Protective effect of zerumbone on sepsis-induced acute lung injury through anti-inflammatory and antioxidative activity via NF-κB pathway inhibition and HO-1 activation.

Sepsis is a systemic illness for which there are no effective preventive or therapeutic therapies. Zerumbone, a natural molecule, has anti-oxidative and anti-inflammatory properties that may help to prevent sepsis. In the present study, we have assessed the protective effect of zerumbone against sepsis-induced acute lung injury (ALI) and its underlying mechanisms. During the experiment, mice were divided into five groups: a sham group, a sepsis-induced ALI group, and three sepsis groups that are pre-treated with zerumbone at different concentrations. We found that zerumbone greatly decreased the sepsis-induced ALI using histological investigations. Also, zerumbone treatment reduced the sepsis-induced inflammatory cytokine concentrations as well as the number of infiltrating inflammatory cells in BALF compared to non-treated sepsis animals. The zerumbone-pretreated sepsis groups had reduced pulmonary myeloperoxidase (MPO) activity than the sepsis groups. Moreover, the mechanism underlying the protective action of zerumbone on sepsis is accomplished by the activation of antioxidant genes such as nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), superoxide dismutase (SOD), and heme oxygenase 1 (HO-1). The obtained results revealed that zerumbone inhibited the sepsis-induced ALI through its anti-inflammatory and antioxidative activity via inhibition of the NF-κB pathway and activation of HO-1 pathway. Our findings demonstrate that zerumbone pretreatment suppresses sepsis-induced ALI via antioxidative activities and anti-inflammatory, implying that zerumbone could be a viable preventive agent for sepsis-induced ALI.

Asiatic acid protects against pressure overload-induced heart failure in mice by inhibiting mitochondria-dependent apoptosis.

BACKGROUND: Mitochondrial dysfunction and subsequent cardiomyocyte apoptosis significantly contribute to pressure overload-induced heart failure (HF). A highly oxidative environment leads to mitochondrial damage, further exacerbating this condition. Asiatic acid (AA), a proven antioxidant and anti-hypertrophic agent, might provide a solution, but its role and mechanisms in chronic pressure overload-induced HF remain largely unexplored. METHODS: We induced pressure overload in mice using transverse aortic constriction (TAC) and treated them with AA (100 mg/kg/day) or vehicle daily by oral gavage for 8 weeks. The effects of AA on mitochondrial dysfunction, oxidative stress-associated signaling pathways, and overall survival were evaluated. Additionally, an in vitro model using hydrogen peroxide-exposed neonatal rat cardiomyocytes was established to further investigate the role of AA in oxidative stress-induced mitochondrial apoptosis. RESULTS: AA treatment significantly improved survival and alleviated cardiac dysfunction in TAC-induced HF mice. It preserved mitochondrial structure, reduced the LVW/BW ratio by 20.24%, mitigated TAC-induced mitochondrial-dependent apoptosis by significantly lowering the Bax/Bcl-2 ratio and cleaved caspase-9/3 levels, and attenuated oxidative stress. AA treatment protected cardiomyocytes from hydrogen peroxide-induced apoptosis, with concurrent modulation of mitochondrial-dependent apoptosis pathway-related proteins and the JNK pathway. CONCLUSIONS: Our findings suggest that AA effectively combats chronic TAC-induced and hydrogen peroxide-induced cardiomyocyte apoptosis through a mitochondria-dependent mechanism. AA reduces cellular levels of oxidative stress and inhibits the activation of the JNK pathway, highlighting its potential therapeutic value in the treatment of HF.

Use of Contezolid for the Treatment of Refractory Infective Endocarditis in a Patient with Chronic Renal Failure: Case Report.

Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) is usually life threatening and difficult to treat. Contezolid is a newly approved oxazolidinone antimicrobial agent showing potent activity against MRSA. We successfully treated a case of refractory IE caused by MRSA with contezolid in a 41-year-old male patient. The patient was admitted due to recurrent fever and chills for more than 10 days. He had chronic renal failure for more than 10 years and under ongoing hemodialysis. The diagnosis of IE was confirmed by echocardiography and positive blood culture of MRSA. Antimicrobial therapy with vancomycin combined with moxifloxacin, and daptomycin combined with cefoperazone-sulbactam failed in the first 27 days. Moreover, the patient had to take oral anticoagulant after removal of tricuspid valve vegetation and tricuspid valve replacement. Contezolid 800 mg was added orally every 12 hours, to replace vancomycin, for its anti-MRSA activity and good safety profile. Temperature normalized after the contezolid add-on treatment for 15 days. No relapse of infection or drug-related adverse reaction was reported at 3-month follow-up since the diagnosis of IE. This successful experience serves as motivation for a well-designed clinical trial to confirm the utility of contezolid in managing IE.

Celastrol confers ferroptosis resistance via AKT/GSK3ß signaling in high-fat diet-induced cardiac injury.

Obesity-induced cardiac dysfunction is a severe global disease associated with high dietary fat intake, and its pathogenesis includes inflammation, oxidative stress, and ferroptosis. Celastrol (Cel) is a bioactive compound isolated from the herb Tripterygium wilfordii, which has a protective influence on cardiovascular diseases. In this study, the role of Cel in obesity-induced ferroptosis and cardiac injury was investigated. We found that Cel alleviated ferroptosis induced by Palmitic acid (PA), exhibiting a decrease in the LDH, CK-MB, Ptgs2, and Lipid Peroxidation levels. After cardiomyocytes were treated with additional LY294002 and LiCl, Cel exerted its protective effect through increased AKT/GSK3ß phosphorylation and decreased level of lipid peroxidation and Mitochondrial ROS. The systolic left ventricle (LV) dysfunction of obese mice was alleviated via ferroptosis inhibition by elevated p-GSK3ß and decreased Mitochondrial ROS under Cel treatment. Moreover, mitochondrial anomalies included swelling and distortion in the myocardium which was relieved with Cel. In conclusion, our results demonstrate that ferroptosis resistance with Cel under HFD conditions targets AKT/GSK3ß signaling, which provides novel therapeutic strategies in obesity-induced cardiac injury.

Adipose tissue macrophage-derived exosomes induce ferroptosis via glutathione synthesis inhibition by targeting SLC7A11 in obesity-induced cardiac injury.

Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of reactive oxygen species (ROS). Long-term high fat diet (HFD) was found to be associated with ferroptosis and cardiac injury. HFD-induced obesity is characterized by sustained, low-grade inflammation in adipose tissue, while macrophage infiltration plays a crucial role in inflammation. Exosomes (Exos) derived from adipose tissue macrophages (ATMs) participate in the physiological processes of recipient cells. In this study, we investigated the role of ATM-Exos in obesity-induced ferroptosis and cardiac injury. We found that HFD-induced obesity resulted in higher mRNA expression levels of specific markers, e.g., prostaglandin endoperoxide synthase 2 (PTGS2), and increased the levels of lipid peroxides, including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Macrophages infiltrated the adipose tissues, as examined by flow cytometry. Exosomes derived from ATM-Exos were analyzed using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Obese ATM-Exos administration induced higher levels of PTGS2, MDA, 4-HNE, lipid ROS, and mitochondrial injury. Obese ATM-Exos further provoked obvious cardiac injury, demonstrated by abnormal levels of cardiac enzymes and inflammatory factors. Systolic left ventricle (LV) function anomalies were induced by ATM-Exos in obese mice. miR-140-5p is abundant in obese ATM-Exos and promotes ferroptosis in cardiomyocytes. Solute carrier family 7 member 11 (SLC7A11) is a downstream target of miR-140-5p, which induces ferroptosis via inhibition of GSH synthesis by targeting SLC7A11. Attenuating exosomal-miR-140-5p expression alleviates ferroptosis and cardiac injury induced by obese ATM exosomes by alleviating GSH inhibition. In summary, the current study provides evidence that obese ATM-exosomal miR-140-5p promotes ferroptosis by regulating GSH synthesis and provides a novel therapeutic strategy for targeting obese ATM-Exos in obesity-induced cardiac injury.

Asiatic Acid Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting the ROS-Mediated Mitochondria-Dependent Apoptosis Pathway.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of heart failure in patients with coronary heart disease (CHD). Mitochondrial dysfunction is the crucial factor of MIRI; oxidative stress caused by mitochondrial reactive oxygen species (ROS) aggravates myocardial cell damage through the mitochondria-dependent apoptosis pathway. Asiatic acid (AA) is a type of pentacyclic triterpene compound purified from the traditional Chinese medicine Centella asiatica, and its protective pharmacological activities have been reported in various disease models. This study is aimed at investigating the protective effects of AA and the underlying mechanisms in MIRI. To achieve this goal, an animal model of MIRI in vivo and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) in vitro were established. The results show that AA exerts a protective effect on MIRI by improving cardiac function and reducing cardiomyocyte damage. Due to its antioxidant properties, AA alleviates mitochondrial oxidative stress, as evidenced by the stable mitochondrial structure, maintained mitochondrial membrane potential (MMP), and reduced ROS generation, otherwise due to its antiapoptotic properties. AA inhibits the mitogen-activated protein kinase (MAPK)/mitochondria-dependent apoptosis pathway, as evidenced by the limited phosphorylation of p38-MAPK and JNK-MAPK, balanced proportion of Bcl-2/Bax, reduced cytochrome c release, inhibition of caspase cascade, and reduced apoptosis. In conclusion, our study confirms that AA exerts cardiac-protective effects by regulating ROS-induced oxidative stress via the MAPK/mitochondria-dependent apoptosis pathway; the results provide new evidence that AA may represent a potential treatment for CHD patients.

Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway.

OBJECTIVE: Neuroinflammation plays a critical role in central nervous system diseases. Exosomal miRNAs released from various cells are implicated in cell-to-cell communication. Prior studies have placed substantial emphasis on the role of cytokines in mast cell-microglia interactions during neuroinflammation. However, it has never been clearly determined whether exosomal miRNAs participate in the interaction between mast cells and microglia and thus mediate neuroinflammation. METHODS: The characteristics of exosomes isolated from cell culture supernatants were confirmed by transmission electron microscopy (TEM), nanoparticle-tracking analysis (NTA) and Western blot. The transfer of PKH67-labelled exosomes and Cy3-labelled miR-409-3p was observed by fluorescence microscopy. Migration and activation of murine BV-2 microglial cells were evaluated through Transwell assays and immunofluorescence staining for Iba1 and CD68. CD86, IL-1ß, IL-6 and TNF-α were assessed via qRT-PCR and ELISA. MiR-409-3p was detected by qRT-PCR. Nr4a2 and NF-κB levels were measured by western blot. Regulatory effects were identified by luciferase reporter assays. RESULTS: Lipopolysaccharide (LPS)-stimulated murine P815 mast cells secreted exosomes that were efficiently taken up by murine BV-2 cells, which promoted murine BV-2 cell migration and activation. LPS-P815 exosomes increased the CD86, IL-1ß, IL-6 and TNF-α levels in murine BV-2 microglia. Furthermore, activated mast cells delivered exosomal miR-409-3p to murine BV-2 microglia. Upregulated miR-409-3p promoted murine BV-2 microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway. CONCLUSION: Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway, which provides evidence that not only cytokines but also exosomal miRNAs participate in neuroinflammation. In the future, targeting exosomal miRNAs may provide new insights into neuroinflammation.

Effect and mechanism of asiatic acid on autophagy in myocardial ischemia-reperfusion injury in vivo and in vitro.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of heart failure in patients with coronary heart disease. The excessive accumulation of reactive oxygen species (ROS) during MIRI induces the overactivation of an autophagic response, which aggravates myocardial cell damage. Asiatic acid (AA) is a triterpenoid compound, which is extracted from Centella asiatica and exhibits a variety of pharmacological effects such as hepatoprotective, neuroprotective and antioxidant. However, the association of AA with autophagy in MIRI is not fully understood. In the present study, the positive effects of AA in MIRI injury were determined via establishing a MIRI mouse model. Pre-treatment with AA was indicated to improve cardiac function and decrease cardiomyocyte autophagy in mice subjected to MIRI. To examine the protective effects of AA and the underlying mechanisms in MIRI, a cardiomyocyte glucose deprivation/reperfusion (OGD) model was established. The administration of AA decreased the levels of ROS and malondialdehyde and increased the levels of superoxide dismutase activity in OGD-treated cells. Using western blotting, it was demonstrated that treatment with AA decreased the phosphorylation of p38 and increased the expression of Bcl-2 in OGD-treated cells. Additionally, the expression of autophagy markers, including beclin-1 and the microtubule-associated proteins 1A/1B light chain 3B II/I ratio, were also decreased in AA treated cells compared with OGD-treated cells. These results demonstrated that AA pretreatment protected cardiomyocytes from ROS-mediated autophagy via a p38 mitogen-activated protein kinase/Bcl-2/beclin-1 signaling pathway in MIRI.

Identification key genes, key miRNAs and key transcription factors of lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common cancers worldwide. The etiology and pathophysiology of LUAD remain unclear. The aim of the present study was to identify the key genes, miRNAs and transcription factors (TFs) associated with the pathogenesis and prognosis of LUAD. METHODS: Three gene expression profiles (GSE43458, GSE32863, GSE74706) of LUAD were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by GEO2R.The Gene Ontology (GO) terms, pathways, and protein-protein interactions (PPIs) of these DEGs were analyzed. Bases on DEGs, the miRNAs and TFs were predicted. Furthermore, TF-gene-miRNA co-expression network was constructed to identify key genes, miRNAs and TFs by bioinformatic methods. The expressions and prognostic values of key genes, miRNAs and TFs were carried out through The Cancer Genome Atlas (TCGA) database and Kaplan Meier-plotter (KM) online dataset. RESULTS: A total of 337 overlapped DEGs (75 upregulated and 262 downregulated) of LUAD were identified from the three GSE datasets. Moreover, 851 miRNAs and 29 TFs were identified to be associated with these DEGs. In total, 10 hub genes, 10 key miRNAs and 10 key TFs were located in the central hub of the TF-gene-miRNA co-expression network, and validated using The Cancer Genome Atlas (TCGA) database. Specifically, seven genes (PHACTR2, MSRB3, GHR, PLSCR4, EPB41L2, NPNT, FBXO32), two miRNAs (hsa-let-7e-5p, hsa-miR-17-5p) and four TFs (STAT6, E2F1, ETS1, JUN) were identified to be associated with prognosis of LUAD, which have significantly different expressions between LUAD and normal lung tissue. Additionally, the miRNA/gene co-expression analysis also revealed that hsa-miR-17-5p and PLSCR4 have a significant negative co-expression relationship (r=-0.33, P=1.67e-14) in LUAD. CONCLUSIONS: Our study constructed a regulatory network of TF-gene-miRNA in LUAD, which may provide new insights about the interaction between genes, miRNAs and TFs in the pathogenesis of LUAD, and identify potential biomarkers or therapeutic targets for LUAD.

Long non­coding RNA MALAT1 serves as an independent predictive biomarker for the diagnosis, severity and prognosis of patients with sepsis.

The present prospective study was conducted to investigate the independent risk and predictive value of plasma long non­coding RNA metastasis­associated lung adenocarcinoma transcript 1 (MALAT1) as a biomarker for the diagnosis, severity and prognosis of sepsis. A total of 120 patients with sepsis and 60 healthy controls (HCs) were recruited. The expression levels of plasma MALAT1 were detected by quantitative PCR. The results demonstrated that the plasma levels of MALAT1 were significantly increased in patients with sepsis compared with HCs (P<0.001), in patients with septic shock compared with in patients without septic shock (P<0.001), and in non­survivors compared with in survivors (P<0.001). MALAT1 plasma levels exhibited weak positive correlation with serum procalcitonin levels (r=0.253; P=0.005), arterial lactate levels (r=0.488; P<0.001), sepsis­related organ failure assessment scores (r=0.566; P<0.001), and acute physiology and chronic health evaluation II scores (r=0.517; P<0.001) in patients with sepsis. Multivariate logistic regression analysis revealed that high MALAT1 expression was an independent risk factor for sepsis (P<0.001), septic shock (P=0.030) and poor prognosis (P=0.015). In addition, the receiver operating characteristic curve exhibited a significant predictive value for MALAT1 in distinguishing patients with sepsis from HCs with an area under the curve (AUC) of 0.910, patients with septic shock from patients without shock with an AUC of 0.836, and non­survivors from survivors with an AUC of 0.886. In conclusion, plasma MALAT1 may serve as a biomarker for the diagnosis, severity and prognosis of sepsis.

Melatonin prevents sepsis-induced renal injury via the PINK1/Parkin1 signaling pathway.

Melatonin (N­acetyl­5­methoxytryptamine; MT) has been shown to have a protective effect against sepsis­induced renal injury, however, the mechanisms underlying the function of MT remain to be elucidated. Therefore, in the present study, the potential mechanisms underlying the preventive role of MT in sepsis­induced renal injury were investigated. Hematoxylin and eosin staining was used to detect the effect of MT on the reduction of renal tissue damage, and immunohistochemistry (IHC), ELISA and western blot analysis were performed to determine the influence of MT on the protein expression of PTEN­induced putative kinase 1 (PINK1), nucleotide­oligomerization binding domain and leucine­rich repeat pyrin domain­containing 3 (NLRP3), apoptosis­associated speck­like protein containing a C­terminal caspase recruitment domain (ASC1), interleukin (IL)­18, IL­1ß, IL­6 and cleaved caspase­1. Finally, a TUNEL assay was used to compare the rate of apoptosis of renal tissues among the sham, cecal ligation and puncture (CLP), and CLP + MT groups. The extent of tissue damage in the CLP group was the highest and the extent of tissue damage in the sham group was the lowest. The IHC and western blot analysis showed that the sham group had the highest protein level of PINK1, whereas the CLP group had the lowest protein level of PINK1. By contrast, the sham group had the lowest protein level of NLRP, whereas the CLP group had the highest level of NLRP3. Furthermore, CLP treatment enhanced the protein expression of ASC1 and cleaved caspase­1, whereas the administration of MT reduced the protein expression of ASC1 and cleaved caspase­1 to a certain degree. Finally, the apoptotic rate was found to be the highest in the CLP group and the lowest in the sham group. Taken together, in evaluating the therapeutic effect of MT on sepsis­induced renal injury, the results of the present study showed that MT alleviated sepsis­induced renal injury by regulating the expression of PINK1, Parkin1, NLRP3, ASC and cleaved caspase­1 in rats.

Role of bone marrow mesenchymal stem cells in the development of PQ­induced pulmonary fibrosis.

Paraquat (PQ) poisoning­induced pulmonary fibrosis is one of the primary causes of mortality in patients with PQ poisoning. The potential mechanism of PQ­induced pulmonary fibrosis was thought to be mediated by inflammation. Recently, bone marrow­derived mesenchymal stem cells (BMSCs) have been considered as a potential strategy for the treatment of fibrotic disease due to their anti­inflammatory and immunosuppressive effects. In the present study, an increased accumulation of BMSCs in a mouse model of PQ­induced pulmonary fibrosis following their transplantation, markedly improving the survival rate of mice with PQ poisoning. In addition, the results indicated that BMSC transplantation may inhibit the production of pro­inflammatory cytokines, including tumor necrosis factor­α interleukin (IL)­1ß, IL­6 and IL­10 in the lung tissues of PQ­poisoned mice, and ultimately attenuate the pulmonary fibrosis. In vitro, BMSCs may suppress PQ­induced epithelial­to­mesenchymal transition and protect pulmonary epithelial cells from PQ­induced apoptosis. These findings suggest that BMSC transplantation may be a promising treatment for pulmonary fibrosis induced by PQ poisoning.

Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice.

Cardiac structural remodeling, including cardiomyocyte apoptosis, interstitial fibrosis, and inflammation, appears to be a key event associated with the progression of left ventricular hypertrophy and heart failure. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica that exhibits antiapoptotic, antifibrotic, and anti-inflammatory activities. In the present study, a transverse aortic constriction (TAC) model was created in mice to mimic the progression of hypertrophy (2 weeks post-TAC) and heart failure (4 weeks post-TAC) to investigate whether the potential therapeutic drug AA ameliorates hypertrophy progression and which mechanisms are involved in this amelioration. Our results demonstrated that AA markedly inhibited the process of progression induced by pressure overload. The increases cardiomyocyte apoptosis and interstitial fibrosis, and inflammatory responses were significantly suppressed by AA. Our investigation revealed that this inhibitory effect was mediated by blocking the activation of both mitochondrial and death receptor-dependent apoptotic signaling pathways. Additional experiments demonstrated that AA attenuated fibrosis by blocking both transforming growth factor-ß1/Smad and interleukin-6, signaling activation. Consequently, these findings indicated that AA attenuated pathological cardiac structural remodeling and preserved cardiac function via multiple intracellular signaling pathways in response to cardiac stimuli.

Asiatic acid inhibits cardiac hypertrophy by blocking interleukin-1ß-activated nuclear factor-κB signaling in vitro and in vivo.

BACKGROUND: Activated interleukin (IL)-1ß signaling pathway is closely associated with pathological cardiac hypertrophy. This study investigated whether asiatic acid (AA) could inhibit IL-1ß-related hypertrophic signaling, and thus suppressing the development of cardiac hypertrophy. METHODS: Transverse aortic constriction (TAC) induced cardiac hypertrophy in C57BL/6 mice and cultured neonatal cardiac myocytes stimulated with IL-1ß were used to evaluate the role of AA in cardiac hypertrophy. The expression of atrial natriuretic peptide (ANP) was evaluated by quantitative polymerase chain reaction (qPCR) and the nuclear factor (NF)-κB binding activity was measured by electrophoretic mobility shift assays (EMSA). RESULTS: AA pretreatment significantly attenuated the IL-1ß-induced hypertrophic response of cardiomyocytes as reflected by reduction in the cardiomyocyte surface area and the inhibition of ANP mRNA expression. The protective effect of AA on IL-1ß-stimulated cardiomyocytes was associated with the reduction of NF-κB binding activity. In addition, AA prevented TAC-induced cardiac hypertrophy in vivo. It was found that AA markedly reduced the excessive expression of IL-1ß and ANP, and inhibited the activation of NF-κB in the hypertrophic myocardium. CONCLUSIONS: Our data suggest that AA may be a novel therapeutic agent for cardiac hypertrophy. The inhibition of IL-1ß-activated NF-κB signaling may be the mechanism through which AA prevents cardiac hypertrophy.

Asiatic acid attenuates cardiac hypertrophy by blocking transforming growth factor-ß1-mediated hypertrophic signaling in vitro and in vivo.

Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. Transforming growth factor-ß1 (TGF-ß1) signaling has been considered as a trigger causally contributing to pathological cardiac hypertrophy. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica and exhibits a variety of pharmacological effects. In this study, we investigated the anti-hypertrophic effects and mechanisms of action of AA in a TGF-ß1-stimulated hypertrophic response using cultured neonatal cardiomyocytes in vitro and in a mouse model of cardiac hypertrophy induced by pressure overload in vivo. Treatment with AA markedly attenuated the TGF-ß1-induced hypertrophic responses of cardiomyocytes as reflected by reduction in the cardiomyocyte surface area and the inhibition of atrial natriuretic peptide (ANP) mRNA expression. The protective effects of AA on hypertrophic cardiomyocytes were associated with the blocking of p38 and extracellular signal­regulated kinase (ERK)1/2 phosphorylation and the reduction of nuclear factor-κB (NF-κB) binding activity. In vivo experiments indicated that the administration of AA prevented cardiac hypertrophy and dysfunction induced by pressure overload. It was found that AA markedly reduced the excessive production of TGF-ß1 in the hypertrophic myocardium, blocked the phosphorylation of p38 and ERK1/2 and inhibited the activation of NF-κB. Our data suggest that AA may be a novel therapeutic agent for cardiac hypertrophy. The inhibition of TGF-ß1­mediated hypertrophic signaling may be the mechanism through which AA prevents cardiac hypertrophy.

Genetic variants at 10p11 confer risk of Tetralogy of Fallot in Chinese of Nanjing.

A recent genome-wide association study (GWAS) has identified a new subset of susceptibility loci of Tetralogy of Fallot (TOF), one form of cyanotic congenital heart disease (CHD), on chromosomes 10p11, 10p14, 12q24, 13q31, 15q13 and 16q12 in Europeans. In the current study, we conducted a case-control study in a Chinese population including 1,010 CHD cases [atrial septal defect (ASD), ventricular septal defect (VSD) and TOF] and 1,962 controls to evaluate the associations of these loci with risk of CHD. We found that rs2228638 in NRP1 on 10p11 was significantly increased the risk of TOF (OR = 1.52, 95% CI = 1.13-2.04, P = 0.006), but not in other subgroups including ASD and VSD. In addition, no significant associations were observed between the other loci and the risk of ASD, VSD or TOF. Our results suggested that the genetic variants on 10p11 may serve as candidate markers for TOF susceptibility in Chinese population.

Intracellular lactate signaling cascade in atrial remodeling of mitral valvular patients with atrial fibrillation.

BACKGROUND: Atrial remodeling has emerged as the structural basis for the maintenance and recurrence of atrial fibrillation. Lactate signaling cascade was recently linked to some cardiovascular disorders for its regulatory functions to myocardial structural remodeling. It was hypothesized that lactate signaling cascade was involved in the maintenance and recurrence of atrial fibrillation by regulating atrial structural remodeling. METHODS: Biopsies of right atrial appendage and clinical data were collected from sex- and age-matched 30 persistent atrial fibrillation, 30 paroxysmal atrial fibrillation, 30 sinus rhythm patients undergoing isolated mitral valve surgery and 10 healthy heart donors. RESULTS: Atrial fibrillation groups had higher atrial lactate expression and this upregulated expression was positively correlated with regulatory indicators of atrial structural remodeling as reflected by severe oxidative stress injury and mitochondrial control of apoptosis. CONCLUSIONS: The present findings suggest a potential role for lactate signaling cascade in the maintenance and recurrence of atrial fibrillation and possibly represent new targets for therapeutic intervention in this disorder.