Beyond its antioxidant properties: Quercetin targets multiple signalling pathways in hepatocellular carcinoma in rats

Salama, Yasmin Ahmed; El-Karef, Amro; Gayyar, Amal Mohamed El; Abdel-Rahman, Noha

doi:10.1016/j.lfs.2019.116933

Cited by 48 publications

(34 citation statements)

References 98 publications

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“…Quercetin (Qu), one kind of flavonoid, is widely distributed in various vegetables and fruits, exhibiting a broad spectrum of biological effects, such as antioxidant, anti-inflammatory and anticancer (Murakami et al, 2008). In the last decade, the anticancer effects of quercetin alone or combination with other drugs have been proposed, and this pharmacological activity has been attributed to its effects on cell cycle arrest, apoptosis and angiogenesis via blocking VEGF/PI3K/Akt in prostate cancer cells (Sun et al, 2018) or ERK signaling pathways in colorectal cancer cells (Salama et al, 2019;Zhang et al, 2019). Nevertheless, the effect of quercetin in AML cells is less studied and the particular mechanisms have not been identified (Lee et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Quercetin Induces Apoptosis via Downregulation of Vascular Endothelial Growth Factor/Akt Signaling Pathway in Acute Myeloid Leukemia Cells

Shi

Yao

et al. 2020

Front. Pharmacol.

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Acute myeloid leukemia (AML) is an aggressive haematological malignancy characterized by highly proliferative accumulation of immature and dysfunctional myeloid cells. Quercetin (Qu), one kind of flavonoid, exhibits anti-cancer property in multiple types of solid tumor, but its effect on acute myeloid leukemia is less studied, and the underlying mechanisms still largely unknown. This study aimed to explore the specific target and potential mechanism of quercetin-induced cell death in AML. First, we found that quercetin induces cell death in the form of apoptosis, which was caspase dependent. Second, we found that quercetin-induced apoptosis depends on the decrease of mitochondria membrane potential (MMP) and Bcl-2 proteins. With quantitative chemical proteomics, we observed the downregulation of VEGFR2 and PI3K/Akt signaling in quercetin-treated cells. Consistently, cell studies also identified that VEGFR2 and PI3K/Akt signaling pathways are involved in the action of quercetin on mitochondria and Bcl-2 proteins. The decrease of MMP and cell death could be rescued when PI3K/Akt signaling is activated, suggesting that VEGFR2 and PI3K/Akt exert as upstream regulators for quercetin effect on apoptosis induction in AML cells. In conclusion, our findings from this study provide convincing evidence that quercetin induces cell death via downregulation of VEGF/Akt signaling pathways and mitochondria-mediated apoptosis in AML cells.

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Section: Introductionmentioning

confidence: 99%

Quercetin Induces Apoptosis via Downregulation of Vascular Endothelial Growth Factor/Akt Signaling Pathway in Acute Myeloid Leukemia Cells

Shi

Yao

et al. 2020

Front. Pharmacol.

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“…TCE-exposed females expressed high levels of proliferation and cell cycle markers, ki67 and cyclnd1 , relative to control females and males, regardless of TCE exposure. Like IL-6 related markers and chemokines/cytokines, KI67 and Cyclin D1 dysregulation is an indicator of many different liver conditions including hepatocellular carcinoma ( Salama et al, 2019 ), nonalcoholic fatty liver disease ( Dey et al, 2019 ), chronic alcohol exposure ( Chavez et al, 2011 ), and liver injury ( Inomata et al, 2018 ). The role of these proteins are not well described in AIH, however; experimentally-induced AIH had altered levels of these proliferation markers ( Huang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Sex-Dependent Effects on Liver Inflammation and Gut Microbial Dysbiosis After Continuous Developmental Exposure to Trichloroethylene in Autoimmune-Prone Mice

et al. 2020

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Trichloroethylene (TCE) is a common environmental toxicant linked with hypersensitivity and autoimmune responses in humans and animal models. While autoimmune diseases are more common in females, mechanisms behind this disparity are not clear. Recent evidence suggests that autoimmunity may be increasing in males, and occupational studies have shown that TCE-mediated hypersensitivity responses occur just as often in males. Previous experimental studies in autoimmune-prone MRL +/+ mice have focused on responses in females. However, it is important to include both males and females in order to better understand sex-disparity in autoimmune disease. In addition, because of an alarming increase in autoimmunity in adolescents, developmental and/or early life exposures to immune-enhancing environmental pollutants should also be considered. Using MRL +/+ mice, we hypothesized that TCE would alter markers related to autoimmunity to a greater degree in female mice relative to male mice, and that TCE would enhance these effects. Mice were continuously exposed to either TCE or vehicle beginning at gestation, continuing during lactation, and directly in the drinking water. Both male and female offspring were evaluated at 7 weeks of age. Sex-specific effects were evident. Female mice were more likely than males to show enhanced CD4 + T cell cytokine responses (e.g., IL-4 and IFN-γ). Although none of the animals developed pathological or serological signs of autoimmune hepatitis-like disease, TCE-exposed female mice were more likely than males in either group to express higher levels of biomarkers in the liver related to regeneration/repair and proliferation. Levels of bacterial populations in the intestinal ileum were also altered by TCE exposure and were more prominent in females as compared to males. Thus, our expectations were correct in that young adult female mice developmentally exposed to TCE were more likely to exhibit alterations in immunological and gut/liver endpoints compared to male mice.

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“…TP53 is one of the four major drivers of PCPL, and it can be deleted or mutate in the late stages of PCPL [51,53]. Studies have shown that quercetin can induce cell cycle arrest and p53/Bax-dependent cell apoptosis, downregulate Akt expression, and inhibit cell differentiation and proliferation [54][55][56][57][58]. β-sitosterol, another important active component of SSG, has important anti-tumour effects, facilitated through its roles in cell cycle arrest and apoptosis induction.…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Determine the Mechanisms of Action of Shuangshen Granules in Suppressing Pancreatic Cancer Precursor Lesions

Jiang

Zhang

Yang

et al. 2020

Preprint

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Background and purpose: Pancreatic cancer is an insidious and highly lethal disease. Recognition and treatment of pancreatic cancer precursor lesions (PCPL) are important measures and can improve patient survival rate. Shuangshen Granules (SSG) have been prescribed for use in clinical practice for more than seven years and are widely used to treat the precursor lesions of various tumours. In this study, we used network pharmacology to explore the pharmacological mechanisms through which SSG suppress PCPL. We aimed to provide a basis for further research and the development of small, molecular, natural chemical drugs.Methods: We first searched databases and screened the bioactive components of SSG and the related targets acting on PCPL to construct a component-target network. Then, network topology analysis was used to analyse the hub target of SSG acting on PCPL. Enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were also performed to determine the potential pathways. Finally, molecular docking simulations were carried out to investigate the interactions between PCPL-target proteins and the active components of SSG.Results: Seven of the main components of SSG affected PCPL, with 100 key targets including 16 hub targets. In addition, GO and KEGG enrichment analysis revealed that SSG regulated 111 molecular functions, 46 cellular components, 2334 biological processes, and 144 related signalling pathways, of which 26 were closely related to PCPL. Results of molecular docking analysis showed that the PCPL-related targets had strong binding properties with the active components of SSG, quercetin, and ginsenoside rh2, mainly TNF, IL-6, AKT1, TP53, and EGFR.Conclusion: This study has revealed the pharmacological and molecular mechanisms through which SSG acts on PCPL. It also provides powerful evidence to support the exploration of the pharmacological mechanisms of action and clinical applications of traditional Chinese medicine.

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Beyond its antioxidant properties: Quercetin targets multiple signalling pathways in hepatocellular carcinoma in rats

Cited by 48 publications

References 98 publications

Quercetin Induces Apoptosis via Downregulation of Vascular Endothelial Growth Factor/Akt Signaling Pathway in Acute Myeloid Leukemia Cells

Quercetin Induces Apoptosis via Downregulation of Vascular Endothelial Growth Factor/Akt Signaling Pathway in Acute Myeloid Leukemia Cells

Sex-Dependent Effects on Liver Inflammation and Gut Microbial Dysbiosis After Continuous Developmental Exposure to Trichloroethylene in Autoimmune-Prone Mice

A Network Pharmacology Approach to Determine the Mechanisms of Action of Shuangshen Granules in Suppressing Pancreatic Cancer Precursor Lesions

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