Indole-3-carbinol inhibits hepatic stellate cells proliferation by blocking NADPH oxidase/reactive oxygen species/p38 MAPK pathway

Ping, Jie; Li, Jing-ting; Liao, Zhang-Xiu; Shang, Liang; Wang, Hui

doi:10.1016/j.ejphar.2010.10.057

Cited by 29 publications

(24 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is reported that the extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinase (MAPK) signaling pathway is involved in the proliferation of HSCs and the ECM synthesis in activated HSCs [26, 27]. Our previous study has indicated that I3C could inhibit the proliferation of HSC by blocking the NADPH oxidase/reactive oxygen species/p38 MAPK signal pathway, which contributes to protective effect of I3C to liver fibrosis in rats [19]. Moreover, in our previous research in vivo , we also proved that I3C could reverse rat liver fibrosis in different models [17, 18], but the molecular mechanism remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it reversed liver fibrosis in rats induced by compound (CCl 4 , ethanol and lipid) [17] or immunologic (porcine serum) factors [18] in vivo . Furthermore, we proved that I3C remarkably inhibited the proliferation of HSC in vitro [19]. Given the tight relationship with HSC apoptosis and reversion of liver fibrosis, we then aimed to elucidate the effect of I3C on the apoptosis of HSC and the underlying mechanism.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Indole-3-Carbinol Induces Apoptosis of Hepatic Stellate Cells through K63 De-Ubiquitination of RIP1 in Rats

Zhu

et al. 2017

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background/Aims: The apoptosis of activated hepatic stellate cells (HSCs) is the central event in the reversal of liver fibrosis. K63 de-ubiquitinated receptor-interacting protein (RIP)1 promotes apoptosis in tumor necrosis factor (TNF)-α signaling pathway. In the previous study, we have proved that indole-3-carbinol (I3C) could reverse different models of liver fibrosis in rats, but the mechanism is still unclear. Thus, the present research aimed to demonstrate the induction of I3C on apoptosis of HSCs and the underlying molecular mechanism. Methods: HSC-T6, an immortalized rat liver stellate cell line, was treated for 24 hours with 25, 50 and 100 µM of I3C. The apoptosis of HSC-T6 was analyzed by flow cytometric analysis, acridine orange staining and RT-PCR, respectively. K63 de-ubiquitination of RIP1 and the expression of ubiquitin ligases and deubiquitinases were analyzed by Co-IP assay and western blot. Knockdown of deubiquitinases was undertaken by small interfering RNA (siRNA). Results: The results of flow cytometric analysis indicated that the apoptotic rate of HSC-T6 was induced by I3C in a dose-dependent manner. Observation by acridine orange staining exhibited nuclear condensation and apoptotic bodies in I3C treated cells. Consistently, the expression ratio of Bax/bcl-2 was markedly increased by I3C. These results indicated that I3C could significantly induce apoptosis of HSC-T6 cells. Furthermore, Co-IP assay revealed K63 de-ubiquitination of RIP1 by I3C, associated with the induction of caspase 8. Although I3C had no effect on the expression of ubiquitin ligases cellular inhibitor of apoptosis 1/2 (cIAP1/2), the protein level of deubiquitinase cylindromatosis (CYLD) was significantly induced by I3C. Moreover, CYLD silencing reversed the pro-apoptosis induction effect of I3C and reduced the expression ratio of Bax/bcl-2 in HSC-T6 cells. Conclusion: These results demonstrated that I3C could induce apoptosis of HSC through RIP1 K63 de-ubiquitination by upregulating deubiquitinase CYLD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Indole-3-Carbinol Induces Apoptosis of Hepatic Stellate Cells through K63 De-Ubiquitination of RIP1 in Rats

Zhu

et al. 2017

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

show abstract

“…TNF␣ also can activate the phosphorylation of p38 and then enhance the antiapoptotic effect of NF-B (Saha et al, 2007). Our experiment showed that I3C can reduce the phosphorylation level of p38 protein (Ping et al, 2011), suggesting that the p38/NF-B pathway participated in the proapoptotic effect of I3C on HSC. Thus, we reversed the effects of I3C by expressing the constitutive form of p38.…”

Section: Discussionmentioning

confidence: 66%

“…We also found that I3C can remarkably protect liver slices from acetaldehyde-induced HSC activation, which shows its antioxidative ability and promotion of ECM degradation (Guo et al, 2010). Recent studies showed that, even at a concentration lower than that of inhibiting HSC proliferation (Ping et al, 2011), I3C could significantly induce HSC apoptosis. In this study, we show that in vivo administration of I3C reduces the extent of fibrotic collagen and promotes the resolution of liver fibrosis in three models of rats.…”

Section: Introductionmentioning

confidence: 83%

See 1 more Smart Citation

RETRACTION: Indole-3-Carbinol Enhances the Resolution of Rat Liver Fibrosis and Stimulates Hepatic Stellate Cell Apoptosis by Blocking the Inhibitor of κB Kinase α/Inhibitor of κB-α/Nuclear Factor-κB Pathway

Ping

Gao²,

Qin³

et al. 2011

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Hepatic stellate cells (HSC) play a pivotal role in liver fibrosis, and the clearance of activated HSC by apoptosis is associated with the resolution of liver fibrosis. The development of strategies that promote this process in a selective way is therefore important. We evaluated the effects of indole-3-carbinol (I3C), a nutritional component derived from vegetables from the Brassica family, on liver fibrosis and HSC apoptosis. The in vivo therapeutic effects of I3C were monitored in three rat models of liver fibrosis induced by porcine serum, bile duct ligation, or multiple hepatotoxic factors, and its proapoptotic effect and molecular mechanism were studied in vitro in HSC-T6, a rat HSC line. The results showed that I3C treatment significantly reduced the number of activated HSC in the livers of rats with liver fibrosis. In histopathology, I3C reduced hepatocyte degeneration and necrosis, accelerated collagen degradation, and promoted the reversal of liver fibrosis. I3C prescribed to HSC-T6 resulted in morphologic alterations typical of apoptosis and DNA cleavage to a nucleosomal ladder. Moreover, I3C significantly increased the HSC-T6 apoptosis rate and the expression ratio of Bax to Bcl-2. High-throughput protein array analysis indicated that the tumor necrosis factor-␣/nuclear factor-B (NF-B) signal pathway participated in I3C-induced HSC-T6 apoptosis. Western blot and electrophoretic mobilityshift assay confirmed that I3C inhibited the phosphorylation of inhibitor of B kinase ␣ and inhibitor of B-␣ and NF-B DNA binding activity. In conclusion, I3C could promote the reverse process of liver fibrosis in vivo and induce apoptosis of activated HSC in vitro, which indicates the use of I3C as a potential therapeutic agent in liver fibrosis treatment.

show abstract

Natural HDAC‐1/8 inhibitor baicalein exerts therapeutic effect in CBF‐AML

et al. 2020

Clinical & Translational Med

View full text Add to dashboard Cite

Background Although targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor‐acute myeloid leukemia (CBF‐AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug‐resistant characteristic. Our purpose is to evaluate the anti‐leukemia effects of Baicalein on CBF‐AML and clarify its underlying mechanism. Methods Enzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT‐qPCR were employed to evaluate the distribution of drugs and the change of ATP‐binding cassette (ABC) transporter genes. CCK8, Annexin V/PI, and FACS staining certified the effects of Baicalein on cell growth, apoptosis, and differentiation. Duolink and IP assay assessed the interaction between HDAC‐1 and ubiquitin, HSP90 and AML1‐ETO, and Ac‐p53 and CBFβ‐MYH11. AML cell lines and primary AML cells‐bearing NOD/SCID mice models were used to evaluate the anti‐leukemic efficiency and potential mechanism of Baicalein in vivo. Results Baicalein showed HDAC‐1/8 inhibition to trigger growth suppression and differentiation induction of AML cell lines and primary AML cells. Although the inhibitory action on HDAC‐1 was mild, Baicalein could induce the degradation of HDAC‐1 via ubiquitin proteasome pathway, thereby upregulating the acetylation of Histone H3 without promoting ABC transporter genes expression. Meanwhile, Baicalein increased the acetylation of HSP90 and lessened its connection to AML1/ETO, consequently leading to degradation of AML1‐ETO in t(8;21)q(22;22) AML cells. In inv(16) AML cells, Baicalein possessed the capacity of apoptosis induction accompanied with p53‐mediated apoptosis genes expression. Moreover, CBFβ‐MYH11‐bound p53 acetylation was restored via HDAC‐8 inhibition induced by Baicalein contributing the diminishing of survival of CD34+ inv(16) AML cells. Conclusions These findings improved the understanding of the epigenetic regulation of Baicalein, and warrant therapeutic potential of Baicalein for CBF‐AML.

show abstract

Indole-3-carbinol inhibits hepatic stellate cells proliferation by blocking NADPH oxidase/reactive oxygen species/p38 MAPK pathway

Cited by 29 publications

References 22 publications

Indole-3-Carbinol Induces Apoptosis of Hepatic Stellate Cells through K63 De-Ubiquitination of RIP1 in Rats

Indole-3-Carbinol Induces Apoptosis of Hepatic Stellate Cells through K63 De-Ubiquitination of RIP1 in Rats

RETRACTION: Indole-3-Carbinol Enhances the Resolution of Rat Liver Fibrosis and Stimulates Hepatic Stellate Cell Apoptosis by Blocking the Inhibitor of κB Kinase α/Inhibitor of κB-α/Nuclear Factor-κB Pathway

Natural HDAC‐1/8 inhibitor baicalein exerts therapeutic effect in CBF‐AML

Contact Info

Product

Resources

About