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• DSS significantly improves NS treatment outcomes compared to western medicine alone. • Network pharmacology analysis identifies multiple active compounds and pathways targeted by DSS. • DSS regulates key targets involved in inflammation, immunity, and renal fibrosis. • Study provides evidence for DSS as a promising treatment option for NS. The purpose of this study was to investigate the efficacy and mechanism of DSS in treating nephrotic syndrome through meta-analysis and network pharmacology methods. To conduct a comprehensive search for randomized controlled trials on the efficacy of Danggui Shaoyao San (DSS) in the treatment of nephrotic syndrome, we searched across eight electronic databases from their establishment to May 1, 2023. The Cochrane Collaboration's Risk of Bias 2 tool was used to evaluate the quality of evidence regarding bias risk and outcomes. Statistical analysis was performed using RevMan software (version 5.4). Furthermore, network pharmacology was employed to validate the underlying mechanism. This study included 14 articles that involved 1256 patients with nephrotic syndrome. The clinical efficacy of DSS against nephrotic syndrome was significantly higher than that of Western medical treatment alone. In comparison with the control groups, which were administered Western medicines alone, the use of DSS significantly increased plasma albumin levels (mean difference [MD] = 4.32, 95 % confidence interval [CI] [2.37, 6.24], p < 0.00001) and reduced 24 h urinary protein excretion (MD = −0.92, 95 % CI [−1.11, −0.73], p < 0.00001), total cholesterol levels (MD = −1.23, 95 % CI [−1.76, −0.70], p < 0.00001), triglyceride levels (MD = −0.37, 95 % CI [−0.54, −0.20], p < 0.00001). Furthermore, the combination of DSS with Western medicines achieved better control of adverse reactions in comparison with the control groups (relative risk = 0.37, 95 % CI [0.29, 0.49], p < 0.00001). Network pharmacology analysis identified 39 important active compounds and 18 core target genes involved in the treatment of primary nephrotic syndrome by DSS. Gene Ontology enrichment analysis identified 2126 biological processes, 64 cellular components, and 115 molecular functions, while Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified 149 signaling pathways. Key active compounds include ginsenoside Rg5, ginsenoside Rg1, schisandrin A, berberine, gallic acid, quercetin, and β-sitosterol, while potential core target genes include IL6, AKT1, TNF, VEGFA, IL1B , and TP53. KEGG pathway analysis indicated that DSS is involved in multiple mechanisms, such as neural development, synaptic plasticity, programmed cell death, inflammation, and immunity. DSS has higher efficacy and safety in the treatment of nephrotic syndrome and acts on nephrotic syndrome via mechanisms that involve multiple targets, components, and pathways. [ABSTRACT FROM AUTHOR]

Clerodendrum viscosum Vent. is a well-known plant in Indian and Chinese traditional medicine systems. While studies showed its crude leaf extract's cytotoxicity against HT-29 and HeLa cells, various non-bioactive compounds present in crude extracts may influence overall bioactivity. This study aimed to separate the most bioactive fractions from Clerodendrum viscosum 's crude extracts that exhibit anticancer potential against HepG2 cells. Crude extracts were fractionated using a solvent-polarity-based process and their anticancer activity was investigated through in vitro, in silico, and network pharmacology approaches. Nonpolar leaf (CVL H) and root (CVR H) fractions showed maximum cytotoxicity in HepG2 cells without affecting noncancer-origin WRL68 cells. Both extracts induced oxidative stress, DNA damage, cell cycle arrest, and apoptosis in HepG2 cells, with CVR H exhibiting a superior effect. GC-MS analysis identified various anticancer phytochemicals differentially present in CVL H and CVR H. Network pharmacology with these phytochemicals predicted Bcl-2 as the primary target, while molecular docking confirmed lupeol, stigmasterol, alpha-amyrin, cycloartenol, and calysterol being the top five phytochemicals exhibiting strong binding against Bcl-2, androgen receptor (AR), and epidermal growth factor receptor (EGFR). Western blot confirmed an elevated Bax/Bcl-2 ratio in HepG2 cells by CVL H and CVR H. In summary, the nonpolar fractions of Clerodendrum viscosum leaf and root crude extracts showed enhanced anticancer activity, suggesting their potential pharmaceutical applications. [Display omitted] • Separation of natural bioactive fractions from medicinal plant Clerodendrum viscosum. • Selective toxicity of nonpolar leaf (CVL H) & root (CVR H) fractions in HepG2 cells. • Mitochondrial dysfunction, DNA damage, apoptosis & cell cycle arrest by CVL H & CVR H. • Main target of CVL H & CVR H for anti-liver cancer activity: Bcl-2. • Low K i for CVL H & CVR H bioactive compounds-key liver cancer protein interactions. [ABSTRACT FROM AUTHOR]

• Clerodendrum glandulosum (CG) species have not been explored for diabetic wound healing. • This species is rich in phenylethanoid glycosides (PhGs), a subclass of polyphenols. • Verbascoside, isoverbascoside, martynoside, and isomartynoside are the four PhGs. • This study explores the diabetic wound healing property of the PhGs in CG by in-silico approaches. The diabetic wound is one of the severe complications of diabetes mellitus, accounting for 20 % of limb amputations in diabetic patients. This creates a need to search for newer natural compounds to target the different molecular pathways of diabetic wounds to accelerate the repair. The phenylethanoid glycosides (PhGs) isolated from Clerodendrum glandulosum (CG) have been shown to exhibit antioxidant, antimicrobial, and anti-inflammatory properties but have never been explored for diabetic wound healing. Thus, this study focuses on exploring the diabetic wound-repairing properties of PhGs through in-silico approaches. The PhGs present in CG were identified through extensive literature searching, which were further subjected to database searching in BindingDB, TargetNet, PharmMapper, Super-PRED, and Swiss Target Prediction to find the potential targets, which included PRKCA, PRKCG, PRKCZ, TDP1, and Pol. Subsequently, these targets were used to determine the disease IDs related to diabetic wounds from databases such as DisGeNET, Gene Expression Omnibus, GeneCards, and OMIM. A network was established using Cytoscape to study the relationship among the PhGs, the protein targets, and their associated disease IDs. The top twenty molecular pathways associated with the target proteins were determined using the ShinyGO database. Genetic enrichment analysis showed that the Sphingolipid signalling pathway included the maximum number of genes and had the lowest false discovery rate value, which concluded that this pathway is the potential target of the PhGs. PRKCA and PRKCZ were found to be the only two genes involved in this pathway, and thus, molecular docking was used to evaluate the binding affinity of the PhGs with the proteins. Docking scores were between -13.2859 and -5.10928, suggesting a strong molecular interaction between the PhGs and their targets. Thus, it is concluded that PhGs present in CG can be the potential compounds to treat diabetic wounds; however, further in-vitro and in-vivo investigations are necessary. [ABSTRACT FROM AUTHOR]

[Display omitted] • Schisandra chinensis (SC)'s components exhibit effectiveness in treating NP/DD. • A complex network of interactions was seen brtween targets of SC and NP/DD. • SC regulates pathways involving TNF, VEGF, and growth hormones in treating NP/DD. • Our results enhances understanding of SC's molecular mechanisms in NP/DD treatment. This study utilized network pharmacology and docking analyses to explore a groundbreaking therapeutic approach for managing the neuropathic pain and depressive disorder (NP/DD) comorbidity. Schisandra chinensis (SC), a common Chinese medicine, has demonstrated numerous beneficial effects in treating neuropsychological disorders. The main objective of this study was to identify potential bioactive components of SC and investigate their interactions with relevant target genes associated with NP/DD. To gain insights into the underlying molecular mechanisms, GO and KEGG analyses were conducted. Furthermore, molecular docking analysis was employed to validate the therapeutic relevance of SC's active ingredients. Seven bioactive components of SC, namely Longikaurin A, Deoxyharringtonine, Angeloylgomisin O, Schisandrin B, Gomisin A, Gomisin G, and Gomisin R, exhibited effectiveness in the treatment of NP/DD. From this list, the first five components were selected for further analysis. The analyses revealed a complex network of interactions between the targets of SC and NP/DD, providing valuable information about the molecular mechanisms involved in the treatment of NP/DD with SC. SC components demonstrated the ability to regulate pathways involving tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), and other growth hormones (GH). Overall, this study contributes to our understanding of the molecular mechanisms underlying the effects of SC in treating NP/DD. Further investigation is necessary to explore the therapeutic potential of SC as a viable strategy for NP/DD comorbidity. These findings lay a solid foundation for future research endeavors in this field, holding potential implications for the development of novel therapeutic interventions targeting NP/DD. [ABSTRACT FROM AUTHOR]

• The composition and bioactivities of essential oil (EO) from Bulbophyllum kwangtungense were investigated for the first time. • Network pharmacology was utilized to evaluate B. kwangtungense EO potential therapeutic effects. • B. kwangtungense EO can be exploited as nature-derived antioxidant preservatives, synergistic antibiotics, and therapeutic agents against oxidative stress. The present study investigates the chemical composition of the essential oil (EO) from Bulbophyllum kwangtungense Schltr., evaluates its antioxidant, enzyme inhibitory activities, and analyzes its therapeutic mechanisms against oxidative damage through network pharmacology. The main components identified were n -hexadecanoic acid (9.95 %), linalool (9.17 %), 1-hexanol (5.16 %), pentadecanoic acid (4.66 %), (Z)-3-hexen-1-ol (3.39 %), phytol (2.67 %), linoleic acid (2.49 %), 1-hexadecanol (2.39 %), α-curcumene (2.28 %). The 2,2′-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS), 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) free radical scavenging capacity was characterized by IC 50 values of 0.43 ± 0.08 mg/mL and 3.87 ± 1.26 mg/mL. The ferric reducing antioxidant power (FRAP) antioxidant value (Trolox equivalent antioxidant concentration) was 116.49 ± 0.26 μM/g. The EO exhibited anti-β-lactamase activity with an IC 50 of 229.4 ± 18.7 μg/mL. The anti-acetylcholinesterase activity was 18.10 ± 2.71% at the 500 μg/mL concentration. The network pharmacology analysis was conducted to reveal potential targets and pathways of oxidative damage involved in the therapeutic effects of our EO. [ABSTRACT FROM AUTHOR]

Post-marketing surveillance found montelukast use was associated with an increased risk of depression. However, results of observational studies are inconsistent. This study aimed to assess whether montelukast exposure is associated with depression and elucidate the possible molecular mechanism. We conducted a cross-sectional study of 9508 adults from the National Health and Nutrition Examination Survey (NHANES) 2007–2016. Multivariable regression was used to evaluate the association between montelukast exposure and depression. Network pharmacology was conducted to identify the mechanisms of montelukast on depression. Montelukast exposure had a higher prevalence of depression (37.4 %). In a multivariable logistic regression model adjusted for sociodemographic, behavioural, and health characteristics, montelukast exposure was associated with depression (odds ratio [OR]: 1.61; confidence interval [CI]: 1.18–2.19). Network pharmacology was identified 69 key targets of montelukast on depression. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested montelukast mainly works through multiple pathways in endocrine resistance, chemical carcinogenesis-receptor activation, estrogen signaling pathway, etc. Cross-sectional data. The study implies a potential positive association between long-term montelukast exposure and depression through multi-faceted mechanisms. It is suggested that attention be given to the possibility of depression in patients undergoing prolonged montelukast therapy. • Montelukast exposure linked to higher depression prevalence (37.4%). • Montelukast use associated with increased depression risk (OR, 1.61; 95% CI, 1.18-2.19). • Montelukast exposure linked to depression via multi-target mechanisms. [ABSTRACT FROM AUTHOR]

• CA is the most abundant bioactive compound found in Vaccinium dunalianum Wight. • A COX-2/1 zebrafish model was set up to illustrate CA's anti-inflammatory effects. • CA's anti-inflammatory mechanism was analyzed with systematic network pharmacology. 6′- O -Caffeoylarbutin (CA) is the most abundant compound found within Vaccinium dunalianum Wight, which is used as a traditional Chinese herbal tea for its effects in lowering uric acid and anti-rheumatoid arthritis. No reports to date, however, have explored the pharmacological impact of CA on inflammatory activity. In this study, the anti-inflammatory targets and molecular mechanisms of CA were evaluated through zebrafish inflammation model, network pharmacology and molecular docking. The results showed that CA was able to inhibit cyclooxygenase (COX-2/1) at a dose-dependent fashion in 12- O -tetradecanoylphorbol-13-acetate (TPA)-treated zebrafish. Network pharmacology analyses was employed to derive 156 putative CA-related anti-inflammatory targets, which were subjected to functional enrichment analyses to obtain 511 associated Gene Ontology (GO) terms and 180 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Moreover, 9 core targets (HRAS, SRC, MMP9, HSP90AA, CASP, ANXA5, EGFR, ESR1, and AKT1) associated with the anti-inflammatory effect of CA were further selected and identified based on network topology analyses and molecular docking. Overall, the results of this study suggest that CA exerts its anti-inflammatory effects through a complex mechanism of action, and these findings offer a robust foundation for future in-depth analyses exploring the pharmacological pathways through which CA can prevent rheumatoid arthritis-associated damage. [ABSTRACT FROM AUTHOR]

• This is the first study to provide an effective and rapid method for evaluating the effectiveness of traditional medicinal parts of Cassia agnes Brenan. • Leaves may be the main medicinal part of Cassia agnes Brenan. • Flavonoids are the main enriched metabolites in leaves of Cassia agnes Brenan. Cassia agnes Brenan , a classic Chinese herbal formula, has been widely used for treating various ailments such as stomach pain, cold, malaria, measles, chicken pox, and constipation. Modern pharmacological studies have shown that different parts of Cassia agnes Brenan have distinct effects. However, there is a lack of literature on the comparative analysis of chemical components across different parts. The aim of this study is to identify the distinct compounds present in Cassia agnes Brenan leaves and fruits and to conduct network pharmacological research on these compounds to identify potential active ingredients. Metabolomics was employed to analyze the chemical composition of various parts of Cassia agnes Brenan. Subsequently, network pharmacological research was conducted to identify potential active compounds. Target prediction and KEGG pathway analysis were performed to analyze the pharmacological effects and mechanisms of Cassia agnes Brenan. Flavonoids were found to be significantly enriched in the leaves compared to the fruits, suggesting that leaves may be the primary medicinal part of Cassia agnes Brenan. Additionally, an effective and rapid method for evaluating the efficacy of traditional medicinal parts of Chinese herbal medicine was established. In this study, we identified potential active compounds in different parts of Cassia agnes Brenan and provided a rapid method for evaluating the efficacy of traditional medicinal parts of Chinese herbal medicine. These findings contribute to the understanding of the pharmacological effects and mechanisms of Cassia agnes Brenan, facilitating further research in this area. [ABSTRACT FROM AUTHOR]

Quetiapine monotherapy is recommended as the first-line option for acute mania and acute bipolar depression. However, the mechanism of action of quetiapine is unclear. Network pharmacology and molecular docking were employed to determine the molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania. Putative target genes for quetiapine were collected from the GeneCard, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and bipolar mania were identified from the DisGeNET and GeneCards databases. A protein-protein interaction (PPI) network was generated using the String database and imported into Cytoscape. DAVID and the Bioinformatics platform were employed to perform the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the top 15 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the interactions between quetiapine and potential targets. Targets for quetiapine actions against bipolar depression (126 targets) and bipolar mania (81 targets) were identified. Based on PPI and KEGG pathway analyses, quetiapine may affect bipolar depression by targeting the MAPK and PI3K/AKT insulin signaling pathways via BDNF, INS, EGFR, IGF1, and NGF, and it may affect bipolar mania by targeting the neuroactive ligand-receptor interaction signaling pathway via HTR1A, HTR1B, HTR2A, DRD2, and GRIN2B. Molecular docking revealed good binding affinity between quetiapine and potential targets. Pharmacological experiments should be conducted to verify and further explore these results. Our findings suggest that quetiapine affects bipolar depression and bipolar mania through distinct biological core targets, and thus through different mechanisms. Furthermore, our results provide a theoretical basis for the clinical use of quetiapine and possible directions for new drug development. • Quetiapine affects bipolar depression and bipolar mania through different mechanisms. • Quetiapine affects depression by targeting MAPK and PI3K/AKT insulin signaling pathways via BDNF, INS, EGFR, IGF1, NGF. • Quetiapine affects mania through neuroactive ligand-receptor interaction pathway via HTR1A, HTR1B, HTR2A, DRD2, GRIN2B. [ABSTRACT FROM AUTHOR]

The exploration of drugs derived from natural sources holds significant promise in addressing current limitations in ovarian cancer (OC) treatments. While previous studies have highlighted the remarkable anti-cancer properties of the natural compound β-sitosterol (SIT) across various tumors, its specific role in OC treatment remains unexplored. This study aims to investigate the anti-tumor activity of SIT in OC using in vitro and in vivo models, delineate potential mechanisms, and establish a preclinical theoretical foundation for future clinical trials, thus fostering further research. Utilizing network pharmacology, we pinpoint SIT as a promising candidate for OC treatment and predict its potential targets and pathways. Through a series of in vitro and in vivo experiments, we unveil a novel mechanism through which SIT mitigates the malignant biological behaviors of OC cells by modulating redox status. Specifically, SIT selectively targets argininosuccinate synthetase 1 (ASS1), a protein markedly overexpressed in OC tissues and cells. Inhibiting ASS1, SIT enhances the interaction between Nrf2 and Keap1, instigating the ubiquitin-dependent degradation of Nrf2, subsequently diminishing the transcriptional activation of downstream antioxidant genes HO-1 and NQO1. The interruption of the antioxidant program by SIT results in the substantial accumulation of reactive oxygen species (ROS) in OC cells. This, in turn, upregulates PTEN, exerting negative regulation on the phosphorylation activation of AKT. The suppression of AKT signaling disrupted downstream pathways associated with cell cycle, cell survival, apoptosis, migration, and invasion, ultimately culminating in the death of OC cells. Our research uncovers new targets and mechanisms of SIT against OC, contributing to the existing knowledge on the anti-tumor effects of natural products in the context of OC. Additionally, this research unveils a novel role of ASS1 in regulating the Nrf2-mediated antioxidant program and governing redox homeostasis in OC, providing a deeper understanding of this complex disease. [Display omitted] • Our study confirmed SIT's potent anti-ovarian cancer activity in vitro and in vivo. • Our study revealed SIT induces ROS accumulation, negatively modulating PTEN/AKT in anti-ovarian cancer action. • Our study demonstrated for the first time the inhibitory effect of SIT on a novel target, ASS1. • Our study unveiled ASS1's regulation of Nrf2 antioxidant program in ovarian cancer by modulating Nrf2-Keap1 interaction, reducing ubiquitination and degradation. [ABSTRACT FROM AUTHOR]

• Pharmacological mechanisms of Cymbopogon citratus against Alzheimer's Disease (AD). • Integration of network pharmacology and molecular modeling approaches. • Compound-target-pathway network elucidated the drug action mechanism in AD. • Active constituents showed appreciable inhibitory effects against IL6 and SRC. • Potential C. citratus ingredients may act on multiple signaling for AD treatment. Alzheimer's disease (AD) is the most common type of dementia, accounting for at least two-thirds of cases of dementia in people age 65 and older. The limited amount of available data and multiple spectra of pathophysiological mechanisms of AD make it a challenging task and a serious economic load on the community health sector. Cymbopogon citratus is a tall perennial fast-growing grass with tuft of lemon-scented leaves from the annulate and sparingly branched rhizomes. A list of studies evidences the therapeutic efficacy of C. citratus against AD, but the precise molecular mechanism is yet to be discovered. This research utilizes network pharmacology and molecular docking approaches to elucidate the multi-target effects of C. Citratus on AD, identifying its active compounds, potential therapeutic targets, and associated signaling pathways. Initially the active compounds of C. citratus , the target genes related to both the C. citratus and the AD were retrieved from literature as well as databases. The PPI network of these target genes was constructed using STRING database and later the hub genes were screened by importing the network into the Cytoscape. The interactions among the target genes and the compounds were also analyzed using Cytoscape. The Gene Ontology (GO) and KEGG pathways of these hub genes were explored to reveal the genes involved in AD-related pathways. These compound-target, genes-pathway networks were explored which uncovered that bioactive compounds of C. citratus may serve as a magic bullet against AD by influencing the target genes involved in the disease pathogenesis. Further, the microarray data was analyzed to explore the expression level of core target genes. Lastly, docking analysis further strengthened the current findings by validating the effective activity of the bioactive compounds against putative target genes. Network pharmacology based analysis highlighted the pathways related to AD, the ten target genes, and the compounds involved in the AD disease mechanism. Through the analysis of microarray expression data, the two genes SRC and IL6 were found to have differential expression. Moreover, the molecular docking analysis predicted the string binding affinity among these genes and active compounds. In summary, our study proposed that five key compounds catechin, apigenin, 8-prenylnaringenin, quercetin, and luteolin contributed to the development of AD by affecting IL6 and SRC genes. The overall integration of network pharmacology with molecular docking unveiled the multi-target pharmacological mechanisms of C. citratus against AD. This study provides convincing evidence that C. citratus might partially alleviate the AD and ultimately lays a foundation for further experimental research on the anti-AD activity of C. citratus. [ABSTRACT FROM AUTHOR]

• The total flavonoids may be the main effective fraction of Artemisia annua L. anti-BRCA. • The quercetin, luteolin, kaempferol were hub compounds of A. annua L. against BRCA. • BICR5, CCNA2, E2F1 and FOS were key targets of A. annua L. against BRCA. • This study provide a theoretical basis for the study of the anti-BRCA effect and clinical application of A. annua l. Artemisia annua L. has been revealed to possess antitumor effect in various human cancers. However, the mechanism of A. annua treating breast cancer (BRCA) has not been clearly elucidated. In present study, the bioactive compounds and mechanism of A. annua in the treatment of BRCA were explored based on network pharmacology and molecular docking. TCMSP database was used to predict the active components and components targets of A. annua. The targets of BRCA were collected through TTD, GeneCards, OMIM, PharmGKB and DisGeNET database. The analysis of GO and KEGG enrichment was conducted for intersection targets. Protein–Protein interaction (PPI) network was constructed using the STRING online database. Candidate core targets were screened using the gene expression analysis and survival analysis. Molecular docking analysis was conducted to verify whether the bioactive compounds had a definite affinity with candidate core targets. Finally, MTT and RT-qPCR experiments of MCF-7 cells and MDA-MB-231 cells were carried out to verify the results of network pharmacology. The quercetin, luteolin, kaempferol were selected as hub compounds of A. annua against BRCA. After the conduction of topological analysis, survival analysis, and gene expression analysis for the potential targets of A. annua against BRCA, 4 candidate hub targets (BICR5, CCNA2, E2F1 and FOS) were identified. Molecular docking results demonstrated that 3 hub components of A. annua had strong binding efficiency with the 4 candidate hub targets. The enrichment analysis of KEGG pathway revealed that A. annua exerted anti-BRCA effects via p53 signaling pathway, etc. After treated with total flavonoids of A. annua (ATF) for 48 h, mRNA expression levels of BICR5, CCNA2, E2F1 and FOS were significantly down-regulated in both MCF-7 cells and MDA-MB-231 cells. The present study reveals the mechanism of A. annua against BRCA through multiple targets, multiple ingredients and multiple signal pathways, and provides more references for its clinical application. [ABSTRACT FROM AUTHOR]

• Viscutins were found to be very promising α-glucosidase inhibitors using molecular docking. • Isomerism in diacylated CGAs was found to have influence on pharmacological properties of these compounds. • Polyphenolic compounds derived from Viscum combreticola were found to be potential therapeutic targets for complications associated with type 2 diabetes mellitus. Viscum combreticola Engl. is currently used in African medicine for treating various ailments including diabetes. However, modernizing plant-based traditional medicine is a considerable challenge due to lack of scientific information linked to its therapeutic efficacy given the complexity of plant extracts. Herein, methanolic extracts were evaluated for their anti-diabetic and antioxidative properties through the α-glucosidase in vitro inhibition assay and LC-ESI-Q-TOF-MS coupled to pre-column DPPH assay, respectively. Furthermore, metabolic profiling of V. combreticola extracts was conducted using UHPLC-q-TOF-MS technique. The identified chemically diverse polyphenols comprising of 19 diacylated chlorogenic acids (CGAs) and 12 flavonoids were explored for their mode of action in managing type 2 diabetes mellitus (T2DM) using network pharmacology. Systematic pharmacological analysis revealed that CGAs and flavonoids characterized by structural similarities or analogous spatial arrangements exhibited interactions with identical target proteins. Isomers of CGAs diacylated at carbon positions 3,4 (3,4-diCQA; 3- p -Co-4-CQA and 3-C-4- p -CoQA) as well as 4,5 (4,5-diCQA;4-C-5- p -CoQA; and 4- p -Co-5-CQA) of quinic acid were found to be hub therapeutic agents against T2DM related target proteins. The investigated CGAs and flavonoids could be playing a major role in the management of T2DM and its complications by synergistically regulating key protein targets. These include matrix metalloproteinase 2 (MMP2), caspase 3 (CASP3), protein kinase C alpha and delta (PRKCA and PRKCD), which are related to T2DM hub pathways such as the lipid and atherosceloresis, AGE-RAGE signalling pathway for diabetes complications and diabetic cardiomyopathy signalling pathways. Finally, molecular docking studies revealed that viscutin 2 and 3,4-diCQA were key potential inhibitors of α-glucosidase and MMP2, respectively. Therefore, the findings of this study suggest that isomerism in compounds might have pharmacological implications. Lastly, the anti-T2DM therapeutic effects of the polyphenols investigated in this study can serve as potential anti-diabetic agents for future experimental validation, particularly paying attention to isomerism. [ABSTRACT FROM AUTHOR]

Since ages, natural products have laid the foundation for the development of promising antimicrobials. With the advent of antimicrobial resistance, the search for effective antimicrobials continues as its shortfall will menace the healthcare system. Natsiatum herpeticum remained the least explored plant despite its ethnopharmacological claims. DNA barcoding was performed to identify and ensure quality control of the plant materials used in the experiment. QToF-MS analysis followed by network pharmacology revealed TNF and IRAK4 to be the two gene targets that can be modulated by the compounds present in the extract. Analysis of potential drug-like compounds using molecular docking (against 1KZN, 2VF5, 2W9S, and 4CJN) and MD simulation suggested compound CPD2 to be the most potent molecule against the bacterial targets. Bacteriostatic activity against E. coli was exhibited by the extract (MIC=50 μg/ml) in the microtiter-plate dilution method. Our results suggest that N. herpeticum not only exhibits potential bacteriostatic activity against E. coli but can also modulate host-immune responses via TNF and IRAK4-associated pathways. [Display omitted] • DNA barcoding using rbcL marker was done. • N. herpeticum modulate host-immune responses via TNF and IRAK4 associated pathways. • Bacteriostatic activity against E. coli was exhibited by the extract (MIC=50 μg/ml). [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect and underlying mechanism of Fructus lycii in improving exercise fatigue. A network pharmacological approach was used to explore potential mechanisms of action of Fructus lycii. Skeletal muscle C2C12 cells and immunofluorescence were employed to verify the effect and mechanism of the representative components in Fructus lycii predicted by network pharmacological analysis. Six potential active components, namely quercetin, β-sitosterol, stigmasterol, 7-Omethylluteolin-6-C-beta-glucoside_qt, atropine, and glycitein, were identified to have potency in improving exercise fatigue via multiple pathways, such as the PI3K-Akt, neuroactive ligand-receptor interaction, IL-17, TNF, and MAPK signaling pathways. The immunofluorescence results indicated that quercetin, a significant active component in Fructus lycii , increased the mean staining area of 2-NBDG, TMRM, and MitoTracker, and decreased the area of CellRox compared to the control. Furthermore, the protein expression levels of p-38 MAPK, p-MAPK, p-JNK, p-PI3K, and p-AKT markedly increased after quercetin treatment. Fructus lycii might alleviate exercise fatigue through multiple components and pathways. Among these, quercetin appears to improve exercise fatigue by enhancing energy metabolism and reducing oxidative stress. The PI3K-AKT and MAPK signaling pathways also appear to play a role in this process. [ABSTRACT FROM AUTHOR]

Influenza is an acute viral respiratory infection that has caused high morbidity and mortality worldwide. Influenza A virus (IAV) has been found to activate multiple programmed cell death pathways, including ferroptosis. Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. However, little is known about how influenza viruses induce ferroptosis in the host cells. In this study, based on network pharmacology, we predicted the mechanism of action of Maxing Shigan decoction (MXSGD) in IAV-induced ferroptosis, and found that this process was related to biological processes, cellular components, molecular function and multiple signaling pathways, where the hypoxia inducible factor-1(HIF-1) signaling pathway plays a significant role. Subsequently, we constructed the mouse lung epithelial (MLE-12) cell model by IAV-infected in vitro cell experiments, and revealed that IAV infection induced cellular ferroptosis that was characterized by mitochondrial damage, increased reactive oxygen species (ROS) release, increased total iron and iron ion contents, decreased expression of ferroptosis marker gene recombinant glutathione peroxidase 4 (GPX4), increased expression of acyl-CoA synthetase long chain family member 4 (ACSL4), and enhanced activation of hypoxia inducible factor-1α (HIF-1α), induced nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) in the HIF-1 signaling pathway. Treatment with MXSGD effectively reduced intracellular viral load, while reducing ROS, total iron and ferrous ion contents, repairing mitochondrial results and inhibiting the expression of cellular ferroptosis and the HIF-1 signaling pathway. Finally, based on animal experiments, it was found that MXSGD effectively alleviated pulmonary congestion, edema and inflammation in IAV-infected mice, and inhibited the expression of ferroptosis-related protein and the HIF-1 signaling pathway in lung tissues. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) has developed into the most common chronic liver disease and can lead to liver cancer. Our laboratory previously developed a novel prescription for NAFLD, "Eight Zhes Decoction" (EZD), which has shown good curative effects in clinical practice. However, the pharmacodynamic material basis and mechanism have not yet been revealed. A strategy integrating lipidomics, network pharmacology and pharmacokinetics was used to reveal the active components and mechanisms of EZD against NAFLD. The histopathological results showed that EZD attenuated the degrees of collagen deposition and steatosis in the livers of nonalcoholic steatofibrosis model mice. Furthermore, glycerophospholipid metabolism, arachidonic acid metabolism, glycerolipid metabolism and linoleic acid metabolism with phospholipase A2 group IVA (PLA2G4A) and cytochrome P450 as the core targets and 12,13- cis -epoxyoctadecenoic acid, 12(S)-hydroxyeicosatetraenoic acid, leukotriene B4, prostaglandin E2, phosphatidylcholines (PCs) and triacylglycerols (TGs) as the main lipids were found to be involved in the treatment of NAFLD by EZD. Importantly, naringenin, artemetin, canadine, and bicuculline were identified as the active ingredients of EZD against NAFLD; in particular, naringenin reduces PC consumption by inhibiting the expression of PLA2G4A and thus promotes sufficient synthesis of very-low-density lipoprotein to transport excess TGs in the liver. This research provides valuable data and theoretical support for the application of EZD against NAFLD. [Display omitted] • Integrated lipidomics, network pharmacology and pharmacokinetics method was applied. • EZD alleviated lipid dysfunction in NAFLD. • Naringenin, artemetin, canadine, and bicuculline were the active ingredients. • PLA2G4A and CYP450 participate in EZD treatment of NAFLD. [ABSTRACT FROM AUTHOR]

• Molecular mechanism behind the health protective effect of Ulmus davidiana is studied using a network pharmacology approach. • A total of 396 targets were identified for screened compounds, with 242 targets specifically associated with gastric cancer. • Key differentially expressed genes (MMP7, TOP2A, CCNB2, MMP12, and CCNB2) were found to be associated with gastric cancer. • The interferon-gamma and CCKR signaling pathway were identified as the most enriched pathways in the gastric cancer network. • Phytochemicals (torilin, 1-hydroxytorilin, and 1-hydroxytorilin A) with high docking scores and interactions with core targets were identified. Ulmus davidiana (UD) , has long been utilized in traditional medicine to treat various diseases, particularly gastric cancer (GC). However, the molecular mechanism behind its health-protective effect has yet to be clarified. An extensive literature search was conducted to collect all reported phytochemicals of the plant, which were then filtered for druglike properties. SwissTargetPrediction was utilized to predict targets for phytochemicals and functional enrichment of targets was performed for GO, pathways, and diseases. A network pharmacology approach was used to investigate all possible targets and targets specifically associated with GC. The expression of target genes was also studied for their expression in the TCGA patient GC dataset from TCGA through GEPIA 2.0. Cytoscape and STRING were used for network construction and analysis, while core targets and filtered phytochemicals were employed for molecular docking. In total, 396 targets for screened compounds, of which 242 targets were associated with GC. Among these, 87 targets were differentially expressed in GC. Several highly differentially expressed genes (MMP7, TOP2A, CCNB2, MMP12, and CCNB2) were found to be strongly associated with gastric cancer. Target enrichment categories were correlated with the known bioactivities of UD such as antioxidant, anti-inflammatory, and anticancer properties. Cancer and neurological complications-related diseases were prevalent in the associated disease network. The interferon-gamma signaling pathway was identified as the most enriched pathway for gastric cancer targets (GT). CCKR signaling was found to be the most connected pathway in the GC network. Core targets (HSP90AA1, STAT3, SRC, ESR1, and EGFR) were determined through protein-protein-interaction network analysis. Molecular docking revealed phytochemicals (torilin, 1-hydroxytorilin, and butyl alpha-D-fructofuranoside) with high docking scores and strong interactions with core targets. The key findings of the study, including phytochemicals, targets, and pathways, are suggested for further validation. [ABSTRACT FROM AUTHOR]

The incidence of Hepatocellular Carcinoma (HCC) in Saudi Arabia is not surprising given the relatively high prevalence of hepatitis C virus (HCV) infection. Hepatitis C is also common in Saudi Arabia with a prevalence rate of 1% to 3% of the population, which further increases the risk of HCC. The incidence of HCC has been increasing in recent years, with HCV-related HCC accounting for a significant proportion of cases. Traditional medicine has long been a part of Saudi Arabian culture, and many medicinal plants have been used for centuries to treat various ailments, including cancer. Following that, this study combines network pharmacology with bioinformatics approaches to potentially revolutionize HCV-related HCC treatment by identifying effective phytochemicals of indigenous plants of Medina valley. Eight indigenous plants including Rumex vesicarius, Withania somnifera, Rhazya stricta, Heliotropium arbainense, Asphodelus fistulosus, Pulicaria incise, Commicarpus grandiflorus, and Senna alexandrina, were selected for the initial screening of potential drug-like compounds. At first, the information related to active compounds of eight indigenous plants was retrieved from public databases and through literature review which was later combined with differentially expressed genes (DEGs) obtained through microarray datasets. Later, a compound-target genes-disease network was constructed which uncovered that kaempferol, rhazimol, beta-sitosterol, 12-Hydroxy-3-keto-bisnor-4-cholenic acid, 5-O-caffeoylquinic acid, 24-Methyldesmosterol, stigmasterone, fucosterol, and withanolide_J decisively contributed to the cell growth and proliferation by affecting ALB and PTGS2 proteins. Moreover, the molecular docking and Molecular Dynamic (MD) simulation of 20 ns well complemented the binding affinity of the compound and revealed strong stability of predicted compounds at the docked site. But the findings were not validated in actual patients, so further investigation is needed to confirm the potential use of selected medicinal plants towards HCV-related HC. [ABSTRACT FROM AUTHOR]

Chang-Kang-Fang (CKF) formula, a Traditional Chinese Medicine (TCM) prescription, has been widely used for the treatment of irritable bowel syndrome (IBS). However, its potential material basis and underlying mechanism remain elusive. Therefore, this study employed an integrated approach that combined ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) with network pharmacology to systematically characterize the phytochemical components and metabolites of CKF, as well as elucidating its underlying mechanism. Through this comprehensive analysis, a total of 150 components were identified or tentatively characterized within the CKF formula. Notably, six N -acetyldopamine oligomers from Cicadae Periostracum and eight resin glycosides from Cuscutae Semen were characterized in this formula for the first time. Meanwhile, 149 xenobiotics (58 prototypes and 91 metabolites) were detected in plasma, urine, feces, brain, and intestinal contents, and the in vivo metabolic pathways of resin glycosides were elaborated for the first time. Furthermore, network pharmacology and molecular docking analyses revealed that alkaloids, flavonoids, chromones, monoterpenes, N -acetyldopamine dimers, p -hydroxycinnamic acid, and Cus-3/isomer might be responsible for the beneficial effects of CKF in treating IBS, and CASP8, MARK14, PIK3C, PIK3R1, TLR4, and TNF may be its potential targets. These discoveries offer a comprehensive understanding of the potential material basis and clarify the underlying mechanism of the CKF formula in treating IBS, facilitating the broader application of CKF in the field of medicine. [ABSTRACT FROM AUTHOR]

[Display omitted] • Atherosclerosis is the etiology of coronary heart disease, the first rank cause of mortality worldwide in metabolic disease group. • Hyperlipidemia (High Total Cholesterol and Low-Density Lipoprotein concentration), inflammation, Endothelial Dysfunction, dysregulation of lipid transport and storage trigger the atherosclerosis plaque development. • The natural product based on vegetables and herbs fermentation is a promising candidate to be develop as a dietary supplement to prevent the disease. • Combination of metabolite screening of the extract, in silico , and in vivo study build a comprehensive mechanism in drug discovery research. Although positive association between fermented vegetables intake with the risk of coronary heart disease (CHD) has increased attention nowadays, the metabolite profiling and the mechanism of action are still elusive. This study designed to investigate the secondary metabolites, hypolipidemic, and anti-atherogenic effect of mixed vegetable fermentation extract (MVFE). The metabolite screening of the MVFE was assessed using the Liquid Chromatography Tandem Mass Spectrophotometer (LC-MS/MS) method. The result of LC-MS/MS was used as ligands to inhibit the binding of oxidized LDL (oxLDL) and Cluster Differentiation 36 (CD36), Scavenger Receptor A1 (SRA1), Lectin-type oxidized LDL receptor 1 (LOX1). This work was performed with molecular docking using Discovery Studio 2021, PyRx 0.9, and Autodock Vina 4.2 followed by analyzing Network Pharmacology, Protein Protein Interaction (PPI) using Cytoscape 3.9.1 and String 2.0.0. Finally, the clinical effect of MVFE was evaluated using in vivo study. Twenty rabbits were assigned to normal, negative control, and MVFE group that were fed with standard diet, high fat diet (HFD), HFD supplemented with MVFE 100, 200 mg/kg BW, respectively. The serum level of Total Cholesterol (TC) and Low-Density Lipoprotein (LDL-c) were detected at the end of week 4. The LC-MS/MS analysis identified 17 compounds categorized as peptides, fatty acids, polysaccharides, nucleoside, flavonoids, flavanols, and phenolic compounds. Based on the docking study, more negative binding affinity was observed in the interaction between metabolites with the scavenger receptors (SR) than simvastatin. The number of nodes and edges based on Network Pharmacology analysis were 268 and 482, respectively. The PPI network showed that MVFE metabolites exerts its athero-protective effect by modulating various cellular processes including inflammation, improvement of endothelial function, and modulation of lipid metabolism. Blood TC and LDL-c concentrations in the negative control (458.82 ± 82.03; 191.87 ± 92.16 mg/dL) were higher significantly compared to the normal group (87.03 ± 29.27; 43.33 ± 5.75 mg/dL). The MVFE administration decreased the TC (100, 200 mg/kg BW MVFE: 269.96 ± 85.34; 130.17 ± 45.02 mg/dL) and LDL-c level (100, 200 mg/kg BW MVFE = 87.24 ± 22.85; 41.82 ± 11.08 mg/dL) dose-dependently (p < 0,001). The secondary metabolites derived from fermented mixed vegetables extract might be developed as a potential strategy to prevent CHD by targeting the multiple pathways in atherosclerosis. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has resulted in excess deaths worldwide. Conventional antiviral medicines have been used to relieve the symptoms, with limited therapeutic effect. In contrast, Lianhua Qingwen Capsule is reported to exert remarkable anti-COVID-19 effect. The current review aims to: 1) uncover the main pharmacological actions of Lianhua Qingwen Capsule for managing COVID-19; 2) verify the bioactive ingredients and pharmacological actions of Lianhua Qingwen Capsule by network analysis; 3) investigate the compatibility effect of major botanical drug pairs in Lianhua Qingwen Capsule; and 4) clarify the clinical evidence and safety of the combined therapy of Lianhua Qingwen Capsule and conventional drugs. Numerous bioactive ingredients in Lianhu Qingwen, such as quercetin, naringenin, β -sitosterol, luteolin, and stigmasterol, were identified to target host cytokines, and to regulate the immune defence in response to COVID-19. Genes including androgen receptor (AR), myeloperoxidase (MPO), epidermal growth factor receptor (EGFR), insulin (INS), and aryl hydrocarbon receptor (AHR) were found to be significantly involved in the pharmacological actions of Lianhua Qingwen Capsule against COVID-19. Four botanical drug pairs in Lianhua Qingwen Capsule were shown to have synergistic effect for the treatment of COVID-19. Clinical studies demonstrated the medicinal effect of the combined use of Lianhua Qingwen Capsule and conventional drugs against COVID-19. In conclusion, the four main pharmacological mechanisms of Lianhua Qingwen Capsule for managing COVID-19 are revealed. Therapeutic effect has been noted against COVID-19 in Lianhua Qingwen Capsule. [ABSTRACT FROM AUTHOR]

Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines (TCMs) for the treatment of diseases. TCMs, in "multi-component, multi-target, multi-pathway" paradigm, show satisfactory clinical results in complex diseases. New ideas and methods are urgently needed to explain the complex interactions between TCMs and diseases. Network pharmacology (NP) provides a novel paradigm to uncover and visualize the underlying interaction networks of TCMs against multifactorial diseases. The development and application of NP has promoted the safety, efficacy, and mechanism investigations of TCMs, which then reinforces the credibility and popularity of TCMs. The current organ-centricity of medicine and the "one disease-one target-one drug" dogma obstruct the understanding of complex diseases and the development of effective drugs. Therefore, more attentions should be paid to shift from "phenotype and symptom" to "endotype and cause" in understanding and redefining current diseases. In the past two decades, with the advent of advanced and intelligent technologies (such as metabolomics, proteomics, transcriptomics, single-cell omics, and artificial intelligence), NP has been improved and deeply implemented, and presented its great value and potential as the next drug-discovery paradigm. NP is developed to cure causal mechanisms instead of treating symptoms. This review briefly summarizes the recent research progress on NP application in TCMs for efficacy research, mechanism elucidation, target prediction, safety evaluation, drug repurposing, and drug design. [ABSTRACT FROM AUTHOR]

The pathogenic hyper-inflammatory response has been regarded as the major cause of the severity and death related to acute lung injury (ALI). Hua-ban decoction (HBD) is a classical prescription in traditional Chinese medicine (TCM). It has been extensively used to treat inflammatory diseases; however, its bioactive components and therapeutic mechanisms remain unclear. Here, we established a lipopolysaccharide (LPS)-induced ALI model that presents a hyperinflammatory process to explore the pharmaco-dynamic effect and underlying molecular mechanism of HBD on ALI. In vivo , we confirmed that in LPS-induced ALI mice, HBD improved pulmonary injury by via down-regulating the expression of proinflammatory cytokines, including IL-6, TNF-α, and macrophage infiltration, as well as macrophage M1 polarization. Moreover, in vitro experiments in LPS-stimulated macrophages demonstrated that the potential bioactive compounds of HBD inhibited the secretion of IL-6 and TNF-α. Mechanically, the data revealed that HBD treatment of LPS-induced ALI acted via NF-κB pathway, which regulated macrophage M1 polarization. Additionally, two major HBD compounds, i.e., quercetin and kaempferol, showed a high binding affinity with p65 and IkBα. In conclusion, the data obtained in this study demonstrated the therapeutic effects of HBD, which indicates the possibility for the development of HBD as a potential treatment for ALI. • HBD improved the lung injury, either by prophylactic or therapeutic administration in LPS-induced ALI mouse model. • HBD acted via NF-κB pathway by an integrative approach of network pharmacology and Western Blot analysis. • Two major HBD compounds, i.e., quercetin and kaempferol, showed a high binding affinity with p65 and IkBα, and inhibited the secretion of IL-6 and TNF-α. [ABSTRACT FROM AUTHOR]

Sepsis-induced liver injury (SILI) is an important cause of septicemia deaths. BaWeiBaiDuSan (BWBDS) was extracted from a formula of Panax ginseng C. A. Meyer , Lilium brownie F. E. Brown ex Miellez var. viridulum Baker , Polygonatum sibiricum Delar. ex Redoute , Lonicera japonica Thunb., Hippophae rhamnoides Linn., Amygdalus Communis Vas, Platycodon grandiflorus (Jacq.) A. DC., and Cortex Phelloderdri. Herein, we investigated whether the BWBDS treatment could reverse SILI by the mechanism of modulating gut microbiota. BWBDS protected mice against SILI, which was associated with promoting macrophage anti-inflammatory activity and enhancing intestinal integrity. BWBDS selectively promoted the growth of Lactobacillus johnsonii (L. johnsonii) in cecal ligation and puncture treated mice. Fecal microbiota transplantation treatment indicated that gut bacteria correlated with sepsis and was required for BWBDS anti-sepsis effects. Notably, L. johnsonii significantly reduced SILI by promoting macrophage anti-inflammatory activity, increasing interleukin-10+ M2 macrophage production and enhancing intestinal integrity. Furthermore, heat inactivation L. johnsonii (HI- L. johnsonii) treatment promoted macrophage anti-inflammatory activity and alleviated SILI. Our findings revealed BWBDS and gut microbiota L. johnsonii as novel prebiotic and probiotic that may be used to treat SILI. The potential underlying mechanism was at least in part, via L. johnsonii -dependent immune regulation and interleukin-10+ M2 macrophage production. Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Developing analytical methods for the chemical components of natural medicines remains a challenge due to its diversity and complexity. Miao-Fu-Zhi-Tong (MFZT) granules, an ethnic Yi herbal prescription, comprises 10 herbs and has been clinically applied for gouty arthritis (GA) therapy. Herein, a series of chemical profiling strategies including in-house library matching, molecular networking and MS/MS fragmentation behavior validation based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were developed for qualitative analysis of MFZT granules. A total of 207 compounds were identified or characterized in which several rare guanidines were discovered and profiled into alkyl substituted or cyclic subtypes. Moreover, network pharmacology analysis indicated that MFZT's anti-gout mechanism was mostly associated with the nuclear factor kappa-B (NF- κ B) signaling, nucleotide oligomerization domain (NOD)-like signaling and rheumatoid arthritis pathways, along with the synergistic effect of 84 potential active compounds. In addition, a quantitative analytical method was developed to simultaneously determine the 29 potential effective components. Among them, berberine, pellodendrine, 3-feruloylquinic acid, neoastilbin, isoacteoside and chlorogenic acid derivatives at higher concentrations were considered as the chemical markers for quality control. These findings provide a holistic chemical basis for MFZT granules and will support the development of effective analytical methods for the herbal formulas of natural medicines. [ABSTRACT FROM AUTHOR]

Angelicae Sinensis Radix (AS) is reproted to exert anti-depression effect (ADE) and nourishing blood effect (NBE) in a rat model of depression. The correlation between the two therapeutic effects and its underlying mechanisms deserves further study. The current study is designed to explore the underlying mechanisms of correlation between the ADE and NBE of AS based on hepatic metabonomics, network pharmacology and molecular docking. According to metabolomics analysis, 30 metabolites involved in 11 metabolic pathways were identified as the potential metabolites for depression. Furthermore, principal component analysis and correlation analysis showed that glutathione, sphinganine, and ornithine were related to pharmacodynamics indicators including behavioral indicators and hematological indicators, indicating that metabolic pathways such as sphingolipid metabolism were involved in the ADE and NBE of AS. Then, a target-pathway network of depression and blood deficiency syndrome was constructed by network pharmacology analysis, where a total of 107 pathways were collected. Moreover, 37 active components obtained from Ultra Performance Liquid Chromatography-Triple-Time of Flight Mass Spectrometer (UPLC-Triple-TOF/MS) in AS extract that passed the filtering criteria were used for network pharmacology, where 46 targets were associated with the ADE and NBE of AS. Pathway enrichment analysis further indicated the involvement of sphingolipid metabolism in the ADE and NBE of AS. Molecular docking analysis indciated that E -ligustilide in AS extract exhibited strong binding activity with target proteins (PIK3CA and PIK3CD) in sphingolipid metabolism. Further analysis by Western blot verified that AS regulated the expression of PIK3CA and PIK3CD on sphingolipid metabolism. Our results demonstrated that sphingolipid metabolic pathway was the core mechanism of the correlation between the ADE and NBE of AS. [ABSTRACT FROM AUTHOR]

• The herbal combination of BD and TC significantly protects kidney function against DCF induced nephrotoxicity, oxidative stress, and inflammation. • Network pharmacology uncovers the therapeutic and multimechanistic role of identified polyphenols against glomerulopathy, inflammation, oxidative stress, etc. • The herbal combination could be used as the best adjuvant to overcome NSAIDs-induced renal impairments and reducing the risk of AKI/CKD. Synergism among herbals or phytochemicals potentiates incredible biological effects thus mitigating several acute and chronic ailments. Boerhaavia diffusa (BD) and Tinospora cordifolia (TC) are well-known medicinal plants used as the folk medicinal regimen for treating various ailments. Due to lack of scientific evidence, the study is aimed to evaluate the synergistic nephroprotective potential of BD and TC herbal combination against diclofenac (DCF)-induced nephrotoxicity. HPTLC analysis was performed for quantification of polyphenols followed by network pharmacological analysis to investigate the multi-mechanistic role of polyphenols in alleviating chronic kidney disease (CKD). The herbal combination exhibited significant (p < 0.05) nephroprotective effect by reducing renal oxidative, and inflammatory stress. Network pharmacological analysis showed multiple physiological roles of polyphenols in kidney malfunction by regulating several genomes involved in inflammation, oxidative stress, renin-angiotensin system (RAS), etc. and thus providing an effective therapeutic regimen as BD and TC in the glance of naturals. [ABSTRACT FROM AUTHOR]

Several studies suggest that Glycyrrhiza glabra (GG) extract could be a useful supplemental source for various cancer treatments. However, very few studies on oral cancer (OC) have been conducted. The present study was aimed at exploring the bioactive compounds (bioactives) along with the mode of action of GG against OC using network pharmacology. Liquid chromatography–mass spectrometry/mass spectrometry was used to identify and analyze compounds from GG. Public databases were used to identify genes associated with the selected bioactives and OC. With the help of Cytoscape software, the association between bioactive and common genes was built, visualized, and investigated. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to investigate protein–protein interactions for intergenic interactions. Finally, the pathway enrichment analysis of common genes was done using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Overall, 378 bioactives were identified in GG. Using public databases, an entire 254 bioactive-related genes and 734 OC-related genes were recognized, with 48 common genes. Cytoscape analysis showed wortmannin as the key bioactive and androgen receptor as the hub gene. The DAVID results revealed that the significant mechanism of action of GG against OC may be to induce apoptosis of cancer cells by deactivating the PI3K-AKT signaling pathway. The key active components and mechanisms of action of GG against OC were investigated. The present study provides scientific suggestions to support the clinical outcome of GG for OC along with a research foundation for additional elaboration on the important bioactives and mechanisms of GG against OC. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the efficacy and therapeutic mechanism of parthenolide (PTL) in breast cancer (BC) through a comprehensive strategy integrating network pharmacology, single-cell RNA sequencing (scRNA-seq) and metabolomics. In network pharmacology, 70 therapeutic targets were identified, of which 16 core targets were filtered out through seven classical algorithms of Cytohubba plugin. Additionally, the hub module of PPI network was extracted using MCODE plugin. Molecular docking and molecular dynamics simulation showed a potent binding affinity between PTL and JNK, subsequently validated by MST and SPR assays. Further, Mendelian randomization analysis indicated that JNK was causally associated with BC. GO and KEGG enrichment analyses revealed that PTL counteracted BC via promoting ROS generation, inducing apoptosis and suppressing proliferation, which potentially involved the coordinated regulation of MAPK and FoxO1 pathways. Moreover, ssGSEA and scRNA-seq analysis suggested that PTL may act on T cell immune microenvironment of BC. Subsequently, these bioinformatics-based predictions were experimentally validated using in-vitro and in-vivo models. Finally, metabolome profiling unveiled that PTL remodeled the glycine, serine and threonine metabolism as well as biosynthesis of unsaturated fatty acids, and thereby contributed to BC inhibition. From molecular, immune and metabolic perspectives, this study not only provided a unique insight into the mechanistic details of PTL against BC, but also proposed a novel promising therapeutic strategy for BC. • A comprehensive interpretation integrating network pharmacology, single-cell RNA sequencing, and metabolomics. • The combination of molecular docking, MD simulation, MST assay, and SPR assay. • The combined application of DEG analysis, LASSO regression analysis and WGCNA algorithm. • In-vitro and in-vivo experimental verification. • Provide a reliable direction on the molecular design of the novel anti-BC agents. [ABSTRACT FROM AUTHOR]

Huperzine A (Hup A), an extract from Huperzia serrata, exerted its anti-inflammation and anti-oxidation effect to protect against neurodegenerative disorders and organ injury. Ferroptosis was indicated to involve in the development of acute lung injury (ALI) accompanying by lipid reactive oxygen species (ROS) overexpressed. However, there is little research focused on the protective effect of Hup A on ALI, and the underlying molecular mechanism remains elusive. This study aims to determine the therapeutic effect of Hup A on ALI in vivo and in vitro. Hup A attenuated lung injury and cellular damage in lipopolysaccharide-induced ALI (LPS-ALI) models, both in vivo and in vitro , accompanied by the upregulation of ferroptosis-associated proteins (SLC7A11 and GPX4). Furthermore, the pretreatment with Hup A decreased the abundance of inflammation factors (IL-6, TNF-α), MDA, lipid ROS, and Fe2+ in the LPS-ALI model, while it also promoted the secretion of SOD and GSH to antagonize peroxidation. Mechanistically, RNA sequencing and network pharmacological analysis synergistically revealed the PI3K/Akt signaling pathway as a potential target of Hup A. In vitro experiments demonstrated that Hup A effectively activated GPX4 through the PI3K/Akt signaling pathway, which was subsequently reversed by LY294002, an inhibitor of the PI3K/Akt signaling pathway. Consequently, our results revealed that Hup A inhibited ferroptosis in LPS-ALI by activating the PI3K-Akt signaling pathway which indicated the potential therapeutical effect of Hup A and further emphasized the pivotal role of ferroptosis in ALI. • The treatment of Hup A effectively ameliorated the LPS-ALI both in vivo and in vitro. • Hup A attenuated lipid ROS levels and conferred protection against ferroptosis. • Hup A inhibits ferroptosis in pulmonary epithelial cells of LPS-ALI by activating the PI3K-Akt signaling pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • Baicalin's targets and pathways for dairy cow fatty liver prevention and treatment were identified and analyzed. • The binding affinity of baicalin to its core target was assessed using molecular docking. • Baicalin inhibits lipid synthesis, promotes lipid oxidation, and regulates SLC2A4, AKT1, EGFR, IL-6, PPAR, and TNF leves. Excessive nonesterified fatty acids (NEFA) impair cellular metabolism and will induce fatty liver formation in dairy cows during the periparturient. Baicalin, an active flavonoid, has great potential efficacy in alleviating lipid accumulation and ameliorating the development of fatty liver disease. Nevertheless, its mechanism remains unclear. Here, the potential mechanism of baicalin on system levels was explored using network pharmacology and in vitro experiments. Firstly, the target of baicalin and fatty liver disease was predicted, and then the protein–protein interaction (PPI) network was constructed. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) (q-value) pathway enrichment is performed through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server. Finally, the results of the network analysis of the in vitro treatment of bovine hepatocytes by NEFA were confirmed. The results showed that 33 relevant targets of baicalin in the treatment of liver fatty were predicted by network pharmacology, and the top 20 relevant pathways were extracted by KEGG database. Baicalin treatment can reduce triglyceride (TAG) content and lipid droplet accumulation in NEFA-treated bovine hepatocytes, and the mechanism is related to inhibiting lipid synthesis and promoting lipid oxidation. The alleviating effect of baicalin on fatty liver may be related to the up-regulation of solute vector family member 4 (SLC2A4), Down-regulated AKT serine/threonine kinase 1 (AKT1), Peroxisome proliferator-activated receptor gamma (PPARG), Epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF), Interleukin 6 (IL-6) were associated. These results suggested that baicalin may modulate key inflammatory markers, and lipogenesis processes to prevent fatty liver development in dairy cows. [ABSTRACT FROM AUTHOR]

[Display omitted] • Comprehensive bioinformatics, network pharmacology, machine learning algorithms, transcriptome sequencing, and molecular docking reveal that COL1A1 is a key target for QingRe HuoXue Formula to regulate atherosclerosis. • QingRe HuoXue Formula can promote the formation of fibrosis in atherosclerotic plaque. • QingRe HuoXue Formula can improve atherosclerosis by regulating lipid metabolism and stabilizing plaque. Atherosclerosis (AS) is the main cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. QingRe HuoXue Formula (QRHXF), a common prescription of traditional Chinese medicine, has a definite effect on the clinical treatment of AS, but its mechanism remains to be further explored. The current study aimed to demonstrate the effectiveness of the QRHXF in the treatment of AS and further reveal its potential pharmacological mechanisms. Explore the potential mechanisms of QRHXF in treating AS through network pharmacology, machine learning, transcriptome analysis, and molecular docking, then validate them through animal experiments and PCR experiments. The results indicate that through network pharmacology and machine learning methods, 10 genes including COL1A1 and CCR7 have been identified as potential candidate genes for QRHXF treatment of atherosclerosis. Molecular docking indicates that the key active compounds of QRHXF have good binding affinity with the predicted genes. Two key genes, COL1A1 and CCR7, were identified through transcriptome sequencing analysis of the aortic tissue of APOE-/- mice in the AS model. Finally, the animal and PCR experiment found that QRHXF can effectively reduce the formation of aortic plaques in APOE-/- mice of the AS model, lower blood lipid levels in mice, and upregulate the mRNA expression level of COL1A1, promoting the formation of fibrosis within plaques. We revealed the inflammatory and immune pathways underlying QRHXF treatment for AS, and verified through transcriptome sequencing and experiments that QRHXF can promote the expression of COL1A1, thereby increasing the stability of AS plaques. [ABSTRACT FROM AUTHOR]

• Valnemulin alleviates DSS-induced cellular and colonic senescence. • Valnemulin alleviate ulcerative colitis by inhibiting colonic senescence. • Valnemulin alleviates DSS-induced senescence by activating AMPK. Ulcerative colitis (UC) is a chronic inflammatory disease that is increasing in prevalence globally. Senescence is characterized by a specific chronic, low-grade, "sterile" inflammatory state known as inflammaging, suggesting that senescence may exacerbate the severity of UC. However, the link between UC and senescence remains unclear. Valnemulin (VAL) is a semi-synthetic derivative of a naturally occurring diterpenoid antibiotic (pleuromutilin), which can inhibit peptidyl transferase. Studies investigating the potential of valnemulin to inhibit senescence and alleviate colitis are currently limited. In this study, we revealed that dextran sulfate sodium (DSS), an inducer of UC, induces senescence in both colon epithelial NCM460 cells and colon tissues. Additionally, VAL, identified from a compound library, exhibited robust anti-senescence activity in DSS-treated NCM460 cells. Identified in our study as an anti-senescence agent, VAL effectively mitigated DSS-induced UC and colonic senescence in mice. Through network pharmacology analysis and experimental validation, the potential signaling pathway (AMPK/NF-κB) for VAL in treating UC was identified. We discovered that DSS significantly inhibited the AMPK signaling pathway and activated the NF-κB signaling pathway. However, supplementation with VAL remarkably restored AMPK activity and inhibited the NF-κB signaling pathway, which led to the inhibition of senescence. In summary, our study demonstrated that DSS-induced UC stimulates the senescence of colonic tissues, and VAL can effectively alleviate DSS-induced colonic damage and reduce colonic senescence. Our research findings provide a new perspective for targeting anti-senescence in the treatment of UC. [ABSTRACT FROM AUTHOR]

Borneol essential oil (BEO), a plant essential oil derived from hydrodistillation of fresh branches and leaves of Cinnamomum camphora (L.). This study optimized cellulase and xylanase-assisted BEO, extraction using an orthogonal design. Additionally, it explored the inhibitory effects of BEO on Propionibacterium acnes and elucidated the anti-bacterial mechanisms via molecular docking. Furthermore, the acne treatment mechanism of BEO was investigated using network pharmacology-molecular docking. The findings indicated that the concentration of borneol in BEO was 2.34 times higher than that achieved through hydrodistillation. This enhancement was achieved by adding enzymes in a volume equivalent to 2 % of the raw material, followed by a 2-hour enzymolysis process conducted at 40℃. BEO exhibited a significant inhibition zone of 31.6±0.5 mm against Propionibacterium acnes. Molecular docking analysis revealed that six, three, and one chemical components in BEO exhibited molecular binding energies exceeding 5.00 kJ/mol with key target proteins involved in the pathogenesis of Propionibacterium acnes : deoxyribonuclease I (DNase I), dermatan sulfate (DsA1), and Christie, Atkins, Munch-Peterson (CAMP), respectively. This indicates a close relationship between the chemical components and the target proteins. Network pharmacology analysis identified 40 common targets between BEO and acne formation, from which 12 key targets were identified. Among these, ovarian steroidogenesis exhibited the highest degree of enrichment in the signaling pathway. These findings provide a scientific foundation for the development of acne treatment cosmetics utilizing BEO. [Display omitted] • Cellulase and xylanase-assisted method improved the effect of BEO extraction. • BEO significantly inhibits P. acnes. • Docking energy between linalool and key proteins of P. acnes is the strongest. • Ovarian steroidogenesis is the most involved signaling pathway in the targets. [ABSTRACT FROM AUTHOR]

Hygrophila salicifolia (Vahl) Nees is a traditional Chinese herbal medicine widely circulated in the Chinese medicinal materials market. It has gained significant popularity for its therapeutic effects in clearing heat and reducing swelling. The present study evaluated the chemical composition, antioxidant capacity, acetylcholinesterase, and α-glucosidase inhibitory effect of this species' essential oil. The major compounds of H. salicifolia essential oil were 1-octen-3-ol (29.0 %), phytol (5.7 %), phytone (4.6 %), cubebol (3.7 %), estragole (3.5 %), 7-epi-silphiperfol-5-ene (3.3 %), and ylangenol (3.1 %). The essential oil of H. salicifolia revealed antioxidant activity against both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals with half-maximal inhibitory concentration (IC 50) values of 2.13 ± 0.17 and 0.22 ± 0.02 mg/mL. The ferric reducing antioxidant power (FRAP) value was 170.97 ± 3.68 μmol·g−1. The essential oil has moderate activity against acetylcholinesterase (IC 50 = 360.4 ± 12.7 μg/mL) and weak activity against α-glucosidase (14.2 % inhibition at 500 μg/mL). Moreover, we conducted in silico network pharmacology analysis and molecular docking to evidence the results of in vitro tests, providing a theoretical foundation for future drug development. The presented results suggest that the essential oil of H. salicifolia possesses the potential to be used in cosmetics, food, and pharmacological industries, emphasizing the need for further investigation. [Display omitted] • The composition and bioactivities of essential oil (EO) from Hygrophila salicifolia were investigated for the first time. • Network pharmacology and molecular docking were utilized to evaluate H. salicifolia EO potential therapeutic effects. • H. salicifolia EO can be potentially used in cosmetics, food and pharmacological industries. [ABSTRACT FROM AUTHOR]

The Qinglongyi-Buguzhi herbal pair (QB) is one of commonly used herbal combinations for treating vitiligo in traditional Chinese medicine, consisting of the exocarp of the immature fruit of Juglans regia L. or Juglans mandshurica Maxim., and dried, mature fruit of Psoralea corylifolia L. However, the active components and potential mechanisms of QB in the treatment of vitiligo are still unclear. The purpose of this study is to clarify the effects and mechanisms of QB on vitiligo treatment through integration of network pharmacology and empirical examinations. The active components and targets of QB as well as the targets linked to vitiligo were obtained from network databases. Visualization networks were constructed with Cytoscape 3.9.1. GO and KEGG enrichment analysis were conducted to investigate the possible mechanism. Molecular docking was employed to evaluate the binding affinities between the primary active ingredients of QB and essential targets of the PI3K/Akt/Nrf2 pathway. In vivo and in vitro experiments were carried out to confirm the results of network pharmacology. We evaluated 44 active compounds and 602 genes from QB, and 107 of these genes linked to vitiligo. GO analysis suggested QB might lessen vitiligo by regulating oxidative stress. KEGG pathway analysis indicated the PI3K/Akt pathway may be crucial for treating vitiligo. Molecular docking results demonstrated the key active ingredients of QB had good binding activity with the major targets in the PI3K/Akt/Nrf2 pathway. In vivo, QB significantly ameliorated vitiligo model mouse's skin pathologies by reducing ROS, elevating CAT and SOD levels. Western blot showed that QB increased the phosphorylation of PI3K and Akt and the expressions of Nrf2 and HO-1 in the skin. In vitro, QB reversed H 2 O 2 -induced oxidative injury of melanocytes, enhanced cell survival rate, reduced ROS level, upregulated SOD and CAT activities, and raised the content of melanin. Moreover, QB upregulated the expression levels of Akt, Nrf2, HO-1 mRNA, Akt phosphorylation, HO-1, and nuclear Nrf2 proteins, and also encouraged the nuclear translocation of Nrf2. However, LY294002 treatment significantly reversed the regulatory effect of QB on oxidative damage of melanocytes. This study revealed that the therapeutic effect of QB on vitiligo was achieved through multiple components, targets and pathways. Experimental investigation demonstrated that QB could improve vitiligo via reducing oxidative stress, which was probably accomplished by activating the PI3K/Akt/Nrf2 signaling pathway. [Display omitted] • QB is safe and effective in the treatment of vitiligo. • The mechanisms of QB in the treatment of vitiligo are explored by the combination of network pharmacology and in vivo and in vitro experiments. • QB may play a therapeutic role in vitiligo by activating PI3K/Akt/Nrf2 signaling pathway to reduce oxidative stress. [ABSTRACT FROM AUTHOR]

Jianwei Xiaoyan Granule (JWXYG) is the traditional Chinese medicine preparation in Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, which has been widely used in clinical treatment of chronic atrophic gastritis (CAG). However, the material basis and potential mechanism of JWXYG in the treatment of CAG are not clear. To explore the material basis and potential mechanism of JWXYG in the treatment of CAG. In this study, the components of JWXYG were analyzed by HPLC-Q-TOF-MS/MS. Then, the CAG model in rats established by a composite modeling method and MC cell model induced by MNNG were used to explore the improvement effect of JWXYG on CAG. Finally, the potential mechanism of JWXYG in the treatment of CAG was preliminarily predicted based on network pharmacology and validated experimentally. Thirty-one components of JWXYG were analyzed through HPLC-Q-TOF-MS/MS, such as albiflorin, paeoniflorin, lobetyolin firstly. Research results in vivo showed that the gastric mucosa became thinner, intestinal metaplasia appeared, the number of glands was reduced, the serum levels of PG I and PG II increased and the contents of G17 and IL-6 reduced in CAG model rats. After 4 weeks of JWXYG (2.70 g/kg) administration, these conditions were significantly improved. In addition, cell viability, migration, and invasion of MNNG-induced MC cells was inhibited by JWXYG treatment (800 μg/mL). Furthermore, the results of network pharmacology indicated that HIF-1 and VEGF signaling pathways might play important roles in the therapeutic process. Then the results of Western blot, immunohistochemistry and immunofluorescence confirmed that with JWXYG treatment, the increased expression of HIF-1α, VEGF and VEGFR2 in gastric issue of CAG rats were restrained. Eventually, potential components of JWXYG in the treatment of CAG were predicted through molecular docking to elucidate the material basis. JWXYG could inhibit angiogenesis by regulating HIF-1α-VEGF pathway to exert therapeutic effects on CAG. Our study explored the potential mechanisms and material basis of JWXYG in the treatment of CAG and provides experimental data for the clinical rational application of JWXYG. [Display omitted] [ABSTRACT FROM AUTHOR]

Artemisia stechmanniana Besser, one of the most prevalent botanical medicines in Chinese, has been traditionally used for hepatitis treatment. However, the bioactive components and pharmacological mechanism on alcohol-induced liver injury remains unclear. To investigate the effect of A. stechmanniana on alcohol-induced liver damage, and further explore its mechanism. Phytochemical isolation and structural identification were used to determine the chemical constituents of A. stechmanniana. Then, the alcohol-induced liver damage animal and cell model were established to evaluate its hepato-protective potential. Network pharmacology, molecular docking and bioinformatics were integrated to explore the mechanism and then the prediction was further supported by experiments. Moreover, both compounds were subjected to ADMET prediction through relevant databases. 28 compounds were isolated from the most bioactive fraction, ethyl acetate extract A. stechmanniana, in which five compounds (abietic acid, oplopanone, oplodiol, hydroxydavanone, linoleic acid) could attenuate mice livers damage caused by alcohol intragastration, reduce the degree of oxidative stress, and serum AST and ALT, respectively. Furthermore, abietic acid and hydroxydavanone exhibited best protective effect against alcohol-stimulated L-O2 cells injury among five bioactive compounds. Network pharmacology and bioinformatics analysis suggested that abietic acid and hydroxydavanone exhibiting drug likeliness characteristics, were the principal active compounds acting on liver injury treatment, primarily impacting to cell proliferation, oxidative stress and inflammation-related PI3K-AKT signaling pathways. Both of them displayed strong binding energies with five target proteins (HRAS, HSP90AA1, AKT1, CDK2, NF-κB p65) via molecular docking. Western blotting results further supported the predication with up-regulation of protein expressions of CDK2, and down-regulation of HRAS, HSP90AA1, AKT1, NF-κB p65 by abietic acid and hydroxydavanone. Alcohol-induced liver injury protection by A. stechmanniana was verified in vivo and in vitro expanded its traditional use, and its two major bioactive compounds, abietic acid and hydroxydavanone exerted hepatoprotective effect through the regulation of PI3K-AKT signaling pathway. [Display omitted] • 28 compounds were isolated from A. stechmanniana. • Abietic acid and hydroxydavanone exhibited the most hepatoprotective effect. [ABSTRACT FROM AUTHOR]

jinkui Shenqi Pill (JSP) is a classic traditional Chinese medicine used to treat "Kidney Yang Deficiency" disease. Previous studies indicate a protective effect of JSP on apoptosis in mouse neurons. This research, combining network pharmacology with in vivo experiments, explores the mechanism of JSP in preventing neural tube defects (NTDs) in mice. Network pharmacology analyzed JSP components and targets, identifying common genes with NTDs and exploring potential pathways. Molecular docking assessed interactions between key JSP components and pathway proteins. In an all-trans retinoic acid (atRA)-induced NTDs mouse model, histopathological changes were observed using HE staining, neuronal apoptosis was detected using TUNEL, and Western Blot assessed changes in the PI3K/AKT signaling pathway and apoptosis-related proteins. Different concentrations of JSP led to varying degrees of reduction in the occurrence of neural tube defects in mouse embryos, with the highest dose showing the most significant decrease. Furthermore, it showed a better reduction in NTDs rates compared to folic acid (FA). Network pharmacology constructed a Drug-Active Ingredient-Gene Target network, suggesting key active ingredients such as Quercetin, Wogonin, Beta-Sitosterol, Kaempferol, and Stigmasterol, possibly acting on the PI3K/Akt signaling pathway. Molecular docking confirmed stable binding structures. Western Blot analysis demonstrated increased expression of p-PI3K, p-Akt, p-Akt1, p-Akt2, p-Akt3, downregulation of cleaved caspase-3 and Bax, and upregulation of Bcl-2, indicating prevention of NTDs through anti-apoptotic effects. We have identified an effective dosage of JSP for preventing NTDs, revealing its potential by activating the PI3K/Akt signaling pathway and inhibiting cell apoptosis in atRA-induced mouse embryonic NTDs. [Display omitted] [ABSTRACT FROM AUTHOR]

Functional dyspepsia (FD) is a prevalent gastrointestinal disorder characterised by high incidence and recurrence rates, posing significant health risks. Erpixing Granules (EPX), approved by the National Food and Drug Administration in 2002, are known for their spleen and stomach invigorating properties, effectively treating FD. However, its mechanism of action remains unclear. This study aims to elucidate EPX's mechanism of treating FD through network pharmacology, and experimental validation using FD animal models. In this study, the chemical composition of EPX in positive and negative ion modes was analyzed by UHPLC-Q-TOF MS. The mass spectral data were processed and analyzed using MS-DIAL software to automatically match compound fragment information and identify the known components with the compound database to obtain the active components of EPX. SwissTargetPrediction was used to obtain EPX targets, while FD-related targets were sourced from GeneCards, OMIM and DisGeNET databases. A protein-protein interaction (PPI) network was constructed using the STRING platform, and potential signalling pathways of EPX were determined through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, an FD model was established in rates by administering a 0.1% iodoacetamide sucrose solution, followed by tail clamp stimulation to experimentally validate the network pharmacology findings. Our results revealed 139 effective ingredients in EPX, targeting 60 core FD-related genes. PPI network analysis identified EGFR, CTNNB1 and NFκB1 as core target genes. The KEGG pathway analysis indicated that EPX can modulate FD progression through the PI3K/AKT signalling pathway. Animal experiments demonstrated EPX's capacity to increase body mass, food intake and food utilisation efficiency in FD rats, alongside increased gastric juice secretion, pepsin activity, trypsin activity, cholesterol, bile acid and bilirubin activity. HE examination revealed that EPX improved the inflammatory infiltration of gastric mucosal cells in rats. Furthermore, EPX also promoted gastric emptying and intestinal propulsion in mice. These results suggest that EPX improves spleen and stomach function, enhances the protective effect on the spleen and stomach and promotes food digestion and absorption. Immunofluorescence studies revealed upregulated expression of PI3K, AKT and ANO1 proteins in gastric tissue following EPX administration, while Western blotting indicated increased expression of SCF and C-kit proteins. Suggesting EPX's anti-FD effect may involve the regulation of the SCF/C-kit signalling pathway and activation of downstream PI3K/AKT signalling pathway, thereby promoting gastrointestinal motility and improving FD symptoms. [Display omitted] • Revealed the pharmacodynamic effect of EPX on iodoacetamide-induced FD rat model. • Clarified that the mechanism by which EPX ameliorates FD is by regulating the relevant proteins of the SCF-/C-kit pathway. • The study lays the experimental foundation for the clinical application of EPX and the development of new drugs. [ABSTRACT FROM AUTHOR]

Chinese herb pairs are the most basic and compressed examples of Chinese herbal combinations and can be used to effectively explain the fundamental concepts of traditional Chinese medicine prescriptions. These pairings have gained significant interest due to their subtle therapeutic benefits, minimal side effects, and efficacy in treating complicated chronic conditions. The Banxia–Xiakucao Chinese herb pair (BXHP) consists of Pinellia ternata (Thunb.) Breit. (Banxia) and Prunella vulgaris L. (Xiakucao). This formula was documented in The Medical Classic of the Yellow Emperor approximately 2000 years ago，and clinical research has demonstrated that BXHP effectively treats insomnia. This study aimed to evaluate the efficacy and therapeutic mechanism of the BXHP through a comprehensive strategy involving network pharmacology, molecular docking, transcriptomics, and molecular biology experimental validation. The composition of BXHP was characterized using the UPLC-Q-TOF-MS. The active compounds were screened to find drug-likeness compounds by analyzing the ADME data. To predict the molecular mechanism of BXHP in sleep deprivation (SD) by network pharmacology and molecular docking. We established a rat model of SD and the in vivo efficacy of BXHP was verified through the pentobarbital sodium righting reflex test, behavioral assays, enzyme-linked immunosorbent assay, transmission electron microscopy, HE staining, and Nissl staining, and the underlying molecular mechanism of BXHP in SD was revealed through transcriptomic and bioinformatic analyses in conjunction with quantitative real-time PCR, Western blot, and immunofluorescence staining. In the present study, we showed for the first time that BXHP reduced sleep latency, prolongs sleep duration, and improves anxiety; lowered serum CORT, IL6, TNF-α and MDA levels; decreased hypothalamic Glu levels; and elevated hypothalamic GABA and 5-HT levels in SD rats. We found 16 active compounds that acted on 583 targets, 145 of which are related to SD. By modularly dissecting the PPI network, we discovered three critical targets, Akt1, CREB1, and PRKACA, all of which play important roles in the effects of BXHP on SD. Molecular docking resulted in the identification of 16 active compounds that strongly bind to key targets. The results of GO and KEGG enrichment analyses of network pharmacology and transcriptomics focused on both the regulation of circadian rhythm and the cAMP signaling pathway, which strongly demonstrated that BXHP affects SD via the cAMP-PKA-CREB-Circadian rhythm pathway. Molecular biology experiments verified this hypothesis. Following BXHP administration, PKA and CREB phosphorylation levels were elevated in SD rats, the cAMP-PKA-CREB signaling pathway was activated, the expression levels of the biological clock genes CLOCK, p-BMAL1/BMAL1, and PER3 were increased, and the rhythmicity of the biological clock was improved. The active compounds in BXHP can activate the cAMP-PKA-CREB-Circadian rhythm pathway, improve the rhythmicity of the biological clock, promote sleep and ameliorate anxiety, which suggests that BXHP improves SD through a multicomponent, multitarget, multipathway mechanism. This study is important for the development of herbal medicines and clinical therapies for improving sleep deprivation. [Display omitted] [ABSTRACT FROM AUTHOR]

Inflammation is directly related to disease progression and contributes significantly to the global burden of disease. Pothos chinensis (Raf.) Merr. (PCM) is commonly used in Yao medicine in China to treat tumors, and orthopedic illnesses such as knee osteoarthritis, and rheumatic bone discomfort. PCM was found to have significant anti-inflammatory properties in previous studies. To explore the active compounds of PCM and their anti-inflammatory pharmacological mechanisms through an integrated strategy of serum pharmacochemistry, network pharmacology, and serum metabolomics. The qualitative and quantitative analyses of the chemical components of PCM were performed using UPLC-QTOF-MS/MS and UPLC, respectively, and the prototype components of PCM absorbed into the blood were analyzed. Based on the characterized absorbed into blood components, potential targets and signaling pathways of PCM anti-inflammatory were found using network pharmacology. Furthermore, metabolomics studies using UPLC-QTOF-MS/MS identified biomarkers and metabolic pathways related to the anti-inflammatory effects of PCM. Finally, the hypothesized mechanisms were verified by in vivo and in vitro experiments. Forty chemical components from PCM were identified for the first time, and seven of them were quantitatively analyzed, while five serum migratory prototype components were found. Network pharmacology KEGG enrichment analysis revealed that arachidonic acid metabolism, Tyrosine metabolism, TNF signaling pathway, NF-κB signaling pathway, and phenylalanine metabolism were the main signaling pathways of PCM anti-inflammatory. Pharmacodynamic results showed that PCM ameliorated liver injury and inflammatory cell infiltration and downregulated protein expression of IL-1β, NF-κB p65, and MyD88 in the liver. Metabolomics studies identified 53 different serum metabolites, mainly related to purine and pyrimidine metabolism, phenylalanine metabolism, primary bile acid biosynthesis, and glycerophospholipid metabolism. The comprehensive results demonstrated that the anti-inflammatory modulatory network of PCM was related to 5 metabolites, 3 metabolic pathways, 7 targets, and 4 active components of PCM. In addition, molecular docking identified the binding ability between the active ingredients and the core targets, and the anti-inflammatory efficacy of the active ingredients was verified by in vitro experiments. Our study demonstrated the anti-inflammatory effect of PCM, and these findings provide new insights into the active ingredients and metabolic mechanisms of PCM in anti-inflammation. [Display omitted] • The chemical composition of PCM was qualitatively and quantitatively analyzed. • PCM modulates LPS-induced inflammatory responses, which is closely related to the inhibition of TLR4/MyD88/NF-κB signaling. • The four active components in PCM were identified and the anti-inflammatory mechanism was preliminarily verified. [ABSTRACT FROM AUTHOR]

Salvia miltiorrhiza Bunge (S. miltiorrhiza) is an important Traditional Chinese herbal Medicine (TCM) used to treat cardio-cerebrovascular diseases. Based on the pharmacodynamic substance of S. miltiorrhiza , the aim of present study was to investigate the underlying mechanism of S. miltiorrhiza against cardiac fibrosis (CF) through a systematic network pharmacology approach, molecular docking and dynamics simulation as well as experimental investigation in vitro. A systematic pharmacological analysis was conducted using the Traditional Chinese Medicine Pharmacology (TCMSP) database to screen the effective chemical components of S. miltiorrhiza , then the corresponding potential target genes of the compounds were obtained by the Swiss Target Prediction and TCMSP databases. Meanwhile, GeneCards, DisGeNET, OMIM, and TTD disease databases were used to screen CF targets, and a protein-protein interaction (PPI) network of drug-disease targets was constructed on S. miltiorrhiza /CF targets by Search Tool for the Retrieval of Interacting Genes/Proteins (STING) database. After that, the component-disease-target network was constructed by software Cytoscape 3.7. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for the intersection targets between drug and disease. The relationship between active ingredient of S. miltiorrhiza and disease targets of CF was assessed via molecular docking and molecular dynamics simulation. Subsequently, the underlying mechanism of the hub compound on CF was experimentally investigated in vitro. 206 corresponding targets to effective chemical components from S. miltiorrhiza were determined, and among them, there were 82 targets that overlapped with targets of CF. Further, through PPI analysis, AKT1 and GSK3β were the hub targets, and which were both enriched in the PI3K/AKT signaling pathway, it was the sub-pathways of the lipid and atherosclerosis pathway. Subsequently, compound-disease-genes-pathways diagram is constructed, apigenin (APi) was a top ingredients and AKT1 (51) and GSK3β (22) were the hub genes according to the degree value. The results of molecular docking and dynamics simulation showed that APi has strong affinities with AKT and GSK3β. The results of cell experiments showed that APi inhibited cells viability, proliferation, proteins expression of α-SMA and collagen I/III, phosphorylation of AKT1 and GSK3β in MCFs induced by TGFβ1. Through a systematic network pharmacology approach, molecular docking and dynamics simulation, and confirmed by in vitro cell experiments, these results indicated that APi interacts with AKT and GSK3β to disrupt the phosphorylation of AKT and GSK3β, thereby inhibiting the proliferation and differentiation of MCFs induced by TGFβ1, which providing new insights into the pharmacological mechanism of S. miltiorrhiza in the treatment of CF. [Display omitted] [ABSTRACT FROM AUTHOR]

Reproductive ability of sows is a primary element influencing the development of pig farming. Herbal extracts of Angelica sinensis (Oliv.) Diels, Astragalus mongholicus Bunge, Eucommia ulmoides Oliv., and Polypodium glycyrrhiza D.C.Eaton showed effects on improvement of reproduction in sows. To investigate the mechanism of the treatment effects by a compound of these four Chinese herbs in a 1:1:1:1 ratio (ALAE) on endometriosis, endometritis, uterine adhesion, intrauterine growth retardation, pre-eclampsia, and its enhancement of reproductive efficiency in sows. Active components of ALAE were identified by using ultra-performance liquid chromatography-mass spectrometry analysis and network pharmacology. Then we used the results to construct a visualization network. Key targets and pathways of ALAE involved in sow reproduction improvement were validated in sow animals and porcine endometrial epithelial cells (PEECs). A total of 62 active compounds were found in ALAE (41 in Polypodium glycyrrhiza D.C.Eaton, 5 in Astragalus mongholicus Bunge, 11 in Eucommia ulmoides Oliv., 5 in Angelica sinensis (Oliv.) Diels) with 563 disease-related targets (e.g. caspase-3, EGFR, IL-6) involved in EGFR tyrosine kinase inhibitor resistance, PI3K-AKT, and other signaling pathways. Molecular docking results indicated GC41 (glabridin), GC18 (medicarpin), EGFR and CCND1 are possible key components and target proteins related to reproductive improvement in sows. In PEECs, EGFR expression decreased at the mRNA and protein levels by three doses (160, 320, and 640 μg/mL) of ALAE. The phosphorylation of downstream pathway PI3K-AKT1 was enhanced. The expression of inflammatory factors (IL-6, IL-1β), ESR1 and caspase-3 decreased through multiple pathways. Additionally, the expression levels of an anti-inflammatory factor (IL-10), angiogenesis-related factors (MMP9, PIGF, PPARγ, IgG), and placental junction-related factors (CTNNB1, occludin, and claudin1) increased. Furthermore, the total born number of piglets, the number of live and healthy litters were significantly increased. The number of stillbirths decreased by ALAE treatment in sow animals. Dministration of ALAE significantly increased the total number of piglets born, the numbers of live and healthy litters and decreased the number of stillbirths through improving placental structure, attenuating inflammatory response, modulating placental angiogenesis and growth factor receptors in sows. The improvement of reproductive ability may be related to activation of the EGFR-PI3K-AKT1 pathway in PEECs. Moreover, ALAE maybe involved in modulation of estrogen receptors, apoptotic factors, and cell cycle proteins. [Display omitted] • ALAE can significantly increase the numbers of live and healthy litters in sows. • ALAE can modulate the placental angiogenesis and attenuate the inflammatory responses in sows. • ALAE improved the sow reproduction by activating the EGFR-PI3K-AKT1 signal pathway in vitro. [ABSTRACT FROM AUTHOR]

As a traditional Chinese medicine, the flower of Rhododendron molle G. Don (RMF) is record in the Chinese pharmacopoeia, and is commonly utilized for treating rheumatoid arthritis (RA) in clinical practice. However, its precise mechanisms necessitate further exploration. To expound the effective components, targets, metabolites, and pathways participated in RMF's anti-RA effects by metabolomics integrated network pharmacology. CIA rats were intragastric administered RMF for 2 weeks, following which the therapeutic effects were comprehensively evaluated. Serum metabolomics was adopted to investigate the differential metabolites (DEMs). UHPLC-Q-Exactive-MS method was applied to identify the components of RMF, and then network pharmacology was utilize to select the component-RA-targets. Molecular docking and Western blotting were utilized to validate the key targets. RA symptoms were alleviated by RMF through the inhibition secretion of pro-inflammatory factors IL-1β, IL-6 and TNF-α, along with relief in bone destruction observed in CIA rats. Four targets, namely AKR1B1, TPH1, CYP1A1, and CYP1A2, were identified, along with their corresponding metabolites, namely D-glucose, D-mannose, L-tryptophan, 11-deoxycorticosterone, and 17α-hydroxyprogesterone. These were found to be involved in three key metabolic pathways: steroid hormone biosynthesis, tryptophan metabolism, and galactose metabolism. Additionally, five significant anti-RA active components were identified from RMF, including Rhodojaponin (Rj)-Ⅱ, Rj-Ⅲ, Rj-Ⅴ, Rj-Ⅵ, and quercetin. The anti-RA mechanisms of RMF were investigated in this study, focusing on active components, upstream targets, and downstream metabolites. These findings lay a foundation for the clinical practice and drug development of RMF. [Display omitted] • RMF alleviated RA symptoms through the inhibition of inflammatory factors and bone destruction. • RMF could interfere with steroid hormone biosynthesis, tryptophan metabolism, and galactose metabolism, which was closely related to five active components. • The proposed methodology elucidated the active components, upstream targets, and downstream metabolites of in the treatment of RA. [ABSTRACT FROM AUTHOR]

• An UHPLC-Q-Exactive Orbitrap mass spectrometry method was established. A total of 150 compounds were identified, including 35 amino acids and their derivatives, 36 organic acids, 20 terpenids, 20 alkaloids, 12 glycosides, 7 flavonoids and 20 others. • The rationality of the cracking reaction of the compound was explored and verified by molecular simulation calculation based on DFT, and the structure of the compound was further confirmed. • The potential mechanism of anti-pneumonia action of Qing-Kai-Ling oral liquid was studied by means of network pharmacology. A total of 90 key targets were screened, and several major signaling pathways of PI3K-AKT, MAPK and TNF were focused on. Qing-Kai-Ling oral liquid is commonly used clinically for the treatment of fever and upper respiratory tract infection. Moreover, studies have shown that Qing-Kai-Ling oral liquid has an anti-pneumonia effect. However, owing to its complex pharmacodynamic material basis, its pharmacological research and clinical application are limited. To address this problem, the chemical constituents of Qing-Kai-Ling oral liquid were identified by ultra-high performance liquid chromatography quadrupole-Exactive Orbitrap mass (UHPLC-Q-Exactive Orbitrap MS) and network pharmacology methods, which were used to predict its potential anti-pneumonia target and signalling pathway. A total of 150 compounds were identified and tentatively characterized, including 35 amino acids and their derivatives, 36 organic acids, 20 terpenoids, 20 alkaloids, 12 glycosides, 7 flavonoids, and 20 others. Among them, 14 compounds were accurately identified by comparing their retention time and mass spectrum data with those of reference substances. Additionally, we performed molecular simulation calculations via Density Function Theory to determine the plausibility of the compound cleavage reactions and further confirm compound structures. Furthermore, 90 key targets were screened through network pharmacology, with the particular focus on the PI3K-AKT, MAPK and TNF signalling pathways. This method achieved the first comprehensive identification of the chemical composition of Qing-Kai-Ling oral liquid and elucidated its potential mechanism of anti-pneumonia. The results provide valuable reference and data support for pharmacodynamic substance research and quality control. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (KOA) is a very common musculoskeletal disorder, and patients with KOA often exhibit significant quadriceps femoris muscle atrophy. It is well established that curcumin (CUR) exerts protective effects on skeletal muscle. However, the efficacy of CUR in treating KOA-induced quadriceps femoris muscle atrophy and its underlying mechanisms remain uncertain. In this study, we employed network pharmacology to investigate the mechanism by which CUR promotes regenerative repair of the quadriceps femoris muscle in rats with KOA. The potential targets of CUR were obtained from Swiss Target Prediction. The targets of skeletal muscle regeneration were identified from GeneCard and OMIM. A Venn diagram was generated to visualize the intersection of CUR targets and skeletal muscle regeneration targets, and the core targets were identified using STRING. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted using DAVID. Finally, the network pharmacology results were further validated by establishing a KOA rat model using the Hulth method. Network pharmacology analysis and molecular docking results revealed that CUR affects skeletal muscle regeneration through multiple targets and pathways. In vivo experimental results were validated by demonstrating that KOA causes atrophy and induces apoptosis in the quadriceps femoris muscle. Furthermore, CUR was shown to inhibit apoptosis in the quadriceps femoris muscle by regulating STAT3 and FOS, as well as the PI3K/AKT signaling pathway. Our study revealed the apoptosis-inhibiting effects of CUR and its underlying mechanisms. Consequently, CUR has the potential to improve quadriceps femoris muscle atrophy caused by KOA. [ABSTRACT FROM AUTHOR]

Centella asiatica Linn Urban (C. asiatica), aka Mandukparni , is one of the flagship herbs used in traditional medicines to effectively manage neurological problems. Although this plant has a wealth of comprehensive preclinical pharmacological profiles, further clinical research and execution of its molecular mode of action are still required. We searched electronic databases (Google Scholar, SciFinder, MEDLINE, Scopus, EMBASE, Science Direct, and PubMed) using relevant key words to retrieve information pertaining to C. asiatica till June 2023 and performed network pharmacology to understand the mechanism related to their neurobiological roles. This study extensively analyses its pharmacological properties, nutritional profile, ethnomedical uses, safety, and mechanistic role in treating neurological and neurodegenerative disorders. Additionally, a network pharmacology study was performed which suggests that its phytomolecules are involved in different neuroactive ligand-receptor pathways, glial cell differentiation, gliogenesis, and astrocyte differentiation. Hopefully, this report will lead to a paradigm shift in medical practice, research, and the creation of phytopharmaceuticals derived from C. asiatica that target the central nervous system. • Centella asiatica is one of the flagship herbs used in Ayurveda and pharma industry to treat neurological problems and improving learning and memory. • Its rich bioactive constituents are reported to be highly effective in improving learning and memory. • Network pharmacology shows its role in different neuroactive ligand-receptor pathways, gliogenesis, glial cell and astrocyte differentiation. [ABSTRACT FROM AUTHOR]

[Display omitted] Copper serves as an indispensable cofactor for all living organisms, and its excessive accumulation has been associated with a variety of diseases. Wilson's disease (WD) serves as an illustrative example of copper toxicity in humans, frequently presenting with liver and/or neuropsychiatric symptoms. The current therapeutic drugs, penicillamine (PA) and zinc gluconate (ZnG), have constraints, and research on their combination efficacy remains insufficient. It has been reported that melatonin (MLT) plays a vital role in binding to transition metals and exhibits strong antioxidant capacity. To investigate the therapeutic efficacy of MLT and combined treatment, rats were randomly divided into the following seven groups: the control (Con) group, copper-laden model rat (Mod) group, PA-treated group, ZnG-treated group, MLT- treated group, PA-ZnG-treated group, and PA-MLT-treated group. Then potential mechanisms and targets were investigated using a combination of metabolomics and network pharmacology and verified by molecular docking and qPCR. The findings revealed that MLT and the combination significantly improved behavior, pathology and copper levels in copper-laden rats. The results of the metabolomics study showed that profoundly altered metabolites were identified, and alanine, aspartate and glutamate metabolism, pyruvate metabolism, citrate cycle (TCA cycle), and glycolysis/gluconeogenesis were explored. In addition, molecular docking showed that MLT had high binding affinity with key targets, and qPCR results revealed that MLT could reverse the mRNA expression of targets GOT2 and PKM2. It was concluded that MLT effectively improves brain injury in copper-laden rats, and this effect was linked with the altered features of the metabolite profiles. [ABSTRACT FROM AUTHOR]