Differential Effects of Silibinin A on Mitochondrial Function in Neuronal PC12 and HepG2 Liver Cells

Esselun, Carsten; Bruns, Bastian; Hagl, Stephanie; Grewal, Rekha; Eckert, G.

doi:10.1155/2019/1652609

Cited by 18 publications

(21 citation statements)

References 46 publications

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“…First, silibinin reduces intracellular levels of oxidative stress and oxidative damage to intracellular targets (Figure 3A-D) and mitochondria (Figure 4B), leading to decreased apoptotic activity (Figure 4A). This observation is consistent with silibinin's ability to reduce in vivo markers of direct oxidative damage in human hepatocytes, such as DNA fragmentation levels, lipid peroxidation, and mitochondrial dysfunction, also reported by other authors [31,32,39,67]. Second, silibinin induces Nrf2-ARE-related protein expression (Figure 5B).…”

Section: Discussionsupporting

confidence: 91%

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

Goh

Tee

2020

IJMS

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Tuberculosis remains a significant infectious lung disease that affects millions of patients worldwide. Despite numerous existing drug regimens for tuberculosis, drug-induced liver injury is a major challenge that limits the effectiveness of these therapeutics. Two drugs that form the backbone of the commonly administered quadruple antitubercular regimen, that is, pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. Yet, we lack safe and effective alternatives to the antitubercular regimen. Consequently, current research largely focuses on exploiting the hepatoprotective effect of nutraceutical compounds as complementary therapy. Silibinin, a herbal product widely believed to protect against various liver diseases, potentially provides a useful solution given its hepatoprotective mechanisms. In our study, we identified silibinin’s role in mitigating PZA- and INH-induced hepatotoxicity and elucidated a deeper mechanistic understanding of silibinin’s hepatoprotective ability. Silibinin preserved the viability of human foetal hepatocyte line LO2 when co-administered with 80 mM INH and decreased apoptosis induced by a combination of 40 mM INH and 10 mM PZA by reducing oxidative damage to mitochondria, proteins, and lipids. Taken together, this proof-of-concept forms the rational basis for the further investigation of silibinin’s hepatoprotective effect in subsequent preclinical studies and clinical trials.

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Section: Discussionsupporting

confidence: 91%

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

Goh

Tee

2020

IJMS

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“…Silybin A lowered nitrosative stress in both a PC12 cell line (from the pheochromocytoma of the rat adrenal medulla) and human hepatoblastoma HepG2 cells. Low concentrations of silybin A (in the range of 25-100 µM) improved basal mitochondrial membrane potential and ATP levels in HepG2 cells, but less so in PC12 cells [135]. Silybin A may be helpful in neurological disorders, although it did not generally improve mitochondrial function.…”

Section: Other Biological Activitiesmentioning

confidence: 89%

Chirality Matters: Biological Activity of Optically Pure Silybin and Its Congeners

Křen

2021

IJMS

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This review focuses on the specific biological effects of optically pure silymarin flavo-nolignans, mainly silybins A and B, isosilybins A and B, silychristins A and B, and their 2,3-dehydro derivatives. The chirality of these flavonolignans is also discussed in terms of their analysis, preparative separation and chemical reactions. We demonstrated the specific activities of the respective diastereomers of flavonolignans and also the enantiomers of their 2,3-dehydro derivatives in the 3D anisotropic systems typically represented by biological systems. In vivo, silymarin flavonolignans do not act as redox antioxidants, but they play a role as specific ligands of biological targets, according to the “lock-and-key” concept. Estrogenic, antidiabetic, anticancer, antiviral, and antiparasitic effects have been demonstrated in optically pure flavonolignans. Potential application of pure flavonolignans has also been shown in cardiovascular and neurological diseases. Inhibition of drug-metabolizing enzymes and modulation of multidrug resistance activity by these compounds are discussed in detail. The future of “silymarin applications” lies in the use of optically pure components that can be applied directly or used as valuable lead structures, and in the exploration of their true molecular effects.

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“…Oxygraph-2k respirometer (Oroboros, Innsbruck, Austria) was used to investigate the respiration of cells as described earlier [ 70 ]. For data evaluation, the software DatLab v. 4.3.2.7 was used.…”

Section: Methodsmentioning

confidence: 99%

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

Esselun

Theyssen

Eckert

2021

IJMS

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(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA’s effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA’s effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis.

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Differential Effects of Silibinin A on Mitochondrial Function in Neuronal PC12 and HepG2 Liver Cells

Cited by 18 publications

References 46 publications

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

Chirality Matters: Biological Activity of Optically Pure Silybin and Its Congeners

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

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