Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial.

BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

Anticancer Effects of Constituents of Herbs Targeting Osteosarcoma.

Osteosarcoma is a rare primary malignancy of bone that is prone to early metastasis. Resection surgery and chemotherapeutic regimens are current standard treatments for osteosarcoma. However, the long-term survival rate of patients with osteosarcoma is low due to a high risk of metastasis. Hence, a new approach is urgently needed to improve the treatment of osteosarcoma. Compared with chemotherapy, natural active constituents isolated from herbs exhibit less adverse effects and better anti-tumor effects. This study aimed to summarize the anticancer effects of constituents of herbs on the progression and metastasis of osteosarcoma cells. It showed that many constituents of herbs inhibited osteosarcoma by targeting proliferation, matrix metalloproteinases, integrin and cadherin, and angiogenesis. The findings might be beneficial for the development of new drugs and treatment strategies.

Critical role of prohibitin in endothelial cell apoptosis caused by glycated low-density lipoproteins and protective effects of grape seed procyanidin B2.

Elevated level of glycated low-density lipoproteins (glyLDL) is believed to contribute to endothelial dysfunction, which is involved in the pathogenesis and acceleration of diabetic vascular diseases. Grape seed procyanidin B2 (GSPB2) has been reported to possess protective effects against endothelial dysfunction. However, the underlying mechanism remains unclear. Prohibitin (PHB) is a multifunctional protein implicated in cellular survival and apoptosis. In this study, we showed that glyLDL treatment decreased protein level of PHB, reduced viability, and increased apoptosis in human umbilical vein endothelial cells (HUVEC). PHB overexpression or GSPB2 significantly attenuated apoptosis induced by glyLDL. Moreover, PHB siRNA increased HUVEC apoptosis, along with defective mitochondria and increased levels of cytosol cytochrome c concentration, caspase-3 activity, Bax/Bcl-2 ratio, and phosphorylated Akt, whereas PHB overexpression or GSPB2 restored these changes. Our study identified PHB as an important player responsible for HUVEC apoptosis induced by glyLDL. GSPB2 protected against HUVEC apoptosis at least in part through upregulating PHB. Targeting PHB could be significant in fighting against diabetic vascular complications.

PIMT prevents the apoptosis of endothelial cells in response to glycated low density lipoproteins and protective effects of grape seed procyanidin B2.

BACKGROUND: The development of diabetic angiopathy is associated with profound vascular endothelial cells (VEC) dysfunction and apoptosis. Glycated low density lipoproteins (gly-LDL) continuously produced in the setting of diabetic patients play an important role in causing VEC dysfunction and apoptosis. However, the underlying molecular mechanism remains largely elusive. Protein L-isoaspartyl methyltransferase (PIMT) is a widely expressed protein repair enzyme by multiple cell types of arterial wall including VEC. Our previous proteomic studies showed that the expression of PIMT was significantly decreased in the aorta of diabetic rats as compared with control rats and treatment with grape seed procyanidin extracts significantly increased the PIMT expression in diabetic rats. We hypothesized that PIMT plays a critical role in gly-LDL induced VEC apoptosis; grape seed procyanidin B2 (GSPB2) protect against gly-LDL induced VEC apoptosis through PIMT regulation. METHODS AND RESULTS: HUVEC transfected negative control and PIMT siRNA were treated with or without GSPB2 (10 µmol/L) for 48 h. Moreover, HUVEC of PIMT overexpression were stimulated by gly-LDL (50 µg/ml) in the presence or absence of GSPB2 (10 µmol/L) for 48 h. Our results showed that gly-LDL downregulated PIMT expression and PIMT overexpression or GSPB2 significantly attenuated gly-LDL induced VEC apoptosis. PIMT siRNA increased VEC apoptosis with up-regulation of p53, cytochrome c release, caspase-9 and caspase-3 activation. Mechanistically, overexpression of PIMT or GSPB2 increased the phosphorylation of ERK1/2 and GSK3ß in the gly-LDL induced VEC. CONCLUSION: In summary, our study identified PIMT as a key player responsible for gly-LDL induced VEC apoptosis and GSPB2 protect against gly-LDL induced VEC apoptosis by PIMT up-regulation. Targeting PIMT including use of GSPB2 could be turned into clinical application in the fighting against diabetic vascular complications.

Proteomic analysis of kidney and protective effects of grape seed procyanidin B2 in db/db mice indicate MFG-E8 as a key molecule in the development of diabetic nephropathy.

Diabetic nephropathy, as a severe microvascular complication of diabetic mellitus, has become the leading cause of end-stage renal diseases. However, no effective therapeutic strategy has been developed to prevent renal damage progression to end stage renal disease. Hence, the present study evaluated the protective effects of grape seed procyanidin B2 (GSPB2) and explored its molecular targets underlying diabetic nephropathy by a comprehensive quantitative proteomic analysis in db/db mice. Here, we found that oral administration of GSPB2 significantly attenuated the renal dysfunction and pathological changes in db/db mice. Proteome analysis by isobaric tags for relative and absolute quantification (iTRAQ) identified 53 down-regulated and 60 up-regulated proteins after treatment with GSPB2 in db/db mice. Western blot analysis confirmed that milk fat globule EGF-8 (MFG-E8) was significantly up-regulated in diabetic kidney. MFG-E8 silencing by transfection of MFG-E8 shRNA improved renal histological lesions by inhibiting phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), Akt and glycogen synthase kinase-3beta (GSK-3ß) in kidneys of db/db mice. In contrast, over-expression of MFG-E8 by injection of recombinant MFG-E8 resulted in the opposite effects. GSPB2 treatment significantly decreased protein levels of MFG-E8, phospho-ERK1/2, phospho-Akt, and phospho-GSK-3ß in the kidneys of db/db mice. These findings yield insights into the pathogenesis of diabetic nephropathy, revealing MFG-E8 as a new therapeutic target and indicating GSPB2 as a prospective therapy by down-regulation of MFG-E8, along with ERK1/2, Akt and GSK-3ß signaling pathway.

Proteomic analysis of aorta and protective effects of grape seed procyanidin B2 in db/db mice reveal a critical role of milk fat globule epidermal growth factor-8 in diabetic arterial damage.

BACKGROUND: Atherosclerosis is one of the major complications of type 2 diabetic patients (T2DM), leading to morbidity and mortality. Grape seed procyanidin B2 (GSPB2) has demonstrated protective effect against atherosclerosis, which is believed to be, at least in part, a result of its antioxidative effects. The aim of this study is to identify the target protein of GSPB2 responsible for the protective effect against atherosclerosis in patients with DM. METHODS AND RESULTS: GSPB2 (30 mg/kg body weight/day) were administrated to db/db mice for 10 weeks. Proteomics of the aorta extracts by iTRAQ analysis was obtained from db/db mice. The results showed that expression of 557 proteins were either up- or down-regulated in the aorta of diabetic mice. Among those proteins, 139 proteins were normalized by GSPB2 to the levels comparable to those in control mice. Among the proteins regulated by GSPB2, the milk fat globule epidermal growth factor-8 (MFG-E8) was found to be increased in serum level in T2DM patients; the serum level of MFG-E8 was positively correlated with carotid-femoral pulse wave velocity (CF-PWV). Inhibition of MFG-E8 by RNA interference significantly suppressed whereas exogenous recombinant MFG-E8 administration exacerbated atherogenesis the db/db mice. To gain more insights into the mechanism of action of MFG-E8, we investigated the effects of MFG-E8 on the signal pathway involving the extracellular signal-regulated kinase (ERK) and monocyte chemoattractant protein-1 (MCP-1). Treatment with recombinant MFG-E8 led to increased whereas inhibition of MFG-E8 to decreased expression of MCP-1 and phosphorylation of ERK1/2. CONCLUSION: Our data suggests that MFG-E8 plays an important role in atherogenesis in diabetes through both ERK and MCP-1 signaling pathways. GSPB2, a well-studied antioxidant, significantly inhibited the arterial wall changes favoring atherogenesis in db/db mice by down-regulating MFG-E8 expression in aorta and its serum level. Measuring MFG-E8 serum level could be a useful clinical surrogate prognosticating atherogenesis in DM patients.

Grape seed procyanidin b2 inhibits human aortic smooth muscle cell proliferation and migration induced by advanced glycation end products.

Advanced glycation end product (AGE)-induced vascular smooth muscle cell (VSMC) proliferation is vital to the progression of diabetic vasculopathy. A grape seed procyanidin extract has been reported to possess anti-oxidative and anti-inflammatory properties and to display a significant cardiovascular protective effect, but little is know about the underlying mechanism. The objective of this present study was to determine whether GSPB2 (grape seed procyanidin B2), which is a dimeric procyanidin and more biologically active, could inhibit AGE-induced VSMC proliferation by affecting the production of ubiquitin COOH-terminal hydrolase 1 (UCH-L1), the degradation of IκB-α and nuclear translocation of NF-κB in human aortic smooth muscle cells (HASMCs). Our data show that GSPB2 preincubation markedly inhibited AGE-induced proliferation and migration of HASMCs in a dose-dependent manner and upregulated the protein level of UCH-L1. Further studies revealed that the GSPB2 pretreatment markedly attenuated the degradation of IκB-α and nuclear translocation of NF-κB by modulating ubiquitination of IκB-α in AGE-exposed HASMCs. These results collectively suggest that AGE-induced HASMC proliferation and migration was suppressed by GSPB2 through regulating UCH-L1 and ubiquitination of IκB-α. GSPB2 may therefore have therapeutic potential in preventing and treating vascular complications of diabetes mellitus.

[Multi-central clinical valuation of SHAO's "five needling methods" for treatment of asthma of deficiency of lung and spleen].

OBJECTIVE: To make multi-central clinical valuation of SHAO's "five needling methods" for treatment of asthma of deficiency of lung and spleen. METHODS: Two hundred and ten cases were randomly divided into a test group and a control group, 105 cases in each group. The test group were treated with SHAO's "five needling methods", with Feishu (BL 13), Dazhui (GV 14), Fengmen (BL 12) selected; the control group were treated with routine needling method, with Dingchuan (EX-B 1), Gaohuang (BL 43), Feishu (BL 13), Taiyuan (LU 9), Pishu (BL 20), etc. selected. The treatment in the two groups was given once each day, for 4 weeks, with one-day interval each 6-consecutive day. RESULTS: Fourteen cases were clinically cured, 42 cases were markedly effective, 32 cases were effective and 6 cases were ineffective in the test group with an effective rate of 93.6%; and 8, 30, 41 and 13 cases in the control group, respectively, with an effective rate of 85.9%, with a significant difference between the two groups (P < 0.05). After treatment, the symptoms and signs, pulmonary function in the test group were better than those in the control group (P < 0.05). CONCLUSION: SHAO's "five needling methods" has significant therapeutic effect for treatment of asthma of deficiency of lung and spleen, which is better than that of the routine needling method.