A review on potential therapeutic targets for the treatment of leishmaniasis.

Leishmania, a protozoan parasite, is responsible for the occurrence of leishmaniasis, a disease that is prevalent in tropical regions. Visceral Leishmaniasis (VL), also known as kala-azar in Asian countries, is one of the most significant forms of VL, along with Cutaneous Leishmaniasis (CL) and Mucocutaneous Leishmaniasis (ML). Management of this condition typically entails the use of chemotherapy as the sole therapeutic option. The current treatments for leishmaniasis present several drawbacks, including a multitude of side effects, prolonged treatment duration, disparate efficacy across different regions, and the emergence of resistance. To address this urgent need, it is imperative to identify alternative treatments that are both safer and more effective. The identification of appropriate pharmacological targets in conjunction with biological pathways constitutes the initial stage of drug discovery. In this review, we have addressed the key metabolic pathways that represent potential pharmacological targets as well as prominent treatment options for leishmaniasis.

Removal of pharmaceutical contaminants from hospital wastewater using constructed wetlands: a review.

AbstractPharmaceutical compounds are a significant source of environmental pollution, particularly in hospital wastewater, which contains high concentrations of such compounds. Constructed wetlands have emerged as a promising approach to removing pharmaceutical compounds from wastewater. This paper aims to review the current state of knowledge on the removal of pharmaceutical compounds from hospital wastewater using constructed wetlands, including the mechanism of removal, removal efficiency, and future prospects. Pharmaceutical contaminants have been considered to be one of the most emerging pollutants in recent years. In this review article, various studies on constructed wetlands are incorporated in order to remove the pharmaceutical contaminants. The nature of constructed wetland can be explained by understanding the types of constructed wetland, characteristics of hospital wastewater, removal mechanism, and removal efficiency. The results of the review indicate that constructed wetlands are effective in removing pharmaceutical compounds from hospital wastewater. The removal mechanism of these compounds involves a combination of physical, chemical, and biological processes, including adsorption, degradation, and uptake by wetland plants. The removal efficiency of constructed wetlands varies depending on several factors, including the type and concentration of pharmaceutical compounds, the design of the wetland system, and the environmental conditions. Further research is necessary to optimize the performance of these systems, particularly in the removal of emerging contaminants, to ensure their effectiveness and long-term sustainability.

NMR based Serum metabolomics revealed metabolic signatures associated with oxidative stress and mitochondrial damage in brain stroke.

Brain stroke (BS, also known as a cerebrovascular accident), represents a serious global health crisis. It has been a leading cause of permanent disability and unfortunately, frequent fatalities due to lack of timely medical intervention. While progress has been made in prevention and management, the complexities and consequences of stroke continue to pose significant challenges, especially, its impact on patient's quality of life and independence. During stroke, there is a substantial decrease in oxygen supply to the brain leading to alteration of cellular metabolic pathways, including those involved in mitochondrial-damage, leading to mitochondrial-dysfunction. The present proof-of-the-concept metabolomics study has been performed to gain insights into the metabolic pathways altered following a brain stroke and discover new potential targets for timely interventions to mitigate the effects of cellular and mitochondrial damage in BS. The serum metabolic profiles of 108 BS-patients were measured using 800 MHz NMR spectroscopy and compared with 60 age and sex matched normal control (NC) subjects. Compared to NC, the serum levels of glutamate, TCA-cycle intermediates (such as citrate, succinate, etc.), and membrane metabolites (betaine, choline, etc.) were found to be decreased BS patients, whereas those of methionine, mannose, mannitol, phenylalanine, urea, creatine and organic acids (such as 3-hydroxybutyrate and acetone) were found to be elevated in BS patients. These metabolic changes hinted towards hypoxia mediated mitochondrial dysfunction in BS-patients. Further, the area under receiver operating characteristic curve (ROC) values for five metabolic features (methionine, mannitol, phenylalanine, mannose and urea) found to be more than 0.9 suggesting their high sensitivity and specificity for differentiating BS from NC subjects.

Clinical metabolomics by NMR revealed serum metabolic signatures for differentiating sarcoidosis from tuberculosis.

BACKGROUND: Pulmonary sarcoidosis (SAR) and tuberculosis (TB) are two granulomatous lung-diseases and often pose a diagnostic challenge to a treating physicians. OBJECTIVE: The present study aims to explore the diagnostic potential of NMR based serum metabolomics approach to differentiate SAR from TB. MATERIALS AND METHOD: The blood samples were obtained from three study groups: SAR (N = 35), TB (N = 28) and healthy normal subjects (NC, N = 56) and their serum metabolic profiles were measured using 1D 1H CPMG (Carr-Purcell-Meiboom-Gill) NMR spectra recorded at 800 MHz NMR spectrometer. The quantitative metabolic profiles were compared employing a combination of univariate and multivariate statistical analysis methods and evaluated for their diagnostic potential using receiver operating characteristic (ROC) curve analysis. RESULTS: Compared to SAR, the sera of TB patients were characterized by (a) elevated levels of lactate, acetate, 3-hydroxybutyrate (3HB), glutamate and succinate (b) decreased levels of glucose, citrate, pyruvate, glutamine, and several lipid and membrane metabolites (such as very-low/low density lipoproteins (VLDL/LDL), polyunsaturated fatty acids, etc.). CONCLUSION: The metabolic disturbances not only found to be well in concordance with various previous reports, these further demonstrated very high sensitivity and specificity to distinguish SAR from TB patients suggesting serum metabolomics analysis can serve as surrogate method in the diagnosis and clinical management of SAR.

Frontonasal Encephalocele Complicated With Pseudotumor Cerebri: A Case Report and Literature Review.

Primary pseudotumor cerebri syndrome (PPTS) is a rare disorder of elevated intracranial pressure (ICP) in the absence of an identifiable underlying etiology. Afflicted patients are usually obese women in their reproductive age presenting with symptoms of elevated ICP. Seldom, patients can present with an encephalocele. We reported a case of a 31-year-old female who initially presented to our center with complaints of headaches, foreign body sensation in the nasal cavity, and decreased ability to smell. Brain computed tomography (CT) scan showed a large intranasal encephalocele and defect along the frontal skull base, through which brain tissue was herniating. The patient was successfully treated surgically by implantation of a lumboperitoneal shunt to manage the high ICP caused by her PPTS. In combination, reconstruction of the frontal skull base defect for the encephalocele was performed. Currently, the patient is doing well despite some on-and-off headaches.

Updates on drug designing approach through computational strategies: a review.

The drug discovery and development (DDD) process in pursuit of novel drug candidates is a challenging procedure requiring lots of time and resources. Therefore, computer-aided drug design (CADD) methodologies are used extensively to promote proficiency in drug development in a systematic and time-effective manner. The point in reference is SARS-CoV-2 which has emerged as a global pandemic. In the absence of any confirmed drug moiety to treat the infection, the science fraternity adopted hit and trial methods to come up with a lead drug compound. This article is an overview of the virtual methodologies, which assist in finding novel hits and help in the progression of drug development in a short period with a specific medicinal solution.

An extensive survey of technological applications in drug discovery and development, encompassing offline and online approaches, is presented in this review. The span of research issues that can be tackled using these advances is vast, opening new horizons for future innovations. The article is designed to incite further research investments into drug development procedures and bridge existing research voids by outlining multiple pharmaceutical products that resulted from employing systematic computational methodologies.

Novel Functionalized Spiro [Indoline-3,5'-pyrroline]-2,2'dione Derivatives: Synthesis, Characterization, Drug-Likeness, ADME, and Anticancer Potential.

A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a-4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed that among all derivatives of SOXs (4a-4h), 4a has a substantial binding affinity (∆G) -6.65, -6.55, -8.73, and -7.27 Kcal/mol with CD-44, EGFR, AKR1D1, and HER-2, respectively. A functional study demonstrated that SOX 4a has a substantial impact on human cancer cell phenotypes exhibiting abnormality in cytoplasmic and nuclear architecture as well as granule formation leading to cell death. SOX 4a treatment robustly induced reactive oxygen species (ROS) generation in cancer cells as observed by enhanced DCFH-DA signals. Overall, our results suggest that SOX (4a) targets CD-44, EGFR, AKR1D1, and HER-2 and induces ROS generation in cancer cells. We conclude that SOX (4a) could be explored as a potential chemotherapeutic molecule against various cancers in appropriate pre-clinical in vitro and in vivo model systems.

Drug repositioning to discover novel ornithine decarboxylase inhibitors against visceral leishmaniasis.

Visceral leishmaniasis (VL) is caused by Leishmania donovani (Ld), and most cases occur in Brazil, East Africa, and India. The treatment for VL is limited and has many adverse effects. The development of safer and more efficacious drugs is urgently needed. Drug repurposing is one of the best processes to repurpose existing drugs. Ornithine decarboxylase (ODC) is an important target against L. donovani in the polyamine biosynthesis pathway. In this study, we have modeled the 3D structure of ODC and performed high-throughput virtual screening of 8630 ZINC database ligands against Leishmania donovani ornithine decarboxylase (Ld ODC), selecting 45 ligands based on their high binding score. It is further validated through molecular docking simulation and the selection of the top two lead molecules (ceftaroline fosamil and rimegepant) for Molecular Dynamics (MD) simulation, Density functional theory (DFT), and molecular mechanics generalized born surface area (MMGBSA) analysis. The results showed that the binding affinities of ceftaroline fosamil, and rimegepant are, respectively, -10.719 and 10.159 kcal/mol. The docking complexes of the two lead compounds, ceftaroline fosamil, and rimegepant, with the target ODC, were found stable during molecular dynamics simulations. Furthermore, the analysis of MMGBSA revealed that these compounds had a high binding free energy. The DFT analysis showed that the top lead molecules were more reactive than the standard drug (pentamidine). In-silico findings demonstrated that ceftaroline fosamil, and rimegepant might be recognized as potent antagonists against ODC for the treatment of VL.

Isatin Conjugates as Antibacterial Agents: A Brief Review.

Pathogenic bacteria, with their innate resistance to drugs, pose a constant threat to human health and well-being and put a persistent strain on the health care system. Development of more effective and safer novel antibacterial drugs is warranted to counter the menace unleashed by pathogenic bacteria. Integration of privileged pharmacophores from various bioactive molecules into a single template is a promising strategy to obtain new leads with unique mechanisms of action to overcome drug resistance. In the past few years, numerous isatin-based hybrid molecules were screened and their pharmacological properties were explored in efforts to develop novel therapeutics. The results of screening show that isatin conjugates exhibit promising activity against a broad range of highly pathogenic gram-positive and gram-negative bacteria and can serve as important leads in the discovery of highly potent broad spectrum antibacterial drugs. Herein, we review the antibacterial bioactive profile of a variety of hybrid isatin derivatives, including isatin-azole, isatin-quinoline/ quinolone, isatin-furan/coumarin, isatin-hydrazone/(thio)semicarbazone, isatin dimers, and isatin- indole hybrids.

Implications of social media misinformation on COVID-19 vaccine confidence among pregnant women in Africa.

It has been over a year since the World Health Organization (WHO) declared the outbreak of COVID-19 as a Public Health Emergency of International Concern and subsequently a global pandemic. The world has experienced a lot of uncertainty since then as we all get used to this new 'normal' with social distancing measures, lockdowns, the emergence of new variants, and an array of hope with the development of vaccines. Having an abstract understanding of vaccine delivery, public perceptions of vaccines, and promoting acceptance of vaccines are critical to tackling the pandemic. The advent of the pandemic has led to the emergence of an 'infodemic' or rampant misinformation surrounding the virus, treatment, and vaccines. This poses a critical threat to global health as it has the potential to lead to a public health crisis by exacerbating disease spread and overwhelming healthcare systems. This 'infodemic' has led to rising vaccine hesitancy which is of paramount concern with the WHO even identifying it as one of the ten main threats to Global health almost 2 years before the approval of COVID-19 vaccines. Pregnant African women are one of the most vulnerable population groups in a region with an already burdened healthcare system. Currently, there isn't ample research in the literature that explores vaccine hesitancy in this subpopulation and the impact of social media misinformation surrounding it. The aim of this paper is to highlight the implications of this 'infodemic' on the pregnant African population and suggest key recommendations for improved healthcare strategies.

Comorbidities Associated With Attention-Deficit/Hyperactivity Disorder in Children and Adolescents at a Tertiary Care Setting.

Studies have revealed high rates of neurodevelopmental and psychiatric comorbid conditions among individuals diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, research on this topic in the Arab world has been limited. This study evaluates the medical, neurodevelopmental, and psychiatric comorbidities in children and adolescents diagnosed with ADHD in Dubai, United Arab Emirates (UAE). A total of 428 pediatric patients diagnosed with ADHD were included. Children and adolescents with ADHD had high rates of comorbid disorders. Twenty comorbid conditions were identified. More than 3 quarters of the study sample had at least 1 comorbid disorder. The most common comorbidity among children was autism spectrum disorder, and among adolescents was anxiety disorders. Comprehensive assessments are highly warranted to identify and manage associated comorbid conditions. Further research is needed in exploring the biopsychosocial factors contributing to the elevated rate of comorbidity in children and adolescents with ADHD.

From black to white: A roadmap to containing the rise of candidiasis amidst COVID-19 and mucormycosis in India.

With numbers of active COVID-19 cases in India falling in recent weeks and the healthcare system finally showing signs of coping with the mucormycosis epidemic, several new reports of COVID-19 cases linked to "white fungus" have emerged. This has led to rising concern with the potential to stretch the capacity of an already burdened healthcare system. Moreover, the implications of this disease in the COVID-19 population and its consequences on the health and socio-economic structure of the country have not been vastly studied. This commentary explores the need for government efforts in the context of containing candidiasis during the pandemic and provides key recommendations on combating this imminent public health challenge.

Synthesis and Characterizations of Nitrogen (N) Doped Strontium Titanate (SrTiO3) Nanoparticles for Enhanced Visible Light Driven Photocatalytic Degradation.

Highly crystalline bare and N-doped SrTiO3 nanoparticles were effectively synthesized with strontium acetate, titanium isopropoxide, hexamethylenetetramine as precursor via citric acid assisted hydrothermal process followed by calcination. The hydrothermally synthesized bare and N-doped SrTiO3 NPs possessed monodispersity throughout with particle size diameter 50±5 nm but because of annealing at 750 °C temperature the synthesized NPs got agglomerate which created rough surface and induces oxygen vacancy in the NPs. Introducing N3- ions impurity into SrTiO3 lattice tailored the electronic band structure of SrTiO3 and extends its absorption into the visible region. It would display the p-type conductivity and facilitate the photoinduced electron-hole pairs towards respective site which diminishes the chances of recombination of electron-hole pairs that enhances photocatalytic degradation reaction. The results showed MB degraded about ~88 in just 140 min and followed first order reaction kinetics with rate constant k = 0.01489 mint-1.

Withdrawal Notice: Computational Druglikeness Assessment, Synthesis, Characterization and In vitro Biological Activity Evaluation of some Novel Mixed Metal Complexes of 2-(butan-2-ylidene) Hydrazinecarbothioamide

The article has been withdrawn at the request of the authors of the journal Combinatorial Chemistry & High Throughput Screening. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Decalcification and bond failure rate in resin modified glass ionomer cement versus conventional composite for orthodontic bonding: A systematic review & meta-analysis.

BACKGROUND: Demineralized white spot lesions (DWSLs) are one of the unfavourable effects of orthodontic treatment. Resin modified glass ionomer cement (RMGIC) was introduced to reduce its occurrence. OBJECTIVE: The study aimed to determine the incidence of DWSLs as primary objective and bond failure rate in brackets bonded with RMGIC versus conventional composite (CC) as secondary objective. MATERIAL AND METHODS: A thorough literature search was done until April 2019 on various databases including Scopus, Web of Science, PubMed, Cochrane database, CINHAL, Dental and Oral Science, and manual search. Only human clinical trials and published in English language were included. We considered the experimental group of orthodontic patients with brackets bonded with RMGIC and the control group with brackets bonded with CC. Blind and induplicate study selection, data extraction, and risk of bias assessment were undertaken. RevMan software was used for data analysis. Odds ratio with 95% confidence intervals (CIs) was used to express the effect estimate of frequency of bracket failure bonded using RMGIC and CC. The risk of bias was assessed using Cochrane risk of bias tool for RCTs and ROBINS-I tool for N-RCTs. Sensitivity analyses and subgroup analysis were performed as well. RESULTS: Out of 2285 articles, nine met the inclusion criteria. Five were RCTs and four were N-RCTs. Out of nine, seven studies were included in the meta-analysis. A random effect model was used. No significant difference was found in the bond failure rate (risk ratio: 1.48; 95% CI: 0.57-3.87; P≤0.42). No difference was found in the occurrence of DWSLs between the two groups. CONCLUSIONS: Due to the limited number of studies and studies with high risk of bias, no strong conclusion can be drawn. More studies need to be done to reasonably conclude that RMGIC is beneficial in reducing the occurrence of DWSLs and have comparable bond failure rate. The protocol was registered on PROSPERO (CRD42019125386) prior to the commencement of the systematic review.

Factors affecting changes in soft tissue profile after various treatment modalities for skeletal Class II malocclusion: A cross-sectional study.

INTRODUCTION: Various treatment modalities are used to treat skeletal Class II malocclusion with different effects on the soft tissue. This study was aimed to determine factors affecting changes in soft tissue profile after various treatment modalities for skeletal Class II malocclusion. MATERIALS AND METHODS: A cross-sectional study was conducted using pre-treatment and post-treatment lateral cephalograms of 141 subjects. The sample consisted of 47 patients treated with Clark's Twin Block, 47 with first premolar extractions, and 47 with Class II elastics. The post-treatment cephalograms were superimposed on pre-treatment radiographs using stable landmarks: anterior wall of sella turcica and anterior cranial base. The changes in profile were evaluated by paired t-test using X-Y co-ordinate system. Changes in profile were predicted by using multi-variable linear regression analysis. Level of significance was kept at P≤0.05. RESULTS: The changes in soft tissue profile were statistically significant for all the landmarks (P<0.001) of nose, upper and lower lip, and chin in horizontal and vertical direction, except subnasale and labrale superius in the horizontal direction. The soft tissue profile changes can be predicted for all landmarks with various prediction powers except pronasale, subnasale, and inferior labial sulcus in the vertical direction. CONCLUSIONS: Almost all the soft tissue landmarks of nose and lower third of the face exhibit downward and forward movement. The changes in the upper lip in both horizontal and vertical directions were found to be more predictable than those occurring in the lower lip.

Computational Drug Designing and Prediction Of Important Parameters Using in silico Methods- A Review.

BACKGROUND: Computational or in silico studies are undertaken to assess the drug like properties of lead compounds. These studies help in fast prediction of relevant properties. OBJECTIVE: Through this review, an effort is made to encapsulate some of the important parameters which should be met by a compound for it to be considered as a potential drug candidate along with an overview of automated softwares which can be used for making various predictions. METHODS: Drug uptake, its absorption, evacuation and associated hazardous effects are important factors for consideration in drug designing and should be known in early stages of drug development. Several important physicochemical properties like molecular weight, polar surface area (PSA), molecular flexibility etc. have to be taken into consideration in drug designing. Toxicological assessment is another important aspect of drug discovery which predicts the safety and adverse effects of a drug. RESULTS: Additionally, bioactivity scores of probable drug leads against various human receptors can also be predicted to evaluate the probability of them to act as a potential drug candidate. The in vivo biological targets of a molecule can also be efficiently predicted by molecular docking studies. CONCLUSION: Some important software like iGEMDOCK, AutoDock, OSIRIS property explorer, Molinspiration, MetaPrint2D, admetSAR and their working methodology and principle of working have been summarized in this review.

Computer-aided drug design and virtual screening of targeted combinatorial libraries of mixed-ligand transition metal complexes of 2-butanone thiosemicarbazone.

The present paper deals with in silico evaluation of 32 virtually designed transition metal complexes of 2-butanone thiosemicarbazone and N,S,O containing donor hetero-ligands namely py, bpy, furan, thiophene, 2-picoline, 1,10-phenanthroline, piperazine and liquid ammonia. The complexes were designed with a view to assess their potential anticancer, antioxidant and antibacterial activity. The absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the chosen ligands were calculated by admetSAR software. Metabolic sites of different ligands likely to undergo metabolism were predicted using Metaprint 2D. The proposed complexes were also evaluated for their drug-like quality based on Lipinski's, Veber, Ghose and leadlikeness filters. Druglikeness and toxicity potential were predicted by OSIRIS property explorer. The pharmacokinetic properties and bioactivity scores were calculated by Molinspiration tool. Bioactivity scores of the complexes were predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G-protein coupled receptor ligands and ion channel modulators. Molecular docking of selected Fe(II) mixed-ligand complexes was performed using AutoDock version 4.2.6 and i-GEMDOCK version 2.1 with two target proteins namely Ribonucleotide reductase (RR) and Topoisomerase II (Topo II). The results were compared with three standard reference drugs viz. Doxorubicin HCl, Letrozole (anticancer) and Tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA) for visualization and projection as scatter and 3D plots. Positive results obtained for hetero-ligands using admetSAR version 1.0 indicated good absorption and transport kinetics of the hetero-ligand complexes through the human intestine and blood-brain barrier. The hetero-ligands were predicted to have no associated mutagenic effect(s) also. However, none of the hetero-ligands was predicted to be Caco-2 (human colon cancer cell line) permeable. Most of the hetero-ligands and the parent ligand (2-butanone thiosemicarbazone) were predicted to undergo Phase-I metabolism prior to excretion using MetaPrint2D software. Pharmacokinetic evaluation of the proposed complexes revealed that all complexes displayed drug-like character and were predicted to have no apparent toxic side-effects. All the proposed complexes showed moderate to good biological activity scores (-5.0 to 0.0). Mixed complexes with bpy, 2-picoline and 1,10-phenanthroline showed significant bioactivity scores (as enzyme inhibitors) in the range 0.02-0.13. Likewise, good docking scores were obtained for Fe (II) complexes with the same ligands. [FeL(2-pic)2] displayed the lowest binding energy (-6.47 kcal/mol) with respect to Topo II followed by [FeL(py)2] (-6.14 kcal/mol) as calculated by AutoDock version 4.2.6. With respect to binding with RR, [FeL(2--pic)2] again displayed the lowest binding energy (-7.21 kcal/mol) followed by [FeL(py)2] (-5.96 kcal/mol). On the basis of docking predictions and various other computational evaluations, four mixed-ligand complexes of Fe in +2 oxidation state with py, bpy, 2--picoline and 1,10-phenanthroline were synthesized with 2-butanone thiosemicarbazone. All the synthesized Fe complexes were characterized using various spectroscopic techniques and tested for their potential anticancer activity in vitro against human breast carcinoma cell line MDA-MB 231 and human lung carcinoma cell line A549 cell line using MTT assay. [FeL(2-pic)2], [FeL(bpy)], and [FeL(py)2] were found to exhibit significant antiproliferative activity with IC50 values in the range of 80-100 µM against breast and lung cancer cells. The synthesized Fe complexes also displayed mild antioxidant activities. The synthesized and studied Fe complexes have the potential for development into future anticancer agents if analyzed and modified further for improvement of their ADMET, solubility and permeability criteria set for potential drug-candidates.