[Mechanism of Fushen Granules treat peritoneal dialysis-related peritonitis by regulating TLR4/NF-κB pathway:based on network pharmacology and animal experiments].

Network pharmacology was employed to probe into the mechanism of Fushen Granules in treating peritoneal dialysis-rela-ted peritonitis(PDRP) in rats. The main active components of Fushen Granules were searched against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and their targets were predicted. PDRP-related targets were retrieved from DisGeNET and other databases. The common targets shared by the drug and the disease were identified by the online tool, and protein-protein interaction(PPI) network of the common targets. The obtained 276 common targets were imported into DAVID for GO function enrichment and KEGG pathway enrichment. The main signaling pathway of Fushen Granules in the treatment of PDRP was predicted as Toll-like receptor 4(TLR4)/nuclear factor(NF)-κB. The rat model of uremia was induced by 5/6 nephrectomy. From two weeks after operation, the rat model of peritoneal dialysis(PD) was established by intraperitoneal injection of 20 mL dialysate with 1.25% glucose every day. The sham operation group and model group received 2 mL normal saline by gavage every day. The rats in Fushen Gra-nules groups were administrated with 2 mL solutions of low-(0.54 g·kg~(-1)), medium-(1.08 g·kg~(-1)) and high-dose(2.16 g·kg~(-1)) Fushen Granules every day. The bifico group received 2 mL(113.4 mg·kg~(-1)) of bifico solution every day. At the end of the 8th week, the levels of serum creatinine(Scr) and blood urea nitrogen(BUN) in each group were measured. The serum levels of hypersensitive C reactive protein(hs-CRP), tumor necrosis factor(TNF)-α, and interleukin(IL)-6 were measured, and the pathological changes in the colon tissue were observed by hematoxylin-eosin(HE) staining. The serum levels of lipopolysaccharide(LPS) and lipopolysaccharide-binding protein(LBP) of rats were measured, and the expression levels of LBP, TLR4, NF-κB p65, inhibitor of κB kinase α(IκBα), TNF-α, and IL-1ß in the colon tissue were determined. Compared with sham operation group, the model group had abnormal structure of all layers of colon tissue, sparse and shorter intestinal villi, visible edema in mucosal layer, wider gap, obvious local inflammatory cell infiltration, significantly decreased body weight(P<0.01), and significantly increased kidney function index(Scr, BUN) content(P<0.01). Serum levels of inflammatory cytokines(hs-CRP, TNF-α, IL-6), LPS and LBP were significantly increased(P<0.01), protein expressions of LBP, TLR4, NF-κB p65, TNF-α and IL-1ß were significantly increased(P<0.01), and protein expressions of IκBα were significantly decreased(P<0.01). Compared with model group, intestinal villi damage in colonic tissue of rats in low-, medium-and high-dose Fushen Granules groups and bifico group were alleviated to different degrees, edema in submucosa was alleviated, space was narrowed, and inflammatory cell infiltration in lamina propria was reduced. The contents of renal function index(Scr, BUN) and serum inflammatory factors(hs-CRP, TNF-α, IL-6) were significantly decreased(P<0.05 or P<0.01) in medium-and high-dose Fushen Granules groups and bifico group(P<0.05 or P<0.01). Serum LPS and LBP contents in Fushen Granules group and bifico group were significantly decreased(P<0.01), protein expressions of LBP, TLR4, NF-κB p65, TNF-α and IL-1ß in Fushen Granules group were significantly decreased(P<0.05 or P<0.01), and protein expressions of IκBα were significantly increased(P<0.01). The expression of LBP protein in bifico group was significantly decreased(P<0.01). The results suggest that Fushen Granules can protect the residual renal function of PD rats, reduce the inflammatory response, and protect the colon tissue. Based on network pharmacology, TLR4/NF-κB pathway may be the main signaling pathway of Fushen granule in the treatment of PDRP. The results showed that Fushen Granules could improve intestinal inflammation and protect intestinal barrier to prevent PDRP by regulating the expression of key factors in TLR4/NF-κB pathway in colon of PD rats.

Atroposelective construction of axially chiral enamides via N-allylic alkylation.

Herein, we report the catalytic asymmetric synthesis of a unique family of axially chiral enamides in good yields with excellent enantioselectivities under mild conditions. These new axially chiral compounds feature a flexible skeleton and a high degree of rotational freedom, which raises difficulties for enantiocontrol. A mechanism model is proposed to interpret the stereoselectivity, in which both the steric difference of the ortho substituents and the π-π stacking interaction may contribute to the stereo-control.

Access to P-stereogenic compounds via desymmetrizing enantioselective bromination.

A novel and efficient desymmetrizing asymmetric ortho-selective mono-bromination of bisphenol phosphine oxides under chiral squaramide catalysis was reported. Using this asymmetric ortho-bromination strategy, a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates were obtained with good to excellent yields (up to 92%) and enantioselectivities (up to 98.5 : 1.5 e.r.). The reaction could be scaled up, and the synthetic utility of the desired P-stereogenic compounds was proved by transformations and application in an asymmetric reaction.

Association Between c-Myc and Colorectal Cancer Prognosis: A Meta-Analysis.

Background: There is debate as to whether c-Myc predicts prognosis in colorectal cancer (CRC). In this study, we aimed to review the association between c-Myc and CRC prognosis. Methods: Pertinent studies were identified by searching electronic databases and carefully reviewing the reference lists of pertinent studies until March 2016. The summary hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated to study the association between c-Myc and CRC prognosis. Results: Eight cohort studies (including seven studies about overall survival [OS] and one study about disease free survival [DFS]) were included. The pooled HR of OS was 1.13 (95% CI: 0.66-1.95). In subgroup analysis, no significant association between c-Myc and CRC prognosis was found in the studies either from Western countries (HR: 0.87, 95% CI: 0.68-1.10) or Asian countries (HR: 1.89, 95% CI: 0.62-5.77). HRs were 0.86 (95% CI: 0.38-1.94) and 1.57 (95% CI: 0.73-3.39) for the studies using univariate analysis and multivariate analysis, respectively. HR from the studies that examined DNA level was significantly different (HR: 2.05, 95% CI: 1.22-3.46); while that about RNA level or protein level was not significantly different. Conclusion: c-Myc was not associated with CRC prognosis in this meta-analysis. However, the conclusion is preliminary and should be examined in future studies.

Methological quality of systematic reviews and meta-analyses on acupuncture for stroke: A review of review.

OBJECTIVE: To assess the methodological quality of systematic reviews and meta-analyses regarding acupuncture intervention for stroke and the primary studies within them. METHODS: Two researchers searched PubMed, Cumulative index to Nursing and Allied Health Literature, Embase, ISI Web of Knowledge, Cochrane, Allied and Complementary Medicine, Ovid Medline, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang and Traditional Chinese Medical Database to identify systematic reviews and meta-analyses about acupuncture for stroke published from the inception to December 2016. Review characteristics and the criteria for assessing the primary studies within reviews were extracted. The methodological quality of the reviews was assessed using adapted Oxman and Guyatt Scale. The methodological quality of primary studies was also assessed. RESULTS: Thirty-two eligible reviews were identified, 15 in English and 17 in Chinese. The English reviews were scored higher than the Chinese reviews (P=0.025), especially in criteria for avoiding bias and the scope of search. All reviews used the quality criteria to evaluate the methodological quality of primary studies, but some criteria were not comprehensive. The primary studies, in particular the Chinese reviews, had problems with randomization, allocation concealment, blinding, dropouts and withdrawals, intent-to-treat analysis and adverse events. CONCLUSIONS: Important methodological flaws were found in Chinese systematic reviews and primary studies. It was necessary to improve the methodological quality and reporting quality of both the systematic reviews published in China and primary studies on acupuncture for stroke.

Hepatocyte growth factor is a prognostic marker in patients with colorectal cancer: a meta-analysis.

Hepatocyte growth factor (HGF) is a crucial factor associated with development, progression and metastasis of colorectal cancer (CRC). However, its prognostic value remains unclear. Thus studies referring to the correlation between HGF and CRC patients' prognosis were included to explore the role of HGF in CRC. At last nine articles were included. The results showed that the over-expression of HGF was associated with a poor prognosis, presented through overall survival (OS, Hazard ratio (HR) = 2.50, 95% confidence interval (CI): 2.12-2.96) and disease-free survival (DFS, HR = 1.99, 95% CI: 1.59-2.50). Subgroup analysis indicated that no significant difference was found between the Asian countries (OS: HR = 2.37; DFS: HR = 2.02) and the non-Asian countries (OS: HR = 3.15; DFS: HR = 1.87), between the studies that used univariate analyses (OS: HR = 2.51; DFS: HR = 2.07) and those that used multivariate analyses (OS: HR = 2.65; DFS: HR = 1.78), and between metastatic CRC (OS: HR = 2.26; DFS: HR = 2.06) and stage I-IV CRC (OS: HR = 3.08; DFS: HR = 0.70). Our meta-analysis has shown that the over-expression of HGF is valuable in CRC prognosis evaluation. This conclusion should be further confirmed by large-sample cohort studies.

SIRT2 regulates microtubule stabilization in diabetic cardiomyopathy.

Stable microtubules (MTs) is involved the mechanism of diabetic cardiomyopathy (DCM), which is induced by acetylation of α-tubulin. The present study investigated whether SIRT2, a deacetylase, regulates MT stability through α-tubulin deacetylation in DCM and whether the receptor of advanced glycation end products (AGEs) signaling pathway is involved in this effect. Type 1 diabetic mellitus (T1DM) rats model was established by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler. MT stability was elevated by ß-tubulin expression density. The protein expression of SIRT2, acetylated α-tubulin and AGEs receptor were detected by immunohistochemistry or Western blots. The interaction of SIRT2 and acetylated α-tubulin was detected by Co-immunoprecipitation. In an animal model of T1DM, Western blots and immunohistochemistry revealed downregulation of SIRT2 but upregulation of the acetylated α-tubulin protein. These effects were reduced by treatment of aminoguanidine, an inhibitor of AGEs production. HDAC6 expression did not regulated in heart. In primary cultures of neonatal rat cardiomyocytes, the AGEs treatment impaired the SIRT2/acetylated α-tubulin signaling pathway, and SIRT2-overexpression reversed the function of AGEs on cardiomyocytes. In addition, gene silencing of AGEs receptor alleviated the impairment effect of AGEs on cardiomyocytes. In conclusion, these data demonstrate that AGEs/AGEs receptor promote MT stabilization via the suppression of the SIRT2/acetylated α-tubulin signaling pathway in DCM development.

Advanced glycation end-products impair Na⁺/K⁺-ATPase activity in diabetic cardiomyopathy: role of the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway.

Decreased Na(+) /K(+) -ATPase activity, and both sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) have been reported to be involved in the development of diabetic cardiomyopathy (DCM). The present study aimed to investigate the advanced glycation end-products (AGE) that impair Na(+) /K(+) -ATPase stability by regulating the AMPK/SIRT1 pathway during progression of DCM. To study type 1 diabetic mellitus (T1DM), a disease model in rats was established by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler, and SIRT1 and AMPK protein expression were detected by immunohistochemistry and western blotting. Na(+) /K(+) -ATPase activity was also monitored. Using in vivo rat models of DCM, we showed that Na(+) /K(+) -ATPase activity decreased when both AMPK and SIRT1 expression were downregulated. In vitro, AGE impaired Na(+) /K(+) -ATPase activity and decreased the AMPK and SIRT1 expression. Sirtuin 1 overexpression increased Na(+) /K(+) -ATPase activity. 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) upregulated SIRT1 expression and increased Na(+) /K(+) -ATPase activity, which could be partially abolished by splitomicin. Our results suggest that the dysfunction of DCM is related to AGE-induced Na(+) /K(+) -ATPase activity impairment through a mechanism involving the AMPK/SIRT1 pathway.

Topology repair of solid models using skeletons.

We present a method for repairing topological errors on solid models in the form of small surface handles, which often arise from surface reconstruction algorithms. We utilize a skeleton representation that offers a new mechanism for identifying and measuring handles. Our method presents two unique advantages over previous approaches. First, handle removal is guaranteed not to introduce invalid geometry or additional handles. Second, by using an adaptive grid structure, our method is capable of processing huge models efficiently at high resolutions.

Robust feature classification and editing.

Sharp edges, ridges, valleys, and prongs are critical for the appearance and an accurate representation of a 3D model. In this paper, we propose a novel approach that deals with the global shape of features in a robust way. Based on a remeshing algorithm which delivers an isotropic mesh in a feature-sensitive metric, features are recognized on multiple scales via integral invariants of local neighborhoods. Morphological and smoothing operations are then used for feature region extraction and classification into basic types such as ridges, valleys, and prongs. The resulting representation of feature regions is further used for feature-specific editing operations.