Discovery of New Hydrazone-Thiazole Polyphenolic Antioxidants through Computer-Aided Design and In Vitro Experimental Validation.

Oxidative stress is linked to a series of diseases; therefore, the development of efficient antioxidants might be beneficial in preventing or ameliorating these conditions. Based on the structure of a previously reported compound with good antioxidant properties and on computational studies, we designed several catechol derivatives with enhanced antioxidant potential. The compounds were synthesized and physicochemically characterized, and their antioxidant activity was assessed through different antiradical, electron transfer and metal ions chelation assays, their electrochemical behavior and cytotoxicity were studied. The results obtained in the in vitro experiments correlated very well with the in silico studies; all final compounds presented very good antioxidant properties, generally superior to those of the reference compounds used. Similarly, the results obtained from studying the compounds' electrochemical behavior were in good agreement with the results of the antioxidant activity evaluation assays. Regarding the compounds' cytotoxicity, compound 7b had a dose-dependent inhibitory effect against all cell lines. In conclusion, through computer-aided design, we developed several catechol thiazolyl-hydrazones with excellent antioxidant properties, of which compound 7b, with two catechol moieties in its structure, exhibited the best antioxidant activity.

A Comparative Study on Cu2+, Zn2+, Ni2+, Fe3+, and Cr3+ Metal Ions Removal from Industrial Wastewaters by Chitosan-Based Composite Cryogels.

Materials coming from renewable resources have drawn recently an increased attention in various applications as an eco-friendly alternative in the synthesis of novel functional materials. Polysaccharides, with their prominent representative - chitosan (CS), are well-known for their sorption properties, being able to remove metal ions from dilute solutions either by electrostatic interactions or chelation. In this context, we proposed here a comparative study on Cu2+, Zn2+, Ni2+, Fe3+, and Cr3+ metal ions removal from industrial wastewaters by CS-based composite cryogels using batch technique. The composite cryogels consisting of CS embedding a natural zeolite, namely clinoptilolite, were synthesized by cryogelation, and their sorption performance were compared to those of CS cryogels and of acid-activated zeolite. A deeper analysis of thermodynamics and kinetics sorption data was performed to get insights into the sorption mechanism of all metal ions onto sorbents. Based on the optimized sorption conditions, the removal of the above-mentioned ions from aqueous solutions by the composite sorbent using dynamic technique was also evaluated.

[Gout, revisited]. / La goutte, revisitée.

In recent decades, gout became the most common inflammatory arthritis and one in which pathogenesis and risk factors are best understood. One of the treatment objectives in current guidelines is "cure". However, audits show that minority of patients with gout receive adequate advice and treatment. Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Accordingly, urate-lowering treatment is underprescribed and often underdosed. The recent introduction of a panel of new treatments of gout and a better understanding of epidemiologic factors (such as the fructose) may improve management of this easily diagnosed and curable form of potentially severe arthritis, worsening probably the cardiovascular prognostic.

[Ultrasonography and rheumatology]. / L'échographie dans la pratique rhumatologique.

Muskuloskeletal ultrasound has been incorporated by rheumatologist to the clinical practice over the past decade. The technical improvements of the devices allowed the production of high quality images contributing to better identification of joint inflammation and structural damage. In this review, we highlight the applications of ultrasound in the study of different rheumatic conditions.

Genetic studies in the Nigerian population implicate an MSX1 mutation in complex oral facial clefting disorders.

BACKGROUND: Orofacial clefts are the most common malformations of the head and neck, with a worldwide prevalence of 1 in 700 births. They are commonly divided into CL(P) and CP based on anatomic, genetic, and embryologic findings. A Nigerian craniofacial anomalies study (NigeriaCRAN) was set up in 2006 to investigate the role of gene-environment interaction in the origin of orofacial clefts in Nigeria. SUBJECTS AND METHODS: DNA isolated from saliva from Nigerian probands was used for genotype association studies and direct sequencing of cleft candidate genes: MSX1 , IRF6 , FOXE1, FGFR1 , FGFR2 , BMP4 , MAFB, ABCA4 , PAX7, and VAX1 , and the chromosome 8q region. RESULTS: A missense mutation A34G in MSX1 was observed in nine cases and four HapMap controls. No other apparent causative variations were identified. Deviation from Hardy Weinberg equilibrium (HWE) was observed in these cases (p = .00002). A significant difference was noted between the affected side for unilateral CL (p = .03) and bilateral clefts and between clefts on either side (p = .02). A significant gender difference was also observed for CP (p = .008). CONCLUSIONS: Replication of a mutation previously implicated in other populations suggests a role for the MSX1 A34G variant in the development of CL(P).

Microparticles of healthy origins improve endothelial progenitor cell dysfunction via microRNA transfer in an atherosclerotic hamster model.

AIM: In this study, we aimed: (i) to obtain and functionally characterize the cultures of late endothelial progenitor cells (EPCs) from the animal blood; (ii) to investigate the potential beneficial effects of circulating microparticles (MPs) of healthy origins on EPC dysfunctionality in atherosclerosis as well as involved mechanisms. METHODS: Late EPCs were obtained and expanded in culture from peripheral blood isolated from two animal groups: hypertensive-hyperlipidaemic (HH) and control (C) hamsters. In parallel experiments, late EPC cultures from HH were incubated with MPs from C group. RESULTS: The results showed that late EPCs display endothelial cell phenotype: (i) have ability to uptake 1,1-dioctadecyl-3,3,3,3 tetramethylindocarbocyanine-labelled acetylated low-density lipoprotein and Ulex europaeus agglutinin lectin-1; (ii) express CD34, CD133, KDR, CD144, vWF, Tie-2. Late EPCs from HH exhibited different morphological and functional characteristics compared to control: (i) are smaller and irregular in shape; (ii) present decreased endothelial surface marker expression; (iii) display reduced proliferation, migration and adhesion; (iv) lose ability to organize themselves into tubular structures and integrate into vascular network; (v) have diminished function of inward rectifier potassium channels. The incubation of late EPCs with MPs improved EPC functionality by miR-10a, miR-21, miR-126, miR-146a, miR-223 transfer and IGF-1 expression activation; the kinetic study of MP incorporation into EPCs demonstrated MP uptake by EPCs followed by the miRNA transfer. CONCLUSION: The data reveal that late EPCs from atherosclerotic model exhibit distinctive features and are dysfunctional, and their function recovery can be supported by MP ability to transfer miRNAs. These findings bring a new light on the vascular repair in atherosclerosis.

Circulating microparticles and endothelial progenitor cells in atherosclerosis: pharmacological effects of irbesartan.

AIMS: This study aimed to (i) employ our newly designed model, the hypertensive-hypercholesterolemic hamster (HH), in order to find out whether a correlation exists between circulating microparticles (MPs), endothelial progenitor cells (EPCs) and their contribution to vascular dysfunction and (ii) to assess the effect of irbesartan treatment on HH animals (HHI). METHODS AND RESULTS: The results showed that compared with the control (C) group, HH displayed: (i) a significant increase in plasma cholesterol and triglyceride concentration, and an augmentation of systolic and diastolic arterial blood pressure, and of heart rate; (ii) a marked elevation of MPs and a significant decrease in EPCs; (iii) structural modifications of the arterial wall correlated with altered protein expression of MMP2, MMP9, MMP12, TIMP1, TIMP2 and collagen type I and III; (iv) a considerably altered reactivity of the arterial wall closely correlated with MPs and EPC adherence; and (v) an inflammatory process characterized by augmented expression of P-Selectin, E-Selectin, von Willebrand factor, tissue factor, IL-6, MCP-1 and RANTES. Additionally, the experiments showed the potential of irbesartan to correct all altered parameters in HH and to mobilize EPCs by NO, chemokines and adhesion molecule-dependent mechanisms. CONCLUSIONS: Hypertension associated with hypercholesterolemia is accompanied by structural modifications and expression of pro-inflammatory molecules by the vessel wall, the alteration of vascular tone, enhanced release of MPs and reduced EPCs; the ratio between the latter two may be considered as a marker of vascular dysfunction. Irbesartan, which exhibits a pharmacological control on the levels of MPs and EPCs, has the potential to restore homeostasis of the arterial wall.

Platelet activation in hypertension associated with hypercholesterolemia: effects of irbesartan.

AIM: The aim of this study was to determine the effect of simultaneous hypertension and hypercholesterolemia on platelet activation, nitric oxide (NO) production and oxidative stress, and to evaluate the role of irbesartan, an angiotensin II type 1 receptor antagonist. METHODS: Golden Syrian hamsters were divided into three groups: controls, C (fed a standard diet); hypertensive-hypercholesterolemic, HH (fed a diet enriched in 3% cholesterol, 15% butter and 8% NaCl, for 4 months); and hypertensive-hypercholesterolemic treated with irbesartan, HHI (fed as HH group, plus irbesartan 10 mg kg(-1) per day, for 4 months). RESULTS: Compared with the C group, platelets isolated from the HH group showed: morphological modifications; increased integrin ß3 exposure and protein expression of P-selectin, FAK, PI3K, Akt and Src; reduced eNOS protein expression and NO production; higher generation of ROS, mostly produced by NADPH-oxidase, cyclooxygenase-1 (COX-1) and 12-lipoxygenase; and enhanced NAD(P)H oxidase activity and protein expression of gp91phox and p22phox subunits, 12-lipoxygenase, COX-1, cPLA(2) and PKC. Compared with the HH group, the treatment with irbesartan (HHI group) significantly attenuates the changes in all the molecules tested, reduces platelet aggregation, and improves intraplatelet redox balance. CONCLUSIONS: Experimental hypertension associated with hypercholesterolemia produces major changes in morphology, signaling mechanisms and oxidative stress in blood platelets. These changes were significantly diminished by irbesartan administration, which functions as an antioxidant on platelets.

A genome-wide linkage scan for cleft lip and cleft palate identifies a novel locus on 8p11-23.

Isolated or nonsyndromic cleft lip and palate (NS CLP) is a complex disorder resulting from multiple genetic and environmental factors. NS CLP has a birth prevalence of 1 per 500 in the Philippines where large families provide an opportunity for gene localization. Genotyping of 392 microsatellite repeat markers at 10 cM intervals over the genome was performed by the Center for Inherited Disease Research (CIDR) on 220 Filipino families with 567 affected and 1,109 unaffected family members genotyped. Among the most statistically significant results from analysis of the genome-wide scan data was a 20 cM region at 8p11-23 in which markers had LODs > or =1.0. This region on 8p11-23 has not been found in any previous genome wide scan nor does it contain any of the candidate genes widely studied in CLP. Fine mapping in 8p11-23 was done in the 220 families plus an additional 51 families, using SNP markers from 10 known genes (FGFR1, NRG1, FZD3, SLC8A1, PPP3CC, EPHX2, BNIP3L, EGR3, PPP2R2A, and NAT1) within the 20 cM region of 8p11-23. Linkage and association analyses of these SNPs yield suggestive results for markers in FGFR1 (recessive multipoint HLOD 1.07) and BAG4 (recessive multipoint HLOD 1.31).