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The relation between hepatic ChREBP level and insulin sensitivity remains equivocal. Our study, however, provides compelling evidence that hepatic ChREBP depletion can significantly enhance insulin sensitivity in high-fat and sucrose-fed mice. We have identified that transcriptional induction of hepatic PTEN is driven by ChREBP. Mechanistically, two critical stimuli are elicited in the hepatic ChREBP knockdown condition. The PTEN level is reduced for one stimulus, thereby promoting hepatic insulin sensitivity. The second stimulus, where reduced hepatic PTEN leads to the enhanced release of FGF21, spreads systemic insulin sensitivity. These findings identify hepatic ChREBP as a critical modulator of systemic insulin signaling and suggest that ChREBP downregulation may lead to protection against insulin resistance. Building on this, our molecular dynamics simulation analysis has led to the discovery of a small molecule, Quercetin, that sequesters ChREBP in the cytosol. We report that Quercetin treatment can sequester ChREBP in the cytosol and abrogate high-fat and sucrose-fed-mediated ChREBP nuclear translocation, thereby mimicking the insulin-sensitizing abilities of the hepatic ChREBP knockdown condition. These findings have significant therapeutic implications, suggesting that liver-selective downregulation of ChREBP could protect against systemic insulin resistance that frequently develops early in the pathogenesis of NAFLD and T2DM. Show less

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup (KSS) significantly attenuated hepatic steatosis in rats. This study explored the main components of KSS and the mechanisms by which it exerts its protective effects against NAFLD. Twenty-four 6-week-old male Sprague-Dowley (SD) rats were randomly assigned to three treatments: feeding a normal standard diet, a high-fat diet, or a high-fat diet plus gavage KSS. The effects of KSS treatment on hepatic lipid accumulation were assessed using biochemical, histological, and molecular experiments. The amounts of KSS ingredients were measured using biochemical assays. Network pharmacology analyses were performed to identify the hub genes of KSS targets and enriched pathways. CCK-8 assay was used to determine the effect of free fatty acids (FFA), lycopene, and estrogen on HepG2 viability. Quantitative Real-Time polymerase chain reaction (qRT-PCR) and Western blot assays were performed to determine the effect of KSS or lycopene on estrogen signaling and expression of lipid metabolism-related molecules. Statistical analyses were performed using GraphPad Prism and SPSS. KSS alleviated fat deposition in rat liver tissue and affected the expression of hepatic lipid synthesis, catabolism, and oxidative molecules. Lycopene was identified as the ingredient with the highest amount in KSS. Network pharmacology analyses showed that the hub genes were enriched in the estrogen signaling pathway. Cellular experiments showed that lycopene increased the expression of Estrogen Receptor α (ERα), Carnitine palmitoyltransferase 1 A ( KSS ameliorated abnormal lipid metabolism in patients with NAFLD. Lycopene was the major component of KSS, and it affected estrogen signaling and the expression of lipid metabolism molecules. In short, both KSS and LYC could change lipid metabolism by lowering lipid accumulation and raising lipolysis. Show less

The angiogenesis phenomenon is crucial for the formation of new blood vessels in cancer cells. The cancerous cells' progress hampers other healthy cells. The main objective of this study is to explore and decipher multimodal natural compounds against VEGFR2, EphB4, FGFR-1, and TIE-2 drug targets to arrest angiogenesis and progression. The receptor-based pharmacophore modeling of VEGFR2, EphB4, FGFR-1, and TIE-2 was developed and validated through enrichment parameters. Further, the validated hypothesis allowed for screening druglike natural product databases such as SuperNatural 3.0, COCONUT, and LOTUS. The common pharmacophoric featured natural compounds were assessed for binding affinities using absolute end-point methods. Finally, density functional theory has been studied to understand the chemical reactivity and stability of the protein complexes. Among all of the screened natural compounds, 17 natural compounds were found to align accurately against validated pharmacophore models having higher fitness scores and align scores. Taking reference drugs sorafenib (VEGFR2), NVP-BHG712 (EphB4), pemiganitib (FGFR-1), and DP1919 (TIE-2), three promising natural compounds CNP0003920, CNP0243075, and CNP0211397 were concluded based on their end-point binding energies, binding interactions, molecular dynamics, and optimal pharmacokinetic and toxicity profiles. The density functional theory (DFT) results suggested that the identified compounds bound with protein complexes are stable. Our findings can represent a promising starting point for developing multimodal analogues VEGFR2, EphB4, FGFR-1, and TIE-2 proteins. Show less

Agitation is a common and difficult-to-manage neuropsychiatric syndrome in dementia. Recently, an association with the autonomous nervous system has been suggested. From the literature researched, however, only two studies investigating autonomic function concomitant to agitation situations appeared; one case series comprised two American veterans with vascular and Alzheimer's dementia, respectively, and in a case series of patients with CLN3 (juvenile neuronal ceroid lipofuscinosis), this was found to be the most common neurodegenerative disease leading to dementia in childhood. In both case series, the measurement of the autonomic system disclosed a parasympathetic withdrawal and sympathetic hyperactivity in the temporal context with agitated behavior. If the time-wise-related autonomic imbalance shown previously can be demonstrated in a larger cohort of patients with Alzheimer's disease, the use of transcutaneous vagal stimulation might be a potential paradigm shift in the treatment of agitation in Alzheimer's disease. Show less

Apolipoprotein C3 (APOC3) was found to induce inflammation in human monocytes. Jarisch-Herxheimer reaction (JHR) was perceived to be caused by immune reactions of dividing spirochaetes to penicillin treatment. The aim of this study was to investigate the role of APOC3 in patients with syphilis and JHR. This prospective cohort study enrolled adult patients with active syphilis with/without JHR. Serum samples were collected before and after administration of the first dose of benzathine penicillin and the serum levels of APOC3 were determined by enzyme-linked immunosorbent assay (ELISA). The APOC3 level and changes in APOC3 level before and after benzathine penicillin treatment in different groups were compared with the Mann-Whitney U test or Kruskal-Wallis test. Forty adult patients with syphilis and 32 controls were enrolled. All 40 patients with syphilis were men who have sex with men, and 30 (75%) were people living with human immunodeficiency virus (HIV). Overall, 19 patients (47%) developed JHR. The active syphilis group had a significantly higher serum APOC3 level (median 38.3 µg/mL, interquartile range [IQR]: 34.5-48.0 µg/mL) than the controls ( p = 0.020). The serum levels of APOC3 were higher in the 21 patients without JHR before and after benzathine penicillin treatment compared with the controls (38.9 µg/mL [IQR: 34.5-66.7 µg/mL] and 39.4 µg/mL [IQR: 33.7-62.9] µg/mL vs 31.8 µg/mL [IQR: 27.5-42.2 µg/mL]). Receiving operating characteristic curve analysis showed that the best cutoff value of APOC3 to predict the absence of JHR before benzathine penicillin therapy compared to the controls was 34.2 µg/mL (area under the curve 0.695, p = 0.017, CI = 0.544-0.846, sensitivity = 0.81, specificity = 0.406). A high baseline serum APOC3 level can predict the absence of JHR in patients with syphilis treated with the first dose of benzathine penicillin. Show less

Natriuretic peptides (NPs) have an important role in lipid metabolism in skeletal muscle and adipose tissue in animals. C-type natriuretic peptide (CNP) is an important NP, but the molecular mechanisms that underlie its activity are not completely understood. Treatment of intramuscular fat (IMF) and subcutaneous fat (SCF) adipocytes with CNP led to decreased differentiation, promoted proliferation and lipolysis, and increased the expression of natriuretic peptide receptor B (NPRB) mRNA. Silencing natriuretic peptide C (NPPC) had the opposite results in IMF and SCF adipocytes. Transcriptome analysis found 665 differentially expressed genes (DEGs) in IMF adipocytes and 991 in SCF adipocytes. Seven genes in IMF adipocytes (FABP4, APOA1, ACOX2, ADIPOQ, CD36, FABP5, and LPL) and eight genes in SCF adipocytes (ACOX3, ACSL1, APOA1, CPT1A, CPT2, FABP4, PDPK1 and PPARα) are related to fat metabolism. Fifteen genes were found to be enriched in the peroxisome proliferator-activated receptor (PPAR) pathway. Integrated analysis identified 113 intersection genes in IMF and SCF adipocytes, two of which (APOA1 and FABP4) were enriched in the PPAR pathway. In conclusion, CNP may regulated lipid metabolism through the NPRB-PPAR pathway in both IMF and SCF adipocytes, FABP4 and APOA1 may be the key genes that mediated CNP regulation of fat deposition. Show less

Wenchang chicken, renowned for its high-quality meat, is the economic meat breed in Hainan Province, China. This study compared cage-rearing (CR) and free-range (FR) groups in terms of growth performance, slaughter performance, meat quality, IMP (inosine monophosphate) content, AAs, FAs, serum lipid metabolites, and transcriptomic and metabolomic analyses. The CR group showed increased body weight, live weight, and abdominal fat but lower leg muscle percentage and breast muscle redness, suggesting flavor differences. CR chickens had higher IMP, threonine (Thr), and pentadecanoic, oleic, and linoleic acids, while glutamate (Glu) and alpha-linolenic acid were lower compared to FR. Glycine was elevated, but histidine, myristic, and tricosanoic acids were lower in CR leg muscle. Serum analysis revealed higher total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), fatty acid synthase (FAS), thyroid-stimulating hormone (TSH), leptin (LEP), and adiponectin (ADP) in the CR group. Transcriptomic and metabolomic studies identified 252 differentially expressed genes and 34 metabolites linked to metabolic pathways. In summary, CR system can improve production performance, FR system is considered more flavorful. The results can act as a theoretical basis for selecting a suitable rearing method for this unique breed. Show less

As global population aging intensifies, mental health issues in older adults are increasingly prominent, with depression being particularly prevalent and detrimental. The study investigated how substituting sedentary behavior (SB) and sleep (SLP) with physical activity (PA) affects depression risk in this population. Meta-analysis was conducted by searching four databases: PubMed, Scopus, SPORTdiscus, and PsycINFO (via EBSCOhost platform) for relevant studies published until January 2025. Regression coefficients (β) with 95% confidence intervals (CIs) for depressive symptoms were estimated. Publication bias was assessed using funnel plots and Egger's tests, and heterogeneity was evaluated using Q tests and the I Among 18,912 participants (53.45% female, ≥60 years) across nine studies, replacing SB with MVPA significantly reduced depression (β = -0.12, 95% CI: -0.20, -0.04), subgroup analyses indicated that reallocating 10, 30 and 60 min/day of SB to MVPA ( Substituting SB and SLP with MVPA is significantly associated with a reduction in depression, whereas no significant association is observed when replaced by LPA. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=546666, identifier CRD42024546666. Show less

Alzheimer's Disease is a chronic progressive neurodegenerative disorder characterized by impaired intellect and cognitive functions. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by initiating the amyloid cascade. Despite significant clinical efforts, most BACE1 inhibitors have failed to yield potent pharmacological effects. Our previous study, identified a group of natural compounds with satisfying pharmacological profiles with high affinity to BACE1, out of which the compound, 'convolidine' emerged as the most promising candidate based on the in-silico parameters such as docking score, interacting residues, binding energy, drug-likeness, ADMET, and biological activity prediction. The present study focused on the inhibitory potential of convolidine against BACE1 using dynamics simulation followed by protein-protein docking and in-vitro validation. Molecular dynamics simulation demonstrated that the BACE1-convolidine complex remained stable throughout the entire 200 ns simulation period. Also, the results of the post-dynamic docking study showed a reduced substrate affinity of BACE1 to its substrate, APP (Amyloid precursor protein), when BACE1 is bound to convolidine, suggesting compounds inhibitory potential. This in-silico assessment was validated in-vitro using a FRET-based BACE1 activity assay, where the result well aligned with the computational predictions. The findings revealed that convolidine could effectively inhibit BACE1, with an IC50 value of 0.49 µM, providing a solid foundation for its development as a promising therapeutic agent for AD management. Show less

Apolipoprotein C3 (APOC3) and angiopoietin-like protein 8 (ANGPTL8) genes are related to lipid metabolism. The relationships between single nucleotide polymorphisms (SNPs) in the APOC3 and ANGPTL8 genes with metabolic dysfunction-associated steatotic liver disease (MASLD) remain controversial. This study aimed to investigate the associations between specific SNPs in the APOC3 and ANGPTL8 genes and MASLD risk, with a particular focus on the mediating role of triglycerides (TG). A total of 440 participants were enrolled and categorised into MASLD and control groups. Genotyping of APOC3 SNPs (rs5128, rs2854116 and rs2854117) and ANGPTL8 SNP (rs2278426) was conducted using polymerase chain reaction-restriction fragment length polymorphism or Sanger sequencing methods. Multivariate logistic regression was employed to estimate the associations between these SNPs and MASLD risk, and mediation analysis was performed to assess the potential mediating effect of TG. We found that APOC3 SNPs were associated with MASLD risk, with increased odds ratios (ORs) indicating a higher risk of MASLD: rs5128 CG + GG genotype (OR = 1.8, 95% CI = 1.1-2.8), rs2854116 TC + CC genotype (OR = 1.9, 95% CI = 1.1-3.1) and rs2854117 CT + TT genotype (OR = 1.9, 95% CI = 1.2-3.2). No association was found between ANGPTL8 rs2278426 and MASLD (p > 0.05). Mediation analysis revealed that TG significantly mediated these relationships, accounting for 80.25% of the effect for rs5128, 64.61% for rs2854116 and 62.59% for rs2854117. In summary, polymorphisms in APOC3 (rs5128, rs2854116 and rs2854117) were associated with MASLD risk, with TG serving as a potential mediating factor. In contrast, ANGPTL8 rs2278426 polymorphism did not show any association with MASLD. Show less

Heart failure (HF) and atherosclerosis represent two major cardiovascular diseases that are intricately linked, both contributing significantly to global morbidity, mortality, and healthcare burden. Despite substantial progress in diagnostic methods and therapeutic strategies, the overall impact of these conditions remains considerable. This is largely due to their complex and overlapping pathophysiological mechanisms, persistent residual atherosclerotic risk, and the ongoing challenges associated with implementing guideline-directed medical therapy for HF in routine clinical practice. Recent advancements in the management of diverse HF phenotypes, lipid abnormalities, atherosclerotic cardiovascular disease (ASCVD), and obesity have facilitated the adoption of multidrug regimens. These include β-blockers, renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1), which have collectively improved outcomes in HF populations. Lipid-lowering therapy, particularly statins, has demonstrated significant efficacy in reducing ASCVD events and slowing HF progression, as well as lowering the risk of HF-related hospitalizations. Elevated lipoprotein(a) [Lp(a)] has emerged as an independent risk factor for both ASCVD and HF, being associated with increased risk of incident HF, disease progression, hospitalization, and adverse outcomes. However, there remains a lack of conclusive evidence as to whether targeted reduction of Lp(a) leads to a decrease in major adverse cardiovascular events or improves HF incidence or outcomes. In parallel, contemporary therapeutic advances in coronary and peripheral artery revascularization, along with novel pharmacologic treatments for obesity such as GLP-1 receptor agonists including semaglutide and tirzepatide have shown beneficial effects in reducing cardiovascular mortality, HF progression, and body weight, irrespective of HF status. These converging therapeutic strategies underscore the close interrelationship between HF and atherosclerosis. This review aims to elucidate the shared pathophysiological mechanisms linking these conditions and to examine their clinical overlap with ischemic heart disease, cerebrovascular disease, peripheral arterial disease, dyslipidemia, and obesity. A comprehensive understanding of these interrelated cardiovascular entities may offer valuable insights to inform future research directions and optimize the clinical management of patients affected by both HF and atherosclerotic disease. 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-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

Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non-coding regions. However, the role of non-coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome-wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib-lenalidomide-dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd-resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9-mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi-omics analysis (H3K27ac ChIP-seq, scRNA-seq, scATAC-seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence-specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. Show less

Kidney renal clear cell carcinoma (KIRC), the predominant subtype of renal cell carcinoma, poses significant health risks. The rapid progression and resistance to targeted therapies highlight the need for new tumor markers and therapeutic targets. FADS1, part of the fatty acid desaturase family, regulates fatty acid synthesis and participates in lipid metabolism. However, its role in KIRC is not well-studied. The study utilized bioinformatics analysis through the TCGA database and other platforms to identify FADS1 expression levels in KIRC. Twenty pairs of KIRC clinical tissue samples were used for qPCR verification. Meanwhile, eight pairs of KIRC clinical tissue samples were used for Western blot verification. Conduct statistical evaluation, including Wilcoxon rank sum test and Kaplan-Meier analysis, to explore the correlation between FADS1 expression and clinical pathological features and immune infiltration. In addition, in vitro experiments were conducted to confirm the biological function of FADS1. The findings indicated that FADS1 is highly expressed in KIRC and contributes to tumor development. FADS1's role in lipid metabolism leads to lipid accumulation within tumor cells, which may influence the occurrence and progression of KIRC. TIMER analysis revealed a correlation between FADS1 expression and the infiltration levels of various immune cells, indicating its potential role in modulating immune characteristics. FADS1 could serve as a prognostic biomarker associated with immunity in KIRC, highlighting its potential as a diagnostic and therapeutic target. The study underscores the importance of further research into FADS1's role in lipid metabolism and immune infiltration to develop effective therapeutic strategies. Show less

Early identification of individuals with low advance care planning (ACP) engagement remains a critical component of clinical care. However, we know little about the heterogeneity of ACP engagement at the individual level. This study identified latent subgroups of ACP engagement using latent profile analysis (LPA), and explored their associations with death attitudes. This study recruited 302 end-stage renal disease (ESRD) patients undergoing dialysis. Data included sociodemographic characteristics, the Advance Care Planning Engagement Survey (ACPES; Chinese version), and the Death Attitude Profile-Revised (DAP-R). Based on multidimensional indicators, LPA was employed to identify distinct ACP engagement profiles. Model fit and classification quality in LPA were evaluated based on class sizes and entropy values. All analyses were completed in SPSS 26.0 and Mplus 8.3, with R3STEP and BCH methods employed to uncover underlying patterns and relationships. Among dialysis-dependent ESRD patients, ACP engagement was categorized into two latent profiles: a "low-ACP Engagement" profile (n = 162, 53.6%) and a "high-ACP Engagement" profile (n = 140, 46.4%), with good classification quality (entropy = 0.909). The profile membership was significantly associated with dialysis vintage, and educational level (both This study identifies two distinct ACP engagement profiles among dialysis-dependent ESRD patients. Findings emphasize the need for tailored interventions, particularly for patients with shorter dialysis vintage and lower education level, and highlight the role of death attitudes in shaping ACP engagement. These findings should be interpreted with caution due to the cross-sectional design and single-center setting. Show less

Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration. Show less

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, amyloid-beta (Aβ) accumulation, and tau protein hyperphosphorylation. In this study, we synthesized novel Ramalin derivatives and evaluated their therapeutic potential against AD, focusing on antioxidant, anti-inflammatory, and neuroprotective activities. RA-2OMe, RA-4OMe, RA-2CF3, and RA-4OCF3 showed strong antioxidant effects, while RA-2OMe exhibited potent NO and NLRP3 inhibition (~20%). RA-NAP, RA-PYD, and RA-2Q showed moderate anti-inflammatory activity. BACE-1 inhibition was significant in RA-3CF3, RA-NAP, and RA-PYD, with IC Show less

Despite advancements in treatment, coronary artery disease (CAD) remains a significant global health concern. Although lipoprotein(a) [Lp(a)] is recognized as a crucial cardiovascular risk factor associated with increased risk, the prognostic value of using Lp(a) levels in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) remains debatable. This review aimed to investigate the association between Lp(a) levels and recurrent ischemic events in patients with ACS undergoing PCI. This systematic review included studies with individuals aged ≥18 years diagnosed with ACS who underwent PCI and had Lp(a) measurements. The included studies were sourced from the PubMed database, with a focus on articles published between January 2020 and January 2025. Keywords related to Lp(a) and cardiovascular diseases were used in the search. Data extraction involved a review of titles and abstracts followed by quality assessment using the QUADAS-2 tool. The final analysis included 10 studies with a combined population of 20,896 patients from diverse regions, including Japan, India, Egypt, China, and South Korea. Key findings indicate that elevated Lp(a) levels are significantly associated with adverse cardiovascular outcomes, including myocardial infarction and mortality, both in hospital and during long-term follow-up. This review highlights Lp(a) as a critical biomarker for predicting recurrent cardiovascular events in ACS patients post-PCI. The consistent correlation between elevated Lp(a) levels and adverse outcomes underscores the necessity of routine monitoring and targeted management of Lp(a) to mitigate residual cardiovascular risk. Show less

Hepatocellular carcinoma (HCC), as a cancer with high morbidity and mortality, urgently requires the development of a clinical prediction model with high robustness and generalizability and its prognostic study of the tumor microenvironment to provide personalized clinical treatment for patients. Key prognostic genes were screened by analyzing mRNA expression data from GTEx and The Cancer Genome Atlas (TCGA) using limma difference analysis, Cox analysis, and machine learning (ML) algorithms. TCGA database was used as a training set, and the International Cancer Genome Consortium database was used as a test set to screen the best prognostic modeling algorithms using a combination of 101 ML algorithms for training and constructing Nomo score plots based on the algorithmic risk scores as well as Shiny online prediction models. Based on shapley additive explanations analysis, drug sensitivity analysis, and immune infiltration analysis were performed on the 6 genes screened to visualize the importance of prognostic genes. HCC tumor mutation load analysis was also performed. A risk prediction model for HCC death was developed based on the RSF algorithm, with an RSF model C-index of 0.765 and AUC values of 0.978, 0.989, and 0.964 for 1-, 3-, and 5-year ROC curves for the Nomo score model, respectively. LPL, RAET1E, RNASEH2A, GTF2H4, SCML2, and PRDM12 were potential diagnostic and prognostic markers, among which SCML2 and PRDM12 were significantly correlated with multiple drugs in drug sensitivity analysis.TP53 mutations were correlated with patients' age, chronological age, gender, histological tumor stage, T stage, and lymph node metastasis. An online HCC mortality risk prediction model was developed using the RSF algorithm. LPL, RAET1E, RNASEH2A, GTF2H4, SCML2, and PRDM12 are potential prognostic target genes, whereas TP53 mutations are associated with clinical features that may inform the development of HCC therapy. Show less

Chronic kidney disease (CKD) is a growing global health burden, strongly associated with cardiovascular disease, the leading cause of mortality in this population. Dyslipidemia is a key metabolic abnormality in CKD, but traditional lipid measures such as total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides often fail to capture the complexity of lipid disturbances in CKD and after kidney transplantation. Apolipoproteins have emerged as more reliable markers of cardiovascular and renal risk. Elevated apolipoprotein B (ApoB), reduced apolipoprotein A1 (ApoA1), and a higher ApoB/ApoA1 ratio are linked to CKD progression, cardiovascular events, and post-transplant complications, including post-transplant diabetes mellitus. Lipoprotein(a), a genetically determined atherogenic lipoprotein, accumulates in CKD due to impaired clearance and further increases cardiovascular risk. Other apolipoproteins, such as APOL1 and APOE, modulate CKD susceptibility through lipid-dependent and independent mechanisms. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of lipid metabolism, and PCSK9 inhibitors may represent a promising therapeutic option, though evidence in advanced CKD and transplant recipients is still limited, especially regarding their effects on apolipoproteins. This review summarizes current evidence on apolipoproteins and PCSK9 in CKD and transplantation, with attention to their potential as biomarkers and therapeutic targets. Show less

The intricate shared genetic architecture underlying halitosis and its related disorders-including salivary secretion disorders, chronic periodontitis, gastroesophageal reflux disease, dental caries, chronic sinusitis, helicobacter pylori infection, and porphyromonas genus abundance-remains incompletely characterized. Our study employed genomic structural equation modeling (Genomic SEM) to define the halitosis common factor (HCF) representing the shared genetic architecture of halitosis-related disorders. Coupled with diverse post-GWAS analytical methods, we aimed to discover susceptible loci and investigate genetic associations with external traits. Furthermore, we explored enriched genetic pathways, cellular layers, and genomic elements. Polygenic risk score analyses, leveraging our integrated GWAS data, were conducted to assess chromosomal-level risk associations for the HCF. A well-fitted genomic SEM integrated GWAS data, revealing the shared genetic architecture of halitosis-related disorders. We identified 23 independent genome-wide significant SNP loci, all previously unreported for this HCF relative to the input single-trait GWAS. Fine-mapping of variants and gene prioritization pinpointed numerous high-confidence putative causal variants and candidate susceptible genes. Subsequent analyses further illuminated the shared genetic architecture underlying HCF and multiple external traits, notably neuropsychiatric characteristics, cognitive function, and inflammatory or metabolic conditions. Notably, this study presents the first comprehensive genetic characterization of halitosis and its related disorders through a GWAS analysis of an unmeasured composite phenotype, providing novel insights into shared etiological pathways potentially linking oral health to systemic factors across these conditions. Show less

Physical fitness in preschoolers, encompassing muscular strength, speed-agility, balance, and cardiorespiratory fitness, serves as a key health indicator. While preschools are ideal settings for promoting physical fitness, the association between preschool-based movement behaviors and physical fitness remains unclear. This cross-sectional study included 1144 Chinese preschoolers aged 3-6 years. Preschool-based movement behaviors including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary behavior (SB), were measured using ActiGraph GT9X accelerometers. Physical fitness was assessed via the PREFIT battery, which includes handgrip strength, standing long jump, 4 × 10 m shuttle run, one-leg stance, and 20 m shuttle run. Compositional linear regression and isotemporal substitution modeling were employed to examine associations and time-reallocation effects, respectively. Greater amounts of MVPA during preschool hours were positively associated with better performance in muscular strength, speed-agility, and cardiorespiratory fitness. Reallocating time from SB or LPA to MVPA enhanced physical fitness, whereas substituting MVPA with SB or LPA reduced fitness levels, demonstrating an asymmetric effect. Moderate-to-vigorous physical activity during preschool hours significantly enhances physical fitness. Prioritizing the implementation of physical activity programs to increase MVPA in preschool settings is crucial for improving physical fitness and addressing insufficient MVPA in this age group. First large-scale study (N = 1144) demonstrating preschool-based moderate-to-vigorous physical activity (MVPA) is essential for developing preschoolers' muscular strength, speed-agility, and cardiorespiratory fitness, complementing existing 24-h movement behavior research. Reveals critical asymmetry: Reducing MVPA time significantly harms fitness, with losses exceeding the benefits from equivalent MVPA increases. Provides objective evidence to guide policymakers in optimizing preschool schedules to prioritize MVPA for enhancing children's physical fitness. Show less

Our previous studies have shown that miR-130b can significantly inhibit subcutaneous fat deposition in pigs. This study aims to further investigate its effect on lipid accumulation at early-stage (24 and 48 h) and late-stage (7 d) adipogenic differentiation and to clarify potential mechanisms using primary rat intramuscular preadipocytes (IMAs). Results showed that at 24 h and 48 h, miR-130b overexpression significantly reduced lipid deposition by inhibiting proliferation and inducing apoptosis. Furthermore, miR-130b overexpression significantly inhibited the expression of cell cycle and apoptosis marker genes. Specifically, the mRNA expression of Show less

Chromobox (CBX) proteins are essential components of the Polycomb group and play pivotal roles in tumor onset, progression, and metastasis. However, the prognostic significance and functions of CBXs in the advancement of breast cancer (BC) have not been sufficiently investigated. A comprehensive analysis of the expression and prognostic relevance of CBX1-8 in BC was conducted comprehensively using The Cancer Genome Atlas (TCGA) and multiple databases. High mRNA expression of CBX2, CBX3, and CBX5 in BC patients was significantly associated with reduced overall survival (OS). Results from univariate and multivariate Cox regression analysis revealed that the mRNA expression level of CBX2 in BC patients served as an independent prognostic factor. In Luminal A and Luminal B BC subtypes, high expression of CBX2 correlated with unfavorable prognosis. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated a strong association between CBX2 and the cell cycle as well as DNA replication processes. CCK-8 and EdU assays demonstrated that silencing CBX2 inhibited the proliferation of T47D and MCF7 cell lines. Moreover, the cell cycle assay indicated that CBX2 silencing led to cell cycle arrest, accompanied by a significant decrease in the levels of CDK4 and CyclinD1. Elevated CBX2 expression significantly correlated with the infiltration of T cells, B cells, macrophages, and dendritic cells in BC. Our findings could provide new perspectives for identifying potential prognostic markers within the CBX family in BC. Targeting CBX2 may present a promising approach to address endocrine resistance in BC therapy. Show less

The fibroblast growth factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope Show less

Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder typically involving the bone marrow with infiltration by small lymphocytes and plasma cells. Studies have identified MYD88 L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas. Detection rates for this mutation have varied depending on the analytic methodology, with previous data suggesting that routine next-generation sequencing (NGS) does not demonstrate the required sensitivity to reliably detect MYD88 L265P. NGS has become part of routine clinical testing because it allows detection of variants across multiple genes. To study the utility of NGS in the detection of MYD88 L265P, we performed droplet digital PCR (ddPCR) and routine NGS on a cohort of 34 cases of lymphoid neoplasms (22 LPL, 4 CLL, 1 MCL, 1 MGUS, 2 plasma cell myeloma, and 4 negative bone marrow cases). We utilized manual review and BAMtools to assess MYD88 L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.4 % variant allele frequency (VAF) with 10 ng DNA input. MYD88 L265P VAF detection by NGS and ddPCR was comparable down to 0.5 % VAF (R Show less

Undifferentiated pleomorphic sarcoma (UPS) is a diagnosis of exclusion; given limited effective treatments and marked heterogeneity, there is a need to identify therapeutic targets, a task facilitated by next-generation sequencing (NGS) in clinical practice. We report 2 STS pts with the diagnosis of UPS, G3 - each treated in a clinical trial (NCT03651374) with UNRESARC protocol consisting of neoadjuvant chemotherapy (CHT), radiotherapy, and surgical resection. Biopsy samples from each patient were subjected to NGS with the TruSight™ Oncology 500 assay (Illumina) and analysed in PierianDX (commercial software). 5 pathogenic alterations were identified: Case A: CCNE1 (6 copies) and MYC (3 copies) amplifications; Case B: CCND1 (3 copies), EGFR (3 copies) and FGFR1 (4 copies) amplifications. Amplifications of cell-cycle associated (CCNE1, CCND1) and apoptosis-related (MYC) genes contribute to uncontrolled proliferation and resistance to apoptosis, while amplifications in receptor tyrosine kinases (EGFR and FGFR1) activate pathways (RAS/MAPK and PI3K/AKT), involved in tumour growth and metastasis. In both patients, a poor pathological response, early local recurrence (LRFS of 9 months in both patients) and progressive disease (PD) when treated with first-line palliative CHT (PFS of 5 months in A and 4 months in B) were noted. All tumours demonstrated a low tumour mutation burden (TMB) (1.6-3.9 mut/Mb) and no microsatellite instability (MSI), explaining no sensitivity to immune checkpoint inhibitors. NGS assays may enable accurate diagnosis and identify predictive biomarkers and novel therapeutic targets - of particular importance in poor-prognosis entities such as UPS. Our report is consistent with the literature classifying UPS as malignancy with a high frequency of CNAs and low TBM. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated Show less

Many factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regulatory factor for Zika virus (ZIKV) infection. Knocking out EXT1 dramatically restricts ZIKV infection, which is not due to the inhibition of virus entry resulting from HS deficiency, but mediated by the downregulation of autophagy. Induction of autophagy promotes ZIKV infection, and attenuated autophagy is found in distinct EXT1 knockout (EXT1-KO) cell lines. Induction of autophagy by rapamycin can relieve the ZIKV production defect in EXT1-KO cells. While over-expressing EXT1 results in the reduction of ZIKV production by targeting the viral envelope (E) protein and non-structural protein NS3 in a proteasome-dependent degradation manner. The different roles of EXT1 in ZIKV infection are further confirmed by the data that knocking down EXT1 at the early stage of ZIKV infection represses viral infection, whereas the increase of ZIKV infection is observed when knocking down EXT1 at the late stage of viral infection. This study discovers previously unrecognized intricate roles of EXT1 in ZIKV infection. Show less

Infantile epileptic spasms syndrome is a severe epilepsy of infancy that is often associated with focal malformations of cortical development. This study aimed to elucidate the genetic landscape and histopathologic aetiologies of infantile epileptic spasms syndrome due to focal malformations of cortical development requiring surgery. Fifty-nine children with a history of infantile epileptic spasms syndrome and focal malformations of cortical development on MRI were studied. Genetic testing of resected brain tissue was performed by high-coverage targeted panel sequencing or exome sequencing. Histopathology and MRI were reviewed, and integrated clinico-pathological diagnoses were established. A genetic diagnosis was achieved in 47 children (80% of cohort). Germline pathogenic variants were identified in 27/59 (46%) children, in Show less