Network Pharmacology Research Articles

Investigating the potential of mono-chalcone compounds in targeting breast cancer receptors through network pharmacology, molecular docking, molecular dynamics simulation, antiproliferative effects, and gene expressions.

The online version contains supplementary material available at 10.1007/s13205-024-03991-y.

Unlocking the antiviral potential of rosmarinic acid against chikungunya virus via IL-17 signaling pathway

BackgroundThe Chikungunya virus is an Alphavirus that belongs to the Togaviridae family and is primarily transmitted by mosquitoes. It causes acute infection characterized by fever, headache, and arthralgia. Some patients also experience persistent chronic osteoarthritis-like symptoms. Dedicated antiviral treatments are currently unavailable for CHIKV. This study aims to explore the potential anti-CHIKV effect of rosmarinic acid using network pharmacology.MethodsThis study employed network pharmacology to predict and verify the molecular targets and pathways associated with ROSA in the context of CHIKV. The analysis outcomes were further validated using molecular docking and in vitro experiments.ResultsThe analysis of CHIKV targets using the Kyoto Encyclopedia of Genes and Genomes and MCODE identified IL-17 as an important pathogenic pathway in CHIKV infection. Among the 30 targets of ROSA against CHIKV, nearly half were found to be involved in the IL-17 signaling pathway. This suggests that ROSA may help the host in resisting CHIKV invasion by modulating this pathway. Molecular docking validation results showed that ROSA can stably bind to 10 core targets out of the 30 identified targets. In an in vitro CHIKV infection model developed using 293T cells, treatment with 60 μM ROSA significantly improved the survival rate of infected cells, inhibited 50% CHIKV proliferation after CHIKV infection, and reduced the expression of TNF-α in the IL-17 signaling pathway.ConclusionThis study provides the first confirmation of the efficacy of ROSA in suppressing CHIKV infection through the IL-17 signaling pathway. The findings warrant further investigation to facilitate the development of ROSA as a potential treatment for CHIKV infection.

Exploring the mechanism of agarwood moxa smoke in treating sleep disorders based on GC–MS and network pharmacology

BackgroundAgarwood moxibustion is a folk therapy developed by individuals of the Li nationality in China. There is evidence that agarwood moxa smoke (AMS) generated during agarwood moxibustion therapy can treat sleep disorders via traditional Chinese medicines’ multiple target and pathway characteristics. However, the specific components and mechanisms involved have yet to be explored.ObjectiveGC–MS (Gas Chromatography–Mass Spectrometry) and network pharmacology were used to investigate AMS’s molecular basis and mechanism in treating sleep deprivation.MethodGC–MS was used to determine the chemical composition of AMS; component target information was collected from TCMSP (Traditional Chinese Medicine Systems Pharmacology), PubChem (Public Chemical Database), GeneCards (Human Gene Database), and DisGeNet (Database of Genes and Diseases) were used to identify disease targets, and JVenn (Joint Venn) was used to identify the common targets of AMS and sleep disorders. STRING was used to construct a protein interaction network, Cytoscape 3.9.1 was used to build a multilevel network diagram of the “core components-efficacy targets-action pathways,” the targets were imported into Metascape and DAVID for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses and Autodock was used for molecular docking. This research used a network pharmacology methodology to investigate the therapeutic potential of Agarwood Moxa Smoke (AMS) in treating sleep problems. Examining the target genes and chemical constituents of AMS offers insights into the molecular processes and targets of the disease.ResultNine active ingredients comprising anti-inflammatory substances and antioxidants, such as caryophyllene and p-cymene, found seven sleep-regulating signaling pathways and eight targets linked to sleep disorders. GC–MS was used to identify the 94 active ingredients in AMS, and the active ingredients had strong binding with the key targets. Key findings included active components with known medicinal properties, such as p-cymene, eucalyptol, and caryophyllene. An investigation of network pharmacology revealed seven signaling pathways for sleep regulation and eight targets linked to sleep disorders, shedding light on AMS’s effectiveness in enhancing sleep quality.ConclusionAMS may alleviate sleep disorders by modulating cellular and synaptic signaling, controlling hormone and neurotransmitter pathways, etc. Understanding AMS’s material basis and mechanism of action provides a foundation for future research on treating sleep disorders with AMS. According to the study, Agarwood Moxa Smoke (AMS) may improve sleep quality by modifying cellular and synaptic signaling pathways for those who suffer from sleep problems. This might lead to the development of innovative therapies with fewer side effects.

Assessing the safety of bedaquiline: insight from adverse event reporting system analysis

BackgroundThe development and marketing of Bedaquiline (BDQ) represent significant advancements in treating tuberculosis, particularly multidrug-resistant forms. However, comprehensive research into BDQ’s real-world safety remains limited.PurposeWe obtained BDQ related adverse event (AE) information from the US Food and Drug Administration’s Adverse Event Reporting System (FAERS) to assess its safety and inform drug usage.MethodsThe AE data for BDQ from 2012 Q4 to 2023 Q3 was collected and standardized. Disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN) was used to quantify signals of BDQ-related AEs. Logistic regression was used to analyze the individual data of hepatotoxicity and drug-induced liver injury, and multiple linear regression models were established. Additionally, network pharmacology was employed to identify the potential biological mechanisms of BDQ-induced liver injury.ResultsWe identified 2017 case reports directly related to BDQ. Our analysis identified 341 Preferred Terms (PTs) characterizing these AEs across 27 System Organ Classes (SOC). An important discovery was the identification of AEs associated with ear and labyrinth disorders, which had not been documented in the drug’s official leaflet before. Subgroup analysis revealed a negative correlation between BDQ-related liver injury and females (OR: 0.4, 95%CI: 0.3–0.6). In addition, via network pharmacology approach, a total of 76 potential targets for BDQ related liver injury were predicted, and 11 core target genes were selected based on the characterization of protein-protein interactions. The pathway linked to BDQ-induced liver injury was identified, and it was determined that the PI3K-Akt signaling pathway contained the highest number of associated genes.ConclusionThe analysis of the FAERS database revealed adverse events linked to BDQ, prompting the use of a network pharmacology approach to study the potential molecular mechanism of BDQ-induced liver injury. These findings emphasized the significance of drug safety and offered understanding into the mechanisms behind BDQ-induced liver injury. BDQ demonstrated distinct advantages, including reduced incidence of certain adverse events compared to traditional treatments such as injectable agents and second-line drugs. However, it is important to acknowledge the limitations of this analysis, including potential underreporting and confounding factors. This study provides valuable insights into the safety of BDQ and its role in the management of MDR-TB, emphasizing the need for continued surveillance and monitoring to ensure its safe and effective use.

Quercetin prevented diabetic nephropathy by inhibiting renal tubular epithelial cell apoptosis via the PI3K/AKT pathway.

Diabetic nephropathy (DN) is the most common and serious complication of diabetes, posing a significant threat to human health. Currently, safe and effective preventive strategies for DN are lacking. The study aimed to explore the preventive effect and the underlying mechanism of quercetin against DN. In the in vivo experiments, we established a mouse model of type 2 diabetes mellitus (T2DM) induced by a combination of high-fat diet (HFD) and streptozotocin (STZ) to explore the preventive effect of quercetin on DN and its protective role against renal tubular epithelial cell apoptosis. Subsequently, in vitro experiments using human tubular epithelial cells (HK-2 cells) were conducted to further validate the protective effects of quercetin on renal tubular epithelial cell apoptosis. Additionally, we employed RNA sequencing analysis (RNA-seq) and network pharmacology analysis to comprehensively elucidate the molecular mechanisms involved. In vivo, we observed a significant increase in the ratio of urinary microalbumin to creatinine in diabetic mice compared to control mice, accompanied by the activation of renal tubular epithelial cell apoptosis. Remarkably, all of these changes were reversed after quercetin treatment. In vitro, high-glucose-induced apoptosis in HK-2 cells was significantly attenuated by quercetin. Subsequent RNA sequencing analysis and network pharmacology analysis revealed that quercetin was most likely to inhibit high-glucose-induced HK-2 cell apoptosis through the PI3K/AKT signaling pathway. Western Blotting results further demonstrated that quercetin could inhibit the activation of the PI3K/AKT signaling pathway in HK-2 cells induced by high glucose. Our results supported that quercetin could prevent DN by inhibiting tubular epithelial cell apoptosis via the PI3K/AKT pathway. Quercetin might be a promising candidate for the prevention of DN.

Mechanism of action of Sambucus williamsii Hance var. miquelii in the treatment of osteoporosis analyzed by UHPLC-HRMS/MS combined network pharmacology and experimental validation

Sambucus williamsii Hance var. miquelii(SWH) is a precious wild Chinese herb whose fruit, rhizome, leaves and root bark can be used as medicine. Sambucus Linn has pharmacological effects such as anti-osteoporosis, promoting fracture healing, anti-viral and anti-inflammatory. In this study, the main chemical components of the alcoholic extracts from SWH were rapidly identified by ultra-high performance liquid chromatography-quadrupole orbit trap high-resolution mass spectrometry (UHPLC- HRMS MS), and a total of 42 compounds were characterized from the alcoholic extracts of SWH. The results of network pharmacological validation showed that kaempferol, quercetin, luteolin, isorhamnetin and morroniside were the main active components, and KEGG enrichment demonstrated that SWH mainly affected the signaling pathways such as PI3K-Akt, TNF and FoxO by modulating the related targets such as AKT1, PIK3R1, EGFR, RELA SRC and PTGS2. The molecular docking results showed binding solid activity between the main active components of SWH and the targets. The network pharmacology was validated by establishing an animal model of osteoporosis (OP) in rats by gavage administration of vitamin A acid. The results of the pharmacological experiments showed that SWH could improve the degree of bone loss in the femur of osteoporotic rats, increase the number of trabeculae and decrease trabeculae porosity, up-regulate the Ca and P content in the serum of OP rats, down-regulate the scope of ALP and BGP in the serum, and promote the calcification of the bone matrix, and then exert the anti-OP efficacy. In this study, network pharmacology and pharmacological experiments verified the pharmacological mechanism of SWH in anti-OP rats. This provides a theoretical basis for the research and development of anti-OP drugs and a reference for the application of other traditional Chinese medicines in treating OP diseases.

Network pharmacology combined with molecular docking and molecular dynamic simulation to reveal the potential mechanism of lentinan ameliorating hyperlipidemia

Hyperlipidemia is closely related to multiple diseases and is characterized by abnormal serum lipid profiles. The biological function of lentinan in mice and rats was studied, but the mechanism of its lipid-lowering effect was not completely clear. In this study, network pharmacological analysis, molecular docking, and molecular dynamics simulation were used to explore the potential mechanism of its lipid-lowering effect and high-fat diet (HFD) mice was used to confirm the predicted mechanism. Our results indicated that lentinan could ameliorate hyperlipidemia by regulating peroxisome proliferator-activated receptors (PPARs), sterol response element-binding protein-1 (SREBP1), and nuclear factor kappa-B (NF-κB) in the hepatic tissues of mices. Further animal experiment showed that lentinan could regulate the mRNA expressions of lipid metabolism-related genes, such as PPARα, PPARδ, PPARγ, cluster of differentiation 36 (CD36) and SREBP-1c. Moreover, lentinan supplementation could reduce the expressions of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and inducible nitric oxide sythase (iNOS). In cell model, lentinan also could inhibit oleic acid-induced lipid droplet formation and the expressions of lipid metabolism-related genes and reduced inflammatory factor expressions in HepG2 cells, which further approved the results of animal experiment. Taken together, our results suggest that lentinan can ameliorate hyperlipidemia via regulating lipid metabolism-related gene expressions and reduce obesity-induced inflammatory response.

Isocucurbitacin B inhibits glioma growth through PI3K/AKT pathways and increases glioma sensitivity to TMZ by inhibiting hsa-mir-1286a

Aim: Glioma accounts for 81% of all cancers of the nervous system cancers and presents one of the most drug-resistant malignancies, resulting in a relatively high mortality rate. Despite extensive efforts, the complete treatment options for glioma remain elusive. The effect of isocucurbitacin B (isocuB), a natural compound extracted from melon pedicels, on glioma has not been investigated. This study aims to investigate the inhibitory effect of isocuB on glioma and elucidate its underlying mechanisms, with the objective of developing it as a potential therapeutic agent for glioma. Methods: We used network pharmacology and bioinformatics analysis to predict potential targets and associated pathways of isocuB in glioma. Subsequently, the inhibitory effect of isocuB on glioma and its related mechanisms were assessed through Counting Kit-8 (CCK-8), wound healing, transwell, Western blot (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and other in vitro experiments, alongside tumor formation experiments in nude mice. Results: Based on this investigation, it suggested that isocuB might inhibit the growth of gliomas through the PI3K-AKT and MAPK pathways. Additionally, we proposed that isocuB may enhance glioma drug sensitivity to temozolomide (TMZ) via modulation of hsa-mir-1286a. The CCK-8 assay revealed that isocuB exhibited inhibitory effects on U251 and U87 proliferation and outperformed TMZ. Wound healing and transwell experiments showed that isocuB inhibited the invasion and migration of U251 cells by suppressing the activity of MMP-2/9, N-cadherin, and Vimentin. The tunnel and flow cytometry (FCM) assays revealed that isocuB induced cell apoptosis through inhibition of BCL-2. Subsequently, we conducted RT-qPCR and Western blot (WB) experiments, which revealed that PI3K/AKT and MAPK pathways might be involved in the mechanism of the inhibition isocuB on glioma. Additionally, isocuB promoted the sensitivity of glioma U251 to TMZ by inhibiting hsa-mir-1286a. Furthermore, we constructed TMZ-resistant U251 strains and demonstrated effective inhibition by isocuB against these resistant strains. Finally, we confirmed that isocuB can inhibit tumor growth in vivo through experiments on tumors in nude mice. Conclusion: IsocuB may protect against glioma by acting on the PI3K/AKT and MAPK pathways and promote the sensitivity of glioma U251 to TMZ by inhibiting hsa-mir-1286a.

Synergistic cytotoxicity and in vitro antioxidant activity of hederagenin and its glycoside from quinoa.

Although a series of studies confirm the bioactivities of hederagenin and its glycosides, their synergistic effects and potential mechanisms are still worthy of further exploration. This work investigated the synergistic cytotoxicity and in vitro antioxidant activity of hederagenin and hederagenin 28-O-β-d-glucopyranoside (28-Glc-hederagenin). Hederagenin and 28-Glc-hederagenin inhibited HeLa cell growth and their combination further strengthened this effect. The combination of hederagenin and 28-Glc-hederagenin significantly increased the rate of apoptotic cells, suggesting the presence of a synergistic effect between the two substances. This combination also enhanced in vitro antioxidant activity compared with individual treatments. A network pharmacology and molecular docking-based approach was performed to explore the underlying mechanisms of hederagenin and 28-Glc-hederagenin against cervical cancer and oxidant damage. This work identified 18 related Kyoto Encyclopedia of Genes and Genome pathways, 202 related biological process terms, 17 related CC terms, and 35 related molecular function terms and then revealed 30 nodes and 196 edges. Subsequently, two highly connected clusters and the top four targets were identified. Molecular docking showed potent binding affinity of hederagenin and 28-Glc-hederagenin toward core targets associated with both cervical cancer and oxidant damage. This work may provide scientific basis for the combined use of hederagenin and its glycosides as dietary supplements.

Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Systematic investigation of the material basis, effectiveness and safety of Thesium chinense Turcz. and its preparation Bairui Granules against lung inflammation

BackgroundThesium chinense Turcz. (Named as Bai Rui Cao in Chinese) and its preparations (e.g., Bairui Granules) have been used to treat inflammatory diseases, such as acute mastitis, lobar pneumonia, tonsillitis, coronavirus disease 2019 (COVID-19), and upper respiratory tract infection. However, the material basis, pharmacological efficiency, and safety have not been illustrated.MethodsAnti-inflammatory activity-guided isolation of constituents has been performed using multiple column chromatography, and their structures were elucidated by NMR spectroscopy and ECD calculations. The inhibitory effects on lung inflammation and safety of the crude ethanol extract (CE), Bairui Granules (BG), and the purified active constituents were evaluated using lipopolysaccharide (LPS)-stimulated acute lung inflammation (ALI) mice model or normal mice.ResultsSeven new compounds (1–7) and fifty-six known compounds (8–63) were isolated from T. chinense, and fifty-four were reported from this plant for the first time. The new flavonoid glycosides 1–2, new fatty acids 4–5, new alkaloid 7 as well as the known constituents including flavonoid aglycones 8–11, lignans 46–54, alkaloids 34 and 45, coumarins 57, phenylpropionic acids 27, and simple aromatic compounds 39, 44 and 58 exhibited anti-inflammatory activity. Network pharmacology analysis indicated that anti-inflammation of T. chinense was attributed to flavonoids and alkaloids by regulating inflammation-related proteins (e.g., TNF, NF-κB, TGF-β). Furthermore, constituents of T. chinense including kaempferol-3-O-glucorhamnoside (KN, also named as Bairuisu I, 19), astragalin (AG, Bairuisu II, 12), and kaempferol (KF, Bairuisu III, 8), as well as CE and BG could alleviate lung inflammation caused by LPS in mice by preventing neutrophils infiltration and the expression of the genes for pro-inflammatory cytokines NLRP3, caspase-1, IL-1β, and COX-2. After a 28-day subacute toxicity test, BG at doses of 4.875 g/kg and 9.750 g/kg (equivalent to onefold and twofold the clinically recommended dose) and CE at a dose of 11.138 g/kg (equivalent to fourfold the clinical dose of BG) were found to be safe and non-toxic.ConclusionsThe discovery of sixty-three constituents comprehensively illustrated the material basis of T. chinense. T. chinense and Bairui Granules could alleviate lung inflammation by regulating inflammation-related proteins and no toxicity was observed under the twofold of clinically used doses.

Target prediction and potential application of dihydroartemisinin on hepatocarcinoma treatment.

With high incidence of hepatocarcinoma and limited effective treatments, most patients suffer in pain. Antitumor drugs are single-targeted, toxicity, causing adverse side effects and resistance. Dihydroartemisinin (DHA) inhibits tumor through multiple mechanisms effectively. This study explores and evaluates safety and potential mechanism of DHA towards human hepatocarcinoma based on network pharmacology in a comprehensive way. Adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of DHA were evaluated with pkCSM, SwissADME, and ADMETlab. Potential targets of DHA were obtained from SwissTargetPrediction, Drugbank, TargetNET, and PharmMapper. Target gene of hepatocarcinoma was obtained from OMIM, GeneCards, and DisGeNET. Overlapping targets and hub genes were identified and analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway. Molecular docking was utilized to investigate the interactions sites and hydrogen bonds. Cell counting kit-8 (CCK8), wound healing, invasion, and migration assays on HepG2 and SNU387 cell proved DHA inhibits malignant biological features of hepatocarcinoma cell. DHA is safe and desirable for clinical application. A total of 131 overlapping targets were identified. Biofunction analysis showed targets were involved in kinase activity, protein phosphorylation, intracellular reception, signal transduction, transcriptome dysregulation, PPAR pathway, and JAK-STAT signaling axis. Top 9 hub genes were obtained using MCC (Maximal Clique Centrality) algorithm, namely CDK1, CCNA2, CCNB1, CCNB2, KIF11, CHEK1, TYMS, AURKA, and TOP2A. Molecular docking suggests that all hub genes form a stable interaction with DHA for optimal binding energy were all less than - 5kcal/mol. Dihydroartemisinin might be a potent and safe anticarcinogen based on its biological safety and effective therapeutic effect.

Danggui-Shaoyao San alleviates cognitive impairment via enhancing HIF-1α/EPO axis in vascular dementia rats

Ethnopharmacological relevanceInvigorating blood circulation to remove blood stasis is a primary strategy in TCM for treating vascular dementia (VaD). Danggui-Shaoyao San (DSS), as a traditional prescription for neuroprotective activity, has been proved to be effective in VaD treatment. However, its precise molecular mechanisms remain incompletely understood. Aim of the studyThe specific mechanism underlying the therapeutic effects of DSS on VaD was explored by employing network pharmacology as well as in vivo and in viro experiment validation. Materials and methodsWe downloaded components of DSS from the BATMAN-TCM database for target prediction. The intersection between the components of DSS and targets, PPI network, as well as GO and KEGG enrichment analysis were then performed. Subsequently, the potential mechanism of DSS predicted by network pharmacology was assessed and validated through VaD rat model induced by 2VO operation and CoCl2-treated PC12 cells. Briefly, the DSS extract were first quantified by HPLC. Secondly, the effect of DSS on VaD was studied using MWM test, HE staining and TUNEL assay. Finally, the molecular mechanism of DSS against VaD was validated by Western blot and RT-QPCR experiments. ResultsThrough network analysis, 137 active ingredients were obtained from DSS, and 67 potential targets associated with DSS and VaD were identified. GO and KEGG analysis indicated that the action of DSS on VaD primarily involves hypoxic terms and HIF-1 pathway. In vivo validation, cognitive impairment and neuron mortality were markedly ameliorated by DSS. Additionally, DSS significantly reduced the expression of proteins related to synaptic plasticity and neuron apoptosis including PSD-95, SYP, Caspase-3 and BCL-2. Mechanistically, we confirmed DSS positively modulated the expression of HIF-1α and its downstream proteins including EPO, p-EPOR, STAT5, EPOR, and AKT1 in the hippocampus of VaD rats as well as CoCl2-induced PC12 cells. HIF-1 inhibitor YC-1 significantly diminished the protection of DSS on CoCl2-induced PC12 cell damage, with decreased HIF-1α, EPO, EPOR expression. ConclusionOur results initially demonstrated DSS could exert neuroprotective effects in VaD. The pharmacological mechanism of DSS may be related to its positive regulation on HIF-1α/EPO pathway.

Unlocking the functional potential of Nitraria schoberi extracts using chemical fingerprinting, biological efficiencies, in silico and network pharmacological approaches

The objective of this investigation was to assess the cytotoxic, antioxidant, and enzyme inhibitory properties of the aerial portions of Nitraria schoberi (family Nitrariaceae). Extracts were prepared by sequential maceration in hexane, dichloromethane (DCM), ethyl acetate and methanol (MeOH) and water extract was prepared by infusion. DCM and MeOH extracts accumulated the highest amount of metabolites where the former was characterized by the presence of octadecyl ferulate (16.96 mg/100 mg), methoxyluteolin (8.48 mg/100 mg) and isorhamnetin (5.35 mg/100 mg) and the alkaloids perlolyrine (5.03 mg/100 mg), (+)-5a-hydroxylemannine (2.43 mg/100 mg) and matrine (2.40 mg/100 mg). Results of antioxidant activity showed that the MeOH extract exerted the highest anti-2,2-diphenyl-1-picrylhydrazyl (DPPH) (28.13 mg Trolox equivalent (TE)/g) and Fe+++ (54.38 mg TE/g) reducing capacity. All extracts exerted significant acetylcholinesterase (3.71–4.37 mg galantamine equivalent (GALAE)/g) and tyrosinase (86.40–109.63 mg kojic acid equivalent (KAE)/g) inhibition activity. The best α-amylase and α-glucosidase inhibition was exhibited by the DCM (0.81 mmol ACAE/g) and MeOH (1.34 mmol ACAE/g) extracts respectively. The highest cytotoxic effect was exerted against the breast adenocarcinoma (MDA-MB-231) (IC50: 26.71 μg/mL) and cervix adenocarcinoma (HELA) (IC50: 29.10 μg/mL) cell lines by the MeOH and DCM extracts respectively. In addition, we performed molecular docking analysis to understand the interaction between chemical components and tested enzymes and cellular targets for cancer. Chrysoeriol-3-O-rutinoside bound strongly to AChE. Furthermore, a good interaction between vascular endothelial growth factor receptor 2 (VEGFR2) and isovitexin-2″-O-arabinoside was observed. We employed network pharmacology to understand the role of N. schoberi's compounds in neurological disorder like Alzheimer and multiple sclerosis. Therefore, the results of this study indicate that N. schoberi may serve as a viable starting point for the future creation of phytopharmaceuticals that target particular diseases associated with oxidative stress, such as diabetes and certain neurological disorders.

Integration of network pharmacology, lipidomics, and transcriptomics analysis to reveal the mechanisms underlying the amelioration of AKT-induced nonalcoholic fatty liver disease by total flavonoids in vine tea.

Nonalcoholic fatty liver disease (NAFLD) is the main reason for chronic liver diseases and malignancies. Currently, there is a lack of approved drugs for the prevention or treatment of NAFLD. Vine tea (Ampelopsis grossedentata) has been used as a traditional Chinese beverage for centuries. Vine tea carries out several biological activities including the regulation of plasma lipids and blood glucose, hepato-protective function, and anti-tumor activity and contains the highest content of flavonoids. However, the underlying mechanisms of total flavonoids from vine tea (TF) in the attenuation of NAFLD remain unclear. Therefore, we investigated the interventions and mechanisms of TF in mice with NAFLD using an integrated analysis of network pharmacology, lipidomics, and transcriptomics. Staining and biochemical tests revealed a significant increase in AKT-overexpression-induced (abbreviated as AKT-induced) NAFLD in mice. Lipid accumulation in hepatic intracellular vacuoles was alleviated after TF treatment. In addition, TF reduced the hepatic and serum triglyceride levels in mice with AKT-induced NAFLD. Lipidomics results showed 32 differential lipids in the liver, mainly including triglycerides (TG), diglycerides (DG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). Transcriptomic analysis revealed that 314 differentially expressed genes were commonly upregulated in the AKT group and downregulated in the TF group. The differential regulation of lipids by the genes Pparg, Scd1, Chpt1, Dgkz, and Pla2g12b was further revealed by network enrichment analysis and confirmed by RT-qPCR. Furthermore, we used immunohistochemistry (IHC) to detect changes in the protein levels of the key proteins PPARγ and SCD1. In summary, TF can improve hepatic steatosis by targeting the PPAR signaling pathway, thereby reducing de novo fatty acid synthesis and modulating the glycerophospholipid metabolism.

Chemical constituents from uncaria laevigata and their vasodilatory activities in vitro and action mechanism

A new triterpenoid compound 1* (scandine A1) was obtained from 95% ethanol extract of Uncaria laevigata. Meanwhile, eleven described compounds were also isolated for the first time from Uncaria laevigata. Herein, compound 2 exhibited strong diastolic cardio-cerebrovascular activity (EC50BA = 9.22 μM and EC50CA = 14.65 μM), which was not been previously described. Compound 1* also showed certain diastolic cardio-cerebrovasculary activity. Network pharmacology indicated that the diastolic cardio-cerebrovascular activity of compound 2 was most correlated with the Ras signalling pathway. Molecular docking confirmed that it exhibited strong binding activity with target protein (matrix metalloproteinase inhibitor-1). Moreover, compound 2 demonstrated significant potential on cardio-cerebrovascular activity in vitro. Overall, compounds 1* and 2 with good diastolic cardio-cerebrovascular activity were discovered in this work.

The mechanism of Xihuang pills' intervention in the tumour immune microenvironment for the treatment of liver cancer based on the STAT3-PDL1 pathway

Ethnopharmacological relevanceXihuang pills, a time-honored Chinese compound formula with a history spanning thousands of years, have demonstrated remarkable efficacy in treating various cancers, such as breast cancer, colon cancer, and liver cancer. Clinical applications over the years have established their effectiveness. Several scholars conducting experimental studies have elucidated the potent tumor-suppressing effects of Xihuang pills. While the inhibition of tumor vascular development and prevention of tumor cell invasion and metastasis have been well-explored mechanisms, the impact on the tumor immune microenvironment has received less attention. This study focuses on investigating the immune microenvironment adjustments induced by Xihuang pills in hepatocellular carcinoma. Aim of the studyTumour cells will find an escape phenomenon during tumour immunotherapy, which will affect immunotherapy results. We will research the regulation of the tumour immune microenvironment, to provide a more complete and precise basis for the elucidation of the mechanism of Xihuang pills in treating cancers. It provides new research ideas for people to treat liver cancer. Materials and methodsThrough in vivo and in vitro assessments confirming the intervention effects of Xihuang pills, we observed alterations in T cell typing, macrophage polarization, and tumor-associated cytokine levels. The primary active ingredients of Xihuang pills were identified using UPLC-MS/GC-MS, and relevant pathways in the treatment of hepatocellular carcinoma were predicted through network pharmacology. Combining the network pharmacology approach, we predicted the pathways relevant to Xihuang pills in treating hepatocellular carcinoma and experimentally validated the involvement of PD-1/PD-L1, a key immunity-related axis. ResultsXihuang Pill has a regulatory effect on the tumor immune microenvironment. ConclusionsThe results indicated that Xihuang pills could impact splenic lymphocyte phenotyping, macrophage polarization, and IL-6 cytokine expression in liver cancer mice. The mechanism of action was associated with the regulation of the PD-1/PD-L1 signaling pathway by the STAT3 protein.

Radix Rehmanniae Praeparata promoted zebrafish fin regeneration through aryl hydrocarbon receptor-dependent autophagy

Headings ethnopharmacological relevanceRehmanniae Radix Praeparata (RRP), a staple in traditional Chinese medicine, is derived from Rehmannia glutinosa Libosch and is renowned for its wound-healing properties. Despite its clinical prevalence, the molecular mechanisms underlying RRP's wound-healing effects have not been fully elucidated. Aim of the studyThis research endeavored to delineate the molecular and cellular mechanisms underlying the beneficial effects of RRP on wound healing, utilizing a zebrafish model. Materials and methodsZebrafish larvae at 3 days post-fertilization were amputated at the fin and subsequently treated with RRP. The pro-wound healing and regenerative effects of RRP were evaluated through morphological analysis, assessment of cell proliferation and apoptosis, Additionally, mechanistic insights were gained through a comprehensive approach encompassing network pharmacology analysis, cell tracing, RNA-sequencing, CRISPR/Cas9 gene editing, and pharmacological inhibition. ResultsOur findings demonstrate that RRP significantly accelerates caudal fin regeneration in zebrafish following injury by suppressing cell apoptosis, promoting cell proliferation, and upregulating the expression of regenerative-related genes. Furthermore, RRP triggers autophagy signals during the regenerative process, which is attenuated by the autophagy inhibitor chloroquine (CQ). Notably, the administration of RRP enhances the expression of ahr1 and ahr2 in the regenerating fin. Genetic knockout of ahr1a, ahr1b, or ahr2 using CRISPR/Cas9, or pharmacological blockade of AHR signals with the antagonist CH-223191, diminishes the regenerative potential of RRP. Remarkably, zebrafish lacking ahr2 completely lose their fin regeneration ability. Additionally, inhibition of AHR signaling suppresses autophagy signaling during fin regeneration. ConclusionsThis study uncovers that RRP stimulates fin regeneration in zebrafish by inducing AHR signals and, at least partially, activating the autophagy process. These findings provide novel insights into the molecular mechanisms underlying the wound-healing effects of RRP and may pave the way for the development of novel therapeutic strategies.

Network pharmacology speaking to ethnopharmacology: new data on an ancient remedy

Network pharmacology as a “green approach”, predicting metabolite behaviours chemically and biologically and guid¬ing biological experimental design, is a new strategy aiming to uncover the mechanism of action of natural products as drug candidates. It provides a powerful way to identify novel mechanisms of natural products with potential thera¬peutic effects. This approach has emerged as a powerful tool to overcome the limitations of traditional methods, such as the ability to predict the adverse effects of a drug and the likelihood of failure during clinical trials, by applying systems biology principles to the field of pharmacology. This method combines the multi-omics dataset, computer modeling, and chemical biology so as to reveal pharmaceutical actions and guide drug discovery. Therefore, computer-aided drug design combined with network pharmacology can be viewed as a novel in silico screening ap¬proach to drug discovery, by utilising chemoinformatics, bioinformatics, structure biology, and chemical biology. This strategy includes target-based virtual screening - molecular docking, ligand similarity-based virtual screening, and inverse screening (Inver-dock), providing a powerful tool for target identification of drug candidates, multitarget dis¬covery, and natural bioactive product profiling. It can also be used for selectivity profiling of drugs, drug repositioning, safety profiling, and metabolism profiling prediction (ADMET).

ANALISIS KETERKAITAN NETWORK PHAMACOLOGY SENYAWA METABOLIT SEKUNDER Abrus precatorius L. SECARA IN SILICO

Cancer remains a global health challenge, prompting extensive research efforts worldwide. Lung cancer, the second most diagnosed cancer, presents a particularly grim survival rate. In Indonesia, cancer incidence ranks significantly, with millions affected and hundreds of thousands succumbing to the disease annually. Traditional medicine persists as a preferred option among many, perceived as safer and more affordable. Abrus precatorius L., an ancient medicinal plant, holds promise in this regard, with a rich history of use and a diverse range of pharmacological activities, including anti-cancer properties. Employing in silico modeling and network pharmacology, this study explores the interaction between Abrus precatorius L. compounds and various proteins associated with cancer. Through bioinformatics tools and databases, 27 bioactive compounds are identified and their physicochemical properties assessed, ensuring adherence to pharmacological guidelines. The study predicts potential protein targets for Abrus precatorius L. compounds, revealing interactions with 453 proteins, including those implicated in cancer pathways. Further analysis using StringDB and DISEASES database establishes protein-protein interaction networks, highlighting key proteins like EGFR and TERT, pivotal in multiple cancer types. The study validates the compounds' adherence to Lipinski's Rule of Five, indicating their potential for pharmacological activity and oral absorption. False Discovery Rate (FDR) analysis confirms significant associations between Abrus precatorius L. compounds and various cancers, further underscoring their therapeutic potential. In conclusion, Abrus precatorius L. compounds, particularly targeting EGFR and TERT proteins, emerge as promising candidates for cancer treatment. Their diverse pharmacological activities and interactions with key cancer-related proteins pave the way for further exploration and development of these compounds as alternative medicinal agents. In vitro and in vivo studies are warranted to validate their efficacy, particularly in addressing the complexities of different cancer types. Ultimately, this research offers valuable insights into leveraging natural compounds for combating cancer, addressing a critical need in global healthcare.