Infection with

Aims: To determine the roles of vitamin D receptor (VDR) in ischemia/reperfusion-induced myocardial injury and to investigate the underlying mechanisms involved. Results: The endogenous VDR expression was detected in the mouse heart, and myocardial ischemia/reperfusion (MI/R) upregulated VDR expression. Activation of VDR by natural and synthetic agonists reduced myocardial infarct size and improved cardiac function. Mechanistically, VDR activation inhibited endoplasmic reticulum (ER) stress (determined by the reduction of CCAAT/enhancer-binding protein homologous protein expression and caspase-12 activation), attenuated mitochondrial impairment (determined by the decrease of mitochondrial cytochrome c release and caspase-9 activation), and reduced cardiomyocyte apoptosis. Furthermore, VDR activation significantly inhibited MI/Rinduced autophagy dysfunction (determined by the inhibition of Beclin 1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, p62 protein abundance, and the restoration of autophagy flux). Moreover, VDR activation inhibited MI/R-induced oxidative stress through a metallothionein-dependent mechanism. The cardioprotective effects of VDR agonists mentioned earlier were impaired in the setting of cardiac-specific VDR silencing. In contrast, adenovirus-mediated cardiac VDR overexpression decreased myocardial infarct size and improved cardiac function through attenuating oxidative stress, and inhibiting apoptosis and autophagy dysfunction. Innovation and Conclusion: Our data demonstrate that VDR is a novel endogenous self-defensive and cardioprotective receptor against MI/R injury, via mechanisms (at least in part) reducing oxidative stress, and inhibiting apoptosis and autophagy dysfunction-mediated cell death. Antioxid. Redox Signal. 22,[633][634][635][636][637][638][639][640][641][642][643][644][645][646][647][648][649][650]

BackgroundEducators continue to search for better strategies for medical education. Although the unifying theme of reforms was “increasing interest in, attention to, and understanding of the knowledge base structures”, it is difficult to achieve all these aspects via a single type of instruction.MethodsWe used related key words to search in Google Scholar and Pubmed. Related search results on this topic were selected for discussion.ResultsDespite the range of different methods used in medical education, students are still required to memorize much of what they are taught, especially for the basic sciences. Subjects like anatomy and pathology carry a high intrinsic cognitive load mainly because of the large volume of information that must be retained. For these subjects, decreasing cognitive load is not feasible and memorizing appears to be the only strategy, yet the cognitive load makes learning a challenge for many students. Cognitive load is further increased when inappropriate use of educational methods occurs, e.g., in problem based learning which demands clinical reasoning, a high level and complex cognitive skill. It is widely known that experts are more skilled at clinical reasoning than novices because of their accumulated experiences. These experiences are based on the formation of cognitive schemata. In this paper we describe the use of cognitive schemata, developed by experts as worked examples to facilitate medical students’ learning and to promote their clinical reasoning.ConclusionWe suggest that cognitive load theory can provide a useful framework for understanding the challenges and successes associated with education of medical professionals.

Rupture of vulnerable plaques is the main trigger of acute cardio-cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture-prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE −/− mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor-related orphan receptor-α (RORα) mediated melatonin-exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte-derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα-STATs pathway in a RORα-dependent manner. In summary, our data provided the first evidence that melatonin-RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture-prone vulnerable plaques. K E Y W O R D S atherosclerosis, macrophage polarization, melatonin, nuclear receptor, RAR-related orphan receptor, vulnerable plaques 2 of 15 | DING et al. 12 of 15 | DING et al. F I G U R E 7 Melatonin regulates macrophage polarization through the signal transducer and activator of transcription (STAT) pathway.A, Flow cytometry analysis of cell surface markers for M1 (CD80 and CD197) and M2 (CD163 and CD206) macrophages during M1 and M2 polarization with vehicle or melatonin/SR3335 treatment. The results showed that co-culture with melatonin significantly reduced IFN-γ and LPSinduced CD80 and CD197 expression, whereas RORα agonism with SR3335 markedly promoted M1 polarization (n = 6 per group). *P < 0.05 or **P < 0.01 versus monocyte; # P < 0.05 versus M0. B and C, Western blotting was conducted on cell lysates with antibodies against P-STAT1, P-STAT3, and P-STAT6; total STAT1, STAT3, and STAT6; and GAPDH. Relative densities of phosphorylated STAT compared with total STAT are shown as histograms (n = 6 per group). *P < 0.05 or **P < 0.01 versus control; ##P < 0.01 versus M1 + siRORα in C. D and E, Western blotting was conducted on cell lysates with antibodies against RORα, P-AMPKα, total AMPKα, and GAPDH. *P < 0.05 versus Mel (0 mmol/L); ##P < 0.01 versus control siRNA

No abstract

Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, antidiabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting that it is important to exploit novel therapeutic targets against diabetic cardiomyopathy. Here, we observed that the nuclear melatonin receptor, the retinoic acid-related orphan receptor-α (RORα), was downregulated in diabetic hearts. By utilizing a mouse line with RORα disruption, we demonstrated that RORα deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of RORα deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction, and oxidative stress by disrupting antioxidant gene expression. By contrast, restoration of cardiac RORα levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of RORα by melatonin and SR1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the RORα inhibitor SR3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac-targeted manipulation of nuclear melatonin receptor RORα may hold promise for delaying diabetic cardiomyopathy development.

No abstract

URL: https://www.clinicaltrials.gov. Unique identifier: NCT01930682.