Roselle (Hibiscus sabdariffa L.) extract as an adjunct to valsartan in patients with mild chronic kidney disease: A double-blind randomized controlled clinical trial.

Objective: The objective of this study was to evaluate the effectiveness of Hibiscus sabdariffa L. extract (HS) as an adjunct to valsartan in the treatment of high blood pressure in patients with mild chronic kidney disease (CKD). Materials and Methods: This trial was conducted in Gorgan, Iran. Seventy-two participants with CKD and high blood pressure were randomly assigned to either the HS group, receiving a 350 mg pill every 12 hr for 90 days along with 40 mg of valsartan every 12 hr, or the control group (40 mg valsartan + 12.5 mg hydrochlorothiazide). The primary objective was to assess the improvement of hypertension, while secondary objectives included the evaluation of proteinuria, albuminuria, kidney function, lipid profile, and electrolyte levels. Molecular docking analysis was performed to examine the mechanisms of action of the isolated components of HS. Results: Out of 80 initial participants, 72 were included in the analysis. Both groups showed a significant reduction in blood pressure (p<0.001). The HS group demonstrated a statistically significant decrease in lipid profile (p<0.001). There were no statistically significant differences between the groups regarding the reduction of renal markers. Molecular docking analysis revealed that the compounds present in HS, particularly its anthocyanins and flavonoids, exhibited greater angiotensin-converting enzyme (ACE) inhibitory potential than hydrochlorothiazide in both domains. Moreover, the compounds met the criteria for drug likeness and Lipinski rules. Conclusion: Adjunctive therapy with HS showed promising results in reducing hypertension and improving lipid profile in patients with CKD.

Comprehensive approach to in silico identification and in vitro validation of anti-filarial hit molecules targeting the dimer interface of thioredoxin peroxidase 1 in Wuchereria bancrofti: a progress in anti-filariasis drug development.

Lymphatic filariasis (LF) remains a significant health challenge for populations in developing countries. LF is a parasitic disease transmitted by mosquitoes, mainly caused by the filarial nematode, Wuchereria bancrofti, prevalent in tropical and subtropical regions. Since the present drugs develop complications, including adverse side effects, lack of specificity, and development of drug resistance, the present study focused on developing the potential anti-filariasis drugs targeting crucial proteins for the nematode life cycle. We have identified the therapeutic compounds by targeting the enzyme thioredoxin peroxidase 1 (WbTPx1), which facilitates the conversion of hydrogen peroxide into water, an essential mechanism by which the nematode survives against oxidative stress in the host. This approach might resolve treatment efficacy and activity difficulties at various stages of filarial parasitic worms. We modeled the structure of WbTPx1 and employed the structure-based virtual screening approach, focusing on the dimer interface region of the protein. ADMET prediction profiles of the non-toxic, top-ranked hits with higher docking scores demonstrate higher affinity to the nematode protein than its human homolog. The molecular dynamic simulation studies show WbTPx1-hit complexes' stability and the intactness of hits in the binding site. Further, in vitro validation of identified hits using Setaria digitata, a cattle nematode, showed better IC50 and higher inhibition than the standard drug ivermectin, indicating the potential to inhibit enzyme activity and the development of drug candidates for controlling LF.

Exploring the active components and potential mechanisms of Alpiniae oxyphyllae Fructus in treating diabetes mellitus with depression by UPLC-Q-Exactive Orbitrap/MS, network pharmacology and molecular docking.

The growing incidence of diabetes mellitus (DM) and depression is a global public health issue. Alpiniae oxyphyllae Fructus (AOF) is a kind of medicinal and edible plant which be found with anti-diabetic property, and could improve depression-like symptoms. This study aimed to screen active targets and potential mechanisms of AOF in treating DM with depression. Injection of streptozotocin (STZ) and exposure to chronic unpredictable mild stress (CUMS) for 4 weeks were used to conduct the DM with depression mice model. Behavioral tests, indexes of glucose metabolism, monoamine neurotransmitters, inflammatory cytokine and oxidative stress were measured. Histopathological change of hippocampus tissue was observing by HE and Nissl staining. UPLC-Q-Exactive Orbitrap/MS, network pharmacology and molecular docking were used to explore the chemical components and mechanisms of AOF on the DM with depression. AOF showed a reversed effect on body weight in DM with depression mice. Glucose metabolism and insulin resistance could be improved by treatment of AOF. In addition, AOF could alleviate depression-like behaviors based on the results of behavior tests and monoamine neurotransmitters. AOF also attenuated STZ-CUMS induced neuron injury in hippocampus. Next, a total of 61 chemical components were identified in the UPLC-Q-Exactive Orbitrap/MS analysis of the extract of AOF. Network pharmacology analysis suggested that 12 active components and 227 targets were screened from AOF, and 1802 target genes were screened from DM with depression, finally 126 intersection target genes were obtained. Drug-disease targets network was constructed and implied that the top five components with a higher degree value includes quercetin, nootkatone, baicalein, (-)-epicatechin and nootkatol. Protein-protein interaction (PPI) network showed that MAPK1, FOS, AKT1, IL6 and TP53 may be the core intersection targets. The mechanism of the effect of AOF on DM with depression was analyzed through gene ontology (GO), and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, mainly involved in AGE/RAGE, PI3K/AKT, and MAPK signaling pathways. The results of molecular docking indicated that quercetin, nootkatone, baicalein, (-)-epicatechin and nootkatol all had good binding to the core intersection targets. Overall, our experimental researches have demonstrated that AOF could exert the dual effects of anti-diabetic and anti-depression on DM with depression mice, through multi-targets and multi-pathways.

Mechanism Analysis of Selenium-Containing Compounds in Alleviating Spinal Cord Injury Based on Network Pharmacology and Molecular Docking Technology.

Spinal cord injury (SCI) is a severe traumatic condition in spinal surgery characterized by nerve damage in and below the injured area. Despite advancements in understanding the pathophysiology of SCI, effective clinical treatments remain elusive. Selenium compounds have become a research hotspot due to their diverse medicinal activities. Previously, our group synthesized a selenium-containing Compound 34# with significant anti-inflammatory activity. This study aimed to explore the anti-SCI effects of selenium-containing compounds using network pharmacology, molecular docking (MD), and ADMET methods. To identify SCI-related targets and those associated with 34#, GeneCards, NCBI, and SEA databases were employed. Eight overlapping targets were considered candidate targets, and molecular docking was performed using the PDB database and AutoDock software. The STRING database was used to obtain protein-protein interactions (PPI). Molecular dynamics simulation, MM/GBSA binding free energy score, and ADMET prediction were used to evaluate the potential targets and drug properties of 34#. Finally, experiments on NSC34 cells and mice were to verify the effects of 34# on SCI. Our results revealed eight candidate targets for 34# in the treatment of SCI. PPI and MD identified ADRB2 and HTR1F as the highest connectivity with 34#. ADMET analysis confirmed the low toxicity and safety of 34#. In vitro and in vivo models validated the anti-SCI effects. Our study elucidated candidate targets for alleviating SCI with 34#, explored PPI and target-related signaling pathways, and validated its anti-SCI effects. These findings enhance our understanding of 34#'s mechanism in treating SCI, positioning it as a potential candidate for SCI prevention.

In Silico Drug Repurposing Against PSMB8 as a Potential Target for Acute Myeloid Leukemia Treatment.

PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the existing literature. The principal aim of this study is to systematically screen an expansive library of molecular entities, curated from various databases to identify the prospective inhibitory agents with an affinity for PSMB8. A comprehensive assortment of molecular compounds obtained from the ZINC15 database was subjected to molecular docking simulations with PSMB8 by using the AutoDock tool in PyRx (version 0.9.9) to elucidate binding affinities. Following the docking simulations, a select subset of molecules underwent further investigation through comprehensive ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis employing AdmetSar and SwissADME tools. Finally, RMSD, RMSF, Rg, and H bond analyses were conducted via GROMACS to determine the best conformationally dynamic molecule that represents the candidate agent for the study. Following rigorous evaluation, Adozelesin, Fiduxosin, and Rimegepant have been singled out based on considerations encompassing bioavailability scores, compliance with filter criteria, and acute oral toxicity levels. Additionally, ligand interaction analysis indicates that Adozelesin and Fiduxosin exhibit an augmented propensity for hydrogen bond formation, a factor recognized for its facilitative role in protein-ligand interactions. After final analyses, we report that Fiduxosin may offer a treatment possibility by reversing the low survival rates caused by PSMB8 high activation in AML. This study represents a strategic attempt to repurpose readily available pharmaceutical agents, potentially obviating the need for de novo drug development, and thereby offering promising avenues for therapeutic intervention in specific diseases.

The influence of drying methods on extract content, tyrosinase activity inhibition, and mechanism in Ascophyllum nodosum: A combined microstructural and kinetic study.

This study evaluates vacuum drying (VD), microwave drying (MD), hot air drying (HAD), and freeze drying (FD), on the color and microstructure changes of Ascophyllum nodosum (A. nodosum), which affect the extraction of polyphenols and flavonoids. During drying, VD and FD show slight color change and looser structure, aiding in active compound preservation and extraction. Polyphenols extracted from A. nodosum (PEAn) using these methods show higher anti-tyrosinase activity, with VD treatment exhibiting the strongest inhibition. Kinetic studies demonstrate competitive inhibition between PEAn and tyrosinase. The binding constant (Ki) values indicate that PEAn treated with VD exhibits the most effective inhibition on tyrosinase, and the Zeta potential suggests the formation of the most stable complex. Circular dichroism (CD) spectroscopy shows significant enzyme rearrangement with VD-treated PEAn. Molecular docking confirms strong binding affinity. This study aims to enhance the utility of A. nodosum and develop novel uses for tyrosinase inhibitors in food.

Inhibition of the Janus kinase protein (JAK1) by the A. Pyrethrum Root Extract for the treatment of Vitiligo pathology. Design, Molecular Docking, ADME-Tox, MD Simulation, and in-silico investigation.

This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo.

A graph neural network approach for predicting drug susceptibility in the human microbiome.

Recent studies have illuminated the critical role of the human microbiome in maintaining health and influencing the pharmacological responses of drugs. Clinical trials, encompassing approximately 150 drugs, have unveiled interactions with the gastrointestinal microbiome, resulting in the conversion of these drugs into inactive metabolites. It is imperative to explore the field of pharmacomicrobiomics during the early stages of drug discovery, prior to clinical trials. To achieve this, the utilization of machine learning and deep learning models is highly desirable. In this study, we have proposed graph-based neural network models, namely GCN, GAT, and GINCOV models, utilizing the SMILES dataset of drug microbiome. Our primary objective was to classify the susceptibility of drugs to depletion by gut microbiota. Our results indicate that the GINCOV surpassed the other models, achieving impressive performance metrics, with an accuracy of 93% on the test dataset. This proposed Graph Neural Network (GNN) model offers a rapid and efficient method for screening drugs susceptible to gut microbiota depletion and also encourages the improvement of patient-specific dosage responses and formulations.

Molecular mechanisms, targets and clinical potential of berberine in regulating metabolism: a review focussing on databases and molecular docking studies.

Background: Metabolic imbalance is the common basis of many diseases. As natural isoquinoline alkaloid, berberine (BBR) has shown great promise in regulating glucose and lipids metabolism and treating metabolic disorders. However, the related mechanism still lacks systematic research. Aim: To discuss the role of BBR in the whole body's systemic metabolic regulation and further explore its therapeutic potential and targets. Method: Based on animal and cell experiments, the mechanism of BBR regulating systemic metabolic processes is reviewed. Potential metabolism-related targets were summarized using Therapeutic Target Database (TTD), DrugBank, GeneCards, and cutting-edge literature. Molecular modeling was applied to explore BBR binding to the potential targets. Results: BBR regulates the whole-body metabolic response including digestive, circulatory, immune, endocrine, and motor systems through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), sirtuin (SIRT)1/forkhead box O (FOXO)1/sterol regulatory element-binding protein (SREBP)2, nuclear factor erythroid 2-related factor (Nrf) 2/heme oxygenase (HO)-1, and other signaling pathways. Through these reactions, BBR exerts hypoglycemic, lipid-regulating, anti-inflammatory, anti-oxidation, and immune regulation. Molecular docking results showed that BBR could regulate metabolism targeting FOXO3, Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (Gpx) 4 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). Evaluating the target clinical effects, we found that BBR has the therapeutic potential of anti-aging, anti-cancer, relieving kidney disease, regulating the nervous system, and alleviating other chronic diseases. Conclusion: This review elucidates the interaction between potential targets and small molecular metabolites by exploring the mechanism of BBR regulating metabolism. That will help pharmacologists to identify new promising metabolites interacting with these targets.

Comprehensive study on pharmacognostic, pharmacological, and toxicological features of Ficus racemosa in Alzheimer's disease using GC-MS and molecular docking analyses.

Background: Alzheimer's disease (AD) presents as a widespread neurodegenerative condition impacting over 55 million individuals globally, with an annual rise of 10 million new cases. Despite its staggering prevalence, the absence of a definitive cure establishes the need for a revisit. Methods: We explore the alternative strategies, focusing on the potential therapeutic efficacy of ethanolic extracts derived from the fruit and leaf of Ficus racemosa Linn. Results: The investigation comprehensively explores pharmacognostic, phytochemical, toxicological, and pharmacological characteristics. In addition to pharmacognostic and physicochemical analyses, toxicological evaluations conducted on experimental animals demonstrated the innocuous nature of the ethanolic extracts (from both fruit and leaf) of F. racemosa, as evidenced by assessments of hemocompatibility, oxidative parameters, and vital organ histology. Phytochemical profiling via GC-MS identified 48 and 80 phytoconstituents in the fruit and leaf extracts, respectively. These constituents were screened for bioactive potential using the "Lipinski Rule of Five," resulting in the selection of 25 and 33 constituents from fruit and leaf extracts, respectively. Subsequent molecular docking studies against the AChE enzyme revealed promising interactions of the selected phytoconstituents. Furthermore, the top-scoring phytoconstituents were subjected to in silico screening to assess their interactions with ß- and γ-secretase enzymes, in addition to the AChE enzyme. The cumulative findings substantiate the therapeutic utility of the plant extracts, particularly in the context of AD. Conclusion: In conclusion, our investigation highlights the promising therapeutic potential of selected phytoconstituents derived from ethanolic extracts of F. racemosa in mitigating AD pathology by targeting key enzyme sites such as AChE, ß-, and γ-secretase.

Morroniside attenuates podocytes lipid deposition in diabetic nephropathy: A network pharmacology, molecular docking and experimental validation study.

BACKGROUND: Dysregulation of lipid metabolism is a key factor influencing the progression of diabetic nephropathy (DN). Morroniside (MOR) is a major active compound isolated from the traditional Chinese herb Cornus officinalis, our previous research found that it can improve the lipid deposition of renal tubular epithelial cells. The purpose of this study is to explore whether MOR can improve podocyte lipid deposition and its mechanism of reducing DN. METHODS: Initially, we used network pharmacology and bioinformatics techniques to predict the relationship between renal lipid metabolism of MOR and DN. Subsequently, the binding activity of MOR with lipid-related proteins was studied by molecular docking to determine how MOR acts through these proteins. After determining the target of MOR, animal experiments and cell tests were carried out to verify it. RESULTS: Using network pharmacology, bioinformatics, and molecular docking, target proteins for MOR treatment of DN were predicted and screened, including PGC-1α, LXRs, ABCA1, PPARY, CD36, and nephrin. It is particularly noted that MOR effectively binds to PGC-1α, while LXRs, ABCA1, PPARY and CD36 are downstream molecules of PGC-1α. Silencing the PGC-1α gene significantly reduced the therapeutic effects of MOR. Conversely, in groups without PGC-1α knockdown, MOR was able to increase the expression levels of PGC-1α and influence the expression of downstream proteins. Furthermore, through in vivo and in vitro experiments, utilizing techniques such as lipid droplet staining, PAS, MASSON staining, immunofluorescence, and Western blot, we found that MOR effectively elevated the expression levels of the podocyte protein nephrin and lipid metabolism-regulating proteins PGC-1α, PPARY, and ABCA1, while significantly inhibiting the expression of the lipid accumulation promoter CD36. CONCLUSION: MOR can regulate the cholesterol efflux in podocytes via the PGC-1α/LXRs/ABCA1 signaling pathway, and control cholesterol intake via the PGC-1α/PPARY/CD36 signaling pathway, thereby ameliorating lipid deposition in DN.

Synthesis, biological evaluation, theoretical calculations, QSAR and molecular docking studies of novel arylaminonaphthols as potent antioxidants and BChE inhibitors.

A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N-ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r, 4u, 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure-activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer's activity, compounds 4 g, 4q, 4r, 4u, and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings.

Synthesis, characterisation, and in vitro antiparasitic activity of new flavanoidal tetrazinan-6'-ones and their binding study with calf thymus DNA using molecular modelling and spectroscopic techniques.

With the developing resistance to traditional antiparasitic medications, the purpose of this study was to efficiently develop a series of six noble flavanoidal tetrazinane-6'-one derivatives by a one-pot reaction pathway. FT-IR, 1HNMR, 13CNMR, and Mass spectra were employed for the structural elucidation of the synthesized compounds (7-12). Clinostomum complanatum, a parasite infection model that has been well-established, demonstrated that all the synthesized compounds are potent antiparasitic agents. DNA is the main target for various medicinal compounds. As a result, thestudy of how small molecules attach to DNA has received a lot of attention. In the present study, we have performed various biophysical techniques to determine the mode of binding of synthesized compounds (7-12) with calf thymus DNA (ct-DNA). It was observed from the UV-visible absorbance and fluorescence spectra that all synthesized compounds (7-12) form complexes with the ct-DNA. The value of binding constant (Kb) was obtained to be in the range of 4.36---24.50 × 103 M - 1 at 298 K. Competitive displacement assay with ethidium bromide (EB), CD spectral analysis, viscosity measurements, and in silico molecular docking confirmed that ligands (7-12) incorporate with ct-DNA through groove binding only. Molecular docking studies were performed for all synthesized compounds with the calf thymus DNA and it was found that all the newly synthesized compounds strongly bind with the chain B of DNA in the minor groove with the value of binding energy in the range of -8.54 to -9.04 kcal per mole and several hydrogen bonding interactions.

Molecular Mechanism of Cynodon dactylon Phytosterols Targeting MAPK3 and PARP1 to Combat Epithelial Ovarian Cancer: A Multifaceted Computational Approach.

Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was employed to investigate the unexplored therapeutic efficacy of Cynodon dactylon phytochemicals against EOC using a multifaceted computational approach. A total of 19 out of 89 rigorously curated phytochemicals were assessed as potential drug targets via ADMET profiling, while protein-protein interaction analysis scrutinized the top 20 hub genes among 264 disease targets, revealing their involvement in cancer-related pathways and underscoring their significance in EOC pathogenesis. In molecular docking, Stigmasterol acetate showed the highest binding affinity (-10.9 kcal/mol) with Poly [ADP-ribose] polymerase-1 (PDB: 1UK1), while Arundoin and Beta-Sitosterol exhibited strong affinities (-10.4 kcal/mol and -10.1 kcal/mol, respectively); additionally, Beta-Sitosterol interacting with Mitogen-activated protein kinase 3 (PDB: 4QTB) showed a binding affinity of -10.1 kcal/mol, forming 2 hydrogen bonds and a total of 10 bonds with 10 residues. Molecular dynamics simulations exhibited the significant structural stability of the Beta-Sitosterol-4QTB complex with superior binding free energy (-36.61 kcal/mol) among the three complexes. This study identified C. dactylon phytosterols, particularly Beta-Sitosterol, as effective in targeting MAPK3 and PARP1 to combat EOC, laying the groundwork for further experimental validation and drug development efforts.

Targeting AFP-RARß complex formation: a potential strategy for treating AFP-positive hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP's intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARß interaction were identified, guiding the definition of AFP's active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARß complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib's stability with AFP. The study suggests Lapatinib's potential in disrupting the AFP-RARß complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.

Study on the interaction mechanism of whey protein isolate with phosphatidylcholine: By multispectral methods and molecular docking.

The elucidation of the interaction mechanism between phospholipids and milk proteins within emulsions is pivotal for comprehending the properties of infant formula fat globules. In this study, multispectral methods and molecular docking were employed to explore the relationship between phosphatidylcholine (PC) and whey protein isolate (WPI). Observations indicate that the binding constant, alongside thermodynamic parameters, diminishes as temperature ascends, hinting at a predominantly static quenching mechanism. Predominantly, van der Waals forces and hydrogen bonds constitute the core interactions between WPI and PC. This assertion is further substantiated by Fourier transform infrared spectroscopy, which verifies PC's influence on WPI's secondary structure. A detailed assessment of thermodynamic parameters coupled with molecular docking reveals that PC predominantly adheres to specific sites within α-lactalbumin, ß-lactoglobulin, and bovine serum albumin, propelled by a synergy of hydrophobic interactions, hydrogen bonding, and van der Waals forces, with binding energies noted at -5.59, -6.71, and -7.85 kcal/mol, respectively. An increment in PC concentration is observed to amplify the emulsification properties of WPI whilst concurrently diminishing the zeta potential. This study establishes a theoretical foundation for applying the PC-WPI interaction mechanism in food.

Synthetic Modification and Insecticidal Activity of 4-epi-cis-Dihydroagarofuran Derivatives.

To synthesize the fundamental framework of dihydroagarofuran, a novel strategy was devised for constructing the C-ring through a dearomatization reaction using 6-methoxy-1-tetralone as the initial substrate. Subsequently, the dihydroagarofuran skeleton was assembled via two consecutive Michael addition reactions. The conjugated diene and trans-dihydroagarofuran skeleton were modified. The insecticidal activities of 33 compounds against Mythimna separata were evaluated. Compounds 11-5 exhibited an LC50 value of 0.378 mg/mL. The activity exhibited a remarkable 29-fold increase compared to positive control Celangulin V, which was widely recognized as the most renowned natural dihydroagarofuran polyol ester insecticidal active compound. Docking experiments between synthetic compounds and target proteins revealed the shared binding sites with Celangulin V. Structure-activity relationship studies indicated that methyl groups at positions C4 and C10 significantly improved insecticidal activity, while ether groups with linear chains displayed enhanced activity; in particular, the allyl ether group demonstrated optimal efficacy. Furthermore, a three-dimensional quantitative structure-activity relationship model was established to investigate the correlation between the skeletal structure and activity. These research findings provide valuable insights for discovering and developing dihydroagarofuran-like compounds.

Renshen Yangrong decoction for secondary malaise and fatigue: network pharmacology and Mendelian randomization study.

Background: Renshen Yangrong decoction (RSYRD) has been shown therapeutic effects on secondary malaise and fatigue (SMF). However, to date, its bioactive ingredients and potential targets remain unclear. Purpose: The purpose of this study is to assess the potential ingredients and targets of RSYRD on SMF through a comprehensive strategy integrating network pharmacology, Mendelian randomization as well as molecular docking verification. Methods: Search for potential active ingredients and corresponding protein targets of RSYRD on TCMSP and BATMAN-TCM for network pharmacology analysis. Mendelian randomization (MR) was performed to find therapeutic targets for SMF. The eQTLGen Consortium (sample sizes: 31,684) provided data on cis-expression quantitative trait loci (cis-eQTL, exposure). The summary data on SMF (outcome) from genome-wide association studies (GWAS) were gathered from the MRC-IEU Consortium (sample sizes: 463,010). We built a target interaction network between the probable active ingredient targets of RSYRD and the therapeutic targets of SMF. We next used drug prediction and molecular docking to confirm the therapeutic value of the therapeutic targets. Results: In RSYRD, network pharmacology investigations revealed 193 possible active compounds and 234 associated protein targets. The genetically predicted amounts of 176 proteins were related to SMF risk in the MR analysis. Thirty-seven overlapping targets for RSYRD in treating SMF, among which six (NOS3, GAA, IMPA1, P4HTM, RB1, and SLC16A1) were prioritized with the most convincing evidence. Finally, the 14 active ingredients of RSYRD were identified as potential drug molecules. The strong affinity between active components and putative protein targets was established by molecular docking. Conclusion: This study revealed several active components and possible RSYRD protein targets for the therapy of SMF and provided novel insights into the feasibility of using Mendelian randomization for causal inference between Chinese medical formula and disease.

Integrating network pharmacology and Mendelian randomization to explore potential targets of matrine against ovarian cancer.

BACKGROUND: Matrine has been reported inhibitory effects on ovarian cancer (OC) cell progression, development, and apoptosis. However, the molecular targets of matrine against OC and the underlying mechanisms of action remain elusive. OBJECTIVE: This study endeavors to unveil the potential targets of matrine against OC and to explore the intricate relationships between these targets and the pathogenesis of OC. METHODS: The effects of matrine on the OC cells (A2780 and AKOV3) viability, apoptosis, migration, and invasion was investigated through CCK-8, flow cytometry, wound healing, and Transwell analyses, respectively. Next, Matrine-related targets, OC-related genes, and ribonucleic acid (RNA) sequence data were harnessed from publicly available databases. Differentially expressed analyses, protein-protein interaction (PPI) network, and Venn diagram were involved to unravel the core targets of matrine against OC. Leveraging the GEPIA database, we further validated the expression levels of these core targets between OC cases and controls. Mendelian randomization (MR) study was implemented to delve into potential causal associations between core targets and OC. The AutoDock software was used for molecular docking, and its results were further validated using RT-qPCR in OC cell lines. RESULTS: Matrine reduced the cell viability, migration, invasion and increased the cell apoptosis of A2780 and AKOV3 cells (P< 0.01). A PPI network with 578 interactions among 105 candidate targets was developed. Finally, six core targets (TP53, CCND1, STAT3, LI1B, VEGFA, and CCL2) were derived, among which five core targets (TP53, CCND1, LI1B, VEGFA, and CCL2) differential expressed in OC and control samples were further picked for MR analysis. The results revealed that CCND1 and TP53 were risk factors for OC. Molecular docking analysis demonstrated that matrine had good potential to bind to TP53, CCND1, and IL1B. Moreover, matrine reduced the expression of CCND1 and IL1B while elevating P53 expression in OC cell lines. CONCLUSIONS: We identified six matrine-related targets against OC, offering novel insights into the molecular mechanisms underlying the therapeutic effects of matrine against OC. These findings provide valuable guidance for developing more efficient and targeted therapeutic approaches for treating OC.

Computational Bio prospecting of Phyto - constituents as potential inhibitors for Peptide deformylase from Streptococcus oralis: an opportunistic pathogen.

Streptococcus oralis an opportunistic bacterium has been reported to be involved in various blood borne infections like subacute bacterial endocarditis, septicaemia, bacterial meningitis and in some cases dental caries too. Among various targets the peptide deformylase, of S.oralis appears to be most potent druggable target as it is involved in protein synthesis is opted for the current study. Due to unavailability of PDB structure of peptide deformylase from S. oralis the study initiates with homology modelling of the protein and 6OW2 of S pneumoniae is considered as the template. Thereafter, Molecular docking, Molecular dynamic simulation, ADME analysis, and MMPBSA analysis was carried out to explore the inhibitory potential of phyto-constituents as potential inhibitors for Peptide deformylase from S.oralis. Actinonin was considered as reference drug. Among 2370 phyto compounds the best observations were recorded for A1-Barrigenol (IMPHY010984) with binding affinity of -8.5kcal/mol. Calculated RMSD, RMSF, Binding Free Energy for IMPHY010984 averaged at about 0.10±0.03nm, 0.08±0.05nm, 131±21kJ/mol respectively whereas the RMSD, RMSF, Binding Free Energy recorded for reference drug averaged at about 0.19±0.04nm, 0.11±0.08nm, -94±18kJ/mol respectively. Based on in silico observations IMPHY010984 is proved out as superior candidate over reference drug. The study reflects the potential of IMPHY010984 as prophylactic therapeutics for S.oralis.