Alpha mangostin Inhibits Hepatic Stellate Cells Activation Through TGF-β/Smad and Akt Signaling Pathways: An in vitro Study in LX2

Rahmaniah, Rahmaniah; Yuyuntia, Yuyuntia; Soetikno, Vivian; Arozal, Wawaimuli; Antarianto, Radiana Dhewayani; Louisa, Melva

doi:10.1055/s-0043-119074

Cited by 19 publications

(23 citation statements)

References 24 publications

(41 reference statements)

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“…The trypan blue exclusion test was performed for the specification of the death/survival of isolated hepatocytes through the destruction of the plasma membrane [18]. In this test, cumene hydroperoxide (a potent oxidizing agent EC50 = 120 µM [19]) was used as a negative control and Gallic acid (a potent antioxidant [20]) was used as a positive control.…”

Section: Evaluation the Cytotoxicitymentioning

confidence: 99%

Contrasting Role of Dose Increase in Modulating Sofosbuvir-Induced Hepatocyte Toxicity

2020

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Sofosbuvir, the oral direct-acting antiviral, is a medication, which used as the effective treatment for hepatitis C infection. Although sofosbuvir thought to have few adverse-effects, there have been some experiences of serious drug-induced hepatotoxicity. In this research, the molecular/cellular pathways that lead to sofosbuvir-induced hepatotoxicity were evaluated on isolated rat hepatocytes. Rat hepatocytes were isolated using collagenase reperfusion technique. In evaluating the different pathways of sofosbuvir-induced hepatotoxicity, ROS formation, mitochondrial membrane potential collapse, lysosomal membrane damage, glutathione depletion, and the percentage of apoptosis versus necrosis were determined. Our data demonstrated that the cytotoxic effect of sofosbuvir in lower concentrations (25, 50 and 100 µM) is mediated by above stream pathways. On the other hand, sofosbuvir acts in opposite directions at higher concentrations (400 µM) and acts as an antioxidant and hepatoprotective. We concluded that sofosbuvir while looking toxic and pro-oxidant in lower concentrations, acts as protective and antioxidant in higher concentrations.

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Section: Evaluation the Cytotoxicitymentioning

confidence: 99%

Contrasting Role of Dose Increase in Modulating Sofosbuvir-Induced Hepatocyte Toxicity

2020

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“…Specifically, PDAC was chosen as the representative IET model. α-mangostin (α-M), a natural xanthone isolated from the pericarps of mangosteen was selected since it had been reported to reduce liver fibrogenesis without obvious hepatotoxicity 22 . Therefore, we hypothesized it might be also effective in PDAC.…”

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confidence: 99%

Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors

et al. 2020

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The failure of immunotherapies in immune-excluded tumor (IET) is largely ascribed to the void of intratumoral cytotoxic T cells (CTLs). The major obstacles are the excessive stroma, defective vasculatures and the deficiency of signals recruiting CTLs. Here we report a dualmechanism based CTLs infiltration enhancer, Nano-sapper, which can simultaneously reduce the physical obstacles in tumor microenvironment and recruiting CTLs to potentiate immunotherapy in IET. Nano-sapper consists a core that co-loaded with antifibrotic phosphatesmodified α-mangostin and plasmid encoding immune-enhanced cytokine LIGHT. Through reversing the abnormal activated fibroblasts, decreasing collagen deposition, normalizing the intratumoral vasculatures, and in situ stimulating the lymphocyte-recruiting chemoattractants expression, Nano-sapper paves the road for the CTLs infiltration, induces the intratumoral tertiary lymphoid structures, thus reshapes tumor microenvironment and potentiates checkpoint inhibitor against IET. This study demonstrates that the combination of antifibrotic agent and immune-enhanced cytokine might represent a modality in promoting immunotherapy against IET.

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“…This increase in proliferation may due to TGF-β/SMADindependent signaling, as the PI3K/Akt pathway can enhance Akt phosphorylation and increase HSC proliferation. A study by Zang et al showed that TGF-β treatment increased the expression level of the proliferation marker Ki-67 in rabbit cornea cells, and Kang et al found that TGF-β1 treatment at 2 ng/mL at 24 and 48 h enhanced the HSC proliferation, whereas α-MG at 10 μM suppressed this proliferation back to normal, which suggested the inhibitory activity of this substance against HSC proliferation [3,6].…”

Section: Discussionmentioning

confidence: 99%

“…HSCs are located in the perisinusoidal space and contain lipid droplets rich in Vitamin A. In the normal liver, stellate cells remain quiescent and play a role in maintaining the basal balance of the matrix membrane [2,3]. In response to liver injury, these cells receive signals from a wide variety of growth factors, cytokines, lipid mediators, and adipokines to promote survival at the sites of liver injury containing damaged hepatocytes and immune cells.…”

Section: Introductionmentioning

confidence: 99%

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The EFFECT OF ALPHA-MANGOSTIN ON TRANSFORMING GROWTH FACTOR BETA 1 (TGF-β1) AND MATRIX METALLOPROTEINASE-3 EXPRESSION IN TGF-β-INDUCED HEPATIC STELLATE CELLS

et al. 2019

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Objective: Alpha-mangostin (α-MG) has been shown to possess antifibrotic effects. However, the specific mechanism of action of this compoundremains poorly understood. Therefore, the aim of this study was to investigate the effect of α-MG on the expression levels of transforming growthfactor (TGF)-β1 and matrix metalloproteinase-3 (MMP3) in hepatic stellate cells (HSCs) induced by TGF-β.Methods: Immortalized HSCs and LX-2 cells were incubated with TGF-β with or without α-MG (5 and 10 μM). The viability of LX-2 cells was assessedusing the Trypan Blue Exclusion Method. The effect of α-MG on cell morphology and the mRNA expression levels of TGF-β1, TGF-β receptor, and MMP3was then evaluated.Results: TGF-β enhanced the proliferation of HSCs and caused significant increases in the expression levels of TGF-β1, TGF-β receptor, and MMP3.α-MG treatment reduced the proliferation of HSCs and decreased the expression levels of TGF-β1, TGF-β1 receptor, and MMP3.Conclusion: α-MG is a potential antifibrotic agent due to its antiproliferative and antifibrogenic effects, mainly by suppressing the expression of TGF-βand MMP3 on the surfaces of activated HSCs.

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Alpha mangostin Inhibits Hepatic Stellate Cells Activation Through TGF-β/Smad and Akt Signaling Pathways: An in vitro Study in LX2

Abstract: Alpha mangostin inhibits hepatic stellate cells proliferation and activation through TGF-β/Smad and Akt signaling pathways in dose dependent manner.

Cited by 19 publications

References 24 publications

Contrasting Role of Dose Increase in Modulating Sofosbuvir-Induced Hepatocyte Toxicity

Contrasting Role of Dose Increase in Modulating Sofosbuvir-Induced Hepatocyte Toxicity

Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors

The EFFECT OF ALPHA-MANGOSTIN ON TRANSFORMING GROWTH FACTOR BETA 1 (TGF-β1) AND MATRIX METALLOPROTEINASE-3 EXPRESSION IN TGF-β-INDUCED HEPATIC STELLATE CELLS

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