Subchronic PCP administration results in a specific hypermethylation in the Pvalb promoter which may contribute to parvalbumin deficits in this animal model of psychosis.

Deficits of brain parvalbumin (PV) are a consistent finding in schizophrenia and models of psychosis. We investigated whether this is associated with abnormal PV gene (PVALB) methylation in the brain in schizophrenia. Bisulfite pyrosequencing was used to determine cytosine (CpG) methylation in a PVALB promoter sequence. Greater PVALB methylation was found in schizophrenia hippocampus, while no differences were observed in prefrontal cortex. LINE-1 methylation, a measure of global methylation, was also elevated in both regions in schizophrenia, although the PVALB change was independent of this effect. These results provide the first evidence that PVALB promoter methylation is abnormal in schizophrenia and suggest that this epigenetic finding may relate to the reduction of PV expression seen in the disease.

Individual variability and inadequate response of negative symptoms are major limitations of antipsychotic treatment in schizophrenia. A functional polymorphism, rs6295, in the 5-HT1A-receptor gene (HTR1A) contributes to this variability in negative symptom response. The DNA sequence containing rs6295 is rich in cytosine methylation (CpG) sites; CpG methylation is an epigenetic factor that, like rs6295, can modify transcriptional control. To investigate whether DNA methylation influences response to antipsychotic treatment, we determined methylation at CpG sites close to rs6295 in DNA from 82 Chinese subjects with a first psychotic episode. Methylation of one CpG site within a recognition sequence for HES transcriptional repressors was found to correlate with changes in total PANSS score (p = 0.006) and negative factor sub-score (p < 0.001) following 10 wk initial antipsychotic treatment, as well as with baseline negative factor score (p = 0.019); the effect on symptom change remained after correction for this baseline score. An effect of rs6295 on negative symptom response was not seen in this sample, which may not have provided sufficient power for the pharmacogenetic association. These preliminary results indicate that epigenetic modification of transcriptional regulation by specific cytosine methylation may modulate HTR1A expression, resulting in effects on emotional dysfunction and negative symptom response to antipsychotic treatment.

Genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism may be important predictors of antipsychotic drug-induced weight gain (AIWG). We tested whether two functional MTHFR polymorphisms are related to AIWG. Weight gain was studied in two cohorts of first-episode, initially drug-naive schizophrenia patients; Chinese Han (n = 182) and Spanish Caucasians (n = 72) receiving antipsychotics for 10 wk and 3 months respectively. Blood DNA was genotyped for 677C/T and 1298A/C MTHFR polymorphisms. Patients with the 677 CC genotype had a significantly greater increase in BMI compared to T-allele carriers in both Chinese (p = 0.012) and Spanish (p = 0.017) samples. The 677C/T MTHFR polymorphism showed an additive effect, but no significant interaction, with the -759C/T HTR2C polymorphism previously associated with AIWG. These results suggest that the 677C/T MTHFR polymorphism might, along with the -759C/T HTR2C polymorphism and other genetic factors, provide a useful marker for the important and limiting side effect of AIWG.

Intravenous infusion of either camboginol or morelloflavone from Garcinia dulcis (GD) exerted diuretic, hypotensive, and vasorelaxant effects in either normotensive or hypertensive rats. This study aims to investigate the effects of GD flower extract on arterial blood pressure (ABP) and renal excretory functions. Male Wistar rats (8-weekold) were divided into 4 groups (group I-IV, n = 6 each) in both acute and sub-chronic protocols. The GD extract was orally administrated to group II-IV at the dose of 50, 100, or 200 mg/kg, respectively, while group I served as vehicle control. The oral administration was performed before the experiment in acute protocol and daily for 2 weeks in the sub-chronic protocol. The ABP and renal excretory functions were measured in the anesthetized rats. The levels of fasting blood glucose (FBG), plasma lipid profiles, and liver enzymes were evaluated in the sub-chronic experiment along with liver histology. The results showed that acute administration of GD extract significantly decreased ABP but increased renal blood flow, glomerular filtration rate, urine flow rate, osmolar clearance, and negative free water clearance when compared with the control. In the sub-chronic protocol, the GD extract significantly decreased ABP but did not alter the renal excretory functions. The plasma levels of FBG, lipid profiles, liver enzymes, and the histology of liver were not changed. It is concluded that acute oral administration of GD extract possessed hypotensive and diuretic effects whereas the sub-chronic treatment of GD showed hypotensive effect and no alterations in liver function, FBG, and plasma lipid profiles.

The hexane insoluble fraction of the Garcinia dulcis (GD) flower extract comprises mainly camboginol and morelloflavone which possess potent in vivo and in vitro antioxidant properties. This study aimed to evaluate the effects of 4-week oral administration of GD flower extract on the arterial blood pressure (ABP) and the excretory function of the kidney in the 2-kidneys-1-clip (2K1C) renovascular hypertensive rats (total=12) compared to sham operated (SO) normotensive Wistar rats (total=12). Four weeks after hypertensive-induced surgery, either 50 mg/kg BW GD flower extract or vehicle was orally administered to the 2K1C or SO groups (n=6/group) daily for four weeks. ABP and the renal excretory function were studied in anesthetized rats, and expression of endothelial nitric oxide synthase (eNOS) mRNA in the isolated thoracic aorta were measured. In the 2K1C rats, GD flower extract significantly decreased ABP while increased significantly eNOS mRNA levels. GD flower extract did not exert a diuretic effect in either SO and 2K1C rats since there was no change in observed urine excretion, but it did tend to attenuated the renal tubular damage caused by renovascular hypertension. GD flower extract was anti-hypertensive in this model of renovascular hypertension and problably acts via the endothelial nitric oxide signaling pathway.

Background. Inflammation and hypertension are primary mechanisms involving in obesity-associated adverse effects of a high-fat diet. The aim of this study was to evaluate the effects of rice bran extract (RBE) on arterial blood pressure, hepatic steatosis, inflammation, and oxidative stress in high-fat diet (HFD)-induced obese mice. Methods. Male ICR mice were divided into four groups, including a normal-diet control group, a high-fat diet (HFD) (60% kcal from fat) group, an HFD group treated with RBE (220 mg/kg/day), and an HFD group treated with 1100 mg/kg/day for eight weeks. Besides body weight and arterial blood pressure, we determined liver values of total cholesterol, triglyceride, as well as percent body fat, tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), nuclear factor kappa-B (NF-κB), matrix metalloprotease-9 (MMP-9), cyclooxygenase-2 (COX-2), and mRNA endothelial nitric oxide synthase (eNOS). Results. The HFD group had increased body weight, increased systolic and diastolic blood pressure, liver total cholesterol, triglyceride, NF-κB, COX-2 and MMP-9 protein levels, and decreased mRNA eNOS in the aorta. Mice of the HFD group receiving RBE had reduced diastolic blood pressure, as well as significantly decreased liver and serum TNF-α and MDA levels in the liver, and reduced NF-κB levels in both the liver and heart. Conclusions. These results demonstrate that RBE decreases diastolic blood pressure, the liver lipid droplet accumulation, liver and myocardial NF-κB, myocardial COX-2 and MMP-9 protein levels, and oxidative stress. Moreover, RBE may improve endothelial function and may alleviate adverse health effects associated with obesity including obesity-associated hypertension.

Ischemia and subsequent reperfusion are known to impair renal function. We examined several agents that might prevent renal impairment or enhance the recovery of renal function after ischemia/reperfusion injury in rats. Different degrees of preventive effects were observed in rats treated with captopril, BQ-123 (endothelin type A receptor antagonist), sodium nitroprusside (SNP, a nitric oxide donor), and losartan (angiotensin II type 1 receptor antagonist). Only minimal changes in renal morphology were observed after treatment with losartan, SNP, captopril, and BQ-123 compared with control animals. On the other hand, lesions were prominent in the N G -nitro-L-arginine-methyl ester (L-NAME)-and L-arginine-treated rats. The Na -K ATPase activity of ischemic kidneys was, however, preserved in all treatment groups, except in those treated with L-arginine and L-NAME, which showed a marked reduction in Na -K ATPase activity. Our post-treatment data suggest that losartan and SNP have the greatest potential for therapeutic use to mitigate post-ischemic renal damage and functional impairment.