Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

Zhang, Xuemin; Hu, Wen‐Yu; Wu, Fang; Xue, Yuan; Ji, Hu

doi:10.1139/cjpp-2014-0464

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…According to the current study, with repeated gentamicin injection, the SIRT1, Nrf2, and HO-1 levels and mRNA expressions were downregulated, as previously described in gentamicin-induced renal injury animal models, resulting in enhanced oxidative, pro-inflammatory, and pro-apoptotic processes in the renal tissue [11,33]. Meanwhile, shikonin therapy elevated SIRT1, Nrf2, and HO-1 protein and mRNA expression in gentamicin-injected groups, which is consistent with previous findings [34][35][36][37]. Moreover, the impact of shikonin on Nrf2/HO-1 signaling activation may also be connected to decreased megalin/cubilin complex expression [38].…”

Section: Discussionsupporting

confidence: 91%

“…Similarly, Tong et al demonstrated that shikonin has renoprotective effects against the high glucose-induced renal proximal tubular cell, which are mediated by reducing oxidative stress via activation of the Akt signaling pathway, with MDA reduction and increased SOD and catalase levels [16]. Additionally, shikonin's antioxidant action is thought to be related to the activation of SIRT1/Nrf2/HO-1, as previously documented [34][35][36][37].…”

Section: Discussionmentioning

confidence: 77%

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Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

et al. 2023

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Gentamicin causes kidney injury due to its accumulation in proximal tubule epithelial cells via the megalin/cubilin/CLC-5 complex. Recently, shikonin has been shown to have potential anti-inflammatory, antioxidant, antimicrobial, and chloride channel-inhibiting effects. The current study investigated the alleviation of gentamicin-induced renal injury by shikonin while preserving its bactericidal effect. Nine-week-old Wistar rats were administered 6.25, 12.5, and 25 mg/kg/day shikonin orally, one hour after the i.p. injection of 100 mg/kg/day gentamicin for seven days. Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture. Furthermore, shikonin restored renal endocytic function, as indicated by suppressing the elevated renal megalin, cubilin, and CLC-5 and enhancing the reduced NHE3 levels and mRNA expressions induced by gentamicin. These potentials could be attributed to the modulation of the renal SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt cascades, which enhanced the renal antioxidant system and suppressed renal inflammation and apoptosis, as indicated by enhancements of SIRT1, Nrf2, HO-1, GSH, SOD, TAC, Iκb-α, Bcl-2, PI3K, and Akt levels and mRNA expressions, with reduction of TLR-4, NF-κB, MAPK, IL-1β, TNF-α, MDA, iNOS, NO, cytochrome c, caspase-3, Bax levels, and Bax/Bcl-2 ratio. Therefore, shikonin is a promising therapeutic agent for alleviating gentamicin-induced renal injury.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 77%

Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

et al. 2023

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“…We found that Shikonin restored the increase in lactate production in tumor tissue of xenograft mice experiencing HMGCR inhibition and reduced the growth of RCC tumors. Moreover, Shikonin is known to exert antitumor effects by itself as it can act as an inhibitor of the TMEM16A chloride channel; it can also prevent activation of the NF-κB pathway and inhibit tumor necrosis factor-α (TNF-α) [63][64][65]. Based on these facts, we propose that Shikonin could be considered as a potential clinical medication for the treatment or prevention of tumor deterioration caused by HMGCR or glycolysis abnormalities in the clinic.…”

Section: Plos Biologymentioning

confidence: 99%

HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma

Huang

Zhao

et al. 2021

PLoS Biol

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Renal cell carcinoma (RCC) is responsible for most cases of the kidney cancer. Previous research showed that low serum levels of cholesterol level positively correlate with poorer RCC-specific survival outcomes. However, the underlying mechanisms and functional significance of the role of cholesterol in the development of RCC remain obscure. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) plays a pivotal role in RCC development as it is the key rate-limiting enzyme of the cholesterol biosynthetic pathway. In this study, we demonstrated that the inhibition of HMGCR could accelerate the development of RCC tumors by lactate accumulation and angiogenesis in animal models. We identified that the inhibition of HMGCR led to an increase in glycolysis via the regulated HSP90 expression levels, thus maintaining the levels of a glycolysis rate-limiting enzyme, pyruvate kinase M2 (PKM2). Based on these findings, we reversed the HMGCR inhibition-induced tumor growth acceleration in RCC xenograft mice by suppressing glycolysis. Furthermore, the coadministration of Shikonin, a potent PKM2 inhibitor, reverted the tumor development induced by the HMGCR signaling pathway.

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“…The apoptosis of these cells is partly mediated by the inactivation of nuclear factor (NF)-κB, which occurrs through the modulation of the EGF receptor signaling pathway and the activation of caspases. The study by Zhang et al (40) demonstrated that shikonin regulates the activation of the NF-κB and phosphatidyl inositol 3-kinase signaling pathways. Shikonin also modulates the expression of cyclin D1, cyclin E, BCL-2 and BCL2 associated X protein, activates caspase-3 and caspase-9, induces cell cycle arrest, and promotes the apoptosis of VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Shikonin‑mediated inhibition of nestin affects hypoxia‑induced proliferation of pulmonary artery smooth muscle cells

Lin

et al. 2018

Mol Med Report

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The imbalance between the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) is of importance in pulmonary vascular remodeling. Shikonin, a naphthoquinone compound extracted from the Chinese medicinal herb Lithospermum erythrorhizon, inhibits the proliferation of rat smooth muscle cells (SMCs). The present study was designed to investigate the effects of shikonin on the proliferation of rat PASMCs and the possible mechanisms involved. Rat PASMCs were cultured under the following five treatment conditions: Normal control; hypoxia for 24 h; hypoxia + 1 µM shikonin for 24 h; hypoxia + 2 µM shikonin for 24 h; and hypoxia + 4 µM shikonin for 24 h. The viability of PASMCs was measured using the Cell Counting Kit‑8 assay, the mRNA expression of nestin (NES) in each group was measured by reverse transcription‑polymerase chain reaction and the protein expression of NES was measured by western blotting. The proliferation of hypoxic PASMCs transfected with NES‑specific small interfering (si)RNA decreased compared with the non‑transfected group. These results indicated that hypoxia induced the proliferation of PASMCs through the enhancement of NES expression. The treatment of hypoxic PASMCs with shikonin resulted in a significant downregulation of NES expression and the inhibition of PASMC proliferation.

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Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

Cited by 8 publications

References 36 publications

Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma

Shikonin‑mediated inhibition of nestin affects hypoxia‑induced proliferation of pulmonary artery smooth muscle cells

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