TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.

When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

Photonic integrated coherent beam combiner based on MMI and the SPGD algorithm.

Atmospheric turbulence severely degrades the optical wavefront of a propagating beam, which greatly reduces the coupling efficiency of free-space optical (FSO) receivers. Among the various methods to mitigate the effects, the use of a multi-channel receiver is more convenient and economical. After passing through the multi-channel receiver, multiple single-mode fibers (SMFs) are output and need to be combined. In this paper, we propose photonic integrated coherent beam combiners based on multimode interference (MMI) and the stochastic parallel gradient descent (SPGD) algorithm, which avoids detecting the light out of each channel and adding the data signal in the electrical domain. First, we propose a 4-channel coherent beam combiner based on a 4×1 MM, and about 21 iterations of the SPGD algorithm are required to enhance the combined optical power to a maximum of 96%. Furthermore, we demonstrate a combination of 16 beams using five 4×1 MMIs, which requires 140 iterations to enhance the combined power to 89%. This study offers theoretical insights to enhance the integration of FSO communication systems.

Fatal arrhythmia associated with novel coronavirus 2019 infection: Case report and literature review.

RATIONALE: The novel coronavirus of 2019 (COVID-19) has inflicted significant harm on the cardiovascular system. Patients presenting with fatal chronic arrhythmias after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are rare, arrhythmia caused by SARS-CoV-2 infection need to be taken seriously. PATIENT CONCERNS: Three female patients were admitted to the hospital with syncopal symptoms. Previously, they had been identified to have COVID-19 infection and none of the patients had a preexisting history of arrhythmia, and upon hospital admission, no electrolyte imbalances associated with arrhythmias were observed. However, following SARS-CoV-2 infection, patients exhibit varying degrees of syncope symptoms. DIAGNOSES: A high-degree atrioventricular block was diagnosed after a comprehensive evaluation of the patient's clinical manifestations and electrocardiogram (ECG) performance. INTERVENTIONS: We performed ECG monitoring of the patient and excluded other causes of arrhythmia. The patient was discharged from the hospital after permanent pacemaker implantation and symptomatic treatment. OUTCOMES: The outpatient follow-ups did not reveal a recurrence of syncope or complications related to the pacemaker in any of the three patients. LESSONS: Some patients did not exhibit any obvious respiratory symptoms or signs following SARS-CoV-2 infection. This suggests that the cardiac conduction system may be the preferred target for some SARS-CoV-2 variants. Therefore, in addition to investigating the causes of malignant arrhythmias, special attention should be paid to SARS-CoV-2 infection in patients with developing arrhythmias. Additionally, permanent pacemaker implantation may be the most suitable option for patients who already have malignant arrhythmias.

Exploring the anti-atherosclerosis mechanism of ginsenoside Rb1 by integrating network pharmacology and experimental verification.

Ginsenoside Rb1 is the major active constituent of ginseng, which is widely used in traditional Chinese medicine for the atherosclerosis treatment by anti-inflammatory, anti-oxidant and reducing lipid accumulation. We explored cellular target and molecular mechanisms of ginsenoside Rb1 based on network pharmacology and in vitro experimental validation. In this study, we predicted 17 potential therapeutic targets for ginsenoside Rb1 with atherosclerosis from public databases. We then used protein-protein interaction network to screen the hub targets. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment showed that the effects of ginsenoside Rb1 were meditated through multiple targets and pathways. Next, molecular docking results revealed that in the 10 core targets, CCND1 has the highest binding energy with ginsenoside Rb1. Vascular cell proliferation plays a critical role in atherosclerosis development. However, the effect and direct target of ginsenoside Rb1 in regulating vascular cell proliferation in atherosclerosis remains unclear. Edu straining results indicated that ginsenoside Rb1 inhibited the cell proliferation of endothelial cells, macrophages, and vascular smooth muscle cells. The protein immunoprecipitation (IP) analysis showed that ginsenoside Rb1 inhibited the vascular cell proliferation by suppressing the interaction of CCDN1 and CDK4. These findings systematically reveal that the anti-atherosclerosis mechanism of ginsenoside Rb1 by integrating network pharmacology and experimental validation, which provide evidence to treat atherosclerosis by using ginsenoside Rb1 and targeting CCND1.

Associations of the triglyceride-glucose index and atherogenic index of plasma with the severity of new-onset coronary artery disease in different glucose metabolic states.

BACKGROUND: The triglyceride-glucose (TyG) index is considered a dependable biomarker for gauging insulin resistance. The atherogenic index of plasma (AIP) represents a marker reflecting atherosclerosis. However, there is currently no study specifically exploring the associations of these two biomarkers with the severity of new-onset coronary artery disease (CAD) under different glucose metabolic states. Therefore, this study aims to evaluate the correlations of these two biomarkers with CAD severity in patients newly diagnosed with CAD under various glucose metabolism conditions. METHOD: Totally 570 subjects first administered coronary angiography were enrolled, including 431 first diagnosed CAD patients and 139 non-CAD patients. CAD severity  was gauged by the quantity of narrowed arteries (single-vessel and multi-vessel CAD). According to WHO diabetes guidelines, glucose metabolic states were divided into normal glucose regulation (NGR), pre-diabetes mellitus (Pre-DM), and diabetes mellitus (DM). The relationships of the TyG index and AIP with CAD severity were validated by logistic regression analysis, including adjustment for traditional cardiovascular risk elements and medical treatments. Their predictive efficacy for CAD was evaluated by receiver operating characteristic (ROC) curves. RESULT: The TyG index and AIP were independently correlated with CAD in accordance with logistic regression analysis (both P < 0.05). Regardless of the glucose metabolic states, there was no statistical correlation between the TyG index and CAD severity. However, AIP in NGR patients was significantly related to CAD severity (P < 0.05). The areas under the curve of the TyG index and AIP for predicting CAD were 0.682 and 0.642 (both P < 0.001), respectively, and their optimal cut-off values were 3.210 (Youden index: 0.305) and 0.095 (Youden index:0.246), respectively. CONCLUSION: The TyG index and AIP have significant associations with CAD. The TyG index had no association with CAD severity, regardless of glucose metabolic states. AIP exhibited a discernible link with CAD severity in NGR patients, but not in the pre-DM or DM populations. The TyG index and AIP have similar predictive values for new-onset CAD.

Antagonism of let-7c reduces atherosclerosis and macrophage lipid accumulation by promoting PGC-1α/LXRα/ABCA1/G1 pathway.

Changes in circulating let-7c were significantly associated with the alter in lipid profile, but its role in intracellular lipid metabolism remains unknown. This work was conducted to explore the effects of let-7c on the lipid accumulation in macrophages and uncover the underlying mechanism. Our results showed that let-7c inhibition relieved atherosclerosis progression in apoE-/- mice. In ox-LDL-treatment macrophages, let-7c knockdown suppressed lipid accumulation but does no affect cholesterol intake. Consistent with this, overexpression of let-7c promoted lipid accumulation by reducing the expression of LXRα and ABCA1/G1. Mechanistically, let-7c targeted PGC-1α to repress the expression of LXRα and ABCA1/G1, thereby regulating cholesterol homeostasis in macrophages. Taken together, these findings suggest that antagonism of let-7c reduces atherosclerosis and macrophage lipid accumulation through the PGC-1α/LXRα/ABCA1/G1 axis.

Associations of the triglyceride-glucose index and remnant cholesterol with coronary artery disease: a retrospective study.

BACKGROUND: Remnant cholesterol (RC) represents a low-cost and readily measured lipid index that contributes significantly to residual cardiovascular disease risk. The triglyceride-glucose (TyG) index exhibits a significant correlation with cardiovascular disease occurrence. However, RC and the TyG index have rarely been examined for their potentials in predicting coronary artery disease (CAD). Accordingly, the study was designed to validate the correlations of these two biomarkers with CAD and to compare the forecasted values of these two biomarkers for newly diagnosed CAD. METHODS: Totally 570 subjects firstly administered coronary angiography were enrolled, including 431 newly diagnosed CAD cases and 139 individuals without CAD. The individuals were classified into two groups according to CAD diagnosis. RC was derived as total cholesterol content (mmol/L) - (high density lipoprotein cholesterol content + low density lipoprotein cholesterol content; both in mmol/L). The TyG index was determined as ln (fasting triglyceride level [mg/dL] × fasting plasma glucose level [mg/dL])/2. RESULTS: Baseline feature analysis revealed significant differences in RC and the TyG index between the CAD and non-CAD groups (both P < 0.001). RC and the TyG index were independent risk factors for CAD in accordance with logistic regression analysis (both P < 0.05). Moreover, spearman correlation analysis elucidated CAD had a more remarkable correlation with the TyG index compared with RC (both P < 0.001). Furthermore, according to receiver operating characteristic curve analysis, the TyG index was better than RC in predicting CAD. CONCLUSIONS: The TyG index and RC have significant associations with CAD. Compared with RC, the TyG index possesses a closer correlation with CAD and a higher predictive value for CAD.

Function and mechanism of lysine crotonylation in health and disease.

Lysine crotonylation is a newly identified posttranslational modification that is different from the widely studied lysine acetylation in structure and function. In the last dozen years, great progress has been made in lysine crotonylation-related studies, and lysine crotonylation is involved in reproduction, development, and disease. In this review, we highlight the similarities and differences between lysine crotonylation and lysine acetylation. We also summarize the methods and tools for the detection and prediction of lysine crotonylation. At the same time, we outline the recent advances in understanding the mechanisms of enzymatic and metabolic regulation of lysine crotonylation, as well as the regulating factors that selectively recognize this modification. Particularly, we discussed how dynamic changes in crotonylation status maintain physiological health and result in the development of disease. This review not only points out the new functions of lysine crotonylation but also provides new insights and exciting opportunities for managing various diseases.

Emerging applications of single-cell profiling in precision medicine of atherosclerosis.

Atherosclerosis is a chronic, progressive, inflammatory disease that occurs in the arterial wall. Despite recent advancements in treatment aimed at improving efficacy and prolonging survival, atherosclerosis remains largely incurable. In this review, we discuss emerging single-cell sequencing techniques and their novel insights into atherosclerosis. We provide examples of single-cell profiling studies that reveal phenotypic characteristics of atherosclerosis plaques, blood, liver, and the intestinal tract. Additionally, we highlight the potential clinical applications of single-cell analysis and propose that combining this approach with other techniques can facilitate early diagnosis and treatment, leading to more accurate medical interventions.

Eupatilin attenuates doxorubicin-induced cardiotoxicity by activating the PI3K-AKT signaling pathway in mice.

Eupatilin is a pharmacologically active flavonoid with a variety of biological activities, such as anticancer, anti-inflammatory, antioxidant, neuroprotective, anti-allergic and cardioprotective effects. However, whether eupatilin has protective effects on doxorubicin-induced cardiotoxicity remains unknown. Thus, this study aimed to investigate the role of eupatilin in doxorubicin-induced cardiotoxicity. Mice were exposed to a single dose of doxorubicin (15 mg/kg) to generate doxorubicin-induced cardiotoxicity or normal saline as a control. To explore the protective effects, mice were intraperitoneally injected with eupatilin daily for 7 days. Then, we examined the changes in cardiac function, inflammation, apoptosis, and oxidative stress to evaluate the effects of eupatilin on doxorubicin-induced cardiotoxicity. Additionally, RNA-seq analysis was introduced to explore the potential molecular mechanisms. Eupatilin ameliorated doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and cardiomyocyte apoptosis and ameliorated doxorubicin-induced cardiac dysfunction. Mechanistically, eupatilin activated the PI3K-AKT signaling pathway, as evidenced by RNA-seq analysis and Western blot analysis. This study provides the first evidence that eupatilin ameliorates doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and apoptosis. Pharmacotherapy with eupatilin provides a novel therapeutic regimen for doxorubicin-induced cardiotoxicity.

Oligomer-Aß42 suppress glioma progression via potentiating phagocytosis of microglia.

AIMS: Glioma is characterized by an immunosuppressed environment and a poor prognosis. The accumulation of Amyloid ß (Aß) leads to an active environment during the early stages of Alzheimer's disease (AD). Aß is also present in glioma tissues; however, the biological and translational implications of Aß in glioma are elusive. METHODS: Immunohistochemical (IHC) staining, Kaplan-Meier (KM) survival analysis and Cox regression analysis on a cohort of 79 patients from our institution were performed to investigate the association between Aß and the malignancy of glioma. Subsequently, the potential of oligomer-Aß42 (OAß42) to inhibit glioma growth was investigated in vivo and in vitro. Immunofluorescence staining and phagocytosis assays were performed to evaluate the activation of microglia. Finally, RNA-seq was utilized to identify the predominant signaling involved in this process and in vitro studies were performed to validate them. RESULTS: A positive correlation between Aß and a favorable prognosis was observed in glioma. Furthermore, OAß42 suppressed glioma growth by enhancing the phagocytic activity of microglia. Insulin-like growth factor 1 (IGF-1) secreted by OAß42-activated microglia was essential in the engulfment process. CONCLUSION: Our study proved an anti-glioma effect of Aß, and microglia could serve as a cellular target for treating glioma with OAß42.

Enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction in patient-specific induced pluripotent stem cell-derived cardiomyocytes with MYH7 mutation.

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is frequently caused by mutations in the ß-cardiac myosin heavy chain gene (MYH7). Abnormal calcium handling and diastolic dysfunction are archetypical features of HCM caused by MYH7 gene mutations. However, the mechanism of how MYH7 mutations leads to these features remains unclear, which inhibits the development of effective therapies. Initially, cardiomyocytes were generated from induced pluripotent stem cells from an eight-year-old girl diagnosed with HCM carrying a MYH7(C.1063 G>A) heterozygous mutation(mutant-iPSC-CMs) and mutation-corrected isogenic iPSCs(control-iPSC-CMs) in the present study. Next, we compared phenotype of mutant-iPSC-CMs to that of control-iPSC-CMs, by assessing their morphology, hypertrophy-related genes expression, calcium handling, diastolic function and myofilament calcium sensitivity at days 15 and 40 respectively. Finally, to better understand increased myofilament Ca2+ sensitivity as a central mechanism of central pathogenicity in HCM, inhibition of calcium sensitivity with mavacamten can improveed cardiomyocyte hypertrophy. Mutant-iPSC-CMs exhibited enlarged areas, increased sarcomere disarray, enhanced expression of hypertrophy-related genes proteins, abnormal calcium handling, diastolic dysfunction and increased myofilament calcium sensitivity at day 40, but only significant increase in calcium sensitivity and mild diastolic dysfunction at day 15. Increased calcium sensitivity by levosimendan aggravates cardiomyocyte hypertrophy phenotypes such as expression of hypertrophy-related genes, abnormal calcium handling and diastolic dysfunction, while inhibition of calcium sensitivity significantly improves cardiomyocyte hypertrophy phenotypes in mutant-iPSC-CMs, suggesting increased myofilament calcium sensitivity is the primary mechanisms for MYH7 mutations pathogenesis. Our studies have uncovered a pathogenic mechanism of HCM caused by MYH7 gene mutations through which enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction. Correction of the myofilament calcium sensitivity was found to be an effective method for treating the development of HCM phenotype in vitro.

IGFBPL1 inhibits macrophage lipid accumulation by enhancing the activation of IGR1R/LXRα/ABCG1 pathway.

Lipid accumulation in macrophages plays an important role in atherosclerosis and is the major cause of atherosclerotic cardiovascular disease. Reducing lipid accumulation in macrophages is an effective therapeutic target for atherosclerosis. Insulin-like growth factor 1 (IGF-1) exerts the anti-atherosclerotic effects by inhibiting lipid accumulation in macrophages. Furthermore, almost all circulating IGF-1 combines with IGF binding proteins (IGFBPs) to activate or inhibit the IGF signaling. However, the mechanism of IGFBPs in macrophage lipid accumulation is still unknown. GEO database analysis showed that among IGFBPS family members, IGFBPL1 has the largest expression change in unstable plaque. We found that IGFBPL1 was decreased in lipid-laden THP-1 macrophages. Through oil red O staining, NBD-cholesterol efflux, liver X receptor α (LXRα) transcription factor and IGR-1 receptor blocking experiments, our results showed that IGFBPL1 inhibits lipid accumulation in THP-1 macrophages through promoting ABCG1-meditated cholesterol efflux, and IGFBPL1 regulates ABCG1 expression and macrophage lipid metabolism through IGF-1R/LXRα pathway. Our results provide a theoretical basis of IGFBPL1 in the alternative or adjunct treatment options for atherosclerosis by reducing lipid accumulation in macrophages.

IGF­1 inhibits palmitic acid­induced mitochondrial apoptosis in macrophages.

Insulin growth factor­1 (IGF­1) is an endocrine regulator that plays an important role in normal growth and development. IGF­1 mediated effects may result in protecting macrophages from immunometabolic response. However, it is unclear whether IGF­1 has a protective effect on fatty acid­induced macrophages damage. In the present study, THP­1 cells were differentiated into macrophages and stimulated with palmitic acid (PA) in the absence or presence of IGF­1. Macrophages apoptosis was measured by Cell Counting Kit­8 assay, flow cytometry, Hoechst 33342 staining and western blotting. The mitochondrial damage was evaluated using JC­1 staining and mitochondrial reactive oxygen species detection. The activation of mitophagy was assessed using immunofluorescence and western blotting. As a result, IGF­1 significantly restored the survival rate in macrophages, while the apoptosis was inhibited through mitochondrial pathway. In addition, IGF­1 protected the mitochondrial damage induced by PA. Furthermore, PA induced mitophagy via phosphatase and tensin homolog­induced putative kinase protein 1/Parkin, which was reversed by IGF­1. Taken together, the present study demonstrated the protective effect of IGF­1 on PA­induced mitochondrial apoptosis in macrophages, which might provide a potential therapeutic strategy for treatment of lipotoxicity.

Oridonin attenuates atherosclerosis by inhibiting foam macrophage formation and inflammation through FABP4/PPARγ signalling.

Both lipid accumulation and inflammatory response in lesion macrophages fuel the progression of atherosclerosis, leading to high mortality of cardiovascular disease. A therapeutic strategy concurrently targeting these two risk factors is promising, but still scarce. Oridonin, the bioactive medicinal compound, is known to protect against inflammatory response and lipid dysfunction. However, its effect on atherosclerosis and the underlying molecular mechanism remain elusive. Here, we showed that oridonin attenuated atherosclerosis in hyperlipidemic ApoE knockout mice. Meanwhile, we confirmed the protective effect of oridonin on the oxidized low-density lipoprotein (oxLDL)-induced foam macrophage formation, resulting from increased cholesterol efflux, as well as reduced inflammatory response. Mechanistically, the network pharmacology prediction and further experiments revealed that oridonin dramatically facilitated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), thereby regulating liver X receptor-alpha (LXRα)-induced ATP-binding cassette transporter A1 (ABCA1) expression and nuclear factor NF-kappa-B (NF-κB) translocation. Antagonist of PPARγ reversed the cholesterol accumulation and inflammatory response mediated by oridonin. Besides, RNA sequencing analysis revealed that fatty acid binding protein 4 (FABP4) was altered responding to lipid modulation effect of oridonin. Overexpression of FABP4 inhibited PPARγ activation and blunted the benefit effect of oridonin on foam macrophages. Taken together, oridonin might have potential to protect against atherosclerosis by modulating the formation and inflammatory response in foam macrophages through FABP4/PPARγ signalling.

Liquid Nanoparticles for Nanocatalytic Cancer Therapy.

Nanotechnology is revolutionizing cancer therapy, and catalyzes the emerging of ion-involved cancer-therapeutic modality, which unfortunately suffers from undesirable nanocarriers for efficient intracellular ion delivery. To radically extricate from this critical issue, the glutathione (GSH)-responsive organosilica network is employed to lock the liquid drops at the nanoscale via a general bottom-up strategy to achieve the systemic delivery of "ion drugs". In this work, a sulfate radical generation donor (Na2 S2 O8 ), as a paradigm "ion drug", is entrapped into this liquid nanoparticle for efficiently delivering to the tumor region. After further surface engineering with pH-responsive tannic acid-Fe2+ framework, these liquid nanoparticles achieve tumor-microenvironmental pH/GSH-dual responsive ion release (Fe2+ /Na+ /S2 O8 2- ) after reaching the tumor sites, where the Fe2+ further triggers S2 O8 2- to generate toxic •SO4 - and •OH, effectively executing cancer cell ferroptosis (Fe2+ , reactive oxygen species-ROS) and pyroptosis (Na+ , ROS). Such a tumor-responsive/specific liquid nanoplatform is highly instructive for further ion-mediated nanomedicine and disease treatment.

Identification of key genes in the pathogenesis of preeclampsia via bioinformatic analysis and experimental verification.

Background: Preeclampsia (PE) is the primary cause of perinatal maternal-fetal mortality and morbidity. The exact molecular mechanisms of PE pathogenesis are largely unknown. This study aims to identify the hub genes in PE and explore their potential molecular regulatory network. Methods: We downloaded the GSE148241, GSE190971, GSE74341, and GSE114691 datasets for the placenta and performed a differential expression analysis to identify hub genes. We performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), Gene Set Enrichment Analysis (GSEA), and Protein-Protein Interaction (PPI) Analysis to determine functional roles and regulatory networks of differentially expressed genes (DEGs). We then verified the DEGs at transcriptional and translational levels by analyzing the GSE44711 and GSE177049 datasets and our clinical samples, respectively. Results: We identified 60 DEGs in the discovery phase, consisting of 7 downregulated genes and 53 upregulated genes. We then identified seven hub genes using Cytoscape software. In the verification phase, 4 and 3 of the seven genes exhibited the same variation patterns at the transcriptional level in the GSE44711 and GSE177049 datasets, respectively. Validation of our clinical samples showed that CADM3 has the best discriminative performance for predicting PE. Conclusion: These findings may enhance the understanding of PE and provide new insight into identifying potential therapeutic targets for PE.

The mitophagy pathway and its implications in human diseases.

Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.

Mutation of aspartic acid 262 on estrogen receptor abrogates estradiol signaling pathway.

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and membrane-initiated non-genomic effects. The mutation of aspartic acid into alanine in vitro revealed the critical role of aspartic acid 258 (corresponding to mouse amino acid site 262) of ERα for non-nuclear function. Our previous in vitro study revealed that this mutation blocked estrogen's non-genomic effects on vascular endothelial H2S release. Here, we studied the in vivo role of the aspartic acid 262 of ERα in the reproductive system and in the vascular tissue. APPROACH AND RESULTS: We generated a mouse model harboring a point mutation of the murine counterpart of this aspartic acid into alanine (ERαD262A). Our results showed that the ERαD262A females are fertile with standard hormonal serum levels, but the uterine development and responded with estrogen and follicular development are disrupted. In line with our previous study, we found that the rapid dilation of the aorta was abrogated in ERαD262A mice. In contrast to the previously reported R264-ERα mice, the classical estrogen genomic effector SP1/NOS3/AP1 and the nongenomic effectors p-eNOs, p-AKT, and p-ERK were disturbed in the ERαD262A aorta. Besides, the serum H2S concentration was decreased in ERαD262A mice. Together, ERαD262A mice showed compromised both genomic and non-genomic actions in response to E2. CONCLUSIONS: These data showed that aspartic acid 262 of ERα are important for both genomic and non-genomic effects of E2. Our data provide a theoretical basis for further selecting an effective non-genomic mouse model and provide a new direction for developing estrogen non-genomic effect inhibitors.

Nicotine induces macrophage pyroptosis via LINC01272/miR-515/KLF6 axis.

Nicotine contributes to the causation of atherosclerosis, which the prominent cellular components are macrophages. Long non-coding RNAs (lncRNAs) play an important role in regulating cell functions such as cell proliferation, differentiation and programmed death. However, the function and mechanism of lncRNAs in nicotine-induced macrophage pyroptosis has not been reported. We screened the deferentially expressed lncRNAs of human carotid artery plaque (GSE97210) and verified them in nicotine-induced pyroptosis of macrophages. Results showed only LINC01272 was up-regulated in a dose-dependent manner in macrophages. The immunofluorescence staining result confirmed that interfering LINC01272 inhibited nicotine-induced macrophage pyroptosis. Through bioinformatics analysis, dual luciferase reporter gene assay and qPCR, we identified miR-515 was significantly negatively correlated with the expression of LINC01272, and KLF6 is the target gene of miR-515. Furthermore, our results demonstrated that LINC01272/miR-515/KLF6 axis meditated nicotine-induced macrophage pyroptosis. In addition, in human peripheral blood mononuclear cells of smoking populations, the expression of GSDMD-N, NLRP3, LINC01272 and KLF6 was significantly increased, while the level of miR-515 was reduced. This study confirmed that nicotine increases the expression of LINC01272 to competitively bind with miR-515 in macrophages, reducing the inhibitory effect of miR-515 on its target gene KLF6, which ultimately induces macrophage pyroptosis.