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Outbreaks of Monkeypox (mpox) in over 100 non-endemic countries in 2022 represented a serious global health concern. Once a neglected disease, mpox has become a global public health issue. A42R profilin-like protein from mpox (PDB ID: 4QWO) represents a potential new lead for drug development and may interact with various synthetic and natural compounds. In this report, the interaction of A42R profilin-like protein with six phytochemicals found in the medicinal plant Ficus religiosa (abundant in India) was examined. Based on the predicted and compared protein–ligand binding energies, biological properties, IC50 values and toxicity, two compounds, kaempferol (C-1) and piperine (C-4), were selected. ADMET characteristics and quantitative structure–activity relationship (QSAR) of these two compounds were determined, and molecular dynamics (MD) simulations were performed. In silico examination of the kaempferol (C-1) and piperine (C-4) interactions with A42R profilin-like protein gave best-pose ligand-binding energies of –6.98 and –5.57 kcal/mol, respectively. The predicted IC50 of C-1 was 7.63 μM and 82 μM for C-4. Toxicity data indicated that kaempferol and piperine are non-mutagenic, and the QSAR data revealed that piperlongumine (5.92) and piperine (5.25) had higher log P values than the other compounds examined. MD simulations of A42R profilin-like protein in complex with C-1 and C-4 were performed to examine the stability of the ligand–protein interactions. As/C and C-4 showed the highest affinity and activities, they may be suitable lead candidates for developing mpox therapeutic drugs. This study should facilitate discovering and synthesizing innovative therapeutics to address other infectious diseases. [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2) inhibitors are nonsteroidal anti-inflammatory drugs that treat inflammation, pain and fever. This study determined the interaction mechanisms of COX-2 inhibitors and the molecular properties needed to design new drug candidates. Using machine learning and explainable AI methods, the inhibition activity of 1488 molecules was modelled, and essential properties were identified. These properties included aromatic rings, nitrogen-containing functional groups and aliphatic hydrocarbons. They affected the water solubility, hydrophobicity and binding affinity of COX-2 inhibitors. The binding mode, stability and ADME properties of 16 ligands bound to the Cyclooxygenase active site of COX-2 were investigated by molecular docking, molecular dynamics simulation and MM-GBSA analysis. The results showed that ligand 339,222 was the most stable and effective COX-2 inhibitor. It inhibited prostaglandin synthesis by disrupting the protein conformation of COX-2. It had good ADME properties and high clinical potential. This study demonstrated the potential of machine learning and bioinformatics methods in discovering COX-2 inhibitors. This study uses machine learning, bioinformatics and explainable artificial intelligence (XAI) methods to discover and design new drugs that can reduce inflammation by inhibiting COX-2. The activity and properties of various molecules are modelled and analysed. The best molecule is selected, and its interaction with the enzyme is investigated. The results show how this molecule can block the enzyme and prevent inflammation. XAI methods are used to explain the molecular features and mechanisms involved. [ABSTRACT FROM AUTHOR]

The Hantaan virus (HTN) is a member of the hantaviridae family. It is a segmented type, negative-strand virus (sNSVs). It causes hemorrhagic fever with renal syndrome, which includes fever, vascular hemorrhage, and renal failure. This illness is one of the most serious hemorrhagic diseases in the world, and it is a major public health concern due to its high mortality rate. The Hantaan virus RNA-dependent RNA polymerase complex (RdRp) is involved in viral RNA transcription and replication for the survival and transmission of this virus. Therefore, it is a primary target for antiviral drug development. Interference with the endonucleolytic "cap-snatching" reaction by the HTN virus RdRp endonuclease domain is a particularly appealing approach for drug discovery against this virus. This RdRp endonuclease domain of the HTN virus has a metal-dependent catalytic activity. We targeted this metal-dependent enzymatic activity to identify inhibitors that can bind and disrupt this endonuclease enzyme activity using in-silico approaches i.e., molecular docking, molecular dynamics simulation, predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) and drug-likeness studies. The docking studies showed that peramivir, and ingavirin compounds can effectively bind with the manganese ions and engage with other active site residues of this protein. Molecular simulations also showed stable binding of these ligands with the active site of HTN RdRp. Simulation analysis showed that they were in constant contact with the active site manganese ions and amino acid residues of the HTN virus endonuclease domain. This study will help in better understanding the HTN and related viruses. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening multiple-organ injury caused by disordered host immune response to microbial infection. However, the correlation between gut microbiota dysbiosis and immune indicators remains unexplored. To address this gap in knowledge, we carried out 16 S rDNA sequencing, analyzed clinical fecal samples from children with sepsis (n = 30) and control children (n = 25), and obtained immune indicators, including T cell subtypes (CD3+, CD3+CD4+, CD3+CD8+, and CD4/CD8), NK cells, cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ), and immunoglobulin indices (IgA, IgE, IgM and IgG). In addition, we analyzed the correlation between gut microbiota dysbiosis and immune indicators, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. We found that children with sepsis exhibited gut bacterial dysbiosis and low alpha diversity. The Spearman's rank correlation coefficient suggested that Rhodococcus erythropolis had a significantly positive correlation with IFN-γ and CD3+ T cells. Klebsiella pneumoniae and Streptococcus mitis were significantly correlated with NK cells. Bacteroides uniformis was significantly positively correlated with IgM and erythrocyte sedimentation rate, and Eubacterium eligens was significantly positively correlated with IL-4 and CD3+CD8+ T cells. The biomarkers discovered in this study had strong discriminatory power. These changes in the gut microbiome may be closely related to immunologic dysfunction and to the development or exacerbation of sepsis. However, a large sample size is required for verification. [ABSTRACT FROM AUTHOR]

Metformin is a regularly prescribed and low-cost generic medication. Metformin has been proposed as a target for Dipeptidyl-peptidase 4 (DPP4) expression in various clinical disorders. We provide insilco investigations on molecular docking and dynamic modeling of metformin and DPP4 potential interactions. Moreover, we conducted bioinformatic studies to highlight the clinical significance of DPP4 expression and mutation in various types of malignancies, as well as the invasion of different immune cells into the tumor microenvironment. We believe the present proposal's findings have crucial implications for understanding how metformin may confer health advantages by targeting DPP4 expression in malignancies. [ABSTRACT FROM AUTHOR]

The azo ligand obtained from the diazotization reaction of 2-aminobenzothiazole and 4-nitroaniline yielded a novel series of complexes with Co(II), Ni(II), Cu(II), and Zn(II) ions. The complexes were investigated using spectral techniques such as UV-Vis, FT-IR, 1H and 13C NMR spectroscopic analyses, LC-MS and atomic absorption spectrometry, electrical conductivity, and magnetic susceptibility. The molar ratio of the synthesized compounds was determined using the ligand exchange ratio, which revealed the metal-ligand ratios in the isolated complexes were 1:2. The synthesized complexes were tested for antimicrobial activity against S. aureus, E. coli, C. albicans, and C. tropicalis bacterial species. Additionally, their binding affinities were predicted using molecular docking analysis, and their pharmacokinetic and drug-likeness properties were evaluated. [ABSTRACT FROM AUTHOR]

Janus kinase 3 (JAK3, NP_000206.2) is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction JAK/STAT pathway. JAK3 gene variants can lead to autosomal recessive severe combined immunodeficiency (SCID), which is T-cell-negative, B-cell-positive, and NK-cell-negative (OMIM: 600802). We have detected one infant suffering from cytomegalovirus, fever, and impaired respiratory function with low lymphocytes and immunoglobulin. Two compound heterozygous variants, c.1914G>T (p.L638=) and c.1048C>T (p.R350W), were identified in the proband, each of which was inherited from one unaffected parent. Analysis of splicing was carried out by the Sanger sequencing and RT-PCR from peripheral blood and a minigene splicing assay which both showed a deletion of exon 14 (128 bp) resulting from the c.1914G>T variant at the mRNA level. Bioinformatic analysis for the reported c.1048C>T (p.R350W) variant suggests that the variant is pathogenic. Based on the clinical characteristics of the patient and the functional verification of the gene variants, our pediatricians finally have diagnosed the infant as SCID (OMIM: 600802). The study is the first study regarding a synonymous variant of JAK3 gene influencing alternative splicing. Our findings expand the mutation spectrum leading to JAK3 deficiency-related diseases and provide exact information for genetic counseling. [ABSTRACT FROM AUTHOR]

Background: Acute necrotizing encephalopathy (ANE) is a devastating neurologic condition that can arise following a variety of systemic infections, including influenza and SARS-Cov-2. The clinical features of COVID-19-associated ANE in pediatric patients based on multi-case data have not yet been described and remain obscure. We reviewed 12 pediatric patients to better describe the clinical features of ANE with COVID-19. Methods: We retrospectively collected and summarized the clinical features of ANE in children with COVID-19. Clinical data were collected from 12 children, including their general status, clinical symptoms, laboratory tests, and neuroimaging features. Results: Among the subjects, 10 were over 5 years old and they accounted for 83.33%. A large percentage of those affected (66.67%) were females. The major manifestations included fever (100%), impaired consciousness (100%), and convulsions (75%). We determined that increased interleukin (IL)-6 and IL-10, and tumor necrosis factor-α and interferon gamma were not predictive of severe ANE and mortality in children with COVID-19 in this study. All children presented with abnormal neuroimaging with multiple and symmetrically distributed lesions, involving the thalamus, basal ganglia, cerebellum, and brain hemispheres. Eight of the 12 children died, resulting in a mortality rate of 66.67%, and 75% of these children were females. Importantly, we found the timely administration of mannitol after an acute onset of convulsions or disturbance of consciousness may be decreased the high mortality induced by ANE children with COVID-19. Conclusion: COVID-19 associated with ANE in children is characterized by sudden symptom onset, rapid disease progression, and high mortality. [ABSTRACT FROM AUTHOR]

Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from −5.5 kcal/mol to −6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from −7.5 kcal/mol to −9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = −9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a WHO Grade IV tumor with poor visibility, a high risk of comorbidity, and exhibit limited treatment options. Resurfacing from second-rate glioma was originally classified as either mandatory or optional. Recent interest in personalized medicine has motivated research toward biomarker stratification-based individualized illness therapy. GBM biomarkers have been investigated for their potential utility in prognostic stratification, driving the development of targeted therapy and customizing therapeutic treatment. Due to the availability of a specific EGFRvIII mutational variation with a clear function in glioma-genesis, recent research suggests that EGFR has the potential to be a prognostic factor in GBM, while others have shown no clinical link between EGFR and survival. The pre-existing pharmaceutical lapatinib (PubChem ID: 208,908) with a higher affinity score is used for virtual screening. As a result, the current study revealed a newly screened chemical (PubChem CID: 59,671,768) with a higher affinity than the previously known molecule. When the two compounds are compared, the former has the lowest re-rank score. The time-resolved features of a virtually screened chemical and an established compound were investigated using molecular dynamics simulation. Both compounds are equivalent, according to the ADMET study. This report implies that the virtual screened chemical could be a promising Glioblastoma therapy. [ABSTRACT FROM AUTHOR]

Repurposing natural compounds as inhibitory targets to combat bacterial virulence is an important potential strategy to overcome resistance to traditional antibiotics, in the present study, the antibacterial activity of micro-curcumin and nano-sized curcumin was investigated against four predominant bacterial pathogens, namely, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis. Curcumin bactericidal susceptibility could be summarized as the order, P. aeruginosa > B. subtilis > S. aureus > E. coli. Molecular docking analysis was conducted to confirm the impact of curcumin on the most vital and positively identified quorum-sensing pathway signaling proteins SecA-SecY, LsrR, PqsR (MvfR), AgrA which act as key players in the bacterial communication systems. The in silico physicochemical properties revealed that curcumin as a nutraceutical can be classified as a drug-like compound. An in vivo infected wound model was employed in four groups of albino rats. Topical application of nano-curcumin lotion showed a marked reduction in wound area (98.8%) as well as nearly 100% reduction in total bacterial viable count compared to the control group, on the fifteenth day post-treatment post-injury. The obtained data suggested that curcumin nanoparticles exhibited superior antibacterial activity and may possess clinical utility as a novel topical antimicrobial and wound healing agent. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX) and Lipoxygenase (LOX) are essential enzymes for arachidonic acid (AA) to eicosanoids conversion. These AA-derived eicosanoids are essential for initiating immunological responses, causing inflammation, and resolving inflammation. Dual COX/5-LOX inhibitors are believed to be promising novel anti-inflammatory agents. They inhibit the synthesis of prostaglandins (PGs) and leukotrienes (LTs), but have no effect on lipoxin formation. This mechanism of combined inhibition circumvents certain limitations for selective COX-2 inhibitors and spares the gastrointestinal mucosa. Natural products, i.e. spice chemicals and herbs, offer an excellent opportunity for drug discovery. They have proven anti-inflammatory properties. However, the potential of a molecule to be a lead/ drug candidate can be much more enhanced if it has the property of inhibition in a dual mechanism. Synergistic activity is always a better option than the molecule's normal biological activity. Herein, we have explored the dual COX/5-LOX inhibition property of the three major potent phytoconsituents (curcumin, capsaicin, and gingerol) from Indian spices using in silico tools and biophysical techniques in a quest to identify their probable inhibitory role as anti-inflammatory agents. Results revealed the dual COX/5-LOX inhibitory potential of curcumin. Gingerol and capsaicin also revealed favorable results as dual COX/5-LOX inhibitors. Our results are substantiated by target similarity studies, molecular docking, molecular dynamics, energy calculations, DFT, and QSAR studies. In experimental inhibitory (in vitro) studies, curcumin exhibited the best dual inhibitory activities against COX-1/2 and 5-LOX enzymes. Capsaicin and gingerol also showed inhibitory potential against both COX and LOX enzymes. In view of the anti-inflammatory potential these spice chemicals, this research could pave the way for more scientific exploration in this area for drug discovery. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and have been linked to immunosuppression and poor prognosis. TAMs have been shown to be harmful in ovarian cancer (OC), with a positive correlation between their high levels of tumors and poor overall patient survival. These cells are crucial in the progression and chemoresistance of OC. The primary pro-tumoral role of TAMs is the release of cytokines, chemokines, enzymes, and exosomes that directly enhance the invasion potential and chemoresistance of OC by activating their pro-survival signalling pathways. TAMs play a crucial role in the metastasis of OC in the peritoneum and ascities by assisting in spheroid formation and cancer cell adhesion to the metastatic regions. Furthermore, TAMs interact with tumor protein p53 (TP53), exosomes, and other immune cells, such as stem cells and cancer-associated fibroblasts (CAFs) to support the progression and metastasis of OC. In this review we revisit development, functions and interactions of TAMs in the TME of OC patients to highlight and shed light on challenges and excitement down the road. [ABSTRACT FROM AUTHOR]

A series of novel guanidines (6 a–j) was synthesized from corresponding thioureas using catalytic mercuric chloride in DMF. The synthesized compounds were characterized by spectroscopic techniques and appraised for Jack Bean Urease (JBU) inhibition. All compounds (6 a–j) exhibited strong potential against JBU whilst compound 6 b (IC50=0.0155±0.00087 μM) and 6 e (IC50=0.0091±0.00036 μM) displayed excellent urease inhibition compared to thiourea (IC50=18.27 μM) used as reference. The kinetic mechanism analyzed by Lineweaver‐Burk plots revealed that 6 b is a mixed‐type inhibitor while 6 e is a non‐competitive inhibitor. Thus, compounds 6 e and 6 b can serve as a structural model for the designing of super‐effective urease inhibitors. Binding affinity and interaction of N‐aryl guanidine analogs were evaluated through molecular docking studies. To evaluate the residual flexibility of receptor through MD simulation, RMSD and RMSF graphs were evaluated to determine the protein structural behavior. It is implied that compound 6 e can serve as a novel molecular template to medicinal chemists for designing more potent urease inhibitors. [ABSTRACT FROM AUTHOR]

The discovery of antiviral approaches to prevent or cure respiratory syncytial virus (RSV) infections is critical, particularly because RSV is one of the most common causes of infant respiratory problems. There is currently no approved vaccination available to treat RSV infections. FDA has approved the drug ribavirin, but it is not sufficient to treat RSV. This work aimed to find and study in silico anti-RSV drugs that target matrix protein and nucleoprotein. In this study, we have identified five drug candidates that had better binding energies than ribavirin. Garenoxacin appeared as top lead compounds between them. AutoDock Vina was used to execute molecular docking of a library of chosen chemicals. The high-score compound was then confirmed using the Maestro 12.3 module's molecular dynamics simulation and the binding energies derived using Prime/Molecular Mechanics Generalized Born Surface Area (Prime/MM-GBSA). Comparative molecular dynamics simulations revealed that garenoxacin has better stability and high residue contacts with high binding affinity than ribavirin. This study showed garenoxacin could prevent RSV infection better than ribavirin. In pursuing a more effective RSV control drug, additional research into these chemicals in vitro and in vivo is essential. [ABSTRACT FROM AUTHOR]

In this study, a hybrid compound library of 72 phytocompounds from two antiviral medicinal plants (Baccaurea ramiflora and Bergenia ciliata) was computationally investigated for their inhibitory potential against SARS-CoV-2 Mpro. Molecular docking showed that 6-O-vanilloylicariside B5, 6-O-vanilloylisotachioside, leucoanthocyanidin 4-(2-galloyl), and p-hydroxybenzoyl bergenin has good binding affinity for Mpro. However, p-hydroxybenzoyl bergenin did not bind at the catalytic cavity. The RMSD and RMSF data obtained from 100 ns MD simulations revealed stable protein–ligand complexes for 6-O-vanilloylicariside B5, 6-O-vanilloylisotachioside, leucoanthocyanidin 4-(2-galloyl). Ligand trajectory study found 6-O-vanilloylisotachioside and leucoanthocyanidin 4-(2-galloyl) to be stable. Studies on ligand interaction profile and timeline interaction profile showed that 6-O-vanilloylisotachioside and leucoanthocyanidin 4-(2-galloyl) interacted with HIS41–CYS145 dyad and other crucial amino acids of the catalytic site cavity during the entire 100 ns MD simulations. Molecular mechanics generalized born solvent accessibility binding free energy calculations, density functional theory analysis, quantitative structure–property relationship studies, and ADMET profiling of 6-O-vanilloylisotachioside and leucoanthocyanidin 4-(2-galloyl) supported the results generated by molecular docking and MD simulations studies. Based on the current computational investigations, we conclude that that 6-O-vanilloylisotachioside of B. ramiflora and leucoanthocyanidin 4-(2-galloyl) of B. ciliata are two potential inhibitors of SARS-CoV-2 Mpro that are worthy of further investigations. [ABSTRACT FROM AUTHOR]

The spectroscopic, solvent effects, reactivity and MD simulations of N'-[(1E)-(2,6-dichlorophenyl-methylidene]adamantane-1-carbohydrazide (DMC) are reported. Solvation free energies of DMC in chloroform, ethanol and acetonitrile are −21.96, −24.39 and −12.31 kcal/mol and ethanol may be better for the solubilization. Electron donating and electron accepting powers are somewhat lower in solution, revealing a certain increase in the tendency to receiving electrons and a decrease in donate electrons in solution, except in acetonitrile, in which showed slightly higher values then in vacuum. ALIE surface show that regions where low energy is required to remove electrons are on benzene ring, chlorine atoms and N5. DMC is forming good contacts with protein's binding site residues and is important in the complex's stability showing antiviral activity. [ABSTRACT FROM AUTHOR]

Lam16A is a novel GH16 β-1,3–1,4-lichenase isolated from the genus Caldicellulosiruptor which can utilize untreated carbohydrate components of plant cell walls. Its catalytic module has been characterized that the six carbohydrate-binding modules (CBMs) were queued in the C-terminus, but their roles were still unclear. Here, full-length and CBM-truncated mutants of Lam16A were purified and characterized through heterologous expression in Escherichia coli. The profiles of these proteins, including the enzyme activity, degrading efficiency, substrate-binding affinity, and thermostability, were explored. Full-length Lam16A with six CBMs showed excellent thermostability and the highest activity against barley β-glucan and laminarin with optimum pH of 6.5. The CBMs stimulated degrading ability of the catalytic module, especially against β-1,3(4)-glucan-based polysaccharides. The released products from β-1,3–1,4-glucan by Lam16A or its truncated mutants revealed an endo-type glycoside hydrolase. Lam16As exhibited strong binding affinities to the insoluble polysaccharides, especially Lam16A-1CBM. The degradation of yeast cell walls by Lam16A enzyme solution relative to the control reduced the absorbance values at OD800 by ~ 85% ± 1.2, enabling the release of up to ~ 0.057 ± 0.0039 µg/mL of the cytoplasmic protein into the supernatant, lowering the viability of the cells by ~ 70.3% ± 6.9, thus causing significant damage in the cell wall structure. Taken together, CBMs could influence the substrate specificity, thermal stability, and binding affinity of β-1,3–1,4-glucanase. These results demonstrate the great potential of these enzymes to promote the bioavailability of β-1,3-glucan oligosaccharides for health benefits. Key points: • Carbohydrate-binding modules strongly influenced the enzyme activity and binding affinity, and further impacted glycoside hydrolase activity. • Lam16A enzymes have sufficient ability to hydrolyze β-1,3–1,4-glucan-based polysaccharides. • Lam16As provide a powerful tool to promote the bioavailability of β-1,3-glucan oligosaccharides. [ABSTRACT FROM AUTHOR]

Even the most effective targeted medicines or debulking surgery may not always result in a full tumor response, leaving patients with residual disease and tumor growth that restricts patient survival. By utilizing MEXPRESS, we investigated the influence of residual HGSOC tumors on patients' overall survival and CTLA-4 expression in residual HGSOC tumors. Keywords: Ovarian cancer; High-grade serous; Debulking surgery; CTLA-4; Residual tumors EN Ovarian cancer High-grade serous Debulking surgery CTLA-4 Residual tumors 2281 2283 3 10/26/23 20231101 NES 231101 To the Editor, Ovarian Cancer (OC) is a global concern, and according to Globocan 2020 projections, the number of women diagnosed with OC worldwide would increase by over 42% by 2040. [Extracted from the article]

We investigated single-cell transcriptomics for LPL and GPIHBP1 expression levels in individual cells by detecting RNA concentration using a single-cell portal https://singlecell.broadinstitute.org/single cell Author contributions AAE-A and ZG: designed the idea and writing the original draft preparation. To the Editor: The current worldwide coronavirus disease epidemic is caused by COVID-19 (SARS-CoV-2), a novel coronavirus structurally linked to the virus that causes severe acute respiratory syndrome (SARS). Substantially, Lipoprotein Lipase (LPL) is the primary enzyme responsible for hydrolyzing circulating triglycerides (TG) and releasing free fatty acids for utilization as energy by the heart muscle. [Extracted from the article]

Massive intra-articular infiltration of proinflammatory macrophages is a prominent feature of rheumatoid arthritis (RA) lesions, which are thought to underlie articular immune dysfunction, severe synovitis and ultimately joint erosion. Here we report an efferocytosis-informed nanoimitator (EINI) for in situ targeted reprogramming of synovial inflammatory macrophages (SIMs) that thwarts their autoimmune attack and reestablishes articular immune homeostasis, which mitigates RA. The EINI consists of a drug-based core with an oxidative stress-responsive phosphatidylserine (PtdSer) corona and a shell composed of a P-selectin-blocking motif, low molecular weight heparin (LMWH). When systemically administered, the LMWH on the EINI first binds to P-selectin overexpressed on the endothelium in subsynovial capillaries, which functions as an antagonist, disrupting neutrophil synovial trafficking. Due to the strong dysregulation of the synovial microvasculature, the EINI is subsequently enriched in the joint synovium where the shell is disassembled upon the reactive oxygen species stimulation, and PtdSer corona is then exposed. In an efferocytosis-like manner, the PtdSer-coroneted core is in turn phagocytosed by SIMs, which synergistically terminate SIM-initiated pathological cascades and serially reestablish intra-articular immune homeostasis, conferring a chondroprotective effect. These findings demonstrate that SIMs can be precisely remodeled via the efferocytosis-mimetic strategy, which holds potential for RA treatment. Proinflammatory macrophages are involved in rheumatoid arthritis (RA). Here the authors use an efferocytosis-mimetic self-deliverable nanoimitator to mitigate RA by targeted reprogramming of synovial inflammatory macrophages, reducing proinflammatory cytokines and reinstating articular immune homeostasis. [ABSTRACT FROM AUTHOR]

Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent coronavirus disease 2019 (COVID-19) battle. Objecting the conserved SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN) together using one ligand is a successful new tactic to stop SARS-CoV-2 multiplication and COVID-19 progression. The current comprehensive study investigated most nucleoside analogs (NAs) libraries, searching for the most ideal drug candidates expectedly able to act through this double tactic. Gradual computational filtration afforded six different promising NAs, riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir. Further biological assessment proved that riboprine and forodesine are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of about 0.21 and 0.45 μM for riboprine and about 0.23 and 0.70 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. These biochemical findings were supported by the prior in silico data. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading. These findings suggest that riboprine and forodesine could serve as prospective lead compounds against COVID-19. [ABSTRACT FROM AUTHOR]

Ravenala madagascariensis is a widely known ornamental and medicinal plant, but with a dearth of scientific investigations regarding its phytochemical and pharmacological properties. Hence, these properties were appraised in this study. The DPPH (154.08 ± 2.43 mgTE/g), FRAP (249.40 ± 3.01 mgTE/g), CUPRAC (384.57 ± 1.99 mgTE/g), metal chelating (29.68 ± 0.74 mgEDTAE/g) and phosphomolybdenum assay (2.38 ± 0.07 mmolTE/g) results demonstrated that the aqueous extract had the most prominent antioxidant activity, while the methanolic extract displayed the best antioxidant potential in the ABTS assay (438.46 ± 1.69 mgTE/g). The HPLC-ESI-Q-TOF-MS-MS analysis allowed the characterization of 41 metabolites. The methanolic extract was the most active against acetylcholinesterase. All extracts were active against the alpha-amylase and alpha-glucosidase enzymes, with the ethyl acetate extract being the most active against the alpha-amylase enzyme, while the methanolic extract showed the best alpha-glucosidase inhibition. A plethora of metabolites bonded more energetically with the assayed enzymes active sites based on the results of the in silico studies. R. madagascariensis extracts used in this study exhibited cytotoxicity against HT29 cells. The IC50 of the methanolic extract was lower (506.99 ug/mL). Based on the heat map, whereby flavonoids were found to be in greater proportion in the extracts, it can be concluded that the flavonoid portion of the extracts contributed to the most activity. [ABSTRACT FROM AUTHOR]

Given the rapid progression of the coronavirus disease 2019 (COVID‐19) pandemic, an ultrafast response was urgently required to handle this major public crisis. To contain the pandemic, investments are required to develop diagnostic tests, prophylactic vaccines, and novel therapies. Lately, nucleoside analog (NA) antivirals topped the scene as top options for the treatment of COVID‐19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections. Meanwhile, the continuous generation of new lineages of the SARS‐CoV‐2 Omicron variant caused a new challenge in the persistent COVID‐19 battle. Hitting the two crucial SARS‐CoV‐2 enzymes RNA‐dependent RNA polymerase (RdRp) and 3'‐to‐5' exoribonuclease (ExoN) collectively together using only one single ligand is a very successful new approach to stop SARS‐CoV‐2 multiplication and combat COVID‐19 irrespective of the SARS‐CoV‐2 variant type because RdRps and ExoNs are broadly conserved among all SARS‐CoV‐2 strains. Herein, the current comprehensive study investigated most NAs libraries, searching for the most ideal drug candidates expectedly able to perfectly act through this double tactic. Gradual computational filtration gave rise to six different promising NAs, which are riboprine, forodesine, tecadenoson, nelarabine, vidarabine, and maribavir, respectively. Further biological assessment proved for the first time, using the in vitro anti‐RdRp/ExoN and anti‐SARS‐CoV‐2 bioassays, that riboprine and forodesine, among all the six tested NAs, are able to powerfully inhibit the replication of the new virulent strains of SARS‐CoV‐2 with extremely minute in vitro anti‐RdRp and anti‐SARS‐CoV‐2 EC50 values of about 0.22 and 0.49 μM for riboprine and about 0.25 and 0.73 μM for forodesine, respectively, surpassing both remdesivir and the new anti‐COVID‐19 drug molnupiravir. The prior in silico data supported these biochemical findings, suggesting that riboprine and forodesine molecules strongly hit the key catalytic pockets of the SARS‐CoV‐2 (Omicron variant) RdRp′s and ExoN′s main active sites. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual‐action inhibitors of SARS‐CoV‐2 replication and proofreading, with their relatively flexible structures open for diverse types of chemical derivatization. In Brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two nucleosides riboprine and forodesine to effectively shut down the polymerase/exoribonuclease‐RNA nucleotides interactions of the SARS‐CoV‐2 Omicron variant and consequently treat COVID‐19 infections, motivating us to rapidly begin the two drugs′ broad preclinical/clinical anti‐COVID‐19 bioevaluations, hoping to combine both drugs soon in the COVID‐19 treatment protocols. [ABSTRACT FROM AUTHOR]

The antipsychotic drug Olanzapine was crystallized with aromatic acid, 2,5-dihydroxybenzoic acid in isopropyl alcohol by slow evaporation which led to the formation of olanzapinium 2,5-dihydroxybenzoate crystalline salt. The structure of the compound was characterized by 1H-NMR, 13C-NMR, and single-crystal X-ray diffraction analysis. The Hirshfeld analyses were performed to quantify the order and nature of intermolecular interactions in the crystal network. Employing computational approaches, the compound was tested for its affinity against antipsychotic activity by molecular docking and molecular dynamic simulation to attest the conformational stability over time step of 100 ns. Besides, bioactivity and ADMET properties were also predicted to ratify the result. The compound asserted neither carcinogenic nor mutagenic activity and has high oral bioavailability. Hence, this synthesized novel compound Olanzapinium 2,5-dihydroxybenzoate recognized in the study possesses high potential as an effective antipsychotic compound, and can further be examined for its efficiency by in vivo studies. The synthesized compound was submitted to NCBI PubChem database using accession substance ID: 441329256. The crystal structure was submitted to CCDC (Cambridge Crystallographic Data Centre) with submission ID: 2010899. [ABSTRACT FROM AUTHOR]

In present study, we used Olea europaea leaf extract to biosynthesize in situ Copper Oxide nanocrystals (CuO @OVLe NCs) with powerful antibacterial and anti-cancer capabilities. Physio-chemical analyses, such as UV/Vis, FTIR, XRD, EDX, SEM, and TEM, were applied to characterize CuO @OVLe NCs. The UV/Vis spectrum demonstrated a strong peak at 345 nm. Furthermore, FTIR, XRD, and EDX validated the coating operation's contact with colloidal CuO @OVLe NCs. According to TEM and SEM analyses, CuO @OVLe NCs exhibited a spherical shape and uniform distribution of size with aggregation, for an average size of ~75 nm. The nanoparticles demonstrated a considerable antibacterial effect against E. faecium bacterial growth, as well as an increased inhibition rate in a dose-dependent manner on the MCF-7, PC3, and HpeG2 cancer cell lines and a decreased inhibition rate on WRL-68. Molecular docking and MD simulation were used to demonstrate the high binding affinity of a ligand (Oleuropein) toward the lectin receptor complex of the outer membrane to vancomycin-resistant E. faecium (VREfm) via amino acids (Leu 195, Thr 288, His 165, and Ser 196). Hence, our results expand the accessibility of OVLe's bioactive components as a promising natural source for the manufacture of physiologically active components and the creation of green biosynthesis of metal nanocrystals. [ABSTRACT FROM AUTHOR]

Since its emergence in early 2019, the respiratory infectious virus, SARS-CoV-2, has ravaged the health of millions of people globally and has affected almost every sphere of life. Many efforts are being made to combat the COVID-19 pandemic's emerging and recurrent waves caused by its evolving and more infectious variants. As a result, novel and unexpected targets for SARS-CoV-2 have been considered for drug discovery. 2′-O-Methyltransferase (nsp10/nsp16) is a significant and appealing target in the SARS-CoV-2 life cycle because it protects viral RNA from the host degradative enzymes via a cap formation process. In this work, we propose prospective allosteric inhibitors that target the allosteric site, SARS-CoV-2 MTase. Four drug libraries containing ~119,483 compounds were screened against the allosteric site of SARS-CoV-2 MTase identified in our research. The identified best compounds exhibited robust molecular interactions and alloscore-score rankings with the allosteric site of SARS-CoV-2 MTase. Moreover, to further assess the dynamic stability of these compounds (CHEMBL2229121, ZINC000009464451, SPECS AK-91811684151, NCI-ID = 715319), a 100 ns molecular dynamics simulation, along with its holo-form, was performed to provide insights on the dynamic nature of these allosteric inhibitors at the allosteric site of the SARS-CoV-2 MTase. Additionally, investigations of MM-GBSA binding free energies revealed a good perspective for these allosteric inhibitor–enzyme complexes, indicating their robust antagonistic action on SARS-CoV-2 (nsp10/nsp16) methyltransferase. We conclude that these allosteric repressive agents should be further evaluated through investigational assessments in order to combat the proliferation of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene–laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient–derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell–specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies. Cavity-filled CARs drive out GBM: Glioblastoma multiforme (GBM) has a high rate of recurrence, which is in part due to residual tumor containing glioma stem cells (GSCs) after surgical debulking. To target these cells, Chen et al. have developed a cavity-injectable hydrogel that contains GSC-targeting nanoparticles able to create chimeric antigen receptor (CAR) macrophages in situ. They show that injection of hydrogel into preclinical humanized mouse models generate CAR macrophages in the resection cavity and prevent postoperative relapse. This represents a promising treatment for patients with GBM and warrants further clinical study. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the third most frequent cause of cancer worldwide and is more prevalent in older individuals of all ages. The recent statistics from World Health Organisation (WHO) on cancer accounted for 1.93 million new cases of colorectal cancer alone, in 2020[1]. The exact cause of this disease is still unknown; however, obesity, sedentary lifestyle, and changed food consumption habit are thought to be driving forces. Earlier clinical studies have found non-steroidal anti-inflammatory drugs (NSAIDs) to be potent in treating colorectal cancer by inhibiting cyclooxygenase enzyme, and further research ascertained cyclooxygenase-2 gene (COX-2) inhibitors to be the most effective chemotherapy treatment. The aim of this study is to find the most effective inhibitor with a superior affinity against COX-2 protein and its pharmacological profile. The pre-established compound, parecoxib (PubChem ID: 119828) was taken up for Structure-based Virtual Screening to identify a novel compound (PubChem ID: 10151468) that has a strong binding affinity than the established compound. Additionally, the comparative studies of both the screened and established compounds were examined using the MD simulation approach to confirm structural stability. Our conclusion suggests that the virtual screened compound (PubChem ID: 10151468) could be a potential therapeutic for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

(1) Background: Essential oil from Vitex negundo is known to have repellent and insecticidal properties toward the Anopheles gambiae and this is linked to its monoterpene and sesquiterpene content. In this work, an effort is made to delineate the constitution of V. negundo essential oil (VNEO) and their interaction with odorant-binding proteins (OBPs) of A. gambiae and hence access its repellent efficiency as cost-effective and safer malaria vector control alternatives. (2) Methods: Anopheles species authentication was performed by genomic DNA analysis and was subjected to behavioral analysis. GC-MS profiling was used to identify individual components of VNEO. Anopheles OBPs were obtained from the RCSB protein data bank and used for docking studies. Determination of ligand efficiency metrics and QSAR studies were performed using Hyper Chem Professional 8.0.3, and molecular dynamics simulations were performed using the Desmond module. (3) Results: GC-MS analysis of VNEO showed 28 compounds (monoterpenes, 80.16%; sesquiterpenes, 7.63%; and unknown constituents, 10.88%). The ligand efficiency metrics of all four ligands against the OBP 7 were within acceptable ranges. β-selinene (−12.2 kcal/mol), β-caryophellene (−9.5 kcal/mol), sulcatone (−10.9 kcal/mol), and α-ylangene (−9.3 kcal/mol) showed the strongest binding affinities for the target proteins. The most stable hydrophobic interactions were observed between β-selinene (Phe111 and Phe120), Sulcatone (Phe54 and Phe120), and α-ylangene (Phe111), while only sulcatone (Tyr49) presented H-bond interactions in the simulated environment. (4) Conclusions: Sulcatone and β-caryophyllene presented the best log p values, 6.45 and 5.20, respectively. These lead phytocompounds can be used in their purest as repellent supplement or as a natural anti-mosquito agent in product formulations. [ABSTRACT FROM AUTHOR]

Diabetes is emerging as an epidemic and is becoming a public health concern worldwide. Diabetic nephropathy is one of the serious complications of diabetes, and about 40% of individuals with diabetes develop diabetic nephropathy. The consistent feature of diabetes and its associated nephropathy is hyperglycemia, and in some cases, hyperamylinemia. Currently, the treatment includes the use of medication for blood pressure control, sugar control, and cholesterol control, and in the later stage requires dialysis and kidney transplantation, making the management of this complication very difficult. Bioactive compounds, herbal medicines, and extracts are extensively used in the treatment and prevention of several diseases, and some are reported to be efficacious in diabetes too. Therefore, in this study, we tried to identify the therapeutic potential of phytochemicals used in in silico docking and molecular dynamic simulation studies using a library of 5284 phytochemicals against the two potential targets of type 2 diabetes-associated nephropathy. We identified two phytochemicals (i.e., gentisic acid and michelalbine) that target human amylin peptide and dipeptidyl peptidase-4, respectively, with good binding affinity. These phytochemicals can be further evaluated using in vitro and in vivo studies for their anti-hyperglycemia and anti-hyperamylinemia effects. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) inhibitors and calcium channel blockers are considered effective therapies for Alzheimer's disease. AChE plays an essential role in the nervous system by catalyzing the hydrolysis of the neurotransmitter acetylcholine. In this study, the inhibition of the enzyme AChE by Sarcorucinine-D, a pregnane type steroidal alkaloid, was investigated with experimental enzyme kinetics and molecular dynamics (MD) simulation techniques. Kinetics studies showed that Sarcorucinine-D inhibits two cholinesterases—AChE and butyrylcholinesterase (BChE)—noncompetitively, with Ki values of 103.3 and 4.66 µM, respectively. In silico ligand-protein docking and MD simulation studies conducted on AChE predicted that Sarcorucinine-D interacted via hydrophobic interactions and hydrogen bonds with the residues of the active-site gorge of AChE. Sarcorucinine-D was able to relax contractility concentration-dependently in the intestinal smooth muscles of jejunum obtained from rabbits. Not only was the spontaneous spasmogenicity inhibited, but it also suppressed K+-mediated spasmogenicity, indicating an effect via the inhibition of voltage-dependent Ca2+ channels. Sarcorucinine-D could be considered a potential lead molecule based on its properties as a noncompetitive AChE inhibitor and a Ca2+ channel blocker. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies." The original version of the article contained an error in the Acknowledgements section, which has now been corrected. The authors express their gratitude to the Deanship of Scientific Research at Majmaah University, Saudi Arabia, for their support in this research work. The correction notice does not provide any additional information about the content of the article or its findings. [Extracted from the article]

This study was aimed to perform the mechanistic investigations of chalcone scaffold as inhibitors of acetylcholinesterase (AChE) enzyme using molecular docking and molecular dynamics simulation tools. Basic chalcones (C1–C5) were synthesized and their in vitro AChE inhibition was tested. Binding interactions were studied using AutoDock and Surflex-Dock programs, whereas the molecular dynamics simulation studies were performed to check the stability of the ligand–protein complex. Good AChE inhibition (IC50 = 22 ± 2.8 to 37.6 ± 0.75 μM) in correlation with the in silico results (binding energies = −8.55 to −8.14 Kcal/mol) were obtained. The mechanistic studies showed that all of the functionalities present in the chalcone scaffold were involved in binding with the amino acid residues at the binding site through hydrogen bonding, π–π, π–cation, π–sigma, and hydrophobic interactions. Molecular dynamics simulation studies showed the formation of stable complex between the AChE enzyme and C4 ligand. [ABSTRACT FROM AUTHOR]

Background and Objective. Trigonella foenum-graecum Linn., also called fenugreek, is a popular medicinal plant cultivated all over the globe. Fenugreek seeds are known for their many medicinal properties. We present our findings on the effect of a 70% aqueous methanolic fenugreek seed extract (Tfg.Cr) on isolated GI smooth muscles (rabbit jejunum and rat ileum) and the effect of extract and its constituent diosgenin on acetylcholinesterase (AChE) enzyme. Results. When tested on the baseline of isolated tissues, Tfg.Cr was devoid of any activity (stimulant or relaxant) till 10 mg/ml. This is an interesting finding, keeping in mind that the fenugreek seeds are used to alleviate constipation and diarrhoea. When Tfg.Cr was tried for any potential AChE inhibitory activity, it did show an inhibitory effect in increasing concentrations (47-380 μg/ml). This inhibitory effect was comparable to the effect produced by a standard AChE inhibitor physostigmine. One of the known fenugreek constituents, diosgenin, was also tested, and it also showed an AChE inhibitory effect in a concentration-dependent manner (11-190 μg/ml). Interaction between diosgenin and AChE was further investigated by molecular docking and molecular dynamics simulations for 100 ns, which showed that diosgenin interacted with the active-site gorge of AChE through hydrophobic, pi-pi stacking, and hydrogen bonds with various amino acids of the AChE enzyme. Conclusion. The results show that the fenugreek extract does not possess any GI stimulant or relaxant activity even though it is used traditionally in GI motility disorders. The extract and diosgenin could inhibit the AChE enzyme pointing towards their benefit to enhance the memory. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) and its receptor play an important role both in physiologic and pathologic angiogenesis, which is identified in ovarian cancer progression and metastasis development. The aim of the present investigation is to identify a potential vascular endothelial growth factor inhibitor which is playing a crucial role in stimulating the immunosuppressive microenvironment in tumor cells of the ovary and to examine the effectiveness of the identified inhibitor for the treatment of ovarian cancer using various in silico approaches. Twelve established VEGF inhibitors were collected from various literatures. The compound AEE788 displays great affinity towards the target protein as a result of docking study. AEE788 was further used for structure-based virtual screening in order to obtain a more structurally similar compound with high affinity. Among the 80 virtual screened compounds, CID 88265020 explicates much better affinity than the established compound AEE788. Based on molecular dynamics simulation, pharmacophore and comparative toxicity analysis of both the best established compound and the best virtual screened compound displayed a trivial variation in associated properties. The virtual screened compound CID 88265020 has a high affinity with the lowest re-rank score and holds a huge potential to inhibit the VGFR and can be implemented for prospective future investigations in ovarian cancer. [ABSTRACT FROM AUTHOR]