Small Molecule Modulators of the Circadian Molecular Clock With Implications for Neuropsychiatric Diseases

Circadian rhythms regulate many biological processes and play fundamental roles in behavior, physiology, and metabolism. Such periodicity is critical for homeostasis because disruption or misalignment of the intrinsic rhythms is associated with the onset and progression of various human diseases and often directly leads to pathological states. Since the first identification of mammalian circadian clock genes, numerous genetic and biochemical studies have revealed the molecular basis of these cell-autonomous and self-sustainable rhythms. Specifically, these rhythms are generated by two interlocking transcription/translation feedback loops of clock proteins. As our understanding of these underlying mechanisms and their functional outputs has expanded, strategies have emerged to pharmacologically control the circadian molecular clock. Small molecules that target the molecular clock may present novel therapeutic strategies to treat chronic circadian rhythm-related diseases. These pharmaceutical approaches may include the development of new drugs to treat circadian clock-related disorders or combinational use with existing therapeutic strategies to improve efficacy via intrinsic clock-dependent mechanisms. Importantly, circadian rhythm disruptions correlate with, and often precede, many symptoms of various neuropsychiatric disorders such as sleep disorders, affective disorders, addiction-related disorders, and neurodegeneration. In this mini-review, we focus on recent discoveries of small molecules that pharmacologically modulate the core components of the circadian clock and their potential as preventive and/or therapeutic strategies for circadian clock-related neuropsychiatric diseases

Proteomic and biochemical analyses reveal the activation of unfolded protein response, ERK-1/2 and ribosomal protein S6 signaling in experimental autoimmune myocarditis rat model

<p>Abstract</p> <p>Background</p> <p>To investigate the molecular and cellular pathogenesis underlying myocarditis, we used an experimental autoimmune myocarditis (EAM)-induced heart failure rat model that represents T cell mediated postinflammatory heart disorders.</p> <p>Results</p> <p>By performing unbiased 2-dimensional electrophoresis of protein extracts from control rat heart tissues and EAM rat heart tissues, followed by nano-HPLC-ESI-QIT-MS, 67 proteins were identified from 71 spots that exhibited significantly altered expression levels. The majority of up-regulated proteins were confidently associated with unfolded protein responses (UPR), while the majority of down-regulated proteins were involved with the generation of precursor metabolites and energy metabolism in mitochondria. Although there was no difference in AKT signaling between EAM rat heart tissues and control rat heart tissues, the amounts and activities of extracellular signal-regulated kinase (ERK)-1/2 and ribosomal protein S6 (rpS6) were significantly increased. By comparing our data with the previously reported myocardial proteome of the Coxsackie viruses of group B (CVB)-mediated myocarditis model, we found that UPR-related proteins were commonly up-regulated in two murine myocarditis models. Even though only two out of 29 down-regulated proteins in EAM rat heart tissues were also dysregulated in CVB-infected rat heart tissues, other proteins known to be involved with the generation of precursor metabolites and energy metabolism in mitochondria were also dysregulated in CVB-mediated myocarditis rat heart tissues, suggesting that impairment of mitochondrial functions may be a common underlying mechanism of the two murine myocarditis models.</p> <p>Conclusions</p> <p>UPR, ERK-1/2 and S6RP signaling were activated in both EAM- and CVB-induced myocarditis murine models. Thus, the conserved components of signaling pathways in two murine models of acute myocarditis could be targets for developing new therapeutic drugs or methods aimed at treating enigmatic myocarditis.</p

Enhanced cardiac expression of two isoforms of matrix metalloproteinase-2 in experimental diabetes mellitus.

BackgroundDiabetic cardiomyopathy (DM CMP) is defined as cardiomyocyte damage and ventricular dysfunction directly associated with diabetes independent of concomitant coronary artery disease or hypertension. Matrix metalloproteinases (MMPs), especially MMP-2, have been reported to underlie the pathogenesis of DM CMP by increasing extracellular collagen content.PurposeWe hypothesized that two discrete MMP-2 isoforms (full length MMP-2, FL-MMP-2; N-terminal truncated MMP-2, NTT-MMP-2) are induced by high glucose stimulation in vitro and in an experimental diabetic heart model.MethodsRat cardiomyoblasts (H9C2 cells) were examined to determine whether high glucose can induce the expression of the two isoforms of MMP-2. For the in vivo study, we used the streptozotocin-induced DM mouse heart model and age-matched controls. The changes of each MMP-2 isoform expression in the diabetic mice hearts were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical stains were conducted to identify the location and patterns of MMP-2 isoform expression. Echocardiography was performed to compare and analyze the changes in cardiac function induced by diabetes.ResultsQuantitative RT-PCR and immunofluorescence staining showed that the two MMP-2 isoforms were strongly induced by high glucose stimulation in H9C2 cells. Although no definite histologic features of diabetic cardiomyopathy were observed in diabetic mice hearts, left ventricular systolic dysfunction was determined by echocardiography. Quantitative RT-PCR and IHC staining showed this abnormal cardiac function was accompanied with the increases in the mRNA levels of the two isoforms of MMP-2 and related to intracellular localization.ConclusionTwo isoforms of MMP-2 were induced by high glucose stimulation in vitro and in a Type 1 DM mouse heart model. Further study is required to examine the role of these isoforms in DM CMP

Safety, efficacy, and response predictors of anticoagulation for the treatment of nonmalignant portal-vein thrombosis in patients with cirrhosis: a propensity score matching analysis

Background/AimsPortal-vein thrombosis (PVT) develops in 10-25% of cirrhotic patients and may aggravate portal hypertension. There are few data regarding the effects of anticoagulation on nonmalignant PVT in liver cirrhosis. The aim of this study was to elucidate the safety, efficacy, and predictors of response to anticoagulation therapy in cirrhotic patients.MethodsPatients with liver cirrhosis and nonmalignant PVT were identified by a hospital electronic medical record system (called BESTCARE). Patients with malignant PVT, Budd-Chiari syndrome, underlying primary hematologic disorders, or preexisting extrahepatic thrombosis were excluded from the analysis. Patients were divided into two groups (treatment and nontreatment), and propensity score matching analysis was performed to identify control patients. The sizes of the thrombus and spleen were evaluated using multidetector computed tomography.ResultsTwenty-eight patients were enrolled in this study between 2003 and 2014: 14 patients who received warfarin for nonmalignant PVT and 14 patients who received no anticoagulation. After 112 days of treatment, 11 patients exhibited significantly higher response rates (complete in 6 and partial in 5) compared to the control patients, with decreases in thrombus size of >30%. Compared to nonresponders, the 11 responders were older, and had a thinner spleen and fewer episodes of previous endoscopic variceal ligations, whereas pretreatment liver function and changes in prothrombin time after anticoagulation did not differ significantly between the two groups. Two patients died after warfarin therapy, but the causes of death were not related to anticoagulation.ConclusionsWarfarin can be safely administered to cirrhotic patients with nonmalignant PVT. The presence of preexisting portal hypertension is a predictor of nonresponse to anticoagulation

Does Low Income Effects 5-Year Mortality of Hepatocellular Carcinoma Patients?

Background: In Korea, the universal health system offers coverage to all members of society. Despite this, it is unclear whether risk of death from hepatocellular carcinoma (HCC) varies depending on income. We evaluated the impact of low income on HCC mortality. Methods: The Korean National Health Insurance sampling cohort was used to identify new HCC cases (n = 7325) diagnosed between 2004 and 2008, and the Korean Community Health Survey data were used to investigate community-level effects. The main outcome was 5-year all-cause mortality risk, and Cox proportional hazard models were applied to investigate the individual- and community-level factors associated with the survival probability of HCC patients. Results: From 2004 to 2008, there were 4658 new HCC cases among males and 2667 new cases among females. The 5-year survival proportion of males was 68%, and the incidence per person-year was 0.768; the female survival proportion was 78%, and the incidence per person-year was 0.819. Lower income was associated with higher hazard ratio (HR), and HCC patients with hepatitis B (HBV), alcoholic liver cirrhosis, and other types of liver cirrhosis had higher HRs than those without these conditions. Subgroup analyses showed that middle-aged men were most vulnerable to the effects of low income on 5-year mortality, and community-level characteristics were associated with survival of HCC patients. Conclusion: Having a low income significantly affected the overall 5-year mortality of Korean adults who were newly diagnosed with HCC from 2004 to 2008. Middle-aged men were the most vulnerable. We believe our findings will be useful to healthcare policymakers in Korea as well as to healthcare leaders in countries with NHI programs who need to make important decisions about allocation of limited healthcare resources according to a consensually accepted and rational framework

Corrected QTc interval combined with troponin value and mortality in acute ischemic stroke

Background and PurposeCardiac biomarkers including, elevated troponin (ET) and prolonged heart rate-corrected QT (PQTc) interval on electrocardiography are known to frequent and have a prognostic significance in patients with acute ischemic stroke (AIS). However, it is still challenging to practically apply the results for appropriate risk stratification. This study evaluate whether combining ET and PQTc interval can better assess the long-term prognosis in AIS patients.MethodsIn this prospectively registered observational study between May 2007 and December 2011, ET was defined as serum troponin-I ≥ 0.04 ng/ml and PQTc interval was defined as the highest tertile of sex-specific QTc interval (men ≥ 469 ms or women ≥ 487 ms).ResultsAmong the 1,668 patients [1018 (61.0%) men; mean age 66.0 ± 12.4 years], patients were stratified into four groups according to the combination of ET and PQTc intervals. During a median follow-up of 33 months, ET (hazard ratio [HR]: 4.38, 95% confidence interval [CI]: 2.94–6.53) or PQTc interval (HR: 1.53, 95% CI: 1.16–2.01) alone or both (HR: 1.77, 95% CI: 1.16–2.71) was associated with increased all-cause mortality. Furthermore, ET, PQTc interval alone or both was associated with vascular death, whereas only ET alone was associated with non-vascular death. Comorbidity burden, especially atrial fibrillation and congestive heart failure, and stroke severity gradually increased both with troponin value and QTc-interval.ConclusionsIn patients with AIS, combining ET and PQTc interval on ECG enhances risk stratification for long-term mortality while facilitating the discerning ability for the burden of comorbidities and stroke severity

Eating habits, obesity related behaviors, and effects of Danhak exercise in elderly Koreans

The aims of this study were to evaluate obesity-related dietary behaviors and to determine long-term exercise effects on obesity and blood lipid profiles in elderly Korean subjects. A total of 120 subjects, aged 60-75 yr, were recruited, and obesity-related dietary behaviors were determined. An exercise intervention was conducted with 35 qualified elderly females for 6 months, and body composition and blood lipids were measured 6 times at 4 week intervals. At baseline, mean BMI (kg/m2) was 24.8 for males and 23.1 for females. The females had better eating habits than the males and were more concerned with reading nutrition labels on food products (P < 0.001); they also preferred convenience foods less than the male subjects (P < 0.05). Obese individuals were more likely than overweight or normal weight individuals to misperceive their weight (P < 0.001). Those with a high BMI responded feeling more depressed (P < 0.01), lacking self-confidence (P < 0.01), and feeling isolated (P < 0.01), as well as having more difficulty doing outdoor activities (P < 0.01). After exercise, body fat (%) and WHR were significantly reduced (P < 0.05), while body weight and BMI were also decreased without statistical significance. Total cholesterol and blood HDL were significantly improved (207.1 mg/dl vs. 182.6 mg/dl, HDL: 45.6 mg/dl vs. 50.6 mg/dl, P < 0.05). Other benefits obtained from exercise were improvements in self-confidence (26.4%), movement (22.6%), stress-relief (18.9%), and depression (13.2%). In conclusion, elderly females had better eating habits and were more concerned with nutrition information and healthy diets compared to elderly males. However, misperceptions of weight and obesity-related stress tended to be very high in females who were overweight and obese, which can be a barrier to maintain normal weight. Long-term Danhak practice, a traditional Korean exercise, was effective at reducing body fat (%) and abdominal obesity, and improved lipid profiles, self-confidence, and stress