Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice

Tsai, Ming-Shiun; Wang, Yinghan; Lai, Yan-Yun; Tsou, Hsi‐Kai; Liou, Gunn‐Guang; Ko, Jiunn‐Liang; Wang, Sue-Hong

doi:10.1016/j.toxlet.2018.03.024

Cited by 89 publications

(64 citation statements)

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“…As we know, oxidative stress injury is one of the most important mechanisms in the study of chemical-induced hepatotoxicity in mice [ 27 ]. The functions of liver endogenous antioxidant enzymes catalase (CAT), glutathione (GSH), superoxide dismutase (SOD) by the induction of CCl 4 to mice are summarize in the study ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

The Liver Protection Effects of Maltol, a Flavoring Agent, on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Inflammatory Response

et al. 2018

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The purpose of this research was to evaluate whether maltol could protect from hepatic injury induced by carbon tetrachloride (CCl4) in vivo by inhibition of apoptosis and inflammatory responses. In this work, maltol was administered at a level of 100 mg/kg for 15 days prior to exposure to a single injection of CCl4 (0.25%, i.p.). The results clearly indicated that the intrapulmonary injection of CCl4 resulted in a sharp increase in serum aspartate transaminase (AST) and alanine transaminase (ALT) activities, tumor necrosis factor-α (TNF-α), irreducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB) and interleukin-1β (IL-1β) levels. Histopathological examination demonstrated severe hepatocyte necrosis and the destruction of architecture in liver lesions. Immunohistochemical staining and western blot analysis suggested an accumulation of iNOS, NF-κB, IL-1β and TNF-α expression. Maltol, when administered to mice for 15 days, can significantly improve these deleterious changes. In addition, TUNEL and Hoechst 33258 staining showed that a liver cell nucleus of a model group diffused uniform fluorescence following CCl4 injection. Maltol pretreatment groups did not show significant cell nuclear condensation and fragmentation, indicating that maltol inhibited CCl4-induced cell apoptosis. By evaluating the liver catalase (CAT), glutathione (GSH), superoxide dismutase (SOD) activity, and further using a single agent to evaluate the oxidative stress in CCl4-induced hepatotoxicity by immunofluorescence staining, maltol dramatically attenuated the reduction levels of hepatic CAT, GSH and SOD, and the over-expression levels of CYP2E1 and HO-1. In the mouse model of CCl4-induced liver injury, we have demonstrated that the inflammatory responses were inhibited, the serum levels of ALT and AST were reduced, cell apoptosis was suppressed, and liver injury caused by CCl4 was alleviated by maltol, demonstrating that maltol may be an efficient hepatoprotective agent.

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Section: Resultsmentioning

confidence: 99%

The Liver Protection Effects of Maltol, a Flavoring Agent, on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Inflammatory Response

et al. 2018

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“…Moreover, mice treated with up to 3000 mg/kg quercetin did not show any toxic effects [20]. Kaempferol, chemical structural analogues of quercetin, with less than a hydroxyl, also exhibited hepatoprotective effect [21], and suppressed hepatic gluconegeonesis [22] and inhibited hepatocellular carcinoma cell [23]. Geniposide, a major characteristic constituent in GF, which exerted protective effects against hepatic steatosis in rats fed with a HFD, the underlying mechanism might be associated with its antioxidant actions or regulation of adipocytokine release and expression of PPARα [24].…”

Section: Discussionmentioning

confidence: 96%

Exploring anti-nonalcoholic fatty liver disease mechanism of Gardeniae Fructus by combining an animal model with network pharmacology and molecular docking

L¹,

Lu²,

Tang³

et al. 2020

Preprint

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Background Gardeniae Fructus (GF), a traditional Chinese medicine in clinic for the treatment of nonalcoholic fatty liver disease (NAFLD). However, the mechanisms of action of GF was still margin. To explore the efficacy and mechanism of action of GF for the treatment of NAFLD, we proposed a strategy combined in vivo efficacy verification, network pharmacology analysis, molecular docking, and validity assay of target protein. Methods Firstly, an animal model induced by the high fat diet feed was established, then orally administrated with GF, the mRNA expression levels of lipogenesis was performed by RT-PCR, the liver tissue specimens were stained by hematoxylin and eosin (H&E), then observed by light microscopy. Secondly, network pharmacology studies clarified the relationship among the active constituents, target protein, and pathways, and then explored by the molecular docking. Finally, validity assay of target protein was performed in surface plasmon resonance (SPR) test. Results GF protected against NAFLD in rats. Network pharmacology showed that quercetin, oleanolic acid, and geniposide, targeted on PPARα, PPARγ, and CA2 genes, through regulating PPAR, AMPK, and cGMP-PKG signal pathways, to protect against NAFLD. And the Conclusion GF could alleviate NAFLD through the molecular mechanisms explored by network pharmacology, molecular docking, and surface plasmon resonance, those method can be effective tools to clarify the mechanisms of actions of traditional Chinese medicine from a holistic perspective.

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“…37 Kaempferol is also a flavonoid, which is abundant in multiple types of foods and beverages, such as tea, broccoli, apples, strawberries, and beans, 38 with antioxidant, anti-inflammatory, and neuroprotective properties. 39,40 The neuroprotective effects of kaempferol were mediated via regulating the protein expression levels of Bcl-2, apoptosis-inducing factor (AIF), and mitogen-activated protein kinase (MAPK). 40 Beta-Sitosterol is one of the most extensively distributed plant sterols, with a structure similar to cholesterol.…”

Section: Discussionmentioning

confidence: 99%

<p>Identifying the Mechanisms and Molecular Targets of Yizhiqingxin Formula on Alzheimer’s Disease: Coupling Network Pharmacology with GEO Database</p>

Zhang

Pan

Cao

et al. 2020

PGPM

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Background: Yizhiqingxin formula (YZQX) is a promising formula for the treatment of Alzheimer's disease (AD) with significant clinical effects. Here, we coupled a network pharmacology approach with the Gene Expression Omnibus (GEO) database to illustrate comprehensive mechanisms and screen for molecular targets of YZQX for AD treatment. Methods: First, active ingredients of YZQX were screened for the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database with the absorption, distribution, metabolism, and excretion (ADME) parameters. Subsequently, putative targets of active ingredients were predicted using the DrugBank database. AD-related targets were retrieved by analyzing published microarray data (accession number GSE5281). Protein-protein interaction (PPI) networks of YZQX putative targets and AD-related targets were constructed visually and merged to identify candidate targets for YZQX against AD using Cytoscape 3.7.2 software. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to further clarify the biological functions of the candidate targets. The gene-pathway network was established to filter for key target genes. Results: Forty-three active ingredients were identified, and 193 putative target genes were predicted. Seven hundred and ten targets related to AD were screened with |log2 FC| > 1 and P < 0.05. Based on the PPI network, 110 target genes of YZQX against AD were identified. Moreover, 32 related pathways including the PI3K-Akt signaling pathway, MAPK signaling pathway, ubiquitin-mediated proteolysis, apoptosis and the NF-kappa B signaling pathway were significantly enriched. In the gene-pathway network, MAPK1, AKT1, TP53, MDM2, EGFR, RELA, SRC, GRB2, CUL1, and MYC targets are putative core genes for YZQX in AD treatment. Conclusion: YZQX against AD may exert its neuroprotective effect via the PI3K-Akt signaling pathway, MAPK signaling pathway, and ubiquitin-mediated proteolysis. YZQX may be a promising drug that can be used in the treatment of AD.

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Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice

Cited by 89 publications

References 50 publications

The Liver Protection Effects of Maltol, a Flavoring Agent, on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Inflammatory Response

The Liver Protection Effects of Maltol, a Flavoring Agent, on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Inflammatory Response

Exploring anti-nonalcoholic fatty liver disease mechanism of Gardeniae Fructus by combining an animal model with network pharmacology and molecular docking

<p>Identifying the Mechanisms and Molecular Targets of Yizhiqingxin Formula on Alzheimer’s Disease: Coupling Network Pharmacology with GEO Database</p>

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