👤 Tianyi Qu

Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain. Therefore, systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines, which may play critical roles in the pathogenesis of sepsis. This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes. First, a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and sepsis. A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetically proxied lipid-modifying therapies on the risk of sepsis, sepsis-related critical care admission, and sepsis-related death. The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines. Finally, enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response. Genetically proxied cholesteryl ester transfer protein (CETP) inhibitors were significantly associated with sepsis-related critical care admission ( This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death. These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines, influencing the inflammatory response pathway. Show less

Cholesteryl ester transfer protein (CETP) plays a key role in lipoprotein metabolism, and its activity has been linked to the risk of atherosclerosis (AS). CETP inhibitors, such as obicetrapib, represent a novel approach in immunotherapy to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) by targeting lipid metabolism. In addition, CETP vaccines are being explored as a novel strategy for the prevention and treatment of ASCVD by inducing the body to produce antibodies against CETP, which is expected to reduce CETP activity, thereby increasing high-density lipoproteins (HDL) levels. This paper provides a comprehensive overview of the structure of CETP, the mechanisms of lipid transfer and the progress of immunotherapy in the last decade, which provides possible ideas for future development of novel drugs and optimization of immunization strategies. Show less

The Mpox virus (MPXV) has emerged as a formidable orthopoxvirus, posing an immense challenge to global public health. An understanding of the regulatory mechanisms of MPXV infection, replication and immune evasion will benefit the development of novel antiviral strategies. Despite the involvement of G-quadruplexes (G4s) in modulating the infection and replication processes of multiple viruses, their roles in the MPXV life cycle remain largely unknown. Here, we found a highly conservative and stable G4 in MPXV that acts as a positive regulatory element for viral immunodominant protein expression. Furthermore, by screening 42 optically pure chiral metal complexes, we identified the Λ enantiomer of a pair of chiral helical compounds that can selectively target mRNA G4 and enhance expression of the 39-kDa core protein encoded by the MPXV Show less

This study aims to investigate associations between omega-3 polyunsaturated fatty acids (PUFAs) and myopia. Two-sample Mendelian randomization (MR) was conducted to estimate the associations between plasma levels of omega-3 PUFAs and three traits of myopia, including myopia, high myopia (HM), and refractive spherical equivalent (RSE). Summary data-based Mendelian randomization (SMR) and colocalization analysis were conducted to examine the associations between the FADS1 and FADS2 genes and three traits of myopia in European populations. The cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNHANES) was performed to explore the relationship in East Asian adolescents. In the Two-sample MR study, plasma levels of total omega-3 PUFAs (0.993[0.990, 0.996]), Docosahexaenoic acid (DHA) (0.992[0.989, 0.996]), and Eicosapentaenoic Acid (EPA) (0.969[0.955, 0.983]) were found to be significantly and inversely associated with myopia in European populations, and similar results were shown in HM and RSE. SMR ( Show less

Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two largest populations of neocortical interneurons, innervate the soma and/or proximal dendrites, and distal dendrites of pyramidal neurons, respectively. Using PV- and SST-specific knockout mouse models, we show that PV+ interneurons require FGFR2, which responds to FGF7, to drive PV+ inhibitory presynaptic maturation on perisomatic regions of Layer V pyramidal neurons. In contrast, SST+ interneurons rely on both FGFR1 and FGFR2, which respond to FGF10 or FGF22, to promote SST+ inhibitory presynaptic maturation on distal dendrites of pyramidal neurons in cortical Layer I. Mechanistically, FGF-FGFR signaling sustains VGAT protein levels in interneurons through PP2A and Akt pathways. Together, these findings demonstrate that distinct FGF ligand-receptor combinations regulate inhibitory presynaptic differentiation by PV+ and SST+ interneurons, contributing to the formation of compartment-specific synaptic patterns. Show less

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population and poses a remarkably serious threat to human health. The effect and potential molecular mechanisms of combined cold exposure and exercise intervention on NAFLD remain unclear. A high-fat diet-induced NAFLD mouse model was used. Twenty-four NAFLD mice were divided into three groups and subjected to cold exposure (5°C), regular-temperature exercise (22°C), or combined cold exposure and exercise (5°C) for 8 wk, 5 d·wk -1 , once daily for 1 h each session. Intervention effects were evaluated through bodyweight, liver mass, liver/bodyweight ratio, blood lipid profile, circulating fibroblast growth factor 21 (FGF21) levels, and liver histopathology. Immunoblotting and quantitative PCR were used to assess the protein and gene expression of liver FGF21, β-klotho, and FGFR1 to preliminarily elucidate the molecular mechanisms underlying NAFLD improvement by combined cold exposure and exercise. Compared with cold exposure or regular-temperature exercise alone, combined cold exposure and exercise significantly reduced the bodyweight, liver weight, and liver/bodyweight ratio in the NAFLD mice. The levels of blood lipids, circulating FGF21, and liver glycogen also significantly decreased. Furthermore, the combined intervention significantly reduced liver fat deposition and fibrosis and significantly increased the expression of FGFR1 and β-klotho proteins, suggesting the activation of the FGF21-β-klotho/FGFR1 signaling pathway. This preclinical study demonstrates that combined cold exposure and exercise synergistically alleviates NAFLD progression in animal models, primarily by activating the FGF21-β-klotho/FGFR1 pathway to enhance lipid metabolism and reduce liver injury. These findings highlight the translational potential of dual environmental and behavioral interventions, providing a mechanistic foundation for developing nonpharmacological therapies targeting metabolic pathways in humans, particularly for NAFLD patients resistant to conventional lifestyle modifications or pharmacotherapy. Show less

Patients with cancer undergoing cisplatin chemotherapy frequently experience cardiotoxic side effects that significantly affect their prognosis and survival rates. Our study found that Panax ginseng root extract exerted a significant protective effect against cisplatin-induced myocardial cell injury. The present study aims to elucidate the underlying mechanisms by which the bioactive components of Panax ginseng mitigate cisplatin-induced cardiotoxicity (CIC). In vitro, the candidate active components were screened by network pharmacological prediction and in neonatal rat ventricular myocytes (NRVMs), and their mechanisms of action were verified by transcriptome sequencing, western blotting, gene overexpression, immunoprecipitation, immunofluorescence, and cellular thermal shift assays. A C57BL/6 CIC mouse model was established to verify the protective effects of the candidate components and the in vivo mechanism of the candidate components. Through network pharmacology prediction and cellular activity screening of ginseng root compounds, ginsenoside Rh2(S) (Rh2) was identified as a significant active component. Transcriptomic, in vitro, and in vivo experiments demonstrated that Rh2 can activate the Pak1/Limk1/cofilin phosphorylation pathway, thereby inactivating the actin-severing protein cofilin and protecting cardiomyocytes from cisplatin-induced actin depolymerization. Additionally, Rh2 suppressed the ROS/caspase-3/GSDME pathway to inhibit cisplatin-induced pyroptosis. Furthermore, co-immunoprecipitation and overexpression experiments confirmed that Rh2 activated the FGFR1/HRAS axis, thereby simultaneously regulating the two aforementioned pathways to combat CIC. This study demonstrated for the first time that Rh2 is the main active component in Panax ginseng that maintains cytoskeletal homeostasis and inhibits pyroptosis by regulating the FGFR1/HRAS pathway to resist CIC. This study aimed to provide a theoretical basis for expanding the targets and pathways of CIC treatment, and for the development of related drugs. Show less

Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is an important mechanism for the onset and development of broncho-pulmonary dysplasia (BPD). Fibroblast growth factor 2 (FGF2) is involved in the development and repair of injury in many organs, particularly the lung. The role of FGF2 in BPD is currently unclear. The aim of our study was to investigate the expression of FGF2 in lung tissue of BPD mice, to further clarify the effect of FGF2 on EMT in alveolar epithelial cells and to actively search for possible signaling pathways. The BPD model was induced by exposure to hyperoxia. Lung tissue samples were collected and hematoxylin and eosin staining was used to determine the modeling effect. Quantitative real-time polymerase chain reaction (QRT-PCR), immunohistochemistry was used to detect FGF2 expression in BPD mice. To further investigate the effect of FGF2 supplementation and deficiency on EMT in alveolar epithelial cells, A549 cells were cryopreserved, resuspended, cultured, and passaged. Transforming growth factor-β1 (TGF-β1) was used to induce EMT. FGF2 small interfering RNA fragments were synthesized and screened. Fibroblast growth factor receptor 1 (FGFR1) expression was inhibited by BGJ398. (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) (MTS) assay was used to detect the effect of FGF2 and infigratinib (BGJ398) on cell proliferation. We used qRT-PCR and Western blot to detect the expression of epithelial cell markers, mesenchymal cell markers and EMT-related signaling pathway proteins. Our results showed that the successful established hyperoxia mice model were characteristic by BPD. Hyperoxia decreased FGF2 on day 4, upregulated FGF2 on day 21, which resulted in EMT. In vitro, we found that FGF2 alone increased the expression of mesenchymal markers, decreased the expression of epithelial markers and activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), small mother against decapentaplegic (Smad), mitogen-activated protein kinase (P38), and extracellular signal-regulated kinase (ERK) signaling pathways. FGF2 could not reverse but synergistically promote Transforming growth factor-β1 (TGF-β1)-induced EMT of alveolar epithelial cells. Silencing FGF2 increased the expression of epithelial marker E-cadherin, inhibited the PI3K/AKT, Smad, and P38 signaling pathways activated by TGF-β1, but activated ERK signaling. FGF2 receptor inhibitor BGJ398 reversed TGF-β1-induced EMT, decreased the expression of FGFR1, and inhibited ERK signaling pathway activation. FGF2 was closely associated with EMT in BPD mice. Both high and low levels of FGF2 promoted EMT in A549. The FGF2 receptor inhibitor BGJ398 reversed TGF-β1-induced EMT in A549 by inhibiting the FGFR1/P-ERK signaling pathway. Show less

Liver diseases, ranging from chronic liver disease (CLD) to acute liver injury (ALI), pose significant global health challenges. Metabolic dysfunction and inflammatory disorders are key to the progression of both CLD and ALI, suggesting that dual-targeting of metabolism and immune response may lead to better clinical performance for patients with liver disease. Interleukin-27 (IL-27) is a classic cytokine known for its immune-modulating role, with many ongoing clinical trials in the context of anti-tumoral therapy and inflammatory bowel disease. Our previous studies have revealed an unexpected role of IL-27 in promoting adipocyte thermogenesis and ameliorating role in systemic metabolism. This review outlines the involvement of the IL-27/IL-27R signaling pathway in hepatic metabolism and immunity, highlighting its potential as a therapeutic target for both CLD and ALI. Meanwhile, when serum IL-27 displays a disease-specific change in dynamic liver diseases, a summary and elaboration on its diagnostic potential are also carried out. Show less

In China, work connectivity behavior after-hours (WCBA) among operating room nurse who are parents (OR nurse-parents) are associated with increased occupational fatigue, whereas psychological detachment may serve as a potential protective factor. A thorough understanding of the relationship among the three factors is conducive to the management of occupational fatigue. Explore the relationship between OR nurse-parents' WCBA and occupational fatigue through Latent Profile Analysis (LPA), and analyze the mediating effect of psychological detachment. This study constituted a secondary analysis of cross-sectional data from a prior study involving OR nurse-parents in 15 tertiary hospitals in Shandong Province, China. Inclusion criteria were: (1) registered nurse with >1 year of OR experience; (2) parent of at least one child aged 0-18 years; (3) voluntary informed consent. Exclusion criteria were: (1) temporary staff or interns; (2) on extended leave during the study; (3) major comorbidities. A two-part analytical strategy was used. First, latent profile analysis identified subgroups by WCBA, psychological detachment, and occupational fatigue, with multinomial logistic regression then examining predictors of profile membership. Second, a parallel mediation analysis tested psychological detachment as a mediator between WCBA and occupational fatigue. Data came from the 724 included OR nurse-parents. LPA revealed a three-profile model: "low WCBA-high psychological detachment-low occupational fatigue group (22%)," "moderate WCBA-moderate psychological detachment-moderate occupational fatigue group (50%)," and "high WCBA-low psychological detachment-high occupational fatigue group (28%)." Multivariate analysis identified working over 10 h daily as a risk factor for the high-risk group. Furthermore, Psychological detachment partially mediated the WCBA- occupational fatigue relationship across all occupational fatigue dimensions, accounting for 17.73%-31.52% of total effects. Mediation analysis confirmed that psychological detachment partially mediates the relationship between WCBA and occupational fatigue. LPA of WCBA, psychological detachment, and occupational fatigue revealed a three-profile solution among operating room nurse-parents in Shandong Province. A critical finding of LPA is that WCBA moderates the relationship between occupational fatigue and psychological detachment, creating a dual effect: while psychological detachment generally reduces occupational fatigue, its benefit diminishes or reverses under moderate WCBA, likely due to unclear communication expectations. Therefore, effective interventions must address both aspects: managing after-hours connectivity to reduce its intrusion and proactively promoting genuine psychological detachment to mitigate fatigue. Show less

Demyelination diseases are characterized by injury to large (A-type) myelinated nerve fibers, and by secondary damage to small (C-type) sensory fibers, which leads to chronic pain symptoms, such as allodynia. The mechanisms underlying the interactions between the two fiber types are not clear. This study aims to investigate the role of lysophosphatidic acid (LPA) signaling in satellite glial cells (SGCs) within the dorsal root ganglia (DRG) in demyelination-induced chronic pain. A demyelination model was established by injecting cobra venom into the tibial nerve of 8-10-week-old Sprague-Dawley rats to selectively damage A-fiber myelin. Myelin morphology was observed via transmission electron microscopy (TEM) at 1, 3, 7, and 14 days post-injection. Pain behaviors (mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain) were assessed to evaluate progression. In vivo electrophysiology was performed to analyze sensory conduction and excitability changes in A- and C-type neurons. Immunofluorescence staining assessed SGC activation, LPA1 receptor (LPA1R) expression, and connexin 43 (Cx43) dynamics in the L4 DRG over time. Pharmacological interventions targeting LPA1R and SGC activation were applied to evaluate their effects on pain behaviors, cytokine release, and neuronal excitability using RT-PCR, ELISA, and spinal electrophysiology. Cobra venom induced a selective A-fiber demyelination and persistent pain in rats. It also upregulated the expression of LPA1R on SGCs that surround large DRG neurons, which normally mediate non-noxious input, and increased gap junction-mediated coupling via Cx43, leading to the activation of SGCs surrounding small nociceptive neurons. The activated SGCs released inflammatory mediators that increased nociceptive neuron excitability, driving chronic pain. In support of these results, pharmacological inhibition of LPA1R-mediated SGCs activation reversed this process. Our study demonstrates that LPA-LPA1R signaling in SGCs drives A-fiber demyelination-induced neuropathic pain by promoting Cx43-mediated SGC-neuron crosstalk and cytokine release. Targeting this pathway may represent a promising strategy to alleviate demyelination-associated chronic pain. Show less

This study used objectively measured data and compositional data analysis to examine the relationship between 24-hour movement behaviors and perceived stress in Chinese university students. Cross-sectional data were collected from 208 Chinese university students (mean age = 20.23 years, 52.9% female). Accelerometers were used to measure 24-hour movement behaviors, including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior (SB), and sleep. The Perceived Stress Scale (PSS-14) assessed perceived stress. Compositional data methods were applied to analyze the relationship between the proportion of time spent in 24-hour activities and perceived stress. Compositional regression analysis indicated that time spent in MVPA ( The proportion of time spent in MVPA and LPA was negatively associated with perceived stress among university students. Replacing sedentary behavior with MVPA or LPA was associated with lower perceived stress. However, these findings should be interpreted with caution due to the study's cross-sectional design and reliance on self-reported sleep data. Show less

The micropapillary (MIP) pattern is a high-grade histological subtype of lung adenocarcinoma (LUAD) with poor prognosis. In this study, surgically resected tumor samples from 101 patients with stage I-III MIP-LUAD (MIP ≥30%) were microdissected to separate MIP components from non-MIP components, all of which underwent RNA and DNA whole-exome sequencing (WES). The genomic and transcriptomic landscapes of MIP and non-MIP components within MIP-enriched tumor tissues demonstrated remarkable similarities, notably marked by high epidermal growth factor receptor (EGFR) alteration frequencies. However, when compared to MIP-naïve LUAD tissues, MIP components showed higher chromosomal instability and revealed 18 enriched alterations, encompassing EGFR mutations, EGFR amplifications, and CDKN2A/CDKN2B deletions, which all linked to upregulation of cell proliferation pathways and downregulation of immune pathways. Shared mutations were observed in 97.8% (91/93) of patients with paired DNA WES data for MIP and non-MIP components within the same tissues, suggesting a common origin. The recurrence-free survival analysis identified MACF1, PCLO, ADGRV1, and Fanconi Anemia pathway mutations as negative indicators. In all, we conducted an in-depth analysis of the molecular characteristics and transformation mechanisms of MIP-LUAD, employing microdissection techniques to investigate the genomic and transcriptomic levels within a substantial cohort, providing insights for precision medicine of this aggressive cancer subtype. © 2025 The Pathological Society of Great Britain and Ireland. Show less

Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less

This study aims to identify genetically influenced metabolites (GIMs) associated with SSBP and elucidate their regulatory pathways through metabolome genome-wide association studies (mGWASs). Untargeted metabolomics and genome-wide genotyping were performed on 54 participants from the Systematic Epidemiological Study of Salt Sensitivity (EpiSS). The mGWAS was conducted on 970 plasma metabolites, and their potential biological mechanisms were explored. The multivariable logistic regression model and mendelian randomization (MR) were employed to investigate the association and causal relationship between GIMs and SSBP. Metabolomic analysis was performed on 100 subjects in the replication analysis to validate the GIMs identified in the discovery set and their causal association with SSBP. The mGWAS revealed associations between 1485 loci and 18 metabolites. After performing linkage disequilibrium analysis, 368 independent mQTLs were identified and annotated to 141 genes. These functional genes were primarily implicated in the signal transduction of sinoatrial node and atrial cardiac muscle cells. Five key genes were identified using CytoHubba, including Show less

Poly(A) binding protein cytoplasmic 4 (PABPC4) has been regarded as a prognostic marker in many malignancies. In this study, we evaluated PABPC4 expression at both messenger ribonucleic acid (mRNA) and protein levels. The prognostic value of PABPC4 in patients with prostate cancer (PCa) was also investigated. The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, our analysis of Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA), and 65 pairs of ribonucleic acid (RNA) sequencing data from our center were employed to detect the expression of PABPC4 in PCa tissues. Tissue microarrays (TMAs) were utilized to detect the expression of the PABPC4 protein, and survival analysis as well as risk factor analysis were conducted. In the 65 pairs of sequencing data, the expression of PABPC4 in tumor tissues was significantly higher than that in paired adjacent tissues (P<0.001), and its expression also presented significant differences among different Gleason groups (P=0.041). In the CPGEA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of PABPC4 in M1 patients was higher than that in M0 patients, although no significant statistical difference was shown (P=0.051). In the TCGA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001). The expression of pT3/4 (pathological tumor stage 3 and pathological tumor stage 4) in high-stage tumor tissues was significantly higher than that in low-stage tumor tissues (pT2) (P=0.02), the expression of pT3/4 in GSE21034 and GSE32571 tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of pT3/4 in primary tumor tissues was higher than that in metastatic tissues in GSE6752 (P<0.001). The TCGA data revealed that patients with high PABPC4 expression had poorer overall survival (OS) than those with low PABPC4 expression (P=0.04), and the TMA data indicated that patients with high PABPC4 expression had a poor prognosis (P=0.004). Our study demonstrated that PABPC4 was overexpressed at mRNA and protein levels in PCa. We found that patients with high PABPC4 expression had a shorter biochemical recurrence (BCR)-free survival and OS, showing its value as a prognostic biomarker in patients with PCa. Show less

Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients. Show less

Inorganic phosphorus (Pi) deficiency significantly impacts plant growth, development, and photosynthetic efficiency. This study evaluated 206 rice accessions from a MiniCore population under both Pi-sufficient (Pi Show less

Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like protein 4 (ANGPTL4) is thought to contribute to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. This study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from an AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 should represent a potential therapeutic strategy. Show less

Renal tubular epithelial cells are vulnerable to stress-induced damage, including excessive lipid accumulation and aging, with ANGPTL4 potentially playing a crucial bridging role between these factors. In this study, RNA-sequencing was used to identify a marked increase in ANGPTL4 expression in kidneys of diet-induced obese and aging mice. Overexpression and knockout of ANGPTL4 in renal tubular epithelial cells (HK-2) was used to investigate the underlying mechanism. Subsequently, ANGPTL4 expression in plasma and kidney tissues of normal young controls and elderly individuals was analyzed using ELISA and immunohistochemical techniques. RNA sequencing results showed that ANGPTL4 expression was significantly upregulated in the kidney tissue of diet-induced obesity and aging mice. In vitro experiments demonstrated that overexpression of ANGPTL4 in HK-2 cells led to increased lipid deposition and senescence. Conversely, the absence of ANGPTL4 appears to alleviate the impact of free fatty acids (FFA) on aging in HK-2 cells. Additionally, aging HK-2 cells exhibited elevated ANGPTL4 expression, and stress response markers associated with cell cycle arrest. Furthermore, our clinical evidence revealed dysregulation of ANGPTL4 expression in serum and kidney tissue samples obtained from elderly individuals compared to young subjects. Our study findings indicate a potential association between ANGPTL4 and age-related metabolic disorders, as well as injury to renal tubular epithelial cells. This suggests that targeting ANGPTL4 could be a viable strategy for the clinical treatment of renal aging. Show less

Secretory factors linked to lymphogenesis, such as vascular endothelial growth factor C (VEGF-C), angiopoietin like protein 4 (ANGPTL4), and activin A (ACV-A), have been recognized as potential markers of chronic inflammatory status and age-related diseases. Furthermore, these factors may also be linked to frailty. The primary objective of this study was to examine the serum VEGF-C, ANGPTL4, and ACV-A levels in young individuals, healthy older individuals, and older individuals with pre-frailty and frailty, and to determine their association with pro-inflammatory factor levels. We conducted an observational study, enrolling a total of 210 older individuals and 20 young healthy volunteers. Participants were divided into four groups based on the Freid frailty phenotype: healthy young group, older patients without frailty group, pre-frail older group, and frail older group. Plasma and peripheral blood mononuclear cells (PBMCs) were collected from all four groups. ELISA was used to measure the serum levels of VEGF-C, ANGPTL4, ACV-A, and pro-inflammatory cytokines, while RT-qPCR was used to measure the transcription level of VEGF-C, ANGPTL4 and ACV-A in PBMCs. In comparison to healthy young individuals and older participants without frailty, older participants with frailty exhibited lower renal function, higher serum levels and transcription levels of VEGF-C, ANGPTL4, ACV-A, and elevated levels of pro-inflammatory cytokines (CRP, IL-1β, and TNF-α). Multiple linear regression analysis revealed that serum levels of VEGF-C, ANGPTL4, and ACV-A were positively correlated with the frailty index, independent of age, eGFR, and comorbidities. Furthermore, the receiver operating characteristic (ROC) curve analysis demonstrated that serum levels of VEGF-C, ANGPTL4, and ACV-A have great accuracy in predicting frailty. Elevated serum levels of VEGF-C, ANGPTL4, and ACV-A are associated with frailty status. Show less

Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background. The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort. In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform. In univariate analysis, The study indicates that there is an association between Show less

Rapid progression of non-target lesions (NTLs) leads to a high incidence of NTL related cardiac events post-PCI, which accounting half of the recurrent cardiac events. It is important to identify the risk factors and establish an accurate clinical prediction model for the rapid progression of NTLs post-PCI. PCSK9 inhibitors lower LDL-c levels significantly, also show the anti-inflammation effect, and may have the potential to reduce the rapid progression of NTLs post-PCI. We tried to test this hypothesis and explore the potential mechanisms. This retrospective study included 1250 patients who underwent the first PCI and underwent repeat coronary angiography for recurrence of chest pain within 24 months. General characteristics, laboratory tests and inflammatory factors(IL-10, IL-6, IL-8, IL-1β, sIL-2R, and TNF-α) were collected. Machine learning (LASSO regression) was mainly employed to select the important characteristic risk factors for the rapid progression of NTLs post-PCI and build prediction models. Finally, mediator analysis was employed to explore the potential mechanisms by which PCSK9 inhibitors reduce the rapid progression of NTLs post-PCI. There were more diabetes, less beta-blockers and PCSK9 inhibitors application, higher HbA1c, LDL-c, ApoB, TG, TC, uric acid, hs-CRP, TNF-α, IL-6, IL-8, and sIL-2R in NTL progressed group. LDL-c, hs-CRP, IL-8, and sIL-2R were characteristic risk factors for the rapid progression of NTLs post-PCI, combining LDL-c, hs-CRP, IL-8, and sIL-2R builds the optimal model for predicting the rapid progression of NTLs post-PCI (AUC = 0.632). LDL-c had a clear and incomplete mediating effect (95% CI, mediating effect: 51.56%) in the reduction of the progression of NTLs by PCSK9 inhibitors, and there was a possible mediating effect of IL-8 (90% CI), and sIL-2R (90% CI). LDL-c, hs-CRP, IL-8, and sIL-2R may be the key characteristic risk factors for the rapid progression of NTLs post-PCI, and combining these parameters might predict the rapid progression of NTLs post-PCI. The application of PCSK9 inhibitors had a negative correlation with the rapid progression of NTLs. In addition to the significant LDL-c-lowering, PCSK9 inhibitors may reduce the rapid progression of NTLs by reducing local inflammation of plaque. ChiCTR2200058529; Date of registration: 2022-04-10. Show less

Lung adenocarcinoma (LUAD), a type of non-small cell lung cancer (NSCLC), originates from not only bronchial epithelial cells but also alveolar type 2 (AT2) cells, which could differentiate into AT2-like cells. AT2-like cells function as cancer stem cells (CSCs) of LUAD tumorigenesis to give rise to adenocarcinoma. However, the mechanism underlying AT2 cell differentiation into AT2-like cells in LUAD remains unknown. We analyze genes differentially expressed and genes with significantly different survival curves in LUAD, and the combination of these two analyses yields 147 differential genes, in which 14 differentially expressed genes were enriched in cell cycle pathway. We next analyze the protein levels of these genes in LUAD and find that Cyclin-A2 (CCNA2) is closely associated with LUAD tumorigenesis. Unexpectedly, high CCNA2 expression in LUAD is restrictedly associated with smoking and independent of other driver mutations. Single-cell sequencing analyses reveal that CCNA2 is predominantly involved in AT2-like cell differentiation, while inhibition of CCNA2 significantly reverses smoking-induced AT2-like cell differentiation. Mechanistically, CCNA2 binding to CDK2 phosphorylates the AXIN1 complex, which in turn induces ubiquitination-dependent degradation of β-catenin and inhibits the WNT signaling pathway, thereby failing AT2 cell maintenance. These results uncover smoking-induced CCNA2 overexpression and subsequent WNT/β-catenin signaling inactivation as a hitherto uncharacterized mechanism controlling AT2 cell differentiation and LUAD tumorigenesis. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the hallmark of aggregation of beta-amyloid (Aβ) into extracellular fibrillar deposition. Accumulating evidence suggests that soluble toxic Aβ oligomers exert diverse roles in neuronal cell death, oxidative stress, neuroinflammation, and the eventual pathogenesis of AD. Aβ is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β-secretase (BACE1) and γ-secretase. The current effect of single targeting is not ideal for the treatment of AD. Therefore, developing multipotent agents with multiple properties, including anti-Aβ generation and anti-Aβ aggregation, is attracting more attention for AD treatment. Previous studies indicated that Quercetin was able to attenuate the effects of several pathogenetic factors in AD. Here, we showed that naturally synthesized Quercetin-3-O-glc-1-3-rham-1-6-glucoside (YCC31) could inhibit Aβ production by reducing β-secretase activity. Further investigations indicated that YCC31 could suppress toxic Aβ oligomer formation by directly binding to Aβ. Moreover, YCC31 could attenuate Aβ-mediated neuronal death, ROS and NO production, and pro-inflammatory cytokines release. Taken together, YCC31 targeting multiple pathogenetic factors deserves further investigation for drug development of AD. Show less

Raddeanin A is a triterpenoid isolated from Anemone raddeana Regel. It exhibits a broad spectrum of biological activities such as anti-tumor and anti-inflammatory, however, its neuroprotective effect in targeting Alzheimer's disease (AD) remains uninvestigated. To provide scientific base for the development of novel AD drug by clarifying the neuroprotective effect and molecular mechanisms of raddeanin A in both in vitro and in vivo AD model. To confirm the neuroprotective role of raddeanin A in the treatment of AD, its mechanisms and effects on β-amyloidosis and Aβ fibrillation was studied in U87 cells. Besides, the improvement on cognitive deficit, pathological defects, reactive astrocyte clusters, inhibition on neuronal inflammation and apoptosis were further studied in 3 x Tg-AD mice model of AD. Real-time PCR, western blot, dot blot, biolayer interferometry and bioinformatics analysis were used to confirm the in vitro effect and targets of raddeanin A on β-amyloidosis and its associated protein network. A series of experiments including Morris water maze, H&E staining, nissl staining and immunofluorescence analysis were conducted to confirm the protective behavioral effect of raddeanin A in the in vivo AD mice model. Raddeanin A was identified to reduce β-amyloidosis in U87 cells and 3 x Tg-AD mice model of AD by decreasing level of BACE1, APP, APP-β and Aβ. Raddeanin A improved behavioral, spatial memory and learning ability in the AD mice. In the cortex and hippocampus, raddeanin A improved the morphology and arrangement of neurons, lower the level of reactive astrocyte marker GFAP and apoptotic marker proteins Bax/Bcl2 ratio. Moreover, raddeanin A upregulated the mRNA and protein level of Prkcα in the hippocampus of AD mice whose neuroprotective effect was exerted possibly via the activation of protein kinase C. As a novel natural agent targeting β-amyloidosis, our results provide the first evidence of the multiple in vitro and in vivo neuroprotective effect of raddeanin A, suggesting its potential therapeutic application in preventing or alleviating the symptoms of AD. Show less

Serum lipids are causally involved in the occurrence of atherosclerosis, but their roles in cerebral small vessel disease remain unclear. This study aimed to investigate the causal roles of lipid or apolipoprotein traits in cerebral small vessel disease and to determine the effects of lipid-lowering interventions on this disease. Data on genetic instruments of lipids/apolipoproteins, as well as characteristic cerebral small vessel disease manifestations, including small vessel stroke (SVS) and white matter hyperintensity (WMH), were obtained from publicly genome-wide association studies. Through 2-sample Mendelian randomization analyses, it was found that decreased levels of high-density lipoprotein cholesterol (odds ratio [OR], 0.85, The present Mendelian randomization study indicates that genetically determined hyperlipidemia is closely associated with a higher risk of cerebral small vessel disease, especially SVS. Lipid-lowering drugs could be potentially considered for the therapies and preventions of SVS rather than WMH. Show less

The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. This study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size. Show less

High-grade serous tubo-ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single-cell RNA and single-cell T-cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRβ+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1-expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRβ+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti-CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA-4/LAG-3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF-1/CSF-1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi-resistant HRD and refractory HRP tumors. Show less

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8 Show less