The role of AQP3 and AQP4 channels in cisplatin-induced cardiovascular edema and the protective effect of melatonin

Molecular Biology Reports - The present study evaluates the development of edema, the change in the AQP3, AQP4, p53 and Bax gene expressions, and the protective effects of melatonin in rat hearts...     

Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide

Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1). In the present paper, we show the first structures of testis ACE [C-ACE, which is identical with the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97? (1 ?=0.1 nm)] and the N-domain of somatic ACE (N-ACE, at 2.15?) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P(1)' residue with the unusual R configuration which, surprisingly, is accommodated by the large S(2)' pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi-pi stacking interactions with the amino benzoyl group of the first molecule locking them in a 'hand-shake' conformation. These features, for the first time, highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors.     

Expression of the Inherently Autoreactive Idiotope 9G4 on Autoantibodies to Citrullinated Peptides and on Rheumatoid Factors in Patients with Early and Established Rheumatoid Arthritis

Background

The pre-symptomatic stage of Rheumatoid arthritis (RA) is associated with pro-inflammatory cytokines and autoantibodies. High levels and epitope spread by Rheumatoid factors (RhF) and autoantibodies to citrullinated proteins signify progression towards disease expression. In established RA, the persistence of high autoantibody levels reflects production by both long-lived plasma cells and short-lived plasmablasts. Neither the relative contributions to pathogenesis by autoantibodies from either source, nor the factors responsible for deciding the fate of autoantigen specific ‘parent’ B-cells, is understood. Phenotypic markers identifying subsets of autoreactive B-cells are therefore of interest in understanding the origin and perpetuation of the autoimmune response in RA. One such phenotypic marker is the rat monoclonal antibody, 9G4, which recognises an idiotope on immunoglobuins derived from the inherently autoreactive VH-gene, VH4-34. We therefore investigated whether the 9G4 idiotope was expressed on autoantibodies in patients with RA.

Methodology/Principal Findings

Sera from 19 patients with established RA and those with <1year history of untreated polyarthritis either resolving into RA (n = 42) or non-RA diagnosis (n = 31) were included. Autoantibodies to cyclic citrullinated peptides (CCP), RhF and co-expression of the 9G4 idiotope were measured by ELISA. 9G4 recognised a population of anti-CCP antibodies in the majority of sera from patients with established disease and also in samples from patients with early disaese. 9G4+RhF levels were generally lower and not associated with positivity for, or levels of 9G4+CCP.

Conclusions/Significance

The persistence of 9G4+ immunoglobulins, of any isotype, in serum is rare. We describe here the novel finding of 9G4 expression on anti-CCP antibodies in patients from the earliest symptoms of RA through to established disease. Our results suggest that 9G4 expression on anti-CCP autoantibodies was not due to polyclonal expansion of VH4-34-encoded immunoglobulins. These studies may therefore provide a new focus for investigation into the evolution of the autoimmune response in RA patients.     

In vitro and histological investigation of antitumor effect of some triazole compounds in colon cancer cell line

1,2,4-Triazoles are used as antifungal, antibacterial, antimicrobial, and antioxidant against some oxidative radical species. Recently, many 1,2,4-triazoles continue to be synthesized. In this study, the effect of the 1,2,4-triazole derivatives on human colon cancer (HT29) was investigated in vitro and in vivo in rats. MTT test was applied to in in vitro experiments. For in vivo study, rats were divided into seven groups as follows: Control group (negative control), azoxymethane (AOM), AOM + cisplatin 15, AOM + L1, AOM + L2, AOM + L3, and AOM + L4. To create colon cancer, the AOM injection was injected subcutaneously at a dose of 15 mg/kg, three times (once weekly). The in vivo studies were completed at 28 weeks. It was found that the 1,2,4-triazole derivatives reduced the cell viability (P < 0.05). In all animals in the experimental groups, mild dysplasia was detected in 100% of the colon mucosal epithelium. Severe dysplasia and adenocarcinoma were observed in L1 groups. As a result, this study determined that the 1,2,4-triazole derivatives exhibit antitumor activity.     

Serum prolidase activity and oxidative–antioxidative status in patients with developmental dysplasia of the hip and its relationship with radiographic severity

Background: We aimed to investigate serum prolidase activity and to investigate its association with oxidative–antioxidative status in patients with developmental dysplasia of the hip (DDH).

Methods: Oxidative status parameters, including lipid hydroperoxide (LOOH), total oxidant status (TOS), and the oxidative stress index (OSI), and antioxidative status parameters, free sulfhydryl groups (Total –SH), and total antioxidative capacity (TAC), as well as serum prolidase activity were assessed in patients with DDH (n?=?93), and in healthy controls (n?=?82). The severity of dysplasia was evaluated according to the Tonnis grading system.

Results: Serum prolidase activity and the oxidant parameters (LOOH, TOS, and OSI) were significantly higher and the antioxidant parameters (Total –SH and TAC) were significantly lower in patients with DDH compared to the controls (P?P?P?Conclusion: Increased levels of serum prolidase activity, LOOH, TOS, and OSI, and decreased levels of total –SH and TAC, may be associated with DDH, and these parameters may be useful adjunctive tools to assess the severity of DDH.     

Investigation of glucose 6-phosphate dehydrogenase (G6PD) kinetics for normal and G6PD-deficient persons and the effects of some drugs

In the present study, blood samples from 1183 children aged 0.5-6 years were taken. Three children were found with G6PD deficiency by examining the enzyme activity and hemoglobin ratio. Some kinetic properties of glucose 6-phosphate dehydrogenase enzyme (G6PD) were studied after the purification of the enzyme with ammonium fractionation, dialysis and 2',5' ADP-Sepharose 4B affinity chromatography from a healthy person and from three G6PD-deficient people. The purity of the enzymes was confirmed by SDS-PAGE electrophoresis. The effects of some drugs which are known inhibitors of G6PD activity were studied. Some of the drugs stimulated the activity of the enzyme in two of the three cases with G6PD deficiency. KM values, Vmax values for G6P and NADP+, optimum pH and optimum temperature for the enzyme from the healthy person and the three G6PD-defficient people are reported.     

The discovery of Lepeophtheirus lichiae Barnard, 1948 (Copepoda: Caligidae) parasitic on leerfish,Lichia amia (Linnaeus) in the Mediterranean Sea

Systematic Parasitology - Lepeophtheirus lichiae Barnard, 1948 (Copepoda: Caligidae), a very rare and poorly known sea louse, is redescribed based on a single newly collected female. The specimen...     

Inhibition of alpha-glucosidase by aqueous extracts of some potent antidiabetic medicinal herbs

Diabetes mellitus is one of the most prevalant diseases of adults. Agents with alpha-glucosidase inhibitory activity have been useful as oral hypoglycemic drugs for the control of hyperglycemia in patients with type 2; noninsulin-dependent, diabetes mellitus (NIDDM). Investigation of some medicinal herbs: Urtica dioica, Taraxacum officinale, Viscum album, and Myrtus communis with alpha-glucosidase inhibitor activity was conducted to identify a prophylactic effect for diabetes in vitro. All plants showed differing potent alpha-glucosidase inhibitory activity. However, Myrtus communis strongly inhibited the enzyme (IC50 = 38 microg/mL). The inhibitory effect of these plants and some common antidiabetic drugs against the enzyme source (baker's yeast, rabbit liver, and small intestine) were also searched. Approximately all inhibitors used in this study showed quite different inhibitory activities, according to alpha-glucosidase origins. Furthermore, subsequent separation of the active material from Myrtus communis by HPLC showed that only one fraction acted as an a-glucosidase inhibitor.     

Immobilization of alpha-glucosidase in chitosan coated polygalacturonic acid

Crude alpha-glucosidase from Baker's yeast was immobilized in polygalacturonic acid beads and coated with chitosan. Chemical and physical characterization were performed by using p-nitrophenyl-alpha-D-glucopyranoside (pNPG) as an artificial substrate. Operation, thermal, pH, and strorage stabilities of the free and immobilized enzyme were also examined. The stabilities of immobilized enzyme were found to be better than that of the free enzyme. Furthermore, the hydrolysis rate of the chitosan coated alpha-glucosidase polygalacturonic acid beads were studied. In conclusion, the enzyme beads appear to have good characteristics and offer the prospect that this system may find application in enzyme immobilization, in addition to controlled drug release studies.