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1.
Mol Autism ; 15(1): 14, 2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570876

RESUMO

BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3-/-) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3-/- mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.


Assuntos
Transtorno Autístico , Animais , Camundongos , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Hipotálamo/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo
2.
J Ethnopharmacol ; 328: 117900, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38432577

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonatum cyrtonema Hua (Huangjing) is a Chinese herb that is considered by ancient Chinese healers to have the effect of nourishing yin and moisturizing the lungs. It is clinically used to treat diseases of the pulmonary system, including non-small cell lung cancer. However, the precise active components and underlying mechanisms of Huangjing in the context of treating NSCLC remain uncertain. AIM OF THE STUDY: This study aimed to explore the active components and mechanisms of Huangjing for the treatment of NSCLC by means of data mining, network pharmacology, and in vitro and vivo experiments. MATERIALS AND METHODS: First, the main active compounds and key targets of Huangjing were predicted by network pharmacology. The potential key targets of Huangjing were molecularly docked with the main active compounds using Pymol. In vivo, we verified whether Huangjing and its main active compound have anti-lung cancer effects. Key targets were verified by PCR and immunohistochemistry. In vitro, we verified the effects of Huangjing's main active compound on the proliferation, apoptosis, and migration of A549 cells by CCK-8, colony formation, wound healing assay, and flow cytometry. Key targets and signaling pathway were validated by PCR and Western blot. RESULTS: The network pharmacology results suggested that ß-sitosterol was the main active substance. TP53, JUN, AKT1, MAPK14, ESR1, RELA, HIF1A, and RXRA were potential targets of Huangjing. Molecular docking results suggested that MAPK14, HIF-1α, and RXRA docked well with ß-sitosterol. In vivo tests also confirmed that Huangjing could significantly inhibit the growth of lung cancer tumors, while PCR and immunohistochemistry results suggested that the expression of HIF-1α was significantly decreased. Critically, KEGG analysis indicated that the PI3K/Akt/HIF-1α signaling pathway was recommended as one of the main pathways related to the anti-NSCLC effect of Huangjing. We conducted in vitro experiments to confirm the significant impact of ß-sitosterol on the proliferation, apoptosis, migration, and colony formation of A549 cells. Furthermore, our findings indicate that a high dosage of ß-sitosterol may effectively decrease the expression of HIF-1α, AKT1, JUN and RELA in A549 cells. Similarly, in vitro experiments also revealed that high doses of ß-sitosterol could inhibit the PI3K/Akt/HIF-1α signaling pathway. CONCLUSIONS: We discovered Huangjing and its main active ingredient, ß-sitosterol, can reduce HIF-1α, AKT1, JUN and RELA expression and decrease non-small cell lung cancer growth through the PI3K/Akt/HIF-1α signaling pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Medicamentos de Ervas Chinesas , Neoplasias Pulmonares , Proteína Quinase 14 Ativada por Mitógeno , Polygonatum , Sitosteroides , Simulação de Acoplamento Molecular , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Farmacologia em Rede , Transdução de Sinais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
3.
Chin J Integr Med ; 30(3): 230-242, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37815727

RESUMO

OBJECTIVE: To examine the therapeutic effect of Fangji Fuling Decoction (FFD) on sepsis through network pharmacological analysis combined with in vitro and in vivo experiments. METHODS: A sepsis mouse model was constructed through intraperitoneal injection of 20 mg/kg lipopolysaccharide (LPS). RAW264.7 cells were stimulated by 250 ng/mL LPS to establish an in vitro cell model. Network pharmacology analysis identified the key molecular pathway associated with FFD in sepsis. Through ectopic expression and depletion experiments, the effect of FFD on multiple organ damage in septic mice, as well as on cell proliferation and apoptosis in relation to the mitogen-activated protein kinase 14/Forkhead Box O 3A (MAPK14/FOXO3A) signaling pathway, was analyzed. RESULTS: FFD reduced organ damage and inflammation in LPS-induced septic mice and suppressed LPS-induced macrophage apoptosis and inflammation in vitro (P<0.05). Network pharmacology analysis showed that FFD could regulate the MAPK14/FOXO signaling pathway during sepsis. As confirmed by in vitro cell experiments, FFD inhibited the MAPK14 signaling pathway or FOXO3A expression to relieve LPS-induced macrophage apoptosis and inflammation (P<0.05). Furthermore, FFD inhibited the MAPK14/FOXO3A signaling pathway to inhibit LPS-induced macrophage apoptosis in the lung tissue of septic mice (P<0.05). CONCLUSION: FFD could ameliorate the LPS-induced inflammatory response in septic mice by inhibiting the MAPK14/FOXO3A signaling pathway.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Radioisótopos de Oxigênio , Sepse , Wolfiporia , Camundongos , Animais , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Sepse/complicações , Transdução de Sinais , Inflamação/tratamento farmacológico
4.
J Tradit Chin Med ; 43(6): 1103-1109, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37946472

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulating Zusanli (ST36), Sanyinjiao (SP6) on inhibition of osteoclastogenesis and the role of the adenosine A2A receptor (A2AR) and the p38α Mitogen-Activated Protein Kinase (MAPK) signaling pathway in mediating this effect. METHODS: Mice with collagen induced arthritis (CIA) received different treatments. Immunohistochemistry and western blotting were used to determine the levels of multiple signaling molecules in these joints [receptor activator of nuclear transcription factor-κB (NF-κB) ligand (RANKL), receptor activator of NF-κB (RANK), tumor necrosis factor receptor associated factor 6 (TRAF6), p38α, NF-κB, and nuclear factor of activated T cells C1 (NFATc1)]. Osteoclasts were identified using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: The immunohistochemistry results indicated upregulation of p38α, NF-κB, and NFATc1 in the CIA-control and CIA-EA-SCH58261 groups, but reduced levels in the CIA-EA group. Western blotting indicated upregulation of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1 in the CIA-control and CIA-EA-SCH58261 groups, but reduced expression in the CIA-EA group. Osteoclasts were more abundant in the CIA-control and CIA-EA-SCH58261 groups than in the CIA-EA group. CONCLUSIONS: EA treatment enhanced the A2AR activity and inhibited osteoclast formation by inhibition of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1. SCH58261 reversed the effect of EA. These results suggest that EA regulated p38α-MAPK signaling by increasing A2AR activity, which inhibited osteoclastogenesis.


Assuntos
Artrite Experimental , Eletroacupuntura , Proteína Quinase 14 Ativada por Mitógeno , Animais , Camundongos , Osteogênese , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Receptor A2A de Adenosina/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Diferenciação Celular , Transdução de Sinais , Ligante RANK/genética , Ligante RANK/metabolismo
5.
Stud Health Technol Inform ; 308: 669-679, 2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-38007798

RESUMO

OBJECTIVE: To analyze the regularity of modern Chinese herbal compound in the treatment of salivation based on data mining technology, and to study the potential mechanism of core Chinese herbal medicine in the treatment of salivation using network pharmacology and molecular docking. METHODS: CNKI, VIP and Wanfang literature databases were searched.Choose a prescription for salivation.Excel2019 was used to establish a database of formulas for the treatment of salivation.The included TCM compounds were analyzed by frequency statistics and association rules using the ancient and modern medical record cloud platform to obtain the core drug pairs.TCMSP and Uniprot were used to search the components and targets of the core drug pairs, and intersected with the disease targets obtained from Genecards, OMIM, TTD, PharmgKb, and DrugBank platforms.Complex networks were constructed by cytoscape3.9.1; PPI networks were completed by STRING platform; GO and KEEG pathway enrichment analysis was performed by R language; finally molecular docking validation was performed using AutoDockTools software; and the results were visualized by Pymol software. RESULTS: 122 prescriptions were obtained, 194 herbs were used, the total frequency was 1047, and the top ten drugs used were Atractylodes macrocephala Koidz, Poria cocos, Glycyrrhiza uralensis, Yizhiren, Citrus sinensis, Codonopsis pilosula, Yam, Pinellia ternate, Zingiber officinale, and Coptis chinensis.After association rule analysis, the core drug pair Codonopsis pilosula - Atractylodes macrocephala Koidz was obtained.Twenty-seven effective active components of core drug pairs were screened, corresponding to 62 targets for the treatment of salivation, and four core targets were MAPK1, TP53, MAPK14, and ESR1.GO enrichment analysis yielded 1789 biological process entries, 81 cellular component entries and 111 molecular function entries.KEGG enrichment analysis resulted in 157 pathways, and the first 30 were selected for visualization.Molecular docking of luteolin, 7-Methoxy-2-methyl isoflavone, Stigmasterol, 3ß-acetoxyatractylone, Frutinone A, 3betaHydroxymethyllenetanshiquinone, glycitein to the core target showed that the key active components had good binding activity to the core target. CONCLUSION: The key active components of Codonopsis pilosula and Atractylodes macrocephala Koidz in the treatment of salivation act on MAPK1, TP53, MAPK14 and ESR1 through Calcium, PI3K Akt and IL-17 signaling pathways to regulate the physiological processes of nerve, muscle, endocrine and reproductive systems and the physiological functions of nerve cells, providing a theoretical reference for the later study of integrated traditional Chinese and western medicine in the treatment of salivation.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Salivação , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases
6.
BMC Complement Med Ther ; 23(1): 361, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37833759

RESUMO

OBJECTIVE: The primary objective of this study is to elucidate the molecular mechanism underlying the reversal of peritoneal fibrosis (PF) by Danshenol C, a natural compound derived from the traditional Chinese medicine Salvia miltiorrhiza. By comprehensively investigating the intricate interactions and signaling pathways involved in Danshenol C's therapeutic effects on PF, we aim to unveil novel insights into its pharmacological actions. This investigation holds the potential to revolutionize the clinical application of Salvia miltiorrhiza in traditional Chinese medicine, offering promising new avenues for the treatment of PF and paving the way for evidence-based therapeutic interventions. METHODS: Firstly, we utilized the YaTCM database to retrieve the structural formula of Danshenol C, while the SwissTargetPrediction platform facilitated the prediction of its potential drug targets. To gain insights into the genetic basis of PF, we acquired the GSE92453 dataset and GPL6480-9577 expression profile from the GEO database, followed by obtaining disease-related genes of PF from major disease databases. R software was then employed to screen for DEG associated with PF. To explore the intricate interactions between Danshenol C's active component targets, we utilized the String database and Cytoscape3.7.2 software to construct a PPI network. Further analysis in Cytoscape3.7.2 enabled the identification of core modules within the PPI network, elucidating key targets and molecular pathways critical to Danshenol C's therapeutic actions. Subsequently, we employed R to perform GO and KEGG pathway enrichment analyses, providing valuable insights into the functional implications and potential biological mechanisms of Danshenol C in the context of PF. To investigate the binding interactions between the core active components and key targets, we conducted docking studies using Chem3D, autoDock1.5.6, SYBYL2.0, and PYMOL2.4 software. We applied in vivo and in vitro experiments to prove that Danshenol C can improve PF. In order to verify the potential gene and molecular mechanism of Danshenol C to reverse PF, we used quantitative PCR, western blot, and apoptosis, ensuring robust and reliable verification of the results. RESULTS: ① Wogonin, sitosterol, and Signal Transducer and Activator of Transcription 5 (STAT5) emerged as the most significant constituents among the small-molecule active compounds and gene targets investigated. ②38 targets intersected with the disease, among which MAPK14, CASP3, MAPK8 and STAT3 may be the key targets; The results of GO and KEGG analysis showed that there was a correlation between inflammatory pathway and Apoptosis. ④Real-time PCR showed that the mRNA expressions of MAPK8 (JNK1), MAPK14 (P38) and STAT3 were significantly decreased after Danshenol C treatment (P < 0.05), while the mRNA expression of CASP3 was significantly increased (P < 0.05)⑤Western blot showed that protein expressions of CASP3 and MAPK14 were significantly increased (P < 0.05), while the expression of STAT3 and MAPK8 was decreased after Danshenol C treatment (P < 0.05). ⑥There was no significant difference in flow analysis of apoptosis among groups. CONCLUSION: The findings suggest that Danshenol C may modulate crucial molecular pathways, including the MAPK, Apoptosis, Calcium signaling, JAK-STAT signaling, and TNF signaling pathways. This regulation is mediated through the modulation of core targets such as STAT3, MAPK14, MAPK8, CASP3, and others. By targeting these key molecular players, Danshenol C exhibits the potential to regulate cellular responses to chemical stress and inflammatory stimuli. The identification of these molecular targets and pathways represents a significant step forward in understanding the molecular basis of Danshenol C's therapeutic effects in PF. This preliminary exploration provides novel avenues for the development of anti-PF treatment strategies and the discovery of potential therapeutic agents. By targeting specific core targets and pathways, Danshenol C opens up new possibilities for the development of more effective and targeted drugs to combat PF. These findings have the potential to transform the landscape of PF treatment and offer valuable insights for future research and drug development endeavors.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Fibrose Peritoneal , Humanos , Caspase 3 , Apoptose , RNA Mensageiro
7.
Eur Rev Med Pharmacol Sci ; 27(19): 9192-9204, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37843333

RESUMO

OBJECTIVE: This study aimed to explore the mechanism of Fuzi Lizhong Tang (FZLZT) in treating gastric cancer using network pharmacology and molecular docking, and to validate the results through in vitro experiments. MATERIALS AND METHODS: Active ingredients and target genes of FZLZT were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, while disease targets of gastric cancer were collected from GeneCards, OMIM, and DrugBank databases. The "herb-active ingredient-target gene" network was constructed using Cytoscape software, and core active ingredients were obtained through topological analysis. Protein-protein interaction analysis was performed using the STRING database, and core targets were obtained through topological analysis. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were performed using the DAVID database. Molecular docking was conducted using AutoDock Vina software to verify the interaction between core ingredients and core targets. Cholecystokinin octapeptide (CCK-8) assay was used to determine the proliferation inhibition effect of FZLZT on AGS, BGC823, HGC-27, MGC-803, and SGC-7901 gastric cancer cell lines, and ANNEXIN V-FITC/PI double staining combined with flow cytometry was used to measure the cell apoptosis rate. RESULTS: Network pharmacology analysis revealed 117 active ingredients and 261 target genes of FZLZT, and 211 overlapping targets with gastric cancer. Ten core active ingredients were identified through topological analysis, including quercetin, 7-methoxy-2-methyl isoflavone, kaempferol, luteolin, naringenin, isorhamnetin, quercetagetin, glycyrrhizic acid A, ß-sitosterol, and medioresinol. GO and KEGG enrichment analysis showed that the mechanism of FZLZT in treating gastric cancer mainly involves cancer, inflammation, metabolism, and blood rheology-related pathways, and may act through 7 core targets (CDKN1A, MYC, MAPK1, MAPK14, RB1, RELA, and STAT3). Molecular docking results further confirmed the prediction of network pharmacology. In vitro experiments showed that FZLZT inhibited the proliferation of all five gastric cancer cell lines, with the strongest effect on SGC-7901 cells, and induced apoptosis in SGC-7901 cells. CONCLUSIONS: FZLZT has a multi-component, multi-target, and multi-pathway characteristic in treating gastric cancer. Its active ingredients may regulate the expression of proteins such as CDKN1A, MYC, MAPK1, MAPK14, RB1, RELA, and STAT3 to activate cancer-related signaling pathways to achieve its therapeutic effect.


Assuntos
Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Simulação de Acoplamento Molecular , Farmacologia em Rede , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
8.
Medicine (Baltimore) ; 102(39): e35106, 2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37773840

RESUMO

BACKGROUND: Guanxinning tablet (GXNT), a Chinese patent medicine, is composed of salvia miltiorrhiza bunge and ligusticum striatum DC, which may play the role of endothelial protection through many pathways. We aimed to explore the molecular mechanisms of GXNT against atherosclerosis (AS) through network pharmacology and molecular docking verification. METHODS: The active ingredients and their potential targets of GXNT were obtained in traditional Chinese medicine systems pharmacology database and analysis platform and bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine databases. DrugBank, TTD, DisGeNET, OMIM, and GeneCards databases were used to screen the targets of AS. The intersection targets gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were performed in DAVID database. GXNT-AS protein-protein interaction network, ingredient-target network and herb-target-pathway network were constructed by Cytoscape. Finally, we used AutoDock for molecular docking. RESULTS: We screened 65 active ingredients of GXNT and 70 GXNT-AS intersection targets. The key targets of protein-protein interaction network were AKT1, JUN, STAT3, TNF, TP53, IL6, EGFR, MAPK14, RELA, and CASP3. The Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling pathway were the main pathways. The ingredient-target network showed that the key ingredients were luteolin, tanshinone IIA, myricanone, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone. The results of molecular docking showed that tanshinone IIA, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone all had good binding interactions with AKT1, EGFR and MAPK14. CONCLUSION: The results of network pharmacology and molecular docking showed that the multiple ingredients within GXNT may confer protective effects on the vascular endothelium against AS through multitarget and multichannel mechanisms. AKT1, EGFR and MAPK14 were the core potential targets of GXNT against AS.


Assuntos
Aterosclerose , Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Humanos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Aterosclerose/tratamento farmacológico , Receptores ErbB , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
9.
Sci Rep ; 13(1): 12607, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37537191

RESUMO

Gastric cancer (GC) remains the third leading cause of cancer-related mortality in the world, and ninety-five percent of GC are stomach adenocarcinomas (STAD). The active ingredients of Croci Stigma, such as Isorhamnetin, Crocin, Crocetin and Kaempferol, all have antitumor activity. However, their chemical and pharmacological profiles remain to be elusive. In this study, network pharmacology was used to characterize the action mechanism of Croci Stigma. All compounds were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database, and active ingredients were selected by their oral bioavailability and drug-likeness index. The targets of Croci Stigma active ingredients were obtained from the traditional Chinese medicine integrated database (TCMID), whereas the related genes of STAD were obtained from DisGeNET platform. Cytoscape was used to undertake visual analyses of the Drug Ingredients-Gene Symbols-Disease (I-G-D) network, and 2 core genes including MAPK14, ERBB3 were obtained, which are the predicted targets of isorhamnetin (IH) and quercetin, respectively. Data analysis from TCGA platform showed that MAPK14 and ERBB3 all upregulated in STAD patients, but only the effect of MAPK14 expression on STAD patients' survival was significant. Molecular docking showed that IH might affect the function of MAPK14 protein, and then the underlying action mechanisms of IH on STAD were experimentally validated using human gastric cancer cell line, HGC-27 cells. The results showed that IH can inhibit cell proliferation, migration, clonal formation, and arrest cell cycle, but promote the apoptosis of HGC-27 cells. qRT-PCR data demonstrated that IH downregulated the MAPK14 mRNA expression and EMT related genes. WB results showed that IH regulates MAPK/mTOR signaling pathway. These findings suggest that IH has the therapeutic potential for the treatment of STAD.


Assuntos
Adenocarcinoma , Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Neoplasias Gástricas , Humanos , Quercetina/farmacologia , Simulação de Acoplamento Molecular , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética
10.
Curr Pharm Des ; 29(16): 1274-1292, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37218202

RESUMO

BACKGROUND: Patients with gastric cancer (GC) are more likely to be infected with 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the prognosis is worse. It is urgent to find effective treatment methods. OBJECTIVE: This study aimed to explore the potential targets and mechanism of ursolic acid (UA) on GC and COVID-19 by network pharmacology and bioinformatics analysis. METHODS: The online public database and weighted co-expression gene network analysis (WGCNA) were used to screen the clinical related targets of GC. COVID-19-related targets were retrieved from online public databases. Then, a clinicopathological analysis was performed on GC and COVID-19 intersection genes. Following that, the related targets of UA and the intersection targets of UA and GC/COVID-19 were screened. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome Analysis (KEGG) pathway enrichment analyses were performed on the intersection targets. Core targets were screened using a constructed protein-protein interaction network. Finally, molecular docking and molecular dynamics simulation (MDS) of UA and core targets were performed to verify the accuracy of the prediction results. RESULTS: A total of 347 GC/COVID-19-related genes were obtained. The clinical features of GC/COVID-19 patients were revealed using clinicopathological analysis. Three potential biomarkers (TRIM25, CD59, MAPK14) associated with the clinical prognosis of GC/COVID-19 were identified. A total of 32 intersection targets of UA and GC/COVID-19 were obtained. The intersection targets were primarily enriched in FoxO, PI3K/Akt, and ErbB signaling pathways. HSP90AA1, CTNNB1, MTOR, SIRT1, MAPK1, MAPK14, PARP1, MAP2K1, HSPA8, EZH2, PTPN11, and CDK2 were identified as core targets. Molecular docking revealed that UA strongly binds to its core targets. The MDS results revealed that UA stabilizes the protein-ligand complexes of PARP1, MAPK14, and ACE2. CONCLUSION: This study found that in patients with gastric cancer and COVID-19, UA may bind to ACE2, regulate core targets such as PARP1 and MAPK14, and the PI3K/Akt signaling pathway, and participate in antiinflammatory, anti-oxidation, anti-virus, and immune regulation to exert therapeutic effects.


Assuntos
COVID-19 , Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Neoplasias Gástricas , Triterpenos , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Farmacologia em Rede , Enzima de Conversão de Angiotensina 2 , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , SARS-CoV-2 , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Ácido Ursólico
11.
Sci Rep ; 13(1): 5417, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-37012370

RESUMO

Depression affects people with multiple adverse outcomes, and the side effects of antidepressants are troubling for depression sufferers. Aromatic drugs have been widely used to relieve symptoms of depression with fewer side effects. Ligustilide (LIG) is the main component of volatile oil in angelica sinensis, exhibiting an excellent anti-depressive effect. However, the mechanisms of the anti-depressive effect of LIG remain unclear. Therefore, this study aimed to explore the mechanisms of LIG exerting an anti-depressive effect. We obtained 12,969 depression-related genes and 204 LIG targets by a network pharmacology approach, which were intersected to get 150 LIG anti-depressive targets. Then, we identified core targets by MCODE, including MAPK3, EGF, MAPK14, CCND1, IL6, CASP3, IL2, MYC, TLR4, AKT1, ESR1, TP53, HIF1A, SRC, STAT3, AR, IL1B, and CREBBP. Functional enrichment analysis of core targets showed a significant association with PI3K/AKT and MAPK signaling pathways. Molecular docking showed strong affinities of LIG with AKT1, MAPK14, and ESR1. Finally, we validated the interactions between these proteins and LIG by molecular dynamics (MD) simulations. In conclusion, this study successfully predicted that LIG exerted an anti-depressive effect through multiple targets, including AKT1, MAPK14, and ESR1, and the pathways of PI3K/AKT and MAPK. The study provides a new strategy to explore the molecular mechanisms of LIG in treating depression.


Assuntos
Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Humanos , Química Computacional , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Biologia Computacional , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
12.
Phytomedicine ; 109: 154596, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610142

RESUMO

BACKGROUND: Shikonin (SK), a botanical drug extracted from Lithospermum erythrorhizon, has been shown to inhibit tumour growth through apoptosis and necrosis. However, whether SK induces pyroptosis in cancer cells is still unknown. PURPOSE: This study aims to investigated the mechanisms of SK-induced pyroptosis in tumour cells and mice. METHODS: In vivo and in vitro methods were used in this study. Cell deaths were analysed by LDH and CCK-8 assay and western blotting. To investigated the signalling pathway of SK-induced pyroptosis, various genes expressions were supressed by shRNA or inhibitors. High-sensitivity mass spectrometry assay was used to identified potential factors that regulate GSDME-mediated pyroptosis. Finally, a mouse model was used to investigate the effect of SK administration on tumour growth in vivo. RESULTS: The activation of BAX/caspase-3 signalling was essential for GSDME-mediated pyroptosis by SK. Mechanistically, the intracellular reactive oxygen species (ROS) generation induced by SK treatment initiated GSDME-dependant pyroptosis. SK stimulation induced protective autophagy in a ROS-dependant manner, and repressed autophagy significantly enhanced SK-induced pyroptosis. Moreover, MAPK14/p38α, a ROS sensor, modulated SK-induced autophagy and ultimately affected GSDME-dependant pyroptosis. CONCLUSION: Here, for the first time we demonstrated that SK treatment induced GSDME-dependant pyroptosis in tumour cells. Our results demonstrated that SK initiates ROS signalling to drive pyroptosis in cancer cells.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Neoplasias , Camundongos , Animais , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Autofagia
13.
Biomed Pharmacother ; 158: 114122, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36566522

RESUMO

Postmenopausal osteoporosis (PMOP) is a common bone disease characterized by decreased bone density and increased bone fragility due to decreased estrogen levels. Qiangguyin (QGY) is transformed from the famous traditional Chinese medicine BuShen Invigorating Blood Decoction. In this study, we used QGY to treat PMOP. We observed that QGY significantly reduced fat accumulation in the chondro-osseous junction. However, its specific mechanism of action remains unclear. To determine the specific molecular mechanism of QGY, we explored the pharmacological mechanism by which QGY reduces fat accumulation in the chondro-osseous junction through network pharmacological analysis. The active components and targets related to PMOP and QGY were screened from different databases, forming a composition-target-disease network. Next, a comprehensive analysis platform including protein-protein interaction (PPI) network, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were established. The results revealed that QGY inhibits adipogenic differentiation by activating the mitogen-activated protein kinase (MAPK) signaling pathway, thus reducing the accumulation of fat in the chondro-osseous junction. For further verification. In vitro and in vivo experiments were carried out. Our data showed that QGY significantly reversed the high expression of fatty acid binding protein 4 (FABP4) and peroxisome proliferator-activated receptor γ (PPARγ). Further, QGY prevents fat accumulation by inhibiting the expression of p38. In summary, the results of this study suggested that QGY-induced phenotypic changes are related to the activation of the p38 MAPK signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Camundongos , Animais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Medicina Tradicional Chinesa
14.
Gene ; 851: 146973, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36306943

RESUMO

BACKGROUND: Yin-chen Wu-ling Powder (YWP) has potential therapeutic effects on cholestatic liver disease (CLD), however, its active compounds and conceivable mechanism are as yet indistinct. METHODS: The network pharmacology and gene function annotation examined the multiple active ingredients, potential targets, and possible mechanisms of YWP in CLD treatment. Then the molecular docking reassured the reliability of the core compounds including the key genes and farnesoid X receptor (FXR). Finally, The Mdr2-/- mice were used to test the effect and mechanism of YWP against CLD. RESULTS: The network analysis identified nine main active ingredients, including quercetin, capillarisin, eupalitin, isorhamnetin, skrofulein, genkwanin, cerevisterol, gederagenin, and sitosterol. The PPI network predicted the ten hub genes involved were AKT1, MAPK1, MAPK14, IL6, RXRA, ESR1, IL10, NCOA1, CAV1, and EGFR. The KEGG and GO analysis showed that YWP might contribute to CLD treatment through the PI3K/Akt and MAKP signalings to manage pathological reactions, for instance, inflammatory responses. The molecular docking displayed a functional similarity among the core compounds with ursodeoxycholic acid (UDCA) and Obeticholic acid (OCA) on the effects on AKT1, MAPK1, MAPK14, RXRA, and ESR, and the affinity to FXR. In addition, the YWP could significantly attenuate hepatic injury and improve inflammatory response in Mdr2-/- mice. The mechanism exploration showed that YWP mainly decreased inflammatory response by inhibiting AKT/P38MAPK signaling. CONCLUSION: This study firstly revealed the multiple active ingredients, potential targets, and possible mechanism of YWP to treat CLD based on network pharmacology Analysis and molecular docking. YWP could alleviate cholestasis in Mdr2-/- mice by impairing inflammation via inhibiting AKT/P38MAPK Signaling.


Assuntos
Colestase , Medicamentos de Ervas Chinesas , Hepatopatias , Proteína Quinase 14 Ativada por Mitógeno , Camundongos , Animais , Pós , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt , Reprodutibilidade dos Testes , Colestase/tratamento farmacológico , Colestase/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Hepatopatias/tratamento farmacológico
15.
Zhongguo Zhong Yao Za Zhi ; 47(20): 5599-5609, 2022 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-36471978

RESUMO

To provide experimental basis and theoretical guidance for further research on the molecular mechanism of notoginsenoside R_1(NGR_1) in the treatment of depression, the present study analyzed the potential mechanism of NGR_1 in the treatment of depression through network pharmacology and verified it by molecular docking and animal experiments. PharmMapper, SwissTargetPrediction, and GeneCards were used to predict the related targets of both NGR_1 and depression to obtain the potential targets of NGR_1 in the treatment of depression. The database for annotation, visualization and integrated discovery(DAVID) was used for GO functional annotation and KEGG pathway enrichment analysis to screen the possible mechanisms of NGR_1 exerting antidepressant effect. Cytoscape 3.9.0 was adopted to construct a protein-protein interaction(PPI) network, and the topological analysis was performed to obtain the core targets. The binding activity of NGR_1 to core targets was tested by molecular docking. The depression model was prepared by injecting lipopolysaccharide(LPS) into the lateral ventricle in mice, and intervened with NGR_1. The antidepressant effect of NGR_1 was detected by behavioral tests and RT-qPCR. The results showed that by network pharmacology, 56 common targets of NGR_1 and depression were predicted, and GO enrichment analysis determined 13 related biological processes, mainly involving G protein-coupled receptor signaling pathway, positive regulation of transcription from RNA polymerase Ⅱ promoter, cytokine-mediated signaling pathway, gene expression, apoptosis, cell proliferation, and signal transduction. In addition, KEGG pathway enrichment analysis identified ten potential pathways, including neuroactive ligand-receptor interaction signaling pathway, lipid and atherosclerosis signaling pathway, cAMP signaling pathway, PI3 K-AKT signaling pathway, and lipid and atherosclerosis signaling pathway. PPI analysis revealed that the core targets included CASP3, VEGFA, IGF1, STAT3, MAPK1, PPARG, MTOR, MAPK14, NR3 C1 and AR, and molecular docking demonstrated that NGR_1 had desirable binding activity to these target proteins. In animal experiments, the results showed that NGR_1 improved the disease behavior of depressed mice, significantly inhibited the neuroinflammatory response(reducing the mRNA expression of Iba-1, TNF-α, IL-1ß, and IL-6), and regulated the mRNA expression of lipid and atherosclerosis signaling pathway-related targets(CASP3, STAT3, MAPK1 and MAPK14). This indicated that the antidepressant mechanism of NGR_1 may be related to the regulation of lipid and atherosclerosis signaling pathway. In conclusion, network pharmacology was used to reveal the core targets and pathways of NGR_1, and some of them were verified in animal experiments, which provided the basis for in-depth exploration on the mechanism of NGR_1 in the treatment of depression.


Assuntos
Experimentação Animal , Aterosclerose , Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Camundongos , Animais , Caspase 3 , Farmacologia em Rede , Simulação de Acoplamento Molecular , Antidepressivos/farmacologia , Lipopolissacarídeos , RNA Mensageiro , Medicamentos de Ervas Chinesas/farmacologia
16.
Zhongguo Zhong Yao Za Zhi ; 47(17): 4765-4777, 2022 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-36164884

RESUMO

Epidemic diseases have caused huge harm to the society. Traditional Chinese medicine(TCM) has made great contributions to the prevention and treatment of them. It is of great reference value for fighting diseases and developing drugs to explore the medication law and mechanism of TCM under TCM theory. In this study, the relationship between the TCM theory of cold pestilence and modern epidemic diseases was investigated. Particularly, the the relationship of coronavirus disease 2019(COVID-19), severe acute respiratory syndrome(SARS), and influenza A(H1 N1) with the cold pestilence was identified and analyzed. The roles of TCM theory of cold pestilence in preventing and treating modern epidemic diseases were discussed. Then, through data mining and textual research, prescriptions for the treatment of cold pestilence were collected from major databases and relevant ancient books, and their medication laws were examined through analysis of high-frequency medicinals and medicinal pairs, association rules analysis, and cluster analysis. For example, the prescriptions with high confidence levels were identified: "Glycyrrhizae Radix et Rhizoma-Bupleuri Radix-Paeoniae Radix Alba" "Glycyrrhizae Radix et Rhizoma-Pinelliae Rhizoma-Bupleuri Radix", and TCM treatment methods with them were analyzed by clustering analysis to yield the medicinal combinations: "Zingiberis Rhizoma-Aconiti Lateralis Radix Praeparata-Ginseng Radix et Rhizoma" "Poria-Atractylodis Macrocephalae Rhizoma" "Cinnamomi Ramulus-Asari Radix et Rhizoma" "Citri Reticulatae Pericarpium-Perillae Folium" "Pinelliae Rhizoma-Magnoliae Officinalis Cortex-Atractylodis Rhizoma" "Paeoniae Radix Alba-Angelicae Sinensis Radix-Glycyrrhizae Radix et Rhizoma-Bupleuri Radix-Scutellariae Radix-Rhizoma Zingiberis Recens" "Ephedrae Herba-Armeniacae Semen Amarum-Gypsum Fibrosum" "Chuanxiong Rhizoma-Notopterygii Rhizoma et Radix-Angelicae Dahuricae Radix-Platycodonis Radix-Saposhnikoviae Radix". Then, according to the medication law for cold pestilence, the antiviral active components of medium-frequency and high-frequency medicinals were retrieved. It was found that these components exerted the antiviral effect by inhibiting virus replication, regulating virus proteins and antiviral signals, and suppressing protease activity. Based on network pharmacology, the mechanisms of the medicinals against severe acute respiratory syndrome coronavirus(SARS-CoV), 2019 novel coronavirus(2019-nCoV), and H1 N1 virus were explored. It was determined that the key targets were tumor necrosis factor(TNF), endothelial growth factor A(VEGFA), serum creatinine(SRC), epidermal growth factor receptor(EGFR), matrix metalloproteinase 9(MMP9), mitogen-activated protein kinase 14(MAPK14), and prostaglandin-endoperoxide synthase 2(PTGS2), which were involved the mitogen-activated protein kinase(MAPK) pathway, advanced glycation end-products(AGE)-receptor for AGE(RAGE) pathway, COVID-19 pathway, and mTOR pathway. This paper elucidated the medication law and mechanism of TCM for the prevention and treatment of epidemic diseases under the guidance of TCM theory of cold pestilence, in order to build a bridge between the theory and modern epidemic diseases and provide reference TCM methods for the prevention and treatment of modern epidemic diseases and ideas for the application of data mining to TCM treatment of modern diseases.


Assuntos
Aconitum , Controle de Doenças Transmissíveis , Doenças Transmissíveis , Medicamentos de Ervas Chinesas , Epidemias , Medicina Tradicional Chinesa , Pinellia , Antivirais , COVID-19/epidemiologia , Sulfato de Cálcio , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Creatinina , Ciclo-Oxigenase 2 , Medicamentos de Ervas Chinesas/uso terapêutico , Fatores de Crescimento Endotelial , Epidemias/prevenção & controle , Receptores ErbB , Humanos , Metaloproteinase 9 da Matriz , Proteína Quinase 14 Ativada por Mitógeno , SARS-CoV-2 , Serina-Treonina Quinases TOR , Fatores de Necrose Tumoral , Tratamento Farmacológico da COVID-19
17.
Dis Markers ; 2022: 2141882, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36157206

RESUMO

Background: Astragalus membranaceus (Huang-qi, AM) and Angelica sinensis (Dang-gui, AS) are common Chinese herbal medicines and have historically been used in spinal cord injury (SCI) therapies. However, the underlying molecular mechanisms of AM&AS remain little understood. The purpose of this research was to explore the bioactive components and the mechanisms of AM&AS in treating SCI according to network pharmacology and the molecular docking approach. Methods: AM&AS active ingredients were first searched from Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Traditional Chinese Medicine Information Database (TCM-ID). Meanwhile, we collected relevant target genes of SCI through the GeneCards database, OMIM database, PharmGkb database, DurgBank database, and TDD database. By utilizing the STRING database, we constructed a network of protein-protein interactions (PPIs). In addition, we used R and STRING to perform GO and KEGG function enrichment analyses. Subsequently, AutoDock Vina was employed for a molecular docking study on the most active ingredients and most targeted molecules to validate the results of the network pharmacology analysis mentioned above. Result: The overall number of AM&AS active compounds identified was 22, while the number of SCI-related targets identified was 159. Then, the 4 key active ingredients were MOL000098 quercetin, MOL000422 kaempferol, MOL000354 isorhamnetin, and MOL000392 formononetin. A total of fourteen core targets were TP53, ESR1, MAPK1, MTC, HIF1A, HSP90AA1, FOS, MAPK14, STAT1, AKT1, EGFR, RELA, CCND1, and RB1. The KEGG enrichment analysis results indicated that lipid and atherosclerosis, PI3K-Akt signaling pathway, human cytomegalovirus infection, fluid shear stress, and atherosclerosis, etc., were enhanced with SCI development. Based on the analyses of docked molecules, four main active compounds had high affinity for the key targets. Conclusions: Altogether, it identified the mechanisms by which AM&AS was used for SCI treatment, namely, active ingredients, targets and signaling pathways. Consequently, further research into AM&AS treating SCI can be conducted on this scientific basis.


Assuntos
Angelica sinensis , Aterosclerose , Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Traumatismos da Medula Espinal , Astragalus propinquus , Medicamentos de Ervas Chinesas/farmacologia , Receptores ErbB , Humanos , Quempferóis , Lipídeos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Quercetina , Traumatismos da Medula Espinal/tratamento farmacológico
18.
J Ethnopharmacol ; 296: 115496, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35750104

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii polyglycosides (TWP) are extracted from Tripterygium wilfordii Hook. f., which has the significant effects of anti-inflammation and immunosuppression and has been widely used to treat autoimmune diseases in traditional Chinese medicine. AIM OF STUDY: In Chinese clinical dermatology, TWP was generally used for the treatment of autoimmune skin diseases including psoriasis (PSO), systemic lupus erythematosus (SLE) and pemphigus (PEM). However, the potential hepatotoxicity (HPT) induced by TWP was also existing with the long-term use of TWP. This study aims to explore the potential shared therapeutic mechanism of TWP treating PSO, SLE, PEM and the possible hepatotoxic mechanism induced by TWP. MATERIALS AND METHODS: Network pharmacology was used to predict the potential targets and pathways in this study. The main bioactive compounds in TWP was screened according to TCMSP, PubChem, ChEMBL databases and Lipinski's Rule of Five. The potential targets of these chemical constituents were obtained from PharmMapper, SEA and SIB databases. The related targets of PSO, SLE, PEM and HPT were collected from GeneCards, DrugBank, DisGeNET and CTD databases. The target network construction was performed through STRING database and Cytoscape. GO enrichment, KEGG enrichment and molecular docking were then performed, respectively. In particular, imiquimod (IMQ)-induced PSO model was selected as the representative for the experimental verification of effects and shared therapeutic mechanisms of TWP. RESULTS: 41 targets were considered as the potential shared targets of TWP treating PSO, SLE and PEM. KEGG enrichment indicated that IL-17 signaling pathway and Th17 cell differentiation were significant in the potential shared therapeutic mechanism of TWP. The animal experimental verification demonstrated that TWP could notably ameliorate skin lesions (P˂0.001), decrease inflammatory response (P˂0.05, P˂0.01, P˂0.001) and inhibit the differentiation of Th1/Th17 cells (P˂0.05, P˂0.01) compared to PSO model group. The molecular docking and qPCR validation then showed that TWP could effectively act on MAPK14, IL-2, IL-6 and suppress Th17 cell differentiation and IL-17 signaling pathway. The possible hepatotoxic mechanism of TWP indicated that there were 145 hepatotoxic targets and it was also associated with IL-17 signaling pathway and Th17 cell differentiation, especially for the key role of ALB, CASP3 and HSP90AA1. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP showed that 28 targets were shared by therapeutic and hepatotoxic mechanisms such as IL-6, IL-2, MAPK14, MMP9, ALB, CASP3 and HSP90AA1. These significant relevant targets were also involved in IL-17 signaling pathway and Th17 cell differentiation. CONCLUSIONS: There were shared disease targets in PSO, SLE and PEM, and TWP could treat them by potential shared therapeutic mechanisms of suppressing IL-17 signaling pathway and Th17 cell differentiation. The possible hepatotoxicity induced by TWP was also significantly associated with the regulation of IL-17 signaling pathway and Th17 cell differentiation. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP also mainly focused on IL-17 signaling pathway and Th17 cell differentiation, which provided a potential direction for the study of the mechanism of "You Gu Wu Yun" theory of TWP treating autoimmune skin diseases in the future.


Assuntos
Doenças Autoimunes , Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Lúpus Eritematoso Sistêmico , Proteína Quinase 14 Ativada por Mitógeno , Psoríase , Dermatopatias , Animais , Caspase 3/metabolismo , Diferenciação Celular , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/toxicidade , Interleucina-17/metabolismo , Interleucina-2 , Interleucina-6 , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Transdução de Sinais , Células Th17 , Tripterygium/química
19.
J Tradit Chin Med ; 42(2): 296-303, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35473352

RESUMO

OBJECTIVE: To predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma by using network pharmacology, and to further explore its potential mechanism in asthma. METHODS: The corresponding targets of rhein were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the rhein-target network was constructed with Cytoscape 3.7.1 software. The Genbank and Drugbank databases were used to collect and screen asthma targets, and the rhein-target-disease interaction network was constructed. A target protein-protein interaction (PPI) network was constructed using the STRING database to screen key targets. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to identify biological processes and signaling pathways. The anti-asthmatic effects of rhein were tested in vitro, and the expression levels of proteins in the mitogen-activated protein kinase/nuclear factor kappa-B (MAPK/ NF-κB) signaling pathway were assessed by western blot analysis. RESULTS: Altogether, 83 targets of rhein were screened in the relevant databases, 989 targets of asthma were obtained in the National Center for Biotechnology Information (NCBI) GENE Database. PPI network analysis and KEGG pathway enrichment analysis predicted that rhein could regulate the epidermal active growth factor receptor (EGFR), mitogen-activated protein kinase 14 (MAPK14), tumour necrosis factor receptor superfamily member 1A (TNFRSF1A), receptor tyrosine-protein kinase erbB-2 (ERBB2), and other signaling pathways. Furthermore, we selected the MAPK signaling pathway to determine the anti-inflammatory effects of rhein. Consistently, further experiments demonstrated that rhein was shown to inhibit HBE cells inflammation. CONCLUSION: The anti-inflammatory mechanism of rhein in the treatment of asthma may be related to EGFR, MAPK14, TNFRSF1A and ERBB2 as well as their signaling pathways. To prevent the exacerbation of asthma, instead of targeting a single pathway or a single target, all these targets and their signaling pathways should be controlled holistically. Rhein may alleviate the inflammation of asthma by inhibiting the MAPK/NF-κB pathway.


Assuntos
Asma , Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Antraquinonas , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Receptores ErbB/genética , Humanos , Inflamação/tratamento farmacológico , NF-kappa B/genética , Farmacologia em Rede
20.
Med Sci Monit ; 28: e934102, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35075100

RESUMO

BACKGROUND Heat-clearing and detoxifying herbs (HDHs) play an important role in the prevention and treatment of coronavirus infection. However, their mechanism of action needs further study. This study aimed to explore the anti-coronavirus basis and mechanism of HDHs. MATERIAL AND METHODS Database mining was performed on 7 HDHs. Core ingredients and targets were screened according to ADME rules combined with Neighborhood, Co-occurrence, Co-expression, and other algorithms. GO enrichment and KEGG pathway analyses were performed using the R language. Finally, high-throughput molecular docking was used for verification. RESULTS HDHs mainly acts on NOS3, EGFR, IL-6, MAPK8, PTGS2, MAPK14, NFKB1, and CASP3 through quercetin, luteolin, wogonin, indirubin alkaloids, ß-sitosterol, and isolariciresinol. These targets are mainly involved in the regulation of biological processes such as inflammation, activation of MAPK activity, and positive regulation of NF-kappaB transcription factor activity. Pathway analysis further revealed that the pathways regulated by these targets mainly include: signaling pathways related to viral and bacterial infections such as tuberculosis, influenza A, Ras signaling pathways; inflammation-related pathways such as the TLR, TNF, MAPK, and HIF-1 signaling pathways; and immune-related pathways such as NOD receptor signaling pathways. These pathways play a synergistic role in inhibiting lung inflammation and regulating immunity and antiviral activity. CONCLUSIONS HDHs play a role in the treatment of coronavirus infection by regulating the body's immunity, fighting inflammation, and antiviral activities, suggesting a molecular basis and new strategies for the treatment of COVID-19 and a foundation for the screening of new antiviral drugs.


Assuntos
Tratamento Farmacológico da COVID-19 , Coronavirus/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Alcaloides/química , Alcaloides/farmacologia , Caspase 3/efeitos dos fármacos , Caspase 3/genética , Coronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Bases de Dados de Produtos Farmacêuticos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Flavanonas/química , Flavanonas/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Interleucina-6/genética , Lignina/química , Lignina/farmacologia , Luteolina/química , Luteolina/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 8 Ativada por Mitógeno/genética , Simulação de Acoplamento Molecular , Subunidade p50 de NF-kappa B/efeitos dos fármacos , Subunidade p50 de NF-kappa B/genética , Naftóis/química , Naftóis/farmacologia , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Mapas de Interação de Proteínas , Quercetina/química , Quercetina/farmacologia , SARS-CoV-2/metabolismo , Transdução de Sinais , Sitosteroides/química , Sitosteroides/farmacologia , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
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