PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis.

OBJECTIVE: The purpose of this study was to investigate the role of the PI3K/Akt signaling pathway in the pathogenesis of ulcerative colitis (UC). MATERIALS AND METHODS: Mucosal biopsy specimens from 54 active UC cases and adjacent normal tissues from 18 colon cancer cases were investigated. Twenty-eight Balb/c mice were randomly divided into four groups. Dextran sulphate sodium (DSS) solution (5%) was used to develop the mouse colitis model. After treatment with wortmannin (a PI3K inhibitor), disease activity index (DAI) and histological score was determined for each group of mice. Expression of phosphorylated Akt (p-Akt) in UC patients and mouse intestinal mucosa was determined by immunohistochemical staining. We also determined the effect of wortmannin on tumor necrosis factor-α (TNF-α) expression in intestinal biopsy tissues of UC patients and mice with DSS-induced colitis. RESULTS: Wortmannin significantly reduced the level of p-Akt and TNF-α in the colitis tissues of UC patients and DSS-treated mice. Wortmannin significantly alleviated the inflammation of colitis as assessed by DAI and histological score in DSS-treated mice. CONCLUSION: The PI3K/Akt signal transduction pathway is involved in the regulation and release of pro-inflammatory cytokines such as TNF-α and plays an important role in the development and progression of UC.

[Blood pressure variability correlates with target-organ damage in elderly patients with hypertension].

OBJECTIVE: To investigate the relationship between blood pressure variability (BPV)and target-organ damage in elderly patients with hypertension. METHODS: A total of 197 elderly patients were included in the study. The participants were divided into two groups: those with hypertension (n=146) and those without hypertension (Control, n=51). The 24 h systolic and diastolic blood pressure variability (24 h SBPV/DBPV),24 h average systolic and diastolic blood pressure (24 h SBP/DBP), day time systolic and diastolic blood pressure variability (d SBPV/DBPV),and night time systolic and diastolic blood pressure variability (n SBPV/DBPV)were measured. The hypertensive group was further divided into low and high variability groups according to the 50th percentile of 24 h SBPV. The carotid artery intima-media thickness (IMT), left ventricular mass index (LVMI), 24 h microalbuminuria (MA) and basic clinical and laboratory parameters were compared among the groups. The correlations between blood pressure variability and IMT, LVMI, and MA were analyzed with multivariable regression analyses. RESULTS: The patients with essential hypertension had significantly higher 24 h SBPV (P < 0.001) and d SBPV (P < 0.05) than those without hypertension. The patients with higher blood pressure variability had greater incidence of plaque and cardiovascular disorder, as well as IMT, LVMI and MA (P < 0.001). The prevalence of diabetes mellitus (DM) differed significantly among the three groups of participants (P < 0.05). The multivariable regression analysis showed that 24 h SBPV was independently correlated with IMT, LVMI and MA. CONCLUSION: Elderly patients with hypertension have high BPV, which is an important independent predictor of target-organ damage.

Blockade of p38 mitogen-activated protein kinase pathway ameliorates delayed gastric emptying in streptozotocin-induced diabetic rats.

BACKGROUND AND AIM: Gastrointestinal dysfunction is one of the major complications of diabetes. The roles of inflammation in diabetes and its associated complications are increasingly recognized. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of pro-inflammatory mediators. The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on delayed gastric emptying in diabetic rats and to elucidate its possible mechanism. METHODS: SB203580 was administered in diabetic rats induced by intraperitoneal injection of streptozotocin. The gastric emptying rate of rats was measured by using phenol red solution, and blood glucose levels and body weights were observed. p38 MAPK activity and iNOS expression were assessed by Western blot analysis. The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were determined by enzyme-linked immunosorbent assay. RESULTS: Gastric emptying was delayed significantly in diabetic rats and improved significantly with SB203580; high glucose significantly activated p38 MAPK and increased the expression of iNOS, TNF-α and IL-1ß. The administration of SB203580 led to a significant decrease in the activation of p38 MAPK and the expression of iNOS, TNF-α and IL-1ß. CONCLUSIONS: Inflammation was associated with the development of delayed gastric emptying, and blockade of p38 MAPK pathway with SB203580 ameliorates delayed gastric emptying in diabetic rats, at least in part, by inhibiting the expression of iNOS, TNF-a and IL-1ß. Therefore, p38MAPK may serve as a novel target for the therapy of diabetes-related gastrointestinal dysmotility.

Tetrandrine suppresses amyloid-ß-induced inflammatory cytokines by inhibiting NF-κB pathway in murine BV2 microglial cells.

Microglial cells play an important role in mediating neuroinflammation in Alzheimer's disease (AD) by production of a series of proinflammatory mediators and clearance of Aß peptides and senile plaques. Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese herb Radix Stephania tetrandra, has been demonstrated to decrease the expression of proinflammatory mediators by inhibition of NF-κB activation. Here we investigated whether tetrandrine may affect the phagocytosis of microglia and the expression of cytokines and NF-κB in murine BV2 microglial cells. We found that fibrillar Amyloid-ß (fAß) induced phagocytosis of microglia and dramatically increased the levels of interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) as well as the expression of phospho NF-κB p65 in microglia cultures. The treatment with tetrandrine resulted in downregulation of phospho NF-κB p65 expression and strikingly reduced the production of IL-1ß and TNF-α. However, tetrandrine did not affect fAß induced phagocytosis of microglia. In conclusion, tetrandrine can decrease microglial detriment of neurotoxicity while maintaining microglial benefit of neuroprotection. Tetrandrine may be an efficacious and promising remedy in the treatment of AD.

Tetrandrine attenuates spatial memory impairment and hippocampal neuroinflammation via inhibiting NF-κB activation in a rat model of Alzheimer's disease induced by amyloid-ß(1-42).

BACKGROUND: The neuroinflammation characterized by glial activation and release of proinflammatory mediators is considered to play a critical role in the pathogenesis of Alzheimer's disease (AD). Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese herb radix Stephania tetrandra, has been demonstrated to decrease the expression of proinflammatory mediators by inhibition of nuclear factor-κB (NF-κB) activation. The purpose of the study was to investigate effects of tetrandrine on experimental model of AD. MATERIALS AND METHODS: Tetrandrine was administered in a rat model of AD induced by amyloid-ß (Aß)(1-42). The learning and memory impairment was examined using Morris water maze; the extent of histological injury in hippocampus was determined by Nissl staining; NF-κB DNA binding activity was assessed by electrophoretic mobility shift assay; the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß was measured by enzyme-linked immunosorbent assay. RESULTS: A significant improvement was observed in learning and memory impairment in rats with tetrandrine, and the increase in NF-κB DNA binding activity, the over-expression in IL-1ß and TNF-α as well as the increased histological injury in hippocampus in rats induced by Aß(1-42) were significantly reduced following administration of tetrandrine. CONCLUSION: Tetrandrine could significantly ameliorate Aß(1-42)-induced spatial learning and memory impairment, and the beneficial effect of tetrandrine treatment could be linked, at least in part, to the inhibition of NF-κB activity and the downregulation of expression of IL-1ß and TNF-α, suggesting that administration of tetrandrine may provide a therapeutic approach for AD.