Effect of Angipars on neuropathic pain in streptozotocin-induced diabetic rats

Introduction: Diabetes is the most common cause of peripheral nerve involvement. Evaluating the effect of antioxidants on diabetic neuropathic pain is important. This study aimed at evaluating the effects of Angipars medicine in the treatment of neuropathic hyperalgesia in single dose streptozotocin-induced diabetic rats. Methods: The study was performed on 50 Spraque dawley rats of 250-300 grams weight. The rats were divided into four groups of control, sham, Angipars-receiving diabetic, and vehicle-receiving diabetic, with at least 8 rats in each group. Diabetes was induced by intraperitoneal injection of 45 mg/kg streptozotocin dissolved in a 0.05 M citrate buffer. After confirming the diabetes, the diabetic rats received (5, 10, 20 mg/kg, intraperitoneal) Angipars and vehicle for 2 weeks. At the end of the eighth week, the control and treated rats were examined through the hot plate and tail flick tests. ANOVA was used to evaluate the statistical difference and P<0.05 was considered as significant. Results: At the end of the eighth week, the response time to thermal hyperalgesia decreased in the vehicle and sham groups compared with the control group. Angipars at doses of 5 and 10 mg increased the response time to thermal hyperalgesia compared to the vehicle and sham groups in hot plate test. In the tail flick test, 10mg Angipars increased the response time to pain similar to the control group. Conclusion: This study showed that, as an antioxidant, Angipars is capable of reducing neuropathic hyperalgesia in animals with diabetes

An Integrated Fuzzy Framework for Analyzing Barriers to the Implementation of Continuous Improvement in Manufacturing

Purpose – Delivering premium services and quality products are critical strategies for success in manufacturing. Continuous improvement (CI), as an underlying foundation for quality management, is an ongoing effort allowing manufacturing companies to see beyond the present to create a bright future. We propose a novel integrated fuzzy framework for analyzing the barriers to the implementation of CI in manufacturing companies. Design/methodology/approach – We use the fuzzy failure mode and effect analysis (FMEA) and a fuzzy Shannon’s entropy to identify and weigh the most significant barriers. We then use fuzzy multi-objective optimization based on ratio analysis (MOORA), the fuzzy technique for order of preference by similarity to ideal solution (TOPSIS), and fuzzy simple additive weighting (SAW) methods for prioritizing and ranking the barriers with each method. Finally, we aggregate these results with Copeland’s method and extract the main CI implementation barriers in manufacturing. Findings – We show “low cooperation and integration of the team in CI activities” is the most important barrier in CI implementation. Other important barriers are “limited management support in CI activities,” “low employee involvement in CI activities,” “weak communication system in the organization,” and “lack of knowledge in the organization to implement CI projects.” Originality/value – We initially identify the barriers to the implementation of CI through rigorous literature review and then apply a unique integrated fuzzy approach to identify the most important barriers based on the opinions of industry experts and academics

IL-27 promotes the expansion of self-renewing CD8(+) T cells in persistent viral infection

Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5(+) TCF1(+) CD8(+) T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5(+) CD8(+) T cell expansion in an IL-27- and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8(+) T cells. We found that CD8(+) T cell-intrinsic IL-27 signaling safeguards the ability of TCF1(hi) cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer

Virus-Induced Type I Interferon Deteriorates Control of Systemic Pseudomonas Aeruginosa Infection

BACKGROUND: Type I interferon (IFN-I) predisposes to bacterial superinfections, an important problem during viral infection or treatment with interferon-alpha (IFN-alpha). IFN-I-induced neutropenia is one reason for the impaired bacterial control; however there is evidence that more frequent bacterial infections during IFN-alpha-treatment occur independently of neutropenia. METHODS: We analyzed in a mouse model, whether Pseudomonas aeruginosa control is influenced by co-infection with the lymphocytic choriomeningitis virus (LCMV). Bacterial titers, numbers of neutrophils and the gene-expression of liver-lysozyme-2 were determined during a 24 hours systemic infection with P. aeruginosa in wild-type and Ifnar(-/-) mice under the influence of LCMV or poly(I:C). RESULTS: Virus-induced IFN-I impaired the control of Pseudomonas aeruginosa. This was associated with neutropenia and loss of lysozyme-2-expression in the liver, which had captured P. aeruginosa. A lower release of IFN-I by poly(I:C)-injection also impaired the bacterial control in the liver and reduced the expression of liver-lysozyme-2. Low concentration of IFN-I after infection with a virulent strain of P. aeruginosa alone impaired the bacterial control and reduced lysozyme-2-expression in the liver as well. CONCLUSION: We found that during systemic infection with P. aeruginosa Kupffer cells quickly controlled the bacteria in cooperation with neutrophils. Upon LCMV-infection this cooperation was disturbed

Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency

Background: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by absence of Wiskott-Aldrich syndrome protein (WASP) expression, resulting in defective function of many immune cell lineages and susceptibility to severe bacterial, viral, and fungal infections. Despite a significant proportion of patients with WAS having recurrent viral infections, surprisingly little is known about the effects of WASP deficiency on antiviral immunity. Objective: We sought to evaluate the antiviral immune response in patients with WASP deficiency in vivo. Methods: Viral clearance and associated immunopathology were measured after infection of WASP-deficient (WAS KO) mice with lymphocytic choriomeningitis virus (LCMV). Induction of antiviral CD8 T-cell immunity and cytotoxicity was documented in WAS KO mice by means of temporal enumeration of total and antigen-specific T-cell numbers. Type I interferon (IFN-I) production was measured in serum in response to LCMV challenge and characterized in vivo by using IFN-I reporter mice crossed with WAS KO mice. Results: WAS KO mice showed reduced viral clearance and enhanced immunopathology during LCMV infection. This was attributed to both an intrinsic CD8 T-cell defect and defective priming of CD8 T cells by dendritic cells (DCs). IFN-I production by WAS KO DCs was reduced both in vivo and in vitro. Conclusions: These studies use a well-characterized model of persistence-prone viral infection to reveal a critical deficiency of CD8 T-cell responses in murine WASP deficiency, in which abrogated production of IFN-I by DCs might play an important contributory role. These findings might help us to understand the immunodeficiency of WAS. © 2012 American Academy of Allergy, Asthma & Immunology

Integrated Ugi-Based Assembly of Functionally, Skeletally, and Stereochemically Diverse 1,4-Benzodiazepin-2-ones

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.This work was financially supported by the Galician Government (Spain), Projects: 09CSA016234PR and GPC-2014-PG037. J.A. thanks FUNDAYACUCHO (Venezuela) for a predoctoral grant and Deputación da Coruña (Spain) for a postdoctoral research grant. A.N.-V. thanks the Spanish government for a Ramón y Cajal research contract

Synthesis, crystal structure, and biological activity of a multidentate calix[4]arene ligand doubly functionalized by 2-hydroxybenzeledene-thiosemicarbazone

The design and synthesis of a novel tert-butyl-calix[4]arene functionalized at 1, 3 positions of the lower rim with two terminal 2-hydroxybenzeledene-thiosemicarbazone moieties is reported. The new ligand with multi-dentate chelating properties was fully characterized by several techniques: ESI-Mass spectroscopy, FT-IR, 1H-NMR, and single crystal X-ray diffraction. The solid state structure confirms that the calix[4]arene macrocycle has the expected open cone conformation, with two opposite phenyl rings inclined outwards with large angles. The conformation of the two alkoxythiosemicarbazone arms produces a molecule with a C2 point group symmetry. An interesting chiral helicity is observed, with the two thiosemicarbazone groups oriented in opposite directions like a two-blade propeller. A water molecule is encapsulated in the center of the two-blade propeller through multiple H-bond coordinations. The antibacterial, antifungal, anticancer, and cytotoxic activities of the calix[4]arene-thiosemicarbazone ligand and its metal derivatives (Co2+, Ni2+, Cu2+, and Zn2+) were investigated. A considerable antibacterial activity (in particular against E. coli, MIC, and MBC = 31.25 \ub5g/mL) was observed for the ligand and its metal derivatives. Significant antifungal activities against yeast (C. albicans) were also observed for the ligand (MIC = 31.25 \ub5g/mL and MBC = 125 \ub5g/mL) and for its Co2+ derivative (MIC = 62.5 \ub5g/mL). All compounds show cytotoxicity against the tested cancerous cells. For the Saos-2 cell line, the promising anticancer activity of ligand L (IC50 < 25 \ub5g/mL) is higher than its metal derivatives. The microscopic analysis of DAPI-stained cells shows that the treated cells change in morphology, with deformation and fragmentation of the nuclei. The hemo-compatibility study demonstrated that this class of compounds are suitable candidates for further in vivo investigations