Macrophage-enriched Sectm1a promotes efficient efferocytosis to attenuate ischemia/reperfusion-induced cardiac injury.

Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.

Generalizable Black-Box Adversarial Attack With Meta Learning.

In the scenario of black-box adversarial attack, the target model's parameters are unknown, and the attacker aims to find a successful adversarial perturbation based on query feedback under a query budget. Due to the limited feedback information, existing query-based black-box attack methods often require many queries for attacking each benign example. To reduce query cost, we propose to utilize the feedback information across historical attacks, dubbed example-level adversarial transferability. Specifically, by treating the attack on each benign example as one task, we develop a meta-learning framework by training a meta generator to produce perturbations conditioned on benign examples. When attacking a new benign example, the meta generator can be quickly fine-tuned based on the feedback information of the new task as well as a few historical attacks to produce effective perturbations. Moreover, since the meta-train procedure consumes many queries to learn a generalizable generator, we utilize model-level adversarial transferability to train the meta generator on a white-box surrogate model, then transfer it to help the attack against the target model. The proposed framework with the two types of adversarial transferability can be naturally combined with any off-the-shelf query-based attack methods to boost their performance, which is verified by extensive experiments. The source code is available at https://github.com/SCLBD/MCG-Blackbox.

Kechuanning Gel Plaster Exerts Anti-inflammatory and Immunomodulatory Effects on Ovalbumin-induced Asthma Model Rats via ERK Pathway.

BACKGROUND: We aimed to evaluate the therapeutic effects of Kechuanning gel plaster on ovalbumin (OVA)-induced rat model of asthma. METHODS: Rats were injected with OVA to induce asthma, and Kechuanning gel plaster was administered after the OVA challenge. The immune cell counts in the bronchial alveolar lavage fluid (BALF) were calculated after Kechuanning gel plaster administration. The levels of immune factors in BALF and serum OVA-specific IgE levels were analyzed. Western blot analysis and immunohistochemistry were carried out to analyze the following proteins: C-FOS, C-JUN, RAS p21 protein activator 1 (RASA1), matrix metalloproteinase 9 (MMP9), RAF1, p-MEK1, tissue inhibitor of metalloproteinase-1 (TIMP1), and p-extracellular signal-regulated kinase 1 (ERK1). RESULTS: Administration of Kechuanning gel plaster led to decreased immune cell counts, inflammatory cytokines (interleukin (IL)-1ß, IL13, and IL17), and OVA-specific IgE expression. Compared to the normal group, the C-FOS, C-JUN, RASA1, MMP9, RAF1, MEK1, TIMP1, and p- ERK1 expressions in the model group were significantly increased, whereas Kechuanning gel plaster administration decreased C-JUN, MMP9, TIMP1, RAF1, MEK1, p-ERK1, C-FOS, and RASA1 protein levels. CONCLUSION: Kechuanning gel plaster exerted its therapeutic effects on OVA-induced asthma model rats through the ERK signaling pathway. Kechuanning gel plaster could be considered as a potential alternative therapeutic agent for the management of asthma.

The Jiangtang Tongmai Prescription Inhibits Inflammation and Fibrosis of Lung Fibroblast Autophagy Induced by Hyperglycemia by Regulating CAV1 Expression.

OBJECTIVE: The lung is one of the target organs of diabetes. This study aimed to probe the protective mechanism of Jiangtang Tongmai Prescription (JTTMP) against diabetic lung injury. METHODS: JTTMP-containing serum was collected, and a high glucose and high-fat diabetic cell model was established. The cells were treated with a drug-containing serum or a CAV1-associated vector. Transfection efficiency was measured by qRT-PCR and western blot, the cell proliferative capacity was tested by CCK-8 assay, and the expression of autophagosome marker LC3B was measured by immunophluorescence assay. Expression levels of the autophagy markers LC3B, p62, and Beclin-1, and the expression levels of the fibrosis markers α-SMA, FN-1, and TGF-ß1 were determined by western blot, and the levels of inflammatory factors TNF-α and IL-1ß in the supernatants were assessed by ELISA. RESULTS: In high glucose and high fat-induced MRC-5 cells, JTTMP-containing serum impeded the abnormal cell proliferation and the expression levels of autophagy markers, fibrosis markers, as well as inflammatory factors. CAV1 expression was decreased in MRC-5 cells treated with JTTMP-containing serum. In MRC-5 cells upon transfection with the CAV1 overexpression vector and treatment with JTTMP-containing serum, increased cell proliferation, increased LC3B, p62, Beclin-1, α-SMA, FN-1, and TGF-ß1, TNF-α, and IL-1ß levels were found compared with cells treated with JTTMP-containing serum alone. CONCLUSION: This study suggests that JTTMP suppresses CAV1 expression to attenuate diabetic lung injury by reducing abnormal proliferation and autophagy, and reducing levels of fibrosis and inflammation.

BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs. METHODS: By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFß/Activin-SMAD2/3 signaling pathway. RESULTS: Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. CONCLUSIONS: Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease.

Macroautophagy/autophagy is the intracellular degradation process of cytoplasmic content and damaged organelles. Autophagy is strongly associated with the progression of Alzheimer disease (AD). Microglia are brain-resident macrophages, and recent studies indicate that autophagy in microglia protects neurons from neurodegeneration. Postnatal neurogenesis, the generation of new neurons from adult neural stem cells (NSCs), is impaired in AD patients as well as in AD animal models. However, the extent to which microglial autophagy influences adult NSCs and neurogenesis in AD animal models has not been studied. Here, we showed that conditional knock out (cKO) of Atg5 (autophagy related 5) in microglia inhibited postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus, but not in the subventricular zone (SVZ) of a 5×FAD mouse model. Interestingly, the protection of neurogenesis by Atg5 in microglia was only observed in female AD mice. To confirm the roles of autophagy in microglia for postnatal hippocampal neurogenesis, we generated additional cKO mice to delete autophagy essential genes Rb1cc1 or Atg14 in microglia. However, these rb1cc1 cKO and atg14 cKO mice did not exhibit neurogenesis defects in the context of a female AD mouse model. Last, we used the CSF1R antagonist to deplete ATG5-deficient microglia and this intervention restored neurogenesis in the hippocampus of 5×FAD mice. These results indicate that microglial ATG5 is essential to maintain postnatal hippocampal neurogenesis in a mouse model of AD. Our findings further support the notion that ATG5 in microglia supports NSC health and may prevent neurodegeneration.Abbreviations: 5×FAD: familial Alzheimer disease; Aß: ß-amyloid; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; ATG: autophagy related; BrdU: 5-bromo-2'-deoxyuridine; CA: Cornu Ammonis; cKO: conditional knock out; CSF1R: colony stimulating factor 1 receptor; Ctrl: control; DCX: doublecortin; DG: dentate gyrus; GFAP: glial fibrillary acidic protein; GZ: granular zone; H&E: hematoxylin and eosin; IF: immunofluorescence; LD: lipid droplet; LDAM: lipid droplets accumulated microglia; LPS: lipopolysaccharides; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; NSCs: neural stem cells; RB1CC1: RB1-inducible coiled-coil 1; SOX2: SRY (sex determining region Y)-box 2; SGZ: subgranular zone; SVZ: subventricular zone; WT: wild type.

Fast Adversarial Training With Adaptive Step Size.

While adversarial training and its variants have shown to be the most effective algorithms to defend against adversarial attacks, their extremely slow training process makes it hard to scale to large datasets like ImageNet. The key idea of recent works to accelerate adversarial training is to substitute multi-step attacks (e.g., PGD) with single-step attacks (e.g., FGSM). However, these single-step methods suffer from catastrophic overfitting, where the accuracy against PGD attack suddenly drops to nearly 0% during training, and the network totally loses its robustness. In this work, we study the phenomenon from the perspective of training instances. We show that catastrophic overfitting is instance-dependent, and fitting instances with larger input gradient norm is more likely to cause catastrophic overfitting. Based on our findings, we propose a simple but effective method, Adversarial Training with Adaptive Step size (ATAS). ATAS learns an instance-wise adaptive step size that is inversely proportional to its gradient norm. Our theoretical analysis shows that ATAS converges faster than the commonly adopted non-adaptive counterparts. Empirically, ATAS consistently mitigates catastrophic overfitting and achieves higher robust accuracy on CIFAR10, CIFAR100, and ImageNet when evaluated on various adversarial budgets. Our code is released at https://github.com/HuangZhiChao95/ATAS.

Lipocalin 10 is essential for protection against inflammation-triggered vascular leakage by activating LDL receptor-related protein 2-slingshot homologue 1 signalling pathway.

AIMS: Systemic inflammation occurs commonly during many human disease settings and increases vascular permeability, leading to organ failure, and lethal outcomes. Lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin family, is remarkably altered in the cardiovascular system of human patients with inflammatory conditions. Nonetheless, whether Lcn10 regulates inflammation-induced endothelial permeability remains unknown. METHODS AND RESULTS: Systemic inflammation models were induced using mice by injection of endotoxin lipopolysaccharide (LPS) or caecal ligation and puncture (CLP) surgery. We observed that the expression of Lcn10 was dynamically altered only in endothelial cells (ECs), but not in either fibroblasts or cardiomyocytes isolated from mouse hearts following the LPS challenge or CLP surgery. Using in vitro gain- and loss-of-function approaches and an in vivo global knockout mouse model, we discovered that Lcn10 negatively regulated endothelial permeability upon inflammatory stimuli. Loss of Lcn10 augmented vascular leakage, leading to severe organ damage and higher mortality following LPS challenge, compared to wild-type controls. By contrast, overexpression of Lcn10 in ECs displayed opposite effects. A mechanistic analysis revealed that both endogenous and exogenous elevation of Lcn10 in ECs could activate slingshot homologue 1 (Ssh1)-Cofilin signalling cascade, a key axis known to control actin filament dynamics. Accordingly, a reduced formation of stress fibre and increased generation of cortical actin band were exhibited in Lcn10-ECs, when compared to controls upon endotoxin insults. Furthermore, we identified that Lcn10 interacted with LDL receptor-related protein 2 (LRP2) in ECs, which acted as an upstream factor of the Ssh1-Confilin signalling. Finally, injection of recombinant Lcn10 protein into endotoxic mice showed therapeutic effects against inflammation-induced vascular leakage. CONCLUSION: This study identifies Lcn10 as a novel regulator of EC function and illustrates a new link in the Lcn10-LRP2-Ssh1 axis to controlling endothelial barrier integrity. Our findings may provide novel strategies for the treatment of inflammation-related diseases.

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma.

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFß/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Genetic ablation of diabetes-associated gene Ccdc92 reduces obesity and insulin resistance in mice.

Multiple genome-wide association studies (GWAS) have identified specific genetic variants in the coiled-coil domain containing 92 (CCDC92) locus that is associated with obesity and type 2 diabetes in humans. However, the biological function of CCDC92 in obesity and insulin resistance remains to be explored. Utilizing wild-type (WT) and Ccdc92 whole-body knockout (KO) mice, we found that Ccdc92 KO reduced obesity and increased insulin sensitivity under high-fat diet (HFD) conditions. Ccdc92 KO inhibited macrophage infiltration and fibrosis in white adipose tissue (WAT), suggesting Ccdc92 ablation protects against adipose tissue dysfunction. Ccdc92 deletion also increased energy expenditure and further attenuated hepatic steatosis in mice on an HFD. Ccdc92 KO significantly inhibited the inflammatory response and suppressed the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in WAT. Altogether, we demonstrated the critical role of CCDC92 in metabolism, constituting a potential target for treating obesity and insulin resistance.

Transcriptome Analysis of Traditional Chinese Medicine 'Kechuanning Plaster' in the Treatment of Asthma.

BACKGROUND: Asthma is a severe chronic inflammatory airway disease. Kechuanning plaster has excellent efficacy in the treatment of asthma. OBJECTIVE: The aim of this study was to analyze the molecular mechanisms of Kechuanning plaster in the treatment of asthma. METHODS: An asthma model was constructed using Sprague Dawley rats. Differentially expressed genes (DEGs) were screened in three rat groups: the control (normal rats), model (asthma rats), and treatment (asthma rats treated with Kechuanning) groups. After enrichment analysis of the DEGs, the protein-protein interactions (PPIs) of the DEGs were analyzed, and transcription factors and microRNAs (miRNAs) that regulate DEGs were predicted. Finally, western blotting (WB) and immunohistochemical (IHC) analysis was performed to validate protein expression. RESULTS: A total of 745 DEGs were identified and enriched in 93 Gene Ontology terms and 25 Kyoto Encyclopedia of Genes and Genomes pathways. A PPI network, consisting of 224 protein nodes and 368 edges, was constructed. The nuclear factor of activated T cells 2 (NFATc2) was predicted to have binding sites in 61 DEGs. The miRNA-target interaction network included 24 DEGs and 9 miRNAs. WB and IHC analysis demonstrated that the fatty acid-binding protein 5 (FABP5) and the chemokine (C-X-C motif) ligand 3 (CXCL3) had higher expression in the model group and lower expression in the control and treatment groups. CONCLUSION: We concluded that FABP5, CXCL3, suppressor of cytokine signaling 3 (SOCS3), E1A binding protein P300 (EP300), NFATc2, microRNA 495 (miR-495), and miR-30 may play important roles in treating asthma.

Loss of Lipocalin 10 Exacerbates Diabetes-Induced Cardiomyopathy via Disruption of Nr4a1-Mediated Anti-Inflammatory Response in Macrophages.

Metabolic disorders (i.e., hyperglycemia, hyperlipidemia, and hyperinsulinemia) cause increased secretion of inflammatory cytokines/chemokines, leading to gradual loss of cardiac resident macrophage population and increased accumulation of inflammatory monocytes/macrophages in the heart. Such self-perpetuating effect may contribute to the development of cardiomyopathy during diabetes. Recent meta-analysis data reveal that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue of patients with heart failure but is increased in the blood of septic patients. However, the functional role of Lcn10 in cardiac inflammation triggered by metabolic disorders has never been investigated. In this study, we demonstrate that the expression of Lcn10 in macrophages was significantly decreased under multiple metabolic stress conditions. Furthermore, Lcn10-null macrophages exhibited pro-inflammatory phenotype in response to inflammation stimuli. Next, using a global Lcn10-knockout (KO) mouse model to induce type-2 diabetes (T2D), we observed that loss of Lcn10 promoted more pro-inflammatory macrophage infiltration into the heart, compared to controls, leading to aggravated insulin resistance and impaired cardiac function. Similarly, adoptive transfer of Lcn10-KO bone marrow cells into X-ray irradiated mice displayed higher ratio of pro-/anti-inflammatory macrophages in the heart and worsened cardiac function than those mice received wild-type (WT) bone marrows upon T2D conditions. Mechanistically, RNA-sequencing analysis showed that Nr4a1, a nuclear receptor known to have potent anti-inflammatory effects, is involved in Lcn10-mediated macrophage activation. Indeed, we found that nuclear translocation of Nr4a1 was disrupted in Lcn10-KO macrophages upon stimulation with LPS + IFNγ. Accordingly, treatment with Cytosporone B (CsnB), an agonist of Nr4a1, attenuated the pro-inflammatory response in Lcn10-null macrophages and partially improved cardiac function in Lcn10-KO diabetic mice. Together, these findings indicate that loss of Lcn10 skews macrophage polarization to pro-inflammatory phenotype and aggravates cardiac dysfunction during type-2 diabetes through the disruption of Nr4a1-mediated anti-inflammatory signaling pathway in macrophages. Therefore, reduction of Lcn10 expression observed in diabetic macrophages may be responsible for the pathogenesis of diabetes-induced cardiac dysfunction. It suggests that Lcn10 might be a potential therapeutic factor for diabetic heart failure.

Tangshen Decoction Enhances Podocytes Autophagy to Relieve Diabetic Nephropathy through Modulation of p-AMPK/p-ULK1 Signaling.

Traditional Chinese medicine has certain advantages in the prevention and treatment of diabetic nephropathy (DN); thus, Chinese medicine therapy is considered as a promising strategy for treating DN. Here, the diabetic nephropathy model was established and intervened with Tangshen Decoction to explore its repair effect on diabetic kidney injury and the mechanism of autophagy. Different doses (10, 20 g·kg-1) of Tangshen Decoction (so-called Tangshen Jian, TSJ) or metformin were used to intervene for 16 weeks. The body weight (BW) and fasting blood glucose (FBG) of rats in each group were regularly monitored; a urine protein test kit (CBB method) was used to detect changes in urine protein (UP) content. The serum biochemical indicators, including Cr (creatinine), BUN (blood urea nitrogen), TC (total cholesterol), and TG (triglyceride), were detected by an automatic biochemical analyzer. HE (hematoxylin-eosin) staining, PAS, and electron microscopy were used to observe the podocyte damage. We showed that administration of TSJ or metformin prevented the increases in FBG level, serum Cr, BUN, TC, and TG level, and urine protein excretion in diabetic nephropathy. Simultaneously, the foot process fusion and fall-off were partially reversed after TSJ treatment. TSJ or metformin markedly upregulated the level of nephrin and podocin, accompanied by evident enhancement of podocyte autophagy and activation of p-AMPK/p-ULK1 signaling in the diabetic nephropathy. Therefore, TSJ may enhance podocyte autophagy to relieve diabetic nephropathy through modulation of p-AMPK/p-ULK1 signaling, which has important application prospects in the clinical treatment of diabetic kidney damage in the future.

Average Top-k Aggregate Loss for Supervised Learning.

In this work, we introduce the average top- k ( ATk) loss, which is the average over the k largest individual losses over a training data, as a new aggregate loss for supervised learning. We show that the ATk loss is a natural generalization of the two widely used aggregate losses, namely the average loss and the maximum loss. Yet, the ATk loss can better adapt to different data distributions because of the extra flexibility provided by the different choices of k. Furthermore, it remains a convex function over all individual losses and can be combined with different types of individual loss without significant increase in computation. We then provide interpretations of the ATk loss from the perspective of the modification of individual loss and robustness to training data distributions. We further study the classification calibration of the ATk loss and the error bounds of ATk-SVM model. We demonstrate the applicability of minimum average top- k learning for supervised learning problems including binary/multi-class classification and regression, using experiments on both synthetic and real datasets.

Xiaotangzhike Pill Attenuates the Progression of Diabetes In Vivo through the Mediation of the Akt/GSK-3ß Axis.

Background: Diabetes seriously threatens the health of people. Traditional Chinese medicine has been proven to inhibit the progression of diabetes. Meanwhile, the Xiaotangzhike pill (XTZK) was known to alleviate the symptom of diabetes. Thus, this research decided to investigate the mechanism underlying the impact of XTZK in diabetes remains unexplored. Methods: To assess the impact of XTZK in diabetes, in vivo model of diabetes was constructed. The contents of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) in the rats were tested by the commercial kits. In addition, Masson and hematoxylin and eosin (H&E) staining were applied for assessing the histological changes and fibrosis in the rats, respectively. Furthermore, a western blot was applied to assess the protein levels. Results: Streptozotocin (STZ) significantly increased the levels of area under the curve (AUC), TG, TC, LDL-C, and decreased the contents of HDL-C in rats, while these phenomena were partially reversed by XTZK. In addition, STZ notably induced inflammatory infiltration and fibrosis in the liver tissues of rats, which was greatly restored by XTZK. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) in the serum of rats were notably upregulated by STZ, while the effect of STZ was markedly abolished by XTZK. Meanwhile, STZ-caused the upregulation of p-Smad2 and α-SMA in rats was restored by XTZK. Furthermore, XTZK notably inhibited the progression of Qi and Yin deficiency syndrome in diabetes through the mediation of the Akt/GSK-3ß axis. Conclusion: The Xiaotangzhike pill attenuates the progression of diabetes through the mediation of the Akt/GSK-3ß axis. Hence, our study might supply a novel insight into discovering new strategies against diabetes.

KLF11 Protects against Venous Thrombosis via Suppressing Tissue Factor Expression.

Krüppel-like factors (KLFs) play essential roles in multiple biological functions, including maintaining vascular homeostasis. KLF11, a causative gene for maturity-onset diabetes of the young type 7, inhibits endothelial activation and protects against stroke. However, the role of KLF11 in venous thrombosis remains to be explored. Utilizing stasis-induced murine deep vein thrombosis (DVT) model and cultured endothelial cells (ECs), we identified an increase of KLF11 expression under prothrombotic conditions both in vivo and in vitro. The expression change of thrombosis-related genes was determined by utilizing gain- and loss-of-function approaches to alter KLF11 expression in ECs. Among these genes, KLF11 significantly downregulated tumor necrosis factor-α (TNF-α)-induced tissue factor (TF) gene transcription. Using reporter gene assay, chromatin immunoprecipitation assay, and co-immunoprecipitation, we revealed that KLF11 could reduce TNF-α-induced binding of early growth response 1 (EGR1) to TF gene promoter in ECs. In addition, we demonstrated that conventional Klf11 knockout mice were more susceptible to developing stasis-induced DVT. These results suggest that under prothrombotic conditions, KLF11 downregulates TF gene transcription via inhibition of EGR1 in ECs. In conclusion, KLF11 protects against venous thrombosis, constituting a potential molecular target for treating thrombosis.

Salidroside induced repair of myocardial infarction through Nrf2/HO-1

Abstract Salidroside (SAL) has been confirmed to have some protective effects against inflammatory injury. However, little information was established as to the mechanism of these protective effects. To this effect, we designed this study to explore the protective effects and mechanisms of SAL against myocardial infarction (MI). A rat MI model was established and divided into five groups (n = 6): sham, MI, MI+SAL, MI+ LY294002 (PI3K inhibitor), and MI+SAL+ LY294002. The cardiac function and histological pathology were analyzed with a color Doppler ultrasonic diagnostic instrument. Anti-oxidative enzyme activities and the production of inflammatory media were assayed by biochemical kits and ELISA. MI size and fibrosis were assayed by Masson's trichrome staining while Bax/Bcl-2 and PI3K/Akt/Nrf2/HO-1 were assayed by Western blotting and immunofluorescence. The results showed that SAL significantly improved the left ventricle ejection fraction and fractional shortening, decreased the MI size and fibrosis, inhibited apoptosis and promoted blood vessel formation. SAL promoted anti-oxidative and anti-inflammatory abilities. Moreover, SAL enhanced PI3K/ Akt/Nrf2/HO-1 expression. To this effect, we designed this study suggested that SAL induced repair of MI via PI3K/A kt/ Nrf2/HO-1.

Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms.

Aortic aneurysm, including thoracic aortic aneurysm and abdominal aortic aneurysm, is the second most prevalent aortic disease following atherosclerosis, representing the ninth-leading cause of death globally. Open surgery and endovascular procedures are the major treatments for aortic aneurysm. Typically, thoracic aortic aneurysm has a more robust genetic background than abdominal aortic aneurysm. Abdominal aortic aneurysm shares many features with thoracic aortic aneurysm, including loss of vascular smooth muscle cells (VSMCs), extracellular matrix degradation and inflammation. Although there are limitations to perfectly recapitulating all features of human aortic aneurysm, experimental models provide valuable tools to understand the molecular mechanisms and test novel therapies before human clinical trials. Among the cell types involved in aortic aneurysm development, VSMC dysfunction correlates with loss of aortic wall structural integrity. Here, we discuss the role of VSMCs in aortic aneurysm development. The loss of VSMCs, VSMC phenotypic switching, secretion of inflammatory cytokines, increased matrix metalloproteinase activity, elevated reactive oxygen species, defective autophagy, and increased senescence contribute to aortic aneurysm development. Further studies on aortic aneurysm pathogenesis and elucidation of the underlying signaling pathways are necessary to identify more novel targets for treating this prevalent and clinical impactful disease.

Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2.

The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice.

Transcriptomic Analysis Exploring the Molecular Mechanisms of Hanchuan Zupa Granules in Alleviating Asthma in Rat.

OBJECTIVE: To investigate the molecular mechanisms of HCZP treatment of asthma. MATERIALS AND METHODS: Thirty Sprague Dawley (SD) rats were divided into normal, asthma, and HCZP groups (n = 10). The asthma model was sensitized by 1 mg ovalbumin (OVA)/aluminum hydroxide Al(OH)3mixture and then challenged with 1% aerosolized OVA for four weeks. Rats in the HCZP group received 10.08 g/kg/d HCZP for four weeks during OVA challenge. Then, lung tissues of rats in each group were collected for RNA sequencing. Moreover, the expression level of some core genes was detected by using western blotting and immunohistochemistry. RESULTS: Inflammatory cell infiltration and pathological damage of the lungs improved in the HCZP group. Compared with the asthma group (0.049 ± 0.002 mm2/mm; 0.036 ± 0.006 mm2/mm; and 0.014 ± 0.001 mm2/mm), total wall thickness (0.042 ± 0.001 mm2/mm), inner wall thickness (0.013 ± 0.001 mm2/mm), and smooth muscle layer thickness (0.012 ± 0.001 mm2/mm) significantly decreased in the HCZP group. Bioinformatics analysis showed that hub genes such as bradykinin receptor B2 (Bdkrb2) and CD4 molecule (Cd4) had different expression patterns between model and HCZP groups. Two transcription factors, forkhead box Q1 (Foxq1) and nuclear factor of activated T cells 2 (Nfatc2), served important regulatory roles in asthma. Compared with the model group, Bdkrb2 protein expression increased and Nfatc2 protein expression decreased in the HCZP group. Discussion and Conclusion. HCZP could alleviate asthma via regulating the expression of several hub genes, which might serve as therapeutic targets for asthma. However, the mechanism of these genes will be studied in the future.