Network pharmacology and bioinformatics approach reveals the therapeutic mechanism of action of curcumin in Alzheimer disease.

Curcumin is a natural anti-inflammatory and antioxidant substance which plays a major role in reducing the amyloid plaques formation, which is the major cause of Alzheimer's disease (AD). Consequently, a methodical approach was used to select the potential protein targets of curcumin in AD through network pharmacology. In this study, through integrative methods, AD targets of curcumin through SwissTargetPrediction database, STITCH database, BindingDB, PharmMapper, Therapeutic Target Database (TTD), Online Mendelian Inheritance in Man (OMIM) database were predicted followed by gene enrichment analysis, network construction, network topology, and docking studies. Gene ontology analysis facilitated identification of a list of possible AD targets of curcumin (74 targets genes). The correlation of the obtained targets with AD was analysed by using gene ontology (GO) pathway enrichment analyses and Kyoto Encyclopaedia of Genes and Genomes (KEGG). We have incorporated the applied network pharmacological approach to identify key genes. Furthermore, we have performed molecular docking for analysing the mechanism of curcumin. In order to validate the temporospatial expression of key genes in human central nervous system (CNS), we searched the Human Brain Transcriptome (HBT) dataset. We identified top five key genes namely, PPARγ, MAPK1, STAT3, KDR and APP. Further validated the expression profiling of these key genes in publicly available brain data expression profile databases. In context to a valuable addition in the treatment of AD, this study is concluded with novel insights into the therapeutic mechanisms of curcumin, will ease the treatment of AD with the clinical application of curcumin.

Adverse pregnancy outcome disclosure and women's social networks: a qualitative multi-country study with implications for improved reporting in surveys.

BACKGROUND: Globally, approximately 6,700 newborn deaths and 5,400 stillbirths occur daily. The true figure is likely higher, with under reporting of adverse pregnancy outcomes (APOs) noted. Decision-making in health is influenced by various factors, including one's social networks. We sought to understand APOs disclosure within social networks in Uganda, Ghana, Guinea-Bissau and Bangladesh and how this could improve formal reporting of APOs in surveys.  METHODS: A qualitative, exploratory multi-country study was conducted within four health and demographic surveillance system sites. 16 focus group discussions were held with 147 women aged 15-49 years, who had participated in a recent household survey. Thematic analysis, with both deductive and inductive elements, using three pre-defined themes of Sender, Message and Receiver was done using NVivo software. RESULTS: Disclosure of APOs was a community concern, with news often shared with people around the bereaved for different reasons, including making sense of what happened and decision-making roles of receivers. Social networks responded with comfort, providing emotional, in-kind and financial support. Key decision makers included men, spiritual and traditional leaders. Non-disclosure was usually to avoid rumors in cases of induced abortions, or after a previous bad experience with health workers, who were frequently excluded from disclosure, except for instances where a woman sought advice on APOs. CONCLUSIONS: Communities must understand why they should report APOs and to whom. Efforts to improve APOs reporting could be guided by diffusion of innovation theory, for instance for community entry and sensitization before the survey, since it highlights how information can be disseminated through community role models. In this case, these gatekeepers we identified could promote reporting of APOs. The stage at which a person is in decision-making, what kind of adopter they are and their take on the benefits and other attributes of reporting are important. In moving beyond survey reporting to getting better routine data, the theory would be applicable too. Health workers should demonstrate a more comforting and supportive response to APOs as the social networks do, which could encourage more bereaved women to inform them and seek care.

Potential Efficacy of ß-Amyrin Targeting Mycobacterial Universal Stress Protein by In Vitro and In Silico Approach.

The emergence of drug resistance and the limited number of approved antitubercular drugs prompted identification and development of new antitubercular compounds to cure Tuberculosis (TB). In this work, an attempt was made to identify potential natural compounds that target mycobacterial proteins. Three plant extracts (A. aspera, C. gigantea and C. procera) were investigated. The ethyl acetate fraction of the aerial part of A. aspera and the flower ash of C. gigantea were found to be effective against M. tuberculosis H37Rv. Furthermore, the GC-MS analysis of the plant fractions confirmed the presence of active compounds in the extracts. The Mycobacterium target proteins, i.e., available PDB dataset proteins and proteins classified in virulence, detoxification, and adaptation, were investigated. A total of ten target proteins were shortlisted for further study, identified as follows: BpoC, RipA, MazF4, RipD, TB15.3, VapC15, VapC20, VapC21, TB31.7, and MazF9. Molecular docking studies showed that ß-amyrin interacted with most of these proteins and its highest binding affinity was observed with Mycobacterium Rv1636 (TB15.3) protein. The stability of the protein-ligand complex was assessed by molecular dynamic simulation, which confirmed that ß-amyrin most firmly interacted with Rv1636 protein. Rv1636 is a universal stress protein, which regulates Mycobacterium growth in different stress conditions and, thus, targeting Rv1636 makes M. tuberculosis vulnerable to host-derived stress conditions.

Elucidating the Role of Santalol as a Potent Inhibitor of Tyrosinase: In Vitro and In Silico Approaches.

This research work focuses on the potential application of an organic compound, santalol, obtained from santalum album, in the inhibition of the enzyme tyrosinase, which is actively involved in the biosynthesis of melanin pigment. Over-production of melanin causes undesirable pigmentation in humans as well as other organisms and significantly downgrades their aesthetic value. The study is designed to explain the purification of tyrosinase from the mushroom Agaricus bisporus, followed by activity assays and enzyme kinetics to give insight into the santalol-modulated tyrosinase inhibition in a dose-dependent manner. The multi-spectroscopic techniques such as UV-vis, fluorescence, and isothermal calorimetry are employed to deduce the efficiency of santalol as a potential candidate against tyrosinase enzyme activity. Experimental results are further verified by molecular docking. Santalol, derived from the essential oils of santalum album, has been widely used as a remedy for skin disorders and a potion for a fair complexion since ancient times. Based on enzyme kinetics and biophysical characterization, this is the first scientific evidence where santalol inhibits tyrosinase, and santalol may be employed in the agriculture, food, and cosmetic industries to prevent excess melanin formation or browning.

Electronic data collection in a multi-site population-based survey: EN-INDEPTH study.

BACKGROUND: Electronic data collection is increasingly used for household surveys, but factors influencing design and implementation have not been widely studied. The Every Newborn-INDEPTH (EN-INDEPTH) study was a multi-site survey using electronic data collection in five INDEPTH health and demographic surveillance system sites. METHODS: We described experiences and learning involved in the design and implementation of the EN-INDEPTH survey, and undertook six focus group discussions with field and research team to explore their experiences. Thematic analyses were conducted in NVivo12 using an iterative process guided by a priori themes. RESULTS: Five steps of the process of selecting, adapting and implementing electronic data collection in the EN-INDEPTH study are described. Firstly, we reviewed possible electronic data collection platforms, and selected the World Bank's Survey Solutions® as the most suited for the EN-INDEPTH study. Secondly, the survey questionnaire was coded and translated into local languages, and further context-specific adaptations were made. Thirdly, data collectors were selected and trained using standardised manual. Training varied between 4.5 and 10 days. Fourthly, instruments were piloted in the field and the questionnaires finalised. During data collection, data collectors appreciated the built-in skip patterns and error messages. Internet connection unreliability was a challenge, especially for data synchronisation. For the fifth and final step, data management and analyses, it was considered that data quality was higher and less time was spent on data cleaning. The possibility to use paradata to analyse survey timing and corrections was valued. Synchronisation and data transfer should be given special consideration. CONCLUSION: We synthesised experiences using electronic data collection in a multi-site household survey, including perceived advantages and challenges. Our recommendations for others considering electronic data collection include ensuring adaptations of tools to local context, piloting/refining the questionnaire in one site first, buying power banks to mitigate against power interruption and paying attention to issues such as GPS tracking and synchronisation, particularly in settings with poor internet connectivity.

Barriers and enablers to reporting pregnancy and adverse pregnancy outcomes in population-based surveys: EN-INDEPTH study.

BACKGROUND: Risks of neonatal death, stillbirth and miscarriage are highest in low- and middle-income countries (LMICs), where data has most gaps and estimates rely on household surveys, dependent on women reporting these events. Underreporting of pregnancy and adverse pregnancy outcomes (APOs) is common, but few studies have investigated barriers to reporting these in LMICs. The EN-INDEPTH multi-country study applied qualitative approaches to explore barriers and enablers to reporting pregnancy and APOs in surveys, including individual, community, cultural and interview level factors. METHODS: The study was conducted in five Health and Demographic Surveillance System sites in Guinea-Bissau, Ethiopia, Uganda, Bangladesh and Ghana. Using an interpretative paradigm and phenomenology methodology, 28 focus group discussions were conducted with 82 EN-INDEPTH survey interviewers and supervisors and 172 women between February and August 2018. Thematic analysis was guided by an a priori codebook. RESULTS: Survey interview processes influenced reporting of pregnancy and APOs. Women found questions about APOs intrusive and of unclear relevance. Across all sites, sociocultural and spiritual beliefs were major barriers to women reporting pregnancy, due to fear that harm would come to their baby. We identified several factors affecting reporting of APOs including reluctance to speak about sad memories and variation in recognition of the baby's value, especially for APOs at earlier gestation. Overlaps in local understanding and terminology for APOs may also contribute to misreporting, for example between miscarriages and stillbirths. Interviewers' skills and training were the keys to enabling respondents to open up, as was privacy during interviews. CONCLUSION: Sociocultural beliefs and psycho-social impacts of APOs play a large part in underreporting these events. Interviewers' skills, careful tool development and translation are the keys to obtaining accurate information. Reporting could be improved with clearer explanations of survey purpose and benefits to respondents and enhanced interviewer training on probing, building rapport and empathy.

Birthweight data completeness and quality in population-based surveys: EN-INDEPTH study.

BACKGROUND: Low birthweight (< 2500 g) is an important marker of maternal health and is associated with neonatal mortality, long-term development and chronic diseases. Household surveys remain an important source of population-based birthweight information, notably Demographic and Health Surveys (DHS) and UNICEF's Multiple Indicator Cluster Surveys (MICS); however, data quality concerns remain. Few studies have addressed how to close these gaps in surveys. METHODS: The EN-INDEPTH population-based survey of 69,176 women was undertaken in five Health and Demographic Surveillance System sites (Matlab-Bangladesh, Dabat-Ethiopia, Kintampo-Ghana, Bandim-Guinea-Bissau, IgangaMayuge-Uganda). Responses to existing DHS/MICS birthweight questions on 14,411 livebirths were analysed and estimated adjusted odds ratios (aORs) associated with reporting weighing, birthweight and heaping reported. Twenty-eight focus group discussions with women and interviewers explored barriers and enablers to reporting birthweight. RESULTS: Almost all women provided responses to birthweight survey questions, taking on average 0.2 min to answer. Of all babies, 62.4% were weighed at birth, 53.8% reported birthweight and 21.1% provided health cards with recorded birthweight. High levels of heterogeneity were observed between sites. Home births and neonatal deaths were less likely to be weighed at birth (home births aOR 0.03(95%CI 0.02-0.03), neonatal deaths (aOR 0.19(95%CI 0.16-0.24)), and when weighed, actual birthweight was less likely to be known (aOR 0.44(95%CI 0.33-0.58), aOR 0.30(95%CI 0.22-0.41)) compared to facility births and post-neonatal survivors. Increased levels of maternal education were associated with increases in reporting weighing and knowing birthweight. Half of recorded birthweights were heaped on multiples of 500 g. Heaping was more common in IgangaMayuge (aOR 14.91(95%CI 11.37-19.55) and Dabat (aOR 14.25(95%CI 10.13-20.3) compared to Bandim. Recalled birthweights were more heaped than those recorded by card (aOR 2.59(95%CI 2.11-3.19)). A gap analysis showed large missed opportunity between facility birth and known birthweight, especially for neonatal deaths. Qualitative data suggested that knowing their baby's weight was perceived as valuable by women in all sites, but lack of measurement and poor communication, alongside social perceptions and spiritual beliefs surrounding birthweight, impacted women's ability to report birthweight. CONCLUSIONS: Substantial data gaps remain for birthweight data in household surveys, even amongst facility births. Improving the accuracy and recording of birthweights, and better communication with women, for example using health cards, could improve survey birthweight data availability and quality.

Termination of pregnancy data completeness and feasibility in population-based surveys: EN-INDEPTH study.

BACKGROUND: Termination of pregnancy (TOP) is a common cause of maternal morbidity and mortality in low- and middle-income countries. Population-based surveys are the major data source for TOP data in LMICs but are known to have shortcomings that require improving. The EN-INDEPTH multi-country survey employed a full pregnancy history approach with roster and new questions on TOP and Menstrual Restoration. This mixed methods paper assesses the completeness of responses to questions eliciting TOP information from respondents and reports on practices, barriers, and facilitators to TOP reporting. METHODS: The EN-INDEPTH study was a population-based cross-sectional study. The Full Pregnancy History arm of the study surveyed 34,371 women of reproductive age between 2017 and 2018 in five Health and Demographic Surveillance System (HDSS) sites of the INDEPTH network: Bandim, Guinea-Bissau; Dabat, Ethiopia; IgangaMayuge, Uganda; Kintampo, Ghana; and Matlab, Bangladesh. Completeness and time spent in answering TOP questions were evaluated using simple tabulations and summary statistics. Exact binomial 95% confidence intervals were computed for TOP rates and ratios. Twenty-eight (28) focus group discussions were undertaken and analysed thematically. RESULTS: Completeness of responses regarding TOP was between 90.3 and 100.0% for all question types. The new questions elicited between 2.0% (1.0-3.4), 15.5% (13.9-17.3), and 11.5% (8.8-14.7) lifetime TOP cases over the roster questions from Dabat, Ethiopia; Matlab, Bangladesh; and Kintampo, Ghana, respectively. The median response time on the roster TOP questions was below 1.3 minutes in all sites. Qualitative results revealed that TOP was frequently stigmatised and perceived as immoral, inhumane, and shameful. Hence, it was kept secret rendering it difficult and uncomfortable to report. Miscarriages were perceived to be natural, being easier to report than TOP. Interviewer techniques, which were perceived to facilitate TOP disclosure, included cultural competence, knowledge of contextually appropriate terms for TOP, adaptation to interviewee's individual circumstances, being non-judgmental, speaking a common language, and providing detailed informed consent. CONCLUSIONS: Survey roster questions may under-represent true TOP rates, since the new questions elicited responses from women who had not disclosed TOP in the roster questions. Further research is recommended particularly into standardised training and approaches to improving interview context and techniques to facilitate TOP reporting in surveys.

Gestational age data completeness, quality and validity in population-based surveys: EN-INDEPTH study.

BACKGROUND: Preterm birth (gestational age (GA) <37 weeks) is the leading cause of child mortality worldwide. However, GA is rarely assessed in population-based surveys, the major data source in low/middle-income countries. We examined the performance of new questions to measure GA in household surveys, a subset of which had linked early pregnancy ultrasound GA data. METHODS: The EN-INDEPTH population-based survey of 69,176 women was undertaken (2017-2018) in five Health and Demographic Surveillance System sites in Bangladesh, Ethiopia, Ghana, Guinea-Bissau and Uganda. We included questions regarding GA in months (GAm) for all women and GA in weeks (GAw) for a subset; we also asked if the baby was 'born before expected' to estimate preterm birth rates. Survey data were linked to surveillance data in two sites, and to ultrasound pregnancy dating at <24 weeks in one site. We assessed completeness and quality of reported GA. We examined the validity of estimated preterm birth rates by sensitivity and specificity, over/under-reporting of GAw in survey compared to ultrasound by multinomial logistic regression, and explored perceptions about GA and barriers and enablers to its reporting using focus group discussions (n = 29). RESULTS: GAm questions were almost universally answered, but heaping on 9 months resulted in underestimation of preterm birth rates. Preference for reporting GAw in even numbers was evident, resulting in heaping at 36 weeks; hence, over-estimating preterm birth rates, except in Matlab where the peak was at 38 weeks. Questions regarding 'born before expected' were answered but gave implausibly low preterm birth rates in most sites. Applying ultrasound as the gold standard in Matlab site, sensitivity of survey-GAw for detecting preterm birth (GAw <37) was 60% and specificity was 93%. Focus group findings suggest that women perceive GA to be important, but usually counted in months. Antenatal care attendance, women's education and health cards may improve reporting. CONCLUSIONS: This is the first published study assessing GA reporting in surveys, compared with the gold standard of ultrasound. Reporting GAw within 5 years' recall is feasible with high completeness, but accuracy is affected by heaping. Compared to ultrasound-GAw, results are reasonably specific, but sensitivity needs to be improved. We propose revised questions based on the study findings for further testing and validation in settings where pregnancy ultrasound data and/or last menstrual period dates/GA recorded in pregnancy are available. Specific training of interviewers is recommended.

Structural Characterization of Ectodomain G Protein of Respiratory Syncytial Virus and Its Interaction with Heparan Sulfate: Multi-Spectroscopic and In Silico Studies Elucidating Host-Pathogen Interactions.

The global burden of disease caused by a respiratory syncytial virus (RSV) is becoming more widely recognized in young children and adults. Heparan sulfate helps in attaching the virion through G protein with the host cell membrane. In this study, we examined the structural changes of ectodomain G protein (edG) in a wide pH range. The absorbance results revealed that protein maintains its tertiary structure at physiological and highly acidic and alkaline pH. However, visible aggregation of protein was observed in mild acidic pH. The intrinsic fluorescence study shows no significant change in the λmax except at pH 12.0. The ANS fluorescence of edG at pH 2.0 and 3.0 forms an acid-induced molten globule-like state. The denaturation transition curve monitored by fluorescence spectroscopy revealed that urea and GdmCl induced denaturation native (N) ↔ denatured (D) state follows a two-state process. The fluorescence quenching, molecular docking, and 50 ns simulation measurements suggested that heparan sulfate showed excellent binding affinity to edG. Our binding study provides a preliminary insight into the interaction of edG to the host cell membrane via heparan sulfate. This binding can be inhibited using experimental approaches at the molecular level leading to the prevention of effective host-pathogen interaction.

Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage.

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodium proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a-o) and carboxylic acids 10(a-b) for the inhibition of Plasmodium N-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. The designed compounds exhibited a glide score of -9.241 to -6.960 kcal/mol for PvNMT and -7.538 kcal/mol for PfNMT model proteins. Development of the synthesized compounds was established via NMR, HRMS and single crystal X-ray diffraction study. The synthesized compounds were evaluated for their in vitro antimalarial efficacy against CQ-sensitive Pf3D7 and CQ-resistant PfINDO lines followed by cell toxicity evaluation. In silico results highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate (9a) as a promising inhibitor with a glide score of -9.084 kcal/mol for PvNMT and -6.975 kcal/mol for PfNMT with IC50 values of 6.58 µM for Pf3D7 line. Furthermore, compounds 9n and 9o exhibited excellent anti-plasmodial activity (Pf3D7 IC50 = 3.96, 6.71 µM, and PfINDO IC50 = 6.38, 2.8 µM, respectively). The conformational stability of 9a with the active site of the target protein was analyzed through MD simulation and was found concordance with in vitro results. Thus, our study provides scaffolds for the development of potent antimalarials targeting both Plasmodium vivax and Plasmodium falciparum.Communicated by Ramaswamy H. Sarma.

Glossary of phytoconstituents: Can these be repurposed against SARS CoV-2? A quick in silico screening of various phytoconstituents from plant Glycyrrhiza glabra with SARS CoV-2 main protease.

World is familiar with the viral pathogen Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2). The principle working enzymes of SARS CoV-2 have been identified as main proteases 3Cl pro which act as main regulators for SARS infection. The need for therapy is required immediately pertaining to the vulnerable conditions. Protein-ligand studies are imperative for understanding the functioning of biological interactions as they are crucial in providing a hypothetical origin for the design and unearthing of novel drug targets. Phytoconstituents from Glycyrrhiza glabra, earlier reported to be anticancerous in nature were used as repurposed drugs against SARS CoV-2 main protease 3Clpro. We analyzed the molecular interactions of protein-phytocompounds, by AutoDock Vina 4.2 tools. The best interactions of each algorithm were subjected to molecular dynamic (MD) simulations to have an insight of the molecular dynamic mechanisms involved. Selected phytoconstituents gave a good score for binding affinity with the main protease 6LU7 of SARS CoV-2 as compared to the antiviral drugs already being used in the disease therapy. DehydroglyasperinC(-8.7,-8.1,-6.7,-7.1)kcal/mol, Licochalcone D(-8.4,-8.2,-7.1,-7.9) kcal/mol, Liquiritin(-8.6,-9.0,-7.2,-7.8) kcal/mol have showed energy interactions with 3Clpro better than many FDA approved repurposed drugs; Remdesvir, Favipiravir, and Hydroxychloroquine. MD Simulation also corelates our findings for molecular docking studies.