9-mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi-omics analysis (H3K27ac ChIP-seq, scRNA-seq, scATAC-seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence-specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. Show less
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate cli Show more
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate clinical characteristics and therapeutic targets concerning FOXO1 fusion status. 65 pediatric RMS patients were enrolled. Clinical data were analyzed using Kaplan-Meier estimates and Cox regression. Surgically resected tumor tissues were subject to single-cell RNA sequencing (scRNA-seq). Patient-derived xenograft (PDX) was establish and dissociated to cells for high-throughput drug screening. Among the 65 patinets (36 patients with embryonal RMSs (ERMSs), 15 patients with alveolar RMSs (ARMSs) and 14 patients with other types of RMSs), 73.3% of ARMSs were defined as fusion positive (FP) while 6 ERMS (ERMS)s were also FP. Cox regression analysis identified FOXO1 fusion as a risk factor alone and combined with pathologic subtype, sex and age or metastasis status. scRNA-seq revealed distinct transcription factor networks between FP and FN RMS, showing up-regulated activity of OLIG2, NHLH1, SNAI1, TFF3 and other TFs related to neural development and differentiation. MAPK, PI3K-Akt, and mTOR pathways were enriched in FP-RMS tumor cells. High-throughput drug screening of PDX-derived cells identified sensitive drugs targeting FP-RMS specific signatures. AMG-337 was selected and validated for its anti-tumor effect. FOXO1 fusion status influences RMS clinical outcomes, including rare FP-ERMS cases. scRNA-seq combined with drug screening identified MET as a promising therapeutic target in FP-RMS. Show less
Male germline development is crucial for the proper establishment of spermatogonial stem cell pool and life-long production of spermatozoa, but the full-term developmental profiling of human male germ Show more
Male germline development is crucial for the proper establishment of spermatogonial stem cell pool and life-long production of spermatozoa, but the full-term developmental profiling of human male germline is not fully understood. Here, by integrating 92,488 human testicular cells spanning from six-week-old embryos to old men, we constructed a comprehensive human male germ cell atlas. Further analysis found that the precursor of undifferentiated spermatogonia underwent regulatory network reconfiguration starting from week 7 post-fertilization, accompanied by WNT6-FZD3/LRP6-JUN/MYC signaling axis. And JUN and MYC were revealed to be candidate core transcription factors that might inhibit spermatogonia differentiation. In addition, the activation of ANGPTL signaling played a role in the maintenance of human spermatogonial stem cells. Finally, by interrogating the scRNA-seq datasets from idiopathic non-obstructive azoospermia (iNOA) patients, we identified several iNOA-dysregulated genes such as CAPN3, FTMT, IZUMO2 and LACE1, which were significantly down-regulated in round spermatids of iNOA patients. Collectively, our work established an atlas of human male germ cell development, revealing the factors that might regulate male germline development and providing iNOA-dysregulated genes for future clinical diagnosis. 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 toleroge Show more
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
Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIP Show more
Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance. Show less
People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, a Show more
People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, and the increased risk of MCI and AD is associated with the lack of estrogen during menopause. Previous studies have shown that Tiao Geng Decoction (TGD) may have antioxidant and anti apoptotic properties, which may prevent neurodegenerative diseases. However, whether TGD is effective in improving mild cognitive impairment due to postmenopausal estrogen deficiency and its potential pharmacological mechanisms remain unclear. The aim of this study was to investigate the possible pharmacological mechanisms of TGD in preventing postmenopausal MCI. We utilized RNA-seq technology to screen for differentially expressed genes (DEGs) and enrichment pathways in the hippocampal tissue of different groups of mice. Additionally, we adopted single-cell sequencing technology to study the cell types of Alzheimer's disease (AD) group and Normal Control (NC) group, the differential marker genes of each cell subgroup, and the GO enrichment analysis of each cell type. Both RNA sequencing and single-cell sequencing results showed a significant correlation between TGD and NF-κb pathway in improving mild cognitive impairment in postmenopausal women. The experimental verification results showed that the spatial learning and memory abilities of APP/PS1 model mice were weakened after ovariectomy, and the reproductive cycle on vaginal smears was in the interphase of diestrus. The levels of serum E2, and P-tau181 in mice were significantly down regulated, while the levels of brain tissue homogenate A β 42, IL-1 β, and IL-18 were significantly up-regulated, indicating successful modeling. Combining Western blotting, RT-qPCR, and transmission electron microscopy analyses, it was found that the low estrogen environment induced by oophorectomy can activate the NF-κb signaling pathway, activate the expression of NLRP3 inflammasome and A β secretase BACE1, and induce neuroinflammatory damage in hippocampal astrocytes. These results conform to the modeling characteristics of MCI. After TGD intervention, the spatial learning and memory abilities of MCI mice were significantly improved. The pharmacological validation results indicated that high concentration doses of TGD had a more significant effect on MCI. Subsequently, we used high concentration TGD (0.32 g/ml) as the traditional Chinese medicine group for further validation, protein blotting and RT-qPCR results indicated that TGD can effectively stimulate the secretion of ER α and ER β, inhibit the NF-κb pathway, downregulate BACE1, and inhibit the expression of NLRP3 inflammasome related proteins. In addition, the immunofluorescence results of hippocampal astrocytes showed that TGD can effectively facilitate the expression of AQP1 and significantly lower the sedimentation of A β compared with the model group. Our research suggests that there is a high correlation between a low estrogen environment and the occurrence and development of MCI. TGD may regulate the ERs/NF - κ b/AQP1 signaling pathway, promote estrogen secretion, activate AQP1, reduce A β deposition, reverse MCI neuroinflammatory injury, improve mild cognitive impairment, and prevent the occurrence of AD. This study revealed for the first time that TGD may be a potential new alternative drug for preventing and improving menopausal MCI. Show less
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediat Show more
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE ε4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The People’s Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (ε2, ε3, and ε4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count × neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with ε3 as the reference. The frequencies of APOE alleles ɛ3, ɛ2, and ɛ4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in ɛ2 carriers than in ɛ3 (373.74*10⁹/L vs. 403.53*10⁹/L, APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses. Show less
Synaptic dysfunction and synapse loss occur in Alzheimer's disease (AD). The current study aimed to identify synaptic-related genes with diagnostic potential for AD. Differentially expressed genes (DE Show more
Synaptic dysfunction and synapse loss occur in Alzheimer's disease (AD). The current study aimed to identify synaptic-related genes with diagnostic potential for AD. Differentially expressed genes (DEGs) were overlapped with phenotype-associated module selected through weighted gene co-expression network analysis (WGCNA), and synaptic-related genes. The overlapped hub genes were further processed using machine learning algorithms, intersected with module gene from protein-protein interaction (PPI) network constructed with DEGs, to yield co-hub genes. The diagnostic potentials of the co-hub genes were examined by receiver operating characteristic (ROC) analysis. Correlation between co-hub genes with clinical features and immune cell infiltration was analyzed. Finally, the expression of co-hub genes was analyzed in several datasets and validated in AD transgenic mice. A total of three co-hub genes were identified, including MAP1B, L1CAM, and GABBR2. GABBR2 showed area under the curve (AUC) values of 0.98, 0.81, and 0.88 in the training and two external validation datasets. GABBR2 was negatively correlate with beta- and gamma-secretase activities, and infiltration of natural killer T cells and effector memory CD8 T cells. Finally, GABBR2 was validated to be downregulated in AD transgenic mice, aligning with bioinformatic findings. GABBR2 overexpression in N2a/APP cells increased ADAM10 while decreased of BACE1, leading to upregulation of sAPPα while downregulation of sAPPβ. In conclusion, GABBR2 acts as a novel biomarker for the diagnosis of AD and negatively correlated with Aβ in AD. Show less
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder Show more
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts' analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. Show less
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein in Show more
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein interactions. In this study, we investigate the role of the PALS1-associated tight junction protein (PATJ), which contains 10 PDZ domains, in the formation of IS and its subsequent impact on T cell activation. To elucidate the function of PATJ, we generated murine models with conditional T cell-specific knockout of We observed a rapid increase in PATJ expression during T cell activation. Conditional knockout of Our study reveals an important role of PATJ in the formation of IS and provides an approach to improve the efficacy of CAR-T therapy. Show less
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointes Show more
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointestinal (GI) tract gene expression to meat quality remains unclear. Here, we performed bulk RNA-seq on 130 samples from Liangshan Black Sheep and Meigu Black Goats, including 10 GI tract segments and semitendinosus muscle, integrating these data with measurements of amino acid composition, fatty acid profiles, and volatile flavor compounds. We found distinct, segment-specific transcriptional programs across the GI tract, with major functional shifts at the rumen-reticulum, omasum-abomasum, and abomasum-duodenum transitions. In the ileum and jejunum, genes involved in lipid metabolism showed links to fatty acid profiles, whereas genes governing amino acid metabolism in the small intestine were connected to the amino acid composition of muscle. Cecum- and colon-enriched genes were linked to flavor precursor biosynthesis. Species-specific differences revealed that sheep muscle contained higher levels of key amino acids (Asp, Glu, Hyp, Cys, Tyr), whereas goats showed higher α-linolenic acid and other polyunsaturated fatty acids. This work establishes a gut-muscle transcriptomic axis in small ruminants, identifying candidate genes (e.g., Show less
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the Show more
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the central nervous system, play a crucial role in modulating the pathological processes associated with AD. Jiajian Shuyu Pills (JJSYP) are frequently employed in the treatment of AD, purportedly by enhancing the physiological functions of human tissues and organs to modulate the immune response. Nevertheless, the underlying mechanisms by which JJSYP exert their therapeutic effects in the context of AD remain inadequately elucidated. This study aimed to assess the effects of JJSYP on cognitive enhancement and the alleviation of neuroinflammation in the treatment of AD, as well as to explore the underlying mechanisms using mouse models. The components of JJSYP in serum were analyzed using HPLC-Q/TOF-MS. APP/PS1 transgenic mice served as AD models in this investigation. Cognitive function in the AD mice was assessed through the Mirror Water Maze Test and the Novel Object Recognition Test. The quantification of apoptotic hippocampal cells was conducted using Nissl staining and TUNEL staining. Immunofluorescence (IF) and Western blot (WB) analyses were employed to examine microglial activation and the expression of relevant proteins. Transcriptomic sequencing analysis and network pharmacology were administrated to explore the potential mechanisms of JJSYP in AD treatment. Inflammatory cytokine levels in the brain were measured using RT-PCR. A total of 74 absorbed prototype components from JJSYP were identified. JJSYP effectively improved cognitive function and neuroapoptosis in AD model mice by modulating the activation of microglia. The JJSYP intervention alleviated neuroinflammation by suppressing microglial activation and reducing the accumulation of amyloid β-protein. Through transcriptome sequencing and WB verification, 34 differentially expressed genes (DEGs) were identified, including ACKR3, NR1H3 and Adra1a. Following treatment with a high dose of JJSYP, both ACKR3 and NR1H3 showed a significant decrease compared to the model group. Conversely, ADRA1A expression was reduced in model group compared to the control group, but increased following high dose JJSYP treatment. Research involving RNA sequencing and network pharmacology indicated that JJSYP altered the activation of CXCL12/ACKR3 signaling pathways in the hippocampus. JJSYP exhibits potential anti-Alzheimer's Disease effects and warrants further investigation and development as a prosper treatment for AD. Show less
Sepsis, characterized as a systemic inflammatory response triggered by pathogen invasion, represents a continuum that may progress from mild systemic infection to severe sepsis, potentially culminatin Show more
Sepsis, characterized as a systemic inflammatory response triggered by pathogen invasion, represents a continuum that may progress from mild systemic infection to severe sepsis, potentially culminating in septic shock and multiple organ dysfunction syndrome. A pivotal element in the pathogenesis and progression of sepsis involves the significant disruption of oncological metabolic networks, where cells within the pathological milieu exhibit metabolic functions that diverge from their healthy counterparts. Among these, purine metabolism plays a crucial role in nucleic acid synthesis. However, the contribution of Purine Metabolism Genes (PMGs) to the defense mechanisms against sepsis remains inadequately explored. Leveraging bioinformatics, this study aimed to identify and substantiate potential PMGs implicated in sepsis. The approach encompassed a differential expression analysis across a pool of 75 candidate PMGs. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were employed to assess the biological significance and pathways associated with these genes. Additionally, Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) methodologies were implemented to identify key hub genes and evaluate the diagnostic potential of nine selected PMGs in sepsis identification. The study also examined the correlation between these hub PMGs and related genes, with validation conducted through expression level analysis using the GSE13904 and GSE65682 datasets. The study identified twelve PMGs correlated with sepsis, namely AK9, ENTPD3, NUDT16, GMPR2, PKM, RRM2B, POLR2J, POLE3, ADCY3, ADCY4, ADSSL1, and AMPD1. Functional analysis revealed their involvement in critical processes such as purine nucleotide and ribose phosphate metabolism. The diagnostic capability of these PMGs to effectively differentiate sepsis cases underscored their potential as biomarkers. This research elucidates twelve PMGs associated with sepsis, providing valuable insights into novel biomarkers for this condition and facilitating the monitoring of its progression. These findings highlight the significance of purine metabolism in sepsis pathogenesis and open avenues for further investigation into therapeutic targets. Show less
Angiopoietin-like 3 (ANGPTL3) is a major regulator of lipoprotein metabolism. ANGPTL3 deficiency results in lower levels of triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C), and may Show more
Angiopoietin-like 3 (ANGPTL3) is a major regulator of lipoprotein metabolism. ANGPTL3 deficiency results in lower levels of triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C), and may protect from cardiovascular disease. ANGPTL3 oligomerizes with ANGPTL8 to inhibit lipoprotein lipase (LPL), the enzyme responsible for plasma triglyceride hydrolysis. Independently of ANGPTL8, oligomers of ANGPTL3 can inhibit endothelial lipase (EL), which regulates circulating HDL-C and LDL-C levels through the hydrolysis of lipoprotein phospholipids. The N-terminal region of ANGPTL3 is necessary for both oligomerization and lipase inhibition. However, our understanding of the specific residues that contribute to these functions is incomplete. In this study, we performed mutagenesis of the N-terminal region to identify residues important for EL inhibition and oligomerization. We also assessed the presence of different ANGPTL3 species in human plasma. We identified a motif important for lipase inhibition, and protein structure prediction suggested that this region interacted directly with EL. We also found that recombinant ANGPTL3 formed a homotrimer and was unable to inhibit EL activity when trimerization was disrupted. Surprisingly, we observed that human plasma contained more monomeric ANGPTL3 than trimeric ANGPTL3. An important implication of these findings is that previous correlations between circulating ANGPTL3 and circulating triglyceride-rich lipoproteins need to be revisited. Show less
Computer vision is increasingly used in farmers' fields and agricultural experiments to quantify important traits. Imaging setups with a sub-millimeter ground sampling distance enable the detection an Show more
Computer vision is increasingly used in farmers' fields and agricultural experiments to quantify important traits. Imaging setups with a sub-millimeter ground sampling distance enable the detection and tracking of plant features, including size, shape, and colour. Although today's AI-driven foundation models segment almost any object in an image, they still fail for complex plant canopies. To improve model performance, the global wheat dataset consortium assembled a diverse set of images from experiments around the globe. After the head detection dataset (GWHD), the new dataset targets a full semantic segmentation (GWFSS) of organs (leaves, stems and spikes) covering all developmental stages. Images were collected by 11 institutions using a wide range of imaging setups. Two datasets are provided: i) a set of 1096 diverse images in which all organs were labelled at the pixel level, and (ii) a dataset of 52,078 images without annotations available for additional training. The labelled set was used to train segmentation models based on DeepLabV3Plus and Segformer. Our Segformer model performed slightly better than DeepLabV3Plus with a mIOU for leaves and spikes of ca. 90 %. However, the precision for stems with 54 % was rather lower. The major advantages over published models are: i) the exclusion of weeds from the wheat canopy, ii) the detection of all wheat features including necrotic and senescent tissues and its separation from crop residues. This facilitates further development in classifying healthy vs. unhealthy tissue to address the increasing need for accurate quantification of senescence and diseases in wheat canopies. Show less
The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in medi Show more
The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in mediating immune suppression. However, the precise mechanisms underlying PMN-MDSCs infiltration into the tumor immune microenvironment (TIME) and their immunosuppressive functions remain poorly understood. In this investigation, we observed that PMN-MDSCs were up-regulated during stomach carcinogenesis, with gastric cancer (GC) cells secreting CCL26 to promote the infiltration of PMN-MDSCs into the TIME via the CX3CR1 receptor. The infiltrating CX3CR1 Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hep Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application. Show less
Dietary interventions with food-derived natural products have emerged as a promising strategy to alleviate obesity. This study aims to investigate the anti-obesity effect of