Effects of butyrate on intestinal ischemia-reperfusion injury via the HMGB1-TLR4-MyD88 signaling pathway.

BACKGROUND: This study combined bioinformatics and experimental verification in a mouse model of intestinal ischemia-reperfusion injury (IRI) to explore the protection mechanism exerted by butyrate against IRI. METHODS: GeneCards, Bioinformatics Analysis Tool for Molecular Mechanisms of Traditional Chinese Medicine and GSE190581 were used to explore the relationship between butyrate and IRI and aging. Protein-protein interaction networks involving butyrate and IRI were constructed via the STRING database, with hub gene analysis performed through Cytoscape. Functional enrichment analysis was conducted on intersection genes. A mouse model of IRI was established, followed by direct arterial injection of butyrate. The experiment comprised five groups: normal, sham, model, vehicle, low-dose butyrate, and high-dose butyrate. Intestinal tissue observation was done via transmission electron microscopy (TEM), histological examination via hematoxylin and eosin (H&E) staining, tight junction proteins detection via immunohistochemistry, and Western blot analysis of hub genes. Drug-target interactions were evaluated through molecular docking. RESULTS: Butyrate protected against IRI by targeting 458 genes, including HMGB1 and TLR4. Toll-like receptor pathway was implicated. Butyrate improved intestinal IRI by reducing mucosal damage, increasing tight junction proteins, and lowering levels of HMGB1, TLR4, and MyD88. Molecular docking showed strong binding energies between butyrate and HMGB1 (-3.7 kcal/mol) and TLR4 (-3.8 kcal/mol). CONCLUSIONS: According to bioinformatics predictions, butyrate mitigates IRI via multiple-target and multiple-channel mechanisms. The extent of IRI can be reduced by butyrate through the inhibition of the HMGB1-TLR4-MyD88 signaling pathway, which is related to senescence.

Bioinformatics identification and validation of maternal blood biomarkers and immune cell infiltration in preeclampsia: An observational study.

Preeclampsia (PE) is a pregnancy complication characterized by placental dysfunction. However, the relationship between maternal blood markers and PE is unclear. It is helpful to improve the diagnosis and treatment of PE using new biomarkers related to PE in the blood. Three PE-related microarray datasets were obtained from the Gene Expression Synthesis database. The limma software package was used to identify differentially expressed genes (DEGs) between PE and control groups. Least absolute shrinkage and selection operator regression, support vector machine, random forest, and multivariate logistic regression analyses were used to determine key diagnostic biomarkers, which were verified using clinical samples. Subsequently, functional enrichment analysis was performed. In addition, the datasets were combined for immune cell infiltration analysis and to determine their relationships with core diagnostic biomarkers. The diagnostic performance of key genes was evaluated using the receiver operating characteristic (ROC) curve, C-index, and GiViTi calibration band. Genes with potential clinical applications were evaluated using decision curve analysis (DCA). Seventeen DEGs were identified, and 6 key genes (FN1, MYADM, CA6, PADI4, SLC4A10, and PPP4R1L) were obtained using 3 types of machine learning methods and logistic regression. High diagnostic performance was found for PE through evaluation of the ROC, C-index, GiViti calibration band, and DCA. The 2 types of immune cells (M0 macrophages and activated mast cells) were significantly different between patients with PE and controls. All of these genes except SLC4A10 showed significant differences in expression levels between the 2 groups using quantitative reverse transcription-polymerase chain reaction. This model used 6 maternal blood markers to predict the occurrence of PE. The findings may stimulate ideas for the treatment and prevention of PE.

Cardiac electrical storm induced by anesthesia was successfully managed during surgery: a case report.

BACKGROUND: At present, the overall number of cardiac storms is small, there is a paucity of published literature describing cardiac storms in patients undergoing superficial surgery under general anesthesia (GA). In recent years, cardiac storm has attracted much clinical attention due to its high mortality, difficult management and poor prognosis. CASE DESCRIPTION: This paper reports a 57-year-old male with cardiac electrical storm. He presented with clinical symptoms such as exudation, bad breath, restricted mouth opening, and mucous leukoplakia on local skin, without history of cardiac disease and cardiovascular disease, undergoing superficial face surgery under GA. At 2 hours after anesthesia induction, several premature ventricular beats were detected on monitoring. Hematocrit and plasma potassium were found to be markedly decreased. The patient subsequently experienced a cardiac electrical storm, with repeated episodes of polymorphic ventricular tachycardia (VT) not degenerating to ventricular fibrillation (VF). Combining these clinical symptoms and examinations, we made the diagnosis of cardiac electrical storm. At the first occurrence of bradycardia, we administered atropine, which resolved bradycardia. However, this was followed 10 minutes later by VT, which we treated with atropine and epinephrine. Epinephrine and amiodarone were given in the second episode; epinephrine and lidocaine were used to treat the third episode. Finally, he was treated successfully with pharmacologic therapy and chest compressions. No abnormal electrocardiograph events occurred in the patient after surgery. CONCLUSIONS: This case highlights the possibility of anesthesia-induced autotransfusion and cardiac electrical storm occurring in patients without known cardiac disease. For this kind of case needs as soon as possible electric defibrillation and electric cardioversion, timely intravenous application effective anti-arrhythmic drugs and other treatment measures. We expect that this case report adds to the existing literature on this subject.

[Clinical observation on treatment of type 2 cardiac and kidney syndrome by combination of traditional Chinese and Western medicines].

Clinical observation on treatment of type 2 cardiac and kidney syndrome by combination of traditional Chinese and Western medicine. The patients were divided into two groups： the simple Western medicine treatment group (control group) and the traditional Chinese medicine and Western medicine treatment group (treatment group). The patients in the two groups were treated with conventional western medicine.The treatment group was given based on Buxin Yishen decoction, a total of three courses of treatment to observe the two groups of patients before and after treatment of total efficacy, cardiac function indicators, changes in renal function indicators. The total efficacy of the treatment group and the control group were 91.80% and 72.41%, respectively. There were significant differences between the two groups (P<0.01). The cardiac function indexes and renal function indexes of the treatment group and the control group before and after treatment (P<0.01). Compared with the two groups, the left ventricular function, Hematuria natriuretic peptide, serum creatinine, urea nitrogen, cystatin-C were improved, and the treatment group (P<0.05~0.01). The results showed that the combination of traditional Chinese and Western medicine treatment can improve the clinical efficacy of type 2 heart and kidney syndrome, significantly improve heart and kidney function, better than conventional Western medicine treatment, and has good safety.

Chinese Herbal Cardiotonic Pill Stabilizes Vulnerable Plaques in Rabbits by Decreasing the Expression of Adhesion Molecules.

The cardiotonic pill (CP), consisting of a mixture of Radix Salviae Miltiorrhizae, Radix Notoginseng, and Borneolum Syntheticum, has been widely used in the prevention and treatment of cardiovascular disease. Adhesion molecules, including intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, are involved in the development of vulnerable plaque. We investigated the effect of the CP in a rabbit model of vulnerable plaque established by local transfection with p53 gene. Compared with the control group, rabbits with vulnerable plaque showed a significantly lower intima-media thickness and plaque burden after CP treatment for 12 weeks. Moreover, the reduction in rate of plaque rupture and vulnerability index was similar. On enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry analysis, the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 was inhibited with CP treatment. CP treatment could postpone atherosclerotic plaque development and stabilize vulnerable plaque by inhibiting the expression of adhesion molecules in treatment of cardiovascular disease.

Asymmetric dimethylarginine predicts left atrial appendage thrombus in patients with non-valvular atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with increased thrombo-embolic events, with thrombi most frequently located in the left atrial appendage (LAA). Asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of nitric oxide synthase, is elevated in subjects with AF. We investigated the relationship between ADMA and risk of LAA thrombus in patients with non-valvular AF. METHODS AND RESULTS: A total of 223 consecutive patients with non-valvular AF were enrolled (63 ± 10 years, 65% male). LAA thrombus was detected in 27 subjects by transesophageal echocardiography. Serum ADMA was significantly increased (2.5 ± 0.6 µmol/L vs 1.8 ± 0.4 µmol/L, p<0.001), while serum nitrite/nitrate was significantly reduced in patients with LAA thrombus (30.3 ± 7.1 µmol/L vs 48.4 ± 9.3 µmol/L, p<0.001). ADMA was positively correlated with age and left atrium diameter, and was negatively correlated with nitrite/nitrate and LAA peak flow velocity. The area under the receiver operating characteristic curve of ADMA predicting thrombus was 0.84. In multivariate logistic regression analysis, ADMA (OR 4.0, 95% CI 1.2-13.0; p=0.003) was one of independent risk factors for LAA thrombus. CONCLUSIONS: Our study suggested that high ADMA was independently associated with the presence of LAA thrombus in patients with non-valvular AF.

Intravascular ultrasound area strain imaging used to characterize tissue components and assess vulnerability of atherosclerotic plaques in a rabbit model.

The purpose of this study was to investigate the association of area strain and tissue components and vulnerability of atherosclerotic plaques in a rabbit model. Forty purebred New Zealand rabbits underwent balloon-induced abdominal aorta endothelium injury, then a high-cholesterol diet for 24 weeks. Intravascular ultrasound (IVUS) images of abdominal aortas were acquired in situ and two consecutive frames near the end-diastole were used to construct an IVUS elastogram. Histologic slices matched with corresponding IVUS images were stained for fatty and collagen components, smooth muscle cells (SMCs) and macrophages. Regions-of-interest (ROIs) in plaques were classified as fibrous, fibro-fatty or fatty according to histologic study. Vulnerability indexes of ROIs were calculated as (fat + macrophage)/(collagen + SMCs). The area strain of these ROIs was calculated by use of an in-house-designed software system with a block-matching-based algorithm. Area strain was significantly higher in fatty ROIs (0.056 ± 0.003) than in fibrous (0.019 ± 0.002, p < 0.001) or fibro-fatty ROIs (0.033 ± 0.003, p < 0.001). The sensitivity and specificity of area strain for fatty ROIs characterization was 75.0% and 80.2% (area under the curve [AUC] 0.858, 95% confidence interval [CI] = 0.800-0.916, p < 0.001) and 75.0% and 75.3% (AUC 0.859, 95% CI = 0.801-0.917, p < 0.001) for fibrous ROIs, as demonstrated by receiver operating characteristic curve analysis. Area strain was positively correlated with vulnerability index (r(2) = 0.495, p < 0.001), fatty components (r(2) = 0.332, p < 0.001) and macrophage infiltration (r(2) = 0.406, p < 0.001); and negatively correlated with collagen and SMC composition (r(2) = 0.115 and r(2) = 0.169, p < 0.001, respectively). Area strain calculation with IVUS elastography based on digital B-mode analysis is feasible and can be useful for tissue characterization and plaque vulnerability assessment.

JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4 (HDAC4) and forming a transcriptional repression complex in the TM promoter.

Thrombomodulin (TM) is an important vascular protective molecule that has anticoagulant, anti-inflammatory and anti-apoptotic properties. TM is downregulated in many thrombotic and vascular diseases. However, the mechanisms responsible for TM suppression are not completely understood. In this study, we investigated the mechanism involved in fatty acid-induced suppression of TM expression in human aortic endothelial cells. We found that palmitic acid inhibited TM expression through the JNK and p38 pathways. ATF-2, a JNK and p38 target transcription factor, was involved in the suppression. ATF-2 can bind to the TM promoter, recruit HDAC4 and form a transcriptional repression complex in the promoter, which may lead to chromatin condensation and transcriptional arrest. This study provides novel insight into TM down-regulation by stress signaling pathways.

Effect of adiponectin overexpression on stability of preexisting plaques by inducing prolyl-4-hydroxylase expression.

BACKGROUND: Although adiponectin has been implicated as an antiinflammatory factor in atherosclerotic lesion development, little is known about its role in advanced atherosclerotic plaque. This study assessed the effect and mechanism of adiponectin on the expression of prolyl 4-hydroxylase (P4H) alpha1 and its role in the stability of preexisting plaque. METHODS AND RESULTS: Atherosclerotic lesions in the carotid arteries of apolipoprotein E-deficient mice were induced by the placement of a perivascular collar. Six weeks after surgery, 120 mice were divided into phosphate-buffered saline (PBS) (n=40), empty adenovirus (Ad.Empty) (n=40) and adiponectin adenovirus (Ad.Adipo) groups (n=40). The number of vulnerable lesions were lower with Ad.Adipo than with Ad.Empty transfection. Mean cap thickness, cap area, cap-to-core ratio and intimal collagen content were all greater with Ad.Adipo than with Ad.Empty transfection; however, the groups did not differ in plaque area or intima-media thickness. Plasma adiponectin level positively correlated with intimal collagen content. Adiponectin transfection conferred enhanced expression of P4H, with no changes in the PBS and Ad.Empty groups. CONCLUSIONS: Adiponectin increases collagen production by inducing the expression of P4H, which may play a major role in the development of the thick fibrous cap of advanced atherosclerotic plaque.

Adiponectin inhibits lipopolysaccharide-induced adventitial fibroblast migration and transition to myofibroblasts via AdipoR1-AMPK-iNOS pathway.

Adiponectin is an important antiatherogenic adipocytokine that inhibits inflammation, insulin resistance, and oxide stress. Inflammation in the vascular adventitia is a crucial factor in the pathogenesis of atherosclerosis. Adventitial fibroblasts (AFs) can proliferate, divide into myofibroblasts, and migrate to the intima to become a new component of atherosclerotic plaque under inflammation and atherosclerosis. We investigated whether adiponectin might prevent AFs from proliferating, migrating, and transforming into myofibroblasts. Cultured AFs were stimulated with lipopolysaccharide (LPS) in the presence or absence of adiponectin. Methyl thiazolyl tetrazolium assay and migration and scratch-wound assays demonstrated that adiponectin reduced the AF proliferation and migration induced by LPS, respectively, whereas treatment with AdipoR1 small interfering (si) RNA (siAdipoR1), AMP-activated protein kinase (AMPK) siRNA (siAMPK), and an AMPK inhibitor reversed the effect. Immunocytochemistry and Western blot revealed that adiponectin reduced the transition of AFs to myofibroblasts, and treatment with siAdipoR1, siAMPK, and the AMPK inhibitor increased the transition. RT-PCR, Western blotting, and nitric oxide (NO) assay showed that adiponectin reduces induced NO synthase (iNOS) and nitrotyrosine expression and NO and ONOO(-) production induced by LPS. Treatment with siAdipoR1, siAMPK, and the AMPK inhibitor significantly attenuated adiponectin-induced phosphorylation of AMPK and its downstream target acetyl-coenzyme A carboxylase and up-regulated iNOS mRNA and protein expression, which resulted in a marked increase of NO and ONOO(-) production. In apolipoprotein E-deficient mice, immunohistochemistry of treated vascular adventitia showed that both iNOS expression and ONOO(-) production could be reversed with an adenovirus-adiponectin vector. Taken together, these results suggest that adiponectin reduces LPS-induced NO production and nitrosative stress and prevents AFs from proliferating, transforming to myoflbroblasts, and migrating to the intima, thus worsening atherosclerosis, by inhibiting the AdipoR1-AMPK-iNOS pathway in AFs.

Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells.

Oxidative stress induced by hyperglycemia is a key factor in the development of cardiovascular diseases in diabetes. Thioredoxin (Trx) system, a major thiol antioxidant system, regulates the reduction of intracellular reactive oxygen species (ROS). In this study, we demonstrated that high glucose significantly increased intracellular ROS levels in human aortic endothelial cells (HAECs). Additionally, high glucose reduced the antioxidant activity of thioredoxin. To investigate the mechanisms involved, we found that glucose enhanced the expression of thioredoxin interacting protein (Txnip), a Trx inhibitory protein, through p38 mitogen-activated protein kinase (MAPK). We also showed that glucose regulated Txnip at transcription level and p38 MAPK and forkhead box O1 transcriptional factor (FOXO1) were involved in the process. Taken together, upregulation of Txnip and subsequent impairment of thioredoxin antioxidative system through p38 MAPK and FOXO1 may represent a novel mechanism for glucose-induced increase in intracellular ROS.

A hypothesis: adiponectin mediates anti-atherosclerosis via adventitia-AMPK-iNOS pathway.

Adiponectin is an adipocyte-derived protein with insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties and is abundantly found in plasma. Vascular adventitia is the outermost connective and supporting tissue of vessels. Recently, increasing evidence has shown that infection in the adventitia is one of the causes of atherosclerosis and restenosis. Our previous study indicated that local transferring adenovirus expressing adiponectin gene (Ad-APN) to intima and adventitia can suppress atherosclerosis, but the exact mechanism is still obscure. We speculate that with infection in the adventitia, adiponectin can activate AMP-activated protein kinase (AMPK) through adiponectin receptors in the membranes of adventitial fibroblasts and then inhibit the expression and activity of inducible nitric oxide synthase (iNOS); secretion of adventitial infective factors; division, proliferation and translation of adventitial fibroblasts; and change of adventitial fibroblasts to myofibroblasts, finally decreasing oxidative/nitrative stress to reduce atherosclerotic plaque area and stabilize atherosclerotic plaques. The proposition may provide clues into the development of a novel treatment for atherosclerosis.

Local adiponectin treatment reduces atherosclerotic plaque size in rabbits.

In this study, we investigated the in vivo role of adiponectin, an adipocytokine, on the development of atherosclerosis in rabbits mainly using adenovirus expressing adiponectin gene (Ad-APN) and intravascular ultrasonography. Serum adiponectin concentrations in rabbits after Ad-APN local transfer to abdominal aortas increased about nine times as much as those before transfer (P < 0.01), about ten times as much as the levels of endogenous adiponectin in adenovirus expressing beta-galactosidase gene (Ad-beta gal) treated rabbits (P < 0.01), and about four times as much as those in the aorta of non-injured rabbits on a normal cholesterol diet (P < 0.01). Ultrasonography revealed a significantly reduced atherosclerotic plaque area in abdominal aortas of rabbits infected through intima with Ad-APN, by 35.2% compared with the area before treatment (P < 0.01), and by 35.8% compared with that in Ad-beta gal-treated rabbits (P < 0.01). In rabbits infected through adventitia, Ad-APN treatment reduced plaque area by 28.9% as compared with the area before treatment (P < 0.01) and 25.6% compared with that in Ad-beta gal-treated rabbits (P < 0.01). Adiponectin significantly suppressed the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1) by 18.5% through intima transfer (P < 0.05) and 26.9% through adventitia transfer (P < 0.01), and intercellular adhesion molecule-1 (ICAM-1) by 40.7% through intima transfer (P < 0.01), and 30.7% through adventitia transfer (P < 0.01). However, adiponectin had no effect on the expression of types I and III collagen. These results suggest that local adiponectin treatment suppresses the development of atherosclerosis in vivo in part by attenuating the expression of VCAM-1 and ICAM-1 in vascular walls.