Characterization of a murine nonalcoholic steatohepatitis model induced by high fat high calorie diet plus fructose and glucose in drinking water.

There are varieties of murine models of nonalcoholic steatohepatitis (NASH) with different pathophysiologic characteristics. For preclinical assessment, a standardized model would allow comparisons of various pharmacotherapeutic candidates in efficacy, pharmacokinetics, pharmaco-metabolism, and adverse effects under a same system. The present study aims to characterize murine NASH models by comparing end-points of major abnormalities. NASH was induced by feeding high fructose/glucose in drinking water (HF/G), high-fat/calorie diet (HFCD), and in combination (HFCD-HF/G) in mice for 8 or 16 weeks. HF/G feeding caused a minimal fat accumulation and increase in free fatty acids (FFA). In contrast, HFCD-HF/G feeding resulted in a remarkable increase in body weight, subcutaneous and visceral adipose tissue, macrosteatosis with a nearly seven-fold increase in triglyceride and FFA content, accompanied with marked hepatocellular injury, inflammatory responses, fibrosis, and insulin resistance, and represented as typical NASH in histopathology, metabolic, and adipokine profiles in a progressive manner. Meanwhile, mice fed HFCD displayed significant steatosis, necroptosis, fibrosis, insulin resistance, metabolic, and adipokine profiles, and the extent is less than those fed HFCD-HF/G. Significant MCP-1, CCR-2, and NLRP-1/3 activation were found in mice fed HFCD and HFCD-HF/G for 16 weeks, whereas gene expression of CPT-1 and ACOX-1 was down-regulated in these two groups in comparison to the controls. Nuclear receptors, such as SREBP-1c, FXR, LXR-α, PPAR-α, and PPAR-γ, were strikingly elevated in the HFCD-HF/G group. In conclusion, feeding HFCD-HF/G resulted in a reliable NASH model in mice with remarkable necroptosis, steatosis, fibrosis, and insulin resistance as well as a disordered profile of lipid metabolism and adipokine, and HFCD caused significant NASH features in histopathology and metabolic profiles only at a late stage. Whereas HF/G feeding barely led to minimal fat accumulation, some changes at molecular levels and metabolic disturbance in mice.

Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling.

AIMS: Activation of hepatic stellate cells (HSCs) plays a pivotal role at the center of the fibrogenic progression in nonalcoholic steatohepatitis (NASH). However, it is poorly understood that how various molecules interact within HSCs during the progression of NASH to fibrosis. The aim of the present study is to delineate how inflammasome molecules, hedgehog signaling and autophagy provoke HSC activation using palmitic acid (PA) as a major insult. MAIN METHODS: Inflammasome activation, hedgehog signaling activity and autophagy in PA-exposed HSCs were determined to investigate their role in activation of human and rodent HSC lines or primary HSCs. KEY FINDINGS: PA treatment elicited HSC activation reflected by increased mRNA levels of transforming growth factor-ß1, connective tissue growth factor, tissue inhibitor of metalloproteinase-1 and procollagen type I (α1). In addition, expression levels of NOD-like receptor protein 3 (NLRP3) and hedgehog signaling transcription factor Gli-1 were increased in PA-exposed HSCs. It's evident that PA treatment resulted in increased production of light chain 3-II and autophagosomes, as well as enhanced autophagy flux reflected by transduction of an adeno-associated viral vector. Whereas, reduced autophagy, which is often seen in the late stage of NASH, provoked inflammasome activation. Moreover, suppressing the Hh signaling pathway by LDE225 blocked production of light chain 3-II and autophagy flux. SIGNIFICANCE: Saturated fatty acids, such as PA, stimulate HSC activation through inflammasomes and hedgehog signaling. Meanwhile, compromised autophagy may facilitate HSC activation, implicating valuable candidates for pharmacologic intervention against the progression of fibrogenesis in NASH.

Furosemide with saline hydration for prevention of contrast-induced nephropathy in patients undergoing coronary angiography: a meta-analysis of randomized controlled trials.

BACKGROUND: The clinical efficacy of furosemide administration in preventing contrast-induced nephropathy (CIN) remains uncertain. This meta-analysis was designed to update data on the incidence of CIN with additional furosemide treatment beyond saline hydration in comparison with hydration alone in patients undergoing percutaneous coronary intervention (PCI). MATERIAL/METHODS: A computerized literature search of MEDLINE, EMBASE, and Cochrane databases was performed. Trials were eligible if they enrolled patients undergoing coronary angiography and randomly allocated participants to receive furosemide administration in addition to saline hydration or saline hydration alone. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for combinations of studies. RESULTS: Five trials involving 1294 patients (640 for additional furosemide treatment and 654 for hydration alone) were included in the meta-analysis. In the synthesis of data, additional furosemide administration had little impact on the incidence of CIN post-PCI compared with peri-procedural saline hydration alone (OR=0.96; 95% CI 0.33-2.84, p=0.95). Moreover, as for the subsequent need for dialysis, there was no statistical significant difference between the 2 groups (OR=1.01; 95% CI 0.38-2.67, p=0.99). Sensitivity analyses did not show any relevant influence on the overall results. There was no publication bias in the meta-analysis. CONCLUSIONS: Furosemide administration did not achieve additional benefit beyond saline hydration in reducing the incidence of CIN in patients undergoing PCI.

Pathological observation of acute myocardial infarction in Chinese miniswine.

The acute myocardial infarction (AMI) model in Chinese miniswine was built by percutaneous coronary artery occlusion. Pathological observation of AMI was performed, and the expression of tumor necrosis factor alpha (TNF-α) in the infarct sites was detected at different days after modeling in Chinese miniswine. The experimental findings may be used as the basis for blood flow reconstruction and intervention after AMI. Seven experimental Chinese miniswine were subjected to general anesthesia and Seldinger right femoral artery puncture. After coronary angiography, the gelfoam was injected via the microtube to occlude the obtuse marginal branch (OM branch). At 1 d, 3 d, 5 d, 7 d, 10 d, 14 d and 17 d after modeling, hetatoxylin-eosin (HE) staining was performed to observe the pathological changes and to detect the expression of TNF-α in the myocardial tissues. Cytoplasmic acidophilia of the necrotic myocardial tissues at 1 d after modeling was enhanced, and cytoplasmic granules were formed; at 3 d, the margins of the necrotic myocardial tissues were infiltrated by a large number of inflammatory cells; at 5 d, the nuclei of the necrotic myocardial cells were fragmented; at 7 d, extensive granulation tissues were formed at the margin of the necrotic myocardial tissues; at 10 d, part of the granulation tissues were replaced by fibrous scar tissues; at 14-17 d, all granulation tissues were replaced by fibrous scar tissues. Immunohistochemical detection indicated that no TNF-α expression in normal myocardial tissues. The TNF-α expression was first detected at 3 d in the necrotic myocardial tissues and then increased at 5 d and 7 d. After reaching the peak at 10 d, the expression began to decrease at 14 d and the decrease continued at 17 d. Coronary angiography showed the disappearance of blood flow at the distal end of OM branch occluded by gelfoam, indicating that AMI model was constructed successfully. The repair of the infarcted myocardium began at 10-17 d after modeling with safe blood flow reconstruction. TNF-α expression in the infarcted myocardium was the highest at 10 d, which can be explained by inflammation and repair of the infarcted myocardium.

Long-term outcomes of drug-eluting versus bare-metal stent for ST-elevation myocardial infarction.

BACKGROUND: Long-term outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) remain uncertain. OBJECTIVE: To investigate long-term outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We performed search of MEDLINE, EMBASE, the Cochrane library, and ISI Web of Science (until February 2013) for randomized trials comparing more than 12-month efficacy or safety of DES with BMS in patients with STEMI. Pooled estimate was presented with risk ratio (RR) and its 95% confidence interval (CI) using random-effects model. RESULTS: Ten trials with 7,592 participants with STEMI were included. The overall results showed that there was no significant difference in the incidence of all-cause death and definite/probable stent thrombosis between DES and BMS at long-term follow-up. Patients receiving DES implantation appeared to have a lower 1-year incidence of recurrent myocardial infarction than those receiving BMS (RR = 0.75, 95% CI 0.56 to 1.00, p= 0.05). Moreover, the risk of target vessel revascularization (TVR) after receiving DES was consistently lowered during long-term observation (all p < 0.01). In subgroup analysis, the use of everolimus-eluting stents (EES) was associated with reduced risk of stent thrombosis in STEMI patients (RR = 0.37, p=0.02). CONCLUSIONS: DES did not increase the risk of stent thrombosis in patients with STEMI compared with BMS. Moreover, the use of DES did lower long-term risk of repeat revascularization and might decrease the occurrence of reinfarction.

Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes.

Ligands that can interact specifically with telomeric multimeric G-quadruplexes could be developed as promising anticancer drugs with few side effects related to other G-quadruplex-forming regions. In this paper, a new cationic porphyrin derivative, m-TMPipEOPP, was synthesized and characterized. Its multimeric G-quadruplex recognition specificity under molecular crowding conditions was compared to its isomer p-TMPipEOPP. The slight structural difference accounts for different multimeric G-quadruplex recognition specificity for the two isomers. p-TMPipEOPP can barely discriminate between multimeric and monomeric G-quadruplexes. By contrast, m-TMPipEOPP can bind with multimeric but not with monomeric G-quadruplexes. p-TMPipEOPP might bind to multimeric G-quadruplexes by two modes: sandwich-like end-stacking mode and pocket-dependent intercalative mode. Increasing the pocket size between adjacent two G-quadruplex units is beneficial for the latter mode. m-TMPipEOPP might bind to multimeric G-quadruplexes by a side binding mode, which confers m-TMPipEOPP with higher multimeric G-quadruplex recognition specificity compared to p-TMPipEOPP. m-TMPipEOPP increases the stability of multimeric G-quadruplex under both dilute and molecular crowding conditions but its G-quadruplex-stabilizing ability is a little weaker than p-TMPipEOPP. These results provide important information for the design of highly specific multimeric G-quadruplex ligands. Another interesting finding is that pocket size is an important factor in determining the stability of multimeric G-quadruplexes.

Long-term Outcomes of Drug-eluting versus Bare-metal stent for ST-elevation Myocardial Infarction / Resultados a Longo Prazo de Eluição de Fármaco versus Stent Metálico para Infarto do Miocárdio com Elevação ST

Background: Long-term outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) remain uncertain. Objective: To investigate long-term outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI). Methods: We performed search of MEDLINE, EMBASE, the Cochrane library, and ISI Web of Science (until February 2013) for randomized trials comparing more than 12-month efficacy or safety of DES with BMS in patients with STEMI. Pooled estimate was presented with risk ratio (RR) and its 95% confidence interval (CI) using random-effects model. Results: Ten trials with 7,592 participants with STEMI were included. The overall results showed that there was no significant difference in the incidence of all-cause death and definite/probable stent thrombosis between DES and BMS at long-term follow-up. Patients receiving DES implantation appeared to have a lower 1-year incidence of recurrent myocardial infarction than those receiving BMS (RR = 0.75, 95% CI 0.56 to 1.00, p= 0.05). Moreover, the risk of target vessel revascularization (TVR) after receiving DES was consistently lowered during long-term observation (all p< 0.01). In subgroup analysis, the use of everolimus-eluting stents (EES) was associated with reduced risk of stent thrombosis in STEMI patients (RR = 0.37, p=0.02). Conclusions: DES did not increase the risk of stent thrombosis in patients with STEMI compared with BMS. Moreover, the use of DES did lower long-term risk of repeat revascularization and might decrease the occurrence of reinfarction. .

Fundamento: Os resultados a longo prazo dos stents farmacológicos (SF) contra stents convencionais (SC) em pacientes com infarto do miocárdio com elevação do segmento ST (IMEST) permanecem incertos. Objetivo: Investigar os resultados a longo prazo dos stents farmacológicos (SF) contra stents convencionais (SC) em pacientes com infarto do miocárdio com elevação do segmento ST (IMEST) . Métodos: Foi realizada pesquisa de dados nas bases de dados MEDLINE, EMBASE, na Cochrane Library, e na ISI Web of Science (até fevereiro de 2013) para estudos clínicos aleatórios que comparam a eficácia durante mais de 12 meses ou a segurança do SF com SC em pacientes com IMEST. Foi apresentada uma estimativa agrupada com risco relativo (RR) e seu intervalo de confiança de 95 % (IC), utilizando modelo de efeitos aleatórios. Resultados: Dez estudos com 7.592 participantes com IMEST foram incluídos. Os resultados gerais mostraram que não houve diferença significativa na incidência de morte por todas as causas e trombose de stent definida/provável entre SF e SC em seguimento de longo prazo. Os pacientes que receberam implante de SF pareciam ter uma incidência de infarto do miocárdio recorrente inferior a1 ano que aqueles que receberam SC (RR = 0,75, 95% CI 0,56-1,00, p = 0,05). Além disso, o risco de revascularização do vaso alvo (RVA) depois de receber o SF diminui consistentemente durante a observação a longo prazo (todos p <0,01). Na análise de subgrupo, o uso de stents com eluição de everolimus (EEE) foi associado a um risco reduzido de trombose de stent em pacientes IMEST (RR = 0,37, p = 0,02). Conclusões: SF não aumentou o risco de trombose de stent em pacientes com IMEST em comparação com SC. Além disso, o uso de SF fez baixar o risco de longo prazo de repetição ...