Network pharmacology and molecular dynamics study of the effect of the Astragalus-Coptis drug pair on diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is the primary cause of end-stage renal disease. The Astragalus-Coptis drug pair is frequently employed in the management of DKD. However, the precise molecular mechanism underlying its therapeutic effect remains elusive. AIM: To investigate the synergistic effects of multiple active ingredients in the Astragalus-Coptis drug pair on DKD through multiple targets and pathways. METHODS: The ingredients of the Astragalus-Coptis drug pair were collected and screened using the TCMSP database and the SwissADME platform. The targets were predicted using the SwissTargetPrediction database, while the DKD differential gene expression analysis was obtained from the Gene Expression Omnibus database. DKD targets were acquired from the GeneCards, Online Mendelian Inheritance in Man database, and DisGeNET databases, with common targets identified through the Venny platform. The protein-protein interaction network and the "disease-active ingredient-target" network of the common targets were constructed utilizing the STRING database and Cytoscape software, followed by the analysis of the interaction relationships and further screening of key targets and core active ingredients. Gene Ontology (GO) function and Kyoto Ency-clopedia of Genes and Genomes (KEGG) pathway enrichments were performed using the DAVID database. The tissue and organ distributions of key targets were evaluated. PyMOL and AutoDock software validate the molecular docking between the core ingredients and key targets. Finally, molecular dynamics (MD) simulations were conducted to simulate the optimal complex formed by interactions between core ingredients and key target proteins. RESULTS: A total of 27 active ingredients and 512 potential targets of the Astragalus-Coptis drug pair were identified. There were 273 common targets between DKD and the Astragalus-Coptis drug pair. Through protein-protein interaction network topology analysis, we identified 9 core active ingredients and 10 key targets. GO and KEGG pathway enrichment analyses revealed that Astragalus-Coptis drug pair treatment for DKD involves various biological processes, including protein phosphorylation, negative regulation of apoptosis, inflammatory response, and endoplasmic reticulum unfolded protein response. These pathways are mainly associated with the advanced glycation end products (AGE)-receptor for AGE products signaling pathway in diabetic complications, as well as the Lipid and atherosclerosis. Molecular docking and MD simulations demonstrated high affinity and stability between the core active ingredients and key targets. Notably, the quercetin-AKT serine/threonine kinase 1 (AKT1) and quercetin-tumor necrosis factor (TNF) protein complexes exhibited exceptional stability. CONCLUSION: This study demonstrated that DKD treatment with the Astragalus-Coptis drug pair involves multiple ingredients, targets, and signaling pathways. We propose a novel approach for investigating the molecular mechanism underlying the therapeutic effects of the Astragalus-Coptis drug pair on DKD. Furthermore, we suggest that quercetin is the most potent active ingredient and specifically targets AKT1 and TNF, providing a theoretical foundation for further exploration of pharmacologically active ingredients and elucidating their molecular mechanisms in DKD treatment.

Insights on the comparative affinity of ribonucleic acids with plant-based beta carboline alkaloid, harmine: Spectroscopic, calorimetric and computational evaluation.

Small molecules as ligands target multifunctional ribonucleic acids (RNA) for therapeutic engagement. This study explores how the anticancer DNA intercalator harmine interacts various motifs of RNAs, including the single-stranded A-form poly (rA), the clover leaf tRNAphe, and the double-stranded A-form poly (rC)-poly (rG). Harmine showed the affinity to the polynucleotides in the order, poly (rA) > tRNAphe > poly (rC)·poly (rG). While no induced circular dichroism change was detected with poly (rC)poly (rG), significant structural alterations of poly (rA) followed by tRNAphe and occurrence of concurrent initiation of optical activity in the attached achiral molecule of alkaloid was reported. At 25 °C, the affinity further showed exothermic and entropy-driven binding. The interaction also highlighted heat capacity (ΔC o p ) and Gibbs energy contribution from the hydrophobic transfer (ΔG hyd) of binding with harmine. Molecular docking calculations indicated that harmine exhibits higher affinity for poly (rA) compared to tRNAphe and poly (rC)·poly (rG). Subsequent molecular dynamics simulations were conducted to investigate the binding mode and stability of harmine with poly(A), tRNAphe, and poly (rC)·poly (rG). The results revealed that harmine adopts a partial intercalative binding with poly (rA) and tRNAphe, characterized by pronounced stacking forces and stronger binding free energy observed with poly (rA), while a comparatively weaker binding free energy was observed with tRNAphe. In contrast, the stacking forces with poly (rC)·poly (rG) were comparatively less pronounced and adopts a groove binding mode. It was also supported by ferrocyanide quenching analysis. All these findings univocally provide detailed insight into the binding specificity of harmine, to single stranded poly (rA) over other RNA motifs, probably suggesting a self-structure formation in poly (rA) with harmine and its potential as a lead compound for RNA based drug targeting.

Manganese(II) and Zinc(II) metal complexes of novel bidentate formamide-based Schiff base ligand: synthesis, structural characterization, antioxidant, antibacterial, and in-silico molecular docking study.

A new bidentate Schiff base ligand (C16H16Cl2N4), condensation product of ethylene diamine and 4-chloro N-phenyl formamide, and its metal complexes [M(C16H16Cl2N4)2(OAc)2] (where M = Mn(II) and Zn(II)) were synthesized and characterized using various analytical and spectral techniques, including high-resolution mass spectrometry (HRMS), elemental analysis, ultraviolet-visible (UV-vis), Fourier-transform infrared (FTIR) spectroscopy, AAS, molar conductance, 1H NMR, and powder XRD. All the compounds were non-electrolytes and nanocrystalline. The synthesized compounds were assessed for antioxidant potential by DPPH radical scavenging and FRAP assay, with BHT serving as the positive control. Inhibitory concentration at 50% inhibition (IC50) values were calculated and used for comparative analysis. Furthermore, the prepared compounds were screened for antibacterial activity against two Gram-negative bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-positive bacteria (Escherichia coli and Salmonella typhi) using disk-diffusion methods, with amikacin employed as the standard reference. The comparison of inhibition zones revealed that the complexes showed better antibacterial activity than the ligand. To gain insights into the molecular interactions underlying the antibacterial activity, the ligand and complexes were analyzed for their binding affinity with S. aureus tyrosyl-tRNA synthetase (PDB ID: 1JIL) and S. typhi cell membrane protein OmpF complex (PDB ID: 4KR4). These analyses revealed robust interactions, validating the observed antibacterial effects against the tested bacterial strains.

YinChen WuLing powder attenuates non-alcoholic steatohepatitis through the inhibition of the SHP2/PI3K/NLRP3 pathway.

Background: YinChen WuLing Powder (YCWLP) has been recommended by consensus for the treatment of non-alcoholic steatohepatitis (NASH); nevertheless, its specific pharmacological mechanisms remain to be elucidated. This study aims to dissect the mechanisms underlying the therapeutic effects of YCWLP on NASH using a hybrid approach that encompasses network pharmacology, molecular docking, and in vitro experimental validation. Methods: We compiled the chemical constituents of YCWLP from the Traditional Chinese Medicine System Pharmacological Database and Analysis Platform (TCMSP), while potential targets were predicted using the SwissTargetPrediction database. To identify NASH-related candidate targets, comprehensive retrieval was carried out using five authoritative databases. Protein-Protein Interaction (PPI) networks of direct targets of YCWLP in NASH treatment were then constructed using the String database, and functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, were conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Core targets were discerned using the Molecular Complex Detection (MCODE) and cytoHubba algorithms. Subsequently, molecular docking of key compounds to core targets was conducted using AutoDock software. Moreover, we established a free fatty acid-induced HepG2 cell model to simulate NASH in vitro, with YCWLP medicated serum intervention employed to corroborate the network pharmacology-derived hypotheses. Furthermore, a combination of enzyme-linked immunosorbent assay (ELISA), and Western blotting analyses was employed to investigate the lipid, hepatic enzyme, SHP2/PI3K/NLRP3 signaling pathway and associated cytokine levels. Results: The network pharmacology analysis furnished a list of 54 compounds from YCWLP and 167 intersecting targets associated with NASH. Through analytic integration with multiple algorithms, PTPN11 (also known as SHP2) emerged as a core target of YCWLP in mitigating NASH. The in vitro experiments validated that 10% YCWLP medicated serum could remarkably attenuate levels of total cholesterol (TC, 1.25 vs. 3.32) and triglyceride (TG, 0.23 vs. 0.57) while ameliorating alanine aminotransferase (ALT, 7.79 vs. 14.78) and aspartate aminotransferase (AST, 4.64 vs. 8.68) leakage in NASH-afflicted cells. In addition, YCWLP significantly enhanced the phosphorylation of SHP2 (0.55 vs. 0.20) and downregulated the expression of molecules within the SHP2/PI3K/NLRP3 signaling axis, including p-PI3K (0.42 vs. 1.02), NLRP3 (0.47 vs. 0.93), along with downstream effectors-cleaved Caspase-1 (0.21 vs. 0.49), GSDMD-NT (0.24 vs. 0.71), mature interleukin-1ß (IL-1ß, 0.17 vs. 0.48), pro-IL-1ß (0.49 vs. 0.89), mature interleukin-18 (IL-18, 0.15 vs. 0.36), and pro-IL-18 (0.48 vs. 0.95). Conclusion: Our research reveals that YCWLP exerts therapeutic effects against NASH by inhibiting lipid accumulation and inflammation, which involves the attenuation of pyroptosis via the SHP2/PI3K/NLRP3 pathway.

Revealing the role of metformin in gastric intestinal metaplasia treatment.

Objective: Gastric intestinal metaplasia (IM) is a precancerous stage associated with gastric cancer. Despite the observed beneficial effects of metformin on IM, its molecular mechanism remains not fully elucidated. This study aims to reveal the effects and potential mechanisms of metformin in treating IM based on both bioinformatics and in vivo investigations. Methods: The seven public databases (GeneCards, DisGeNET, OMIM, SuperPred, Pharm Mapper, Swiss Target Prediction, TargetNet) were used in this work to identify targeted genes related to intestinal metaplasia (IM) and metformin. The shared targeted genes between metformin and IM were further analyzed by network pharmacology, while the interactions in-between were investigated by molecular docking. In parallel, the therapeutic effect of metformin was evaluated in IM mice model, while the core targets and pathways effected by metformin were verified in vivo. Results: We screened out 1,751 IM-related genes and 318 metformin-targeted genes, 99 common genes identified in between were visualized by constructing the protein-protein interaction (PPI) network. The top ten core targeted genes were EGFR, MMP9, HIF1A, HSP90AA1, SIRT1, IL2, MAPK8, STAT1, PIK3CA, and ICAM1. The functional enrichment analysis confirmed that carcinogenesis and HIF-1 signaling pathways were primarily involved in the metformin treatment of IM. Based on molecular docking and dynamics, we found metformin affected the function of its targets by inhibiting receptor binding. Furthermore, metformin administration reduced the progression of IM lesions in Atp4a-/- mice model significantly. Notably, metformin enhanced the expression level of MUC5AC, while inhibited the expression level of CDX2. Our results also showed that metformin modulated the expression of core targets in vivo by reducing the activity of NF-κB and the PI3K/AKT/mTOR/HIF-1α signaling pathway. Conclusion: This study confirms that metformin improves the efficacy of IM treatment by regulating a complex molecular network. Metformin plays a functional role in inhibiting inflammation/apoptosis-related pathways of further IM progression. Our work provides a molecular foundation for understanding metformin and other guanidine medicines in IM treatment.

Unusual norcucurbitacin glycosides from the roots of Siraitia grosvenorii.

Siraitia grosvenorii Swingle is one of the first approved medicine food homology species in China, and it has been used as a natural sweetener in the food industry and as a traditional medicine to relieve cough and reduce phlegm. However, many S. grosvenorii roots are discarded yearly, which results in a great waste of resources. Twelve undescribed norcucurbitacin-type triterpenoid glycosides, siraitiaosides A-L (1-12), and six known analogs (13-18) were isolated from the roots of S. grosvenorii. The structures of isolated norcucurbitacin glycosides were elucidated by comprehensive data analyses, including HRESIMS, UV, IR, NMR, ECD calculations, and X-ray crystallography analysis. Siraitiaosides A-E (1-5) featured an unusual 19,29-norcucurbitacin framework while siraitiaosides F-L (6-12) featured a rare 29-norcucurbitacin framework. Notably, compound 4 displayed moderate anti-acetylcholinesterase (AChE) activity with an IC50 of 21.0 µM, meanwhile, compounds 16 and 18 exhibited pronounced cytotoxic activities against MCF-7, CNE-1, and HeLa cancer cell lines with IC50 values of 2.1-15.2 µM. In silico studies showed that compound 4 bound closely to AChE with a binding energy of -5.04 kcal/mol, and compound 18 could tightly bind to PI3K, AKT1, ERK2, and MMP9 proteins that related to autophagy, apoptosis, migration/invasion, and growth/proliferation. In summary, the roots of Siraitia grosvenorii have potential medicinal values due to the multiple bioactive components.

Discerning computational, in vitro and in vivo investigations of self-assembling empagliflozin polymeric micelles in type-2 diabetes.

BACKGROUND: Empagliflozin (EMPA) is an SGLT2 inhibitor, a new class of anti-diabetic medication, indicated for treating type-2 diabetes. Its low permeability, poor solubility and bioavailability limits its use in management of diabetes. The study was aimed to formulate EMPA loaded polymeric micelles (PMs) to overcome these obstacles in oral absorption. METHODOLOGY: In silico studies-molecular docking, molecular dynamic simulation (MDS), and quantum chemical calculation were employed to study the interaction of EMPA with different polymers. EMPA loaded TPGS polymeric micelles (EMPA-TPGS-PMs) were formulated by direct dissolution method and characterized in terms of surface morphology, entrapment, particle size, in vitro drug release, and in vitro cytotoxicity (HEK293 cells). In vivo pharmacokinetic and pharmacodynamic studies were also performed. RESULTS: The results suggested a good interaction between TPGS and EMPA with lowest binding energy compared to other polymers. Further MDS results and DFT calculations validated the stable binding of the complex hence TPGS was selected for further wet lab experiments. The EMPA-TPGS complex displayed lower value of Total energy (T.E.) than its individual components, indicating the overall stability of the complex while, the energy band gap (∆E) value lied between the two individual molecules, signifying the better electron transfer between HOMO and LUMO of the complex. Based on the solubility, entrapment and cytotoxicity studies, 5% TPGS was selected for formulating drug loaded micelles. EMPA-TPGS5-PMs presented a size of 9.008 ± 1.25 nm, Polydispersity index (PDI) of 0.254 ± 0.100, a controlled release behaviour upto 24 h. SEM and AFM images of the nanoformulation suggested spherical particles whereas, DSC, and PXRD studies confirmed the loss of crystallinity of EMPA. A 3.12-folds higher AUC and a greater reduction in blood glucose levels was exhibited by EMPA-TPGS5-PMs in comparison to EMPA-SUSP in mice model. CONCLUSION: EMPA-TPGS-PMs has exhibited better bio absorption and therapeutic effectiveness in diabetes treatment. This improved performance would open the possibility of dose reduction, reduced dosing frequency & dose-related side effects, improving pharmaco-economics and thereby improved overall compliance to the patient. However, this translation from bench to bedside would necessitate studies in higher animals and human volunteers.

Exploring the potential mechanism of Chinese herbal medicine Fuzi on aplastic anemia based on UHPLC-MS/MS method combined with network pharmacology and molecular docking.

To reveal the potential mechanism of the effect of Chinese Herbal Medicine Fuzi on Aplastic anaemia (AA) according to the network pharmacology approach and molecular docking. According to Ultra High Performance Liquid Chromatography Mass Spectrometry (UHPLC-MS/MS), 146 chemical ingredients of Fuzi were obtained. By SwissADME online system analysis, a total of 55 compounds such as Magnoflorine, Scutellarein, Luteolin and Gingerol may be the main active components of Fuzi and 145 common targets related to AA were predicted. 17 targets such as MAPK1, AKT1 and GRB2 were considered as hub targets. KEGG and GO enrichment analysis obtained 122 signalling pathways and 950 remarkable results. These results suggested that Fuzi exerted pharmacological effects on AA mainly by regulating PI3K-Akt, MAPK and JAK-STAT signalling pathways and epithelial cell proliferation, cell differentiation, regulate energy production and other biological processes. Meanwhile, molecular docking results showed that the hub targets had good binding ability with the main active ingredients.

A novel mutation Trp-2027-Gly in acetyl-CoA carboxylase confers resistance to cyhalofop-butyl in Chinese sprangletop (Leptochloa chinensis).

BACKGROUND: Chinese sprangletop [Leptochloa chinensis (L.) Nees] control is threatened by resistance to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. In this study, a L. chinensis population, HFLJ18, that survived cyhalofop-butyl [aryloxyphenoxypropionate (APP) herbicide, CyB] treatment was collected from a rice field in Lujiang County, Anhui Province, China. This study aimed to evaluate the susceptibility of HFLJ18 to herbicides with different modes-of-action and investigate the potential mechanisms of resistance to CyB. RESULTS: The HFLJ18 population exhibited high levels of resistance to CyB (10.92-fold) and showed resistance to the ACCase inhibitors metamifop (4.63-fold) and fenoxaprop-P-ethyl (8.39-fold), but was susceptible to clethodim, pinoxaden, florpyrauxifen-benzyl, oxadiazon and pretilachlor. Target gene sequencing revealed a novel Trp-to-Gly substitution at codon position 2027 of ACCase in the resistant plants. Molecular docking revealed that the spatial structure of ACCase changed significantly following the substitution, as indicated by reduced H-bonds. A newly derived cleaved amplified polymorphic sequence (dCAPS) marker was subsequently developed to detect the Trp-2027-Gly mutation in the ACCase of L. chinensis. Additionally, pretreatment with the cytochrome P450 (P450) inhibitor piperonyl butoxide (PBO) and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) did not reverse resistance to CyB, suggesting that nontarget-site resistance mechanisms were not involved in CyB resistance in the HFLJ18 population. CONCLUSION: Overall, the resistance to CyB in the HFLJ18 population derived from the mutation of ACCase gene, and to the best of our knowledge, this is the first report of the ACCase Trp-2027-Gly mutation conferring resistance to ACCase-inhibiting herbicides in grass species. © 2024 Society of Chemical Industry.

Deciphering the multi-target therapeutic capabilities of Ocimum tenuiflorum Linn. Compounds against systemic lupus erythematosus and inflammatory bowel disease: a network pharmacology and molecular modelling approach.

The coexistence of Systemic Lupus Erythematosus (SLE) and Inflammatory Bowel Disease (IBD) is a rare and hard-to-diagnose multisystem autoimmune disorder. Allopathic treatment approaches often fall short in managing both conditions simultaneously, as specific medications targeting this dual manifestation are lacking. In such instances, herbal medicine can offer a potential solution through its holistic approach. Ocimum tenuiflorum (O. tenuiflorum) a rich source of bioactive compounds belonging to Lamiaceae family. This study employs network pharmacology and molecular modelling to unveil the multi-target and multi-pathway mechanisms of O. tenuiflorum as a complementary therapy. A total of 423 common targets were obtained, among which AKT1, TNF, SRC, EGFR, HIF1A, HSP9AA, BCL2, and STAT3 were identified as the key targets. Lastly, molecular modelling validated the strong binding affinity between O. tenuiflorum 's compounds and the identified targets. In conclusion, these investigations provide new insight for further study of O. tenuiflorum towards the management of SLE and IBD.

Structure-Assisted Design of Chitosanase Product Specificity for the Production of High-Degree Polymerization Chitooligosaccharides.

Chitosanases are valuable enzymatic tools in the food industry for converting chitosan into functional chitooligosaccharides (COSs). However, most of the chitosanases extensively characterized produced a low degree of polymerization (DP) COSs (DP = 1-3, LdpCOSs), indicating an imperative for enhancements in the product specificity for the high DP COS (DP >3, HdpCOSs) production. In this study, a chitosanase from Methanosarcina sp. 1.H.T.1A.1 (OUC-CsnA4) was cloned and expressed. Analysis of the enzyme-substrate interactions and the subsite architecture of the OUC-CsnA4 indicated that a Ser49 mutation could modify its interaction pattern with the substrate, potentially enhancing product specificity for producing HdpCOSs. Site-directed mutagenesis provided evidence that the S49I and S49P mutations in OUC-CsnA4 enabled the production of up to 24 and 26% of (GlcN)5 from chitosan, respectively─the wild-type enzyme was unable to produce detectable levels of (GlcN)5. These mutations also altered substrate binding preferences, favoring the binding of longer-chain COSs (DP >5) and enhancing (GlcN)5 production. Furthermore, molecular dynamics simulations and molecular docking studies underscored the significance of +2 subsite interactions in determining the (GlcN)4 and (GlcN)5 product specificity. These findings revealed that the positioning and interactions of the reducing end of the substrate within the catalytic cleft are crucial factors influencing the product specificity of chitosanase.

Preparation, characterization, and mechanism of DPP-IV inhibitory peptides derived from Bactrian camel milk.

In this study, double enzyme hydrolysis significantly enhanced the DPP-IV inhibition rate compared to single enzyme. The α + K enzymes exhibited the highest inhibition rate. Ultrasonic pretreatment for 30 min improved the hydrolysis efficiency and DPP-IV inhibition rate, potentially due to the structural changes in hydrolysates, such as the increased surface hydrophobicity, and reduced particle size, α-helix and ß-turn. Six peptides were screened and verified in vitro. QPY, WPEYL, and YPPQVM displayed competitive inhibition, while LPAAP and IPAPSFPRL displayed mixed competitive/non-competitive inhibition. The interactions between these six peptides and DPP-IV primarily occurred through hydrogen bonds, electrostatic and hydrophobic interactions. Network pharmacological analysis indicated that LPAAP might inhibit DPP-IV activity trough interactions with diabetes-related targets such as CASP3, HSP90AA1, MMP9, and MMP9. These results uncover the potential mechanism of regulating blood glucose by camel milk hydrolysates, establishing camel milk peptide as a source of DPP-IV inhibitory peptide.

Analysis of the prognostic value of mitochondria-related genes in patients with acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of death worldwide. Mitochondrial dysfunction is a key determinant of cell death post-AMI. Preventing mitochondrial dysfunction is thus a key therapeutic strategy. This study aimed to explore key genes and target compounds related to mitochondrial dysfunction in AMI patients and their association with major adverse cardiovascular events (MACE). METHODS: Differentially expressed genes in AMI were identified from the Gene Expression Omnibus (GEO) datasets (GSE166780 and GSE24519), and mitochondria-related genes were obtained from MitoCarta3.0 database. By intersection of the two gene groups, mitochondria-related genes in AMI were identified. Next, the identified genes related to mitochondria were subject to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Protein-protein interaction (PPI) network was constructed, and key genes were screened. Then, targeted drug screening and molecular docking were performed. Blood samples from AMI patients and healthy volunteers were analyzed for the key genes expressions using quantitative real time polymerase chain reaction (qRT-PCR). Later, receiver operating characteristic (ROC) curves assessed the diagnostic value of key genes, and univariate and multivariate COX analyses identified risk factors and protective factors for MACE in AMI patients. RESULTS: After screening and identification, 138 mitochondria-related genes were identified, mainly enriched in the processes and pathways of cellular respiration, redox, mitochondrial metabolism, apoptosis, amino acid and fatty acid metabolism. According to the PPI network, 5 key mitochondria-related genes in AMI were obtained: translational activator of cytochrome c oxidase I (TACO1), cytochrome c oxidase subunit Va (COX5A), PTEN-induced putative kinase 1 (PINK1), SURF1, and NDUFA11. Molecular docking showed that Cholic Acid, N-Formylmethionine interacted with COX5A, nicotinamide adenine dinucleotide + hydrogen (NADH) and NDUFA11. Subsequent basic experiments revealed that COX5A and NDUFA11 expressions were significantly lower in the blood of patients with AMI than those in the corresponding healthy volunteers; also, AMI patients with MACE had lower COX5A and NDUFA11 expressions in the blood than those without MACE (P < 0.01). ROC analysis also showed high diagnostic value for COX5A and NDUFA11 [area under the curve (AUC) > 0.85]. In terms of COX results, COX5A, NDUFA11 and left ventricular ejection fraction (LVEF) were protective factors for MACE in AMI, while C-reactive protein (CRP) was a risk factor. CONCLUSION: COX5A and NDUFA11, key mitochondria-related genes in AMI, may be used as biomarkers to diagnose AMI and predict MACE.

In silico and ADMET molecular analysis targeted to discover novel anti-inflammatory drug candidates as COX-2 inhibitors from specific metabolites of Diospyros batokana (Ebenaceae).

Diospyros batokana (Ebenaceae) is a valuable medicinal plant that grows in the wild in Zambia. The aqua crude plant extract is valuable in treating oxidative stress and microbes-related diseases. In this study, bioactive metabolites from the leaf of the plant were tentatively identified using ultra-high-pressure liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS). Raw LCMS data were processed using MZmine3.6. Pyrenophorol, N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl]-2,2-diphenylacetamide, losartan, and isoarthonin, (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide were among the many metabolites identified from the plant studied using LCMS-MZmine 3.6. Furthermore, in silico anti-inflammatory molecular docking was applied to the five (5) metabolites with the aim of predicting the ability of the metabolites to inhibit the COX-2 enzyme. The docking simulation for the five metabolites was executed using the Auto-dock tools. The lowest binding energy of the complexes was visualized using Discovery Studio, 2021 Client l molecular viewer. Pyrenophorol, (N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl] -2,2-diphenylacetamide) and losartan were found to provide the lowest binding energy to COX-2 compared to the standard anti-inflammatory drug, diclofenac. Furthermore, binding affinities, inhibition constants, and ligand efficiencies demonstrated that pyrenophorol, N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl]-2,2-diphenylacetamide, losartan, isoarthonin and (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide could be useful as anti-inflammatory drug candidates supporting the traditional uses of D. batokana. However, the bioavailability radar and physicochemical properties only predict losartan, pyrenophorol, and (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide to be bioavailable and suitable drug candidates. In silico and ADMET analysis, shows that the five metabolites could be used as anti-inflammatory drugs comparable to the standard drugs, diclofenac and ibuprofen. However, in vitro and in vivo studies are needed to further support our findings.

Understanding the Molecular Landscape of Endometriosis: A Bioinformatics Approach to Uncover Signaling Pathways and Hub Genes.

Background: Endometriosis is a chronic gynecological disorder characterized by the ectopic growth of endometrial tissue outside the uterus, leading to debilitating pain and infertility in affected women. Despite its prevalence and clinical significance, the molecular mechanisms underlying the progression of endometriosis remain poorly understood. This study employs bioinformatics tools and molecular docking simulations to unravel the intricate genetic and molecular networks associated with endometriosis progression. Objectives: The primary objectives of this research are to identify differentially expressed genes (DEGs) linked to endometriosis, elucidate associated biological pathways using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), construct a Protein-Protein Interaction (PPI) network to identify hub genes, and perform molecular docking simulations to explore potential ligand-protein interactions associated with endometriosis. Methods: Microarray data from Homo sapiens, specifically Accession: GDS3092 Series = GSE5108 (Platform: GPL2895), were retrieved from the NCBI Gene Expression Omnibus (GEO). The data underwent rigorous preprocessing and DEG analysis using NCBI GEO2. Database for Annotation, Visualization, and Integrated Discovery analysis was employed for functional annotation, and a PPI network was constructed using the STITCH database and Cytoscape 3.8.2. Molecular docking simulations against target proteins associated with endometriosis were conducted using MVD 7.0. Results: A total of 1 911 unique elements were identified as DEGs associated with endometriosis from the microarray data. Database for Annotation, Visualization, and Integrated Discovery analysis revealed pathways and biological characteristics positively and negatively correlated with endometriosis. Hub genes, including BCL2, CCNA2, CDK7, EGF, GAS6, MAP3K7, and TAB2, were identified through PPI network analysis. Molecular docking simulations highlighted potential ligands, such as Quercetin-3-o-galactopyranoside and Kushenol E, exhibiting favorable interactions with target proteins associated with endometriosis. Conclusions: This study provides insights into the molecular signatures, pathways, and hub genes associated with endometriosis. Utilizing DAVID in this study clarifies biological pathways associated with endometriosis, revealing insights into intricate genetic networks. Molecular docking simulations identified ligands for further exploration in therapeutic interventions. The consistent efficacy of these ligands across diverse targets suggests broad-spectrum effectiveness, encouraging further exploration for potential therapeutic interventions. The study contributes to a deeper understanding of endometriosis pathogenesis, paving the way for targeted therapies and precision medicine approaches to improve patient outcomes. These findings advance our understanding of the molecular mechanisms in endometriosis (EMS), offering promising avenues for future research and therapeutic development in addressing this complex condition.

Causal relationship between complement C1QB and colorectal cancer: a drug target Mendelian randomization study.

Background: Colorectal cancer is influenced by several factors such as unhealthy habits and genetic factors. C1QB has been linked to a number of malignancies. However, uncertainty surrounds the connection between C1QB and CRC. Therefore, this study aimed to explore a bidirectional causal relationship of C1QB as a drug target in CRC through Mendelian randomization (MR) analysis. Methods: The GWASs for C1QB and CRC were obtained from the Integrative Epidemiology Unit Open GWAS database. There were five strategies to investigate MR. Sensitivity analysis was carried out via tests for heterogeneity, horizontal pleiotropy and leave-one-out effects to evaluate the dependability of the MR analysis results. Furthermore, colocalization analysis of C1QB and CRC, protein-protein interaction network and drug prediction according to exposure factors as well as phenotype scanning were performed. Results: The results of forward MR analysis demonstrated that C1QB was a risk factor for CRC (OR = 1.104, p = 0.033). However, we did not find a causal relationship between CRC and C1QB (reverse MR). Rs294180 and rs291985 corresponded to the same linkage interval and had the potential to influence C1QB and CRC, respectively. The PPI results demonstrated that C1QB interacted with 10 genes (C1QA, C1QC, C1R, C1S, C2, C4A, C4B, CALR, SERPING1, and VSIG4). Additionally, 21 medications were predicted to match C1QB. Molecular docking data, including for benzo(a)pyrene, 1-naphthylisothiocyanate, calcitriol and medroxyprogesterone acetate, revealed excellent binding for drugs and proteins. Moreover, we identified 29 diseases that were associated with C1QB and related medicines via disease prediction and intersection methods. As a therapeutic target for CRC, phenotypic scanning revealed that C1QB does not significantly affect weight loss, liver cirrhosis, or nonalcoholic fatty liver disease, but might have protective impacts on ovarian cancer and melanoma. Conclusion: The results highlight a causal relationship between C1QB and CRC and imply an oncogenic role for C1QB in CRC, as potential drug targets. Drugs designed to target C1QB have a greater chance of success in clinical trials and are expected to help prioritize CRC drug development and reduce drug development costs. That provided a theoretical foundation and reference for research on CRC and C1QB in MR.

Synthesis, characterization, and mechanistic insights into the enhanced anti-inflammatory activity of baicalin butyl ester via the PI3K-AKT pathway.

Objective: To investigate the anti-inflammatory activity and mechanism of Baicalin derivative (Baicalin butyl ester, BE). Methods: BE was synthesized and identified using UV-Vis spectroscopy, FT-IR spectroscopy, mass spectrometry (MS) and high-performance liquid chromatography (HPLC) methods. Its anti-inflammatory potential was explored by an in vitro inflammation model. Network pharmacology was employed to predict the anti-inflammatory targets of BE, construct protein-protein interaction (PPI) networks, and analysis topological features and KEGG pathway enrichment. Additionally, molecular docking was conducted to evaluate the binding affinity between BE and its core targets. qRT-PCR analysis was conducted to validate the network pharmacology results. The organizational efficiency was further evaluated through octanol-water partition coefficient and transmembrane activity analysis. Results: UV-Vis, FT-IR, MS, and HPLC analyses confirmed the successfully synthesis of BE with a high purity of 93.75%. In vitro anti-inflammatory research showed that BE could more effectively suppress the expression of NO, COX-2, IL-6, IL-1ß, and iNOS. Network pharmacology and in vitro experiments validated that BE's anti-inflammatory effects was mediated through the suppression of SRC, HSP90AA1, PIK3CA, JAK2, AKT1, and NF-κB via PI3K-AKT pathway. Molecular docking results revealed that the binding affinities of BA to the core targets were lower than those of BE. The Log p-value of BE (1.7) was markedly higher than that of BA (-0.5). Furthermore, BE accumulated in cells at a level approximately 200 times greater than BA. Conclusion: BE exhibits stronger anti-inflammatory activity relative to BA, possibly attributed to its better lipid solubility and cellular penetration capabilities. The anti-inflammatory mechanism of BE may be mediated through the PI3K-AKT pathway.

Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines.

Introduction: Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6. Methods: We designed and synthesized a range of substituted thiazolo-pyridopyrimidines (4a-p). Computational ADME/T analysis and molecular docking were performed using the crystal structure of CDK4/6. Subsequently, we synthesized the top-scoring compounds, characterized them using IR, NMR, and Mass spectroscopy, and assessed their impact on MCF-7 and MDAMB-231 cell lines using the SRB assay. To further evaluate stability, molecular dynamics simulations were conducted for the two most promising compounds within the binding site. Results: The docking scores indicated stronger interactions for compounds 4a, 4c, 4d, and 4g. As a result, these specific compounds (4a, 4c, 4d, and 4g) were chosen for synthesis and subsequent screening to assess their cytotoxic effects. Remarkably, compounds 4c and 4a exhibited the most promising activity in terms of their IC50 values across both tested cell lines. Furthermore, molecular dynamics simulation studies uncovered an elevated level of stability within the 4c-6OQO complex. Conclusion: By integrating insights from computational, in vitro, and molecular dynamics simulation findings, compound 4c emerges as a leading candidate for future investigations. The presence of a polar hydroxyl group at the C2 position of the 8-phenyl substitution on the pyridopyrimidine rings appears to contribute to the heightened activity of the compound. Further enhancements to cytotoxic potential could be achieved through structural refinements.

From waste to wonder: exploring the hypoglycemic and anti-oxidant properties of corn processing by-products.

Introduction: The industrial processing of corn (Zeamays L.) generates by-products such as corn silk, straw peels, and straw core, which contribute to adverse environmental impacts. Our study aimed to investigate sustainable approaches for mitigating these effects by evaluating the hypoglycemic potential and mechanisms of ethyl acetate fractions derived from these corn derivatives. Methods: We employed glucose consumption assays, high glucose stress tests, UPLC-QE-Orbitrap-MS analysis, molecular docking, and simulations to assess their components and efficacy. Antioxidant capacities were evaluated using DPPH, FRAP, ABTS, and •OH scavenging assays. Results: Notably, the ethyl acetate fraction extracted from straw peels (SPE) exhibited a high concentration of flavonoids and phenolic compounds along with pronounced hypoglycemic activity and antioxidant capacity. SPE significantly enhanced glucose consumption in insulin-resistant HepG2 cells while protecting HUVECs against damage caused by high glucose levels. Molecular docking analyses confirmed the interaction between active compounds and α-glucosidase as well as α-amylase, while molecular dynamic simulations indicated stability at their binding sites. Discussion: In conclusion, the hypoglycemic and antioxidative properties observed in corn by-products such as straw peels, corn silk, and straw core can be attributed to the inhibition of α-glucosidase and α-amylase activities, coupled with their rich phenolic and flavonoid content. These findings highlight the potential of these by-products for applications in healthcare management and their sustainable utilization, demonstrating significant value in the use of agricultural residues.

A Novel Compound with Kokumi Properties: Enzymatic Preparation and Taste Presentation Evaluation of N-Lauroyl Phenylalanine.

To satisfy the demands of the food industry, innovative flavor enhancers need to be developed urgently to increase the food flavor. In our work, N-lauroyl phenylalanine (LP) was prepared from phenylalanine (l-Phe) and lauric acid (Lau) in water through the use of commercial enzymes (Promatex, Sumizyme FP-G, and Trypsin), and its flavor-presenting properties and mechanism were investigated. The highest LP yields obtained under one-factor optimized conditions were 61.28, 63.43, and 77.58%, respectively. Sensory assessment and an e-tongue test revealed that 1 mg/L LP enhanced the kokumi, saltiness, and umami of the simulated chicken broth solution and attenuated the bitterness of the l-isoleucine solution. The molecular simulation results suggested that the mechanisms of LP enhancement of kokumi and umami were related to hCaSR and hT1R1-hT1R3, and that hydrophobic forces and hydrogen bonds were involved in the binding of LP to taste receptors. The results implied that LP is a potential flavor enhancer for food applications.