PMID: 

Acta Pharm Sin B. 2019 Jul ;9(4):745-757. Epub 2019 Feb 22. PMID: 31384535

Abstract Title: 

Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway.

Abstract: 

Non-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models bothand. Thestudy was performed using male C57BL/6 mice fed with methionine- choline-deficient diet and simultaneously treated with silibinin for 6 weeks. Thestudy was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-downfor 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated themRNA expression ofand, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A. These effects were confirmed by theexperiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress.

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PMID: 

Cancer Manag Res. 2019 ;11:7111-7122. Epub 2019 Jul 26. PMID: 31440098

Abstract Title: 

Silibinin restores the sensitivity of cisplatin and taxol in A2780-resistant cell and reduces drug-induced hepatotoxicity.

Abstract: 

Purpose: Ovarian cancer is the most lethal cancer among all gynaecological malignancies. The combination theraputics of cisplatin and taxol is widely used in clinicals for ovarian cancer treatment. However, long-term use of cisplatin and taxol induces strong tolerance and hepatotoxicity. Since silibinin is a commonly used anti-hepatotoxic drug in Europe and Asia, the aim of this study was to determine whether silibinin could restore the sensitivity of combination use of cisplatin and taxol in drug-resistant human ovarian cancer cells and reduce drug-induced hepatotoxicity.Patients and methods: Normal hepatocyte LO2 cells and A2780/DDP cells were treated with silibinin, cisplatin, taxol, cisplatin and taxol plus silibinin for 48 h. Cell viability was determined by MTT and long-term proliferation assay, while apoptosis and cell cycle progression were assessed by flow cytometric analysis. DNA damage was evluated by immunofluorescence assays. The metastatic activity of A2780/DDP was determined by cell adhesion assay.Results: The addition of silibinin on cisplatin and/or toxal could sensitize the antitumor activity of cisplatin and toxal on A2780/DDP cells, supress cell-matrix adhesion of A2780/DDP, inhibit the cell proliferation, result in A2780/DDP cells apoptosis. In addition, silibinin could effectively reduce cisplatin and/or toxal-induced hepatotoxicity by protecting DNA from damage and restoring the potential of cell proliferation in cisplatin and/or toxal-treated LO2 cells.Conclusion: Our results suggest that silibinin could restore the sensitivity of cisplatin and taxol in drug-resistant human ovarian cancer cells and reduce durg-induced hepatotoxicity in cell level.

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PMID: 

Mol Cell Biochem. 2019 Oct 14. Epub 2019 Oct 14. PMID: 31612353

Abstract Title: 

Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion.

Abstract: 

Human triple negative breast cancer cells, MDA-MB-231, show typical epithelial to mesenchymal transition associated with cancer progression. Mitochondria play a major role in cancer progression, including metastasis. Changes in mitochondrial architecture affect cellular migration, autophagy and apoptosis. Silibinin is reported to have anti-breast cancer effect. We here report that silibinin at lower concentrations (30-90 μM) inhibits epithelial to mesenchymal transition (EMT) of MDA-MB-231, by increasing the expression of epithelial marker, E-cadherin, and decreasing the expression of mesenchymal markers, N-cadherin and vimentin. Besides, silibinin inhibition of cell migration is associated with reduction in theprotein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) and paxillin. In addition, silibinin treatment increases mitochondrial fusion through down-regulating the expression of mitochondrial fission-associated protein dynamin-related protein 1 (DRP1) and up-regulating the expression of mitochondrial fusion-associated proteins, optic atrophy 1, mitofusin 1 and mitofusin 2. Silibinin perturbed mitochondrial biogenesis via down-regulating the levels of mitochondrial biogenesis regulators including mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor gamma coactivator (PGC1) and nuclear respiratory factor (NRF2). Moreover, DRP1 knockdown or silibinin inhibited cell migration, and MFN1&2 knockdown restored it. Mitochondrial fusion contributes to silibinin's negative effect on cell migration. Silibinin decreased reactive oxygen species (ROS) generation, leading to inhibition of the NLRP3 inflammasome activation. In addition, knockdown of mitofusin 1&2 (MFN 1&2) relieved silibinin-induced inhibition of NLRP3 inflammasome activation. Repression of ROS contributes to the inhibition of the expression of NLRP3, caspase-1 and IL-β proteins as well as of cell migration. Taken together, our study provides evidence that silibinin impairs mitochondrial dynamics and biogenesis, resulting in reduced migration and invasion of the MDA-MB-231 breast cancer cells.

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PMID: 

Artif Cells Nanomed Biotechnol. 2019 Dec ;47(1):4059-4065. PMID: 31631701

Abstract Title: 

Silibinin declines blue light-induced apoptosis and inflammation through MEK/ERK/CREB of retinal ganglion cells.

Abstract: 

: This study aimed to assess the protective effects of silibinin on blue light-emitting diode (LED)-induced retinal ganglion cells (RGCs) damage.: Silibinin was applied in RGCs damagemodel to test its protective effects. Cell viability was assessed with the MTT method and cell apoptosis was evaluated by TUNEL and Annexin V/propidium iodide staining. The expressions of apoptosis related proteins and influenced signalling pathways were measured using western blotting and immunohistochemistry. Inflammatory factors induced by RGC damage were detected using ELISA method.: It was found that silibinin in 50 and 100 μM treatment showed a significant protective effect in RGCs under blue light damage. Apoptosis assay showed that silibinin treatment could significantly improve the apoptotic status of RGCs. When the potentially affected signal pathway was considered, blue light would down-regulate the expression of MEK1/ERK/CREB. The levels of inflammatory factors (TNF-α, IL-1β, IL-6 and IL-10) were significantly regulated by silibinin treatment.: Silibinin pretreatment would demonstrate protective effect against blue light induced acute RGCs damage. Silibinin treatment has a direct suppression of apoptosis and inflammation through the activation of MEK/ERK/CREB pathway.

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PMID: 

Physiol Behav. 2020 Jan 1 ;213:112689. Epub 2019 Oct 25. PMID: 31669775

Abstract Title: 

Silibinin ameliorates STZ-induced impairment of memory and learning by up- regulating insulin signaling pathway and attenuating apoptosis.

Abstract: 

Alzheimer's disease (AD) is a neurodegenerative disease, mainly characterized by cognitive dysfunction and memory impairment. Due to its pathological similarities to type 2 diabetes mellitus (T2DM), such asβ-amyloid deposition, oxidative stress, inflammation, disordered glucose metabolism, impaired signaling pathways of insulin and insulin-like growth factor-1 (IGF-1), we speculate that AD is another form of brain diabetes. Clarifying the relationship between T2DM and AD is important for us to betterunderstand the exact pathological mechanisms of AD. Silibinin, a polyphenolic flavonoid extracted from the seeds of Silybum marianum, exerts hepatoprotective, anti- diabetic and neuroprotective effects. Streptozotocin (STZ), which is used to disrupt the insulin signal transduction pathway, could well mimic the sporadic AD models by intracerebroventricular (ICV) injection. Therefore, we selected ICV injection of STZ (ICV-STZ) to investigate the neuroprotective effects of silibinin in rats and to make a foundation for further exploring the relationship between AD and T2DM. ICV-STZ obviously caused memory damage, sharply reduced the number of nissl bodies and destroyed morphological structure of hippocampal neuronal cells, while silibinin attenuated the damages. Moreover, silibinin significantly decreased STZ-induced tau hyperphosphorylation (ser404) in hippocampus and cerebral cortex, markedly inhibited apoptosis of neurons induced by STZ, and up-regulated insulin signal transduction pathway. Silibinin exerts neuroprotective effect in STZ-treated rats, indicating the potential of silibinin for the treatment of AD patients with T2DM in future.

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PMID: 

Drug Des Devel Ther. 2019 ;13:3117-3126. Epub 2019 Aug 29. PMID: 31695328

Abstract Title: 

Silibinin attenuates high-fat diet-induced renal fibrosis of diabetic nephropathy.

Abstract: 

Aim: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Silibinin is a flavonoid compound which has medicinal value. Previous studies revealed that silibinin exhibited an anti-fibrotic effect. However, whether silibinin could attenuate high-fat diet (HFD)-induced renal fibrosis remains unclear. Therefore, this study aimed to explore the molecular mechanism by which silibinin regulated renal fibrosis induced by HFD.Methods: In the present study, human renal glomerular endothelial cells (HRGECs) were treated with various concentrations of silibinin. Then, cell viability and apoptosis were measured by MTT assay and flow cytometry, respectively. In addition, HRGECs were exposed to 100 nM TGF-β1 for mimicking in vitro renal fibrosis. The expressions of collagen I, fibronectin, and α-SMA were detected by reverse transcription-quantitative polymerase chain reaction and Western blot. Protein levels of p-IκB and p-p65 were examined by Western blot; meanwhile, level of NF-κB was measuredby immunofluorescence staining. Furthermore, HFD-induced mouse model of renal fibrosis was established. The mouse body weight, fasting glucose, kidney weight/body weight, microalbuminuria, kidney histopathology, and fibrotic area were measured to assess the severity of renal fibrosis.Results: Low concentration of silibinin (≤50 μM) had no cytotoxicity, while high concentration of silibinin (≥75 μM) exhibited significant cytotoxicity. Additionally, TGF-β1 increased the expressions of collagen I, fibronectin, α-SMA, p-IκB, and p-p65 and decreased the level NF-κB, while these effects were notably reversed by 50μM silibinin. Moreover, both 50 and 100 mg/kg silibinin greatly decreased HFD-induced the upregulation of kidney weight/body weight, microalbuminuria, and fibrotic area. 100 mg/kg silibinin markedly reduced collagen I, fibronectin, and p-p65 expressions in mice renal tissues.Conclusion: Silibinin was able to attenuate renal fibrosis in vitro and in vivo via inhibition of NF-κB. These data suggested that silibinin may serve as a potential agent to alleviate the renal fibrosis of DN.

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PMID: 

Iran J Basic Med Sci. 2019 Sep ;22(9):968-976. PMID: 31807239

Abstract Title: 

The protective effects of silymarin on ischemia-reperfusion injuries: A mechanistic review.

Abstract: 

Ischemia-reperfusion injuries (IRI) occur in different clinical conditions such as stroke, trauma, organ transplantation, and so on. Ischemia damages mainly arise from oxygen depletion in tissues. The lack of oxygen as the last acceptor of electron in the respiratory chain causes a decrease in ATP production and eventually leads to disruption of membrane transport, acidosis, cellular edema and membrane distortion of organelles, and cells. Reperfusion can intensify ischemic injuries by the infiltration of inflammatory cells and also oxygen and calcium overloading. Since the tissue antioxidant contents decreased due to increased generation of reactive oxygen species (ROS) during IRI, the application of antioxidants is considered an appropriate strategy to ameliorate IRI. Silymarin constitutes about 70-80% of silybum marianum dry extract and is known as a strong free radical scavenger with anti-inflammatory properties. In several studies, silibinin as a major component of Silymarin could provide protective effects in various tissue IRI by different mechanisms such as scavenging free radicals, decreasing inflammatory cytokines, inhibiting cellular death, and increasing the expression of antioxidant enzymes. To clarify functional mechanisms, the present article evaluates studies about silymarin effects in different tissues IRI.

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PMID: 

Anticancer Agents Med Chem. 2019 Dec 20. Epub 2019 Dec 20. PMID: 31858905

Abstract Title: 

The Anticancer Properties of Silibinin: its Molecular Mechanism and Therapeutic Effect in Breast Cancer.

Abstract: 

BACKGROUND: Silibinin (SB), the main component of silymarin (SM) is a natural substance obtained from the seeds of the milk thistle. SM contains up 70% of SB as two isoforms: A and B. It has antioxidant and anti-inflammatory effect on hepatocytes, and is known to inhibit cell proliferation, induce apoptosis and curb angiogenesis. SB has demonstrated activity against many cancers, such as skin, liver, lung, bladder and breast carcinomas.RESULTS: This review presents current knowledge of the use of SM in breast cancer, this being one of the most common types of cancer in women. It describes selected molecular mechanisms of the action of SM; for example, although SB influences both estrogen receptors (ER),α and β, it has opposite effects on the two. Its action on ERα influences the PI3K/AKT/mTOR and RAS/ERK signaling pathways, while by up-regulating ERβ, it increases the numbers of apoptotic cells. In addition, ERα is involved in SB-induced autophagy, while ERβ is not. Interestingly, SB also inhibits metastasis by suppressing TGF-β2 expression, thus suppressing epithelial to mesenchymal transition (EMT). It also influences migration and invasive potential via the Jak2/STAT3 pathway.CONCLUSION: SB may be a promising enhancement of BC treatment: when combined with chemotherapeutic drugs such as carboplatin, cisplatin and doxorubicin, the combination exerts a synergistic effect against cancer cells. This may be of value when treating aggressive types of mammary carcinoma.

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PMID: 

Pharmacol Res. 2019 Nov 6 ;151:104519. Epub 2019 Nov 6. PMID: 31706011

Abstract Title: 

Combinational applicaton of silybin and tangeretin attenuates the progression of non-alcoholic steatohepatitis (NASH) in mice via modulating lipid metabolism.

Abstract: 

Silybin (SB) is widely used to treat chronic liver diseases, especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR, PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH. Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH.

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PMID: 

Am J Chin Med. 2019 ;47(8):1833-1851. Epub 2019 Dec 3. PMID: 31795743

Abstract Title: 

Aged Citrus Peel (Chenpi) Prevents Acetaminophen-Induced Hepatotoxicity by Epigenetically Regulating Nrf2 Pathway.

Abstract: 

Excessive consumption of analgesic drug acetaminophen (APAP) can cause severe oxidative stress-mediated liver injury. Here, we investigated the protective effect and mechanism of aged citrus peel (Chenpi, CP), a Chinese herb usually used in foods in Asia, against APAP-induced hepatotoxicity. CP water (CP-WE), ethanolic (CP-EE), and water extraction residue ethanolic (CP-WREE) extracts were prepared. We found that CP-WREE contained higher content of bioactive flavonoids, including narirutin, nobiletin, and tangeretin, and more effectively enhanced the Nrf2 pathway in ARE-luciferase reporter gene transfected human HepG2-C8 cells. In mouse AML-12 hepatocytes, CP-WREE minimized APAP-induced damage and lipid peroxidation and increased mRNA and protein expressions of Nrf2 and its downstream defense enzymes (HO-1, NQO1, and UGT1A). CP-WREE also downregulated HDACs and DNMTs, upregulated KDMs, and increased the unmethylated Nrf2 promoter level. Additionally, CP-WREE blockedDNA methyltransferase activity. Taken together, CP-WREE might attenuate oxidative stress-induced hepatotoxicity through epigenetically regulating Nrf2-mediated cellular defense system.

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