Chrysin Ameliorates Cyclosporine-A-Induced Renal Fibrosis by Inhibiting TGF-β1-Induced Epithelial–Mesenchymal Transition

Hung

et al. 2021

Cells

CCL17, a chemotactic cytokine produced by macrophages, is known to promote inflammatory and fibrotic effects in multiple organs, but its role in mediating renal fibrosis is unclear. In our study cohort of 234 chronic kidney disease (CKD) patients and 65 healthy controls, human cytokine array analysis revealed elevated CCL17 expression in CKD that correlated negatively with renal function. The area under the receiver operating characteristic curve of CCL17 to predict the development of CKD stages 3b–5 was 0.644 (p < 0.001), with the optimal cut-off value of 415.3 ng/mL. In vitro over-expression of CCL17 in HK2 cells had no effect on cell viability, but increased cell motility and the expression of α-SMA, vimentin and collagen I, as shown by western blot analysis. In a unilateral ureteral obstruction (UUO) mouse model, we observed significantly increased interstitial fibrosis and renal tubule dilatation by Masson’s Trichrome and H&E staining, and markedly increased expression of CCL17, vimentin, collagen I, and α-SMA by IHC stain, qRTPCR, and western blotting. CCL17 induced renal fibrosis by promoting the epithelial-mesenchymal transition, resulting in ECM accumulation. CCL17 may be a useful biomarker for predicting the development of advanced CKD.

Section: Resultsmentioning

confidence: 99%

C-C Motif Chemokine Ligand-17 as a Novel Biomarker and Regulator of Epithelial Mesenchymal Transition in Renal Fibrogenesis

Hsieh

Hung

et al. 2021

Cells

“…In this study, β-catenin was not only the core target of all AO targets but also the most important target of AO in the treatment of AD. Among 13 phytochemicals of AO that bind to GSK3β, chrysin can also target Akt and MAPKs to affect protein phosphorylation ( Liu et al, 2016 ; Nagavally et al, 2021 ). Pinocembrin, which is a flavonoid, exerts neuroprotective effects through the GSK3β and Akt signaling pathways ( Kim et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Targets and mechanisms of Alpinia oxyphylla Miquel fruits in treating neurodegenerative dementia

Zeng

Liu

et al. 2022

Front. Aging Neurosci.

The dried and ripe fruits of Alpinia oxyphylla and ripe fruits of Alpinia oxyphylla Miquel (AO) have the effects of tonifying kidney-essence and nourishing intelligence and thus have been widely used in treating dementia. Alzheimer’s disease (AD) is a typical form of neurodegenerative dementia with kidney-essence deficiency in Traditional Chinese Medicine (TCM). So far, there is a lack of systematic studies on the biological basis of tonifying kidney-essence and nourishing intelligence and the corresponding phytochemicals. In this study, we investigated the targets of AO in tonifying kidney-essence and nourishing intelligence based on the key pathophysiological processes of neurodegenerative dementia. According to ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry data and Lipinski’s rule of five, 49 bioactive phytochemicals from AO were identified, and 26 of them were found to target 168 key molecules in the treatment of neurodegenerative dementia. Nine phytochemicals of AO were shown to target acetylcholinesterase (ACHE), and 19 phytochemicals were shown to target butyrylcholinesterase (BCHE). A database of neurodegenerative dementia with kidney-essence deficiency involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-β-D-fructopyranoside, dibutyl phthalate, chrysin, yakuchinone A, rhamnetin, and rhamnocitrin were identified as the key phytochemicals from AO that regulate the pathogenesis of neurodegenerative dementia in a multitargeted manner. The approach of studying the pharmacological mechanism underlying the effects of medicinal plants and the biological basis of TCM syndrome may be helpful in studying the translation of TCM.

“…Other anti-fibrosis signal pathways were also reported in the EMT process. For instance, EMT and glomerulosclerosis in rats with chronic kidney disease were suppressed by JAK/STAT signaling pathway ( Zhao et al, 2019 ), and cyclosporine-A-induced renal fibrosis was ameliorated by chrysin by the inhibition of TGF-beta-induced EMT ( Nagavally et al, 2021 ). In addition, the PI3K-Akt signaling pathway, a major regulator of anti-inflammation, has been reported to prevent renal fibrosis by attenuating renal tubular epithelial cell–mesenchymal transition ( Hu et al, 2021 ; Zhang Q et al, 2020 ; Wang et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology and Experimental Verification Strategies to Illustrate the Mechanism of Jian-Pi-Yi-Shen Formula in Suppressing Epithelial–Mesenchymal Transition

Zhao

et al. 2022

Front. Pharmacol.

Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese medicine, has been recommended to treat renal fibrosis for decades. Previous studies had shown that JPYSF could inhibit epithelial–mesenchymal transition (EMT), an important regulatory role in renal fibrosis. However, the mechanism of JPYSF action is largely unknown. In this study, network pharmacology and experimental verification were combined to elucidate and identify the potential mechanism of JPYSF against renal fibrosis by suppressing EMT at molecular and pathway levels. Network pharmacology was first performed to explore the mechanism of JPYSF against renal fibrosis targeting EMT, and then a 5/6 nephrectomy (5/6 Nx)-induced rat model of renal fibrosis was selected to verify the predictive results by Masson’s trichrome stains and western blot analysis. Two hundred and thirty-two compounds in JPYSF were selected for the network approach analysis, which identified 137 candidate targets of JPYSF and 4,796 known therapeutic targets of EMT. The results of the Gene Ontology (GO) function enrichment analysis included 2098, 88, and 133 GO terms for biological processes (BPs), molecular functions (MFs), and cell component entries, respectively. The top 10 enrichment items of BP annotations included a response to a steroid hormone, a metal ion, oxygen levels, and so on. Cellular composition (CC) is mainly enriched in membrane raft, membrane microdomain, membrane region, etc. The MF of JPYSF analysis on EMT was predominately involved in proximal promoter sequence-specific DNA binding, protein heterodimerization activity, RNA polymerase II proximal promoter sequence-specific DNA binding, and so on. The involvement signaling pathway of JPYSF in the treatment of renal fibrosis targeting EMT was associated with anti-fibrosis, anti-inflammation, podocyte protection, and metabolism regulation. Furthermore, the in vivo experiments confirmed that JPYSF effectively ameliorated interstitial fibrosis and inhibited the overexpression of α-SMA, Wnt3a, and β-catenin, and increased the expression of E-cadherin by wnt3a/β-catenin signaling pathway in 5/6 Nx-induced renal fibrosis rats. Using an integrative network pharmacology-based approach and experimental verification, the study showed that JPYSF had therapeutic effects on EMT by regulating multi-pathway, among which one proven pathway was the Wnt3a/β-catenin signaling pathway. These findings provide insights into the renoprotective effects of JPYSF against EMT, which could suggest directions for further research of JPYSF in attenuating renal fibrosis by suppressing EMT.