Corrigendum to "A narrative review of approved and emerging anti-obesity medications" [Saudi Pharm. J. 31(10) (2023) 101757].

[This corrects the article DOI: 10.1016/j.jsps.2023.101757.].

Molecular and metabolic characterization of petroleum hydrocarbons degrading Bacillus cereus.

Hydrocarbon constituents of petroleum are persistent, bioaccumulated, and bio-magnified in living tissues, transported to longer distances, and exert hazardous effects on human health and the ecosystem. Bioaugmentation with microorganisms like bacteria is an emerging approach that can mitigate the toxins from environmental sources. The present study was initiated to target the petroleum-contaminated soil of gasoline stations situated in Lahore. Petroleum degrading bacteria were isolated by serial dilution method followed by growth analysis, biochemical and molecular characterization, removal efficiency estimation, metabolites extraction, and GC-MS of the metabolites. Molecular analysis identified the bacterium as Bacillus cereus, which exhibited maximum growth at 72 hours and removed 75% petroleum. Biochemical characterization via the Remel RapID™ ONE panel system showed positive results for arginine dehydrolase (ADH), ornithine decarboxylase (ODC), lysine decarboxylase (LDC), o-nitrophenyl-ß-D-galactosidase (ONPG), p-nitrophenyl-ß-D-glucosidase (ßGLU), p-nitrophenyl-N-acetyl-ß-D-glucosaminidase (NAG), malonate (MAL), adonitol fermentation (ADON), and tryptophane utilization (IND). GC-MS-based metabolic profiling identified alcohols (methyl alcohol, o-, p- and m-cresols, catechol, and 3-methyl catechol), aldehydes (methanone, acetaldehyde, and m-tolualdehyde), carboxylic acid (methanoic acid, cis,cis-muconic acid, cyclohexane carboxylic acid and benzoic acid), conjugate bases of carboxylic acids (benzoate, cis,cis-muconate, 4-hydroxybenzoate, and pyruvate) and cycloalkane (cyclohexene). It suggested the presence of methane, methylcyclohexane, toluene, xylene, and benzene degradation pathways in B. cereus.

In-silico characterization of GABAT protein found in gut-brain axis associated bacteria of healthy individuals and multiple sclerosis patients.

Background: Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation and demyelination of neurons. There is evidence to suggest that level of a neurotransmitter gamma-aminobutyric acid (GABA), due to the degradation by γ-aminobutyric acid transaminase (GABAT), is reduced in certain areas of the brain in MS patients. MS is always accompanied by gut bacteria dysbiosis. In healthy individuals, Faecalibacterium sp. while in MS patients A. calcoaceticus, Clostridium sp. and S. typhimurium are found abundantly. Although all these microbes produce GABAT but only in MS patients this enzyme significantly degrades GABA. Objective: Present study is an attempt to characterize the GABAT protein sequences of these bacteria. Methodology: Sequences of GABAT protein were retrieved from Uniprot database. Sequences were analyzed by Protparam, Gneg-mPLoc, SOSUI, PFP-FunDSeqE, Pepwheel program, PROTEUS and Alphafold and SAVES servers, MEME suite and HDOCK server. Results: In healthy individuals gastrointestinal tract (GIT) bacteria, GABAT protein was present in inner-membrane with α helix content (61 and 62%) and ß sheet content (5%), 4-helical cytokines functional domains. It has greater number of B-cell epitopes and more complex 3D configuration as compared to MS patients GIT bacterial enzymes. Conclusion: Present study might enable us to modify the GABAT encoding gene and enzyme through site-directed mutagenesis in pathogenic bacteria thus reducing their potential of causing MS.

Exploring the association of ESR1 and ESR2 gene SNPs with polycystic ovary syndrome in human females: a comprehensive association study.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) affects a significant proportion of human females worldwide and is characterized by hormonal, metabolic, and reproductive dysfunctions, including infertility, irregular menstrual cycles, acanthosis nigricans, and hirsutism. Mutations in the estrogen receptor genes ESR1 and ESR2, involved in normal follicular development and ovulation, can contribute to development of the PCOS. The present study focuses on investigating the potential correlation between single nucleotide polymorphisms (SNPs) of ESR1 and ESR2 genes and the incidence of this syndrome. METHODS: For this study, SNPs in ESR1 and ESR2 genes were retrieved from the ENSEMBL database and analyzed for their effect on mutated proteins using different bioinformatics tools including SIFT, PolyPhen, CADD, REVEL, MetaLR, I-Mutant, CELLO2GO, ProtParam, SOPMA, SWISS-MODEL and HDDOCK. RESULTS: All the SNPs documented in the present study were deleterious. All the SNPs except rs1583384537, rs1450198518, and rs78255744 decreased protein stability. Two variants rs1463893698 and rs766843910 in the ESR2 gene altered the localization of mutated proteins i.e. in addition to the nucleus, proteins were also found in mitochondria and extracellular, respectively. SNPs rs104893956 in ESR1 and rs140630557, rs140630557, rs1596423459, rs766843910, rs1596405923, rs762454979 and rs1384121511 in ESR2 gene significantly changed the secondary structure of proteins (2D). SNPs that markedly changed 3D configuration included rs1554259481, rs188957694 and rs755667747 in ESR1 gene and rs1463893698, rs140630557, rs1596423459, rs766843910, rs1596405923, rs762454979 and rs1384121511 in ESR2 gene. Variants rs1467954450 (ESR1) and rs140630557 (ESR2) were identified to reduce the binding tendency of ESRα and ß receptors with estradiol as reflected by the docking scores i.e. -164.97 and -173.23, respectively. CONCLUSION: Due to the significant impact on the encoded proteins, these variants might be proposed as biomarkers to predict the likelihood of developing PCOS in the future and for diagnostic purposes.

Fetal monitoring technologies for the detection of intrapartum hypoxia - challenges and opportunities.

Intrapartum fetal hypoxia is related to long-term morbidity and mortality of the fetus and the mother. Fetal surveillance is extremely important to minimize the adverse outcomes arising from fetal hypoxia during labour. Several methods have been used in current clinical practice to monitor fetal well-being. For instance, biophysical technologies including cardiotocography, ST-analysis adjunct to cardiotocography, and Doppler ultrasound are used for intrapartum fetal monitoring. However, these technologies result in a high false-positive rate and increased obstetric interventions during labour. Alternatively, biochemical-based technologies including fetal scalp blood sampling and fetal pulse oximetry are used to identify metabolic acidosis and oxygen deprivation resulting from fetal hypoxia. These technologies neither improve clinical outcomes nor reduce unnecessary interventions during labour. Also, there is a need to link the physiological changes during fetal hypoxia to fetal monitoring technologies. The objective of this article is to assess the clinical background of fetal hypoxia and to review existing monitoring technologies for the detection and monitoring of fetal hypoxia. A comprehensive review has been made to predict fetal hypoxia using computational and machine-learning algorithms. The detection of more specific biomarkers or new sensing technologies is also reviewed which may help in the enhancement of the reliability of continuous fetal monitoring and may result in the accurate detection of intrapartum fetal hypoxia.

Cichorium intybus L. significantly alleviates cigarette smoke-induced acute lung injury by lowering NF-κB pathway activation and inflammatory mediators.

Background: Cigarette smoke (CS) is one of the primary causes of acute lung injury (ALI) via provoking pulmonary inflammation and oxidative stress. Despite substantial studies, no effective treatment for ALI is presently available. Purpose: New prospective treatment options for ALI are required. Thus, this project was designed to investigate the in vivo and in vitro protective effects of 70 % methanolic-aqueous crude extract of whole plant of Cichorium intybus (Ci.Mce) against CS-induced ALI. Study design: /methods: Initially, male Swiss albino mice were subjected to whole-body CS exposure for 10 continuous days to prepare CS-induced ALI models. Normal saline (10 mL/kg), Ci.Mce (100, 200, 300 mg/kg), and Dexamethasone (1 mg/kg) were orally administered to respective animal groups 1 h prior to CS-exposure. 24 hrs after the last CS-exposure, BALF and lungs were harvested to study the key characteristics of ALI. Next, HPLC analysis was done to explore the phytoconstituents. Results: Ci.Mce exhibited significant reductions in lung macrophage and neutrophil infiltration, lung weight coefficient, and albumin exudation. Additionally, it effectively ameliorated lung histopathological alterations and hypoxemia. Notably, Ci.Mce exerted inhibitory effects on the excessive generation of IL-6, IL-1ß, and KC in both CS-induced ALI murine models and CSE-stimulated RAW 264.7 macrophages. Noteworthy benefits included the attenuation of oxidative stress induced by CS, evidenced by decreased levels of MDA, TOS, and MPO, alongside enhanced TAC production. Furthermore, Ci.Mce demonstrated a marked reduction in CS-induced NF-κB expression, both in vivo and in vitro. Conclusion: Consequently, Cichorium intybus could be a therapeutic option for CS-induced ALI due to its ability to suppress inflammatory reactions, mitigate oxidative stress, and quell NF-κB p65 activation.

Assessment of Knowledge and attitude towards Stroke among the UAE population during the COVID-19 pandemic: A cross-sectional study.

Background: Despite significant advancements in healthcare, the burden of stroke continues to rise in the developed world, especially during the COVID-19 pandemic. Association between COVID-19 infection and stroke is well established. Factors identified for the delay in presentation and management include a lack of awareness regarding stroke. We aimed to assess the general public knowledge and attitudes on stroke and stroke risk factors in the United Arab Emirates during the COVID-19 pandemic. Methods: A cross-sectional study was conducted between September 2021 and January 2022 among adults≥ 18 years old. Participants completed a self-administered questionnaire on sociodemographic characteristics and stroke knowledge and attitudes. Knowledge and attitude scores were calculated based on the number of correct responses. Linear regression analysis was performed to determine the factors related to knowledge and attitude towards stroke. Results: Of the 500 respondents, 69.4% were females, 53.4% were aged between 18 and 25, and nearly half were students (48.4%). The mean knowledge score was 13.66 (range 2-24). Hypertension (69%), smoking (63.2%), stress (56.4%) obesity/overweight (54.4%), and heart disease (53.6%) were identified as risk factors. Overall, the knowledge of signs/symptoms was suboptimal. The mean attitude score was 4.41 (range, 1-6); 70.2% would call an ambulance if someone were having a stroke. A monthly income of 11,000-50,000 AED and being a student were associated with positive knowledge. Being a non-health worker and lacking access to electronic media sources were associated with worse attitudes. Conclusion: Overall, we identified poor knowledge and suboptimal attitudes toward stroke. These findings reflect the need for effective public health approaches to improve stroke awareness, knowledge, and attitudes for effective prevention in the community. Presently, this is of utmost necessity, given the increased occurrence of stroke and its severity among COVID-19 patients.

Development and Characterization of Interstitial-Fluid-Mimicking Solutions for Pre-Clinical Assessment of Hypoxia.

Asphyxia, a leading cause of illness and death in newborns, can be improved by early detection and management. Arterial blood gas (ABG) analysis is commonly used to diagnose and manage asphyxia, but it is invasive and carries risks. Dermal interstitial fluid (ISF) is an alternative physiological fluid that can provide valuable information about a person's health. ISF is more sensitive to severe hypoxia and metabolic disorders compared to blood, making it an attractive option for minimally invasive asphyxia detection using biosensors. However, obtaining ISF samples from humans is challenging due to ethical concerns and sampling difficulties. To address this, researchers are developing ISF-mimicking solutions as substitutes for early testing and evaluation of biosensors. This paper focuses on the development of these solutions for bench-based testing and validation of continuous asphyxia-monitoring biosensors. With an understanding of the factors influencing system quality and performance, these solutions can aid in the design of biosensors for in vivo monitoring of dermal ISF. Monitoring interstitial fluid pH levels can provide valuable insights into the severity and progression of asphyxia, aiding in accurate diagnosis and informed treatment decisions. In this study, buffer solutions were prepared to mimic the pH of ISF, and their electrical properties were analyzed. The results suggest that certain buffers can effectively mimic metabolic acidosis associated with asphyxia (pH < 7.30), while others can mimic metabolic alkalosis (pH > 7.45). Overall, this research contributes to the development of ISF-mimicking solutions and lays the groundwork for biosensor systems that monitor dermal ISF in real time.

Discovery of druggable potent inhibitors of serine proteases and farnesoid X receptor by ligand-based virtual screening to obstruct SARS-CoV-2.

The coronavirus, a subfamily of the coronavirinae family, is an RNA virus with over 40 variations that can infect humans, non-human mammals and birds. There are seven types of human coronaviruses, including SARS-CoV-2, is responsible for the recent COVID-19 pandemic. The current study is focused on the identification of drug molecules for the treatment of COVID-19 by targeting human proteases like transmembrane serine protease 2 (TMPRSS2), furin, cathepsin B, and a nuclear receptor named farnesoid X receptor (FXR). TMPRSS2 and furin help in cleaving the spike protein of the SARS-CoV-2 virus, while cathepsin B plays a critical role in the entry and pathogenesis. FXR, on the other hand, regulates the expression of ACE2, and its inhibition can reduce SARS-CoV-2 infection. By inhibiting these four protein targets with non-toxic inhibitors, the entry of the infectious agent into host cells and its pathogenesis can be obstructed. We have used the BioSolveIT suite for pharmacophore-based computational drug designing. A total of 1611 ligands from the ligand library were docked with the target proteins to obtain potent inhibitors on the basis of pharmacophore. Following the ADMET analysis and protein ligand interactions, potent and druggable inhibitors of the target proteins were obtained. Additionally, toxic substructures and the less toxic route of administration of the most potent inhibitors in rodents were also determined computationally. Compounds namely N-(diaminomethylene)-2-((3-((1R,3R)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclopentyl)propyl)amino)-2-oxoethan-1-aminium (26), (1R,3R)-3-(((2-ammonioethyl)ammonio)methyl)-1-((4-propyl-1H-imidazol-2-yl)methyl)piperidin-1-ium (29) and (1R,3R)-3-(((2-ammonioethyl)ammonio)methyl)-1-((1-propyl-1H-pyrazol-4-yl)methyl)piperidin-1-ium (30) were found as the potent inhibitors of TMPRSS2, whereas, 1-(1-(1-(1H-tetrazol-1-yl)cyclopropane-1­carbonyl)piperidin-4-yl)azepan-2-one (6), (2R)-4-methyl-1-oxo-1-((7R,11S)-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,11-methanopyrido[1,2-a]azocin-9-yl)pentan-2-aminium (12), 4-((1-(3-(3,5-dimethylisoxazol-4-yl)propanoyl)piperidin-4-yl)methyl)morpholin-4-ium (13), 1-(4,6-dimethylpyrimidin-2-yl)-N-(3-oxocyclohex-1-en-1-yl)piperidine-4-carboxamide (14), 1-(4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(3,5-dimethylisoxazol-4-yl)propan-1-one (25) and N,N-dimethyl-4-oxo-4-((1S,5R)-8-oxo-5,6-dihydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-3(2H,4H,8H)-yl)butanamide (31) inhibited the FXR preferentially. In case of cathepsin B, N-((5-benzoylthiophen-2-yl)methyl)-2-hydrazineyl-2-oxoacetamide (2) and N-([2,2'-bifuran]-5-ylmethyl)-2-hydrazineyl-2-oxoacetamide (7) were identified as the most druggable inhibitors whereas 1-amino-2,7-diethyl-3,8-dioxo-6-(p-tolyl)-2,3,7,8-tetrahydro-2,7-naphthyridine-4­carbonitrile (5) and (R)-6-amino-2-(2,3-dihydroxypropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (20) were active against furin.

A narrative review of approved and emerging anti-obesity medications.

Background: Recently, many drugs have been approved for halting overweight and obesity-few types of research shifted to using Anti-obesity medications (AOM) solely for well-being and shape-keeping. Objective: This narrative review's objective was to explore the use of AOM in relation to their medical indications, efficacy, and cardiovascular safety. Methods and materials: We have conducted a narrative review of the literature on approved/non-approved AOM used for obesity and overweight. We have shed light on the emerging trials of therapies and evolving remedies. Results: Recently, there has been an enormous change in the use of AOM with high consumption that deserves extensive surveillance for the long-term consequences and impact on social, mental, and physical health. Nearly six AOMs and combined therapy are approved by the Food and Drug Administration. The recent guidelines for obesity management have shifted the focus from weight loss to goals that the patient considers essential and toward targeting the root cause of obesity. Conclusion: The use of AOM increased enormously despite its sometimes-dubious safety and ineffectiveness. The public and medical professionals should be vigilant to the real-world benefits of anti-obesity drugs and their achieved effectiveness with an improved safety profile.

Identification of Potent Inhibitors Targeting EGFR and HER3 for Effective Treatment of Chemoresistance in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Despite the existence of various therapeutic options, NSCLC is still a major health concern due to its aggressive nature and high mutation rate. Consequently, HER3 has been selected as a target protein along with EGFR because of its limited tyrosine kinase activity and ability to activate PI3/AKT pathway responsible for therapy failure. We herein used a BioSolveIT suite to identify potent inhibitors of EGFR and HER3. The schematic process involves screening of databases for constructing compound library comprising of 903 synthetic compounds (602 for EGFR and 301 for HER3) followed by pharmacophore modeling. The best docked poses of compounds with the druggable binding site of respective proteins were selected according to pharmacophore designed by SeeSAR version 12.1.0. Subsequently, preclinical analysis was performed via an online server SwissADME and potent inhibitors were selected. Compound 4k and 4m were the most potent inhibitors of EGFR while 7x effectively inhibited the binding site of HER3. The binding energies of 4k, 4m, and 7x were -7.7, -6.3 and -5.7 kcal/mol, respectively. Collectively, 4k, 4m and 7x showed favorable interactions with the most druggable binding sites of their respective proteins. Finally, in silico pre-clinical testing by SwissADME validated the non-toxic nature of compounds 4k, 4m and 7x providing a promising treatment option for chemoresistant NSCLC.

High throughput biochemical profiling, and functional potential analysis for valorization of grape peduncles.

Vitis vinifera L., commonly known as grape is a major fruit crop in the world. Grapes seem to confer health benefits due to their chemical components, biological and antioxidant activities. The present study is conducted to evaluate the biochemical constituents, antioxidant, and antimicrobial potential of ethanolic grape peduncles (EGP) extract. The result of phytochemical analysis revealed the presence of various phytochemicals such as flavonoid, tannin, carbohydrates, alkaloids, cardiac glycoside, phenol, steroid, terpenoids, quinones and anthraquinones. Furthermore, total phenolic content (TPC) and total flavonoid contents (TFC) were 7.35 ± 0.25 mg GAE/g (Gallic Acid Equivalent per gram) and 29.67 ± 0.13 mg QE/g (Quercetin Equivalent per gram) respectively. DPPH (2, 2-diphenyl-1-picrylhydrazyl) free radical scavenging assay revealed IC50 = 159.3 µg/mL. The antibacterial and antifungal study disclosed that the extract was highly potent against Salmonella typhi with maximum zone of inhibition of 27.2 ± 1.60 mm and Epidermophyton floccosum with 74 ± 1.81% inhibition. The extract was analyzed for its cytotoxicity and antileishmanial activity and showed no activity against HeLa cell line and promastigotes of Leishmania major. Elements Fe, Mn, Ni, Pb and Cd were determined by atomic absorption spectroscopy and approximately 50 compounds were identified by Gas Chromatography-Mass Spectrometry (GC-MS). Current work suggest that grape peduncles can be a promising source of bioactive medicinal component.

Identification of Potential Inhibitors for the Treatment of Alkaptonuria Using an Integrated In Silico Computational Strategy.

Alkaptonuria (AKU) is a rare genetic autosomal recessive disorder characterized by elevated serum levels of homogentisic acid (HGA). In this disease, tyrosine metabolism is interrupted because of the alterations in homogentisate dioxygenase (HGD) gene. The patient suffers from ochronosis, fractures, and tendon ruptures. To date, no medicine has been approved for the treatment of AKU. However, physiotherapy and strong painkillers are administered to help mitigate the condition. Recently, nitisinone, an FDA-approved drug for type 1 tyrosinemia, has been given to AKU patients in some countries and has shown encouraging results in reducing the disease progression. However, this drug is not the targeted treatment for AKU, and causes keratopathy. Therefore, the foremost aim of this study is the identification of potent and druggable inhibitors of AKU with no or minimal side effects by targeting 4-hydroxyphenylpyruvate dioxygenase. To achieve our goal, we have performed computational modelling using BioSolveIT suit. The library of ligands for molecular docking was acquired by fragment replacement of reference molecules by ReCore. Subsequently, the hits were screened on the basis of estimated affinities, and their pharmacokinetic properties were evaluated using SwissADME. Afterward, the interactions between target and ligands were investigated using Discovery Studio. Ultimately, compounds c and f were identified as potent inhibitors of 4-hydroxyphenylpyruvate dioxygenase.

Macrophages M2 polarization is involved in lapatinib-mediated chemopreventive effects in the lung cancer.

M2 polarized tumor-associated macrophages (TAMs) have a multifunctional role in cancer initiation, progression, metastasis, and contribute to chemotherapeutic resistance. Therefore, identifying M2 polarized TAMs is a potential target for cancer therapeutic intervention. The underlying mechanism that target the TAMs M2 polarized macrophages remains primarily uncharacterized; however, only a few compounds have been identified that inhibit TAMs M2 polarized macrophages. In this research, we investigated that lapatinib could effectively suppress the expression of IL_13-induced M2 polarized macrophages surface markers i.e., CD163 and CD206, and downregulation of M2 genes such as Fizz1, Mrc1, Arg1, IL-10, Ym1, nd CCL2 in vitro. Moreover, lapatinib abrogated the M2 polarized macrophage-mediated cancer cells invasion and migration. Mechanistically, in our study, lapatinib inhibited IL-13 triggered STAT6 phosphorylation. Furthermore, in LLCs tumor model, lapatinib significantly reduced tumorigenesis, followed by the downregulation of percentages of M2 marker CD206+ and CD68+ in the tumor. This downregulation correlates with chemopreventive effect of lapatinib. All taken together, these results demonstrated that lapatinib effectively prevents the macrophage M2 polarization and indicates a potential mechanism for preventing the tumor growth via M2 polarized polarization intervention.

Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer's Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties.

Alzheimer's disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer's disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4-6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, 1H- and 13C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC50 value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC50 value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer's disease (AD).

Identification of NS2B-NS3 Protease Inhibitors for Therapeutic Application in ZIKV Infection: A Pharmacophore-Based High-Throughput Virtual Screening and MD Simulations Approaches.

Zika virus (ZIKV) pandemic and its implication in congenital malformations and severe neurological disorders had created serious threats to global health. ZIKV is a mosquito-borne flavivirus which spread rapidly and infect a large number of people in a shorter time-span. Due to the lack of effective therapeutics, this had become paramount urgency to discover effective drug molecules to encounter the viral infection. Various anti-ZIKV drug discovery efforts during the past several years had been unsuccessful to develop an effective cure. The NS2B-NS3 protein was reported as an attractive therapeutic target for inhibiting viral proliferation, due to its central role in viral replication and maturation of non-structural viral proteins. Therefore, the current in silico drug exploration aimed to identify the novel inhibitors of Zika NS2B-NS3 protease by implementing an e-pharmacophore-based high-throughput virtual screening. A 3D e-pharmacophore model was generated based on the five-featured (ADPRR) pharmacophore hypothesis. Subsequently, the predicted model is further subjected to the high-throughput virtual screening to reveal top hit molecules from the various small molecule databases. Initial hits were examined in terms of binding free energies and ADME properties to identify the candidate hit exhibiting a favourable pharmacokinetic profile. Eventually, molecular dynamic (MD) simulations studies were conducted to evaluate the binding stability of the hit molecule inside the receptor cavity. The findings of the in silico analysis manifested affirmative evidence for three hit molecules with -64.28, -55.15 and -50.16 kcal/mol binding free energies, as potent inhibitors of Zika NS2B-NS3 protease. Hence, these molecules holds the promising potential to serve as a prospective candidates to design effective drugs against ZIKV and related viral infections.

Designing multi-epitope monkeypox virus-specific vaccine using immunoinformatics approach.

BACKGROUND: Monkeypox virus is an enveloped DNA virus that belongs to Poxviridae family. The virus is transmitted from rodents to primates via infected body fluids, skin lesions, and respiratory droplets. After being infected with virus, the patients experience fever, myalgia, maculopapular rash, and fluid-filled blisters. It is necessary to differentiate monkeypox virus from other poxviruses during diagnosis which can be appropriately envisioned via DNA analysis from swab samples. During small outbreaks, the virus is treated with therapies administered in other orthopoxviruses infections and does not have its own specific therapy and vaccine. Consequently, in this article, two potential peptides have been designed. METHODS: For the purpose of designing a vaccine, protein sequences were retrieved followed by the prediction of B- and T-cell epitopes. Afterward, vaccine structures were predicted which were docked with toll-like receptors. The docked complexes were analyzed with iMODS. Moreover, vaccine constructs nucleotide sequences were optimized and expressed in silico. RESULTS: COP-B7R vaccine construct (V1) has antigenicity score of 0.5400, instability index of 29.33, z-score of - 2.11-, and 42.11% GC content whereas COP-A44L vaccine construct (V2) has an antigenicity score of 0.7784, instability index of 23.33, z-score of - 0.61, and 48.63% GC content. It was also observed that COP-A44L can be expressed as a soluble protein in Escherichia coli as compared to COP-B7R which requires a different expression system. CONCLUSION: The obtained results revealed that both vaccine constructs show satisfactory outcomes after in silico investigation and have significant potential to prevent the monkeypox virus. However, COP-A44L gave better results.

Anti-inflammatory and anti-oxidant properties of Ipomoea nil (Linn.) Roth significantly alleviates cigarette smoke (CS)-induced acute lung injury via possibly inhibiting the NF-κB pathway.

Acute respiratory distress syndrome (ARDS), a serious manifestation of acute lung injury (ALI), is a debilitating inflammatory lung disease that is caused by multiple risk factors. One of the primary causes that can lead to ALI/ARDS is cigarette smoke (CS) and its primary mode of action is via oxidative stress. Despite extensive research, no appropriate therapy is currently available to treat ALI/ARDS, which means there is a dire need for new potential approaches. In our study we explored the protective effects of 70 % methanolic-aqueous extract of Ipomoea nil (Linn.) Roth, named as In.Mcx against CS-induced ALI mice models and RAW 264.7 macrophages because Ipomoea nil has traditionally been used to treat breathing irregularities. Male Swiss albino mice (20-25 ± 2 g) were subjected to CS for 10 uninterrupted days in order to establish CS-induced ALI murine models. Dexamethasone (1 mg/kg), In.Mcx (100 200, and 300 mg/kg) and normal saline (10 mL/kg) were given to respective animal groups, 1 h before CS-exposure. 24 h after the last CS exposure, the lungs and bronchoalveolar lavage fluid (BALF) of all euthanized mice were harvested. Altered alveolar integrity and elevated lung weight-coefficient, total inflammatory cells, oxidative stress, expression of pro-inflammatory cytokines (IL-1ß and IL-6) and chemokines (KC) were significantly decreased by In.Mcx in CS-exposed mice. In.Mcx also revealed significant lowering IL-1ß, IL-6 and KC expression in CSE (4 %)-activated RAW 264.7 macrophage. Additionally, In.Mcx showed marked enzyme inhibition activity against Acetylcholinesterase, Butyrylcholinesterase and Lipoxygenase. Importantly, In.Mcx dose-dependently and remarkably suppressed the CS-induced oxidative stress via not only reducing the MPO, TOS and MDA content but also improving TAC production in the lungs. Accordingly, HPLC analysis revealed the presence of many important antioxidant components. Finally, In.Mcx showed a marked decrease in the NF-κB expression both in in vivo and in vitro models. Our findings suggest that In.Mcx has positive therapeutic effects against CS-induced ALI via suppressing uncontrolled inflammatory response, oxidative stress, lipoxygenase and NF-κB p65 pathway.

Carveol ameliorates mercury-induced oxidative stress, neuroinflammation, and neurodegeneration in a mouse brain.

BACKGROUND: Mercury compounds are the world's third most hazardous substance. Mercury (II) chloride, also known as mercuric chloride (HgCl2), has been shown to have neurotoxic properties in a variety of forms. In numerous investigations, oxidative stress has been established as a key contributor to HgCl2-induced neurotoxicity. Carveol has been researched as an antioxidant and Nrf2-activator in several studies. This study was conducted to investigate if the carveol could protect mice against HgCl2-induced neuronal damage. METHODS: Mice were exposed to a dose of 0.4 mg/kg of HgCl2 and 20 mg/kg of carveol for 21 days. Animals were then subjected to behavioral evaluation through various methods such as open field test (OFT), elevated plus maze test (EPM), morris-water maze test (MWM), and Y-maze test. RESULTS: Results indicated hippocampal-related behavior anomalies which were improved significantly after carveol treatment. Oxidative stress was accompanied by excessive neuroinflammation, which was demonstrated by elevated levels of inflammatory markers such as TNF-α, p-NFkB, and COX-2, and were measured by Western blot, ELISA, and immunohistochemistry. These elevated levels of inflammatory markers were significantly mitigated upon treatment with carveol. To further investigate the participation of the JNK pathway, we used SP-600125 to inhibit JNK, which enhanced the neuroprotective effects of carveol. Moreover, molecular docking and modeling studies were used to validate these effects. CONCLUSION: Our findings indicate that carveol can inhibit the p-JNK pathway, thereby inhibiting HgCl2-induced apoptosis and downregulating the expression of inflammatory mediators.