In vitro and in vivo evaluation of the antimicrobial, antioxidant, cytotoxic, hemolytic activities and in silico POM/DFT/DNA-binding and pharmacokinetic analyses of new sulfonamide bearing thiazolidin-4-ones.

In this work, Schiff bases and Thiazolidin-4-ones, were synthesized using Sonication and Microwave techniques, respectively. The Schiff base derivatives (3a-b) were synthesized via the reaction of Sulfathiazole (1) with benzaldehyde derivatives (2a-b), followed by the synthesis of 4-thiazoledinone (4a-b) derivatives by cyclizing the synthesized Schiff bases through thioglycholic acid. All the synthesized compounds were characterized by spectroscopic techniques such as FT IR, NMR and HRMS. The synthesized compounds were tested for their in vitro antimicrobial and antioxidant and in vivo cytotoxicity and hemolysis ability. The synthesized compounds displayed better antimicrobial and antioxidant activity and low toxicity in comparison to reference drugs and negative controls, respectively. The hemolysis test revealed the compounds exhibit lower hemolytic effects and hemolytic values are comparatively low and the safety of compounds is in comparison with standard drugs. Theoretical calculations were carried out by using the molecular operating environment (MOE) and Gaussian computing software and observations were in good agreement with the in vitro and in vivo biological activities. Petra/Osiris/Molinspiration (POM) results indicate the presence of three combined antibacterial, antiviral and antitumor pharmacophore sites. The molecular docking revealed the significant binding affinities and non-bonding interactions between the compounds and Erwinia Chrysanthemi (PDB ID: 1SHK). The molecular dynamics simulation under in silico physiological conditions revealed a stable conformation and binding pattern in a stimulating environment. HighlightsNew series of Thaiazolidin-4-one derivatives have been synthesized.Sonication and microwave techniques are used.Antimicrobial, Antioxidant, cytotoxicity, and hemolysis activities were observed for all synthesized compounds.Molecular Docking and DFT/POM analyses have been predicted.Communicated by Ramaswamy H. Sarma.

Green synthesis, antibacterial and antifungal evaluation of new thiazolidine-2,4-dione derivatives: molecular dynamic simulation, POM study and identification of antitumor pharmacophore sites.

In this study, a series of thiazolidine-2,4-dione derivatives 3a-i were synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative strains of Bacillus licheniformis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Newly prepared thiazolidine (TZD) derivatives were further screened separately for in vitro antifungal activity against cultures of fungal species, namely, Aspergillus niger, Alternaria brassicicola, Chaetomium murorum, Fusarium oxysporum, Lycopodium sp. and Penicillium notatum. The electron-donating substituents (-OH and -OCH3) and electron-withdrawing substituents (-Cl and -NO2) on the attached arylidene moieties of five-membered heterocyclic ring enhanced the broad spectrum of antimicrobial and antifungal activities. The molecular docking study has revealed that compound 3h strongly interacts with the catalytic residues of the active site of the ß-carbonic anhydrase (P. aeruginosa) and has the best docking score. In silico pharmacokinetics studies showed the drug-likeness and non-toxic nature of the synthesized compounds, which indicates the combined antibacterial, antiviral and antitumor pharmacophore sites of the targeted drug. This work demonstrates that potential TZD derivatives bind to different types of bacterial and fungal pathogens for circumventing their activities and opens avenues for the development of newer drug candidates that can target bacterial and fungal pathogens.Communicated by Ramaswamy H. Sarma.

INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family.

Congenital cataract (CC) is clinically and genetically highly heterogeneous. Here, we enrolled a consanguineous kindred (LUCC15) from Pakistan, with 3 affected individuals suffering with CC. Exome sequencing revealed a transition mutation [c.149 T > C; p.(Ile50Thr)] in INPP5K. Inositol polyphosphate-5-phosphatase K, encoded by INPP5K, is involved in dephosphorylation of phosphatidylinositol (PtdIns) 4,5-bisphosphate, and PtdIns 3,4,5-trisphosphate. Recently, pathogenic variants in INPP5K have been reported in families with congenital muscular dystrophies, intellectual disability, and cataract. In our family LUCC15, mild to moderate intellectual disability along with speech impairment was observed in 2 affected individuals. Magnetic resonance imaging of brain and muscles tissues did not reveal any cerebellar or muscular atrophy. However, electromyography of both upper and lower limbs revealed irritable myopathy. Comparison of clinical phenotype of all the known affected individuals, including LUCC15 family, homozygous for INPP5K alleles revealed reduced penetrance of muscular dystrophy and intellectual disability. Similarly, skeletal muscle abnormalities were highly variable among inpp5ka zebrafish mutants analyzed in this study. These phenotypic variabilities may be due to epigenetic factors and/or genetic modifiers.

A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred.

Skeletal dysplasias (SDs) are highly heterogeneous disorders composed of 40 clinical sub-types that are part of 456 well-delineated syndromes in humans. Here, we enrolled consanguineous kindred from a remote area of Sindh province of Pakistan, with 14 affected individuals suffering with short stature, kyphoscoliosis, joint dislocations, clubfoot, heart valve anomalies and progressive bilateral mixed hearing loss. To identify pathogenic variants in this family, whole exome sequencing (WES) was performed in one affected and one normal individual, which revealed a novel transversion mutation (c.802G>T; p.Glu268*) in CHST3 associated with the phenotype. CHST3 encodes a chondroitin 6-O-sulfotransferase-1 (C6ST-1) enzyme that is essential for the sulfation of proteoglycans found in cartilages. Previously, mutations in CHST3 have largely been reported in sporadic cases of SD, primarily with severe spinal abnormalities, joint dislocations, joint contractures, and clubfoot. Clinical and radiological examination of the affected individuals in this family provides new insights into phenotypic spectrum of CHST3 alleles and disease progression with age.

Effect of exposure to silica in inducing autoimmune hepatitis: an experimental animal-controlled study.

OBJECTIVE: The aim of this experimental study is to investigate the effect of subcutaneous and oral sodium silicate in inducing the autoimmune hepatitis. MATERIALS AND METHODS: Twelve Brown Norway rats were studied, six rats were challenged with Sodium Silicate and the rest were challenged with normal saline as a control group. At 14th week post-sodium silicate or normal saline exposure, the rats were sacrificed. Histopathological studies were conducted in six positive autoantibodies responding silicate group rats and then compared with an equal number of negative autoantibodies responding control rats. RESULTS: The liver findings from sodium silicate group of animals showed a histopathological reaction in 3/6 (50%) compared with 0/6 of the corresponding control saline group (p = 0.09). However, the absolute differences in the percentage between the two groups was 50%, the subcutaneous sodium silicate sub-group showed hepatic tissue response close to being statistically significant level (p = 0.05). CONCLUSIONS: After correlating the results with autoantibodies including serum antinuclear antibodies and anti ribo-nucleoprotein response of the same rats, it is concluded that sodium silicate play a role in inducing the autoimmune hepatitis in a genetically susceptible rat model.

Effect of environmental air pollution on type 2 diabetes mellitus.

OBJECTIVE: Air pollution is a novel risk factor for insulin resistance and occurrence of type 2 diabetes mellitus (T2DM), but the evidence is limited and diverse. Therefore, the aim of this study was to assess the effect of environmental air pollution on incidence of type 2 diabetes mellitus. METHODS: In this study, we identified 102 published studies through a systematic data base search including ISI-Web of Science, EMBASE and PubMed. We searched the related literature by using the key terms including diabetes mellitus, air pollution, occupational and environmental pollution, gaseous, NO2, particulate matter pollutants PM2.5, and PM10. Studies in which diabetes mellitus, insulin resistance, air pollution, occupational and environmental pollution was discussed were included in the study. No confines on publication status, study design or language of publication were considered. Descriptive and quantitative information were extracted from the selected literature. Finally we included 21 publications and remaining studies were excluded. RESULTS: Air pollution is a leading cause of insulin resistance and incidence of type 2 diabetes mellitus. The association between air pollution and diabetes is stronger for traffic associated pollutants, gaseous, nitrogen dioxide, tobacco smoke and particulate matter. CONCLUSIONS: Exposure to air pollutants is significantly associated with increased risk of type 2 diabetes mellitus. It is suggested that, environmental protection officials must take high priority steps to minimize the air pollution, hence to decrease the incidence of type 2 diabetes mellitus.

Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: an observation.

Fourteen patients were treated over 2 years with cervical vagus nerve stimulation (VNS) for adjunctive therapy of severe, treatment-resistant depression. Here, we report the serendipitous observation that this treatment was associated with highly significant, gradual weight loss despite the patients' report of not dieting or exercising. The weight loss was proportional to the initial BMI, that is, the more severe the obesity, the greater the weight loss. Weight loss did not correlate with changes in mood symptoms. The vagus nerve carries visceral information to and from the brain; modulation of its activity may alter eating behavior. Chronic cervical VNS may merit controlled study for the treatment of severe obesity.

Infective endocarditis in children--incidence, pattern, diagnosis and management in a developing country.

BACKGROUND: In developing countries, patients with infective endocarditis are referred late, there is low yield of blood cultures and incidence of rheumatic heart disease is still high. OBJECTIVE: Evaluate clinical pattern, assess diagnostic criteria in our settings and determine outcome. SETTING: A tertiary referral center for paediatric and adult cardiology. PATIENTS AND METHODS: All children with infective endocarditis admitted to a single center from April 1997 to March 2000 were analysed. The diagnosis was based on Duke's criteria, which proposed two major and six minor criteria. Minor criteria were expanded to include raised acute phase reactants and presence of newly diagnosed or increasing splenomegally. The patients were stratified as definite, possible and rejected cases. RESULTS: Of 1402 hospital admissions, 45 patients fulfilled the diagnostic criteria for infective endocarditis giving an incidence of 32 per 1000 hospital admissions. The mean age was 7.9 +/- 4 years (4 months to 16 years) with only two patients under 1 year of age. Rheumatic heart disease was the underlying lesion in 24 patients (53%) while congenital heart lesions occurred in 20 patients (45%). Previous antibiotic treatment was given in 26 patients (58%) definitely. Blood cultures were positive in 21 patients (47%); Streptococcus Viridans being the most common organism, while vegetations on echocardiography were present in 32 patients (71%). Surgery was undertaken in four patients and five patients left against medical advise. Of 10 patients with aortic valve involvement, there were three deaths (30%) and overall mortality was 13% (six patients). CONCLUSIONS: The incidence of infective endocarditis is 32 per 1000 (3.2%) hospital admissions in a tertiary paediatric cardiology referral center. Rheumatic heart disease is still the most common underlying heart lesion. Blood cultures are positive in less than 50% of cases and echocardiography in expert hands is a more sensitive tool in our set up. Mortality is still high and aortic valve involvement in particular, carried poor prognosis.

Individual Xenopus histone genes are replication-independent in oocytes and replication-dependent in Xenopus or mouse somatic cells.

We have assessed the response of many histone H3 mRNAs and an H1C mRNA in Xenopus tissue culture cells after treatment with the DNA synthesis inhibitor hydroxyurea. The amount of the histone mRNAs falls rapidly in response to the inhibitor. This response is prevented by cycloheximide. Cloned Xenopus histone genes were transfected into mouse cells and a cell line was obtained in which the Xenopus genes were actively expressed giving rise to mRNA with correct 5'-termini. The Xenopus genes were correctly regulated at the level of mRNA amounts in the mouse cell line. Nuclear microinjection experiments with Xenopus oocytes and S1 nuclease analysis of normal ovary RNA showed that the H1C gene, and probably also two H3 genes, which are replication-dependent in somatic cells are expressed in oocytes and are therefore replication-independent in this cell type. The same promoters are used in both replication-dependent and independent expression.