Search Results (109)

Background/Objectives: Hypercholesterolemia remains a major risk factor for cardiovascular disease and a leading cause of global mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein receptors (LDLR), thereby reducing LDL-cholesterol (LDL-C) clearance. While monoclonal antibodies (mAbs) targeting PCSK9 are effective, their short half-life requires frequent dosing and incurs high treatment costs. This study evaluates a novel peptide-based Anti-PCSK9 product aimed at providing sustained LDL-C reduction. Methods: A novel PCSK9 based-peptide conjugated to diphtheria toxoid (DT) was evaluated in various preclinical models: high-fat diet-fed C57BL/6 mice, APOB100/hCETP transgenic mice, BALB/c mice and normocholesterolemic non-human primates. Immunogenicity (Anti-PCSK9 antibody titers, binding affinity by SPR), pharmacodynamics (LDL-C levels, inhibition of PCSK9-LDLR interaction) and safety were assessed. Toxicity was evaluated in rodents, rabbits and dogs through clinical monitoring, histopathology, organ function and safety pharmacology studies. Results: The Anti-PCSK9 product induced robust and long-lasting immune response in all models antibody titers in BALB/c mice peaked by week 6 and persisted for 12 months. LDL-C reductions of 44% in APOB100/hCETP mice and 37% in C57BL/6 mice correlated with high antibody titers and strong PCSK9-binding affinities (85 and 49 RU), leading to 59% and 58% inhibition of PCSK9-LDLR interaction, respectively. Non-human primates showed sustained responses. No systemic toxicity was observed; injection-site reactions were mild and reversible. No adverse effects were detected on cardiovascular, neurological, or respiratory systems. Conclusions: This peptide-based Anti-PCSK9 therapy offers sustained efficacy and safety, representing a promising long-acting alternative for managing hypercholesterolemia. Full article

As the world’s largest developing and carbon-emitting country, China is accelerating its greenhouse gas (GHG) emission reduction process, and it is of vital importance in achieving the goals set out in the Paris Agreement. This paper examines the historical development and current operation of China’s carbon emissions trading market (CETM). The current progress of research on the implementation of carbon emissions trading policy (CETP) is described in four dimensions: environment, economy, innovation, and society. The results show that CETP generates clear environmental and social benefits but exhibits mixed economic and innovation effects. Furthermore, this paper analyses the challenges of China’s carbon market, including the green paradox, the low carbon price, the imperfections in cap setting and allocation of allowances, the small scope of coverage, and the weakness of the legal supervision system. Ultimately, this paper proposes recommendations for fostering China’s CETM with the anticipation of offering a comprehensive outlook for future research. Full article

Background: Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Full article

Purpose: We aimed to investigate whether genetic variants susceptible to age-related macular degeneration (AMD) are associated with intraocular inflammation after brolucizumab administration in eyes that have exudative AMD. Methods: A total of 206 eyes from 206 patients (156 men/50 women, 74.0 ± 8.4 years; treatment-naïve, 128 [62.1%]; switching, 78 [37.9%]) were included in this study. All patients were treated with intravitreal brolucizumab at least once. The genotyping of ARMS2 A69S (rs10490924), CFH I62V (rs800292), CFH (rs1329428), SKIV2L (rs429608), C3 (rs2241394), cholesteryl ester transfer protein (CETP) (rs3764261), and ADAMTS9 (rs6795375) was performed using TaqMan technology. Results: Out of the 206 patients who were included, 21 eyes from 21 patients (10.2%) exhibited intraocular inflammation (IOI). Four (19.0%) exhibited severe IOI, including retinal vasculitis and/or retinal vascular occlusion, and 17 (81.0%) showed mild IOI. The frequency of the T allele of the CETP gene was significantly lower in patients who developed IOI compared to patients who did not develop IOI (T allele frequency: 9.5% vs. 23.5%, p = 0.036). After adjusting for confounding factors, the T allele remained significantly associated with protection against IOI (p = 0.028, 95% confidence interval: 0.098–0.88). Conclusions: The T allele of the CETP gene, a risk allele for AMD and the protective allele for atherosclerosis, may be associated with protection against IOI after brolucizumab administration in eyes that have exudative AMD. Full article

In recent years, a pressing global challenge has been that increasingly stringent environmental regulations have failed to prevent global climate change. In this context, exploring the synergistic effects of a policy mix approach has emerged as a promising strategy to turn the tide. Given that companies are the primary sources of carbon emissions, this study adopts a novel micro-level perspective. It employs the difference-in-differences method and establishes a two-way fixed effects model to empirically examine the interactive effects of the Low-Carbon City Pilot (LCCP) and the Carbon Emissions Trading Pilot (CETP) on corporate low-carbon development. Based on data availability and relevance, it uses a sample of Chinese listed industrial companies in 2007–2020. The findings indicate that the CETP enhances corporate carbon performance, whereas the LCCP has no significant impact on its own. However, the combined implementation of the two policies has resulted in a synergistic effect, with green innovation playing a mediating role in this process. The study also identifies the presence of a “green paradox” under heavily polluting industries and a weakening of the policies’ effectiveness in Western China and among non-high-tech firms. For emerging countries undergoing low-carbon transitions, it is essential to design context-specific policy combinations that maximize the effectiveness of environmental regulations. Full article

Background: Cardiovascular disease remains the leading cause of death worldwide, and dyslipidemia is a critical, modifiable risk factor. Aim: We sought to evaluate the relationship between polymorphisms in CETP (rs3764261), APOA5 (rs662799), IL6 (rs1800796), and PON1 (Q192R) and lipid parameters, and to assess their contribution to dyslipidemia and overall cardiovascular risk in an urban cohort from Cauca, Colombia. Methods: In this cross-sectional observational study, 304 participants aged 40–69 years were enrolled. Clinical, anthropometric, and biochemical data were collected, and genotyping was performed for the four target polymorphisms. We used descriptive statistics to characterize the sample, non-parametric tests to compare lipid levels by genotype, and multivariable logistic regression to identify independent predictors of dyslipidemia. Results: Individuals with dyslipidemia exhibited significantly higher total cholesterol and VLDL levels, lower HDL levels, and an elevated Castelli II index compared with the non-dyslipidemia group. Although CETP genotype frequencies differed between groups, only the APOA5 rs662799 variant was significantly associated with increased VLDL levels, suggesting its potential role as a genetic biomarker of cardiovascular risk. Conclusions: Our findings underscore the interplay between metabolic factors and genetic variants in the pathogenesis of dyslipidemia. Notably, the APOA5 rs662799 polymorphism emerged as a key determinant of VLDL concentration, highlighting its promise for personalized cardiovascular risk stratification and management in this population. Full article

Diabetes mellitus (DM) and tuberculosis (TB) are two global health challenges that significantly impact population health, with DM increasing susceptibility to TB infections. However, early risk prediction methods for DM patients complicated with TB (DM–TB) are lacking. This study mined transcriptome data of DM–TB patients from the GEO database (GSE181143 and GSE114192) and used differential analysis, weighted gene co-expression network analysis (WGCNA), intersecting immune databases, combined with ten machine learning algorithms, to identify immune biomarkers associated with DM–TB. An early alert model for DM–TB was constructed based on the identified core differentially expressed genes (DEGs) and validated through a prospective cohort study and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for gene expression levels. Furthermore, we performed a detailed immune status analysis of DM–TB patients using the CIBERSORT algorithm. We identified 1090 DEGs associated with DM–TB and further pinpointed CETP (cholesteryl ester transfer protein) (AUC = 0.804, CI: 0.744–0.864), TYROBP (TYRO protein tyrosine kinase binding protein) (AUC = 0.810, CI: 0.752–0.867), and SECTM1 (secreted and transmembrane protein 1) (AUC = 0.811, CI: 0.757–0.864) as immune-related biomarkers for DM–TB patients. An early alert model was developed based on these three genes (AUC = 0.86, CI: 0.813–0.907), with a sensitivity of 0.80829 and a specificity of 0.75758 at a Youden index of 0.56587. External validation using the GSE114192 dataset showed an AUC of 0.901 (CI: 0.847–0.955). Population cohort research and RT-qPCR verified the expression levels of these three genes, demonstrating consistency with trends seen in the training set. KEGG enrichment analysis revealed that NF-κB and MAPK signaling pathways play crucial roles in the DM–TB pathogenic mechanism, and immune infiltration analysis showed significant suppression of certain adaptive immune cells and activation of inflammatory cells in DM–TB patients. This study identified three potential immune-related biomarkers for DM–TB, and the constructed risk assessment model demonstrated significant predictive efficiency, providing an early screening strategy for DM–TB. Full article

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes significant global morbidity, including fever, rash, and persistent arthralgia. Utilizing untargeted lipidomics, we investigated how CHIKV infection alters host cell lipid metabolism in Vero cells. CHIKV infection induced marked catabolism of hexosylceramides, reducing their levels while increasing ceramide byproducts. Functional studies revealed a reliance on fatty acid synthesis, β-oxidation, and glycosphingolipid biosynthesis. Notably, inhibition of uridine diphosphate glycosyltransferase 8 (UGT8), essential for galactosylceramide production, significantly impaired CHIKV replication and entry in Vero cells. Sensitivity of CHIKV to UGT8 inhibition was reproduced in a disease-relevant cell line, mouse hepatocytes (Hepa1-6). CHIKV was also sensitive to evacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, though the mechanism of inhibition appeared independent of CETP itself, suggesting an off-target effect. These findings highlight specific lipid pathways, particularly glycosphingolipid metabolism, as critical for CHIKV replication and further refine our understanding of how CHIKV exploits host lipid networks. This study provides new insights into CHIKV biology and suggests that targeted investigation of host lipid pathways may inform future therapeutic strategies. Full article

Background: Understanding gene–diet interactions is crucial for establishing dietary guidelines for cardiovascular diseases (CVD). This study analyzed the interaction between dietary intake and six genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNP) associated with high-density lipoprotein (HDL) cholesterol levels and their impact on CVD risk. Methods: A total of 68,806 participants in the Korean Genome and Epidemiology Study (KoGES) were analyzed. Six target SNPs (LPL: rs17482753; ABCA1: rs1883025; APOA5: rs651821; LIPC: rs1077835; CETP: rs17231506; and LIPG: rs9953437) were extracted from genome-wide SNP genotype data. Dietary intake was assessed using a food frequency questionnaire. SNP genotyping was conducted using the Korea Biobank Array (Korean Chip), a specialized genotyping platform designed for GWAS of blood biochemical traits in the Korean population. SNP–diet interactions on CVD risk were analyzed using generalized linear models (GLM). Results: Among the six SNPs, ABCA1: rs1883025 and APOA5: rs651821 showed significant gene–diet interactions. For rs1883025 (ABCA1), carriers of the T allele exhibited reduced HDL cholesterol levels. However, in the high-protein intake group, individuals with the T/T genotype had a significantly lower risk of ischemic stroke compared to those in the low-protein intake group (interaction p-value = 0.044). For rs651821 (APOA5), carriers of the T allele also had lower HDL cholesterol levels, but individuals with the C/C genotype (wild-type homozygotes) in the low-fat intake group showed a significantly reduced risk of coronary artery disease (interaction p-value = 0.0155). Conclusions: This study suggests potential interactions between polymorphisms associated with low HDL cholesterol and dietary patterns, particularly high-protein and low-fat diets, in relation to CVD risk. These findings highlight the importance of personalized dietary recommendations based on genetic profiles to reduce CVD risk. They provide a basis for future research aimed at developing precision nutrition guidelines and targeted interventions to manage hypo-HDL cholesterolemia and nutrition-related CVD risks. Full article

In the process of China’s path to modernization, the concept of harmonious coexistence between man and nature has become increasingly prominent. In the dual context of the development of human society and the improvement of ecological wellbeing, how to reasonably exert environmental regulation policies to actively address the problem of ecological overload has become an important challenge that we need to face urgently. Therefore, based on the panel data of 30 provinces in China from 2005 to 2021, this paper uses the three-dimensional ecological footprint model to evaluate the degree of interference of human activities on the ecological level and selects the difference-in-differences model to examine the impact of external policy shocks, namely, a carbon emissions trading pilot (CETP) policy, on ecological pressure and its transmission mechanism. The results show that moderate government intervention, unified market regulation, and positive industrial response jointly enhance the mitigation effect of CETP on ecological pressure. In areas with strong environmental regulation and a high level of green credit, the incentive effect of the carbon trading mechanism is more significant. In the context of the transformation from industrial civilization to ecological civilization, the findings provide practical guidance and paths for how regions and enterprises can effectively respond to CETP and how governments, markets, and industries can jointly reduce the ecological pressure on the environment. Full article

Background/Objectives: Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The objective of this study was to investigate butyrate-induced thermogenesis in white adipose tissue and its underlying mechanism. Methods: We studied the effects of butyrate on diet-induced obesity in the humanized APOE*3-Leiden.CETP transgenic mouse model and explored factors related to white adipose browning. Specifically, mice were challenged with a high-fat diet supplemented with butyrate. Adiposity was measured to assess obesity development. Energy metabolism was detected using an indirect calorimetry system. RNA-seq analysis was conducted to analyze the transcription landscape of WAT and responsible targets. Furthermore, the revealed molecular mechanism was verified in vitro. Results: Butyrate alleviated high-fat diet-induced obesity and promoted energy expenditure accompanied by brown adipose tissue activation and WAT browning. Mechanistically, RNA-seq analysis revealed that butyrate downregulated HDAC9 in WAT. Additionally, butyrate decreased HDAC9 while increasing thermogenesis in vitro. Inhibition of HDAC9 with TMP269 promoted thermogenic gene expression, mimicking the effects of butyrate. Conclusions: Butyrate protects against diet-induced obesity accompanied by decreasing the expression of HDAC9 in white adipose tissue and inducing browning. This study reveals a new mechanism whereby butyrate activates adaptive thermogenesis and provides new insights for the development of weight-loss drugs targeting adipose HDAC9. Full article

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation. Full article

China faces issues such as air pollution and global climate change, and the Carbon Emission Trading Policy (CETP) has attracted considerable attention as a core policy tool for achieving the “dual carbon” goals. Based on panel data from the Pearl River–West River Economic Belt (PRWREB) from 2008 to 2021, we use the Synthetic Control Method (SCM) and Spatial Difference-in-Differences (S-DID) models to explore the pollution reduction and carbon reduction effects of the CETP and its spatial heterogeneity. Our analysis reveals several interesting insights. First, the CETP has promoted a 34.1% overall reduction in pollution and carbon levels in the pilot areas, with sustained effects. Moreover, spatial spillover effects can reduce the pollution and carbon levels in the economic belt by 29.9%. Second, the pollution and carbon reduction effects of the CETP are more significant in regions with better economic development and active carbon trading. It has the best synergistic reduction effects on CO₂ and SO₂ but is less effective in reducing PM_2.5. Third, the spillover effects of the CETP on technological innovation are greater than the direct effects, with the most noticeable pollution and carbon reduction outcomes. The overall negative effect on industrial structure is that it fails to promote pollution and carbon reduction. The emission reduction mechanisms vary for different targets: CO₂ and PM_2.5 are related to energy efficiency, SO₂ to advancing industrial structure, and smoke and dust to technological innovation. Based on the research conclusions, we propose to improve the coordinated governance system for carbon and pollution, advance pollution and carbon reduction according to local conditions, and implement targeted emission reduction and efficiency enhancement. Full article

Single nucleotide polymorphisms (SNPs) have been associated with the development of cardiovascular diseases (CVDs). This study correlated eight SNPs with the risk factors of CVD in a black elderly population. Genotyping was used to detect eight polymorphisms; rs675 (ApoA-IV), rs699 (Angiotensinogen (AGT)), rs247616 and rs1968905 (Cholesteryl ester transfer protein (CETP)), rs1801278 (Insulin receptor substrate 1 (IRS-1)), rs1805087 (Methylenetetrahydrofolate reductase (MTHFR)) and rs28362286 and rs67608943 (Proprotein convertase subtilisin/kexin type 9 (PCSK9)), as well as their genotypes in deoxyribonucleic acid (DNA) extracted from peripheral blood. The cardiovascular risk (CVR) measurements were conducted on a Konelab 20i Thermo Scientific autoanalyzer and an enzyme-linked immunoassay (ELISA) assay. International Business Machines Corporation (IBM)^® Statistical Package for the Social Sciences ^® (SPSS) version 28 was used for statistical analysis. The heterozygous and homozygous genotypes of the eight polymorphisms were detected with the corresponding CVD risk factors. Subgroup analysis indicated that certain genotype carriers exhibited variations in their concentrations of CVR factors compared to others; however, these differences did not reach statistical significance. For example, carriers of the G genotype of the rs699 polymorphism showed marginally different blood pressure readings compared to the AG genotype carriers. The multiple linear regression analysis indicated that the only significant association was between PCSK9 and the rs28362286 (p = 0.029) polymorphism. The findings of our study show that single nucleotide polymorphisms are disseminated across the human genome. The heterozygous and homozygous genotypes of the SNPs require further investigation as they may have independent and possible collective roles in increasing the risk of CVDs. Full article

Dietary fats influence gene expression and several metabolic pathways. Therefore, it is crucial to study the role of personal genotypes in the interaction between fat consumption and cardiometabolic markers. This research aimed to determine the interaction of the rs708272 polymorphism of CETP and the fatty acid intake with changes in the HOMA-IR in adults living with overweight or obesity. The current study was a secondary analysis of an 8-week controlled clinical trial. The final sample for this analysis comprised 78 Mexican adults with the Cholesteryl Ester Transfer Protein (CETP) rs708272 polymorphism who followed a dietary intervention. Using an interaction analysis, we evaluated the fatty acid intake and the genotypes of rs708272, with changes in blood glucose, insulin, and the HOMA-IR from baseline to endpoint. Our findings suggest a significant interaction between the trans fatty acid intake and the GG genotype with changes in glucose (p = 0.024), insulin (p = 0.004), and the HOMA-IR (p = 0.002). The higher the consumption of trans fatty acids, the less these markers of glucose metabolism were reduced. carriers of the GG genotype may benefit from limiting dietary trans fatty acid intake, as there was no reduction in plasma glucose and insulin despite a hypocaloric dietary intervention in adults with overweight and obesity. Full article