Asialoglycoprotein receptor 1 (ASGR1) is associated with lipid metabolism and coronary artery disease (CAD) risk, but its expression patterns, diagnostic performance, and prognostic significance in hypertensive patients with CAD remain unelucidated. This single-center study enrolled 345 hypertensive patients between 2022 and 2025 (59 with hypertension alone, 286 with hypertension and CAD). Plasma ASGR1 levels were measured by enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curves, Spearman correlation, and Cox proportional hazards modeling were performed to assess the diagnostic efficacy of ASGR1 in CAD and its prognostic value for all-cause rehospitalization. Plasma ASGR1 levels were significantly higher in hypertensive patients with CAD than in those with hypertension alone (p < 0.001) and higher ASGR1 expression is accompanied by more severe coronary lesions and adverse clinical phenotypes. Inflammatory markers, liver injury biomarkers and cardiac injury biomarkers were positively correlated with ASGR1, whereas high-density lipoprotein cholesterol (HDL-C) was negatively correlated. ASGR1 showed excellent diagnostic ability for CAD in hypertensive patients with area under the curve of 0.937 (95% CI: 0.906-0.960). Multivariate analysis showed that each 1-unit increase in ASGR1 was associated with a 37% higher risk of CAD (odds ratio 1.37, 95% CI: 1.24-1.52, p < 0.001). Longitudinally, elevated baseline ASGR1 was independently associated with an increased risk of all-cause rehospitalization (adjusted hazard ratio 1.97, 95% CI: 1.16-3.35, p = 0.012). These findings support ASGR1 may serve as a diagnostic biomarker and prognostic indicator for hypertensive patients with CAD.

Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG’s Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.

Mutations in the Paraoxonase 1 (Pon1) gene underlie aging, cardiovascular disease, and impairments of the nervous and gastrointestinal systems and are linked to the intestinal microbiome. The potential role of Pon1 in modulating the intestinal microbiota and serum metabolites is poorly understood. The present study demonstrated that mice with genomic excision of Pon1 by a multiplexed guide RNA CRISPR/Cas9 approach exhibited disrupted gut microbiota, such as significantly depressed alpha-diversity and distinctly separated beta diversity, accompanied by varied profiles of circulating metabolites. Furthermore, genomic knock in of Pon1 exerted a distinct effect on the intestinal microbiome and serum metabolome, including dramatically enriched Aerococcus, linoleic acid and depleted Bacillus, indolelactic acid. Specifically, a strong correlation was established between bacterial alterations and metabolites in Pon1 knockout mice. In addition, we identified metabolites related to gut bacteria in response to Pon1 knock in. Thus, the deletion of Pon1 affects the gut microbiome and functionally modifies serum metabolism, which can lead to dysbiosis, metabolic dysfunction, and infection risk. Together, these findings put forth a role for Pon1 in microbial alterations that contribute to metabolism variations. The function of Pon1 in diseases might at least partially depend on the microbiome. Mutations in Pon1 gene underlie aging, CVD, and impairments of gastrointestinal systems, which are linked to gut microbiome. As the potential role of Pon1 in modulating intestinal microbiota and serum metabolites is poorly understood, Pon1 KO and OE mice were examined in present study. We found that the host's Pon1 affects the resident species, especially by altering the diversity and taxonomic composition of intestinal flora, which potentially contributes to development of diseases ascribed to the variations in Pon1 gene.image

Background Type 1 diabetes is believed to be an autoimmune condition, characterized by destruction of insulin-producing cells, due to the detrimental inflammation in pancreas. Growing evidences have indicated the important role of type I interferon in the development of type 1 diabetes. Methods Trex1 -deficient rats were generated by using CRISPR-Cas9. The fasting blood glucose level of rat was measured by a Roche Accuchek blood glucose monitor. The levels of insulin, islet autoantibodies, and interferon-β were measured using enzyme-linked immunosorbent assay. The inflammatory genes were detected by quantitative PCR and RNA-seq. Hematein-eosin staining was used to detect the pathological changes in pancreas, eye and kidney. The pathological features of kidney were also detected by Masson trichrome and periodic acid-Schiff staining. The distribution of islet cells, immune cells or ssDNA in pancreas was analyzed by immunofluorescent staining. Results In this study, we established a Trex1 -deletion Sprague Dawley rat model, and unexpectedly, we found that the Trex1 −/− rats spontaneously develop type 1 diabetes. Similar to human diabetes, the hyperglycemia in rats is accompanied by diabetic complications such as diabetic nephropathy and cataract. Mechanistical investigation revealed the accumulation of ssDNA and the excessive production of proinflammatory cytokines, including IFN-β, in Trex1 null pancreas. These are likely contributing to the inflammation in pancreas and eventually leading to the decline of pancreatic β cells. Conclusions Our study links the DNA-induced chronic inflammation to the pathogenesis of type 1 diabetes, and also provides an animal model for type 1 diabetes studies.

In the November 2023 issue of eBioMedicine, Maaike van Gerwen et al. presented their work "Per- and Polyfluoroalkyl substances (PFAS) Exposure and Thyroid Cancer Risk", which reports an association between PFAS exposure and thyroid cancer using both a cross-sectional and longitudinal study design.1Van Gerwen M. Colicino E. Guan H. et al.Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer risk.eBioMedicine. 2023; https://doi:10.1016/j.ebiom.2023.104831Summary Full Text Full Text PDF PubMed Google Scholar The study found a 56% increased rate of thyroid cancer diagnosis per doubling of linear perfluorooctanesulfonic acid (n-PFOS) in plasma; importantly, a similar result was also observed when including papillary thyroid cancer cases only. Moreover, this positive association remained in subset analysis investigating exposure timing on thyroid cancer. Thyroid cancer is the most common endocrine malignancy with incidence steadily increasing over past decades. Besides commonly known factors such as overdiagnosis, obesity, and ionizing radiation exposure, unavoidable environmental risks such as the exposure of persistent organic pollutants (POPs) affect thyroid hormonal homeostasis.2Liu M. Zhang G. Meng L. et al.Associations between novel and legacy per- and polyfluoroalkyl substances in human serum and thyroid cancer: a case and healthy population in shandong province, East China.Environ Sci Technol. 2022; 56: 6144-6151https://doi:10.1021/acs.est.1c02850Crossref PubMed Scopus (27) Google Scholar PFAS are a large class of man-made chemicals widely used in consumer products and industrial processes. As well-known "forever chemicals", PFAS are very persistent due to the stable carbon to fluorine chemical bond, and their adverse health effects, including thyroid hormone disruption, have been frequently investigated.3Braun J.M. Enhancing regulations to reduce exposure to PFAS–federal action on "forever chemicals".N Engl J Med. 2023; 388: 1924-1926https://doi:10.1056/NEJMp2303333Crossref PubMed Scopus (3) Google Scholar However, we still don't know whether PFAS are thyroid carcinogens. Obviously, van Gerwen's results provide strong epidemiological evidence to support the hypothesis that PFAS exposure might be a risk factor for thyroid cancer, especially for papillary thyroid cancer, which accounts for 80%–85% of all thyroid cancer cases. Concerns about the adverse effects of PFAS on human health initiated in the late 1990s after the Parkersburg (West Virginia, USA) PFOA water contamination incident. From then on, PFAS have been frequently and widely detected in human biomonitoring, confirming the fact that people are universally exposed to PFAS. Recently, a growing number of laboratory and epidemiological studies have demonstrated that PFAS may disturb the hypothalamus-pituitary-thyroid (HPT) axis, interfere with thyroid function and contribute to the risk of thyroid cancer. A high-throughput screening found that many types of PFAS can inhibit iodine uptake by suppressing sodium iodide symporter (NIS) that regulates iodide uptake into the thyroid gland.4Stoker T.E. Wang J. Murr A.S. Bailey J.R. Buckalew A.R. High-throughput screening of ToxCast PFAS chemical library for potential inhibitors of the human sodium iodide symporter.Chem Res Toxicol. 2023; 36: 380-389https://doi:10.1021/acs.chemrestox.2c00339Crossref PubMed Scopus (1) Google Scholar Animal and cell line studies found that PFAS could disrupt thyroid hormones, alter thyroid related gene expression, and change the transcriptome of central tissues of the HPT-axis.5Davidsen N. Ramhøj L. Lykkebo C.A. et al.PFOS-induced thyroid hormone system disrupted rats display organ-specific changes in their transcriptomes.Environ Pollut. 2022; 305119340https://doi:10.1016/j.envpol.2022.119340Crossref PubMed Scopus (13) Google Scholar,6Zhang S. Chen K. Li W. et al.Varied thyroid disrupting effects of perfluorooctanoic acid (PFOA) and its novel alternatives hexafluoropropylene-oxide-dimer-acid (GenX) and ammonium 4,8-dioxa-3H-perfluorononanoate (ADONA) in vitro.Environ Int. 2021; 156106745https://doi:10.1016/j.envint.2021.106745Crossref Scopus (24) Google Scholar Meanwhile, epidemiological studies also demonstrated that PFAS exposure can disrupt thyroid function.7Liu J. Song L. Zhan J. Zhong Y. Shi Z. Occurrence of legacy and alternative per- and polyfluoroalkyl substances in serum from high exposure population and their disrupting effects on serum lipids and thyroid function.Sci Total Environ. 2023; 878162988https://doi:10.1016/j.scitotenv.2023.162988Crossref Scopus (3) Google Scholar Chemicals that interfere with thyroid hormone homeostasis may increase the risk and severity of thyroid cancer, and therefore whether PFAS are thyroid carcinogens is a matter of great concern. Studies on the association between PFAS exposure and risk of thyroid cancer are still limited at present. In an ecological study, residents living in a community with heavy PFAS contamination in drinking water experienced a significantly higher risk of thyroid cancer.8Messmer M.F. Salloway J. Shara N. Locwin B. Harvey M.W. Traviss N. Risk of cancer in a community exposed to per- and poly-fluoroalkyl substances.Environ Health Insights. 2022; 1611786302221076707https://doi:10.1177/11786302221076707Google Scholar A previous study from van Gerwen and colleagues reported significant correlation between certain PFAS in community water systems and thyroid cancer incidence.9Alsen M. Leung A.M. van Gerwen M. Per- and polyfluoroalkyl substances (PFAS) in community water systems (CWS) and the risk of thyroid cancer: an ecological study.Toxics. 2023; 11https://doi:10.3390/toxics11090786Crossref PubMed Scopus (1) Google Scholar These studies supported the hypothesis that higher PFAS exposure might link to thyroid cancer. However, inconsistent results were also observed. Two case–control studies from China reported negative associations between PFAS exposure and thyroid cancer risk.2Liu M. Zhang G. Meng L. et al.Associations between novel and legacy per- and polyfluoroalkyl substances in human serum and thyroid cancer: a case and healthy population in shandong province, East China.Environ Sci Technol. 2022; 56: 6144-6151https://doi:10.1021/acs.est.1c02850Crossref PubMed Scopus (27) Google Scholar,10Li H. Yang M. Yang J. et al.Per- and polyfluoroalkyl substances and the associated thyroid cancer risk: a case-control study in China.Chemosphere. 2023; 337139411https://doi:10.1016/j.chemosphere.2023.139411Crossref Scopus (2) Google Scholar Contradictory results may be related to dissimilar study designs, population heterogeneity, sample sizes, and statistical methods. Thus, further research is needed to collect more evidence. van Gerwen's result suggests that the elimination of certain PFAS with high health risks should be accelerated. Some regulatory rules on PFAS have been introduced. A number of legacy PFAS have been added to the list of persistent organic pollutants under the Stockholm Convention. PFOA, PFOS, their salts and related compounds were added to "the List of Strictly Controlled Emerging Pollutants" set by the Chinese government. In February 2023, the European Chemicals Agency (ECHA) proposed that the manufacture and use of all PFAS must be banned immediately. Moreover, World Health Organization (WHO), the USA and EU have all set strict standards for PFAS in drinking water. Due to the implemention of these regulations in the past decade, decreasing contamination of PFAS can be observed. However, current rules only focus on legacy PFAS. Novel PFAS such as F-53B and GenX, which act as substitutes of legacy PFAS, haven't been evaluated and included in regulation due to the lack of data. Thus, more research is needed to fully reveal the health risks of PFAS, particularly on novel substitutes. Even though some PFAS have been proved to be harmful to the environment and human health, a blanket ban on all PFAS immediately may not be the most effective and sustainable strategy. PFAS are composed of a large group of chemicals with dissimilar molecular structures and properties. Current epidemiological studies, like van Gerwen's work, normally include a few PFAS simultaneously, and the results showed that most PFAS had no significant association with health effects. That is, it is too early to conclude that every PFAS will pose significant risks, and therefore it is unreasonable to ban all PFAS in a rush. Besides, alternative materials may not be safer. More time and effort are needed to gather epidemiological and toxicological studies on PFAS, and policymakers should carefully weigh up the evidence when considering PFAS regulation. Literature search and writing, Li Jing. Writing-Review and Editing, Zhixiong Shi. All authors have read and agreed to the published version of the manuscript. The authors have no conflict of interest to declare. Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer riskThis study reports associations between exposure to PFAS and increased rate of (papillary) thyroid cancer. Thyroid cancer risk from PFAS exposure is a global concern given the prevalence of PFAS exposure. Individual PFAS studied here are a small proportion of the total number of PFAS supporting additional large-scale prospective studies investigating thyroid cancer risk associated with exposure to PFAS chemicals. Full-Text PDF Open Access

Phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1) is regarded as a tumor suppressor and plays an important role in cancer cell biology, while relatively few studies have examined Pink1 in breast cancer, especially in vivo. The aims of this study were to investigate Pink1 expression in different subtypes of breast cancer tissues and cell lines and explore the effect of Pink1 protein on breast cancer. In these experiments, Pink1 expression was investigated using the tissue microarray immunohistochemistry (TMA-IHC) method in 150 samples of breast cancer tissues with different subtypes, and strong staining of Pink1 was significantly correlated with the histological grade of breast cancer (p = 0.015). In addition, Pink1 messenger RNA (mRNA) displayed much higher expression levels in breast cancer cell lines than in MCF-10A breast epithelial cells. Moreover, proteomic data obtained by isobaric tags for relative and absolute quantification (iTRAQ) showed that Pink1 deletion induced a distinct proteomic profile in MDA-MB-231 cells, and enrichment analysis showed that the differential proteins were concentrated mainly in energy metabolism-related pathways. Moreover, Seahorse XF analysis showed that Pink1 knockout reduced the glycolytic ability of MDA-MB-231 cells. Our findings indicated that Pink1 may be an indicator of malignancy in breast cancer and that it presents oncogenic properties in breast cancer, which raises another perspective for understanding the regulatory role of Pink1 in breast cancer.

Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.

Endosulfan, an organochlorine pesticide, was found in human blood, and its possible cardiovascular toxicity has been suggested. However, the mechanism about endothelial cell injuries induced by endosulfan has remained unknown. In the present study, human umbilical vein endothelial cells (HUVECs) were chosen to explore the toxicity mechanism and were treated with 0, 1, 6, and 12 μg/mL−1 endosulfan for 24 h, respectively. The results showed that exposure to endosulfan could inhibit the cell viability, increase the release of lactate dehydrogenase (LDH), damage the ultrastructure, and lead to apoptosis and necroptosis in HUVECs. Furthermore, endosulfan upregulated the expressions of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like (MLKL), caspase 8, and caspase 3, which means the activation of RIPK1 pathways. In addition, endosulfan promoted the increases of ROS, IL-1α, and IL-33 levels while antioxidant N-acetyl-l-cysteine (NAC) effectively attenuated the cytotoxicity from endosulfan. Taken together, these results have demonstrated that endosulfan induces the apoptosis and necroptosis of HUVECs, where the RIPK pathway plays a pro-necroptotic role and NAC plays an anti-necroptotic role. Our results may contribute to understanding cellular mechanisms for endosulfan-induced cardiovascular toxicity.