Network pharmacology and molecular docking study-based approach to explore mechanism of benzimidazole-based anthelmintics for the treatment of lung cancer.

Emerging studies have reported the potential anticancer activity of benzimidazole-based anthelmintics (BBA) against lung cancer (LC). However, mechanism underlying the anticancer activity of BBA is unclear. Therefore, in the current study, network pharmacology and molecular docking-based approach were used to explore the potential molecular mechanism for the treatment of LC. The potential targets for BBA were obtained from multiple databases including SwissTargetPrediction, Drug Bank, Therapeutic Target Database, and Comparative Toxicogenomics Database while LC targets were collected from DisGeNet gene discovery platform, Integrated Genomic Database of NSCLC, Catalogue of Somatic Mutations in Cancer and Online Mendelian Inheritance in Man database. Protein-protein interaction (PPI) diagram of common targets was constructed using STRING online platform. Topological analysis was performed using Cytoscape and gene enrichment analysis was conducted using FunRich software. Highest degree targets were then confirmed using molecular docking and molecular dynamics simulations. The BBA were prioritized according to their S scores, with ricobendazole ranking highest followed by flubendazole, fenbendazole, mebendazole, triclabendazole, albendazole, oxibendazole, parbendazole, thiabendazole and oxfendazole. The potential targets of BBA identified using topological analysis and molecular docking were found to be CCND1 (cyclin D1), EGFR (Epidermal Growth Factor Receptor), ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2/CD340), PTGS2 (Prostaglandin-endoperoxide synthase 2), and SRC (Proto-oncogene tyrosine-protein kinase). Furthermore, molecular dynamics confirmed that CCND1 and EGFR are the potential targets of ricobendazole for the treatment of LC. BBA can be further explored as a therapeutic strategy for the treatment of lung cancer under in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Anesthesia Services in Low- and Middle-Income Countries: The Fragile Point for Safe Surgery and Patient Safety.

The Safe Surgery Saves Life campaign of the World Health Organization advocates patient safety best practices during surgical procedures. Anesthesia service is indivisible from the patient safety best practices. Although anesthesia services are safer than ever before, safe delivery of anesthesia service and patient safety depends significantly on the availability of qualified anesthesiologists, the knowledge and competency of anesthesiologists, the work environment, and the availability of essential equipment and monitoring facilities. Despite anesthesiologists being the midstream of perioperative care, their role and service are often underacknowledged, especially in low- and middle-income countries (LMICs). Anesthesia services in LMICs face myriad challenges such as a shortage of skilled personnel, inadequate resources, limited training opportunities, and minimal administrative say, which act as the fragile point in the chain of safe surgery delivery. Specific solutions should focus on strengthening the anesthesia workforce, providing fair remuneration and incentives, advocating for anesthesia autonomy, and facilitating access to educational resources. Nevertheless, managing these problems requires a collaborative effort involving governments, healthcare organizations, and international stakeholders to develop sustainable solutions and prioritize the well-being of both anesthesia providers and patients. This editorial focuses on it briefly, emphasizing the anesthesia of rural healthcare service and patient safety.

Multicomponent Domino Reaction for Concise Access to 2-Amino-Substituted 1,3,4 Oxadiazoles via Smiles Rearrangement.

A multicomponent domino reaction has been developed for the preparation of N-substituted 2-amino-1,3,4-oxadiazoles directly from various hydrazides (32 examples). The formation of 2-amino-1,3,4-oxadiazole involves the Smiles rearrangement of thiazolidinone, which results in the formation of carbodiimide intermediate that concomitantly undergoes amide-imidic acid tautomerism followed by cyclization. The protocol developed has wide applicability and provides the desired 2-amino-1,3,4-oxadiazole in excellent yields. The GSD studies of NMR spectra of aliphatic substrates (4di, 4dh) revealed the formation of three products, whereas, in the case of allylic and benzylic substrates, thiazolidinones were obtained as the sole products. Furthermore, to elucidate the plausible mechanism, DFT studies were performed affirming carbodiimide as the crucial intermediate for the interconversion of thiazolidinone to oxadiazole.

Atypical Presentations of Myocardial Infarction: A Systematic Review of Case Reports.

There is a rising incidence of coronary artery diseases and myocardial infarction (MI). Mortality associated with acute MI (AMI) is directly linked to the time to receive treatment and missed diagnoses. Although health professionals are aware of typical AMI presentation, atypical MI is difficult to diagnose, which on the other hand, is likely to have an impact on morbidity and mortality. Therefore, it is prudent to know such atypical presentations, especially for emergency and primary care physicians. We aimed to systematically evaluate the clinical presentations of atypical MI and analyze them to characterize the common clinical presentations of atypical MI. We researched the PubMed database, did citation tracking, and performed Google Scholar advanced search to find the cases reported on the atypical presentation of MI published from January 2000 to September 2022. Articles of all languages were included; Google Translate was used to translate articles published in languages other than English. A total of 496 (56 PubMed articles, 340 citations from included PubMed articles, and 100 articles from Google Scholar advanced search) were screened; 52 case reports were evaluated, and their data were analyzed. Atypical presentations of myocardial infarction are vast; patients may have chest pain without typical characteristics of angina pain or may not have chest pain. No typical characterization could be done. Most patients were in their fifth decade or above of their life and commonly presented with pain and discomfort in the abdomen, head, and neck regions. Prodromal symptoms were consistent findings, and many patients had two to three comorbidities out of four common comorbidities, i.e., diabetes, hypertension, dyslipidemia, and substance abuse. A patient who is 50 years old or more, having comorbidities such as diabetes, hypertension, dyslipidemia, history of tobacco or marijuana usage, presenting with prodromal symptoms like shortness of breath, dizziness, fatigue, syncope, gastrointestinal discomfort or head/neck pain should be suspected for atypical MI.

An Updated and Focused Review on Heterocyclic Inhibitors for SARSCoV and SARS-CoV-2 3CLpro.

BACKGROUND: SARS-CoV and SARS-CoV-2 are exceedingly contagious and typically result in major respiratory illnesses (acute respiratory syndrome). The public health is facing enormous challenges across all the nations due to these newly emerging pathogens. Reliable and systematic examination of SARS-CoV and COVID-19 will assist in identifying infectious persons accurately. Based on the biological, chemical, and genetic link of SARS CoV-2 towards SARS-CoV, the recurrence of different anti-SARS-CoV natural drug molecules may be beneficial in the advancement of anti-COVID-19 herbal drug molecules. Here in this review, we evaluated SAR research that has recently been published as well as molecular docking analysis of previously synthesised compounds that have been targeted against SARS-CoV and SARS-CoV-2, respectively. This investigation might assist scientists in creating novel and revolutionary molecules that could target SAR-CoV-2. OBJECTIVES: The review highlights the heterocyclic inhibitors' ability to successfully inhibit SARSCoV and SARS-CoV-2. The meticulously described structure-activity relationship of potential SARS-CoV and SARS-CoV-2 inhibiting compounds has been addressed in this review. EVIDENCE ACQUISITION: We conducted a thorough literature assessment employing electronic databases for scientific articles highlighting potential heterocyclic inhibitors for SARS-CoVand SARSCoV- 2, published from 2010 to 2021. We recovered 415 articles, but only 220 were involved and conversed in this manuscript. The article apprehended appropriate research considering three areas: 1) SAR activity, 2) Molecular docking, and 3) Biological activity and future prospects on SARS-CoV-2. METHODS: The potential compounds with decent inhibitory activity have been discussed and reviewed along with their inhibition potential, expressed in terms of IC50 value. RESULTS: Heterocyclic scaffolds reflect an extensive spectrum of therapeutic activity and might function as an initiating concept for the designing and discovery of potential inhibitors for SARS-CoV and SARS-CoV-2 treatment. CONCLUSION: The points highlighted here may prove to be a vital tool for medicinal chemists working/ investigating more potent and efficacious scaffolds in treating SARS-CoV and SARS-CoV-2.

BPTF promotes the progression of distinct subtypes of breast cancer and is a therapeutic target.

Purpose: To assess the biomarker and functional role of the chromatin remodeling factor, bromodomain PHD finger transcription factor (BPTF), in breast cancer progression. Methods: BPTF copy number was assessed using fluorescence in situ hybridization. BPTF expression was regulated in breast cancer cells by shRNA/siRNA-mediated gene silencing and BPTF cDNA overexpression. The effects of regulating BPTF expression were examined on key oncogenic signaling pathways and on breast cancer cell proliferation, apoptosis, and cell cycle progression, as well as in xenograft models. The consequences of pharmacological bromodomain inhibition, alone or in combination with other targeted agents, on breast cancer progression were assessed in culture and in xenograft models. Results: BPTF copy number was gained in 34.1% and separately amplified in 8.2% of a breast cancer tissue cohort. Elevated BPTF copy number was significantly associated with increasing patient age and tumor grade and observed in both ER-positive and triple-negative breast cancer (TNBC) subtypes. BPTF copy number gain and amplification were also observed in The Cancer Genome Atlas (TCGA) breast cancer cohort. Stable shRNA-mediated silencing of BPTF significantly inhibited cell proliferation and induced apoptosis in TNBC and ER-positive human breast cancer cell lines. BPTF knockdown suppressed signaling through the phosphoinositide 3 kinase (PI3K) pathway, including reduced expression of phosphorylated AKT (Ser473), phosphorylated GSK-ß (Ser9), and CCND1. These findings were confirmed following transient BPTF knockdown by a distinct siRNA in TNBC and ER-positive breast cancer cells. Stable suppression of BPTF expression significantly inhibited the in vivo growth of TNBC cells. Conversely, BPTF cDNA overexpression in TNBC and ER-positive breast cancer cells enhanced breast cancer cell proliferation and reduced apoptosis. BPTF targeting with the bromodomain inhibitor bromosporine, alone or in combination with the PI3K pathway inhibitor gedatolisib, produced significant anti-tumor effects against TNBC cells in vitro and in vivo. Conclusion: These studies demonstrate BPTF activation in distinct breast cancer subtypes, identify pathways by which BPTF promotes breast cancer progression, and suggest BPTF as a rational target for breast cancer therapy.

Prognostic Significance of Serum Biochemistry Profile in Children With Severe Acute Malnutrition.

Background Malnutrition is a condition caused by defective nutrition in which either deficiency or excess of energy, protein, or micronutrients cause any measurable adverse effects on tissues/body form (body shape, size, composition), function, and clinical outcome. Children with a weight-for-height below -3 standard deviations (SD) of the mean based on the WHO standards have a high risk of death exceeding nine-fold that of children with a weight-for-height above 1 SD. In severe acute malnutrition (SAM) liver function tests, renal function tests, and serum electrolytes are deranged but their correlation with the prognosis is not well defined. So, there was a need for a study to know the prognostic significance. For this purpose, the current study was conducted in the pediatric ward of Uttar Pradesh University of Medical Sciences (UPUMS), Saifai, UP, India. Method This is an observational cross-sectional study conducted in the Department of Pediatrics, UPUMS (Saifai, UP, India) from January 2018 to July 2019 after approval from the institutional ethical committee. We enrolled 100 children with SAM who fulfilled the inclusion criterion after obtaining proper and well-informed consent. Result We studied children aged six to 59 months. The mean age of admitted patients in our study was nearly 24 months (24.18 months). The median age that was most common at the time of admission is nearly 1 year (13 months). In our study relation of serum sodium and serum potassium with the survival of SAM was found statistically significant. Conclusion Severe acute malnutrition is both a medical and social disorder. The risk of mortality increases as the severity of malnutrition increases. High-risk cases can be identified and can be treated aggressively and on a priority basis. Serum electrolyte disturbances in SAM are one of the most important predictors of the severity.

Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4.

Extra domain A of cellular fibronectin (FN-EDA) is known to cause insulin resistance, atherosclerosis, tissue fibrosis, ischemic stroke and exaggerated myocardial reperfusion injury through Toll-like receptor 4 (TLR4). However, the FN-EDA-TLR4 interacting site is not well established. Therefore, in-silico approaches have been used to study FN-EDA and TLR4 interactions at the interface. In the present study, molecular docking studies of FN-EDA with TLR4-myeloid differentiation factor 2 (MD2) heterodimer have been performed to unravel the FN-EDA-TLR4 interacting sequence. Furthermore, the modulatory role of FN-EDA adjacent domains FNIII(11) and FNIII(12) on its interaction with TLR4-MD2 was investigated. The results show that FN-EDA interacting sequence "SPEDGIRELF" selectively interacts with TLR4 directly near its central and C-terminal domain region. The regulatory domains, FN type III 11 facilitate and 12 impede the FN-EDA-TLR4 interaction. Furthermore, the molecular dynamic simulation studies confirmed that FN-EDA forms a stable complex with TLR4-MD2 heterodimer. In conclusion, FN-EDA interacts and forms a stable complex through its "SPEDGIRELF" sequence at the central and C-terminal domain region of TLR4. The revelation of FN-EDA and TLR4 interacting sites may help design novel therapeutics for drug discovery research.

Synthesis and biological evaluation of novel 2-azido muramyl dipeptide as NOD2 agonistic adjuvants.

Novel 2-Azido muramyl dipeptide was synthesized by the bio-isosteric replacement of the N-acetyl group of the muramic acid fragment with the azide functionality at the C2 position. In order to examine the effect of hydrophilic-lipophilic balance on the adjuvant activity, derivatives were synthesized by removing protecting groups sequentially to tune the polarity. Amongst five novel azido derivatives of MDP studied here, di- and mono-benzylated azido derivatives 10 and 11 exhibited good DENV specific antibody(IgG) response with Th1 polarization compared to parent compound Muramyl dipeptide (MDP) whereas all five new derivatives responded positively to NOD2 agonistic assays with compound 10 showing highest stimulation.

Nanonization of Magnoflorine-Encapsulated Novel Chitosan-Collagen Nanocapsules for Neurodegenerative Diseases: In Vitro Evaluation.

Neurodegeneration is one of the most common diseases in the aged population, characterized by the loss in the function of neuronal cells and their ultimate death. One of the common features in the progression of this type of diseases is the oxidative stress. Drugs which are currently being used have been found to show lateral side effects, which is partly due to their inefficiency to cross blood-brain barrier. Nanoencapsulation of bioactive compounds is a profound approach in this direction and has become a method of choice nowadays. This study involved the evaluation of the anti-oxidative properties of magnoflorine (MF), which is an aporphine quaternary alkaloid, and synthesis of MF-loaded chitosan-collagen nanocapsules (MF-CCNc) for its better efficacy as a potent anti-oxidant. Physiochemical characterization of the synthesized nanocapsules was done by using dynamic light scattering and transmission electron microscopy. It revealed that the synthesized nanocapsules are of small size range, as small as 12 ± 2 nm, and are more or less of spherical shape. Sustained release was shown by MF in the in vitro drug release studies. Both MF and MF-CCNc were found to have good anti-oxidant potential with IC50 < 25 µg/mL. No major cytotoxicity was shown by the synthesized nanocapsules on SH-SY5Y cells. In silico anti-acetylcholinesterase (AChE) studies were also done, and they revealed that MF can be a potent inhibitor of AChE.

Current Status of Novel Pyridine Fused Derivatives as Anticancer Agents: An Insight into Future Perspectives and Structure Activity Relationship (SAR).

Cancer is a heterogeneous disease characterized by an abnormal and uncontrolled division of the cells leading to tumors that invade the adjacent normal tissues. After cardiovascular diseases, it is the second most prevalent disease accounting for one in every six deaths worldwide. This alarming rate thus, demands an urgent need to investigate more effective drugs to combat the said disease. Oxygen and nitrogen-based heterocyclic compounds have shown remarkable therapeutic activity towards several diseases, including cancer. In this review, we have attempted to summarize the work done in the last decade (2009-2019), highlighting the anticancer activity of pyrido fused fivemembered heterocyclic ring derivatives. Additionally, we have focused on seven heterocyclic pyridine fused rings: Imidazopyridine, Triazolopyridine, Pyrrolopyridine, Pyrazolopyridines, Thienopyridine, and Isoxazolopyridine. A total of forty-nine compounds have been studied based on their invitro cytotoxic activity and their structure-activity relationship, underlining the anticancer activity of their various pharmacophores and substituents. This review, therefore, aims to draw the attention of the researchers worldwide towards the enormous scope of development of heterocyclic drug compounds, focussing mainly on pyrido fused five-membered heterocyclic rings as anticancer drugs.

GPR119 agonists: Novel therapeutic agents for type 2 diabetes mellitus.

Diabetes mellitus type 2 (T2D) is a group of genetically heterogeneous metabolic disorders whose frequency has gradually risen worldwide. Diabetes mellitus Type 2 (T2D) has started to achieve a pandemic level, and it is estimated that within the next decade, cases of diabetes might get double due to increase in aging population. Diabetes is rightly called the 'silent killer' because it has emerged to be one of the major causes, leading to renal failure, loss of vision; besides cardiac arrest in India. Thus, a clinical requirement for the oral drug molecules monitoring glucose homeostasis appears to be unmet. GPR119 agonist, a family of G-protein coupled receptors, usually noticed in ß-cells of pancreatic as well as intestinal L cells, drew considerable interest for type 2 diabetes mellitus (T2D). GPR119 monitors physiological mechanisms that enhance homeostasis of glucose, such as glucose-like peptide-1, gastrointestinal incretin hormone levels, pancreatic beta cell-dependent insulin secretion and glucose-dependent insulinotropic peptide (GIP). In this manuscript, we have reviewed the work done in the last five years (2015-2020) which gives an approach to design, synthesize, evaluate and study the structural activity relationship of novel GPR119 agonist-based lead compounds. Our article would help the researchers and guide their endeavours in the direction of strategy and development of innovative, effective GPR119 agonist-based compounds for the management of diabetes mellitus type 2.

Novel 1,2,3-triazole-tethered Pam3CAG conjugates as potential TLR-2 agonistic vaccine adjuvants.

A focused library of water soluble 1,2,3-triazole tethered glycopeptide conjugates derived from variety of azido-monosaccharides and aliphatic azido-alcohols were synthesized through manipulation at the C-terminus of Pam3CAG and screened for their potential as TLR2 agonistic adjuvants against HBsAg antigen. In vitro ligand induced TLR2 signal activation was observed with all the analogues upon treatment with HEK blue TLR2 cell lines. Conjugate derived from ribose (6e), which exhibited pronounced HBsAg specific antibody (IgG) titer also shown enhanced CD8+ population indicating superior cell mediated immunity compared to standard adjuvant Pam3CSK4. Further, docking studies revealed ligand induced heterodimerization between TLR1 and 2. Overall, the result indicates the usefulness of novel conjugates as potential vaccine adjuvant.

Bilateral Pneumonia in a Patient with Chronic Bronchiectasis Caused by Achromobacter xylosoxidans Subspecies denitrificans.

Achromobacter xylosoxidans is a gram-negative bacillus that has a multitude of inherent and acquired antimicrobial resistance. It is a rare, isolated pathogen in patients without cystic fibrosis (CF). We report the case of a 76-year-old Caucasian male with a history of chronic obstructive pulmonary disease (COPD), previous Mycobacterium-avium intracellulare (MAI) infection, and chronic bronchiectasis who did not respond to three courses of outpatient antibiotics for a chronic cough. He also had a 21-lb weight loss. The diagnosis of Achromobacter xylosoxidans subspecies denitrificans was made through bronchoscopy with bronchoalveolar lavage (BAL). There are few case reports describing Achromobacter xylosoxidans subspecies denitrificans in non-CF patients. Achromobacter xylosoxidans colonization might be linked to predisposing lung damage such as in CF and bronchiectasis. The bacterium is frequently multidrug-resistant. More studies are needed to develop recommendations for clinical guidelines to address the increasing antibiotic resistance to Achromobacter xylosoxidans.

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4-b)indoles.

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED50 = 28.36 µmol/kg po in mice) showed improved inhibition for collagen (IC50 = 6.7 µM), CRP-XL (IC50 = 53.5 µM), and convulxin (CVX) (IC50 = 5.7 µM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC50 = 10.4 µM; CRP-XL, IC50 = 158 µM; CVX, IC50 = 11 µM) than any of its enantiomers S (6c) (collagen, IC50 = 25.3 µM; CRP-XL, IC50 = 181.4 µM; CVX, IC50 = 9 µM) and R (6d) (collagen, IC50 = 126.3 µM; CRP-XL, IC50 > 500 µM; CVX, IC50 = 86.8 µM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.

Organocatalyzed asymmetric Michael addition by an efficient bifunctional carbohydrate-thiourea hybrid with mechanistic DFT analysis.

A series of thiourea based bifunctional organocatalysts having d-glucose as a core scaffold were synthesized and examined as catalysts for the asymmetric Michael addition reaction of aryl/alkyl trans-ß-nitrostyrenes over cyclohexanone and other Michael donors having active methylene. Excellent enantioselectivities (<95%), diastereoselectivities (<99%), and yields (<99%) were attained under solvent free conditions using 10 mol% of 1d0. The obtained results were explained through DFT calculations using the B3LYP/6-311G(d,p)//B3LYP/6-31G(d) basic set. The QM/MM calculations revealed the role of cyclohexanone as a solvent as well as reactant in the rate determining step imparting 31.91 kcal mol-1 of energy towards the product formation.

A TICT based NIR-fluorescent probe for human serum albumin: a pre-clinical diagnosis in blood serum.

A TICT based NIR-fluorescent probe 3 has been designed and synthesized, which selectively detects HSA with fluorescence enhancement in blood plasma with a detection limit of 11 nM among the various proteins, nucleotides and thiols tested.

Angiotensin-converting enzyme gene insertion/deletion polymorphism studies in Asian Indian pregnant women biochemically identifies gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is defined as glucose intolerance first recognized during pregnancy. Insertion/deletion (I/D) polymorphism of a 287 bp Alu repetitive sequence in intron 16 of the angiotensin-converting enzyme (ACE) gene has been widely investigated in Asian Indian populations with different ethnic origins. The present study examined possible association between I/D polymorphism of the ACE gene and GDM in Asian Indian pregnant women. METHODS: A total of 200 pregnant women (100 GDM and 100 non-GDM) were recruited in this study and I/D polymorphism of a 287 bp Alu1 element inside intron 16 of the ACE gene was examined by polymerase chain reaction (PCR)-based gel electrophoresis. RESULT: The distribution of the variants like II, ID, and DD genotypes of ACE gene showed differences between normal GDM versus non-GDM subjects, and the frequency of the ID+ DD Vs II genotype was significant (p=0.0002) in the GDM group. CONCLUSION: ACE gene polymorphism was associated with GDM in Asian Indian pregnant women.

Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: a pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues.

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.