Tyrosinase inhibition: conformational analysis based studies on molecular dynamics calculations of bipiperidine based inhibitors.

Two series of variably N-substituted biperidines were synthesized by condensing various acid chlorides, alkyl halides and anhydrides with 1,4-bipiperidine. The new compounds were tested as tyrosinase inhibitors and a structure-activity relationship (SAR) study was carried out. Potent inhibition was observed in the case of the 4'-methylbenzyl substitution on this atom (IC50 = 1.72 microM) with this compound being a lead for future drug design. Additionally, calculations of the important QSAR molecular descriptors were done on the biperidine analogues after their 2 ps molecular dynamics (MD) simulations using molecular mechanics force field (MMFF) approaches. Using MD simulations potential and total energies were calculated for the energy minimized models of bipiperidine and the most active analogs 2, 3, 4, 6, 8 and 10

Induction of apoptosis of human primary osteoclasts treated with extracts from the medicinal plant Emblica officinalis

<p>Abstract</p> <p>Background</p> <p>Osteoclasts (OCs) are involved in rheumatoid arthritis and in several pathologies associated with bone loss. Recent results support the concept that some medicinal plants and derived natural products are of great interest for developing therapeutic strategies against bone disorders, including rheumatoid arthritis and osteoporosis. In this study we determined whether extracts of <it>Emblica officinalis </it>fruits display activity of possible interest for the treatment of rheumatoid arthritis and osteoporosis by activating programmed cell death of human primary osteoclasts.</p> <p>Methods</p> <p>The effects of extracts from <it>Emblica officinalis </it>on differentiation and survival of human primary OCs cultures obtained from peripheral blood were determined by tartrate-acid resistant acid phosphatase (TRAP)-positivity and colorimetric MTT assay. The effects of <it>Emblica officinalis </it>extracts on induction of OCs apoptosis were studied using TUNEL and immunocytochemical analysis of FAS receptor expression. Finally, <it>in vitro </it>effects of <it>Emblica officinalis </it>extracts on NF-kB transcription factor activity were determined by gel shift experiments.</p> <p>Results</p> <p>Extracts of <it>Emblica officinalis </it>were able to induce programmed cell death of mature OCs, without altering, at the concentrations employed in our study, the process of osteoclastogenesis. <it>Emblica officinalis </it>increased the expression levels of Fas, a critical member of the apoptotic pathway. Gel shift experiments demonstrated that <it>Emblica officinalis </it>extracts act by interfering with NF-kB activity, a transcription factor involved in osteoclast biology. The data obtained demonstrate that <it>Emblica officinalis </it>extracts selectively compete with the binding of transcription factor NF-kB to its specific target DNA sequences. This effect might explain the observed effects of <it>Emblica officinalis </it>on the expression levels of interleukin-6, a NF-kB specific target gene.</p> <p>Conclusion</p> <p>Induction of apoptosis of osteoclasts could be an important strategy both in interfering with rheumatoid arthritis complications of the bone skeleton leading to joint destruction, and preventing and reducing osteoporosis. Accordingly, we suggest the application of <it>Emblica officinalis </it>extracts as an alternative tool for therapy applied to bone diseases.</p

The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor

The mitogen-activated protein kinase-activated protein kinase MK5 is ubiquitously expressed in vertebrates and is implicated in cell proliferation, cytoskeletal remodeling, and anxiety behavior. This makes MK5 an attractive drug target. We tested several diterpenoid alkaloids for their ability to suppress MK5 kinase activity. We identified noroxoaconitine as an ATP competitor that inhibited the catalytic activity of MK5 in vitro (IC50 = 37.5 μM; Ki = 0.675 μM) and prevented PKA-induced nuclear export of MK5, a process that depends on kinase active MK5. MK5 is closely related to MK2 and MK3, and noroxoaconitine inhibited MK3- and MK5- but not MK2-mediated phosphorylation of the common substrate Hsp27. Molecular docking of noroxoaconitine into the ATP binding sites indicated that noroxoaconitine binds more strongly to MK5 than to MK3. Noroxoaconitine and derivatives may help in elucidating the precise biological functions of MK5 and may prove to have therapeutic values

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Induction of apoptosis of human primary osteoclasts treated with extracts from the medicinal plant Emblica officinalis

Background: Osteoclasts (OCs) are involved in rheumatoid arthritis and in several pathologies associated with bone loss. Recent results support the concept that some medicinal plants and derived natural products are of great interest for developing therapeutic strategies against bone disorders, including rheumatoid arthritis and osteoporosis. In this study we determined whether extracts of Emblica officinalis fruits display activity of possible interest for the treatment of rheumatoid arthritis and osteoporosis by activating programmed cell death of human primary osteoclasts. Methods: The effects of extracts from Emblica officinalis on differentiation and survival of human primary OCs cultures obtained from peripheral blood were determined by tartrate-acid resistant acid phosphatase (TRAP)- positivity and colorimetric MTT assay. The effects of Emblica officinalis extracts on induction of OCs apoptosis were studied using TUNEL and immunocytochemical analysis of FAS receptor expression. Finally, in vitro effects of Emblica officinalis extracts on NF-kB transcription factor activity were determined by gel shift experiments. Results: Extracts of Emblica officinalis were able to induce programmed cell death of mature OCs, without altering, at the concentrations employed in our study, the process of osteoclastogenesis. Emblica officinalis increased the expression levels of Fas, a critical member of the apoptotic pathway. Gel shift experiments demonstrated that Emblica officinalis extracts act by interfering with NF-kB activity, a transcription factor involved in osteoclast biology. The data obtained demonstrate that Emblica officinalis extracts selectively compete with the binding of transcription factor NF-kB to its specific target DNA sequences. This effect might explain the observed effects of Emblica officinalis on the expression levels of interleukin-6, a NF-kB specific target gene. Conclusion: Induction of apoptosis of osteoclasts could be an important strategy both in interfering with rheumatoid arthritis complications of the bone skeleton leading to joint destruction, and preventing and reducing osteoporosis. Accordingly, we suggest the application of Emblica officinalis extracts as an alternative tool for therapy applied to bone diseases

Effects of plant extracts on gene expression profiling: from macrorrays to microarray technology

Lead Molecules from Natural Products: Discovery and New Trends provides the reader with a thorough overview of current discoveries and trends in Natural Products research. This book consists of 22 chapters from well known scientists all over the world, with topics ranging from Natural Product Chemistry and Phytochemistry in their most basic form, to Molecular Biology and in silico drug design. Contributors describe their own laboratory experiences, revealing their findings, the legal issues encountered. The chapters, all of equally high quality, summarize years of extensive research in each area, and provide insight in the new themes of natural product research. The information will help to predict promising leads, useful for physicians in the treatment of different diseases and disease manifestations

Prevalence and multidrug-resistant pattern of Salmonella from the eggs and egg-storing trays of retail markets of Bangladesh

Aim: Salmonellosis is one of the most common and widely distributed foodborne illnesses in human, and multidrugresistance of Salmonella spp. has increased in developing countries with the indiscriminate use of antibiotics in the poultry production system. A cross-sectional study was conducted on randomly selected retail markets of Chittagong City Corporation to determine the prevalence and antimicrobial resistance pattern of Salmonella isolated from commercial layer eggs, eggshell surface, and egg-storing trays. Materials and Methods: Chicken eggs, egg surface, and egg-storing trays samples from the retail markets were collected for isolating Salmonella spp. (bacteriological culture methods) followed by antimicrobial susceptibility testing (disc diffusion method) against Salmonella isolates during the period from July to December 2013. Results: Out of the 310 layer eggs, egg surface, and egg-storing trays samples, the highest prevalence of Salmonella spp. was found in eggs trays (57.15%) and the lowest (13.33%) in eggs and the prevalence differed significantly (p0.05). Isolated Salmonella was tested for resistance to eight different antimicrobial agents, using disc diffusion method. Among eight antimicrobial tested (n=111), 100% resistance were found to ampicillin and amoxicillin followed by erythromycin (60-100%), tetracycline (72-93%), ciprofloxacin (22-66%), colistin (27-66%), enrofloxacin (42-54%), and pefloxacin 23.07% across the study sites. Ciprofloxacin remained sensitive in 40.9% cases and, pefloxacin and colistin appeared to be almost sensitive (61-72%) against Salmonella isolates at studied areas. Salmonella isolates showed multidrug-resistance pattern up to five of the eight antimicrobials tested. Conclusion: It can be said that the rational use of antibiotics needs to be adopted in commercial poultry farming system of Bangladesh to prevent the emergence of drug-resistance Salmonella to protect the public health consequences

Occurrence of diseases and disease conditions in cattle and goats at the Upazilla Veterinary Hospital, Debidwar, Comilla

Objective: A significant number of animals enrolled at UVH regularly from surrounding villages for treating their sick animals, de-worming, vaccination purposes. Therefore, a study was done to define the occurrence of common diseases and disease conditions in cattle and goats at the Upazilla Veterinary Hospital, Debidwar under Comilla district. Materials and methods: Data on various diseases were collected from the record book of hospital during April 2016 to March 2017. The total number of animals were 889, among which cattle were 637 (71.65%) and goats were 252 (28.35%). The presumptive diagnosis was performed based on general examination, physical examination, and clinical examination of animals, and microscopic examination based on common laboratory techniques. Results: Based on clinical examinations, 14 different types of diseases and disease conditions were detected. In cattle (N=637; 71.65%), where FMD (14.44%, n=92), mastitis (6.59%, n=42), digestive disorders (19%, n=121), respiratory disorders (6.12%, n=39), parasitic infestations such as mixed infestation of both ecto- and endo-parasites (34.22%, n=218), acidosis (1.88%, n=12), myiasis (6.12%, n=39), corneal opacity (1.57%, n=10), protozoal diseases (1.26%, n=8), BQ (2.20%, n=14), milk fever (0.94%, n=6), reproductive disorders (4.87%, n=31) and others (0.75%, n=5) were detected. Age wise prevalence in young and adult were (38.62%, n=246) and (61.38%, n=391), respectively. Moreover, sex wise prevalence in male and female were (34.85%, n=222) and (65.15%, n=415) respectively. In goat, (N= 252; 28.35%) 11 different types of diseases and disease conditions such as PPR (12.30%, n=31), mastitis (2.38%, n=6), digestive disorders (19.84%, n=50), parasitic infestation (29.76%, n=75), respiratory disorders (15.08, n=38), myiasis (11.11%, n=28), corneal opacity (4.76%, n=12), acidosis (1.98%, n=5) protozoal diseases such as babesiosis, anaplasmosis (0.79%, n=2) and reproductive disorders (1.59%, n=4), correspondingly. Sex wise prevalence in male and female goat were (44.05%, n=111) and (55.95%, n=141), respectively. Conclusion: All the diseases and disease conditionswere recorded more or less frequently among all age group of cattle and goats though some of the specific diseases and disease conditionshad specific age and species susceptibility such as black quarter in young cattle and PPR in young goats, respectively. A comprehensive updated data with the total population record of that area and proper analysis is needed to identify the actual level of disease and disease conditions in UVH. [J Adv Vet Anim Res 2018; 5(2.000): 117-122