scholarly journals An Integration of Network Pharmacology and Experimental Verification to Investigate the Mechanism of Guizhi to Treat Nephrotic Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Dan He ◽  
Qiang Li ◽  
Guangli Du ◽  
Guofeng Meng ◽  
Jijia Sun ◽  
...  

Background: Guizhi has the pharmacological activity of anti-inflammatory. However, the effect mechanism of Guizhi against nephrotic syndrome (NS) remains unclear. A network pharmacological approach with experimental verification in vitro and in vivo was performed to investigate the potential mechanisms of Guizhi to treat NS.Methods: Active compounds and potential targets of Guizhi, as well as the related targets of NS were obtained from the public databases. The intersecting targets of Guizhi and NS were obtained through Venny 2.1.0. The key targets and signaling pathways were determined by protein-protein interaction (PPI), genes ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis. And the overall network was constructed with Cytoscape. Molecular docking verification was carried out by AutoDock Vina. Finally, in vitro and in vivo experiments were performed to verify the mechanism of Guizhi to treat NS.Results: 63 intersecting targets were obtained, and the top five key targets mainly involed in NF- Kappa B and MAPK signaling pathway. In the overall network, cinnamaldehyde (CA) was the top one active compound with the highest degree value. The molecular docking showed that the top five key targets were of good binding activity with the active components of Guizhi. To in vitro experiment, CA, the main active component of Guizhi, inhibited the secretion of IL-1β, IL-6, TNF-α in LPS challenged RAW264.7 cells, and down regulated the protein expression of p-NF-κB p65 and p-p38 MAPK in LPS challenged RAW264.7 cells. In vitro experiment showed that, 24 urinary protein and renal function were increased in ADR group. To western blot, CA down regulated the protein expression of p-p38 MAPK in rats of adriamycin-induced nephropathy.Conclusion: CA might be the main active component of Guizhi to treat NS, and the underlying mechanism might mainly be achieved by inhibiting MAPK signaling pathway.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Konishi ◽  
Shotaro Isozaki ◽  
Shin Kashima ◽  
Kentaro Moriichi ◽  
Satoshi Ichikawa ◽  
...  

AbstractIntake of probiotics or fermented food produced by some probiotic bacteria is believed to exert anti-tumor functions in various cancers, including pancreatic cancer, because several studies have demonstrated the anti-tumor effects of probiotic bacteria in vitro and in vivo in animal carcinogenesis models. However, the mechanisms underlying the anticancer effects of probiotics on pancreatic cancer have not been clarified. In this study, we assessed the anti-tumor effects of probiotic bacteria against pancreatic cancer cells. Among the known probiotic bacteria, Aspergillus oryzae exhibited a strong pancreatic tumor suppression effect. The culture supernatant of A. oryzae was separated by HPLC. Heptelidic acid was identified as an anti-tumor molecule derived from A. oryzae by LC–MS and NMR analysis. The anti-tumor effect of heptelidic acid was exhibited in vitro and in vivo in a xenograft model of pancreatic cancer cells. The anti-tumor effect of heptelidic acid was exerted by the p38 MAPK signaling pathway. Heptelidic acid traverses the intestinal mucosa and exerts anti-tumor effects on pancreatic cancer cells. This is a novel anti-tumor mechanism induced by beneficial bacteria against pancreatic cancer in which bacterial molecules pass through the intestinal tract, reach the extra-intestinal organs, and then induce apoptosis via an inducible signaling pathway.


2020 ◽  
Author(s):  
Jing Shi ◽  
Cao Guo ◽  
Junli Ma

Abstract Background: A major reason for treatment failure of cancer is acquisition of drug resistance. The specific mechanisms underlying hepatocellular carcinoma (HCC) chemoresistance need to be fully elucidated. lncRNAs involve in drug resistance in some cancers, however, the exact functions of lncRNA colon cancer-associated transcript 1 (CCAT1) in oxaliplatin resistance in HCC need to be elucidated.Methods: Functional analysis of CCAT1 on oxaliplatin sensitivity was performed in HCC cell lines HCCLM3 and HepG2, and in a subcutaneous tumor model receiving OXA treatment. Furthermore, the downstream signaling targets of CCAT1 in HCC were explored. Results: CCAT1 promoted HCC proliferation and reduced the apoptosis induced by oxaliplatin. Knockout of CCAT1 could increased chemosensitivity in vitro and in vivo. Further study found that QKI-5 was an important mediator and blocking of QKI-5/p38 MAPK signaling pathway enhanced oxaliplatin sensitivity.Conclusions: CCAT1 promoted proliferation and oxaliplatin resistance by QKI-5/p38 MAPK signaling pathway in HCC. Targeting CCAT1 in combination with chemotherapeutics may be a promising alternative to reverse drug resistance in HCC treatment.


2021 ◽  
Vol 12 ◽  
Author(s):  
Grazia Maugeri ◽  
Claudio Bucolo ◽  
Filippo Drago ◽  
Settimio Rossi ◽  
Michelino Di Rosa ◽  
...  

This study aimed to investigate the high glucose damage on human retinal pigment epithelial (RPE) cells, the role of p38 MAPK signaling pathway and how dimethyl fumarate can regulate that. We carried out in vitro studies on ARPE-19 cells exposed to physiological and high glucose (HG) conditions, to evaluate the effects of DMF on cell viability, apoptosis, and expression of inflammatory and angiogenic biomarkers such as COX-2, iNOS, IL-1β, and VEGF. Our data have demonstrated that DMF treatment attenuated HG-induced apoptosis, as confirmed by reduction of BAX/Bcl-2 ratio. Furthermore, in RPE cells exposed to HG we observed a significant increase of iNOS, COX-2, and IL-1β expression, that was reverted by DMF treatment. Moreover, DMF reduced the VEGF levels elicited by HG, inhibiting p38 MAPK signaling pathway. The present study demonstrated that DMF provides a remarkable protection against high glucose-induced damage in RPE cells through p38 MAPK inhibition and the subsequent down-regulation of VEGF levels, suggesting that DMF is a small molecule that represents a good candidate for diabetic retinopathy treatment and warrants further in vivo and clinical evaluation.


2021 ◽  
Author(s):  
lu wang ◽  
Wenxiang Zhu ◽  
Rui Sun ◽  
Jing Liu ◽  
Qihong Ma ◽  
...  

Abstract Background Pulmonary fibrosis (PF) is a devastating lung disease. The two drugs approved by the FDA, pirfenidone and nintedanib, can only delay the progression of the disease but cannot cure the disease. These drugs also present adverse effects. Wen-yu-jin (WYJ) obtained from steamed roots of Curcuma wenyujin showed a variety of pharmacological activities. In this study we investigated whether WYJ present anti-lung fibrosis effects. Methods Ultra-high pressure liquid chromatography combined with linear ion trap-orbital tandem mass spectrometry (UHPLC-LTQ-orbital trap) was used to identify chemical composition of WYJ. PF-related and WYJ-related targets were obtained from public databases. Network pharmacological was performed to acquire potential targets and major signaling pathways. The binding activity of composition with core targets was predicted by molecular docking. Based on the predicted results, the anti-lung fibrosis effect of WYJ was verified in vivo and in vitro experiments. Results 23 major compositions of WYJ were identified based on UHPLC-LTQ-Orbitrap. According to the results of network pharmacology, MAPK signaling pathway might play an important role in WYJ against lung fibrosis and STAT3 also could be the potential therapeutic targets. Molecular docking results indicated that most of the compositions have good binding activities with core targets. In vivo and in vitro experiments showed that WYJ alleviated process of fibrosis by inhibiting MAPK signaling pathway and the levels of phosphorylated STAT3 (p-STAT3). Conclusion According to the results of network pharmacology and molecular docking, in vivo and in vitro experiments further verified potential targets and molecular mechanism of WYJ against lung fibrosis. Our study provided a novel approach to explain the pharmacological basis of other herbs.


2021 ◽  
Author(s):  
Zurong Zhai ◽  
Yanlin Ren ◽  
Chuanjun Shu ◽  
Dongyin Chen ◽  
Xia Liu ◽  
...  

Abstract Background: Triple negative breast cancer (TNBC) is a type of breast cancer with poor prognosis, and still has no adequate therapeutic target and ideal medicine. The public database and the relative studies have shown that low expression of JWA is closely related to the poor overall survival in many cancers including breast cancer. However, the precise biological functions and behind mechanisms of JWA in TNBC are still unclear.Methods: Both TCGA and GEO databases were used to confirm the relationship between expression levels of JWA and overall survival in TNBC cases. JAC1, an agonistic small compound of JWA gene, was used in TNBC models in vitro and in vivo. The routine cellular and molecular assays include CCK-8, colony formation, EdU incorporation, the flow cytometry, Western blot, immunohistochemistry, immune-fluorescence microscopy and reporter gene assays were conducted in this study.Results: Low expression of JWA was associated with poor prognosis in TNBC patients. JAC1 treatment inhibited TNBC cells proliferation and promoted apoptosis in vitro and in vivo. JAC1 specifically combined and targeted YY1 to eliminate its transcriptional inhibition on JWA gene. At the same time, JAC1 promoted ubiquitination and degradation of YY1. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cells through the p38 MAPK signaling pathway. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC through p-Akt signaling pathway.Conclusions: We discovered for the first time that JAC1 is a YY1 targeting compound and maybe a potential therapeutic agent for TNBC.


2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Qi Shang ◽  
Xiang Yu ◽  
Hui Ren ◽  
Gengyang Shen ◽  
Wenhua Zhao ◽  
...  

Extracts from plastrum testudinis (PTE) are active compounds that have been used to treat bone diseases in traditional Chinese medicine for thousands of years. In previous studies, we demonstrated their effects on glucocorticoid-induced osteoporosis both in vivo and in vitro. However, the mechanisms by which PTE regulates the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (rBMSCs) in vitro remain poorly understood. In this study, rBMSCs were treated with medium (CON), PTE, osteogenic induction (OI), and a combination of PTE and OI (PTE+OI) over a 21-day period. We found that PTE significantly promoted rBMSCs osteogenic differentiation and mineralisation after 21 days of culturing. Moreover, PTE+OI further enhanced the differentiation and mineralisation process. PTE upregulated STE20, IGF1R, and p38 MAPK mRNA expression and downregulated TRAF6 mRNA expression. The extracts inhibited TRAF6 protein expression and promoted STE20, IGF1R, and phosphorylated p38 MAPK protein expression. Our results imply that PTE promotes the proliferation and osteogenic differentiation of rBMSCs by upregulating p38 MAPK, STE20, and IGF1R and downregulating TRAF6 expression, which may provide experimental evidence of the potential of PTE in the treatment of osteoporosis.


2020 ◽  
Vol Volume 14 ◽  
pp. 2667-2684 ◽  
Author(s):  
Xing Zhou ◽  
Xingchun Wu ◽  
Luhui Qin ◽  
Shunyu Lu ◽  
Hongliang Zhang ◽  
...  

2020 ◽  
Vol 117 (19) ◽  
pp. 10246-10253 ◽  
Author(s):  
Xin Yang ◽  
Shun Deng ◽  
Xuegao Wei ◽  
Jing Yang ◽  
Qiannan Zhao ◽  
...  

The evolution of insect resistance to pesticides poses a continuing threat to agriculture and human health. While much is known about the proximate molecular and biochemical mechanisms that confer resistance, far less is known about the regulation of the specific genes/gene families involved, particularly by trans-acting factors such as signal-regulated transcription factors. Here we resolve in fine detail the trans-regulation of CYP6CM1, a cytochrome P450 that confers resistance to neonicotinoid insecticides in the whitefly Bemisia tabaci, by the mitogen-activated protein kinase (MAPK)-directed activation of the transcription factor cAMP-response element binding protein (CREB). Reporter gene assays were used to identify the putative promoter of CYP6CM1, but no consistent polymorphisms were observed in the promoter of a resistant strain of B. tabaci (imidacloprid-resistant, IMR), which overexpresses this gene, compared to a susceptible strain (imidacloprid-susceptible, IMS). Investigation of potential trans-acting factors using in vitro and in vivo assays demonstrated that the bZIP transcription factor CREB directly regulates CYP6CM1 expression by binding to a cAMP-response element (CRE)-like site in the promoter of this gene. CREB is overexpressed in the IMR strain, and inhibitor, luciferase, and RNA interference assays revealed that a signaling pathway of MAPKs mediates the activation of CREB, and thus the increased expression of CYP6CM1, by phosphorylation-mediated signal transduction. Collectively, these results provide mechanistic insights into the regulation of xenobiotic responses in insects and implicate both the MAPK-signaling pathway and a transcription factor in the development of pesticide resistance.


2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Feng He ◽  
Zonghui Xiao ◽  
Hailan Yao ◽  
Sen Li ◽  
Miao Feng ◽  
...  

Abstract Background The P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in CVB3-induced diseases. We previously demonstrated microRNA-21 has potential inhibitory effect on the MAP2K3 which locates upstream of P38 MAPK and was upregulated in mouse hearts upon CVB3 infection. However, the effect and underlying mechanism of miRNA-21 on CVB3 infection remain unclear. Methods We detected continuous changes of cellular miRNA-21 and P38 MAPK proteins expression profiling post CVB3 infection in vitro within 12 h. P38 MAPK signaling was inhibited by the specific inhibitor, small interfering RNA and miRNA-21 mimic in vitro, CVB3 replication, cell apoptosis rate and proliferation were detected. Viral load in the mice heart, cardiomyocyte apoptosis rate and histological of the heart were also detected in the mice model of viral myocarditis pretreated with miRNA-21-lentivirus. Results We observed significant upregulation of miRNA-21 expression followed by suppression of the MAP2K3/P38 MAPK signaling in CVB3-infected Hela cells. The inactivation of the MAP2K3/P38 MAPK signaling by P38 MAPK specific inhibitor, small interfering RNA against MAP2K3, or miRNA-21 overexpression significantly inhibited viral progeny release from CVB3-infected cells. Mechanistically, when compared with control miRNA, miRNA-21 showed no effect on capsid protein VP1 expression and viral load within host cells, while significantly reversing CVB3-induced caspase-3 activation and cell apoptosis rate, further promoting proliferation of infected cells, which indicates the inhibitory effect of miRNA-21 on CVB3 progeny release. In the in vivo study, when compared with control miRNA, miRNA-21 pretreatment remarkably inactivated the MAP2K3/P38 MAPK signaling in mice and protected them against CVB3 infection as evidenced by significantly alleviated cell apoptosis rate, reduced viral titers, necrosis in the heart as well as by remarkably prolonged survival time. Conclusions miRNA-21 were reverse correlated with P38 MAPK activation post CVB3 infection, miRNA-21 overexpression significantly inhibited viral progeny release and decreased myocytes apoptosis rate in vitro and in vivo, suggesting that miRNA-21 may serve as a potential therapeutic agent against CVB3 infection through targeting the MAP2K3/P38 MAPK signaling.


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