Enhancement of non-covalent interaction between soy protein isolate and quercetin by sodium alginate.

Effects of sodium alginate (SA) on the non-covalent interaction between soybean protein isolate (SPI) and quercetin (Que) were investigated by multispectral technology, molecular docking and dynamics simulation technology. Structural alterations of the binary complexes were observed after SA addition, characterized by a red shift of maximum fluorescence emission wavelength. The introduction of 0.1% (w/v) SA led to a reduction of 12.3% in the α-helix and ß-sheet structures, accompanied by 12.6% increase in the ß-turn and random coil conformations. The binding of SA to SPI provided electrostatic interactions and facilitated the subsequent binding of SPI to Que. Molecular docking confirmed that hydrophobic interactions and electrostatic interactions were also the main driving force. Molecular dynamics simulation emphasized that the ternary complexes with SA exhibited greater stability compared to the binary ones. The foaming and emulsifying properties of SPI-Que complexes were enhanced by 33.76% and 68.28%, respectively, due to the addition of SA.

Exploring the high-quality ingredients and mechanisms of Da Chuanxiong Formula in the treatment of neuropathic pain based on network pharmacology, molecular docking, and molecular dynamics simulation.

Da Chuanxiong Formula (DCXF) is a traditional herbal prescription used for pain management. It consists of Chuanxiong Rhizoma (CR) and Gastrodiae Rhizoma (GR). Despite its long history of use, the underlying therapeutic mechanism of DCXF remains insufficiently understood. Therefore, in this study, key target genes were obtained through network pharmacology research methods and molecular docking techniques, including transient receptor potential vanilloid 1 (TRPV1), adenosine A2a receptor (ADORA2A), nuclear receptor subfamily 3 group C member 1 (NR3C1), and protein kinase C beta (PRKCB). Molecular dynamics simulations demonstrated the favorable binding between all four key genes and their corresponding compounds. Notably, chronic constriction injury (CCI) treatment resulted in a significant decrease in mechanical threshold and thermal latency period for rat foot contraction, which was ameliorated upon administration of DCXF. Furthermore, real-time quantitative reverse transcription PCR (RT-qPCR) and western blot (WB) analyses indicated an upregulation of TRPV1, ADORA2A, NR3C1, and PRKCB expression in the rat dorsal root ganglion following CCI, which was attenuated by treatment with DCXF. The expressions of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6), in the rat dorsal root ganglion were assessed using ELISA, confirming consistent trends with the aforementioned findings. The results of this study offer a promising theoretical foundation for the utilization of DCXF in the treatment of neuropathic pain (NP).

Inhibition of protein tyrosine phosphatase 1B by serratane triterpenes from Huperzia serrata and their molecular docking study.

During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitory compounds from the natural resources, two new serratane triterpenes, 3-O-dihydro-p-coumaroyltohogenol (1) and 21-O-acetyltohogenol (2), along with four known serratane triterpenes (3-6), were isolated from the whole plant of Huperzia serrata. The chemical structures of compounds 1 and 2 were determined by NMR study, HRMS analysis, and chemical modification. All isolates were evaluated for their PTP1B inhibitory activities. Among the isolates, compounds 1, 3, 5 and 6 exhibit moderate inhibitory activities against PTP1B. Kinetic studies demonstrated that they are competitive inhibitors. Molecular docking studies support these experimental results by showing that compounds 1, 3, 5 and 6 interact with the active site of PTP1B, clarifying the structure-activity relationship. This study suggests that serratane triterpenes from H. serrata have potential as starting skeletons for anti-diabetes or anti-obesity agents.

Investigating Xiaochaihu Decoction's fever-relieving mechanism via network pharmacology, molecular docking, dynamics simulation, and experiments.

Xiaochaihu Decoction（XCHD）is a classic prescription for the treatment of fever, but the mechanism is not clear. In this study, We elucidated the mechanism of action through network pharmacology and molecular docking. A rat fever model was established to verify the prediction results of network pharmacology. The analysis revealed that 120 intersection targets existed between XCHD and fever. The TP53, STAT3, RELA, MAPK1, AKT1, TNF and MAPK14 as potential core targets of XCHD in fever treatment. GO and KEGG pathway enrichment analyses indicated that XCHD may act through pathways such as the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, IL-17 signaling pathway. Molecular docking results demonstrated that quercetin, kaempferol, ß-sitosterol, stigmasterol and baicalein exhibited strong binding activity to key targets. Animal experiments showed that XCHD significantly reduced body temperature and levels of IL-1ß, IL-6, TNF-α, NO, PGE2, and cAMP in rats with fever. Importantly, no significant difference was observed between the XCHD self-emulsifying nano phase plus suspension phase and XCHD group. XCHD exerts its therapeutic effects on fever through a multi-ingredient, multi-target, and multi-pathway approach.

Identification of the potential Pan-CDK antagonists: tracing the path of virtual screening and inhibitory activity on lung cancer cells.

Cyclin-dependent kinases (CDKs) are overexpressed in tumor cells, and their aberrant activation can promote the progression of non-small-cell lung cancer (NSCLC). We utilized structure-based virtual screening and experimental validation to screen for potential CDKs antagonists among TargetMol natural products. Molecular docking and molecular dynamics simulation results indicate that Dolastatin 10 exhibits strong interactions with multiple subtypes of CDKs (CDK1, CDK2, CDK3, CDK4, and CDK6), forming stable CDKs-Dolastatin 10 complex compounds. Furthermore, in vitro experiments demonstrate that Dolastatin 10 significantly inhibits the viability, migration, and invasion of H1299 cells in a concentration-dependent manner, arresting the cell cycle at the G2/M phase by inducing cell senescence. These findings suggest that Dolastatin 10 may serve as a potential CDKs antagonist deserving further investigation.

Uncovering the anti-breast cancer activity potential of east Kalimantan propolis by In vitro and bioinformatics analysis.

Numerous side effects of breast cancer drugs have prompted researchers to explore more into new therapeutic approaches derived from natural substances. In this context, our study focused on uncovering the potential of East Kalimantan propolis from Trigona apicalis for breast cancer treatment including the underlying mechanisms through bioinformatics approached. We conducted integrated in vitro and bioinformatics analysis of network pharmacology, molecular docking, molecular dynamics and MM-GBSA analysis. Initially, in vitro cytotoxic assay demonstrated the anti-breast cancer activity potential of ethanol extract of East Kalimantan propolis, particularly its ethyl acetate fraction, which exhibited similar activity to doxorubicin, as indicated by their IC50 value. This study revealed eight propolis compounds, consisting of flavonoids and phenolic acids, in East Kalimantan propolis. By integrating microarray datasets (GSE29431, GSE36295, and GSE42568) analysis with potential targets derived from propolis compounds, 39 shared target genes were identified. Subsequently, GO and KEGG pathway, protein-protein interaction (PPI) network, core hub genes and gene expression analysis revealed three major targets, namely, PTGS2, CXCL2, and MMP9. Among them, only MMP9 was highly expressed in breast cancer than normal. Moreover, molecular docking revealed the six of propolis compounds which exhibited pronounced binding affinity towards MMP-9, better than marimastat as control drug. Dynamic simulation confirmed the stability of chrysin and quercetin as best compounds. Additionally, MM-GBSA analysis revealed a relative binding energy for chrysin (-25.6403 kcal/mol) that was comparable to marimastat (-27.3827 kcal/mol). In conclusion, this study reveals how East Kalimantan Propolis affect breast cancer and emphasizes MMP9 as a key target for future therapeutics.

Green synthesized extracts/Au complex of Phyllospongia lamellosa: Unrevealing the anti-cancer and anti-bacterial potentialities, supported by metabolomics and molecular modeling.

The anti-cancer and anti-bacterial potential of the Red Sea sponge Phyllospongia lamellosa in its bulk (crude extracts) and gold nanostructure (loaded on gold nanaoparticles) were investigated. Metabolomics analysis was conducted, and subsequently, molecular modeling studies were conducted to explore and anticipate the P. lamellosa secondary metabolites and their potential target for their various bioactivities. The chloroformic extract (CE) and ethyl acetate extract (EE) of the P. lamellosa predicted to include bioactive lipophilic and moderately polar metabolites, respectively, were used to synthesize gold nanoparticles (AuNPs). The prepared AuNPs were characterized through transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), and UV-vis spectrophotometric analyses. The cytotoxic activities were tested against MCF-7, MDB-231, and MCF-10A. Moreover, the anti-bacterial, antifungal, and anti-biofilm activity were assessed. Definite classes of metabolites were identified in CE (terpenoids) and EE (brominated phenyl ethers and sulfated fatty amides). Molecular modeling involving docking and molecular dynamics identified Protein-tyrosine phosphatase 1B (PTP1B) as a potential target for the anti-cancer activities of terpenoids. Moreover, CE exhibited the most powerful activity against breast cancer cell lines, matching our molecular modeling study. On the other hand, only EE was demonstrated to possess powerful anti-bacterial and anti-biofilm activity against Escherichia coli. In conclusion, depending on their bioactive metabolites, P. lamellosa-derived extracts, after being loaded on AuNPs, could be considered anti-cancer, anti-bacterial, and anti-biofilm bioactive products. Future work should be completed to produce drug leads.

Site specific binding pattern of benzodiazepines with GABAA receptor and related impact on their activities in the human body: An in silico method based study.

Despite of being the drugs of the same therapeutic class (Benzodiazepines), each of them shows different actions prominently. It is commonly seen that Bromazepam, Clonazepam, and, Alprazolam are prescribed for the treatment of anxiety disorders, panic disorders, and phobias. On the other hand, Midazolam, Temazepam, Flurazepam, and Nitrazepam are indicated for the treatment of insomnia and Lorazepam is considered as a drug having anticonvulsant effects. As the mechanism of action is the same, there should be some differences in the binding patterns with the proteins that create differences in their impacts on the body. A deep screening of the binding patterns of the available Benzodiazepines in the market to the GABAA receptor will be beneficial to find out the responsible amino acids for being accountable for showing any specific action. This reveal will help design new molecules with the highest beneficial effect and lowest toxicity in the body. The in silico method provides the initial level of understanding regarding the binding patterns, performing in vitro and in vivo experiments will be more specific to claim the benefits of newly designed drugs.

Co-Expression Network Analysis and Molecular Docking Demonstrate That Diosgenin Inhibits Gastric Cancer Progression via SLC1A5/mTORC1 Pathway.

Background: Tumor-Node-Metastasis (TNM) stage of gastric cancer (GC) is one of the main factors affecting clinical outcome. The aim of this study was to explore the targets related to TNM stage of GC, and screening natural bioactive drug. Methods: RNA sequencing data of the TCGA-STAD cohort were downloaded from UCSC database. Genes associated with TNM staging were identified by weighted gene co-expression network analysis (WGCNA). Univariate Cox regression, least absolute shrinkage and selection operator (LASSO), extreme gradient boosting (Xgboost), random forest (RF) and cytohubba plug-in of cytoscope were applied to screen hub genes. Natural bioactive ingredients were available from the HERB database. Molecular docking was used to evaluate the binding activity of active ingredients to the hub protein. CCK-8, flow cytometry, transwell and Western blot assays were used to analyze the effects of diosgenin on GC cells. Results: 898 TNM-related genes were screened out through WGCNA. Three genes associated with GC progression/prognosis were identified, including nuclear receptor subfamily 3 group C member 2 (NR3C2), solute carrier family 1 member 5 (SLC1A5) and FAT atypical cadherin 1 (FAT1) based on the machine learning algorithms and hub co-expression network analysis. Diosgenin had good binding activity with SLC1A5. SLC1A5 was highly expressed in GC and was closely associated with tumor stage, overall survival and immune infiltration of GC patients. Diosgenin could inhibit cell viability and invasive ability, promote apoptosis and induce cell cycle arrest in G0/G1 phase. In addition, diosgenin promoted cleaved caspase 3 expression and inhibited Ki67, cyclin D1, p-S6K1, and SLC1A5 expression levels, while the mTORC1 activator (MHY1485) reversed this phenomenon. Conclusion: For the first time, this work reports diosgenin may inhibit the activation of mTORC1 signaling through targeting SLC1A5, thereby inhibiting the malignant behaviors of GC cells.

Network pharmacology- and molecular docking-based exploration of the molecular mechanism underlying Jianpi Yiwei Recipe treatment of gastric cancer.

BACKGROUND: Traditional Chinese medicine (TCM) is widely used as an important complementary and alternative healthcare system for cancer treatment in Asian countries. Network pharmacology, which utilizes various database platforms and computer software to study the interactions between complex drug components in vivo, is particularly useful for studying the pharmacodynamic mechanisms of multi-pathway and multi-target Chinese medicines. AIM: To explore the potential targets and function of Jianpi Yiwei Recipe treatment of gastric cancer (GC) through network pharmacology and molecular docking. METHODS: Data on the components of Jianpi Yiwei Recipe (Radix Astragali, Radix Codonopsis, Agrimonia eupatoria, Atractylodes macrocephala Koidz., Poria cocos, stir-baked rhizoma dioscoreae, Amomum villosum Lour., fried Fructus Aurantii, pericarpium citri reticulatae, Rhizoma Pinelliae Preparata, and Radix Glycyrrhizae Preparata) were collected and screened by using the TCM systems pharmacology database and analysis platform (TCMSP). Then the targets of these compounds were predicted. GC-related targets were screened using the GeneCards database. Venn diagram was used to identify common targets. An active ingredient-core target interaction network and a protein-protein interaction (PPI) network were built. Moreover, we performed gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses on the core targets and validated them by molecular docking. RESULTS: TCMSP screening revealed 11 active components and 184 targets, whereas GeneCards found 10118 disease-related targets, with 180 shared targets between them. Topology analysis of the PPI network identified 38 targets, including ATK1, TP53, and tumor necrosis factor, as key targets for the treatment of GC by Jianpi Yiwei Recipe. Quercetin, naringenin, luteolin, etc., may be the main active components of Jianpi Yiwei Recipe. GO enrichment analysis identified 2809, 1218, and 553 functions related to biological process, molecular function, and cellular component, respectively. KEGG pathway enrichment analysis revealed 167 related pathways, mainly involved in cancer, endocrine resistance, and AGE-RAGE signaling in diabetic complication. Validation with molecular docking analysis showed docking of key active components with core targets. CONCLUSION: Jianpi Yiwei Recipe plays a therapeutic role in GC through multiple components, targets, and pathways. These findings form a basis for follow-up exploration of Jianpi Yiwei Recipe in the treatment of GC.

Antiviral Activity, Pharmacoinformatics, Molecular Docking, and Dynamics Studies of Azadirachta indica Against Nipah Virus by Targeting Envelope Glycoprotein: Emerging Strategies for Developing Antiviral Treatment.

The Nipah virus (NiV) belongs to the Henipavirus genus is a serious public health concern causing numerous outbreaks with higher fatality rate. Unfortunately, there is no effective medication available for NiV. To investigate possible inhibitors of NiV infection, we used in silico techniques to discover treatment candidates in this work. As there are not any approved treatments for NiV infection, the NiV-enveloped attachment glycoprotein was set as target for our study, which is responsible for binding to and entering host cells. Our in silico drug design approach included molecular docking, post-docking molecular mechanism generalised born surface area (MM-GBSA), absorption, distribution, metabolism, excretion/toxicity (ADME/T), and molecular dynamics (MD) simulations. We retrieved 418 phytochemicals associated with the neem plant (Azadirachta indica) from the IMPPAT database, and molecular docking was used to ascertain the compounds' binding strength. The top 3 phytochemicals with binding affinities of -7.118, -7.074, and -6.894 kcal/mol for CIDs 5280343, 9064, and 5280863, respectively, were selected for additional study based on molecular docking. The post-docking MM-GBSA of those 3 compounds was -47.56, -47.3, and -43.15 kcal/mol, respectively. As evidence of their efficacy and safety, all the chosen drugs had favorable toxicological and pharmacokinetic (Pk) qualities. We also performed MD simulations to confirm the stability of the ligand-protein complex structures and determine whether the selected compounds are stable at the protein binding site. All 3 phytochemicals, Quercetin (CID: 5280343), Cianidanol (CID: 9064), and Kaempferol (CID: 5280863), appeared to have outstanding binding stability to the target protein than control ribavirin, according to the molecular docking, MM-GBSA, and MD simulation outcomes. Overall, this work offers a viable approach to developing novel medications for treating NiV infection.

The Inhibition of RXRα and RXRß Receptors Provides Valuable Insights for Potential Prostate Cancer Treatment, in silico Molecular Docking and Molecular Dynamics Studies.

INTRODUCTION: Prostate cancer has emerged as a widespread health concern, with systemic inflammation believed to substantially contribute to its development and progression. The presence of systemic inflammatory responses has been established as an independent predictor of unfavorable long-term outcomes in prostate cancer patients. The goal of this study is to inhibit RXRα and RXRß receptors, which are involved in prostate cancer, with Luteolin, Formononetin, and Kaempferol, with varying success. METHODS: Retinoid X receptors (RXRs) hold crucial roles within the nuclear receptor (NR) superfamily, and compelling evidence from preclinical studies underscores the therapeutic potential of targeting RXRs for treating neurodegenerative and inflammatory conditions. Consequently, the ability to regulate and modulate RXRs using phytoestrogen ligands, Formononetin, Kaempferol, and Luteolin, assume paramount importance in treatment strategies. RESULTS: The comprehensive in silico findings of this study vividly demonstrate the remarkable efficacy of Luteolin in inhibiting and modulating RXRα and RXRß, while Formononetin emerges as a notably potent suppressor of RXRß. Kaempferol, as the third compound, also exhibits commendable inhibitory attributes, although its impact is slightly less pronounced compared to the other two. DISCUSSION: These findings highlight the notable binding and inhibition capabilities to RXRα and RXRß, offering valuable insights for potential prostate cancer treatment avenues warranting further exploration through in vitro and in vivo analyses.

Discovery of 1,2,3-triazole-based pleuromutilin derivatives as potent gram-positive antibacterial agents.

A novel class of pleuromutilin derivatives possessing 1,2,3-triazole as the linker connected to phenyl analogues were designed. The antibacterial properties of the prepared compounds were assessed in vitro against five strains (E. coli, S. aureus, S. epidermidis, and E. faecalis). Most of the tested compounds displayed potent antibacterial activities against gram-positive bacteria and 14-O-[2-(4-((2,4-dinitrophenoxy)-methyl-1H-1,2,3-triazol-1-yl) acetamide)-2-methylpropan-2-yl) thioacetyl]mutilin (7c) exerted antibacterial activities against S. aureus, MRSA and S. epidermidis with MIC values 0.0625 µg/mL, representing 64-fold, 4-fold and 8-fold higher than tiamulin respectively. Compound 6e, 7c and 8c were chosen to carry out killing kinetics, which exhibited concentration-dependent effect. Subsequently, molecular modeling was conducted to further explore the binding of compound 6e, 7a, 7c, 8c and tiamulin with 50S ribosomal subunit from deinococcus radiodurans. The investigation revealed that the main interactions between compound 7c and the ribosomal residues were three hydrogen bonds, π-π, and p-π conjugate effects. Additionally, the free binding energy and docking score of 7c with the ribosome demonstrated the lowest values of -11.90 kcal/mol and -7.97 kcal/mol, respectively, consistent with its superior antibacterial activities.

Unveiling the Antimicrobial, Anti-Biofilm, and Anti-Quorum-Sensing Potential of Paederia foetida Linn. Leaf Extract against Staphylococcus aureus: An Integrated In Vitro-In Silico Investigation.

Antimicrobial resistance poses a global health threat, with Staphylococcus aureus emerging as a notorious pathogen capable of forming stubborn biofilms and regulating virulence through quorum sensing (QS). In the quest for novel therapeutic strategies, this groundbreaking study unveils the therapeutic potential of Paederia foetida Linn., an Asian medicinal plant containing various bioactive compounds, contributing to its antimicrobial activities, in the battle against S. aureus. Through a comprehensive approach, we investigated the effect of ethanolic P. foetida leaf extract on S. aureus biofilms, QS, and antimicrobial activity. The extract exhibited promising inhibitory effects against S. aureus including the biofilm-forming strain and MRSA. Real-time PCR analysis revealed significant downregulation of key virulence and biofilm genes, suggesting interference with QS. Biofilm assays quantified the extract's ability to disrupt and prevent biofilm formation. LC-MS/MS analysis identified quercetin and kaempferol glycosides as potential bioactive constituents, while molecular docking studies explored their binding to the QS transcriptional regulator SarA. Computational ADMET predictions highlighted favorable intestinal absorption but potential P-glycoprotein interactions limiting oral bioavailability. While promising anti-virulence effects were demonstrated, the high molecular weights and excessive hydrogen bond donors/acceptors of the flavonoid glycosides raise concerns regarding drug-likeness and permeability. This integrated study offers valuable insights for developing novel anti-virulence strategies to combat antimicrobial resistance.

Screening and Evaluation of Potential Efflux Pump Inhibitors with a Seaweed Compound Diphenylmethane-Scaffold against Drug-Resistant Escherichia coli.

Drug-resistant efflux pumps play a crucial role in bacterial antibiotic resistance. In this study, potential efflux pump inhibitors (EPIs) with a diphenylmethane scaffold were screened and evaluated against drug-resistant Escherichia coli. Twenty-four compounds were docked against the drug-binding site of E. coli multidrug transporter AcrB, and 2,2-diphenylethanol (DPE), di-p-tolyl-methanol (DPT), and 4-(benzylphenyl) acetonitrile (BPA) were screened for their highest binding free energy. The modulation assay was further used for EPI evaluation, revealing that DPE, DPT, and BPA could reduce the drug IC50 value in E. coli strains overexpressing AcrB, indicating their modulation activity. Only DPE and BPA enhanced intracellular dye accumulation and inhibited the efflux of ethidium bromide and erythromycin. In addition, DPE and BPA showed an elevated post-antibiotic effect on drug-resistant E. coli, and they did not damage the permeability of the bacterial outer membrane. The cell toxicity test showed that DPE and BPA had limited human-cell toxicity. Therefore, DPE and BPA demonstrate efflux pump inhibitory activity, and they should be further explored as potential enhancers to improve the effectiveness of existing antibiotics against drug-resistant E. coli.

Identification of Interleukin (IL)-33 Inhibitory Constituents from Canavalia gladiata Pods.

Interleukin (IL)-33, a member of the IL-1 cytokine family, plays a vital role in immune system regulation and inflammation, with oxidative stress being implicated in its expression. During the search for compounds from natural sources with potential as therapeutic agents for allergic diseases via IL-33 signal modulation, we discovered significant IL-33 inhibitory activity in the methanol extract of Canavalia gladiata (sword bean) pods. Through chromatographic separation and liquid chromatography-mass spectrometry, we isolated 11 compounds (1-11) from the methanol extract. Furthermore, we assessed the inhibitory effects of these substances on IL-33/ST2 signaling in processes related to inflammatory and autoimmune diseases using an enzyme-linked immunosorbent assay. Among them, compounds 7, 10, and 11 exhibited substantial IL-33 inhibitory efficacy, with values reaching 78%, 86%, and 79% at 100 µM, respectively. Remarkably, compounds 7, 10, and 11 demonstrated significant and dose-dependent inhibition of IL-33 signaling at concentrations of 10, 50, and 100 µM. Computational molecular docking and dynamic simulations further elucidated the underlying mechanisms. These findings have promising pharmacological implications for allergy prevention and treatment associated with flavonoid glycosides derived from C. gladiata.

Novel Antioxidant Self-Assembled Peptides Extracted from Azumapecten farreri Meat: In Vitro- and In Silico-Assisted Identification.

Previous studies have found that the self-assembled supramolecules of Azumapecten farreri meat peptides have antioxidant effects. Therefore, this study aims to isolate and identify novel antioxidant peptides with self-assembly characteristics and analyze their structure-activity relationship through molecular docking and molecular dynamics simulation. The in vitro results show that as the purification steps increased, the antioxidant activity of peptides became stronger. Additionally, the purification step did not affect its pH-responsive self-assembly. Using LC-MS/MS, 298 peptide sequences were identified from the purified fraction PF1, and 12 safe and antioxidant-active peptides were acquired through in silico screening. The molecular docking results show that they had good binding interactions with key antioxidant-related protein ligands (KEAP1 (Kelch-like ECH-associated protein 1) and MPO (myeloperoxidase)). The peptide QPPALNDSYLYGPQ, with the lowest docking energy, was selected for a 100 ns molecular dynamics simulation. The results show that the peptide QPPALNDSYLYGPQ exhibited excellent stability when docked with KEAP1 and MPO, thus exerting antioxidant effects by regulating the KEAP1-NRF2 pathway and inhibiting MPO activity. This study further validates the antioxidant and self-assembling properties of the self-assembled supramolecules of Azumapecten farreri meat peptide and shows its potential for developing new, effective, and stable antioxidants.

Study on a Mechanism of Improving MaAPX1 Protein Activity by Mutating Methionine to Lysine.

Ascorbate peroxidases (APXs) are key components of the ascorbate-glytathione cycle, which plays an important role in removing excess reactive oxygen species (ROS) in plants. Herein, MaAPX1 was verified as being involved in the ripening and senescence of banana fruit, exhibiting responsiveness to the accumulation of ROS and the oxidation of proteins. Site-directed mutation was applied to explore the mechanism of MaAPX1 activity changes. We found that the 32-site cysteine (Cys, C) served as a potential S-nitrosylation site. The mutant MaAPX1C32S activity was decreased significantly when Cys32 was mutated to serine (Ser, S). Intriguingly, the neighboring conserved 36-site methionine (Met, M), which is adjacent to Cys32, displayed an enzyme activity that was approximately five times higher than that of the wild-type MaAPX1 when mutated to lysine (Lys, K). Utilizing LC-MS/MS spectroscopy coupled with stopped-flow analysis showed that the enhanced MaAPX1M36K activity might be due to the increased S-nitrosylation level of Cys32 and the promotion of intermediate (compound I, the first intermediate product of the reaction of APX with H2O2) production. Molecular docking simulations showed that the S-N bond between Cys32 and Lys36 in MaAPX1M36K might have a function in protecting the thiol of Cys32 from oxidation. MaAPX1M36K, a promising mutant, possesses immense potential for improving the antioxidant capabilities of APX in the realm of bioengineering technology research.

Phytochemical Characterization and Antioxidant Activity Evaluation for Some Plant Extracts in Conjunction with Pharmacological Mechanism Prediction: Insights into Potential Therapeutic Applications in Dyslipidemia and Obesity.

Lipid metabolism dysregulation can lead to dyslipidemia and obesity, which are major causes of cardiovascular disease and associated mortality worldwide. The purpose of the study was to obtain and characterize six plant extracts (ACE-Allii cepae extractum; RSE-Rosmarini extractum; CHE-Cichorii extractum; CE-Cynarae extractum; AGE-Apii graveolentis extractum; CGE-Crataegi extractum) as promising adjuvant therapies for the prevention and treatment of dyslipidemia and its related metabolic diseases. Phytochemical screening revealed that RSE was the richest extract in total polyphenols (39.62 ± 13.16 g tannic acid/100 g dry extract) and phenolcarboxylic acids (22.05 ± 1.31 g chlorogenic acid/100 g dry extract). Moreover, the spectrophotometric chemical profile highlighted a significant concentration of flavones for CGE (5.32 ± 0.26 g rutoside/100 g dry extract), in contrast to the other extracts. UHPLC-MS quantification detected considerable amounts of phenolic constituents, especially chlorogenic acid in CGE (187.435 ± 1.96 mg/g extract) and rosmarinic acid in RSE (317.100 ± 2.70 mg/g extract). Rosemary and hawthorn extracts showed significantly stronger free radical scavenging activity compared to the other plant extracts (p < 0.05). Pearson correlation analysis and the heatmap correlation matrix indicated significant correlations between phytochemical contents and in vitro antioxidant activities. Computational studies were performed to investigate the potential anti-obesity mechanism of the studied extracts using target prediction, homology modeling, molecular docking, and molecular dynamics approaches. Our study revealed that rosmarinic acid (RA) and chlorogenic acid (CGA) can form stable complexes with the active site of carbonic anhydrase 5A by either interacting with the zinc-bound catalytic water molecule or by directly binding Zn2+. Further studies are warranted to experimentally validate the predicted CA5A inhibitory activities of RA and CGA and to investigate the hypolipidemic and antioxidant activities of the proposed plant extracts in animal models of dyslipidemia and obesity.

Licofelone, a Dual COX/LOX Inhibitor, Ameliorates Paclitaxel-Induced Mechanical Allodynia in Rats in a Cannabinoid Receptor-Dependent Manner.

The use of paclitaxel as a chemotherapeutic drug is limited by the development of dose-dependent paclitaxel-induced neuropathic pain (PINP). Recently, we observed that the combination of indomethacin plus minocycline (IPM) attenuates PINP in a mouse model in a cannabinoid (CB) receptor-dependent manner. Indomethacin inhibits cyclooxygenase (COX) activity, and minocycline inhibits 5-lipoxygenase (5-LOX) activity. Male Sprague Dawley rats with paclitaxel-induced mechanical allodynia were treated with indomethacin, minocycline, IPM combination, licofelone (a dual COX/LOX inhibitor), or their vehicles. AM251, a CB1 receptor antagonist, and AM630, a CB2 receptor antagonist, were administered before the IPM combination or licofelone. Mechanical allodynia was measured using a dynamic plantar aesthesiometer. Molecular docking was performed using CB-Dock2. Licofelone and IPM combination had antiallodynic effects, which were significantly higher than either indomethacin or minocycline alone. AM251 and AM630 blocked the antiallodynic effects of IPM combination and licofelone. Molecular docking showed that licofelone binds to both CB1 and CB2 receptors with a high affinity similar to the phytocannabinoid 1-trans-delta-9-tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2. Licofelone inhibits COX and LOX and/or directly interacts with CB receptors to produce antiallodynic effects in a rat model of PINP. The findings further suggest that licofelone could be a therapeutic agent for managing PINP.