Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Assessing attitudes towards biostatistics education among medical students: adaptation and preliminary evaluation of the Chinese version survey of attitudes towards statistics (SATS-36).

BACKGROUND: Despite the numerous advantages of mastering biostatistics, medical students generally perceive biostatistics as a difficult and challenging subject and even experience anxiety during the courses. Evidence for the correlation between students' academic achievements and their attitudes, indicating that attitudes at the beginning of the biostatistics course may affect cognitive competence at the end of the course and subsequently influence student academic performance. However, there are current disagreements regarding the measurement and evaluation of attitudes related to statistics. Thus, there is a need for standard instruments to assess them. This study was conducted to develop a Chinese version of the Survey of Attitudes Toward Statistics (SATS-36) in order to acquire a valid instrument to measure medical students' attitudes toward biostatistics under Chinese medical educational background. METHODS: The Chinese version SATS-36 was developed through translation and back-translation of the original scale, with subsequent revisions based on expert advice to ensure the most appropriate item content. The local adaption was performed with a cohort of 1709 Chinese-speaking medical undergraduate and graduate students enrolled in biostatistics courses. And then, the reliability, validity and discrimination of the questionnaires were evaluated through correlation coefficient calculation, factor analysis, parallel analysis and other methods. RESULTS: The Chinese version SATS-36 consisted of 36 items and loaded a five-factor structure by factor analysis, which offered an alternative similar but not equal to that original six-factor structure. The cumulative variance contribution rate was 62.20%, the Cronbach's α coefficient was 0.908, the Guttman split-half reliability coefficient was 0.905 and the test-retest reliability coefficient was 0.752. Discriminant analysis revealed small to large significant differences in the five attitude subscales. CONCLUSIONS: The Chinese version SATS-36 with good validity and reliability in this study can be used to evaluate the learning framework of Chinese medical students.

Endovascular Treatment for Isolated Infected Iliac Artery Aneurysms.

PURPOSE: Isolated infected iliac artery aneurysms (IIIAAs) are extremely rare, life-threatening, and intractable. This study aimed to evaluate the outcomes of endovascular treatment in patients with IIIAAs. METHODS: A retrospective study was conducted for all patients who underwent endovascular treatment for IIIAAs between June 2012 and June 2022 in 3 hospitals. The clinical data and follow-up outcomes were reviewed and assessed. RESULTS: Fifteen patients were included in this study. The median age was 69 years, 12 patients (80%) were men, and 8 (53%) had hypertension. Most of the patients presented with abdominal or lumbar pain (87%) and fever (60%). The offending pathogen was identified in 11 patients (73%). Fifteen patients had a total of 16 IIIAAs, with 12 (75%) involving the common iliac artery. The immediate technical success rate was 100%, and the 30-day mortality was 7%. Infection-related complications occurred in 2 patients (13%) during hospitalization who were treated by open surgery at a later stage. The median follow-up was 23 months (range: 6-80 months, mean: 32 ± 25 months). Aneurysm recurrence was identified in one patient (7%) 5 months after endovascular repair. It was managed by endovascular stent-graft repair with percutaneous catheter drainage. No patients died during the follow-up period. CONCLUSION: Endovascular treatment is feasible, safe, and effective for patients with IIIAAs, achieving acceptable clinical outcomes. Infection surveillance with essential reintervention should be considered for potential infection-related complications. CLINICAL IMPACT: This study first reported that 15 patients underwent endovascular treatment for primary isolated infected iliac artery aneurysms (IIIAAs). It showed a good early and midterm outcomes. This is the first and largest multi-center study and the first literature review of IIIAAs. It provides an evidence that endovascular treatment is feasible, safe, and effective to treat IIIAAs. It suggests endovascular treatment is a promising alternative or a bridge to conventional open surgery for IIIAAs. This may promote endovascular therapy in the management of IIIAAs. It would help clinicians to make an appropriate treatment choice for IIIAAs.

Acinetobacter baumannii among Patients Receiving Glucocorticoid Aerosol Therapy during Invasive Mechanical Ventilation, China.

Acinetobacter baumannii is a nosocomial pathogen associated with severe illness and death. Glucocorticoid aerosol is a common inhalation therapy in patients receiving invasive mechanical ventilation. We conducted a prospective cohort study to analyze the association between glucocorticoid aerosol therapy and A. baumannii isolation from ventilator patients in China. Of 497 enrolled patients, 262 (52.7%) received glucocorticoid aerosol, and A. baumannii was isolated from 159 (32.0%). Glucocorticoid aerosol therapy was an independent risk factor for A. baumannii isolation (hazard ratio 1.5, 95% CI 1.02-2.28; p = 0.038). Patients receiving glucocorticoid aerosol had a higher cumulative hazard for A. baumannii isolation and analysis showed that glucocorticoid aerosol therapy increased A. baumannii isolation in most subpopulations. Glucocorticoid aerosol was not a direct risk factor for 30-day mortality, but A. baumannii isolation was independently associated with 30-day mortality in ventilator patients. Physicians should consider potential A. baumannii infection when prescribing glucocorticoid aerosol therapy.

Recent advances in nanomaterial-assisted detection coupled with capillary and microchip electrophoresis.

Nanomaterials have drawn much attention because of their unique properties enabling them to play important roles in various applications in different areas. This review covers literature data in the Web of Science from January 2017 to August 2020, focusing on the applications of nanomaterials (nanoparticles, quantum dots, nanotubes, and graphene) in CE and MCE to achieve enhanced sensitivity of several detection techniques: fluorescence, colorimetry, amperometry, and chemiluminescence /electrochemiluminescence. For the articles surveyed, the types of nanomaterials used, detection mechanisms, analytical performance, and applications are presented and discussed.

Up-regulation of paired-related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a.

Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). The aim of this study is to investigate whether the transcriptional factor paired-related homeobox 2 (Prrx2) regulates Wnt5a gene expression and the role in myocardial fibrosis following MI. The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodelling was assessed by measuring interstitial fibrosis performed with Masson staining. Cell differentiation was examined by analysis the expression of alpha-smooth muscle actin (α-SMA). Both Prrx2 and Wnt5a gene expressions were up-regulated in mice following MI, accompanied with increased mRNA and protein levels of α-SMA, collagen I and collagen III, compared to mice with sham surgery. Adenovirus-mediated gene knock down of Prrx2 increased survival rate, alleviated cardiac fibrosis, decreased infarction sizes and improved cardiac functions in mice with MI. Importantly, inhibition of Prrx2 suppressed ischaemia-induced Wnt5a gene expression and Wnt5a signalling. In cultured cardiac fibroblasts, TGF-ß increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. Further, overexpression of Prrx2 or Wnt5a mirrored the effects of TGF-ß on cell differentiations of cardiac fibroblasts. Gene silence of Wnt5a also ablated cell differentiations induced by Prrx2 overexpression in cardiac fibroblasts. Mechanically, Prrx2 was able to bind with Wnt5a gene promoter to up-regulate Wnt5a gene expression. In conclusions, targeting Prrx2-Wnt5a signalling should be considered to improve cardiac remodelling in patients with ischaemic heart diseases.

Label-free, sensitive colorimetric detection of mercury(II) by target-disturbed in situ seeding growth of gold triangular nanoprisms.

Gold nanomaterials have been used extensively in colorimetric detection of mercuric ions (Hg2+) due to their shape- and size-dependent, ultrastrong localized surface plasmon resonance (LSPR). Conventional detection was performed by first synthesizing the nanomaterials, and then applying them to signal-transducing reactions. We herein report a convenient method for detecting Hg2+ based on gold triangular nanoprisms (AuTNPs). During the seeding-growth process, Hg2+ added to the growth solution was co-reduced and deposited on the high-energy facets of the gold seeds, affecting the deposition patterns of the subsequently generated Au0 and ultimately leading to the formation of defective AuTNPs. Morphological changes were reflected by the in-plane dipole LSPR wavelength shift, which was proportionally related to the concentration of Hg2+. To improve the selectivity, the interference from Ag+ was eliminated by a stepwise preparation-selective precipitation approach. Under the optimized conditions, Hg2+ could be selectively detected with 20 min, with a detection limit of 0.12 nM. Finally, the method was successfully applied to detecting trace Hg2+ in fortified drinking, mineral and rain water samples, with recoveries ranging from 95.17% to 110.6%.

Pirfenidone Inhibits Hypoxic Pulmonary Hypertension through the NADPH/ROS/p38 Pathway in Adventitial Fibroblasts in the Pulmonary Artery.

Hypoxic pulmonary hypertension (HPH) is a devastating disease characterized by progressive vasoconstriction and vascular remodeling. Pirfenidone (PFD) inhibits the progression of HPH, though the molecular mechanisms remain unknown. This study is aimed at determining the role and mechanism of PFD in HPH in human pulmonary artery adventitial fibroblasts (HPAAFs), which were cultured under normal or hypoxic conditions. NOX4 and Rac1 were inhibited or overexpressed by shRNA or pcDNA3.1, respectively. Proliferation of HPAAFs was quantified by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays to assess cellular metabolic activity, cell counts, and ethynyldeoxyuridine (EdU) assays to detect DNA synthesis. Migration of HPAAFs was assessed by a wound healing assay. The expression levels of smooth muscle alpha-actin (a-SMA) and procollagen I (COL1A1) were assessed by RT-PCR and western blot analysis. PFD suppressed hypoxia-induced proliferation and migration of HPAAFs. Compared with the hypoxic control group, PFD reduced the expression of a-SMA and procollagen I (COL1A1). PFD reduced hypoxia-induced phosphorylation of p38 through the NOX4/reactive oxygen species (ROS) signaling pathway. Moreover, Rac1 also decreased hypoxia-induced phosphorylation of p38, without any cross-interaction with NOX4. These findings demonstrate that PFD is a novel therapeutic agent to prevent cell proliferation, migration, and fibrosis, which might be useful in inhibiting vascular remodeling in patients with HPH.

Regulatory T cells protected against abdominal aortic aneurysm by suppression of the COX-2 expression.

CD4+ CD25+ regulatory T cells (Tregs) have been shown to protect against the development of abdominal aortic aneurysm (AAA). Cyclooxygenase-2 (COX-2), a pro-inflammatory protein, can convert arachidonic acid into prostaglandins (PGs). The present study was aimed to investigate the effect of Tregs on COX-2 expression in angiotension II (Ang II)-induced AAA in ApoE-/- mice. Tregs were injected via tail vein in every 2 weeks. Ang II was continuously infused by a micropump for 28 days to induce AAA. In vivo, compared with the control group, adoptive transfer of Tregs significantly reduced the incidence of AAA, maximal diameter, and the mRNA and protein expression of COX-2 in mice. Immunofluorescence showed that Tregs treatment reduced COX-2 expression both in smooth muscle cells (SMCs) and macrophages in AAA. In vitro, the Western blot analysis showed that Tregs reduced Ang II-induced COX-2 expression in macrophages and SMCs. Meanwhile, ELISA showed that Tregs reduced Ang II-induced prostaglandin E2 (PGE2 ) secretion. Moreover, Tregs increased SMC viability and induced transition of macrophages phenotype from M1 to M2. In conclusion, Tregs treatment dramatically decreased the expression of COX-2 in vivo and in vitro, suggesting that Tregs could protect against AAA through inhibition of COX-2. The study may shed light on the immune treatment of AAA.

A gold nanorod-based plasmonic platform for multi-logic operation and detection.

A multi-logic gate platform was designed based on morphological changes of gold nanorods (AuNRs) resulted from the iodine-mediated etching. By utilizing the anti-etching effects of mercapto compounds and Au-Hg amalgams as well as the etch-promoting effect of Cu2+, we successfully built five logic gates, namely, AND, NOR, XNOR, YES and IMPLY, along with a three-input combinational logic gate XNOR-IMPLY. The platform was versatile and easy to use, did not require complex surface modification or separation/purification steps as the conventional AuNR-based logic gates did. The logic operations, accompanied by distinct color changes, enabled multi-task detection by naked-eye for 'have' or 'none' discrimination or highly sensitive and selective analysis by spectroscopy with wide linear ranges.

Remifentanil Protects against Lipopolysaccharide-Induced Inflammation through PARP-1/NF-κB Signaling Pathway.

Sepsis is a leading cause of death in patients with severe infection worldwide. Remifentanil is an ultra-short-acting, potent opioid analgesic. In the study, we aimed to investigate the role and underlying mechanism of remifentanil in lipopolysaccharide- (LPS-) induced inflammation in human aortic endothelial cells (HAECs). HAECs were pretreated with phosphate-buffered saline (PBS) or remifentanil (2.5 µM) for 30 min, then stimulated by LPS (10 µg/ml) for another 24 h. Poly(ADP-ribose) polymerase 1 (PARP-1) was inhibited by small interfering RNA (siRNA). Superoxide anion production and DNA damage were analyzed by dihydroethidium (DHE) staining and comet assay. The inducible nitric oxide synthase (iNOS), intercellular adhesion molecule 1 (ICAM-1), PARP-1, poly(ADP-ribose) (PAR), and nuclear factor-kappa B p65 (NF-κB p65) expressions were analyzed by RT-PCR or western blotting analysis. NF-κB p65 nuclear translocation was assessed by immunofluorescence. Compared with the control group, pretreatment with remifentanil significantly reduced superoxide anion production and DNA damage, with downregulation of iNOS, ICAM-1, and PARP-1 expressions as well as PAR expression. Moreover, pretreatment with PARP-1 siRNA or remifentanil inhibited LPS-induced NF-κB p65 expression and nuclear translocation. Remifentanil reduced LPS-induced inflammatory response through PARP-1/NF-κB signaling pathway. Remifentanil might be an optimal choice of analgesia in septic patients.

Inhibition of cardiac hypertrophy by aromadendrin through down-regulating NFAT and MAPKs pathways.

Cardiac hypertrophy is a maladaptive response to pressure overload and it's an important risk factor for heart failure and other adverse cardiovascular events. Aromadendrin (ARO) has remarkable anti-lipid peroxidation efficacy and is a potential therapeutic medicine for the management of diabetes and cardiovascular diseases. In this study, we established the cardiac hypertrophy cell model in rat neonatal ventricular cardiomyocytes (RNVMs) with phenylephrine. The cell model was characterized by the increased protein synthesis and cardiomyocyte size, which can be normalized by ARO treatment in both concentration- and time-dependent manner. In transverse aortic constriction (TAC) induced cardiac hypertrophy model, ARO administration improved the impairment of cardiac function and alleviated the cardiac hypertrophy indicators, like ventricular mass/body weight, myocyte cross-sectional area, and the expression of ANP, BNP and Myh7. ARO treatment also suppressed the cardiac fibrosis and the correlated fibrogenic genes. Our further investigation revealed ARO could down-regulate pressure overload-induced Malondialdehyde (MDA) and 4-HNE expression, restore the decrease of GSH/GSSG ratio, meanwhile prevent nuclear translocation of NFAT and the activation of MAPKs pathways. Collectively, ARO has a protective effect against experimental cardiac hypertrophy in mice, suggesting its potential as a novel therapeutic drug for pathological cardiac hypertrophy.

Predictive Value of Serum Albumin Level for the Prognosis of Severe Sepsis Without Exogenous Human Albumin Administration: A Prospective Cohort Study.

BACKGROUND:: The prognostic significance of serum albumin levels in patients with sepsis has previously been reported; however, these studies have not excluded the potential confounding effect of exogenous albumin administration. In this study, we investigate the predictive value of serum albumin for the prognosis of severe sepsis without the interference of exogenous albumin administration. METHODS:: A prospective cohort study was conducted from April to November 2014 in the internal and surgical intensive care units of a tertiary care hospital. During the study period, due to a supply shortage, patients were not treated with human albumin. Serum albumin levels were measured, and laboratory and clinical data were collected at the onset of severe sepsis. Prognostic factors were analyzed using receiver operating characteristic curve and multivariate Cox proportional hazard regression analysis. Survival was assessed by Kaplan-Meier method. RESULTS:: One hundred sixteen patients were included in the study. The overall 28-day mortality was 26.7%. The most common infection sources were lower respiratory tract, abdomen/pelvis, and bloodstream. Compared to patients who survived, those who died had lower serum albumin levels and higher Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Receiver operating characteristic curves demonstrate that albumin level is a strong predictor of 28-day mortality, and the optimal cutoff value maximizing sensitivity and specificity is 29.2 g/L. Through multivariate Cox regression analysis, low serum albumin levels (<29.2 g/L) and APACHE II scores are identified as independent risk factors for mortality. Patients with lower serum albumin levels more often had abdominal/pelvic sources of infection, acute kidney or liver injury, septic shock, and higher APACHE II and SOFA scores. The 28-day survival rate was lower for patients with serum albumin below 29.2 g/L than for patients with serum albumin at or above this level. CONCLUSION:: Having excluded potential confounding effect of exogenous albumin administration, low serum albumin levels are associated with an increased risk of death in patients with severe sepsis.

Isoquercitrin protects against pulmonary hypertension via inhibiting PASMCs proliferation.

Pulmonary vascular remodelling is a common feature among the heterogeneous disorders that cause pulmonary arterial hypertension (PAH), and pulmonary arterial smooth muscle cells (PASMCs) proliferation impact the long-term prognosis of the patient. Isoquercitrin (IQC) is a flavonoid with anti-oxidative, anti-inflammatory and anti-proliferative activations. This study aimed to investigate whether IQC could prevent PASMCs proliferation and vascular remodelling in monocrotaline (MCT) induced PAH. Male Wistar rats were administered with Vehicle or 0.1% IQC maintain feed after MCT (40 mg/kg) injection. Haemodynamic changes, right ventricular hypertrophy and lung morphological features were assessed 3 weeks later. MCT-induced PAH, pulmonary vascular remodelling and PASMCs proliferation in Vehicle-treated rats. IQC reduced the right ventricle systolic pressure (RVSP), the ratio of RV/LV+S and the RV hypertrophy. IQC significantly alleviated the expression of proliferating cell nuclear antigen (PCNA), smooth muscle α-actin (α-SMA), and the percentage of fully muscularized small arterioles. In vitro studies, PASMCs were pretreated with IQC and stimulated with platelet-derived growth factor (PDGF)-BB (20 ng/mL). IQC suppressed PDGF-BB-induced PASMCs proliferation and caused G0/G1 phase cell cycle arrest. IQC downregulated the expression of Cyclin D1 and CDK4 as well as inhibited p27Kip1 degradation. Meanwhile, IQC negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rß, Akt/GSK3ß and ERK1/2. IQC ameliorated MCT-induced pulmonary vascular remodelling via suppressing PASMCs proliferation and blocking PDGF-Rß signalling pathway.

Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia.

Hypoxia-induced pulmonary arterial hypertension (HPAH) is a refractory disease characterized by increased proliferation of pulmonary vascular smooth cells and progressive pulmonary vascular remodeling. The level of nitric oxide (NO), a potential therapeutic vasodilator, is low in PAH patients. L-arginine can be converted to either beneficial NO by nitric oxide synthases or to harmful urea by arginase. In the present study, we aimed to investigate whether an arginase inhibitor, S-(2-boronoethyl)-L-cysteine ameliorates HPAH in vivo and vitro. In a HPAH mouse model, we assessed right ventricle systolic pressure (RVSP) by an invasive method, and found that RSVP was elevated under hypoxia, but was attenuated upon arginase inhibition. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions, and their proliferative capacity was determined by cell counting and flow cytometry. The levels of cyclin D1, p27, p-Akt, and p-ERK were detected by RT-PCR or Western blot analysis. Compared to hypoxia group, arginase inhibitor inhibited HPASMCs proliferation and reduced the levels of cyclin D1, p-Akt, p-ERK, while increasing p27 level. Moreover, in mouse models, compared to control group, hypoxia increased cyclin D1 expression but reduced p27 expression, while arginase inhibitor reversed the effects of hypoxia. Taken together, these results suggest that arginase plays an important role in increased proliferation of HPASMCs induced by hypoxia and it is a potential therapeutic target for the treatment of pulmonary hypertensive disorders.

HMGB1 mediates hyperglycaemia-induced cardiomyocyte apoptosis via ERK/Ets-1 signalling pathway.

Apoptosis is a key event involved in diabetic cardiomyopathy. The expression of high mobility group box 1 protein (HMGB1) is up-regulated in diabetic mice. However, the molecular mechanism of high glucose (HG)-induced cardiomyocyte apoptosis remains obscure. We aimed to determine the role of HMGB1 in HG-induced apoptosis of cardiomyocytes. Treating neonatal primary cardiomyocytes with HG increased cell apoptosis, which was accompanied by elevated levels of HMGB1. Inhibition of HMGB1 by short-hairpin RNA significantly decreased HG-induced cell apoptosis by reducing caspase-3 activation and ratio of Bcl2-associated X protein to B-cell lymphoma/leukemia-2 (bax/bcl-2). Furthermore, HG activated E26 transformation-specific sequence-1 (Ets-1), and HMGB1 inhibition attenuated HG-induced activation of Ets-1 via extracellular signal-regulated kinase 1/2 (ERK1/2) signalling. In addition, inhibition of Ets-1 significantly decreased HG-induced cardiomyocyte apoptosis. Similar results were observed in streptozotocin-treated diabetic mice. Inhibition of HMGB1 by short-hairpin RNA markedly decreased myocardial cell apoptosis and activation of ERK and Ets-1 in diabetic mice. In conclusion, inhibition of HMGB1 may protect against hyperglycaemia-induced cardiomyocyte apoptosis by down-regulating ERK-dependent activation of Ets-1.

Poly(ADP-ribose) polymerase 1 inhibition protects against low shear stress induced inflammation.

BACKGROUND: Atherosclerosis begins as local inflammation of vessels at sites of disturbed flow, where low shear stress (LSS) leads to mechanical irritation and plaque development and progression. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with the inflammation response during atherosclerosis. We investigated the role and underlying mechanism of PARP-1 in LSS-induced inflammation in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: HUVECs were simulated by LSS (0.4Pa). PARP-1 expression was inhibited by ABT888 or siRNA. The inducible nitric oxide synthase (iNOS) and intercellular adhesion molecular-1 (ICAM-1) expression was regulated by LSS in a time dependent manner. LSS could increase superoxide production and 3-nitrotyrosine formation. LSS induced DNA damage as assessed by H2A.X phosphorylation and comet assay. Compared with cells under static, LSS increased PARP-1 expression and PAR formation via MEK/ERK signaling pathway. PARP-1 inhibition increased Sirt1 activity through an increased intracellular nicotinamide adenine dinucleotide (NAD(+)) level. Moreover, PARP-1 inhibition attenuated LSS-induced iNOS and ICAM-1 upregulation by inhibiting nuclear factor kappa B (NF-κB) nuclear translocation and activity, with a reduced NF-κB phosphorylation. CONCLUSIONS: LSS induced oxidative damage and PARP-1 activation via MEK/ERK pathway. PARP-1 inhibition restored Sirt1 activity by increasing NAD(+) level and decreased iNOS and ICAM-1 expression by inhibiting NF-κB nuclear translocation and activity as well as NF-κB phosphorylation. PARP-1 played a fundamental role in LSS induced inflammation. Inhibition of PARP-1 might be a mechanism for treatment of inflammation response during atherosclerosis.

Poly(ADP-ribose) polymerase inhibition prevents reactive oxygen species induced inhibition of aldehyde dehydrogenase2 activity.

Lipid peroxidation plays a critical role in cardiovascular diseases. Aldehydes are the major end products of lipid peroxidation and can be metabolized into less reactive chemical species by aldehyde dehydrogenase 2 (ALDH2). However, ALDH2 dehydrogenase activity can be affected by many factors including reactive oxygen species. To elucidate how reactive oxygen species inhibit ALDH2 dehydrogenase activity, we stimulated human aortic endothelial cells (HAECs) with oxidized low-density lipoproteins (ox-LDL) and performed a myocardial ischemia-reperfusion model. Ox-LDL treatment and ischemia-reperfusion injury inhibited ALDH2 dehydrogenase activity. Poly(ADP-ribose) polymerase (PARP) was activated by ox-LDL stimulation and ischemia-reperfusion injury and PARP inhibition partly restored ALDH2 dehydrogenase activity in ox-LDL treated HAECs and ischemia-reperfusion rat hearts. SIRT3 was upregulated by ox-LDL stimulation and ischemia-reperfusion injury and downregulated by PARP inhibition. Using siRNA to knock down SIRT3, we demonstrated that SIRT3 mediated deacetylation decreased ALDH2 dehydrogenase activity and PARP inhibition partly restored ALDH2 dehydrogenase activity through preventing SIRT3 expression and subsequently preserving ALDH2 acetylation.