Uncovering Mechanisms of Zanthoxylum piperitum Fruits for the Alleviation of Rheumatoid Arthritis Based on Network Pharmacology

Zanthoxylum piperitum fruits (ZPFs) have been demonstrated favorable clinical efficacy on rheumatoid arthritis (RA), but its compounds and mechanisms against RA have not been elucidated. This study was to investigate the compounds and mechanisms of ZPFs to alleviate RA via network pharmacology. The compounds from ZPFs were detected by gas chromatography–mass spectrometry (GC-MS) and screened to select drug-likeness compounds through SwissADME. Targets associated with bioactive compounds or RA were identified utilizing bioinformatics databases. The signaling pathways related to RA were constructed; interactions among targets; and signaling pathways-targets-compounds (STC) were analyzed by RPackage. Finally, a molecular docking test (MDT) was performed to validate affinity between targets and compounds on key signaling pathway(s). GC-MS detected a total of 85 compounds from ZPFs, and drug-likeness properties accepted all compounds. A total of 216 targets associated with compounds 3377 RA targets and 101 targets between them were finally identified. Then, a bubble chart exhibited that inactivation of MAPK (mitogen-activated protein kinase) and activation of PPAR (peroxisome proliferator-activated receptor) signaling pathway might be key pathways against RA. Overall, this work suggests that seven compounds from ZPFs and eight targets might be multiple targets on RA and provide integrated pharmacological evidence to support the clinical efficacy of ZPFs on RA.

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Elucidating Drug-Like Compounds and Potential Mechanisms of Corn Silk (Stigma Maydis) against Obesity: A Network Pharmacology Study

Current Issues in Molecular Biology ◽

10.3390/cimb43030133 ◽

2021 ◽

Vol 43 (3) ◽

pp. 1906-1936

Author(s):

Ki-Kwang Oh ◽

Md. Adnan ◽

Dong-Ha Cho

Keyword(s):

Native Americans ◽

Signaling Pathways ◽

Signaling Pathway ◽

Protein S ◽

Gas Chromatography Mass Spectrometry ◽

Network Pharmacology ◽

Bioactive Constituents ◽

Lipinski’S Rule ◽

Protein Protein Interaction ◽

Corn Silk

Corn silk (Stigma Maydis) has been utilized as an important herb against obesity by Chinese, Korean, and Native Americans, but its phytochemicals and mechanisms(s) against obesity have not been deciphered completely. This study aimed to identify promising bioactive constituents and mechanism of action(s) of corn silk (CS) against obesity via network pharmacology. The compounds from CS were identified using Gas Chromatography Mass Spectrometry (GC-MS) and were confirmed ultimately by Lipinski’s rule via SwissADME. The relationships of the compound-targets or obesity-related targets were confirmed by public bioinformatics. The signaling pathways related to obesity, protein-protein interaction (PPI), and signaling pathways-targets-bioactives (STB) were constructed, visualized, and analyzed by RPackage. Lastly, Molecular Docking Test (MDT) was performed to validate affinity between ligand(s) and protein(s) on key signaling pathway(s). We identified a total of 36 compounds from CS via GC-MS, all accepted by Lipinski’s rule. The number of 36 compounds linked to 154 targets, 85 among 154 targets related directly to obesity-targets (3028 targets). Of the final 85 targets, we showed that the PPI network (79 edges, 357 edges), 12 signaling pathways on a bubble chart, and STB network (67 edges, 239 edges) are considered as therapeutic components. The MDT confirmed that two key activators (β-Amyrone, β-Stigmasterol) bound most stably to PPARA, PPARD, PPARG, FABP3, FABP4, and NR1H3 on the PPAR signaling pathway, also, three key inhibitors (Neotocopherol, Xanthosine, and β-Amyrone) bound most tightly to AKT1, IL6, FGF2, and PHLPP1 on the PI3K-Akt signaling pathway. Overall, we provided promising key signaling pathways, targets, and bioactives of CS against obesity, suggesting crucial pharmacological evidence for further clinical testing.

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CLINICAL EFFICACY AND SAFETY OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA AGONISTS IN RHEUMATOID ARTHRITIS: AN OPEN-LABEL CONTROLLED STUDY

Medical Immunology (Russia) ◽

10.15789/1563-0625-2014-1-71-80 ◽

2014 ◽

Vol 16 (1) ◽

pp. 71 ◽

Cited By ~ 1

Author(s):

V. S. Shirinsky ◽

O. A. Polovnikova ◽

N. Yu. Kalinovskaya ◽

I. V. Shirinsky

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Efficacy ◽

Controlled Study ◽

Peroxisome Proliferator ◽

Efficacy And Safety ◽

Open Label ◽

Peroxisome Proliferator Activated Receptor ◽

Receptor Alpha

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Gabapentin Reduces Alcohol Intake in Rats by Regulating NF-κB Signaling Pathway Via PPAR γ

Alcohol and Alcoholism ◽

10.1093/alcalc/agab065 ◽

2021 ◽

Author(s):

Jing Li ◽

Kewei Xu ◽

Hao Ding ◽

Qiaozhen Xi

Keyword(s):

Locomotor Activity ◽

Signaling Pathway ◽

Specific Inhibitor ◽

Underlying Mechanism ◽

Ethanol Consumption ◽

Diglycidyl Ether ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Tnf Α

Abstract Aims Increasing preclinical and clinical reports have demonstrated the efficacy of gabapentin (GBP) in treating alcohol use disorder (AUD). However, the mechanism of the effects of GBP in AUD is largely unknown. Herein, we sought to investigate the effect of GBP in a rat model of AUD and explore the underlying mechanism. Methods The intermittent access to 20% ethanol in a 2-bottle choice (IA2BC) procedure was exploited to induce high voluntary ethanol consumption in rats. The rats were treated daily for 20 days with different doses of GBP, simultaneously recording ethanol/water intake. The locomotor activity and grooming behavior of rats were also tested to evaluate the potential effects of GBP on confounding motor in rats. The levels of IL-1β and TNF-α in serum and hippocampus homogenate from the rats were detected by using ELISA. The expressions of peroxisome proliferator-activated-receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) in the hippocampus were determined by immunofluorescence and western blot. Results GBP reduced alcohol consumption, whereas increased water consumption and locomotor activity of rats. GBP was also able to decrease the levels of IL-1β and TNF-α in both serum and hippocampus, in addition to the expression of NF-κB in the hippocampus. Furthermore, these effects attributed to GBP were observed to disappear in the presence of bisphenol A diglycidyl ether (BADGE), a specific inhibitor of PPAR-γ. Conclusions Our findings revealed that GBP could activate PPAR-γ to suppress the NF-κB signaling pathway, contributing to the decrease of ethanol consumption and ethanol-induced neuroimmune responses.

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Anxa2 gene silencing attenuates obesity-induced insulin resistance by suppressing the NF-κB signaling pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00242.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. C223-C234 ◽

Cited By ~ 5

Author(s):

Yong Wang ◽

Yun-Sheng Cheng ◽

Xiao-Qiang Yin ◽

Gang Yu ◽

Ben-Li Jia

Keyword(s):

Insulin Resistance ◽

Gene Silencing ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Cell Model ◽

Global Scale ◽

Differentially Expressed ◽

Cytokine Signaling ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Insulin resistance (IR) continues to pose a major threat to public health due to its role in the pathogenesis of metabolic syndrome and its ever-increasing prevalence on a global scale. The aim of the current study was to investigate the efficacy of Anxa2 in obesity-induced IR through the mediation of the NF-κB signaling pathway. Microarray analysis was performed to screen differentially expressed genes associated with obesity. To verify whether Anxa2 was differentially expressed in IR triggered by obesity, IR mouse models were established in connection with a high-fat diet (HFD). In the mouse IR model, the role of differentially expressed Anxa2 in glycometabolism and IR was subsequently detected. To investigate the effect of Anxa2 on IR and its correlation with inflammation, a palmitic acid (PA)-induced IR cell model was established, with the relationship between Anxa2 and the NF-κB signaling pathway investigated accordingly. Anxa2 was determined to be highly expressed in IR. Silencing Anxa2 was shown to inhibit IR triggered by obesity. When Anxa2 was knocked down, elevated expression of phosphorylated insulin receptor substrate 1 (IRS1), IRS1 and peroxisome proliferator-activated receptor coactivator-1a, and glucose tolerance and insulin sensitivity along with 2-deoxy-d-glucose uptake was detected, whereas decreased expression of suppressor of cytokine signaling 3, IL-6, IL-1β, TNF-α, and p50 was observed. Taken together, the current study ultimately demonstrated that Anxa2 may be a novel drug strategy for IR disruption, indicating that Anxa2 gene silencing is capable of alleviating PA or HFD-induced IR and inflammation through its negative regulatory role in the process of p50 nuclear translocation of the NF-κB signaling pathway.

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Microarray profiling analysis identifies the mechanism of miR‐200b‐3p/mRNA‐CD36 affecting diabetic cardiomyopathy via peroxisome proliferator activated receptor‐γ signaling pathway

Journal of Cellular Biochemistry ◽

10.1002/jcb.27795 ◽

2018 ◽

Vol 120 (4) ◽

pp. 5193-5206 ◽

Cited By ~ 6

Author(s):

Liqiong Xu ◽

Wei Chen ◽

Min Ma ◽

Anfang Chen ◽

Chengyue Tang ◽

...

Keyword(s):

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Microarray Profiling ◽

Profiling Analysis

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Keratinocyte-Derived Vascular Endothelial Growth Factor Biosynthesis Represents a Pleiotropic Side Effect of Peroxisome Proliferator-Activated Receptor-γ Agonist Troglitazone but Not Rosiglitazone and Involves Activation of p38 Mitogen-Activated Protein Kinase: Implications for Diabetes-Impaired Skin Repair

Molecular Pharmacology ◽

10.1124/mol.108.049395 ◽

2008 ◽

Vol 74 (4) ◽

pp. 952-963 ◽

Cited By ~ 17

Author(s):

Dana Schiefelbein ◽

Oliver Seitz ◽

Itamar Goren ◽

Jan Philipp Dißmann ◽

Helmut Schmidt ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Vascular Endothelial ◽

Peroxisome Proliferator Activated Receptor ◽

Skin Repair ◽

Mitogen Activated Protein ◽

Endothelial Growth Factor

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High Sugar Intake and Development of Skeletal Muscle Insulin Resistance and Inflammation in Mice: A Protective Role for PPAR-δAgonism

Mediators of Inflammation ◽

10.1155/2013/509502 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 19

Author(s):

Elisa Benetti ◽

Raffaella Mastrocola ◽

Mara Rogazzo ◽

Fausto Chiazza ◽

Manuela Aragno ◽

...

Keyword(s):

Skeletal Muscle ◽

Signaling Pathways ◽

Gastrocnemius Muscle ◽

Metabolic Diseases ◽

Whole Body ◽

Intercellular Adhesion Molecule ◽

Fibroblast Growth Factor 21 ◽

Peroxisome Proliferator ◽

Intercellular Adhesion Molecule 1 ◽

Peroxisome Proliferator Activated Receptor

Peroxisome Proliferator Activated Receptor (PPAR)-δagonists may serve for treating metabolic diseases. However, the effects of PPAR-δagonism within the skeletal muscle, which plays a key role in whole-body glucose metabolism, remain unclear. This study aimed to investigate the signaling pathways activated in the gastrocnemius muscle by chronic administration of the selective PPAR-δagonist, GW0742 (1 mg/kg/day for 16 weeks), in male C57Bl6/J mice treated for 30 weeks with high-fructose corn syrup (HFCS), the major sweetener in foods and soft-drinks (15% wt/vol in drinking water). Mice fed with the HFCS diet exhibited hyperlipidemia, hyperinsulinemia, hyperleptinemia, and hypoadiponectinemia. In the gastrocnemius muscle, HFCS impaired insulin and AMP-activated protein kinase signaling pathways and reduced GLUT-4 and GLUT-5 expression and membrane translocation. GW0742 administration induced PPAR-δupregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-κB and expression of inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1 were attenuated by drug treatment. These effects were accompanied by reduction in the serum concentration of interleukin-6 and increase in muscular expression of fibroblast growth factor-21. Overall, here we show that PPAR-δactivation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.

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Regulator 1-Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Signaling Pathway in Investigating the Pathological Characteristics and Molecular Mechanism of Liver Cirrhosis Complicated by Acute Kidney Injury

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2859 ◽

2022 ◽

Vol 12 (1) ◽

pp. 112-120

Author(s):

Jieqi Gong ◽

Huanhua Lu

Keyword(s):

Acute Kidney Injury ◽

Liver Cirrhosis ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Kidney Injury ◽

Male Rats ◽

Control Group ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Duct Ligation

The objective of this study was to investigate the molecular mechanism of the histopathological characteristics of liver cirrhosis (LC) complicated with acute kidney injury (AKI) and the signaling pathway of silent information regulator 1 (SIRT1)-peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) during the pathogenesis of LC. 20 healthy male rats with AKI complicated by laparoscopic cholecystectomy were selected and divided randomly into control group (C group), lipopolysaccharide (LPS) group, bile duct ligation (BDL) group, and model group (lipopolysaccharide+BDL) (D group). The indexes of all the rats were determined, including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), sarcoplasmic enzyme (Scr), and blood urea nitrogen (BUN); the SIRT1 and PGC-1α expressions in renal tissues of rats from each group was detected. Results showed that the AST and ALT levels in BDL group and D group were higher markedly than those before surgery (P < 0.05). The serum levels of Scr and BUN in D group 4 hours after LPS injection increased hugely compared with before injection (P < 0.05). Compared with BDL group, the protein levels of SIRT1 and PGC-1α in renal tissue of group D were decreased sharply (P < 0.05), and the SIRT1 protein expression was positively correlated with PGC-1α (r = 0.836 and P < 0.01). When LC were complicated with AKI, SIRT1 activity was reduced and PGC-1α expression was inhibited. Moreover, SIRT1-PGC-1α signaling pathway played a protective role in pathogenesis of LC complicated with AKI.

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A Network Pharmacology Approach to Explore Mechanism of Action of Longzuan Tongbi Formula on Rheumatoid Arthritis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/5191362 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 5

Author(s):

An Huang ◽

Gang Fang ◽

Yuzhou Pang ◽

Zongran Pang

Keyword(s):

Rheumatoid Arthritis ◽

Signaling Pathway ◽

Active Rheumatoid Arthritis ◽

Trp Channels ◽

Network Pharmacology ◽

Mtor Signaling Pathway ◽

Active Ingredients ◽

Major Pathway ◽

Pharmacological Mechanism ◽

Ppar Signaling

Longzuan Tongbi Formula (LZTB) is an effective proved prescription in Zhuang medicine for treating active rheumatoid arthritis (RA). However, its active ingredients, underlying targets, and pharmacological mechanism are still not clear in treating RA. We have applied network pharmacology to study LZTB and found that 8 herbs in LZTB and 67 compounds in the 8 herbs are involved in the regulation of RA-related genes; we have conducted pathway analysis of overlapping genes and found that 7 herbs participate in the regulations of 24 pathways associated with RA and that 5 herbs in the 7 herbs and 25 compounds in the 5 herbs participate in the regulation of hsa05323 (rheumatoid arthritis). The results indicated that all herbs in LZTB and some compounds in those herbs participate in the treatment of RA; 25 compounds are main active ingredients and hsa05323 (rheumatoid arthritis) is the major pathway in the treatment of RA. We have also found that three pathways (inflammatory mediator regulation of TRP channels, PPAR signaling pathway, and mTOR signaling pathway) might have some effect on the treatment of RA.

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