Polystyrene nanoplastics and cadmium co-exposure aggravated cardiomyocyte damage in mice by regulating PANoptosis pathway.

Micro/nanoplastics (M/NPs) are the novel contaminants ubiquitous in the environment. Cadmium (Cd), a kind of heavy metal pollutant widely distributed, could potentially co-exist with PS-NPs in the environment. However, their combined effects on cardiomyocyte and its molecular mechanism in mammals remained ambiguous. Here, we examined whether PANoptosis, an emerging and complicated kind of programmed cell death, was involved in PS-NPs and Cd co-exposure-elicited cardiac injury. In this study, 60 male mice were orally subjected to environmentally relevant concentrations of PS-NPs (1 mg/kg) and/or CdCl2 (1.5 mg/kg) for 35 days. As we speculated, PS-NPs and Cd co-exposure affected the expression of pyroptosis(Caspase-1, Cleaved-Caspase-1, GSDMD, N-GSDMD, AIM2, Pyrin, NLRP3, IL-18, IL-1ß)-, apoptosis(Caspase-3, Cleaved-Caspase-3, Caspase-8, Cleaved-Caspase-8, Caspase-7, BAX)- and necroptosis (t-RIPK3, p-RIPK3, t-RIPK1, p-RIPK1, t-MLKL, p-MLKL, ZBP1)-related genes and protein, resulting in growth restriction and damaged myocardial microstructure in mice. Notably, the combined effects on Cd and PS-NPs even predominantly aggravated the toxic damage. Intriguingly, we fortuitously discovered PS-NPs and/or Cd exposure facilitated linear ubiquitination of certain proteins in mice myocardium. In summation, this study shed light toward the effects of Cd and PS-NPs on cardiotoxicity, advanced the understanding of myocardial PANoptosis and provided a scientific foundation for further exploration of the combined toxicological effects of PS-NPs and heavy metals.

N-acetylcysteine combined with insulin attenuates myocardial injury in canines with type 1 diabetes mellitus by modulating TNF-α-mediated apoptotic pathways and affecting linear ubiquitination.

The exact pathogenesis of type 1 diabetes mellitus (DM) is still unclear. Numerous organs, including the heart, will suffer damage and malfunction as a result of long-term hyperglycemia. Currently, insulin therapy alone is still not the best treatment for type 1 DM. In order to properly treat and manage patients with type 1 DM, it is vital to seek a combination that includes both insulin and additional medications. This study aims to explore the therapeutic effect and mechanism of N-acetylcysteine (NAC) combined with insulin on type 1 DM. By giving beagle canines injections of streptozotocin (STZ) and alloxan (ALX) (20 mg/kg each), a model of type 1 DM was created. The results showed that this combination could effectively control blood sugar level, improve heart function, avoid the damage of mitochondria and myocardial cells, and prevent the excessive apoptosis of myocardial cells. Importantly, the combination can activate nuclear factor kappa-B (NF-κB) by promoting linear ubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB-essential modulator (NEMO) and inhibitor of NF-κB (IκB) phosphorylation. The combination can increase the transcription and linear ubiquitination of Cellular FLICE (FADD-like IL-1ß-converting enzyme) -inhibitory protein (c-FLIP), diminish the production of cleaved-caspase-8 p18 and cleaved-caspase-3 to reduce apoptosis. This study confirmed that NAC combined with insulin can promote the linear ubiquitination of RIPK1, NEMO and c-FLIP and regulate the apoptosis pathway mediated by TNF-α to attenuate the myocardial injury caused by type 1 DM. Meanwhile, the research served as a resource when choosing a clinical strategy for DM cardiac complications.

Differential diagnosis of secondary hypertension based on deep learning.

Secondary hypertension is associated with higher risks of target organ damage and cardiovascular and cerebrovascular disease events. Early aetiology identification can eliminate aetiologies and control blood pressure. However, inexperienced doctors often fail to diagnose secondary hypertension, and comprehensively screening for all causes of high blood pressure increases health care costs. To date, deep learning has rarely been involved in the differential diagnosis of secondary hypertension. Relevant machine learning methods cannot combine textual information such as chief complaints with numerical information such as the laboratory examination results in electronic health records (EHRs), and the use of all features increases health care costs. To reduce redundant examinations and accurately identify secondary hypertension, we propose a two-stage framework that follows clinical procedures. The framework carries out an initial diagnosis process in the first stage, on which basis patients are recommended for disease-related examinations, followed by differential diagnoses of different diseases based on the different characteristics observed in the second stage. We convert the numerical examination results into descriptive sentences, thus blending textual and numerical characteristics. Medical guidelines are introduced through label embedding and attention mechanisms to obtain interactive features. Our model was trained and evaluated using a cross-sectional dataset containing 11,961 patients with hypertension from January 2013 to December 2019. The F1 scores of our model were 0.912, 0.921, 0.869 and 0.894 for primary aldosteronism, thyroid disease, nephritis and nephrotic syndrome and chronic kidney disease, respectively, which are four kinds of secondary hypertension with high incidence rates. The experimental results show that our model can powerfully use the textual and numerical data contained in EHRs to provide effective decision support for the differential diagnosis of secondary hypertension.

lncRNA NBR2 attenuates angiotensin II-induced myocardial hypertrophy through repressing ER stress via activating LKB1/AMPK/Sirt1 pathway.

Myocardial hypertrophy leads to heart failure (HF), and emerging researchers have illustrated that long noncoding RNAs (lncRNAs) modulate myocardial hypertrophy. Here, we explored the role and mechanism of a novel lncRNA, NBR2, in modulating angiotensin II (Ang II)-induced myocardial hypertrophy. First, we examined plasma NBR2 levels in 25 patients with HF and myocardial hypertrophy and ten healthy donors and analyzed the correlation between NBR2 profiles and patients' clinical indicators. In addition, the overexpression experiment of NBR2 was carried out to probe the influence of NBR2 on myocardial hypertrophy. lncRNA NBR2 was down-regulated in plasma of patients with HF and myocardial hypertrophy (vs. healthy controls), and its level was negatively correlated with cardiac function (represented by left ventricular end-diastolic diameter and left ventricular ejection fraction) and degree of myocardial hypertrophy. Besides, Ang II treatment intensified the hypertrophy of human myocardial cell lines (HCM and AC16) and curbed the NBR2 expression. Overexpressing lncRNA NBR2 alleviated Angiotension II-induced myocardial hypertrophy and declined the profiles of hypertrophic markers. Moreover, up-regulating lncRNA NBR2 weakened Ang II-mediated endoplasmic reticulum (ER) stress and activated the LKB1/AMPK/Sirt1 pathway. Interfering with the LKB1/AMPK/Sirt1 axis abated the lncRNA NBR2-mediated inhibitory effect on myocardial hypertrophy and ER stress. This study confirmed that lncRNA NBR2 dampened myocardial hypertrophy and ER stress by modulating the LKB1/AMPK/Sirt1 pathway. Our study provides the first evidence that lncRNA NBR2 is positively associated with myocardial hypertrophy.

Gene regulatory network analysis identifies key genes and regulatory mechanisms involved in acute myocardial infarction using bulk and single cell RNA-seq data.

Cardiovascular and cerebrovascular diseases are leading causes of death worldwide, accounting for more than 40% of all deaths in China. Acute myocardial infarction (AMI) is a common cardiovascular disease and traditionally divided into ST-segment (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), which are known with different prognoses and treatment strategies. However, key regulatory genes and pathways involved in AMI that may be used as potential biomarker for prognosis are unknown. In this study, we employed both bulk and single-cell RNA-seq to construct gene regulatory networks and cell-cell communication networks. We first constructed weighted gene co-expression networks for differential expressed genes between STEMI and NSTEMI patients based on whole-blood RNA-seq transcriptomics. Network topological attributes (e.g., node degree, betweenness) were analyzed to identify key genes involved in different functional network modules. Furthermore, we used single-cell RNA-seq data to construct multilayer signaling network to infer regulatory mechanisms of the above key genes. PLAUR (receptor for urokinase plasminogen activator) was found to play a vital role in transducing inter-cellular signals from endothelial cells and fibroblast cells to intra-cellular pathways of myocardial cells, leading to gene expression involved in cellular response to hypoxia. Our study sheds lights on identifying molecular biomarkers for diagnosis and prognosis of AMI, and provides candidate key regulatory genes for further experimental validation.

p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart.

In the mammalian heart, the left ventricle (LV) rapidly becomes more dominant in size and function over the right ventricle (RV) after birth. The molecular regulators responsible for this chamber-specific differential growth are largely unknown. We found that cardiomyocytes in the neonatal mouse RV had lower proliferation, more apoptosis, and a smaller average size compared with the LV. This chamber-specific growth pattern was associated with a selective activation of p38 mitogen-activated protein kinase (MAPK) activity in the RV and simultaneous inactivation in the LV. Cardiomyocyte-specific deletion of both the Mapk14 and Mapk11 genes in mice resulted in loss of p38 MAPK expression and activity in the neonatal heart. Inactivation of p38 activity led to a marked increase in cardiomyocyte proliferation and hypertrophy but diminished cardiomyocyte apoptosis, specifically in the RV. Consequently, the p38-inactivated hearts showed RV-specific enlargement postnatally, progressing to pulmonary hypertension and right heart failure at the adult stage. Chamber-specific p38 activity was associated with differential expression of dual-specific phosphatases (DUSPs) in neonatal hearts, including DUSP26. Unbiased transcriptome analysis revealed that IRE1α/XBP1-mediated gene regulation contributed to p38 MAPK-dependent regulation of neonatal cardiomyocyte proliferation and binucleation. These findings establish an obligatory role of DUSP/p38/IRE1α signaling in cardiomyocytes for chamber-specific growth in the postnatal heart.

Ginsenoside Rb1 inhibits free fatty acids­induced oxidative stress and inflammation in 3T3­L1 adipocytes.

Free fatty acids (FFAs) increase in visceral fat and are inferred to be one of the underlying inducers of adipose tissue inflammation. In our previous study, it was demonstrated that ginsenoside Rb1 stimulates endothelial nitric oxide synthase (eNOS) and Sirtuin 1 to protect against endothelial cell senescence. In the present study, 3T3­L1 adipocytes were exposed to 0.5 mM FFAs with or without Rb1 (10­40 µM). Monocyte chemotactic protein­1 (MCP­1) and interleukin­6 (IL­6) secretion was measured using ELISA. Tumor necrosis factor­α (TNF­α) expression and nuclear factor­κB (NF­κB) p65 phosphorylation were detected using western blot analysis. Oxidative stress was determined via measuring intracellular reactive oxygen species (ROS) and nitric oxide (NO) production. The results demonstrated that MCP­1 and IL­6 secretion, as well as TNF­α expression, were significantly increased following FFA treatment, which was attenuated by Rb1 in a dose­dependent manner. Furthermore, Rb1 attenuated FFA­induced NF­κB phosphorylation, suggesting that the inhibitory effect of Rb1 on inflammatory cytokines was partially mediated through blockade of NF­κB phosphorylation. Further experiments demonstrated that Rb1 ameliorated FFA­induced ROS generation and NO reduction through upregulation of superoxide dismutase 2 and eNOS expression. Taken together, these results demonstrate proinflammatory and pro­oxidant effects of FFA on 3T3­L1 adipocytes, which are effectively ameliorated by Rb1. Suppression of inflammatory responses and oxidative stress may be a novel mechanism for attenuating the effect of Rb1 on adipocyte dysfunction.

Adenosine monophosphate-activated protein kinase attenuates cardiomyocyte hypertrophy through regulation of FOXO3a/MAFbx signaling pathway.

Control of cardiac muscle mass is thought to be determined by a dynamic balance of protein synthesis and degradation. Recent studies have demonstrated that atrophy-related forkhead box O 3a (FOXO3a)/muscle atrophy F-box (MAFbx) signaling pathway plays a central role in the modulation of proteolysis and exert inhibitory effect on cardiomyocyte hypertrophy. In this study, we tested the hypothesis that adenosine monophosphate-activated protein kinase (AMPK) activation attenuates cardiomyocyte hypertrophy by regulating FOXO3a/MAFbx signaling pathway and its downstream protein degradation. The results showed that activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated cardiomyocyte hypertrophy induced by angiotensin II (Ang II). The antihypertrophic effects of AICAR were blunted by AMPK inhibitor Compound C. In addition, AMPK dramatically increased the activity of transcription factor FOXO3a, up-regulated the expression of its downstream ubiquitin ligase MAFbx, and enhanced cardiomyocyte proteolysis. Meanwhile, the effects of AMPK on protein degradation and cardiomyocyte hypertrophy were blocked after MAFbx was silenced by transfection of cardiomyocytes with MAFbx-siRNA. These results indicate that AMPK plays an important role in the inhibition of cardiomyocyte hypertrophy by activating protein degradation via FOXO3a/MAFbx signaling pathway.

Advanced glycation end products upregulate angiopoietin-like protein 4 expression by activating the renin-angiotensin system in endothelial cells.

The aim of the present study was to investigate the effects of advanced glycation end products (AGEs) on the expression of angiopoietin-like protein 4 (ANGPTL4) and the mechanisms of the effects in endothelial cells. Endothelial cells were incubated with various concentrations of AGEs for 24 h and the expression of ANGPTL4 was detected by quantitative polymerase chain reaction and western blot analysis. The concentration of angiotensin II (Ang II) in conditioned media and cell lysates was measured by enzyme-linked immunosorbent assays. Fluorescein isothiocyanate-labeled dextran filtration assays and transendothelial electrical resistance were performed to evaluate endothelial permeability. AGEs (80 µg/ml) increased the expression of ANGPTL4 and the levels of Ang II (P<0.05). Incubation with AGEs also resulted in a significant increase in endothelial permeability (P<0.05). However, pretreatment with the Ang II receptor blocker losartan (10-5 M) reduced the effects of AGEs (P<0.05). AGEs upregulated the expression of ANGPTL4 by activating a local renin-angiotensin system in endothelial cells. This may be a new mechanism by which AGEs increase endothelial permeability.

Ginsenoside Rb1 prevents H2O2-induced HUVEC senescence by stimulating sirtuin-1 pathway.

PURPOSES: We have previously reported that Ginsenoside Rb1 may effectively prevent HUVECs from senescence, however, the detailed mechanism has not demonstrated up to now. Recent studies have shown that sirtuin-1 (Sirt1) plays an important role in the development of endothelial senescence. The purpose of this study was to explore whether Sirt1 is involved in the action of Ginsenoside Rb1 regarding protection against H2O2-induced HUVEC Senescence. METHODS AND RESULTS: Senescence induced by hydrogen peroxide (H2O2) in human umbilical vein endothelial cells (HUVECs) was examined by analyzing plasminogen activator inhibitor-1 (PAI-1) expression, cell morphology, and senescence-associated beta-galactosidase (SA-ß-gal) activity. The results revealed that 42% of control-treated HUVECs were SA-ß-gal positive after treatment by 60 µmol/L H2O2, however, this particular effect of H2O2 was decreased more than 2-fold (19%) in the HUVECs when pretreated with Rb1 (20 µmol/L) for 30 min. Additionally, Rb1 decreased eNOS acetylation, as well as promoted more NO production that was accompanied by an increase in Sirt1 expression. Furthermore, upon knocking down Sirt1, the effect of Rb1 on HUVEC senescence was blunted. CONCLUSIONS: The present study indicated that Ginsenoside Rb1 acts through stimulating Sirt1 in order to protect against endothelial senescence and dysfunction. As such, Sirt1 appears to be of particular importance in maintaining endothelial functions and delaying vascular aging.

Association of serum gamma-glutamyltransferase with arterial stiffness in established coronary artery disease.

Serum gamma-glutamyltransferase (GGT) has been reported to predict vascular risk. We enrolled 978 patients (507 men and 471 women) with established coronary artery disease (CAD). The GGT, brachial-ankle pulse wave velocity ([baPWV] to assess arterial stiffness), and conventional risk factors were evaluated. The means of baPWV tend to increase in both genders according to GGT tertiles. Body mass index, GGT, logarithmical (systolic blood pressure [LnSBP]), uric acid (UA), total bilirubin, Ln (cholinesterase), and Ln (total cholesterol) were correlated with baPWV in men in a multivariate model. However, only GGT, LnSBP, UA, and Ln (high-density lipoprotein cholesterol) were correlated with baPWV in women. The GGT was a significant determinant for increased baPWV both in men (ß = 0.017; P < .001) and in women (ß = 0.015; P < .001). In conclusion, GGT was independently associated with increased arterial stiffness both in men and in women with established CAD.

Proteasome inhibition attenuates heart failure during the late stages of pressure overload through alterations in collagen expression.

Although the role of the ubiquitin-proteasome system (UPS) in cardiac hypertrophy induced by pressure overload has been consistently studied, the fundamental importance of the UPS in cardiac fibrosis has received much less attention. Our previous study found that proteasome inhibitor (MG132) treatment attenuated cardiac fibrosis and heart failure during the early and middle stages of pressure overload. However, the effects of this inhibitor on late-stage pressure overload hearts remain unclear and controversial. The present study was designed to investigate the effects and possible mechanisms of MG132 on cardiac fibrosis and dysfunction during the late stages of pressure overload. Male Sprague Dawley rats with abdominal aortic constriction (AAC) or a sham operation received an intraperitoneal injection of MG132 (0.1 mg kg⁻¹ day⁻¹) or vehicle for 16 weeks. Left ventricular (LV) function, collagen deposition and Ang II levels were evaluated at study termination. Ang II-stimulated adult rat cardiac fibroblasts were utilized to examine the effects of MG132 on collagen synthesis and the relationship between the renin-angiotensin-aldosterone system (RAAS) and the UPS. MG132 treatment attenuated ventricular dysfunction by suppressing cardiac fibrosis rather than inhibiting cardiac hypertrophy during the late-stages of pressure overload. We also found that Ang II activates UPS in the heart and MG132 attenuates Ang II-induced collagen synthesis via suppression of the NF-κB/TGF-ß/Smad2 signaling pathways. Proteasome inhibition therefore could provide a new promising therapeutic strategy to prevent cardiac fibrosis and progression of heart failure even during the late-stages of pressure overload.

Association of arterial stiffness with serum bilirubin levels in established coronary artery disease.

OBJECTIVE: Elevated serum bilirubin concentrations protect from atherosclerotic diseases, however it is not clear whether or not higher serum bilirubin concentrations have the same effect in coronary artery disease (CAD). The brachial-ankle pulse wave velocity (baPWV) is a reproducible method to assess arterial stiffness. This study was aimed to investigate the relationship between serum total bilirubin (TB) and baPWV in patients with established CAD. METHODS: We enrolled 638 patients (390 men, 248 women) with established CAD. TB was divided into tertiles. Simple and multiple linear regression analyses were used to assess the correlation between baPWV and TB. RESULTS: The mean baPWV tended to decrease in men according to TB tertiles: Tertile 1=2,126.0, Tertile 2=1,832.5, and Tertile 3=1,692.5 cm/s. Likewise, the mean baPWV tended to decrease in women according to TB tertiles: Tertile 1=1,920.8, Tertile 2=1,829.0, and Tertile 3=1,701.3 cm/s. Univariate analysis showed that age, BMI, TB, ALT, GGT, Cho, SBP, DBP, UA, and TC were significantly associated with baPWV in men. In women, age, BMI, current smoker, Cho, SBP, DBP, UA, TC, TG, HDL-C, and LDL-C were significantly associated with baPWV. BMI, LnSBP, UA, TB, LnCho, and LnTC were correlated with baPWV in men in the multivariate model. However, only LnSBP, UA, and LnHDL-C were correlated with baPWV in women. TB was found to be a significant determinant for decreased baPWV only in men (ß=-0.136; p<0.001). CONCLUSION: Our findings show that the level of total serum bilirubin is negatively correlated with arterial stiffness in men with established CAD.

Relationship between arterial stiffness assessed by brachial-ankle pulse wave velocity and coronary artery disease severity assessed by the SYNTAX score.

AIM: The SYNTAX score is a semi-quantitative angiographic tool used to determine the extent and severity of coronary artery disease (CAD). Automatic computer-assisted measurement of the brachial-ankle pulse wave velocity (baPWV) is a reproducible and valid method by which to assess arterial stiffness. Limited information is available for the association between the SYNTAX score and arterial stiffness in a CAD patient. We aim to assess the association between arterial stiffness determined by PWV and CAD severity assessed by angiography and the SYNTAX score. METHODS: 321 subjects underwent measurement of both baPWV and angiography from 2010 to 2011. BaPWV was divided into tertiles. Multiple logistic and linear regression analyses were used to evaluate the relationship between the SYNTAX score and baPWV. RESULTS: After adjusting for age, body mass index, smoking habits, family history of CAD, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), total cholesterol, triglycerides, LDL-cholesterol, fasting glucose, serum creatinine, uric acid and cysteine proteinase, analyses revealed that baPWV groups were significantly associated with the SYNTAX score. Compared with the lowest baPWV tertile, the adjusted odds ratios (ORs) of having a SYNTAXHIG for the MID and HIG baPWV tertiles were 4.76 (95% confidence interval: 1.71-6.33) and 4.13 (95% confidence interval: 1.12-5.27), respectively. We also used multiple linear regression analyses to assess the association between baPWV and the SYNTAX score, which showed that baPWV was associated with the SYNTAX score. CONCLUSION: Arterial stiffness determined by PWV is related to CAD severity assessed by angiography and the SYNTAX score.

Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-κB pathway in microglia cells.

Microglial activation plays an important role in neuroinflammation, which contributes to neuronal damage, and inhibition of microglial activation may have therapeutic benefits that could alleviate the progression of neurodegeneration. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit NF-κB activation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated primary microglia. Our results show that artemisinin significantly inhibited LPS-induced production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO). Artemisinin significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) and increased the protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Artemisinin treatment significantly inhibited basal and LPS-induced migration of BV-2 microglia. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in LPS-stimulated primary microglia, and this increase could be prevented by artemisinin. The inhibitory effects of artemisinin on LPS-stimulated microglia were blocked after IκB-α was silenced with IκB-α siRNA. Our results suggest that artemisinin is able to inhibit neuroinflammation by interfering with NF-κB signaling. The data provide direct evidence of the potential application of artemisinin for the treatment of neuroinflammatory diseases.

Predictors of clinical SYNTAX score in coronary artery disease: serum uric acid, smoking, and Framingham risk stratification.

BACKGROUND: High serum uric acid (SUA) has been well demonstrated to be associated with morbidity and mortality in the general population as well as in patients with coronary artery disease (CAD). Recent studies show that the clinical SYNTAX score (CSS) is a new tool for the risk stratification of patients with complex CAD. In this study, we aimed to evaluate whether SUA was associated with the complexity of CAD as evaluated by the CSS. METHODS: The study population consisted of 451 patients (69% male) who underwent coronary angiography for the assessment of CAD. A lesion was defined as significant if it caused a 50% reduction of the luminal diameter by visual estimation in vessels ≥1.5 mm. CSS was calculated by multiplying the SYNTAX score by a modified value of age, creatinine, and ejection fraction (ACEF) score (age/ejection fraction +1 for each 10 mL the creatinine clearance <60 mL/min per 1.73 m²). RESULTS: All subjects were divided into three groups according to CSS tertiles: CSSLOW (CSS 2-11; n = 147), CSSMID (CSS 12-21; n = 152), and CSSHIGH (CSS 22-68; n = 152). The SUA level was prominently related with CSS (5.29 ± 1.23 mg/dL, 6.92 ± 1.23 mg/dL, and 8.31 ± 1.46 mg/dL; P<.001). SUA was a significant predictor of CSS after adjustment for other risk factors (OR, 2.68; P<.001). CONCLUSION: SUA level was significantly associated with the severity and complexity of CAD evaluated by CSS. Further prospective clinical studies are needed to clarify the exact physiopathologic role of SUA in CAD.

Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses.

BACKGROUND: In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors. METHODOLOGY/PRINCIPAL FINDINGS: Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [³H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha). CONCLUSIONS/SIGNIFICANCE: Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.

Soluble vascular endothelial growth factor (VEGF) receptor-1 inhibits migration of human monocytic THP-1 cells in response to VEGF.

OBJECTIVE: We aimed to investigate the regulation and contribution of vascular endothelial growth factor (VEGF) and sFlt-1(1-3) to human monocytic THP-1 migration. MATERIALS AND METHODS: Ad-sFlt-1/FLAG, a recombinant adenovirus carrying the human sFlt-1(1-3) (the first three extracellular domains of FLT-1, the hVEGF receptor-1) gene, was constructed. L929 cells were infected with Ad-sFlt-1/FLAG and the expression of sFlt-1 was detected by immunofluorescent assay and ELISA. Corning(®) Transwell(®) Filter Inserts containing polyethylene terephthalate (PET) membranes with pore sizes of 3 µm were used as an experimental model to simulate THP-1 migration. Five VEGF concentrations (0, 0.1, 1, 10 and 100 ng/ml), four concentrations of sFlt-1(1-3)/FLAG expression supernatants (0.1, 1, 10 and 100 ng/ml), and monocyte chemoattractant protein-1 (MCP-1, 10 ng/ml) were used to test the ability of THP-1 cells to migrate through PET membranes. RESULTS: The sFlt-1(1-3) gene was successfully recombined into Ad-sFlt-1/FLAG. sFlt-1(1-3) was expressed in L929 cells transfected with Ad-sFlt-1/FLAG. THP-1 cell migration increased with increasing concentrations of VEGF, while cell migration decreased with increasing concentrations of sFlt1(1-3)/FLAG. sFlt1(1-3)/FLAG had no effect on MCP-1-induced cell migration. CONCLUSIONS: This study demonstrated that VEGF is able to elicit a migratory response in THP-1 cells, and that sFlt-1(1-3) is an effective inhibitor of THP-1 migration towards VEGF.

MG132 treatment attenuates cardiac remodeling and dysfunction following aortic banding in rats via the NF-κB/TGFß1 pathway.

Although MG132, a proteasome inhibitor, is suggested to impede secondary cardiac remodeling after hypertension, the mechanism and optimal duration of treatment remain unknown. This study was designed to investigate the effects and possible mechanism of MG132 on hypertension-induced cardiac remodeling. Male Sprague-Dawley rats subjected to abdominal aortic constriction (AAC) or sham operation received an intraperitoneal injection of MG132 (0.1mgkg(-1)day(-1)) or vehicle over a 2- or 8-week period. In the end, left ventricular (LV) function was evaluated with echocardiography and pressure tracing. Collagen deposition within the LV myocardium was assessed with Masson's trichrome staining. Ubiquitin-proteasome system (UPS), NF-κB, I-κB, TGFß1 and Smad2 within the LV tissue were evaluated. In addition, angiotensin II within both plasma and LV tissue was also examined. Compared with the sham groups, the vehicle-treated AAC group exhibited a higher angiotensin II level, LV/body weight ratio, septal and posterior wall thicknesses, and a markedly reduced cardiac function (P<0.05). Treatment with MG132 for 8 weeks attenuated these cardiac remodeling parameters and improved cardiac function (P<0.01). 2- and 8-week hypertension led to activation of UPS, which was followed by activation of NF-κB and increased expression of TGFß1 and Smad2 (P<0.01). MG132 significantly inhibited NF-κB activity and down-regulate the levels of TGFß1 and Smad2 expression by 2 and still at 8 weeks (P<0.01). Short- and long-term treatment with MG132 significantly attenuated hypertension-induced cardiac remodeling and dysfunction, which may be mediated by the NF-κB/TGFß1 signaling pathway.