This study aimed to elucidate the molecular mechanisms by which celastrol (Cel) alleviates atherosclerosis (AS) through the regulation of macrophage autophagy. An AS model was established using ApoE C Show more
This study aimed to elucidate the molecular mechanisms by which celastrol (Cel) alleviates atherosclerosis (AS) through the regulation of macrophage autophagy. An AS model was established using ApoE Cel markedly reduced aortic plaque formation, ameliorated dyslipidemia, attenuated inflammatory responses, and enhanced plaque stability in ApoE Cel exerts anti-atherosclerotic effects by activating macrophage autophagy via the AMPK/ULK1 pathway, thereby improving lipid metabolism, reducing inflammation, and stabilizing plaques. These findings highlight the therapeutic potential of Cel and provide new insights into autophagy-targeted strategies against AS. Show less
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic mo Show more
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic modalities to revolutionize clinical management and enhance patient outcomes. The recent seminal discovery by Swamynathan et al. has unveiled menadione, a vitamin K precursor, as a potent inducer of triaptosis-a novel regulated cell death pathway mediated through the oxidative modulation of phosphatidylinositol 3-kinase PIK3C3/VPS34. This mechanistically distinct cell death paradigm, characterized by its intimate association with endosomal dysfunction and oxidative stress-induced cellular catastrophe, has demonstrated remarkable therapeutic efficacy in preclinical prostate cancer models, outperforming conventional therapeutic regimens and emerging as a potential paradigm-shifting strategy in oncology. This comprehensive review provides a critical synthesis of the triaptosis discovery landscape, elucidating its molecular intricacies and pathophysiological implications. We systematically examine the multifaceted roles of endosomal biology in oncogenesis and tumor progression, while offering a nuanced perspective on redox homeostasis in malignant cells and the therapeutic potential of oxidative stress modulation. Furthermore, we address the inherent dichotomy of oxidative stress induction in cancer therapy, balancing its therapeutic promise against potential adverse effects. Looking toward the horizon of cancer research, we explore transformative therapeutic strategies leveraging triaptosis induction and its potential applications beyond oncology, aiming to catalyze a new era of precision medicine that ultimately enhances patient survival and quality of life. Show less
The differential diagnosis between Tuberculosis (TB) and Non-tuberculous Mycobacteria (NTM) has historically been constrained by the inadequate sensitivity and specificity of current diagnostic method Show more
The differential diagnosis between Tuberculosis (TB) and Non-tuberculous Mycobacteria (NTM) has historically been constrained by the inadequate sensitivity and specificity of current diagnostic methods. Furthermore, distinguishing between Active Tuberculosis (ATB) and Latent Tuberculosis Infection (LTBI) poses significant challenges. This study aims to develop a molecular differentiation system for ATB, LTBI, and NTM by integrating plasma proteomics with multi-dimensional analytical techniques, while also exploring key biomarkers associated with disease progression and treatment response. Using label-free quantitative technology, we conducted a plasma proteomics analysis across five groups: ATB, LTBI, NTM, Cured Patients (CPs), and Healthy Donors (HD). Differentially Expressed Proteins (DEPs) were identified through screening (FC > 1.5 or <0.67, P < 0.05), followed by Gene Ontology/KEGG pathway enrichment, STRING interaction network, and Mfuzz dynamic clustering analysis to systematically elucidate molecular characteristics. Experimental data were validated through a multidimensional quality control system (Pearson correlation coefficient, peptide distribution, molecular weight distribution, etc.). Enzyme-linked immunosorbent assay (ELISA) was employed to detect the plasma expression levels of target proteins across the groups and to facilitate comparisons. This study identified 1,338 non-redundant proteins across five cohorts. Comparative analysis revealed 142 DEPs across the three comparative groups (ATB, LTBI, and NTM), which were primarily localized in the extracellular domain. Key findings include: 27 DEPs in the ATB-LTBI group, primarily enriched in inflammatory responses (such as A2M, IL-1R2) and epithelial barrier functions (TGM3, KRT3); 69 DEPs in the ATB-NTM group, characterized by significant changes in immunoglobulin light chains (IGLV2-11) and innate immune effector molecules (S100A8); 46 DEPs in the NTM-LTBI group, closely related to lipid metabolism (APOC3) and extracellular matrix remodeling (FN1). KEGG pathway analysis revealed that DEPs in the ATB-LTBI group were enriched in nitrogen metabolism pathways, those in the ATB-NTM group were associated with thyroid hormone synthesis, and the NTM-LTBI group was involved in phagosome function. Dynamic clustering results showed six treatment response modules: Cluster 1/2 (riboflavin metabolism, complement coagulation pathway) were activated post-treatment, Cluster 3/4 (proteasome, cardiac signaling pathway) exhibited partial reversal in expression, and Cluster 5/6 (platelet activation, cytoskeleton) showed delayed regression. Research confirmed 10 differential proteins between the ATB-CPs and ATB-HD groups, including S100A8, LTA4H, and DEFA1B, which constitute a molecular fingerprint specific to ATB. ELISA validation confirmed significantly elevated S100A8 and GPX3 in ATB group, while NTM group showed higher FGB and lower ATRN levels. This study systematically reveals the plasma proteomic characteristics under infection statuses caused by different mycobacteria. A discrimination framework for ATB/LTBI/NTM was constructed based on disease-specific differential proteins, overcoming the limitations of traditional diagnostic techniques in distinguishing infection states. Through dynamic analysis of six temporal therapeutic modules, the reprogramming patterns of the host protein network during tuberculosis treatment were elucidated. This research lays a multidimensional molecular foundation for the precise typing, personalized treatment, and prognostic evaluation of mycobacterial infections. Show less
Although the human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes tha Show more
Although the human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from both cerebellum and frontal cortex of AD/ADRD patients and normal controls. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we pinpointed two likely causal genes, Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and three-dimensional (3D) genome data. Via CRISPRi experiments, we found that perturbation of rs4788201 and rs62056801 significantly inhibited the expression of their target genes, SEZ6L2 and KANSL1, in human iPSC-derived neurons. This cell subtype-specific regulatory landscape in the human cerebellum identified here offers novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied. Show less
Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 Show more
Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation. DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S. Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival. The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets. Show less
Women with autoimmune diseases (AIDs) experience chronic immune dysregulation and hormonal fluctuations, both of which may influence breast cancer risk. However, it remains unclear whether this risk i Show more
Women with autoimmune diseases (AIDs) experience chronic immune dysregulation and hormonal fluctuations, both of which may influence breast cancer risk. However, it remains unclear whether this risk is driven mainly by its treatment or the underlying disease, highlighting the need for integrating real-world data and genetic evidence. The FDA Adverse Event Reporting System (FAERS) were utilized to identify breast cancer safety signals among women with AIDs, analyzing 11,479 reports from 2004 to 2024. Disproportionality analyses using Reporting Odds Ratio (ROR) and Information Component (IC) were conducted. Then, we mapped these drugs to their target genes and performed mendelian randomization (MR) to assess their causal relationships with breast cancer. Finally, we investigated shared genetic architecture between breast cancer and AIDs using global and local genetic correlation, cross-trait meta-analysis, and transcriptome-wide association studies. We identified 13 immunosuppressive drugs (TNF inhibitors, interleukin inhibitors, and monoclonal antibodies), 3 immunostimulants and 16 adjunctive drugs associated with increased breast cancer reporting in patients with AIDs. The drugs with the highest case reports for positive disproportionality analysis were interferon beta-1a (N: 1731, IC [IC025] 1.56 [1.49]), natalizumab (798, 0.65 [0.54]), and infliximab (741, 0.64 [0.53]). MR results revealed causal links between 9 drug targets and breast cancer risk, such as FDPS (OR: 0.66, p: 1.33E-08), CALCRL (OR: 0.887, p: 4.77E-06) and PARP1 (OR: 1.051, p: 3.50E-06). Global genetic correlation identified significant shared heritability between breast cancer and 3 specific AIDs, including type 1 diabetes mellitus (rg: -0.242, p: 0.95E-4), ulcerative colitis (rg: 0.125, p: 0.29E-2), and migraine (rg: 0.078, p: 0.79E-2). Specifically, the most notable genetic overlap was observed between breast cancer and type 1 diabetes mellitus, with significant shared risk SNPs (rs12046289 and rs6679677) and susceptibility genes (ADCY3 and CENPO). Our study uncovered several immune-related drugs associated with increased breast cancer reporting in women with AIDs. This risk may be explained by several potential drug targets with causal roles, or by the shared genetic comorbidity between specific AIDs and breast cancer. These insights emphasize the need for tailored breast cancer surveillance and highlight potential molecular targets for intervention in vulnerable populations. Show less
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a li Show more
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a lipoprotein lipase (LPL) activity inhibitor, can inhibit triglycerides (TGs) decomposition, and fibroblast growth factor 21 (FGF21) enhances fatty acids' β-oxidation in liver. We constructed a novel fusion protein combining the anti-ANGPTL3 nanobody FD03 and FGF21 (FD03-FGF21), which exerted appropriate binding affinities to ANGPTL3 and β-Klotho respectively. Our results showed FD03-FGF21 restored bioactivity of LPL which inhibited by ANGPTL3 and activated downstream pathway of FGF21 in iLite FGF21 assay-ready cells. Next, FD03-FGF21 showed a significant therapeutic effect in MAFLD mice, including attenuation of metabolic dyslipidemia, hepatic lipid accumulation, and impaired glucose tolerance. Compared to other treatments, FD03-FGF21 achieved the most significant therapeutic effect with a 79.78 % attenuation of low-density lipoprotein cholesterol (LDL-C) and a 95.8 % reduction of hepatic lipid accumulation. Mechanistically, transcriptomic analysis revealed that differential expression genes (DEGs) were principally clustered into lipid metabolism and oxidative stress pathways after the fusion protein treatment, especially the key lipid metabolism genes of LDLR and CD36 were significantly upregulated and downregulated respectively, as confirmed by WB. Furthermore, lipidomic and metabolomic analysis indicated the fusion protein ameliorated disorders in lipid and protein metabolism mainly through the downregulation of DG and upregulation of PC. Hepatic oxidative stress and inflammation were significantly reduced after administration of the fusion protein in MAFLD mice. Collectively, FD03-FGF21 represents an effective therapeutic strategy for MAFLD therapy through ameliorating lipid metabolism and oxidative stress. Show less
Nolan Priedigkeit, Beth Harrison, Robert Shue+27 more · 2025 · Clinical cancer research : an official journal of the American Association for Cancer Research · added 2026-04-24
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to li Show more
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. Show less
Metal-organic frameworks (MOFs) have been considered as ideal platforms to achieve long persistent luminescence (LPL), to utilize as optical recording devices, security systems and sensors. Despite th Show more
Metal-organic frameworks (MOFs) have been considered as ideal platforms to achieve long persistent luminescence (LPL), to utilize as optical recording devices, security systems and sensors. Despite the rapid emergence, it is still a challenge to develop single-component red LPL MOFs. In this work, two hetero-ligand MOFs are synthesized using a D-π-A-type ligand (source of red phosphorescence) and a monocyclic carboxylic ligand (appropriate void constructer), which show efficient red LPL after removal of wide excitations at ambient conditions. Experiment and calculation suggest that the effective red LPL originates from the D-π-A-type ligand, while the auxiliary carboxylic ligand mediates the orientation/arrangement of the D-π-A linker in MOFs affecting phosphorescence. The MOFs are further used in the field of multiple message encryption, initiating a new perspective for designing new red LPL MOFs. Show less
To explore the optimal row-ratio in mechanized hybrid rice seed production, a field experiment was conducted in 2024 at Qionglai and Mianzhu using 'Tiantai A' × 'Taihui 808'. Three row-ratio treatment Show more
To explore the optimal row-ratio in mechanized hybrid rice seed production, a field experiment was conducted in 2024 at Qionglai and Mianzhu using 'Tiantai A' × 'Taihui 808'. Three row-ratio treatments (H1: 18:6, H2: 24:6, and H3: 30:6) were tested using agricultural unmanned aerial vehicles (AUAVs) for pollination assistance. The results showed that row-ratio had little effect on sterile line flowering dynamics. The index of flowers meeting (IFM) was 0.71-0.72 at Qionglai and 0.81-0.86 at Mianzhu, with 11 to 12 days of flowering duration. As the row-ratio increased, total pollen quantity in the panicle layer and grain filling rate (GFR) decreased, while grain infection rate (GIR) increased. The responses of grain blighted rate (GBR), grain empty rate (GER), and fertilization success rate (FSR) to row-ratio varied between sites. Pollen density and GFR followed the pattern of near region (NR) > central region (CR) > far region (FR). Within the panicle, pollen density was generally highest in the upper panicle layer (UPL), followed by the middle (MPL) and lower (LPL) layers, with partial exceptions observed in the H2 and H3 treatments at Mianzhu. The vertical distribution of GFR varied by site: at Qionglai, it was apical parts of panicle (APP) > median parts (MPP) > basal parts (BPP), whereas at Mianzhu the order was MPP > APP > BPP. With wider row-ratios, yield per unit area (YUA) and GFR declined (H1 > H2 > H3), while 1,000-grain weight increased or decreased and then increased. Under H1, yields reached 2,107.50 kg ha Show less
The etiology of spontaneous abortion (SA) is complex, and the underlying mechanisms remain largely elusive. Environmental toxins have been implicated in the increased occurrence of SA. However, the as Show more
The etiology of spontaneous abortion (SA) is complex, and the underlying mechanisms remain largely elusive. Environmental toxins have been implicated in the increased occurrence of SA. However, the association between aminomethylphosphonic acid (AMPA) exposure and SA has not yet been established. We found that AMPA, along with the lactate were significantly elevated in villous tissues from SA patients compared to normal controls, with a robust positive correlation between AMPA and lactate concentrations. More importantly, AMPA exposure induced SA in C57BL/6 mice probably through the dysfunctions of human trophoblast cell. Further studies indicated that the L-lactate production which can be induced by AMPA via PPARγ/ANGPTL4 pathway caused similar defects of human trophoblast cells. A global elevation of protein lactylation has been detected in the villous tissues from SA patients as well as AMPA or lactate treated human trophoblast cells. Pan-Kla antibody coimmunoprecipitation coupled with mass spectrometry of AMPA or lactate treated human trophoblast cells revealed JunB, which was reduced in the placenta villus from SA patients and AMPA/lactate treated human trophoblast cells, could be lactylated at lysine (K) 36. JunB K36R mutation abolished JunB lactylation and ameliorated AMPA induced JunB loss via ubiquitination in human trophoblast cells. In comparison to wild type JunB, JunB K36R mutation had better protective roles in AMPA induced trophoblast dysfunctions. In conclusion, our results demonstrate that AMPA exposure promotes lactate production via the PPARγ/ANGPTL4 pathway, which subsequently inhibits the proliferation, migration and invasion of trophoblasts through JunB K38 lactylation, ultimately leading to SA. Show less
Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea-cycle disorder, results in hyperammonemia initiating a sequence of adverse events that can lead to coma and death if not treated rapidly. The Show more
Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea-cycle disorder, results in hyperammonemia initiating a sequence of adverse events that can lead to coma and death if not treated rapidly. There is a high unmet need for an effective therapeutic for this disorder, especially in early neonatal patients where mortality is excessive. However, development of an adeno-associated virus (AAV)-based approach is hampered by large cDNA size and high protein requirement. We developed an oversized AAV vector as a gene therapy to treat Show less
Little is known about the importance of blood lipids for risk of myocardial infarction (MI) in Chinese vs. European populations. We compared the associations with MI of apolioprotein B (ApoB) vs. low- Show more
Little is known about the importance of blood lipids for risk of myocardial infarction (MI) in Chinese vs. European populations. We compared the associations with MI of apolioprotein B (ApoB) vs. low-density lipoprotein cholesterol (LDL-C) and remnant-cholesterol (remnant-C) vs. triglycerides in the China Kadoorie Biobank (CKB) and UK Biobank (UKB). Plasma levels of LDL-C, high-density lipoprotein-cholesterol (HDL-C), apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1), non-HDL-C, remnant-C, LDL-C/ApoB, and HDL-C/ApoA1 ratios were measured in a nested case-control study of MI (948 cases, 6101 controls) in CKB and a prospective study (5344 cases in 279 989 participants) in UKB. Associations of lipids with MI were assessed using logistic regression in CKB and Cox regression in UKB after adjustment for confounders and correction for regression dilution. The mean levels of LDL-C were about 30% lower in CKB than in UKB [2.3 (0.6) vs. 3.7 (0.8) mmol/L], but mean levels of HDL-C were comparable [1.3 (0.3) vs. 1.5 (0.4) mmol/L], as were those for triglycerides [1.8 (1.1) vs. 1.7 (1.1) mmol/L]. While the rate ratios (RRs) of MI for 1 SD higher usual levels of LDL-C in Chinese were about half those in Europeans (1.27; 1.13-1.44 vs. 1.55; 1.49-1.61), the corresponding RRs for ApoB or non-HDL with MI were comparable between Chinese and Europeans. The findings reinforce current guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in China that advocate initiation of statin treatment in individuals at high-risk of ASCVD rather than high levels of LDL-C. Show less
Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide, with cancer stemness and metastasis being critical factors contributing to poor prognosis. While circular R Show more
Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide, with cancer stemness and metastasis being critical factors contributing to poor prognosis. While circular RNAs are emerging as important regulators in cancer progression, the role of circGIGYF1 in CRC development is poorly understood. Here, we found that downregulated circGIGYF1 is linked to poor survival rate in CRC patients. circGIGYF1 inhibits CRC stemness, epithelial-mesenchymal transition, and metastatic potential both in vitro and in vivo. Mechanistically, circGIGYF1 promotes the interaction between WWP2 and HOXD13, enhancing HOXD13 ubiquitination and subsequent degradation. This degradation prevented HOXD13 from binding to the CTNNB1 promoter, thereby suppressing Wnt/β-catenin signalling pathway activation. Importantly, circGIGYF1 overexpression or HOXD13 knockdown significantly reduces tumor growth and liver metastasis in mouse models. These findings reveal a circGIGYF1/WWP2/HOXD13/β-catenin regulatory axis in CRC progression and highlight circGIGYF1 as a potential therapeutic target for developing strategies to combat CRC metastasis and recurrence. Show less
Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer's disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL Show more
Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer's disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL3 mRNA expression was abnormally upregulated in the brains of AD transgenic mice. Moreover, the levels of CCL3 in the serum of AD patients were significantly elevated and negatively correlated with their cognitive abilities. However, the role of CCL3 in AD neuroinflammation and pathological damages remains elusive. Using behavioral, histological, and biochemical methods, outcomes of CCL3 antibody treatment on neuropathology and cognitive deficits were studied in the APPswe/PS1dE9 mice. In the present study, we reported that CCL3 protein expression was increased in the APPswe/PS1dE9 mice, whereas blockage of CCL3 with neutralizing antibody potently inhibited CCL3 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, CCL3 antibody significantly improved the learning and memory abilities of APPswe/PS1dE9 mice. In addition, CCL3 antibody treatment decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that CCL3 antibody treatment alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated NF-κB signaling pathway in APPswe/PS1dE9 mice was inhibited by CCL3 antibody treatment. Collectively, our findings provide evidence that CCL3 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. Show less
A meta-analysis was conducted to assess the effects of citric acid (CA) on silage fermentation, and then used whole-plant cassava silage as a model to explore the underlying microbiological mechanisms Show more
A meta-analysis was conducted to assess the effects of citric acid (CA) on silage fermentation, and then used whole-plant cassava silage as a model to explore the underlying microbiological mechanisms with metagenomic and metabolomic data. The meta-analysis revealed that CA supplementation increased the dry matter, crude protein, water-soluble carbohydrate, and lactic acid contents in silage, but decreased the pH, dry matter loss, and the contents of fiber, NH 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 predic Show more
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
Metastatic spread of cancer is the leading cause of death in patients with epithelial ovarian cancer (EOC), and elucidation of the molecular mechanisms underlying this process is a major focus of canc Show more
Metastatic spread of cancer is the leading cause of death in patients with epithelial ovarian cancer (EOC), and elucidation of the molecular mechanisms underlying this process is a major focus of cancer research. Fibroblast growth factor-inducible 14 (Fn14) has been shown to regulate wound repair, inflammation, angiogenesis, and chemoresistance, but its functional role in metastasis in EOC is still unknown. Here it is reported that Fn14 is identified as a cancer metastasis suppressor that inhibits the migratory and invasive potential of EOC cells by down-regulating epithelial-mesenchymal transition (EMT). Mechanistically, it is identified that Fn14 promotes acetylation-dependent protein degradation of Slug, a key transcriptional factor associated with EMT. The deacetylase Sirtuin 2 (SIRT2) has been reported to be involved in the deacetylation of Slug protein to stabilize it and then prevent its degradation in the nucleus. The results showed that Fn14 alters the subcellular localization of (SIRT2) by interacting with SIRT2, leading to reduced SIRT2 shuttling into the nucleus and subsequently promoting the acetylated degradation of Slug. Collectively, the work has demonstrated for the first time that Fn14 inhibits EOC metastasis by regulating SIRT2-mediated Slug deacetylation, providing a new perspective and method for the development of future novel therapeutic strategies for the treatment of EOC metastasis. Show less
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from Show more
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. Show less
Mengru Pan, Yifan Qian, Linlin Jiang+2 more · 2025 · Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology · Taylor & Francis · added 2026-04-24
To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism. Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA Show more
To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism. Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA) were established to evaluate the impact of GIP on androgen synthesis Administration of GIP significantly reduced testosterone secretion in a DHEA-induced PCOS mouse model. Consistent with these findings, GIP treatment decreased testosterone release and downregulated the expression of GIP receptor (GIPR), steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and cytochrome P450 family 17 subfamily A member 1 (CYP17A1) in NCI-H295R cells. Notably, RNA-seq revealed that Our study demonstrated that the administration of GIP reduces androgen synthesis in PCOS mouse models and at the cellular level, suggesting its potential as a novel therapeutic target for managing PCOS. Show less
Schizophrenia (SCZ) is a major neurodevelopmental disorder that exhibits poor response to current therapeutic interventions. Dysregulation of glutamate metabolism (GM) has been strongly associated wit Show more
Schizophrenia (SCZ) is a major neurodevelopmental disorder that exhibits poor response to current therapeutic interventions. Dysregulation of glutamate metabolism (GM) has been strongly associated with the development of SCZ, through mechanisms involving NMDA receptor dysfunction and neuroimmune imbalance. This study utilized Mendelian randomization (MR) to explore the causal association between 1400 blood metabolites and SCZ. Differentially Expressed GM-related Genes (GMDEGs) were identified via GEO transcriptome data integration, and consensus clustering techniques were employed to delineate the molecular subtypes. Using the key GM genes, a diagnostic model was developed and combined with CIBERSORT and MCPcounter analyses to assess immune infiltration. Moreover, the Drug Signatures Database (DSigDB) was used to identify potential targeted drugs, with their binding stability verified through Molecular Docking (MD) and dynamics simulations. Mendelian randomization identified 23 SCZ-related plasma metabolites, with glutamate exhibiting the most significant effect (P < 2.72e-31). Further analysis uncovered 25 Differentially Expressed Genes (DEGs) involved in GM, among which ASL, SLC1A5, and CLN3 were validated as the core targets. Immunoassays demonstrated that these DEGs were involved in the regulation of neutrophil and T cell infiltration. SCZ was categorized into C1 and C2 subtypes based on the expression profiles of these three hub glutamate metabolism genes. A diagnostic model integrating ASL, SLC1A5, and CLN3 was developed, which could identify potential therapeutic agents like Tanespimycin with an AUC of 0.844. Moreover, MD experiments confirmed strong binding affinities between tanespimycin and SLC1A5 (-7.7812 kcal/mol), geldanamycin and SLC1A5 (-7.1142 kcal/mol), cyclosporin A and CLN3 (-7.3049 kcal/mol). Meanwhile, molecular dynamics simulations indicated stable binding interactions. This study demonstrates the potential causal association of GM-related genes in SCZ, developed a precise diagnostic model, and proposed novel targeted therapeutic strategies. 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 Show more
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 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
Sepsis is associated with high morbidity and high mortality and has strongly motivated intense studies into its mechanisms. Antibiotics, aimed to eradicate bacteria, have some impact on the immune sys Show more
Sepsis is associated with high morbidity and high mortality and has strongly motivated intense studies into its mechanisms. Antibiotics, aimed to eradicate bacteria, have some impact on the immune system due to anti-inflammatory properties. Tigecycline, an antibiotic of the glycylcycline class, is commonly used for severe infections. This study aimed to investigate tigecycline's mechanism on the inflammatory response of sepsis to find new targets for sepsis treatment. The objective included (i) to observe the changes in inflammatory factors in LPS (lipopolysaccharide) induced septic mice after tigecycline administration, (ii) to detect the effect of tigecycline on macrophages NF-κB (nuclear factor kappa B) signalling. For LPS-induced sepsis in mice and intervention with tigecycline, mice were first injected with tigecycline (6.5 mg/kg) via tail vein followed by LPS (15 mg/kg). Luminex analysis was performed on 16 mediators. NF-κB signalling pathway antibody chip detected the expression of target sites in macrophages of the LPS group and tigecycline + LPS group. Tigecycline has inhibitory effects on LPS-induced inflammatory response in septic mice, decreasing the concentrations of IL (interleukin)-6, IL-27, TNF-α (tumour necrosis factor-α), TNF RII, IFN-γ (interferon-gamma), CCL5/RANTES (CC Motif Chemokine Ligand) while increasing IL-6Rα, IL-10, and TWEAK (TNF-related weak inducer of apoptosis). Tigecycline downregulated phosphorylation levels of key sites JNK (c-Jun N-terminal kinase)1/2/3, p-p65 (s468) and p-p105/p50 (s907) in NF-κB signalling. Tigecycline may inhibit the excessive immune response induced by LPS in sepsis, which may cause a potential protective effect on the host through immune regulation. Show less
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining Show more
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF. Show less
Deep brain stimulation (DBS) has emerged as a prospective treatment for psychiatric disorders; for example, DBS targeting the nucleus accumbens (NAc) abolishes addictive behaviors. However, neither th Show more
Deep brain stimulation (DBS) has emerged as a prospective treatment for psychiatric disorders; for example, DBS targeting the nucleus accumbens (NAc) abolishes addictive behaviors. However, neither the core pathway nor the cellular mechanisms underlying these therapeutic effects are known. Here, morphine-induced conditioned place preference (CPP) in mice as an addiction model and NAc-DBS combined with adeno-associated virus gene delivery for activity-dependent tagging, transgenic and chemogenetic manipulation of recruited neuronal networks are used. It is reported that a cortical-accumbal pathway and local fibroblast growth factor 1 (FGF1) signaling in the medial prefrontal cortex (mPFC) are critical for NAc-DBS to be effective in altering morphine CPP. It is shown that NAc-DBS retrogradely activates mPFC neurons projecting to the NAc, and chemogenetic activation/inhibition of these DBS-activated neuron ensembles in the mPFC reproduces the NAc-DBS effects on CPP. Sustained therapeutic effects accompany reductions in local FGF1 binding to fibroblast growth factor receptor 1 (FGFR1) in these neurons. Additionally, overexpressing FGF1 in the mPFC-NAc pathway abolishes the therapeutic effects of NAc-DBS. These results demonstrate that the mPFC-NAc pathway forms a top-down motif to regulate the therapeutic effects of subcortical DBS on addiction. These results support the potential for addiction treatments involving FGF1 signaling and highlight the mPFC as a target for noninvasive brain stimulation. Show less
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expr Show more
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of Two de novo heterozygous and eight biallelic Show less
Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile toward a synthetic phenotype plays a critical role in atherosclerosis. Although the redox-sensitive sentrin/Small Ubiqui Show more
Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile toward a synthetic phenotype plays a critical role in atherosclerosis. Although the redox-sensitive sentrin/Small Ubiquitin-like Modifier (SUMO)-specific protease 3 (SENP3), which preferentially deconjugates SUMO2/3, has been linked to oxidative stress, its role in atherosclerosis remains poorly defined. In this study, we demonstrate that SENP3 is significantly upregulated in human and mouse atherosclerotic lesions and in VSMCs exposed to pro-atherogenic stimuli. Using smooth muscle-specific Senp3 knockout mice (ApoE Show less