scholarly journals Verification of the Potential Targets of the Herbal Prescription Sochehwan for Drug Repurposing Processes as Deduced by Network Pharmacology

Processes ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 2034
Author(s):  
Dong-Woo Lim ◽  
Da-Hoon Kim ◽  
Ga-Ram Yu ◽  
Won-Hwan Park ◽  
Jai-Eun Kim
Keyword(s):  
Signaling Pathways ◽  
Drug Repurposing ◽  
Mapk Signaling ◽  
Integrated System ◽  
Mitogen Activated Protein Kinase ◽  
Raw 264.7 Cells ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Inflammatory Status ◽  
Herbal Prescription

Network pharmacology (NP) is a useful, emerging means of understanding the complex pharmacological mechanisms of traditional herbal medicines. Sochehwan (SCH) is a candidate herbal prescription for drug repurposing as it has been suggested to have beneficial effects on metabolic syndrome. In this study, NP was adopted to complement the shortcomings of literature-based drug repurposing strategies in traditional herbal medicine. We conducted in vitro studies to confirm the effects of SCH on potential pharmacological targets identified by NP analysis. Herbal compounds and molecular targets of SCH were explored and screened from a traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and an oriental medicine advanced searching integrated system (OASIS). Forty-seven key targets selected from a protein-protein interaction (PPI) network were analyzed with gene ontology (GO) term enrichment and KEGG pathway enrichment analysis to identify relevant categories. The tumor necrosis factor (TNF) and mitogen-activated protein kinase (MAPK) signaling pathways were presented as significant signaling pathways with lowest p-values by NP analysis, which were downregulated by SCH treatment. The signal transducer and activator of transcription 3 (STAT3) was identified as a core key target by NP analysis, and its phosphorylation ratio was confirmed to be significantly suppressed by SCH. In conclusion, the NP-based approach used for target prediction and experimental data obtained from Raw 264.7 cells strongly suggested that SCH can attenuate inflammatory status by modulating the phosphorylation status of STAT3.

scholarly journals Exploring the mechanism of (-)-Epicatechin on premature ovarian insufficiency based on network pharmacology and experimental evaluation

2021 ◽  
Vol 41 (2) ◽  
Author(s):  
Fei Yan ◽  
Qi Zhao ◽  
Huanpeng Gao ◽  
Xiaomei Wang ◽  
Ke Xu ◽  
...  
Keyword(s):  
Gene Ontology ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Related Factor ◽  
Nrf2 Signaling Pathway

Abstract Methods: Relevant potential targets for EC were obtained based on Traditional Chinese Medicine System Pharmacology Database (TCMSP), a bioinformatics analysis tool for molecular mechanism of Traditional Chinese Medicine (BATMAN-TCM) and STITCH databases. The Online Mendelian Inheritance in Man (OMIM) and GeneCards databases were utilized to screen the known POI-related targets, while Cytoscape software was used for network construction and visualization. Then, the Gene Ontology (GO) and pathway enrichment analysis were carried out by the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. Furthermore, KGN cells were performed to validate the predicted results in oxidative stress (OS) model, and antioxidant effect was examined. Results: A total of 70 potential common targets for EC in the treatment of POI were obtained through network pharmacology. Metabolic process, response to stimulus and antioxidant activity occupied a leading position of Gene Ontology (GO) enrichment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that PI3K/protein kinase B (AKT), TNF, estrogen, VEGF and MAPK signaling pathways were significantly enriched. In addition, cell experiments showed that EC exhibited antioxidant effects in an H2O2-mediated OS model in ovarian granulosa cells by regulating the expression of PI3K/AKT/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and multiple downstream antioxidant enzymes. Conclusion: EC could regulate multiple signaling pathways and several biological processes (BPs). EC had the ability to down-regulate elevated OS level through the PI3K/AKT/Nrf2 signaling pathway and represented a potential novel treatment for POI.

scholarly journals MAP Kinase OsMEK2 and OsMPK1 Signaling for Ferroptotic Cell Death in Rice-Magnaporthe oryzae Interactions

2020 ◽  
Author(s):  
Sarmina Dangol ◽  
Raksha Singh ◽  
Khoa Nam Nguyen ◽  
Yafei Chen ◽  
Juan Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Map Kinase ◽  
Signaling Pathways ◽  
Magnaporthe Oryzae ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Microbial Pathogens ◽  
Blast Disease ◽  
Related Cell ◽  
Mitogen Activated Protein

ABSTRACTMitogen-activated protein kinase (MAPK) signaling is required for plant cell death responses to invading microbial pathogens. Ferric ions and reactive oxygen species (ROS) accumulate in rice (Oryza sativa) tissues undergoing cell death during Magnaporthe oryzae infection. Here, we report that rice MAP kinase (OsMEK2 and OsMPK1) signaling cascades are involved in iron- and ROS-dependent ferroptotic cell death responses of rice to M. oryzae infection. OsMEK2 interacted with OsMPK1 in the cytoplasm, and OsMPK1 moved from the cytoplasm into the nucleus to bind to the OsWRKY90 transcription factor. OsMEK2 expression may trigger OsMPK1-OsWRKY90 signaling pathways in the nucleus. Avirulent M. oryzae infection in ΔOsmek2 mutant rice did not trigger iron and ROS accumulation and lipid peroxidation, and also downregulated OsMPK1, OsWRKY90, OsRbohB, and OsPR-1b expression. However, OsMEK2 overexpression induced ROS-and iron-dependent cell death in rice during M. oryzae infection. The downstream MAP kinase (OsMPK1) overexpression induced ROS- and iron-dependent ferroptotic cell death in the compatible rice-M. oryzae interaction. These data suggest that the OsMEK2-OsMPK1-OsWRKY90 signaling cascade is involved in the ferroptotic cell death in rice. The small-molecule inducer erastin triggered iron- and lipid ROS-dependent, but OsMEK2-independent, ferroptotic cell death in ΔOsmek2 mutant plants during M. oryzae infection. Disease-related cell death was lipid ROS-dependent and iron-independent in the ΔOsmek2 mutant plants. These combined results suggest that OsMEK2 and OsMPK1 expression positively regulates iron- and ROS-dependent ferroptotic cell death via OsMEK2-OsMPK1-OsWRKY90 signaling pathways, and blast disease (susceptibility)-related cell death was ROS-dependent but iron-independent in rice-M. oryzae interactions.

scholarly journals The effects of 50 Hz magnetic field–exposed cell culture medium on cellular functions in FL cells

2019 ◽  
Vol 60 (4) ◽  
pp. 424-431 ◽  
Author(s):  
Yue Fei ◽  
Liling Su ◽  
Haifeng Lou ◽  
Chuning Zhao ◽  
Yiqin Wang ◽  
...  
Keyword(s):  
Cell Viability ◽  
Signaling Pathways ◽  
Relative Permittivity ◽  
Culture Medium ◽  
Biological Effects ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
International Agency ◽  
Dependent Manner

Abstract Although extremely low frequency magnetic fields (ELF-MFs) have been classified as a possible carcinogen for humans by the International Agency for Research on Cancer (IARC), their biological effects and underlying mechanisms are still unclear. Our previous study indicated that ELF-MF exposure influenced the relative permittivity of the saline solution, suggesting that the MF exposure altered physical properties of the solution. To explore the biophysical mechanism of ELF-MF–induced biological effects, this study examined the effects of 50 Hz sinusoidal MF at 0–4.0 mT on the permittivity of culture medium with phase-interrogation surface plasmon resonance (SPR) sensing. Then, the biological effects of MF pre-exposed culture medium on cell viability, the mitogen-activated protein kinase (MAPK) signaling pathways, oxidative stress, and genetic stabilities were analyzed using Cell Counting Kit-8, western blot, flow cytometry, γH2AX foci formation, and comet assay. The results showed that SPR signals were decreased under MF exposure in a time- and dose-dependent manner, and the decreased SPR signals were reversible when the exposure was drawn off. However, MF pre-exposed culture medium did not significantly change cell viability, intracellular reactive oxygen species level, activation of the MARK signaling pathways, or genetic stabilities in human amniotic epithelial cells (FL cells). In conclusion, our data suggest that the relative permittivity of culture medium was influenced by 50 Hz MF exposure, but this change did not affect the biological processes in FL cells.

scholarly journals Understanding MAPK Signaling Pathways in Apoptosis

2020 ◽  
Vol 21 (7) ◽  
pp. 2346 ◽  
Author(s):  
Jicheng Yue ◽  
José M. López
Keyword(s):  
Signaling Pathways ◽  
Positive Feedback ◽  
Cell Model ◽  
Mapk Signaling ◽  
Feedback Loops ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Mechanisms ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Mapk Signaling Pathways

MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.

scholarly journals Deciphering Molecular Mechanism of the Neuropharmacological Action of Fucosterol through Integrated System Pharmacology and In Silico Analysis

Marine Drugs ◽  
2019 ◽  
Vol 17 (11) ◽  
pp. 639 ◽  
Author(s):  
Md. Abdul Hannan ◽  
Raju Dash ◽  
Abdullah Al Mamun Sohag ◽  
Il Soo Moon
Keyword(s):  
Protein Kinase ◽  
In Silico ◽  
In Silico Analysis ◽  
Integrated System ◽  
Mitogen Activated Protein Kinase ◽  
Network Pharmacology ◽  
Present System ◽  
Toll Like Receptor ◽  
System Pharmacology ◽  
Silico Analysis

Fucosterol is an algae-derived unique phytosterol having several medicinal properties, including antioxidant, anti-inflammatory, anticholinesterase, neuroprotective, and so on. Accumulated evidence suggests a therapeutic promise of fucosterol in neurodegeneration; however, the in-depth pharmacological mechanism of its neuroprotection is poorly understood. Here, we employed system pharmacology and in silico analysis to elucidate the underlying mechanism of neuropharmacological action of fucosterol against neurodegenerative disorders (NDD). Network pharmacology revealed that fucosterol targets signaling molecules, receptors, enzymes, transporters, transcription factors, cytoskeletal, and various other proteins of cellular pathways, including tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), neurotrophin, and toll-like receptor (TLR) signaling, which are intimately associated with neuronal survival, immune response, and inflammation. Moreover, the molecular simulation study further verified that fucosterol exhibited a significant binding affinity to some of the vital targets, including liver X-receptor-beta (LXR-), glucocorticoid receptor (GR), tropomyosin receptor kinase B (TrkB), toll-like receptor 2/4 (TLR2/4), and β -secretase (BACE1), which are the crucial regulators of molecular and cellular processes associated with NDD. Together, the present system pharmacology and in silico findings demonstrate that fucosterol might play a significant role in modulating NDD-pathobiology, supporting its therapeutic application for the prevention and treatment of NDD.

scholarly journals Targeting ERK-Hippo Interplay in Cancer Therapy

2020 ◽  
Vol 21 (9) ◽  
pp. 3236 ◽  
Author(s):  
Karel Vališ ◽  
Petr Novák
Keyword(s):  
Cancer Therapy ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cross Talk ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Targeted Inhibition

Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.

scholarly journals Leptin-mediated differential regulation of microsomal triglyceride transfer protein in the intestine and liver affects plasma lipids

2020 ◽  
Vol 295 (13) ◽  
pp. 4101-4113 ◽  
Author(s):  
Jahangir Iqbal ◽  
Eduardo Mascareno ◽  
Streamson Chua ◽  
M. Mahmood Hussain
Keyword(s):  
Signaling Pathways ◽  
Short Form ◽  
Microsomal Triglyceride Transfer Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Chow Diet ◽  
Peripheral Tissues ◽  
Transfer Protein ◽  
Hepatic Cells ◽  
Huh7 Cells

The hormone leptin regulates fat storage and metabolism by signaling through the brain and peripheral tissues. Lipids delivered to peripheral tissues originate mostly from the intestine and liver via synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins. An intracellular chaperone, microsomal triglyceride transfer protein (MTP), is required for the biosynthesis of these lipoproteins, and its regulation determines fat mobilization to different tissues. Using cell culture and animal models, here we sought to identify the effects of leptin on MTP expression in the intestine and liver. Leptin decreased MTP expression in differentiated intestinal Caco-2 cells, but increased expression in hepatic Huh7 cells. Similarly, acute and chronic leptin treatment of chow diet-fed WT mice decreased MTP expression in the intestine, increased it in the liver, and lowered plasma triglyceride levels. These leptin effects required the presence of leptin receptors (LEPRs). Further experiments also suggested that leptin interacted with long-form LEPR (ObRb), highly expressed in the intestine, to down-regulate MTP. In contrast, in the liver, leptin interacted with short-form LEPR (ObRa) to increase MTP expression. Mechanistic experiments disclosed that leptin activates signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling pathways in intestinal and hepatic cells, respectively, and thereby regulates divergent MTP expression. Our results also indicated that leptin-mediated MTP regulation in the intestine affects plasma lipid levels. In summary, our findings suggest that leptin regulates MTP expression differentially by engaging with different LEPR types and activating distinct signaling pathways in intestinal and hepatic cells.

scholarly journals Asperuloside and Asperulosidic Acid Exert an Anti-Inflammatory Effect via Suppression of the NF-κB and MAPK Signaling Pathways in LPS-Induced RAW 264.7 Macrophages

2018 ◽  
Vol 19 (7) ◽  
pp. 2027 ◽  
Author(s):  
Jingyu He ◽  
Xianyuan Lu ◽  
Ting Wei ◽  
Yaqian Dong ◽  
Zheng Cai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Signaling Pathways ◽  
Mapk Signaling ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Mapk Signaling Pathways ◽  
Inflammatory Effect

Hedyotis diffusa is a folk herb that is used for treating inflammation-related diseases in Asia. Previous studies have found that iridoids in H. diffusa play an important role in its anti-inflammatory activity. This study aimed to investigate the anti-inflammatory effect and potential mechanism of five iridoids (asperuloside (ASP), asperulosidic acid (ASPA), desacetyl asperulosidic acid (DAA), scandoside methyl ester (SME), and E-6-O-p-coumaroyl scandoside methyl ester (CSME)) that are presented in H. diffusa using lipopolysaccharide (LPS)—induced RAW 264.7 cells. ASP and ASPA significantly decreased the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in parallel with the inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 mRNA expression in LPS-induced RAW 264.7 cells. ASP treatment suppressed the phosphorylation of the inhibitors of nuclear factor-kappaB alpha (IκB-α), p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). The inhibitory effect of ASPA was similar to that of ASP, except for p38 phosphorylation. In summary, the anti-inflammatory effects of ASP and ASPA are related to the inhibition of inflammatory cytokines and mediators via suppression of the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, which provides scientific evidence for the potential application of H. diffusa.

Electromyostimulation with blood flow restriction enhances activation of mTOR and MAPK signaling pathways in rat gastrocnemius muscles

2019 ◽  
Vol 44 (6) ◽  
pp. 637-644
Author(s):  
Toshiharu Natsume ◽  
Toshinori Yoshihara ◽  
Hisashi Naito
Keyword(s):  
Blood Flow ◽  
Signaling Pathways ◽  
Muscle Hypertrophy ◽  
Gastrocnemius Muscle ◽  
Lactate Concentration ◽  
Mapk Signaling ◽  
Blood Flow Restriction ◽  
Mitogen Activated Protein Kinase ◽  
Flow Restriction ◽  
Mapk Signaling Pathways

Neuromuscular electrical stimulation (NMES) combined with blood flow restriction (BFR) induces muscle hypertrophy. However, cellular mechanisms underlying the muscle hypertrophy induced by NMES combined with BFR remain unclear. We tested the hypothesis that NMES combined with BFR would enhance the mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling pathways. Age-matched male Wistar rats (6 months old, n = 7 per group) were assigned randomly to control, BFR alone (BFR), NMES alone (NMES), and NMES combined with BFR (NMES/BFR) groups. NMES induced 25 isometric contractions lasting 8 s with 4-s resting periods between contractions in the gastrocnemius muscle. Four sets in total were performed, with 1-min intervals between sets. A latex cuff was placed on the proximal portion of the hind limb and BFR at 200 mm Hg was conducted in 4 sets (each set 5 min) with 1-min rest intervals between sets. Venous blood was collected from the lateral tail vein to determine pH, H+ concentration, and lactate concentration before and immediately after the treatments. Expression levels of proteins related to muscle hypertrophy were determined by Western blot analysis. The application of NMES/BFR promoted muscle fatigue more than NMES alone. NMES/BFR induced greater changes in accumulation of metabolites and increase in gastrocnemius muscle weight. The phosphorylation of mTOR and MAPK signaling-related proteins was also enhanced following NMES/BFR, compared with other conditions. Thus, NMES enhanced the activation of mTOR and MAPK signaling pathways when combined with BFR.

scholarly journals Analysis of the Molecular Mechanisms of the Effects of Prunella vulgaris against Subacute Thyroiditis Based on Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Xin Shen ◽  
Rui Yang ◽  
Jianpeng An ◽  
Xia Zhong
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Subacute Thyroiditis ◽  
Network Pharmacology ◽  
Pharmacokinetic Parameters ◽  
Pathway Enrichment Analysis ◽  
Prunella Vulgaris ◽  
Protein Protein Interaction

Prunella vulgaris (PV) has a long history of application in traditional Chinese and Western medicine as a remedy for the treatment of subacute thyroiditis (SAT). This study applied network pharmacology to elucidate the mechanism of the effects of PV against SAT. Components of the potential therapeutic targets of PV and SAT-related targets were retrieved from databases. To construct a protein-protein interaction (PPI) network, the intersection of SAT-related targets and PV-related targets was input into the STRING platform. Gene ontology (GO) analysis and KEGG pathway enrichment analysis were carried out using the DAVID database. Networks were constructed by Cytoscape for visualization. The results showed that a total of 11 compounds were identified according to the pharmacokinetic parameters of ADME. A total of 126 PV-related targets and 2207 SAT-related targets were collected, and 83 overlapping targets were subsequently obtained. The results of the KEGG pathway and compound-target-pathway (C-T-P) network analysis suggested that the anti-SAT effect of PV mainly occurs through quercetin, luteolin, kaempferol, and beta-sitosterol and is most closely associated with their regulation of inflammation and apoptosis by targeting the PIK3CG, MAPK1, MAPK14, TNF, and PTGS2 proteins and the PI3K-Akt and TNF signaling pathways. The study demonstrated that quercetin, luteolin, kaempferol, and beta-sitosterol in PV may play a major role in the treatment of SAT, which was associated with the regulation of inflammation and apoptosis, by targeting the PI3K-Akt and TNF signaling pathways.

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