Recent advances and structure-activity relationship studies of DPP-4 inhibitors as anti-diabetic agents.

Diabetes mellitus (DM) is one of the largest public health problems worldwide and in the last decades various therapeutic targets have been investigated. For the treatment of type-2 DM (T2DM), dipeptidyl peptidase-4 (DPP-4) is one of the well reported target and has established safety in terms of cardiovascular complexicity. Preclinical and clinical studies using DPP-4 inhibitors have demonstrated its safety and effectiveness and have lesser risk of associated hypoglycaemic effect making it suitable for elderly patients. FDA has approved a number of structurally diverse DPP-4 inhibitors for clinical use. The present manuscript aims to focus on the well reported hybrid and non-hybrid analogues and their structural activity relationship (SAR) studies. It aims to provide structural insights for this class of compounds pertaining to favourable applicability of selective DPP-4 inhibitors in the treatment of T2DM.

Artificial intelligence and machine-learning approaches in structure and ligand-based discovery of drugs affecting central nervous system.

CNS disorders are indications with a very high unmet medical needs, relatively smaller number of available drugs, and a subpar satisfaction level among patients and caregiver. Discovery of CNS drugs is extremely expensive affair with its own unique challenges leading to extremely high attrition rates and low efficiency. With explosion of data in information age, there is hardly any aspect of life that has not been touched by data driven technologies such as artificial intelligence (AI) and machine learning (ML). Drug discovery is no exception, emergence of big data via genomic, proteomic, biological, and chemical technologies has driven pharmaceutical giants to collaborate with AI oriented companies to revolutionise drug discovery, with the goal of increasing the efficiency of the process. In recent years many examples of innovative applications of AI and ML techniques in CNS drug discovery has been reported. Research on therapeutics for diseases such as schizophrenia, Alzheimer's and Parkinsonism has been provided with a new direction and thrust from these developments. AI and ML has been applied to both ligand-based and structure-based drug discovery and design of CNS therapeutics. In this review, we have summarised the general aspects of AI and ML from the perspective of drug discovery followed by a comprehensive coverage of the recent developments in the applications of AI/ML techniques in CNS drug discovery.

Trends in attitudinal acceptance of wife-beating, domestic violence, and help-seeking among married women in Nepal.

This study aimed to assess the nature and magnitude of perceptions of wife-beating among women and men in Nepal and experiences of domestic violence (DV) and help-seeking among DV victims. The Nepal Demographic Health Surveys (NDHS) (2001, 2006, 2011, 2016) included questions on whether women and men justify wife-beating and whether DV victims sought help (NDHS 2011 and 2016). Covariates in regression models were guided by the socioecological model. We estimated odds ratios for dichotomous outcomes. Compiled data from Multiple Indicator Cluster Surveys was used to understand trends. About 29.1% women justified wife-beating in 2001, 24.2% in 2006, and 29.1% in 2016. About 32.4% of women experienced any DV in 2011 and 28.0% in 2016. In 2011 about 21.8% of those abused sought help and in 2016 about 25.8% sought help. Women who justified wife-beating were more likely to experience DV in 2011 (OR 5.8, p < 0.001) and in 2016 (OR 1.5, p < 0.001) and less likely to seek help in 2011 (OR 0.3, p < 0.001) and in 2016 (OR 0.8, p < 0.001). Perceptions of wife-beating play an important role in actual experiences of DV and help-seeking behavior of DV victims. Societal and individual beliefs are intertwined, and cultural norms have a great bearing on these beliefs. Both individual and wider societal-level acceptance of violence needs to be addressed simultaneously.

Promising Schiff bases in antiviral drug design and discovery.

Emerging and re-emerging illnesses will probably present a new hazard of infectious diseases and have fostered the urge to research new antiviral agents. Most of the antiviral agents are analogs of nucleosides and only a few are non-nucleoside antiviral agents. There is quite a less percentage of marketed/clinically approved non-nucleoside antiviral medications. Schiff bases are organic compounds that possess a well-demonstrated profile against cancer, viruses, fungus, and bacteria, as well as in the management of diabetes, chemotherapy-resistant cases, and malarial infections. Schiff bases resemble aldehydes or ketones with an imine/azomethine group instead of a carbonyl ring. Schiff bases have a broad application profile not only in therapeutics/medicine but also in industrial applications. Researchers have synthesized and screened various Schiff base analogs for their antiviral potential. Some of the important heterocyclic compounds like istatin, thiosemicarbazide, quinazoline, quinoyl acetohydrazide, etc. have been used to derive novel Schiff base analogs. Keeping in view the outbreak of viral pandemics and epidemics, this manuscript compiles a review of Schiff base analogs concerning their antiviral properties and structural-activity relationship analysis.

Quantum Chemical and Docking Insights into Bioavailability Enhancement of Curcumin by Piperine in Pepper.

We combine quantum chemical and molecular docking techniques to provide new insights into how piperine molecule in various forms of pepper enhances bioavailability of a number of drugs including curcumin in turmeric for which it increases its bioavailability by a 20-fold. We have carried out docking studies of quantum chemically optimized piperine structure binding to curcumin, CYP3A4 in cytochrome P450, p-Glycoprotein and UDP-glucuronosyltransferase (UGT), the enzyme responsible for glucuronosylation, which increases the solubility of curcumin. All of these studies establish that piperine binds to multiple sites on the enzymes and also intercalates with curcumin forming a hydrogen bonded complex with curcumin. The conjugated network of double bonds and the presence of multiple charge centers of piperine offer optimal binding sites for piperine to bind to enzymes such as UDP-GDH, UGT, and CYP3A4. Piperine competes for curcumin's intermolecular hydrogen bonding and its stacking propensity by hydrogen bonding with enolic proton of curcumin. This facilitates its metabolic transport, thereby increasing its bioavailability both through intercalation into curcumin layers through intermolecular hydrogen bonding, and by inhibiting enzymes that cause glucuronosylation of curcumin.

Correction of a Forefoot Deformity Caused by a Large, Solitary Metatarsal Osteochondroma in an Adolescent: A Case Report.

Solitary osteochondroma is the most common bone tumor, accounting for 20% to 50% of all benign bony tumors. Osteochondromas are usually found on the metaphysis of the long bones near the physis; the bones of the foot are less commonly involved. We describe a 13-year-old female with a large osteochondroma arising from the fourth metatarsal. Pressure from the tumor on the adjacent metatarsals had deformed her forefoot, creating cosmetic and functional problems. The second and third toes were deviated laterally at the metatarsophalangeal joint, and the fourth and fifth toes were deviated medially. In addition, the fourth and fifth toes were flexed at the proximal interphalangeal joint. We excised the osteochondroma and stabilized the metatarsophalangeal joints. After 3 years, the cosmetic and functional results were satisfactory. The subluxation at the metatarsophalangeal joints had resolved without treatment. Her Revised Foot Function Index score had improved from 141 preoperatively to 95 postoperatively, and her Manchester-Oxford Foot Questionnaire score had improved from 25 to 0. This case is a rare example of a large metatarsal osteochondroma in a growing child in which pressure from the tumor caused secondary forefoot deformities. The management of this case also shows the potential for the forefoot to remodel itself during adolescence, after the tumor has been resected and the joints stabilized.

Acute Compartment Syndrome of the Foot due to Infection After Local Hydrocortisone Injection: A Case Report.

High-energy trauma associated with calcaneal fracture or Lisfranc fracture dislocation and midfoot crushing injuries are known causes of compartment syndrome in the foot. Suppurative infection in the deep osseofascial compartments can also cause compartment syndrome. We describe the case of a 29-year-old female who had developed a suppurative local infection that resulted in acute compartment syndrome after receiving a local hydrocortisone injection for plantar fasciitis. We diagnosed the compartment syndrome, and fasciotomy was promptly undertaken. After more than 2 years of follow-up, she had a satisfactory functional outcome without substantial morbidity. To our knowledge, no other report in the English-language studies has described compartment syndrome due to abscess formation after a local injection of hydrocortisone. The aim of our report was to highlight this rare, but serious, complication of a routine outpatient clinical procedure.

Formulation of Phytosomes Containing Rubia cordifolia Extract for Neuropathic Pain: In Vitro and In Vivo Evaluation.

This study aimed to develop a delivery system for the dried aqueous extract of Rubia cordifolia leaves (RCE) that could improve the neuroprotective potential of RCE by improving the bioavailability of the chief chemical constituent rubiadin. Rubiadin, an anthraquinone chemically, is a biomarker phytoconstituent of RCE. Rubiadin is reported to have strong antioxidant and neuroprotective activity but demonstrates poor bioavailability. In order to resolve the problem related to bioavailability, RCE and phospholipids were reacted in disparate ratios of 1:1, 1:2, and 1:3 to prepare phytosome formulations PC1, PC2, and PC3, respectively. The formulation PC2 showed particle size of 289.1 ± 0.21 nm, ζ potential of -6.92 ± 0.10 mV, entrapment efficiency of 72.12%, and in vitro release of rubiadin of 89.42% at pH 7.4 for a period up to 48 h. The oral bioavailability and neuroprotective potential of PC2 and RCE were assessed to evaluate the benefit of PC2 formulation over the crude extract RCE. Formulation PC2 showed a relative bioavailability of 134.14% with a higher neuroprotective potential and significantly (p < 0.05) augmented the nociceptive threshold against neuropathic pain induced by partial sciatic nerve ligation method. Antioxidant enzyme levels and histopathological studies of the sciatic nerves in various treatment groups significantly divulged that PC2 has enough potential to reverse the damaged nerves into a normal state. Finally, it was concluded that encapsulated RCE as a phytosome is a potential carrier system for enhancing the delivery of RCE for the efficient treatment of neuropathic pain.

Facile construction of multifunctional xNiCo2O4/BiVO4 heterojunction with accelerated charge transfer for efficient photocatalytic treatment of Cr (VI), MB and TC under visible light.

The release of industrial effluents, comprising of organic dyes, antibiotics, and heavy metals poses substantial environmental and ecological threats. Among the different approaches, the utilization of heterogeneous photocatalysis based on semiconducting metal oxides is of paramount important to removal of organic ( MB dye and TC antibiotic) and inorganic pollutants ( Cr (VI) ) in wastewater. In this work, a new approach for creating type-II heterojunction photocatalysts named xNiCo2O4/BiVO4 or BNC is suggested. The as-prepared samples were thoroughly examined by means of several sophisticated analytical tools to investigate their physicochemical properties. These composites were utilized in the decomposition of MB dye, TC drug and the reduction of Cr (VI) under visible light irradiation. According to the findings, the creation of type-II heterojunction at BiVO4-NiCo2O4 interface greatly improved charge transportation while successfully preventing electron-hole recombination. Among the various composites studied, BNC-2 demonstrated an enhanced photocatalytic activity towards degradation of MB and TC, which were found to be 91 % over a period of 150 min and 95 % within only 60 min, respectively. Moreover, the photocatalytic reduction of Cr (VI) was accomplished 96 % within just 25 min. Additionally, it is discovered that BNC-2 displayed promising photostability and recyclability with a retention of >90 % after five consecutive cycles. The enhanced photocatalytic activity of BNC-2 is evidently attributed to the expedited separation and transfer of charges, as proven by photocurrent measurement, photoluminescence and electrochemical impedance spectroscopy analyses. Hence, the current amalgamation of NiCo2O4 and BiVO4 heterojunction composite has paved novel paths towards photocatalytic removal of organic as well as inorganic contaminants.

An In Silico Approach to Exploring the Antinociceptive Biological Activities of Linalool and its Metabolites.

Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α2-adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs.

Structural and electrical properties of NASICON type solid electrolyte nanoscaled glass-ceramic powder by mechanical milling for thin film batteries.

During last two decades, lithium-based glasses have been studied extensively as electrolytes for solid-state secondary batteries. For practical use, solid electrolyte must have high ionic conductivity as well as chemical, thermal and electrochemical stability. Recent progresses have focused on glass electrolytes due to advantages over crystalline solid. Glass electrolytes are generally classified into two types oxide glass and sulfide glass. Oxide glasses do not react with electrode materials and this chemical inertness is advantageous for cycle performances of battery. In this study, major effort has been focused on the improvement of the ion conductivity of nanosized LiAlTi(PO4)3 oxide electrolyte prepared by mechanical milling (MM) method. After heating at 1000 degrees C the material shows good crystallinity and ionic conductivity with low electronic conductivity. In LiTi2(PO4)3, Ti4+ ions are partially substituted by Al3+ ions by heat-treatment of Li20-Al2O3-TiO2-P2O5 glasses at 1000 degrees C for 10 h. The conductivity of this material is 1.09 x 10(-3) S/cm at room temp. The glass-ceramics show fast ion conduction and low E(a) value. It is suggested that high conductivity, easy fabrication and low cost make this glass-ceramics promising to be used as inorganic solid electrolyte for all-solid-state Li rechargeable batteries.

Impact of botanical oils on polyunsaturated fatty acid metabolism and leukotriene generation in mild asthmatics.

BACKGROUND: Dietary supplementation with botanical oils that contain n-6 and n-3 eighteen carbon chain (18C)-PUFA such as γ linolenic acid (GLA, 18:3n-6), stearidonic acid (SDA, 18:4n-3) and α linolenic acid (ALA, 18:3n-3) have been shown to impact PUFA metabolism, alter inflammatory processes including arachidonic acid (AA) metabolism and improve inflammatory disorders. METHODS: The diet of mild asthmatics patients was supplemented for three weeks with varying doses of two botanical seed oils (borage oil [Borago officinalis, BO] and echium seed oil [Echium plantagineum; EO]) that contain SDA, ALA and GLA. A three week wash out period followed. The impact of these dietary manipulations was evaluated for several biochemical endpoints, including in vivo PUFA metabolism and ex vivo leukotriene generation from stimulated leukocytes. RESULTS: Supplementation with several EO/BO combinations increased circulating 20-22 carbon (20-22C) PUFAs, including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and dihommo-gammalinolenic acid (DGLA), which have been shown to inhibit AA metabolism and inflammation without impacting circulating AA levels. BO/EO combinations also inhibited ex vivo leukotriene generation with some combinations attenuating cysteinyl leukotriene generation in stimulated basophils by >50% and in stimulated neutrophils by >35%. CONCLUSIONS: This study shows that dietary supplementation with BO/EO alters 20-22C PUFA levels and attenuates leukotriene production in a manner consistent with a reduction in inflammation.

'College choice' under the COVID-19 pandemic: Sustainability of engineering campuses for future enrollments.

Engineering profession for students and diverse students for Engineering Campuses (ECs) is the prestige to have for both. Worldwide higher education has been impacted by COVID-19 pandemic, but particularly pulling padlocked doors of Indian engineering campuses (ECs) down. Students' attitudes regarding choice, liking, and preferences were also affected. Knowing how tough 'college choice' was before the pandemic, one can guess how difficult it will be today. The objective of this study was to explore students' perceptions of choice characteristics related to ECs and diverse students enabling choice decisions under the COVID-19 situation, and to discover any possible relationships among them. Research questions were qualitatively examined with the statistical confirmation of related hypothesizes by utilizing ANOVA and Regression analysis. A self-reported quantitative survey composed of a closed-ended structured questionnaire was administered on the students of first-year engineering who had recently enrolled in ECs of North Maharashtra Region of India, after pandemic hitting India. According to the study, ECs have several characteristics impacting students' selection of ECs under pandemic. The influence of proximity, image and reputation, educational quality, and curriculum delivery was significant in contributing sustainability of ECs. This influence was significant across students' psychological and behavioural biases on likes, choices, and preferences. Furthermore, multiple relationships were noted within the sub-groups of demographic, geographic, socioeconomic, academic performance, and psychological and behavioural traits due to the impact of ECs' characteristics on sustainability. The study has provided a framework for policymakers and administrators to strengthen repositioning towards sustainability while capturing potentially diverse enrolments. Even if we have to coexist with pandemic forever or with more similar pandemics, the findings of this study may undergo a fundamental transformation for ECs (existing and forthcoming). On the other hand, by understanding the importance and relations of choice characteristics may smoothen the complex nature of "college choice" for prospective students.

Nanotechnology-Based Drug Delivery of Topical Antifungal Agents.

Among the various prominent fungal infections, superficial ones are widespread. A large number of antifungal agents and their formulations for topical use are commercially available. They have some pharmacokinetic limitations which cannot be retracted by conventional delivery systems. While nanoformulations composed of lipidic and polymeric nanoparticles have the potential to overcome the limitations of conventional systems. The broad spectrum category of antifungals i.e. azoles (ketoconazole, voriconazole, econazole, miconazole, etc.) nanoparticles have been designed, prepared and their pharmacokinetic and pharmacodynamic profile was established. This review briefly elaborates on the types of nano-based topical drug delivery systems and portrays their advantages for researchers in the related field to benefit the available antifungal therapeutics.

Preclinical to Clinical Profile of Curcuma longa as Antidiabetic Therapeutics.

Natural product substances have historically served as the most significant source of new leads for pharmaceutical development. Presently, drug discovery and development have adopted rational approaches to explore herbal resources for treating lifestyle-related diseases such as diabetes. For the treatment of diabetes, Curcumin longa has been extensively studied for evaluation of its antidiabetic potential using various in vivo and in vitro models. Literature resources such as PubMed and Google Scholar have been extensively searched to collect documented studies. Various parts of the plant and extracts have proven antidiabetic effects, namely, anti-hyperglycemic, antioxidant, and anti-inflammatory action, through different mechanisms. It is reported that the plant extract or its phytoconstituents regulate glucose and lipid metabolism. The reported study concluded the diversified antidiabetic role of C. longa and its phytoconstituents and, thus, its potential use as an antidiabetic agent.

Mutation informatics: SARS-CoV-2 receptor-binding domain of the spike protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) undergoes mutations at a high rate and with frequent genetic reassortment (antigenic drift/shift), leading to variability in targets. The receptor-binding domain (RBD) of the spike (S) protein has a major role in the binding of SARS-CoV-2 with human angiotensin-converting enzyme 2 (ACE2). Mutations at the RBD influence the binding interaction at the SARS-CoV-2 S-ACE2 interface and impact viral pathogenicity. Here, we discuss different reported mutations of concern in RBD, physicochemical characteristic changes resulting from mutated amino acids and their effect on binding between the RBD and ACE2. Along with mutation informatics, we highlight recently developed small-molecule inhibitors of RBD and the ACE2 interface. This information provides a rational basis for the design of inhibitors against the multivariant strains of SARS-CoV-2.

Domestic Violence and Sterilization Skew in India: An Instrumental Variable Analysis.

The objective of this study was to assess the prevalence of domestic violence in ever-married women in India and analyze the relationship between domestic violence and use of female sterilization as contraception. We analyzed data from the National Family Health Survey 2005-2006 (NFHS3). The Domestic Violence Module of the survey included abuse experiences and reproductive health outcomes of ever-married women aged 15 to 49 years (n = 69,704). The main outcome of interest was female sterilization and domestic violence experience was the main independent variable. Covariates in our multivariate regression models were guided by the socioecological model for domestic abuse. We estimated a reference linear probability model for the dichotomous outcome. We also employed an instrumental variables procedure to strengthen causal inference under such potential sources of bias as measurement error in reporting domestic violence and omitted variables. The reference model showed an increase of 2.1 percentage points (p < .001) in the probability of female sterilization associated with exposure to domestic violence. After correcting the estimate for the measurement error and omitted variable bias, we found that domestic violence was associated with an increase in female sterilization by 6.4 percentage points (p < .001), which is 18% higher than the rate of sterilization among non-victims. In conclusion, our findings imply that domestic violence may lead abuse victims to opt for female sterilization as contraception. Domestic violence is a significant obstacle to efficient contraceptive use. Programs directed toward violence prevention should work conjointly with family planning programs in India.

Willingness to use and satisfaction of primary care services among locals and migrants in Shenzhen, China.

The Chinese government has been reforming the health care system by developing a primary care system. The objectives of this study were to compare the willingness to use and satisfaction with community health care centres (CHCs), a component within the Chinese primary care system, between locals and migrants living in Luohu, Shenzhen, China. A 2019 cross-sectional survey data that interviewed 1,205 adult residents living in Luohu district were used for secondary data analysis. Two identifications of migrants were used for analysis, Shenzhen hukou status and urban village status. Linear probability models were used to determine relationship between migrants' status and the outcome variable of willingness to use CHCs and order logistic regression were used to determine the association between migrants' status and the outcome variable of satisfaction with CHCs. Among participants, 37.6% of the participants had Shenzhen hukou. Using the classification of urban village status, 29.1% of participants were urban villagers. Urban villagers were less likely to know the location of nearest CHCs and less likely to select CHCs as their frequently used health care institutions. No statistically significant difference was found on willingness to use CHCs or satisfaction with CHCs between Shenzhen hukou and non-Shenzhen hukou. But urban villagers were more satisfied with attitude and medical skills of health care workers. Our findings indicated that policymakers and social professionals need to adjust the organization and functioning of primary care institutions in the community to increase awareness and utilization of primary care services.

Prospective mode of action of Ivermectin: SARS-CoV-2.

The well-known anti-helminthic drug ivermectin (IVM) has been established as an example of drug repurposing for the management of SARS-CoV-2 infection. Various study has been done to understand the inhibitory mechanism of IVM against SARS-CoV-2 targets. Broadly, IVM has been categorized as a host-directed agent and the proposed mechanism involves inhibition of the IMPα/ß1-mediated nuclear import of viral proteins. In addition, in vitro/in vivo and molecular docking/dynamic simulation studies suggested multitargets mechanism of IVM against SARS-CoV-2. Present manuscript attempts to provide an overview of the detailed mechanism of action based on experimental and computational studies. The knowledge of binding interaction of IVM and SARS-CoV-2 targets will give the direction to developed new and potential anti-COVID agents.

Drug Repurposing Strategies for Non-cancer to Cancer Therapeutics.

Global efforts invested in the prevention and treatment of cancer need to be repositioned to develop safe, effective, and economic anticancer therapeutics by adopting rational approaches of drug discovery. Drug repurposing is one of the established approaches to reposition old, clinically approved off-patent noncancer drugs with known targets into newer indications. The literature review suggests a key role of drug repurposing in the development of drugs intended for cancer as well as noncancer therapeutics. A wide category of noncancer drugs such as, drugs acting on CNS, anthelmintics, cardiovascular drugs, antimalarial drugs, anti-inflammatory drugs, have come out with interesting outcomes during preclinical and clinical phases. In the present article, a comprehensive overview of the current scenario of drug repurposing for the treatment of cancer has been focused. The details of some successful studies along with examples have been included followed by associated challenges.