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The present study aimed to investigate whether klotho gene delivery attenuated renal hypertrophy and fibrosis in streptozotocin-induced diabetic rats. A recombinant adeno-associated virus (rAAV) carrying mouse klotho full-length cDNA (rAAV.mKL), was constructed for in vivo investigation of klotho expression. Diabetes was induced in rats by a single tail vein injection of 60 mg/kg streptozotocin. Subsequently, the diabetic rats received an intravenous injection of rAAV.mKL, rAAV.green fluorescent protein (GFP) or phosphate-buffered saline (PBS). The Sprague-Dawley rat group received PBS and served as the control group. After 12 weeks, all the rats were sacrificed and ELISA, immunohistochemical and histological analyses, fluorescence microscopy, semi-quantitative reverse transcription-polymerase chain reaction and western blottin were performed. A single dose of rAAV.mKL was found to prevent the progression of renal hypertrophy and fibrosis for at least 12 weeks (duration of study). Klotho expression was suppressed in the diabetic rats, but was increased by rAAV.mKL delivery. rAAV.mKL significantly suppressed diabetes-induced renal hypertrophy and histopathological changes, reduced renal collagen fiber generation and decreased kidney hypertrophy index. In addition, rAAV.mKL decreased the protein expression levels of fibronectin and vimentin, while it downregulated the mRNA expression and activity of Rho-associated coiled-coil kinase (ROCK)I in the kidneys of the diabetic rats. These results indicated that klotho gene delivery ameliorated renal hypertrophy and fibrosis in diabetic rats, possibly by suppressing the ROCK signaling pathway. This may offer a novel approach for the long-term control and renoprotection of diabetes. [ABSTRACT FROM AUTHOR]

A selective methodology for preparing highly substituted aminopyrazoles has been demonstrated. Starting with an acetophenol core, the corresponding substituted isoxazole is prepared in two steps. The isoxazole is transformed into a benzopyran. Alkylation of the aminobenzopyranone gives N-substituted aminobenzopyranone derivatives that react with substituted hydrazine to give aminopyrazoles. This versatile synthesis enables the preparation of highly substituted aminopyrazoles for use as key synthetic building blocks for biologically active molecules. In addition, this process represents the first amine alkylation of aminobenzopyranones. [ABSTRACT FROM AUTHOR]

Owing to their strong migratory capacity, tumor tropism, and tumor inhibitory effect, neural stem cells (NSCs) have recently emerged as one of the most attractive gene delivery vectors for cancer therapy. However, further animal studies found that proportional NSC vectors were distributed to nontarget organs after intravenous injection and the nonspecific transgene expression led to significant cytotoxic effects in these organs. Hence, an expression cassette that controls the transgene expression within NSC vectors in a tumor site-specific manner is desired. Considering hypoxia as a hallmark of tumor microenvironment, we have developed a novel NSC vector platform coupling transcriptional targeting with microRNA (miRNA) regulation for tumor hypoxia targeting. This combinatorial vector employed a hypoxia-responsive promoter and repeated targeting sequences of an miRNA that is enriched in NSCs but down regulated upon hypoxia induction to control the transgene expression. This resulted in significantly improved hypoxic selectivity over the use of a control vector without miRNA regulation. Thus, incorporating miRNA regulation into a transcriptional targeting vector adds an extra layer of security to prevent off-target transgene expression and should be useful for the development of NSC vectors with high targeting specifcity for cancer therapy. [ABSTRACT FROM AUTHOR]

The role of inflammation in acute coronary syndrome (ACS) and the mechanism by which statin treats ACS is explored. Serum high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) levels were measured in 50 patients with ACS [including 30 cases with unstable angina (UA) and 20 patients with acute myocardial infarction (AMI)], 34 patients with stable angina (SA), and 30 controls. Patients in the ACS group were randomly assigned to a simvastatin group (including a simvastatin AMI subgroup,n= 11 and a simvastatin UA subgroup,n= 14) and a routine group (including a routine AMI subgroup,n= 9 and a routine UA subgroup,n= 16). The simvastatin group was given simvastatin 20?mg/day and the routine group a placebo. After a 3-week follow-up, serum hs-CRP, IL-6 levels, and serum lipid concentrations were measured again. Both serum IL-6 and hs-CRP levels were significantly higher in the ACS group (including the UA and AMI subgroups) than in the SA and control groups (P<0.001). After 3 weeks of treatment with simvastatin, the serum IL-6, hs-CRP, total cholesterol, and low-density lipoprotein cholesterol levels were decreased significantly in the simvastatin group (P<0.001), but no significant changes were observed in the routine group. No relationship was observed between the rate of decrease of serum IL-6 or hs-CRP and serum lipids levels. The hs-CRP level showed a significant correlation with IL-6 by Spearman’s rank correlation analysis (P<0.01). Inflammation plays an important role in the initiation of ACS. Simvastatin possesses an anti-inflammatory effect, independent of its lipid-lowering action, which may play an important role in the early treatment of ACS. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to identify and determine the content of toxic components(diester‑type alkaloids) in Aconitum brachypodum, providing scientific support for the safe clinical use of this medicinal herb and offering a basis for quality control. Methods: Acidic water was used to extract the alkaloids from Aconitum brachypodum, which were then extracted with petroleum ether. Toxic components were separated and extracted with chloroform from the acid water, with the phenolic acidic fractions absorbed by alkaline oxidized alumina. The toxic components were identified by thin‑layer chromatography (TLC), and the content was measured by ultraviolet (UV)–visible spectrophotometry. Results: A method for special thin‑layer identification of toxic components and general determination of total alkaloid content in Aconitum brachypodum was established. The mean content of toxic diterpenoid alkaloids in Aconitum brachypodum cultivated in the Dongchuan district of Kunming was approximately 0.30%. Conclusion: Selective extraction of toxic alkaloids in Aconitum brachypodum by chemical methods, identification by TLC, and content determination by UV–visible spectrophotometry can control the toxicity of this herb, guide production, and ensure clinical safety. [ABSTRACT FROM AUTHOR]

The article presents a study that reports the induction of selective vesicle fusion with biological recognition motifs not natively associated with lipid bilayer fusion, thus broadening the scope of recognition-guided membrane activation. The study employs vancomycin glycopeptide and D-Ala-D-Ala-Oh dipeptide as surface-bound fusogens.

Selective membrane mergers may be driven by small-molecule recognition between synthetic surface-displayed fusogens which bear vancomycin glycopeptide and its native binding target, D-Ala-D-Ala dipeptide. These recognition motifs are membrane anchored by antimicrobial peptide magainin II and a phosphatidylethanolamine lipid derivative, respectively. We report herein characterization of this synthetic membrane fusion reaction with regard to the following: effects of fusogen concentration, lipid composition, and membrane charge. Our findings indicate that these parameters are determinants of fusion rate, vesicle stability, peptide binding, catalytic fusion and membrane disruption during fusion. Notably, these data indicate the importance of coupling between molecular recognition and insertion for bilayer activation as well as the critical role of membrane subdomain formation for membrane fusion reactivity. These phenomena are general to lipid membrane chemistry, and therefore these findings provide a guideline for understanding more complex biomembrane systems. [ABSTRACT FROM AUTHOR]