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Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator-activated receptor delta (PPARδ) has been shown to modulate vascular smooth muscle cell (SMC) phenotypic switching, and, hence, atherosclerotic plaque stability. Melatonin reportedly plays a beneficial role in cardiovascular diseases; however, the mechanisms underlying improvements in atherosclerotic plaque vulnerability remain unknown. In this study, we assessed the role of melatonin in regulating SMC phenotypic switching and its consequential contribution to the amelioration of atherosclerotic plaque vulnerability and explored the mechanisms underlying this process. We analyzed features of atherosclerotic plaque vulnerability and markers of SMC phenotypic transition in high-cholesterol diet (HCD)-fed apolipoprotein E knockout (ApoE -/- ) mice and human aortic SMCs (HASMCs). Melatonin reduced atherosclerotic plaque size and necrotic core area while enhancing collagen content, fibrous cap thickness, and smooth muscle alpha-actin positive cell coverage on the plaque cap, which are all known phenotypic characteristics of vulnerable plaques. In atherosclerotic lesions, melatonin significantly decreased the synthetic SMC phenotype and KLF4 expression and increased the expression of PPARδ, but not PPARα and PPARγ, in HCD-fed ApoE -/- mice. These results were subsequently confirmed in the melatonin-treated HASMCs. Further analysis using PPARδ silencing and immunoprecipitation assays revealed that PPARδ plays a role in the melatonin-induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPARδ-mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Purpose: Vascular smooth muscle cells (SMCs) undergo phenotypic switching during sustained inflammation, contributing to an unfavourable atherosclerotic plaque phenotype. PPARδ plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we explored the pathological roles of PPARδ in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidated the underlying mechanisms., Experimental Approach: Plasma levels of PPARδ were measured in patients with acute coronary syndrome (ACS) and stable angina (SA). SMC contractile and synthetic phenotypic markers, endoplasmic reticulum (ER) stress, and features of atherosclerotic plaque vulnerability were analysed for the brachiocephalic artery of apolipoprotein E-knockout (ApoE -/- ) mice, fed a high-cholesterol diet (HCD) and treated with or without the PPARδ agonist GW501516. In vitro, the role of PPARδ was elucidated using human aortic SMCs (HASMCs)., Key Results: Patients with ACS had significantly lower plasma PPARδ levels than those with SA. GW501516 reduced atherosclerotic plaque vulnerability, a synthetic SMC phenotype, ER stress markers, and NLRP3 inflammasome expression in HCD-fed ApoE -/- mice. ER stress suppressed PPARδ expression in HASMCs. PPARδ activation inhibited ER stress-induced synthetic phenotype development, ER stress-NLRP3 inflammasome axis activation and matrix metalloproteinase 2 (MMP2) expression in HASMCs. PPARδ inhibited NFκB signalling and alleviated ER stress-induced SMC phenotypic switching., Conclusions and Implications: Low plasma PPARδ levels may be associated with atherosclerotic plaque vulnerability. Our findings provide new insights into the mechanisms underlying the protective effect of PPARδ on SMC phenotypic switching and improvement the features of atherosclerotic plaque vulnerability., (© 2023 British Pharmacological Society.)

The quantitative relationship between serum albumin level and surgical outcomes has not been clearly established. This study included 3732 patients with colon cancer who underwent a potentially curative colectomy. Post-operative mortality and morbidity were analysed according to the patients' demographic data, pre-operative comorbidities, and tumour-related factors. Age, asthma, renal impairment, and albumin level were significantly associated with post-operative morbidity and mortality in the multivariate analyses. Logistic regression analysis revealed linear relationships of post-operative morbidity and mortality with albumin level. The morbidity and mortality rates decreased by 7.3% and 15.6%, respectively, for each 0.1 g/dL increase in albumin level. This finding remained significant in the hypoalbuminaemia subgroup but not in the normoalbuminaemia subgroup. That is, the morbidity and mortality rates significantly decreased by 8.7% and 17.7%, respectively (both P < 0.001), in the former group and decreased by 2.7% (P = 0.112) and 11.6% (P = 0.092), respectively, in the latter group. This study demonstrated that serum albumin level linearly predicted the post-operative morbidity and mortality among the colorectal cancer patients. Pre-operative serum albumin level may therefore be used as a continuous rather than a categorical marker of disease severity, especially among patients with hypoalbuminaemia., (© 2015 John Wiley & Sons Ltd.)

Background: This study was undertaken to evaluate the preventive effect of α-lipoic acid (LA) on chronic mild portal endotoxaemia-mediated subacute hepatic inflammation and pancreatic β cell dysfunction in rats., Materials and Methods: Male Sprague-Dawley rats were randomly assigned into four groups: those with intraportal vehicle (saline) or low-dose lipopolysaccharide (LPS) (0·42 ng/kg/min) infusion, combined with oral administration of vehicle or LA, a potent antioxidant (60 mg/kg/day) for 4 weeks. The hyperglycaemic clamp and euglycaemic clamp techniques were used to access the glucose-stimulated insulin secretion and systemic insulin sensitivity in vivo., Results: Body weight, fasting plasma glucose and insulin were not different among groups. In rats with chronic intraportal LPS infusion, plasma C-reactive protein, amylase, superoxide levels, the contents of thiobarbituric acid-reactive substance, tumour necrosis factor α and interleukin 6 in liver and pancreas and also the gene expression of Toll-like receptor 4 in liver were significantly increased as compared with those with LA cotreatment. The histopathological examination showed that inflammatory changes were clearly visible in liver and pancreatic islets of LPS-infused rats and rarely observed in those cotreated with LA. In addition, low-dose intraportal LPS infusion also significantly impaired glucose-stimulated insulin secretion but not affect the systemic insulin sensitivity and metabolic clearance rate of insulin. LA administration markedly reversed LPS-induced β cell dysfunction., Conclusions: α-Lipoic acid cotreatment could significantly prevent mild portal endotoxaemia-induced chronic hepatic inflammation and impaired pancreatic insulin secretion in absence of changing systemic insulin resistance., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: The aim was to examine whether the inhibition of selective cyclooxygenase (COX) 2 activation could suppress the development of inflammatory reaction in visceral and subcutaneous abdominal fats of high-fat-induced obese rats., Materials and Methods: The rats were fed separately regular diet (CONT), high-fat diet ad libitum or energy-restrictedly (HFr) for 12 weeks. Rats fed high-fat diet ad libitum were further divided into those co-treated with vehicle (HFa), a selective COX2 inhibitor-celecoxib (HFa-Cel) or nimesulide (HFa-Nim). Oral glucose tolerance test (OGTT) was performed at the end of weeks 4, 8, 12. Another set of rats with similar grouping was divided into those with a 4-, 8- or 12-week intervention for tissue sampling., Results: Body and epididymal fat weights were increased similarly in HFa, HFa-Cel and HFa-Nim. Time-dependent increases in plasma insulin, triglyceride, impaired OGTT shown in HFa were significantly reversed in HFa-Cel and HFa-Nim. The obese-linked increases in gene expressions of COX-2, monocyte chemoattractant protein-1 (MCP-1) and tumour necrosis factor-alpha (TNF-alpha) in epididymal and subcutaneous fats (especially in the former) were significantly suppressed in HFa-Cel and HFa-Nim. The protein contents of MCP-1 and TNF-alpha in epididymal fats were changed consistently with their gene expressions. Plasma MCP-1 was increased time-dependently in HFa and suppressed in HFa-Cel and HFa-Nim. The increased CD68 positive cells showed in both epididymal and subcutaneous fats of HFa were significantly attenuated in HFa-Cel and HFa-Nim., Conclusions: Our findings suggest that COX2 activation is crucially involved in the development of inflammatory response in adipose tissues of high-fat-induced obese rats.

Background: The effects of cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) inhibition on insulin resistance in subjects with the metabolic syndrome remain elusive. Aims of this study were to examine the effects of COX1 and COX2 inhibitors on whole body and muscular insulin resistance in fructose-fed rats, an animal model of the metabolic syndrome., Materials and Methods: The rats on regular or 60% fructose-enriched diets for 6 weeks were further divided into rats combined with or without piroxicam (a selective COX1 inhibitor) or celecoxib (a selective COX2 inhibitor) treatment for an additional 2 weeks. Euglycaemic hyperinsulinaemic clamp (EHC) with a tracer dilution method was performed at the end of the study., Results: The present result showed that fructose-induced increases in systolic blood pressure and fasting plasma insulin levels were significantly suppressed in rats treated with celecoxib but not piroxicam. In the EHC period, celecoxib significantly reversed fructose-induced decreases in whole body glucose uptake, mainly by glucose storage. Hepatic glucose production and whole body glycolysis were not significantly changed among groups. Celecoxib but not piroxicam significantly reversed fructose-induced decreases in glycogen synthase activities in red and white quadriceps muscles and insulin-stimulated membrane GLUT4 recruitment in soleus muscles. Celecoxib and piroxicam both significantly diminished fructose-induced increases in plasma thromboxane B2 and 6-keto prostaglandin (PG) F1alpha; but only celecoxib treatment significantly attenuated a fructose-induced increase in 8-isoprostane levels. Plasma PGE metabolites were not different among groups., Conclusions: This study demonstrates that a therapeutic dose of celecoxib, but not piroxicam, could significantly attenuate fructose-induced whole body and muscular insulin resistance in rats.

Background: Portal endotoxaemia has been speculated to be crucially involved in the pathogenesis of chronic hepatic inflammation, which is highly associated with the development of type 2 diabetes mellitus. This study tests whether portal endotoxaemia is a pathogenic link between chronic subacute hepatic inflammation and pancreatic beta-cell dysfunction., Materials and Methods: Rats were randomly assigned into two groups: rats with intraportal saline or low-dose lipopolysaccharide (LPS) infusion for 4 weeks. Pathological changes in the liver were evaluated via histological and biochemical examination. Pancreatic insulin secretion was evaluated by in vivo hyperglycaemic clamp study., Results: White blood cell count was significantly increased after intraportal LPS infusion for 4 weeks. Plasma amylase and chemoluminescence counts indicating superoxide levels were significantly increased after LPS treatments for 2 and 4 weeks. Intraportal low-dose LPS infusion significantly increased tumour necrosis factor-alpha and interleukin-6 contents in liver and pancreas. Circulating C-reactive protein, thiobarbituric acid reactive substances (TBARS) and endotoxin levels were not different among groups. The first- and second-phase insulin secretions in hyperglycaemic clamp were significantly decreased in LPS-treated rats. The histopathological scores, de novo production of reactive oxygen substrate and TBARS contents in the liver and pancreas were significantly increased in LPS-infused rats. Leucocyte infiltration was clearly visible in pancreatic islets of LPS-treated rats., Conclusions: The present study demonstrated that mild portal endotoxaemia caused subacute hepatic inflammation and impaired pancreatic insulin secretion, implicating that portal endotoxaemia is a potential risk factor to link chronic subacute hepatic inflammation and pancreatic beta-cell dysfunction.

The steady-state kinetics of the creatine kinase reaction in rabbit skeletal muscle in vivo was investigated using inversion and saturation magnetization transfer techniques. Both techniques determined the forward rate of this reaction (creatine phosphate ATP) as approximately 0.3 s-1. This corresponds to a flux of 10 mumol creatine phosphate/s/g muscle. The saturation transfer technique underestimated the reverse reaction by approximately 56%. This result is likely due to the participation of ATP in other interactions in skeletal muscle not involving creatine phosphate.