👤 Fang Luo

The role of lipid markers in acute coronary syndrome remains incompletely understood, particularly for novel indices such as the Castelli risk indices (CRI-I, CRI-II) and cholesterol index (CHOINDEX). This study aims to elucidate the relationship between novel lipid markers and plaque rupture. In this single-center retrospective study, 649 patients with acute coronary syndrome undergoing optical coherence tomography were stratified into plaque rupture (n = 130) and non-rupture (n = 519) groups. Lipid indices included the following: CRI-I - total cholesterol/high-density lipoprotein cholesterol (HDL-C), CRI-II - low-density lipoprotein cholesterol (LDL-C)/HDL-C, and CHOINDEX - LDL-C/HDL-C. Multivariable logistic regression identified independent predictors of plaque rupture. Model performance was assessed using area under the curve and integrated discrimination improvement. The plaque rupture group had higher proportions of males (89.2% vs. 80%; P = 0.01) and smokers (57.7% vs. 44.9%; P = 0.009), with elevated LDL-C mean 3.14 vs. 2.83 mmol/l), apolipoprotein B (APOB; 1.03 vs. 0.85 g/l), CRI-I (4.75 vs. 3.91), CRI-II (3.11 vs. 2.45), and CHOINDEX (1.97 vs. 1.65; all P <0.01). Multivariable analysis identified CRI-I (odds ratio [OR], 1.57), CRI-II (OR, 2.09), CHOINDEX (OR, 0.40), and APOB (OR, 5.50) as independent predictors. The combined model (traditional factors + novel indices) showed superior discrimination (area under the curve = 0.775 vs. 0.622; integrated discrimination improvement = 0.059; P <0.001). The combined assessment of CRI-II, CRI-I, CHOINDEX, and APOB, in conjunction with traditional cardiovascular risk factors, exhibits robust diagnostic efficacy for plaque rupture. Show less

To investigate the relationship between serum lipid levels and the risk of Chronic obstructive pulmonary disease (COPD) in the UK Biobank. We performed this prospective study in 381,938 adults without COPD from UK Biobank. Serum high-density cholesterol (HDL-C), low-density cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA) and apolipoprotein B (ApoB) were measured and classified into quintiles. Restricted cubic spline (RCS) analysis was applied to visualize the dose-response relationship between lipids and COPD risk and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). We documented 10,443 incident COPD cases. Nonlinear relationships were found between HDL-C, LDL-C, TC, ApoA, ApoB and COPD risk with RCS analysis (P values for non-linearity < 0.05). Accordingly, multivariable-adjusted regression analysis indicated abnormal HDL-C and ApoA, and low LDL-C, TC and ApoB were associated with increased risk of COPD. Compared to intermediate quintile (Q3) group, both high or low HDL-C and ApoA were associated with risk of COPD. Corresponding HRs (95% CIs) were 1.15 (1.08-1.22), 1.16 (1.09-1.23) in Q1 group and 1.08 (1.01-1.16), 1.07 (1.00-1.14) in Q5 group. For LDL-C, TC and ApoB, there were more than 29% higher risk was observed in Q1 group with HRs (95% CIs) of 1.34 (1.27-1.42), 1.38 (1.30-1.46) and 1.29 (1.21-1.37), while HRs (95% CIs) were 0.88 (0.83-0.94), 0.92 (0.86-0.98) and 0.90 (0.84-0.95) in Q5 groups. We also observed the interactions between specific lipids and age at recruitment, sex and smoking status with stratified analysis. Our study provides the first evidence demonstrating the associations between six major serum lipids and COPD risk, revealing multiple nonlinear relationships. There were U-shaped associations between serum HDL-C, ApoA and COPD risk, and L-shaped associations between LDL-C, TC, ApoB and COPD risk. Show less

Citrus pulp (CP) is rich in pectin, which exhibits anti-inflammatory, antioxidant, and hypolipidemic properties. Despite these advantages, the application of CP in aquafeed remains limited. This study investigated the effects of dietary CP inclusion on the glucolipid metabolism of largemouth bass (Micropterus salmoides). Juveniles were fed diets containing varying levels of CP (0%, 3%, 6%, 9%, 12%, or 15%) for 58 days. Adding 3-6% CP in feed has no adverse effect on growth performance. Dietary CP had direct effects on lipid and glucose metabolism. For lipid metabolism, the inclusion of 3-12% CP resulted in reduced serum complement 3, complement 4, total cholesterol and triglyceride levels, as well as low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio. Additionally, the inclusion upregulated the relative expression levels of lipid metabolism-related genes such as ppar-α, cpt-1α, and apoa1, but downregulated the relative expression level of apob in liver. However, higher doses (>12%) of CP led to increased serum LDL-C and HDL-C levels. Regarding glucose metabolism, the inclusion of 3-12% CP enhanced hepatic glucose-6-phosphate dehydrogenase (G6PDH), phosphoenolpyruvate carboxykinase (PEPCK), hexokinase and phosphofructokinase-6 (PFK-6) activities as well as serum insulin, insulin-like growth factor 1, growth hormone, G6PDH, PEPCK, hexokinase and PFK-6 levels. Additionally, the inclusion upregulated the relative expression levels of glucose metabolism-related genes such as glut2, glut4, gk, hk, pk, pfk, pepck, g6pase, fbp1, ir, irs1, and pik3r1 in liver. However, higher doses (>12%) of CP did not improve the indicators of glucose metabolism and even downregulated the relative expression level of irs1. In summary, the recommended dietary inclusion of CP is between 3% and 12%, as this range can enhance lipid and glucose metabolism in largemouth bass, and the addition of 6% CP had the most beneficial effect on the glucolipid metabolism of largemouth bass. © 2025 Society of Chemical Industry. Show less

Crystals or stones within the gallbladder wall in patients with gallbladder stones (GBS) have been occasionally reported, but their clinical features and aetiology remain unclear. This retrospective study analysed 323 consecutive patients with GBS who underwent rigid choledochoscopic gallbladder-preserving cholecystolithotomy to determine the detection rate, clinical features, and potential risk factors of gallbladder intramural stones (IS). IS were found in 24.1% (78/323) of patients, characterised by distinct cholangioscopic findings, including stone shadows, yellow floating bands, or a combination of both within the gallbladder wall. Compared to patients without IS, those with IS had a higher prevalence of Clonorchis sinensis (C. sinensis) eggs (60.3% vs. 40.8%, P < 0.05) and elevated serum cholesterol, LDL cholesterol, and Apo-B levels (P < 0.05). However, stone composition and C. sinensis egg detection rates did not differ between intraluminal stones and IS within the same patient (P > 0.05). Logistic regression analysis revealed that IS were associated with C. sinensis infection and elevated Apo-B levels. In conclusion, IS share homology with intraluminal stones in the same patient with GBS and exhibit unique appearances in rigid choledochoscopy. For patients with GBS and IS, elevated serum Apo-B levels and C. sinensis infection were independent risk factors. Show less

Recent studies suggest that dyslipidaemia may play a critical role in the progression of cardiovascular disease in Takayasu arteritis (TA), although the exact relationship between dyslipidaemia and TA disease activity remains unclear, which is the focus of this study. We evaluated dyslipidaemia and atherosclerosis in a cohort of untreated female patients. Fifty untreated female patients with TA (median age 30 years) and 98 healthy controls matched for age and body mass index (median age 30 years) were assessed for lipid profiles [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), ApoB, ApoE, lipoprotein(a)], inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)], and atherosclerotic plaque frequency. TA patients exhibited significantly higher levels of TG and the non-HDL-C/HDL-C ratio than the control group, whereas TC, HDL-C, LDL-C, and ApoA1 levels were significantly lower. Pearson's correlation analysis indicated a positive correlation between CRP and ApoB, as well as the non-HDL-C/HDL-C ratio, and negative correlations with TG, HDL-C, and ApoA1. Atherosclerotic plaques were detected in 14.3% of the TA patients. Multivariate regression analysis revealed that the presence of atherosclerotic plaques was associated only with age, independent of inflammatory markers and lipoprotein levels. The results of this study indicate that untreated female TA patients exhibit a markedly dysregulated serum lipid profile. Atherosclerosis in early TA was not related to lipids or markers of inflammation. Show less

Dyslipidemia has been proved to play a pivotal role in biological aging. Atherogenic Index of Plasma (AIP), derived from serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C), is an effective biomarker of dyslipidemia. However, whether AIP can be used as an indicator of biological aging remains unclear. This study aims to investigate the relationship between AIP and biological aging in the US adult population. 4,471 American adults with age over 20 years from the National Health and Nutrition Examination Survey (NHANES) database were included in this study. Biological aging was assessed by phenotypic age acceleration (PhenoAgeAccel). Multivariable linear regression models, subgroup analyses and interaction tests were employed to explore the association between AIP and PhenoAgeAccel. Furthermore, adjusted restricted cubic spline (RCS) analyses were employed to assess potential nonlinear relationships, while mediation analysis was utilized to identify the mediating effects of homeostatic model assessment of insulin resistance (HOMA-IR). Besides, network pharmacology was performed to determine the potential mechanisms underlying dyslipidemia-related aging acceleration. A total of 4,471 participants were included in this study, the median chronological age, PhenoAge and PhenoAgeAccel for the overall population were 49 (35-64) years, 42.85 (27.30-59.68) years, and - 6.92 (- 10.52 to -2.46) years, respectively. In the fully adjusted model, one unit increase of AIP was correlated with 1.820-year increase in PhenoAgeAccel (β = 1.820, 95% CI: 1.085-2.556), which was more pronounced among individuals being female, diabetic and hypertensive. Furthermore, RCS analysis revealed a nonlinear relationship between AIP and PhenoAgeAccel, with an inflection point identified at -0.043 for AIP via threshold and saturation effect analysis. AIP demonstrated a positive correlation with PhenoAgeAccel both before (β = 6.550, 95% CI: 5.070-8.030) and after (β = 3.898, 95% CI: 2.474-5.322) this inflection point. Additionally, HOMA-IR was found to mediate 39.21% of the association between AIP and PhenoAgeAccel. Finally, network pharmacology analysis identified INS, APOE, APOB, IL6, IL10, PPARG, MTOR, ACE, PPARGC1A, and SERPINE1 as core targets in biological aging, which were functionally linked to key signaling pathways like AMPK, apelin, JAK-STAT, FoxO, etc. CONCLUSIONS: An elevated AIP was notably and positively correlated with accelerated aging, suggesting that AIP may serve as an effective predictor to evaluate accelerated aging. Show less

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

Hepatic VLDL overproduction, tightly modulated by insulin signaling, plays a pivotal role in the progression of atherosclerosis (AS). The present study aimed to investigate whether inhibition of hepatic VLDL overproduction is a novel therapeutic strategy for the homogeneous tea polysaccharide (TPS3A) to ameliorate AS under insulin resistance (IR) conditions and the potential molecular basis involved. Results showed that TPS3A supplementation effectively alleviated systemic IR and delayed atherosclerotic plaque progression in HFD-exposed ApoE Show less

The per-particle pathogenicity of very-low-density lipoprotein (VLDL) and lipoprotein(a) [Lp(a)] with risk of valvular heart diseases (VHD) other than aortic stenosis compared with low-density lipoprotein (LDL) remains unclear. Single-nucleotide polymorphism specific clusters associated with LDL cholesterol (LDL-C), VLDL cholesterol (VLDL-C) and Lp(a) were identified. The relationships of genetically predicted variation in apolipoprotein B (apoB) in these lipoproteins with risk of VHD and its major types (aortic stenosis, aortic regurgitation, and mitral regurgitation) were evaluated to determine the comparative pathogenicity by Mendelian randomization (MR) analyses. The VHD odds ratio (OR) per 1 g/L higher apoB was 1.09 [95 % confidence interval (CI) 1.04-1.15] in LDL vs. 1.45 (95 % CI 1.25-1.69) in VLDL vs. 2.71 (95 % CI 1.92-3.82) in Lp(a) based on the cluster-based MR analyses. The polygenic scores for each lipoprotein weighted by apoB similarly showed a greater OR of VHD per 1 g/L apoB in VLDL [1.20 (95 % CI 1.06-1.37)] and in Lp(a) [2.54, (95 % CI 1.95-3.32)] compared with that in LDL [1.05 (95 % CI 1.01-1.08)]. Multivariable MR analyses further revealed the strong effects of VLDL-C and Lp(a) on VHD risk independent of LDL-C. In addition, significant associations between Lp(a) and all three major types of VHD were observed, while LDL and VLDL had no impact on aortic and mitral regurgitation. VLDL and Lp(a) appear to have significantly greater per-particle pathogenicity in VHD compared to LDL. The distinct impacts of lipoproteins on different VHD subtypes suggest the inadequacy of just focusing on LDL-lowering treatment for valve disorders. Show less

Aromatase, encoded by Cyp19a1, is the rate limiting enzyme in biosynthesis of estrogens, and excessive aromatase can reduce the semen quality in roosters. Seminal plasma extracellular vesicles (SPEV) are nanoscale vesicles that carry and transmit signaling molecules, thereby affecting semen quality. Currently it is still unclear whether SPEV are involved in the process of that aromatase affects the quality semen in chicken. To clarify this issue, lentivirus carrying Cyp19a1 (LV-CYP19A1) for over-expression of aromatase was constructed and injected to testis of 35-week-old roosters. Semen quality and seminal plasma hormone were measured, and SPEV were also extracted and proteome sequencing was performed after treatment of LV-CYP19A1. The results indicated that semen volume, fertility, sperm motility, testosterone (T) levels were significantly decreased, and estradiol (E Our results reveal that aromatase can down-regulate the protein expression related to regulation of ATP synthesis and metabolism, and sperm motility in SPEV, thereby reducing semen quality in roosters. Show less

The genetic landscape of cardiometabolic risk factors has been explored extensively. However, insight in the effects of genetic variation on these risk factors over the life course is sparse. Here, we performed genome-wide interaction studies (GWIS) on different cardiometabolic risk factors to identify age-specific genetic risks. This study included 270,276 unrelated European-ancestry participants from the UK Biobank (54.2% women, a median age of 58 [interquartile range (IQR): 50, 63] years). GWIS models with interaction terms between genetic variants and age were performed on apolipoprotein B (ApoB), low-density lipoprotein-cholesterol (LDL-C), log-transformed triglycerides (TG), body mass index (BMI) and systolic blood pressure (SBP). Replication was subsequently performed in the Copenhagen General Population Study (CGPS) and the Estonian Biobank (EstBB). Multiple lead variants were identified to have genome-wide significant interactions with age (P Show less

Cardiovascular outcome trials are being considered for therapeutics that silence apolipoprotein C3 (APOC3) or angiopoietin-like 3 (ANGPTL3) because of their abilities to lower triglyceride-rich lipoproteins (TRLs) and their remnants in individuals with increased cardiovascular disease (CVD) risk Show less

The emerging N-acetylgalactosamine-small interfering RNA (GalNAc-siRNA) conjugates lead the way for liver-targeting delivery to exert gene-silencing therapeutic effects. To facilitate the drug development of GalNAc-siRNA, further detailed understanding of the key modality-specific mechanisms underlying the temporal discordance between pharmacokinetics and pharmacodynamics and how these processes can be extrapolated from animals to humans is needed. A mechanistic minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK-PD) model for an investigational new apolipoprotein C-III (APOC3)-silencing GalNAc-siRNA (RBD5044) was developed using available pharmacokinetic/pharmacodynamic (PK/PD) data. The aim was to explore hepatic-targeting delivery processes, the PK/PD relationship, and interspecies translation. First, multiple PK/PD datasets from mice were satisfactorily fitted using the mPBPK-PD model. Second, we translated the mice model to the monkey model, validated it, and then extrapolated from mice and monkeys to humans to simulate the PK/PD characteristics. We then mechanistically summarized and proposed the essential in vivo delivery processes of GalNAc-siRNA after subcutaneous administration (termed "ADUEB": Absorption [into system circulation], Disposition [distribution to liver target and elimination], Uptake [into hepatocytes], Escape [from endosome and lysosome compartments], and Binding [with argonaute2 to form RNA-induced silencing complex]). The targeting delivery coefficients of these processes achieved with the model using RBD5044 and the published data of another GalNAc-siRNA (fitusiran) quantitatively reflected the delivery efficiency and rate-limiting factors in targeted hepatocytes. This study successfully constructed the mPBPK-PD model and conducted interspecies extrapolation for a GalNAc-siRNA targeting APOC3. Promising quantitative insights into a hepatic-targeted GalNAc-siRNA delivery system are provided to characterize the unique temporal disconnection of PK/PD properties and evaluate the key in vivo delivery processes. It will promote model-informed strategies and quantitative mechanistic understanding to support efficient drug development, evaluation, and clinical application of this modality in the future. Show less

Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE ε4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The People’s Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (ε2, ε3, and ε4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count × neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with ε3 as the reference. The frequencies of APOE alleles ɛ3, ɛ2, and ɛ4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in ɛ2 carriers than in ɛ3 (373.74*10⁹/L vs. 403.53*10⁹/L, APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses. Show less

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by β-amyloid (Aβ) deposition, neurofibrillary tangles, neuronal loss, and neuroinflammation. It represents a growing global health crisis. Although astrocytes contribute to neuroinflammatory cascades, their molecular regulators in AD progression remains elusive. Here, through single-cell transcriptomic analysis, we identified SerpinA3N as a disease-progressive modulator upregulated in AD astrocytes, with expression levels correlating with pathological severity. Astrocytic SerpinA3N knockdown in AD mice rescued cognitive deficits across multiple behavioral tests, and concurrently attenuated neuroinflammatory responses, as evidenced by decreased astrocytic/microglial activation and reduced cytotoxic substance release. Moreover, histopathological analyses demonstrated decreased neuronal loss and Aβ deposition following SerpinA3N knockdown. Mechanistically, we elucidated that SerpinA3N cooperated with APOE to exacerbate AD pathology through NFκB signaling activation. Our study uncovers a novel astrocyte-mediated pathogenic cascade driving AD progression and establishes SerpinA3N as a promising therapeutic target for neuroinflammation modulation in AD. Show less

Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less

Sparstolonin B (SSNB) and Curcumin (Cur), from a pair of compatible herbs, were previously identified as anti-inflammation and T helper 17 (Th17) modulation reagents. However, their compatible roles in atherosclerosis (AS) and underlying mechanisms remain uninvestigated. In vivo, the apoE The gene-disease interaction and hub gene network reveals Th17-associated genes in the pathogenesis of atherosclerosis. In vitro, SSNB and Cur reduced oxLDL-induced BMDC activation by downregulating CD36. SSNB showed stronger inhibition to inflammatory activation of DC, while Cur more intensively suppressed co-stimulatory molecules. For the Th17/Treg bias in co-culture of BMDC and CD4 Our findings reveal, for the first time, that SSNB and Cur alleviate AS by modulating Th17-stromal cell interactions, with the IL-17RA-TAK1-NF-κB pathway as a related mediator. Notably, SSNB and Cur exhibit distinct anti-atherogenic roles. SSNB primarily targets TLR4/CD36 to inhibit DC activation, Th17 differentiation, VSMC inflammation and mainly inhibited TAK1 phosphorylation, while Cur more significant inhibited macrophage inflammation, and more directly inhibited NF-κB P65 phosphorylation. This study will be valuable for developing novel and precise adjuvant therapies for AS. Show less

Growing evidence have indicated the bidirectional relationships between various inflammatory cytokines and prostate cancer (PCa), but the causality between genetic susceptibility to inflammatory cytokines and PCa was still in initial exploratory phase. This bidirectional Mendelian randomization (MR) research was manipulated to draw causative inferences and the effect of direction between 91 inflammatory cytokines and PCa. Genetic data of PCa were originated from a publicly accessible genome-wide association study with 3269 individuals and 459,664 controls, and inflammatory cytokines summarized by a protein quantitative trait locus study were embodied 14,824 participants. We considered inverse variance weighted as a primarily statistical approach, and utilized MR-Egger regression, weighted median, MR-PRESSO, and simulation extrapolation method to enhance the accuracy of the ultimate outcome. In sensitivity analysis, MR-Egger method and Cochran Q statistic of inverse variance weighted were employed to access the heterogeneity. The results suggested a causal relationship between fms-related tyrosine kinase 3 ligand (Flt3L), recombinant monocyte chemotactic protein (MCP) 2, MCP4, and the incidence of PCa (odds ratio [OR]: 1.0016, 95% confidence interval [CI]: 1.0000-1.0032, P = .045; OR: 0.9979, 95% CI: 0.9958-1.0000, P = .045; OR: 1.0012, 95% CI: 1.0001-1.0023, P = .031). In addition, reverse analysis showed that PCa was correlated with the elevated level of adenosine deaminase, axin-1, C-X-C motif chemokine ligand 6, Flt3L, interleukin (IL)-24, and IL-33 (Beta: 1.7661, 95% CI: 0.2092-3.3229, P = .026; Beta: 1.9185, 95% CI: 0.1548-3.6822, P = .033; Beta: 1.9681, 95% CI: 0.4207-3.5155, P = .013; Beta: 1.6589, 95% CI: 0.0733-3.2446, P = .040; Beta: 2.2091, 95% CI: 0.4682-3.9500, P = .013; Beta: 1.8438, 95% CI: 0.0815-3.6061, P = 040). This study highlighted the causality between several inflammatory factors and the setting of PCa. Specifically, the results suggested that Flt3L and MCP4 may be risk factors for PCa, whereas MCP2 may be a favorable factor for PCa. Conversely, adenosine deaminase, axin-1, C-X-C motif chemokine ligand 6, IL-24, IL-33, and Flt3L were involved in the downstream of PCa progression. Show less

This study aimed to investigate the anti-tumour effect and the possible molecular mechanism of Tianma granules on colorectal cancer (CRC). The therapeutic effect of Tianma granules on CRC cell lines (HT116 and SW480) and AOM/DSS-induced CRC mouse models was evaluated. Tianma granules can attenuate weight loss and increase the survival rate of CRC mice, restore reduced colon length, reduce tumour numbers and increase goblet cell numbers in CRC mice. Tianma granules also downregulated the level of CRC-specific markers (COX2 and MUC2), inhibited the inflammation (decreased TNF-α, IL-1β, IL-6 levels and increased INF-γ level), and promoted apoptosis (decreased TUNEL positive cell rate; decreased Bax and Cleaved caspase3 protein levels and increased Bcl2 level) in CRC mice. In vitro, Tianma granules can inhibit the viability, proliferation, migration and invasion of CRC cells, while promoting cell apoptosis, cell cycle arrest and cell senescence. Tianma granules promoted AXIN1 protein levels and inhibited p-GSK-3β, β-catenin, Wnt5a and Cyclin D1 and c-Myc protein levels. Moreover, the network pharmacology analysis and in vitro validation revealed berberine might be the key compound responsible for Tianma granules' pharmacological actions. In conclusion, Tianma granules can inhibit inflammation and tumour progression in AOM/DSS-induced CRC mice, as well as inhibit CRC cell malignant phenotype. The protection of Tianma granules against CRC may be achieved by inhibiting the Wnt signalling pathway. Show less

To explore the mechanism by which BALB/c mice were infected by intraperitoneal injection with TgCtwh3 wild type (TgCtwh3 WT) and TgCtwh3 Δ BALB/c mice injected with TgCtwh3 Δ Our results indicated that the GRA15 Show less

Aβ is believed to play a significant role in synaptic degeneration observed in Alzheimer's disease and is primarily investigated as a secreted peptide. However, the contribution of intracellular Aβ or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system in rat hippocampal slice culture. Here, these proteins/peptides were overexpressed in a single neuron, surrounded by thousands of untransfected neurons. Surprisingly, we found that APP induced dendritic spine loss only when co-expressed with BACE1. This effect was mediated by β-CTF, a β-cleavage product of APP, through an endosome-related pathway independent of Aβ. Neuronal expression of β-CTF in mouse brains resulted in defective synaptic transmission and cognitive impairments, even in the absence of amyloid plaques. These findings unveil a β-CTF-initiated mechanism driving synaptic toxicity irrespective of amyloid plaque formation and suggest a potential intervention by inhibiting the endosomal GTPase Rab5. Show less

Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD. Show less

Neuroblastoma (NB) is the most common solid tumor in children, characterized by high recurrence rates, drug resistance, and significant mortality. In this study, we analyzed the proteomic profiles of NB tissue samples alongside other pathological categories, including ganglioneuroma (GN) and ganglioneuroblastoma (GNB). Using weighted gene co-expression network analysis (WGCNA), the core prognostic gene models associated with histopathology of NB were identified. Furthermore, by mapping our core prognostic gene models onto drug-perturbed transcriptome profiles from the L1000FWD and CMap databases, repurposing drug candidates were screened and validated for NB. Our proteomic analysis reveals that pathways associated with the cell cycle and DNA replication are significantly upregulated in NB, while oxidative phosphorylation, pyruvate metabolism, and the TCA cycle are notably downregulated compared to GNB and GN. By applying WGCNA, we identified a core prognostic gene model strongly associated with the unfavorable subtype and high MKI of NB and primarily related to chromatin binding and mRNA metabolic process. Protein-protein interaction network analysis identified 15 hub genes in this core prognostic module: SMARCA4, SMARCA5, SMARCC2, SMARCC1, PBRM1, BRD3, ARID1A, BRD2, ARID1B, KDM1A, TP53BP1, ALYREF, CBX1, SF3B1, and ADNP, which mainly related to chromatin remodeling. Notably, SMARCA4 and ALYREF are also high-risk genes of mortality and validated as potential prognostic biomarkers for NB. Through repurposing drugs screening, mocetinostat and clofarabine were validated as effective treatments in two NB cell lines. Mocetinostat and clofarabine offer valuable insights for the development of novel targeted therapies in neuroblastoma. Show less

Pancreatic adenocarcinoma (PAAD) remains highly lethal because of chemotherapy resistance and immunosuppressive microenvironments. Tertiary lymphoid structures (TLSs) were analysed in PAAD to develop personalised therapeutic strategies. Nine TLS-related genes (CCR6, CD1d, CD79B, CETP, EIF1AY, LAT, PTGDS, RBP5 and SKAP1) were selected for integrative analysis of TLS status in relation to clinical outcomes, immune cell infiltration, tumour mutational burden (TMB) and drug resistance. High TLS scores (TLS_H) were associated with improved overall survival (OS) and progression-free survival (PFS), independent of age or tumour grade. Twelve immune cell types differed across TLSs. Single-cell RNA-seq analysis revealed that the 9 TLS-related genes were enriched in distinct immune cell populations. Combining TLS and TMB improved survival prediction. Notably, the TLS_H group demonstrated enhanced sensitivity to chemotherapeutics including AZD8055, axitinib, vorinostat, nilotinib, camptothecin and paclitaxel. Real-time fluorescent quantitative PCR (RT-qPCR) validation in Mia PaCa2 and Jurkat cells indicated that LAT, RBP5 and SKAP1 may play important roles in modulating sensitivity to these chemotherapeutics. These findings establish TLS as a potential biomarker for PAAD, enabling personalised chemotherapy selection by integrating immune contexture and genomic drivers to improve clinical outcomes. Show less

CLN3 disease is a rare fatal juvenile neurodegenerative lysosomal storage disease. Challenges in tracking underlying disease biology have hindered the identification of effective therapeutic targets and the ability to execute clinical trials in this rare disease. While diagnostic biomarkers are readily available, biomarkers that reflect the underlying core lysosome dysfunction are lacking. In the present study, CLN3 Show less

CLN3 mutation causes Juvenile neuronal ceroid lipofuscinosis (JNCL, also known as Batten disease), an early onset neurodegenerative disorder. Patients who suffer from Batten disease often die at an early age. However, the mechanisms underlying how CLN3 loss develops Batten disease remain largely unclear. Here, using Show less

Glioblastoma is the most aggressive form of primary brain tumor, characterized with poor prognosis and resistance to conventional therapies. Increasing evidence points to oxidative stress and redox dysregulation as important contributors to glioblastoma progression. Previously, chloride intracellular channel protein 4 (CLIC4), a redox-sensitive protein, has been implicated in cancer biology. However, its roles in glioblastoma remain poorly understood. Here, we found that CLIC4 expression is upregulated in glioblastoma tissues and cell lines, and is positively correlated with tumor malignancy and poor survival outcomes in patients with glioblastoma. Gene silencing of CLIC4 significantly reduces glioblastoma cell viability, migration, and proliferation in vitro and suppress tumor growth in vivo. Mechanistically, CLIC4 appears to maintain redox homeostasis by regulating mitochondrial functions, including membrane potential, mass, ROS production, and the activity of complexes III and IV. Moreover, a G-quadruplex (G4) structure located in CLIC4 promoter region is related to CLIC4 upregulation by oxidative stress in glioblastoma. This G4 structure can be readily oxidized to a parallel conformation, thereby enhancing its binding with DHX36 protein to promote gene transcription. Collectively, these findings position CLIC4 as a pivotal modulator of oxidative stress in glioblastoma and a potential target for developing therapeutic approaches for the treatment of glioblastoma. Show less

The balance between proliferation and persistence of pseudorabies virus (PRV) in the host is crucial for its long-term survival. Understanding the mechanisms that regulate viral survival may offer new strategies for disease prevention and control. The immediate-early gene 180 (IE180) is essential for PRV replication, and we previously identified a G-quadruplex (PQS18-1) located in the 3' untranslated region (3'UTR) of IE180 that enhances its expression and promotes viral replication. However, the mechanisms by which this G-quadruplex is unwound and contributes to immune evasion remain unclear. In this study, we identified the host helicase DHX36 as a binding partner of PQS18-1 through RNA pull-down assays. Both in vitro and cellular experiments demonstrated that DHX36 destabilizes the G-quadruplex, thereby suppressing gene expression and regulating PRV replication. Our findings reveal a novel host-virus interaction mechanism involving G-quadruplex structures and helicase activity, which may offer new targets for therapeutic intervention. Show less

1. Copy number variation (CNV) is an important source for identifying genetic differences. This study compared the genome-wide CNV and their regions (CNVR) across 16 Chinese local duck breeds and detected key genes and pathways involved in growth and reproduction-related traits using this dataset.2. Breakdancer, Pindel and CNVnator were used to detect reliable CNV, and HandyCNV was used to obtain CNVR. Selection signatures were analysed in meat (MD) and egg-laying ducks (ED) compared to wild ducks (WD) using fixation and differentiation index DIsv methods. A Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to identify key pathways and related genes.3. Principal component analysis (PCA) using CNV data clustered 127 ducks into 4 populations: WD, MD, ED and meat+egg-type ducks (MED). In total, 237,630 CNV and 6,176 CNVR were detected across these samples. Intersection analysis identified 1,384 common CNVR and 2,105 unique CNVR. The KEGG analysis showed that common CNVR were enriched in 7 basic life activity pathways, while unique CNVR were enriched in 9 population-specific pathways. Compared to WD, MD selection signatures were found in 4 enriched pathways and 8 genes ( Show less