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Synthesis of silver nanoparticles–chitosan composite particles sphere (AgNPs-chi-spheres) has been completed and its characterization was fulfilled by UV–vis spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and zetasizer nano. UV–vis spectroscopy characterization showed that AgNPs-chi-spheres gave optimum absorption at a wavelength of 410 nm. The XRD spectra showed that the structure of AgNPs-chi-spheres were crystalline and spherical. Characterization by SEM showed that AgNPs-chi-spheres, with the addition of 20% of NaOH, resulted in the lowest average particle sizes of 46.91 nm. EDX analysis also showed that AgNPs-chi-spheres, with the addition of a 20% NaOH concentration, produced particles with regular spheres, a smooth and relatively nonporous structure. The analysis using zetasizer nano showed that the zeta potential value and the polydispersity index value of the AgNPs-chi-sphere tended to increase with an increased NaOH concentration. The results of the microbial activity screening showed that the AgNP-chi-Spheres with highest concentration of NaOH, produced the highest inhibition zone diameters against S. aureus, E. coli, and C. albicans, with inhibition zone diameters of 19.5, 18.56, and 12.25 nm, respectively.

Background: Tapering of disease-modifying antirheumatic drugs (DMARDs) to drug-free remission is an attractive treatment goal for patients with rheumatoid arthritis, although long-term effects of tapering and withdrawal remain unclear. We compared 3-year risks of flare between three conventional synthetic DMARD treatment strategies in patients with rheumatoid arthritis in sustained remission., Methods: In this open-label, randomised controlled, non-inferiority trial, we enrolled patients aged 18-80 years with rheumatoid arthritis who had been in sustained remission for at least 1 year on stable conventional synthetic DMARD therapy. Patients from ten hospitals in Norway were randomly assigned (2:1:1) with centre stratification to receive stable conventional synthetic DMARDs, half-dose conventional synthetic DMARDs, or half-dose conventional synthetic DMARDs for 1 year followed by withdrawal of all conventional synthetic DMARDs. The primary endpoint of this part of the study was disease flare over 3 years, analysed as flare-free survival and risk difference in the per-protocol population with a non-inferiority margin of 20%. This trial is registered with ClinicalTrials.gov (NCT01881308) and is completed., Findings: Between June 17, 2013, and June 18, 2018, 160 patients were enrolled and randomly assigned to receive stable-dose conventional synthetic DMARDs (n=80), half-dose conventional synthetic DMARDs (n=42), or half-dose conventional synthetic DMARDs tapering to withdrawal (n=38). Four patients did not receive the intervention and 156 patients received the allocated treatment strategy. One patient was excluded due to major protocol violation and 155 patients were included in the per-protocol analysis. 104 (67%) of 156 patients were women and 52 (33%) were men. 139 patients completed 3-years follow-up without major protocol violation; 68 (87%) of 78 patients in the stable-dose group, 36 (88%) of 41 patients in the half-dose group and 35 (95%) of 37 patients in the half-dose tapering to withdrawal group. During the 3-year study period, 80% (95% CI 69-88%) were flare-free in the stable-dose group, compared with 57% (41-71%) in the half-dose group and 38% (22-53%) in the half-dose tapering to withdrawal group. Compared with stable-dose conventional synthetic DMARDs, the risk difference of flare was 23% (95% CI 6-41%, p=0·010) in the half-dose group and 40% (22-58%, p<0·0001) in the half-dose tapering to withdrawal group, non-inferiority was therefore not shown. Adverse events were reported in 65 (83%) of 78 patients in the stable-dose group, 36 (90%) of 40 patients in the half-dose group, and 36 (97%) of 37 patients in the half-dose tapering to withdrawal group. One death occurred in the stable-dose conventional synthetic DMARD group (sudden death considered unlikely related to the study medication)., Interpretation: Two conventional synthetic DMARD tapering strategies were associated with significantly lower rates of flare-free survival compared with stable conventional synthetic DMARD treatment, and the data do not support non-inferiority. However, drug-free remission was achiveable for a significant subgroup of patients. This trial provides information on risk and benefits of different treatment strategies important for shared decision making., Funding: Research Council of Norway and South-Eastern Norway Regional Health Authority., Competing Interests: Declaration of interests KEK and NPS report grants from The Research Council of Norway and from The South-Eastern Norway Regional Health Authority during the conduct of the study. A-BA reports personal fees from AbbVie, Eli Lilly, Novartis, and Pfizer, outside the submitted work. ICO reports grants from EU commission, personal fees from Dilafor AB, the European Medicines Agency, and the European Clinical Research Infrastructure Network, outside the submitted work and serves on a data safety monitoring board for Oslo University Hospital. CS reports personal fees from UCB outside the submitted work. TMM reports personal fees from Boehringer outside the submitted work. GB reports personal fees from UCB outside the submitted work and is a board member of Norwegian Society of Rheumatology. HH reports personal fees from UCB outside the submitted work. M-KAL reports personal fees from AbbVie outside the submitted work. TU reports personal fees from Eli Lilly, Galapagos, Pfizer, and UCB, outside the submitted work. TKK reports grants and personal fees from AbbVie, Novartis, Pfizer, and UCB; grants from Bristol Myers Squibb, Galapagos; and personal fees from Gilead, Janssen, Sandoz, and Grünenthal, outside the submitted work. DHS reports grants from CorEvitas, Horizon, Janssen, and Moderna and personal royalties on several UpToDate chapters, outside the submitted work; and is an unpaid board member of CARRA. DvdH reports personal fees from AbbVie, ArgenX, Bayer, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Pfizer, Takeda, and UCB, outside the submitted work; is an associate editor for Annals Rheumatic Diseases; is a director for Imaging Rheumatology BV; is an editorial board member Journal of Rheumatology and RMD Open; and is an advisor assessment for Axial Spondyloarthritis international Society. EAH reports grants from The Research Council of Norway and The South-Eastern Norway Regional Health Authority during the conduct of the study; personal fees from Pfizer, AbbVie, UCB, Boehringer Ingelheim, Eli Lilly, Galapagos, Gilead, and Novartis, outside the submitted work. SL reports grants from The Research Council of Norway and The South-Eastern Norway Regional Health Authority during the conduct of the study. JS, HF, CAH, ÅL, IJWH, IMH and EM declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The eye-seeking fly Musca sorbens can act as a vector for ocular Chlamydia trachomatis , causing trachoma, yet there has been very little research on control measures. We investigated whether insect repellent products, specifically insecticide-treated clothing, could provide personal protection to the user from eye-seeking flies., Methods: We first conducted a series of phase I laboratory studies to inform our choice of field intervention. We then conducted a phase II randomised controlled trial testing the efficacy of permethrin-treated scarves (PTS) in reducing fly-face contact in Oromia, Ethiopia. Children aged 4-10 years in full health and with no known adverse reactions to permethrin or other insecticides were allocated to either arm using restricted randomisation. Intervention arm children wore Insect Shield® versatile wraps (as PTS) for 28 days. The primary outcomes, fly-eye, -nose and -mouth contact, were assessed on the first day (0/30/60/180 minutes), on day 7 and on day 28. All participants present per timepoint were included in analyses. This trial was registered with ClinicalTrials.gov (NCT03813069)., Findings: Participants were recruited to the field trial between 29/10/2019 and 01/11/2019, 58 were randomised to test or control arm. More fly (-eye, -nose and -mouth) contacts were observed in the PTS arm at baseline. After adjusting for baseline contact rates, across all timepoints there was a 35% decrease in fly-eye contacts in the PTS relative to control arm (rate ratio [RR] 0.65, 95% CI 0.52-0.83). Similar cross-timepoint reductions were seen for fly-nose and fly-mouth contacts (RR 0.69, 95% CI 0.51-0.92 and RR 0.79, 95% CI 0.62-1.01, respectively). All children were included on day 0. Two in the control arm were absent on day 7, one left the study and four were excluded from analysis at day 28. No adverse events occurred in the trial., Interpretation: Musca sorbens flies are sufficiently repelled by PTS to reduce fly-eye contacts for the wearer, thus possibly reducing the risk of trachoma transmission. Permethrin-treated scarves may therefore an alternative to insecticide space spraying for protection from these flies., Funding: Wellcome Trust., Competing Interests: The authors have nothing to disclose., (© 2022 The Authors.)

Background: Globally, road traffic accidents are the leading causes of death among young people in general, and the main cause of death among young people aged 15-29 years. Recently, in Ethiopia, the number of road traffic accidents has been increasing. The study aimed to identify the potential factors associated with the number of human deaths by road traffic accidents in the Oromia Regional State, Ethiopia., Methods: We used data obtained from the Oromia region traffic police office recorded on daily basis road traffic accidents from July 2016 up to July 2017. Count regression models were was used to analyses the factors associated with the number of human deaths from road traffic accidents., Results: Age of the driver's 31-50 years (AOR = 0.289, 95%CI: 0.175, 0.479) and higher than 50 years old (AOR = 0.311, 95%CI: 0.129, 0.751), driver's years of experience 5-10 years (AOR = 0.014, 95%CI: 0.007, 0.027), and more than 10 years (AOR = 0.101, 95%CI: 0.057, 0.176), automobile vehicle type (AOR = 8.642, 95%CI: 2.7644, 27.023), vehicle years of service 5-10 years (AOR = 2.484, 95%CI: 1.194, 5.169), and more than 10 years (AOR = 2.639, 95%CI: 1.268, 5.497), vehicle upside down accidents (AOR = 5.560, 95%CI: 2.506, 12.336), turning illegal position (AOR = 0.454, 95%CI: 0.226, 0.913), residential areas (AOR = 108.506, 95%CI: 13.725, 857.798), and working areas (AOR = 129.606, 95%CI: 16.448, 1021.263) were significant associated number of human deaths per road traffic accident factors in the study area., Conclusion: Human deaths per road traffic accidents occurred due to the younger age of the driver, driver's lack of sufficient experience, vehicle serviced for long years, driving on a wet road, driving in the afternoon, driving near/around residential places and vehicle to driver's relation. Thus, the regional traffic police should give special attention to younger drivers, less experienced drivers, old vehicles, driving near residential areas, driving automobiles, and driving in the afternoon to control traffic system to reduce the number of human deaths pear road traffic accident., Competing Interests: The authors declare that they have no competing interests.

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear., Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission., Design, Setting, and Participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019., Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80)., Main Outcomes and Measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin., Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred., Conclusions and Relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT01881308.

Background . Under-five mortality has continued a key challenge to public health in Ethiopia, and other sub-Saharan Africa countries. The threat of under-five mortality is incessant and more studies are needed to generate new scientific evidence. This study aimed to model the number of under-five deaths a mother has experienced in her lifetime and factors associated with it in Ethiopia. Method . A retrospective cross-sectional study based on data obtained from the Ethiopian Demographic and Health Survey (DHS), 2016 was used. The response variable was the total number of under-five children died per mother in her lifetime. Variables such as maternal socioeconomic and demographic characteristics, health, and environmental factors were considered as risk factors of under-five mortality. Hurdle negative binomial (HNB) regression analysis was employed to determine the factors associated with under-five mortality. Results . The data showed that 27.2% (95%CI: 0263, 0.282) of women experienced under-five deaths. The study revealed the age of mother at first birth, the age of mother at the time of under-five mortality occurred, number of household members, household access to electricity, region, educational level of the mother, sex of household head, wealth index, mother residing with husband/partner at the time of under-five mortality occurred as factors associated with under-five mortality. Age of mother at first birth 18 to 24 (IRR = .663; 95%CI: 0.587, 0.749), 25 or higher years old (IRR = 0.424; 95%CI: 0.306, 0.588), access to electricity (IRR = 0.758; 95%CI: 0.588, 0.976), primary education level of the mother (IRR = 0.715; 95%CI: 0.584, 0.875) and the richer wealth index (IRR = 0.785; 95%CI: 0.624, 0.988) were associated with reduced incidence of under-five mortality controlling for other variables in the model. Whereas older age of mother 35 to 39 (IRR = 5.252; 95%CI: 2.992, 9.218), 40 to 44 (IRR = 7.429; 95%CI: 4.188, 13.177), 45 to 49 (IRR = 8.697; 95%CI: 4.853, 15.585), being a resident of the Benishangul-gumuz region (IRR = 1.781; 95%CI: 1.303, 2.434), female household head (IRR = 1.256; 95%CI: 1.034, 1.525) were associated with an increased incidence of under-five mortality. Conclusion . The findings suggested that early age of mothers' at first birth and old ages of mothers', female household head and being uneducated were found to increase the incidence of the under-five mortality, whereas access to electricity and living with husband was statistically associated with reduced incidence of under-five mortality. The implication of this study is that policymakers and stakeholders should provide health education for mothers not to give birth at an earlier age and improve living standards to achieve sustainable development goals., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: The use of substances such as cigarettes, khat, alcohol, and other illicit drugs like hashish, heroine, cannabis, and cocaine is a global major public threat, which affects young adult people particularly in developing countries. This study aims to assess the risk factors associated with substance use and exposure to sexually explicit materials among high-school adolescents in north Shewa zone, Oromia region., Method: A cross-sectional study was conducted to assess substance use and exposure to sexually explicit materials among high-school adolescents in North Shewa zone, Oromiya, Ethiopia, using a structured self-administered questionnaire adapted from the 2008 "Community That Care Youth Survey" for adolescent substance use and problem behaviors. The study used descriptive statistics and logistic regression analysis to identify the significant factors associated with substance use and exposure to sexually explicit materials among high school adolescents in the study area., Result: The prevalence of lifetime and current substance use was 47.7% (95% CI: 0.427, 0.527) and 30.4% (95% CI: 0.258, 0.350), respectively. 17.8% use khat in their life and 16.6% used khat in the past 30 days; 42.2% ever used alcohol and 26.1% currently uses alcohol; 4.8% and 4.5% used cigarette in lifetime and in the past 30 days, while 16.4% use other illicit drugs in lifetime and 8.4% use illicit drugs in the past 30 days, respectively. Distributions of substance use by sex indicate that male adolescents are more like likely 61.1% use substances than females. While, the prevalence of exposure to sexually explicit materials among high school adolescents was 35.8% (95% CI: 0.310, 0.406). Factors positively associated with increased substance use were being male (OR = 2.334, 95% CI: 1.549, 9.926), living through high level of family conflict (OR = 6.25, 95% CI: 1.745, 10.00), poor family management OR = 27.084, 95% CI: 1.624, 45.56), peer pressure (OR = 12.882, 95% CI: 1.882, 88.153), poor academic performance (OR = 14.48, 95% CI: 1.290, 162.58), and low school commitment (OR = 11.951, 95% CI: 1.418, 100.73). While, being male (OR = 7.52, 95% CI: 2.611, 21.739), age 14-16 (OR = 0.201, 95% CI: 0.071, 0.565), friends watch/read sexually explicit materials (OR = 5.376, 95% CI: 1.010, 28.571), and khat chewing (OR = 12.5, 95% CI: 2.924, 25.632) were factors significantly associated with high-school adolescents exposure to sexually explicit materials., Conclusion: The magnitude of prevalence for substance uses and exposure to sexually explicit materials in the study area was still higher. Therefore, interventions that focus on family management, peer pressure, and school commitment are required to decrease the prevalence of substance uses and exposure to sexually explicit materials among high-school adolescents., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Berhanu Teshome Woldeamanuel et al.)

Eye-to-eye transmission of Chlamydia trachomatis , the causative agent of trachoma, may be plausibly interrupted if faces are kept free of ocular and nasal discharge. Between April and June 2018, 83 children aged 1-9 years with active trachoma were recruited from 62 households and allocated to a face cleaning protocol: face washing with water, face washing with water and soap, or face wiping. Faces were examined for the presence of ocular and nasal discharge, and swabs were taken from faces and hands to test for C. trachomatis at baseline, immediately post protocol, and after 1, 2, and 4 hours (washing protocols). Washing with soap was more effective at removing ocular discharge than either washing with water (89% and 27% of discharge removed, respectively, P = 0.003) or wiping with a hand (42%, P = 0.013). The reduction in prevalence of ocular discharge was sustained for at least four hours. The prevalence of C. trachomatis on face swabs was reduced by all washing protocols. The importance of soap should not be overlooked during facial cleanliness promotion.

Purpose: Despite the fact that hyper-activation of Wnt/β-catenin signaling pathway has been seen in many cancers, including liver, colorectal and lung carcinoma, no small molecule inhibitors are available that specifically target this pathway. In this study, we analyzed the impact of dinactin (DA), an antibiotic ionophore produced by Streptomyces species, as an effective small molecule targeting Wnt/β-catenin signaling pathway in cancer cells., Methods: We performed MTT assays to investigate cell viability and proliferation after exposure to small molecules. Protein expression analysis was carried out by western blotting. Top-Flash reporter assays were used to score for β-catenin signaling and cell cycle analysis was carried out by flow cytometry., Results: In the first set of experiments, DA was seen to selectively inhibit the proliferation of HCT-116 and HepG2 cancer cells, unlike HEK-293 cells (a low tumorigenic cell line), in apoptosis-independent manner. Further, DA was seen to block the G1/S progression and decrease the expression of cyclin D1 in cancer cells. Since cyclin D1 is the downstream target gene of Wnt/β-catenin signaling, we examined the impact of DA on TCF-dependent β-catenin activity using Top-Flash reporter assay. Interestingly, DA significantly decreased Top-Flash activity at lower nano-molar concentrations when compared with salinomycin in HCT-116 and HepG2 cells., Conclusion: We report the identification of dinactin as a natural product-based small molecule that effectively blocks the Wnt/β-catenin signaling pathway in cancer cells at nano-molar concentration. We anticipate that DA could be developed as a novel drug for anti-cancer therapy and for the management of neuropathic pain.

Current long duration treatment options and the emergence of drug resistance in tuberculosis (TB) have led to renewed interest in discovery of novel anti-tubercular agents or the scaffolds exhibiting enhanced efficacy with current anti-TB drugs. Herein, dinactin, a potent bioactive macrotetrolide isolated from Streptomyces puniceus AS13, was evaluated against Mycobacterium tuberculosis H37Rv and other susceptible and drug-resistant clinical isolates of M. tuberculosis. In vitro pharmacological assays showed that dinactin is bactericidal against laboratory standard strain M. tuberculosis H37Rv (minimum inhibitory concentration [MIC] 1 µg/mL and minimum bactericidal concentration [MBC] 4 µg/mL). Dinactin also retained its activity against various clinical isolates, including multidrug-resistant strains of M. tuberculosis. Whole cell interaction assays with standard first- and second-line anti-TB drugs showed the synergistic interaction of dinactin with rifampicin or amikacin, reflecting its suitability for use in combination regimens. The killing kinetics studies of dinactin against M. tuberculosis H37Rv revealed that it has strong concentration-dependent anti-TB activity that is also dependent on time. The kill curve also showed dynamic killing capacity of dinactin as it exhibited bactericidal potential at all concentrations tested. Kill curve data demonstrated that dinactin, like isoniazid, exerts its strong tuberculocidal activity within the first two days of exposure. This evidence strongly supports further evaluation of dinactin as a new option in the treatment of TB., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A highly active actinobacterial strain isolated from untapped areas of Northwestern Himalayas and characterised as Streptomyces puniceus strain AS13 by 16S rRNA gene sequencing was selected for production of bioactive metabolites. The bioassay-guided fractionation of microbial cultured ethyl acetate extract of the strain, led to isolation of macrotetrolide compound 1 (Dinactin) and compound 2 (1-(2,4-dihydroxy-6-methylphenyl)-ethanone). Structures of the isolated compounds were elucidated by [corrected] interpretation of NMR and other spectroscopic data including HR-ESI-MS, FT-IR. These compounds are reported for first time from Streptomyces Puniceus. Compound 1 exhibited strong anti-microbial activity against all tested bacterial pathogens including Mycobacterium tuberculosis. The MIC values of compound 1 against Gram negative and Gram positive bacterial pathogens ranged between 0.019 - 0.156μgml -1 and 1μgml -1 against Mycobacterium tuberculosis H37Rv. Dinactin exhibited marked anti-tumor potential with IC 50 of 1.1- 9.7μM in various human cancerous cell lines and showed least cytotoxicity (IC 50 ∼80μM) in normal cells (HEK-293). Dinactin inhabited cellular proliferation in cancer cells, reduced their clonogenic survival as validated by clonogenic assay and also inhabited cell migration and invasion characteristics in colon cancer (HCT-116) cells. Our results expressed the antimicrobial potential of dinactin and also spotted its prospective as an antitumor antibiotic., (Copyright © 2017. Published by Elsevier GmbH.)

A cost-effective, scalable, and environmentally benign process is herein reported for the synthesis of pantoprazole sodium sesquihydrate: 5-(difluromethoxy)-2-[{(3,4-dimethoxy-2-pyridinyl)methyl}sulfinyl]-1 H -benzimidazole sodium sesquihydrate. At least two of the three main synthetic steps (coupling and oxidation) have been carried out for the first time in water, with no need to isolate and purify the intermediates, affording the corresponding pantoprazole sodium in good yield and purity. Minimum organic solvents, in terms of both the number of solvents and the volume of solvent used, are employed to make this process both economical and environment friendly. Furthermore, in situ transformation of pantoprazole sodium heterosolvate, due to the association between molecules of water and solvent used, to pantoprazole sodium sesquihydrate is described., Competing Interests: The authors declare no competing financial interest.

A new eudesmane sesquiterpenoid (1), and a new homologue of virginiae butanolide E (2) along with butyl isobutyl phthalate (3) were isolated from, actinomycete-Lentzea violacea strain AS08 isolated from north western Himalayas by stressing on modified one strain-many compounds (OSMAC) method. The structures of the new compounds were elucidated by extensive spectroscopic analyses including 1D, 2D NMR along with HR-ESI-MS and FT-IR data. Herein, a distinctive method was added for inspecting secretory profile of the strain by quantification of extract value of cell free supernatant in different types of culture media fallowed by HPLC profiling of respective extracts, which revealed a highly altered metabolic profile of the strain and formed the base for the selection of media. The compounds 1 and 2 showed moderate activity against Gram negative (MIC ∼32-64µgml -1 ) in comparison to Gram positive bacterial pathogens. Compound 1 exhibited significant activity in human cancerous cell lines (IC 50 ∼19.2µM)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: Glycyrrhiza glabra is a high-value medicinal plant thriving in biodiversity rich Kashmir Himalaya. The present study was designed to explore the fungal endophytes from G. glabra as a source of bioactive molecules., Methods and Results: The extracts prepared from the isolated endophytes were evaluated for anti-microbial activities using broth micro-dilution assay. The endophytic strain coded as A2 exhibiting promising anti-bacterial as well as anti-tuberculosis activity was identified as Fusarium solani by ITS-5.8S ribosomal gene sequencing technique. This strain was subjected to large-scale fermentation followed by isolation of its bioactive compounds using column chromatography. From the results of spectral data analysis and comparison with literature, the molecules were identified as 3,6,9-trihydroxy-7-methoxy-4,4-dimethyl-3,4-dihydro-1H-benzo[g]isochromene-5,10-dione (1), fusarubin (2), 3-O-methylfusarubin (3) and javanicin (4). Compound 1 is reported for the first time from this strain. All the four compounds inhibited the growth of various tested bacterial strains with MIC values in the range of <1 to 256 μg ml -1 . Fusarubin showed good activity against Mycobacterium tuberculosis strain H37Rv with MIC value of 8 μg ml -1 , whereas compounds 1, 3 and 4 exhibited moderate activity with MIC values of 256, 64, 32 μg ml -1 , respectively., Conclusions: To the best of our knowledge, this is the first study that reports significant anti-tuberculosis potential of bioactive molecules from endophytic F. solani evaluated against the virulent strain of M. tuberculosis. This study sets background towards their synthetic intervention for activity enhancement experiments in anti-microbial drug discovery programme., Significance and Impact of the Study: Due to the chemoprofile variation of same endophyte with respect to source plant and ecoregions, further studies are required to explore endophytes of medicinal plants of all unusual biodiversity rich ecoregions for important and or novel bioactive molecules., (© 2017 The Society for Applied Microbiology.)

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.

We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30-60min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Ethno-Pharmacological Relevance: The roots of Thalictrum minus are traditionally used in the treatment of inflammation and infectious diseases such as bovine mastitis. However, there are no reports available in literature till date regarding the antibacterial studies of T. minus against bovine mastitis., Aim of the Study: The present study was undertaken to evaluate the antibacterial potential of crude extract of T. minus (root) and some of its isolated constituents against bovine mastitis in order to scientifically validate its traditional use., Materials and Methods: A total of three alkaloid compounds were isolated from the DCM: MeOH extract of roots of T. minus using silica gel column chromatography. Structural elucidation of the isolated compounds was done by using spectroscopic techniques like mass spectrometry and NMR spectroscopy. Pathogens were isolated from cases of bovine mastitis and identified by using 16S rRNA gene sequencing. The broth micro-dilution method was used to evaluate the antibacterial activities of DCM: MeOH extract and isolated compounds against mastitis pathogens., Results: The three isolated compounds were identified as benzylisoquinoline alkaloids (1) 5'-Hydroxythalidasine, (2) Thalrugosaminine and (3) O-Methylthalicberine. Compounds (2) and (3) are reported for the first time from the roots of T. minus. Five mastitis pathogens viz., Staphylococcus xylosus, Staphylococcus lentus, Staphylococcus equorum, Enterococcus faecalis and Pantoea agglomerans were identified on the basis of sequence analysis of isolates using the nucleotide BLAST algorithm. This study reports for the first time the isolation and molecular characterization of mastitis pathogens from Kashmir valley, India. The DCM: MeOH extract exhibited broad spectrum antibacterial activities that varied between the bacterial species (MIC=250-500µg/ml). 5'-Hydroxythalidasine and Thalrugosaminine showed promising antibacterial activity with MIC values of 64-128µg/ml while Staphylococcus species were found to be the most sensitive strains., Conclusions: The antibacterial activities of the DCM: MeOH extract and isolated compounds support the traditional use of T. minus in the treatment of bovine mastitis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Ethno-Pharmacological Relevance: The underground parts of Aquilegia fragrans are traditionally used for the treatment of wounds and various inflammatory diseases like bovine mastitis. However, there are no reports on the phytochemical characterization and antibacterial studies of A. fragrans., Aim of the Study: To isolate compounds from the methanol extract of the underground parts of A. fragrans and determine their antibacterial activity against the pathogens of bovine mastitis. The study was undertaken in order to scientifically validate the traditional use of A. fragrans., Materials and Methods: Five compounds were isolated from the methanol extract of the underground parts of A. fragrans using silica gel column chromatography. Structural elucidation of the isolated compounds was done using spectral data analysis and comparison with literature. High performance liquid chromatography (HPLC) was used for the qualitative and quantitative determination of isolated compounds in the crude methanol extract. The methanol extract and isolated compounds were evaluated for antibacterial activities against mastitis pathogens using broth micro-dilution technique., Results: The five isolated compounds were identified as (1) 2, 4-dihydroxyphenylacetic acid methyl ester (2) β-sitosterol (3) Aquilegiolide (4) Glochidionolactone-A and (5) Magnoflorine. A quick and sensitive HPLC method was developed for the first time for qualitative and quantitative determination of four isolated marker compounds from A. fragrans. The crude methanol extract and compound 5 exhibited weak antibacterial activities that varied between the bacterial species (MIC=500-3000 µg/ml)., Conclusions: The above results show that the crude methanol extract and isolated compounds from A. fragrans exhibit weak antibacterial activities. Further phytochemical and pharmacological studies are required for proper scientific validation of the folk use of this plant species in the treatment of various inflammatory diseases like bovine mastitis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110α and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Resistance to chemotherapy represents a major obstacle in correcting colorectal carcinomas (CRC). Inspite of recent advances in the treatment of metastatic disease, the prognosis of the patients remains poor. RLX, a vasicinone analogue has been reported to possess potent bronchodilator, anti-asthmatic and anti-inflammatory properties. However, its anti-cancer activity is unknown., Results: Here, we report for the first time that RLX has anti-cancer property against panel of human cancer cell lines and most potent activity was found against HCT-116 cells with IC50 value of 12 μM and have further investigated the involvement of NFκB and caspase-3 in RLX action in CRC apoptosis. Following RLX and BEZ-235 treatment in HCT-116, we observed significant down-regulation of NFκB (1 to 0.1 fold) and up-regulation of caspase-3 (1 to 2 fold) protein expressions. Additionally, morphological studies revealed membrane blebbing, cell shrinkage, chromatin condensation and finally apoptosis in HCT-116 cells., Conclusions: Overall, these findings indicate that RLX is a potent small molecule which triggers apoptosis, and promising potential candidate to be a chemotherapeutic agent.

A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O-cyclohexylidene-d-glyceraldehyde in ∼43% overall yields.

In the presence of NBS and a catalytic amount of a Lewis acid, 2,3-unsaturated allyl glycosides [6-(allyloxy)-3,6-dihydro-2-(hydroxymethyl)-2H-pyran-3-ol] have been successfully used as versatile glycosyl donors for the stereoselective α-glycosylation of a variety of alcohols comprising sensitive functions such as acetonide, keto, nitro, and ester in 50-90% yields. The methodology offers an equally facile alternative to 4-pentenyl replacement in unsaturated sugars., (© 2011 American Chemical Society)