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Marjan Gharagozloo - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulatory effects of Silymarin in patients with β-thalassemia major
International Immunopharmacology, 2013Co-Authors: Marjan Gharagozloo, Mehran Karimi, Zahra AmirghofranAbstract:Abstract Objective Silymarin, a flavonolignan complex isolated from milk thistle, is a cytoprotective, antioxidant, and hepatoprotective agent. The present study was designed to investigate the immunomodulatory effects of orally administered Silymarin in patients with β-thalassemia major. Methods The immunomodulatory effects of Silymarin were investigated in a 12-week clinical trial in two groups of patients. In combined therapy group (n = 25), patients continued desferrioxamine at the dose of 40 mg/kg/day and Legalon® tablets (420 mg daily) were added to desferrioxamine. In Silymarin group (n = 5), patients who were unable or unwilling to use desferrioxamine received only Silymarin. Immunological tests were assessed at the beginning and the end of the trial. Results No differences were detected between treatment groups regarding the percentage of lymphocyte subsets, concentration of serum immunoglobulins, complement levels, or T cell proliferation in vitro. Serum tumor necrosis factor (TNF-α) levels were significantly decreased in both groups, whereas the serum levels of neopterin significantly decreased in both groups after Silymarin therapy. The analysis of cell culture supernatants of activated T cells showed increased production of interferon gamma (IFNγ) and interleukin (IL)-4 after Silymarin treatment in both groups. Conclusion Silymarin stimulates cell-mediated immune response in β-thalassemia major, possibly through a direct action on cytokine-producing mononuclear cells. Because of its immunostimulatory, antioxidant, and iron-chelating activities, Silymarin could be a good candidate in the therapy of chronic iron overload in combination with routine iron chelators in clinical use like desferrioxamine.
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combined therapy of Silymarin and desferrioxamine in patients with β thalassemia major a randomized double blind clinical trial
Fundamental & Clinical Pharmacology, 2009Co-Authors: Marjan Gharagozloo, Mehran Karimi, Behjat Moayedi, Maryam Zakerinia, Mehrdad Hamidi, Mohammad Reza Maracy, Zahra AmirghofranAbstract:Silymarin, a flavonolignan complex isolated from Silybum marianum, has a strong antioxidant, hepatoprotective, and iron chelating activities. The present study was designed to investigate the therapeutic activity of orally administered Silymarin in patients with thalassemia major under conventional iron chelation therapy. A 3-month randomized, double-blind, clinical trial was conducted in 59 beta-thalassemia major patients in two well-matched groups. Patients were randomized to receive a Silymarin tablet (140 mg) three times a day plus conventional desferrioxamine therapy. The second group received the same therapy but a placebo tablet instead of Silymarin. Clinical laboratory tests were assessed at the beginning and the end of the trial, except for serum ferritin level that was assessed at the middle of the trial as well. Results of this study revealed that the combined therapy was well tolerated and more effective than desferrioxamine in reducing serum ferritin level. Significant improvement in liver alkaline phosphatase and glutathione levels of red blood cells was also observed in Silymarin-treated beta-thalassemia patients. However, no significant difference in serum ferritin levels was detected between Silymarin and placebo groups after 1.5 and 3 months treatment, probably because of insufficient sample size to detect subtle changes in ferritin levels between groups. This is the first report showing the beneficial effects of Silymarin in thalassemia patients and suggests that Silymarin in combination with desferrioxamine can be safely and effectively used in the treatment of iron-loaded patients.
Zahra Amirghofran - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulatory effects of Silymarin in patients with β-thalassemia major
International Immunopharmacology, 2013Co-Authors: Marjan Gharagozloo, Mehran Karimi, Zahra AmirghofranAbstract:Abstract Objective Silymarin, a flavonolignan complex isolated from milk thistle, is a cytoprotective, antioxidant, and hepatoprotective agent. The present study was designed to investigate the immunomodulatory effects of orally administered Silymarin in patients with β-thalassemia major. Methods The immunomodulatory effects of Silymarin were investigated in a 12-week clinical trial in two groups of patients. In combined therapy group (n = 25), patients continued desferrioxamine at the dose of 40 mg/kg/day and Legalon® tablets (420 mg daily) were added to desferrioxamine. In Silymarin group (n = 5), patients who were unable or unwilling to use desferrioxamine received only Silymarin. Immunological tests were assessed at the beginning and the end of the trial. Results No differences were detected between treatment groups regarding the percentage of lymphocyte subsets, concentration of serum immunoglobulins, complement levels, or T cell proliferation in vitro. Serum tumor necrosis factor (TNF-α) levels were significantly decreased in both groups, whereas the serum levels of neopterin significantly decreased in both groups after Silymarin therapy. The analysis of cell culture supernatants of activated T cells showed increased production of interferon gamma (IFNγ) and interleukin (IL)-4 after Silymarin treatment in both groups. Conclusion Silymarin stimulates cell-mediated immune response in β-thalassemia major, possibly through a direct action on cytokine-producing mononuclear cells. Because of its immunostimulatory, antioxidant, and iron-chelating activities, Silymarin could be a good candidate in the therapy of chronic iron overload in combination with routine iron chelators in clinical use like desferrioxamine.
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combined therapy of Silymarin and desferrioxamine in patients with β thalassemia major a randomized double blind clinical trial
Fundamental & Clinical Pharmacology, 2009Co-Authors: Marjan Gharagozloo, Mehran Karimi, Behjat Moayedi, Maryam Zakerinia, Mehrdad Hamidi, Mohammad Reza Maracy, Zahra AmirghofranAbstract:Silymarin, a flavonolignan complex isolated from Silybum marianum, has a strong antioxidant, hepatoprotective, and iron chelating activities. The present study was designed to investigate the therapeutic activity of orally administered Silymarin in patients with thalassemia major under conventional iron chelation therapy. A 3-month randomized, double-blind, clinical trial was conducted in 59 beta-thalassemia major patients in two well-matched groups. Patients were randomized to receive a Silymarin tablet (140 mg) three times a day plus conventional desferrioxamine therapy. The second group received the same therapy but a placebo tablet instead of Silymarin. Clinical laboratory tests were assessed at the beginning and the end of the trial, except for serum ferritin level that was assessed at the middle of the trial as well. Results of this study revealed that the combined therapy was well tolerated and more effective than desferrioxamine in reducing serum ferritin level. Significant improvement in liver alkaline phosphatase and glutathione levels of red blood cells was also observed in Silymarin-treated beta-thalassemia patients. However, no significant difference in serum ferritin levels was detected between Silymarin and placebo groups after 1.5 and 3 months treatment, probably because of insufficient sample size to detect subtle changes in ferritin levels between groups. This is the first report showing the beneficial effects of Silymarin in thalassemia patients and suggests that Silymarin in combination with desferrioxamine can be safely and effectively used in the treatment of iron-loaded patients.
Rajesh Agarwal - One of the best experts on this subject based on the ideXlab platform.
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multitargeted therapy of cancer by Silymarin
Cancer Letters, 2008Co-Authors: Kumaraguruparan Ramasamy, Rajesh AgarwalAbstract:Silymarin, a flavonolignan from milk thistle (Silybum marianum) plant, is used for the protection against various liver conditions in both clinical settings and experimental models. In this review, we summarize the recent investigations and mechanistic studies regarding possible molecular targets of Silymarin for cancer prevention. Number of studies has established the cancer chemopreventive role of Silymarin in both in vivo and in vitro models. Silymarin modulates imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis. In addition, Silymarin also showed anti-inflammatory as well as anti-metastatic activity. Further, the protective effects of Silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. This review focuses on the chemistry and analogues of Silymarin, multiple possible molecular mechanisms, in vitro as well as in vivo anti-cancer activities, and studies on human clinical trials.
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chemopreventive efficacy of Silymarin in skin and prostate cancer
Integrative Cancer Therapies, 2007Co-Authors: Gagan Deep, Rajesh AgarwalAbstract:Prevention and therapeutic intervention by phytochemicals are newer dimensions in the arena of cancer management. In this regard, the cancer chemopreventive role of Silymarin (Silybum marianum) has been extensively studied and has shown anticancer efficacy against various cancer sites, especially skin and prostate. In skin cancer, Silymarin treatment inhibits ultraviolet B radiation or chemically initiated or promoted carcinogenesis. These effects of Silymarin against skin carcinogenesis have been attributed to its strong antioxidant and anti-inflammatory action as well as its inhibitory effect on mitogenic signaling. Similarly, Silymarin treatment inhibits 3, 2-dimethyl-4-aminobiphenyl–induced prostate carcinogenesis and retards the growth of advanced prostate tumor xenograft in athymic nude mice. In prostate cancer, Silymarin treatment down-regulates androgen receptor–, epidermal growth factor receptor–, and nuclear factor-κB– mediated signaling and induces cell cycle arrest. Extensive preclinical findings have supported the anticancer potential of Silymarin, and now its efficacy is being evaluated in cancer patients.
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anticancer potential of Silymarin from bench to bed side
Anticancer Research, 2006Co-Authors: Rajesh Agarwal, Charu Agarwal, Haruyo Ichikawa, Rana P Singh, Bharat B AggarwalAbstract:: Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although Silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that Silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of Silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that Silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, Silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that Silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of Silymarin against various cancers.
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inhibition of human carcinoma cell growth and dna synthesis by silibinin an active constituent of milk thistle comparison with Silymarin
Cancer Letters, 1999Co-Authors: Neehar Bhatia, Jifu Zhao, Douglas M Wolf, Rajesh AgarwalAbstract:Several studies from our laboratory have shown the cancer chemopreventive and anti-carcinogenic effects of Silymarin, a flavonoid antioxidant isolated from milk thistle, in long-term tumorigenesis models and in human prostate, breast and cervical carcinoma cells. Since Silymarin is composed mainly of silibinin with small amounts of other stereoisomers of silibinin, in the present communication, studies were performed to assess whether the cancer preventive and anti-carcinogenic effects of Silymarin are due to its major component silibinin. Treatment of different prostate, breast, and cervical human carcinoma cells with silibinin resulted in a highly significant inhibition of both cell growth and DNA synthesis in a time-dependent manner with large loss of cell viability only in case of cervical carcinoma cells. When compared with Silymarin, these effects of silibinin were consistent and comparable in terms of cell growth and DNA synthesis inhibition, and loss of cell viability. Based on the comparable results of silibinin and Silymarin, we suggest that the cancer chemopreventive and anti-carcinogenic effects of Silymarin reported earlier are due to the main constituent silibinin.
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Anticarcinogenic effect of a flavonoid antioxidant, Silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated c
Clinical Cancer Research, 1998Co-Authors: Xiaolin Zi, D. K. Feyes, Rajesh AgarwalAbstract:There is an increasing interest in identifying potent cancer preventive and therapeutic agents against breast cancer. Silymarin, a flavonoid antioxidant isolated from milk thistle, exerts exceptionally high to complete anticarcinogenic effects in tumorigenesis models of epithelial origin. In this study, we investigated the anticarcinogenic effect of Silymarin and associated molecular mechanisms, using human breast carcinoma cells MDA-MB 468. Silymarin treatment resulted in a significantly high to complete inhibition of both anchorage-dependent and anchorage-independent cell growth in a dose- and time-dependent manner. The inhibitory effects of Silymarin on cell growth and proliferation were associated with a G1 arrest in cell cycle progression concomitant with an induction of up to 19-fold in the protein expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21. Following Silymarin treatment of cells, an incremental binding of Cip1/p21 with CDK2 and CDK6 paralleled a significant decrease in CDK2-, CDK6-, cyclin D1-, and cyclin E-associated kinase activity with no change in CDK2 and CDK6 expression but a decrease in G1 cyclins D1 and E. Taken together, these results suggest that Silymarin may exert a strong anticarcinogenic effect against breast cancer and that this effect possibly involves an induction of Cip1/p21 by Silymarin, which inhibits the threshold kinase activities of CDKs and associated cyclins, leading to a G1 arrest in cell cycle progression.
Santosh K Katiyar - One of the best experts on this subject based on the ideXlab platform.
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Silymarin targets β catenin signaling in blocking migration invasion of human melanoma cells
PLOS ONE, 2011Co-Authors: Mudit Vaid, Ram Prasad, Santosh K KatiyarAbstract:Metastatic melanoma is a leading cause of death from skin diseases, and is often associated with activation of Wnt/β-catenin signaling pathway. We have examined the inhibitory effect of Silymarin, a plant flavanoid from Silybum marianum, on cell migration of metastasis-specific human melanoma cell lines (A375 and Hs294t) and assessed whether Wnt/β-catenin signaling is the target of Silymarin. Using an in vitro invasion assay, we found that treatment of human melanoma cell lines with Silymarin resulted in concentration-dependent inhibition of cell migration, which was associated with accumulation of cytosolic β-catenin, while reducing the nuclear accumulation of β-catenin (i.e., β-catenin inactivation) and reducing the levels of matrix metalloproteinase (MMP) -2 and MMP-9 which are the down-stream targets of β-catenin. Silymarin enhanced: (i) the levels of casein kinase 1α, glycogen synthase kinase-3β and phosphorylated-β-catenin on critical residues Ser45, Ser33/37 and Thr41, and (ii) the binding of β-transducin repeat-containing proteins (β-TrCP) with phospho forms of β-catenin in melanoma cells. These events play important roles in degradation or inactivation of β-catenin. To verify whether β-catenin is a potent molecular target of Silymarin, the effect of Silymarin was determined on β-catenin-activated (Mel 1241) and β-catenin-inactivated (Mel 1011) melanoma cells. Treatment of Mel 1241 cells with Silymarin or FH535, an inhibitor of Wnt/β-catenin pathway, significantly inhibited cell migration of Mel 1241 cells, which was associated with the elevated levels of casein kinase 1α and glycogen synthase kinase-3β, and decreased accumulation of nuclear β-catenin and inhibition of MMP-2 and MMP-9 levels. However, this effect of Silymarin and FH535 was not found in Mel 1011 melanoma cells. These results indicate for the first time that Silymarin inhibits melanoma cell migration by targeting β-catenin signaling pathway.
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Silymarin protects epidermal keratinocytes from ultraviolet radiation induced apoptosis and dna damage by nucleotide excision repair mechanism
PLOS ONE, 2011Co-Authors: Santosh K Katiyar, Sudheer K Mantena, Syed M MeeranAbstract:Solar ultraviolet (UV) radiation is a well recognized epidemiologic risk factor for melanoma and non-melanoma skin cancers. This observation has been linked to the accumulation of UVB radiation-induced DNA lesions in cells, and that finally lead to the development of skin cancers. Earlier, we have shown that topical treatment of skin with Silymarin, a plant flavanoid from milk thistle (Silybum marianum), inhibits photocarcinogenesis in mice; however it is less understood whether chemopreventive effect of Silymarin is mediated through the repair of DNA lesions in skin cells and that protect the cells from apoptosis. Here, we show that treatment of normal human epidermal keratinocytes (NHEK) with Silymarin blocks UVB-induced apoptosis of NHEK in vitro. Silymarin reduces the amount of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers (CPDs) and as measured by comet assay, and that ultimately may lead to reduced apoptosis of NHEK. The reduction of UV radiation-induced DNA damage by Silymarin appears to be related with induction of nucleotide excision repair (NER) genes, because UV radiation-induced apoptosis was not blocked by Silymarin in NER-deficient human fibroblasts. Cytostaining and dot-blot analysis revealed that Silymarin repaired UV-induced CPDs in NER-proficient fibroblasts from a healthy individual but did not repair UV-induced CPD-positive cells in NER-deficient fibroblasts from patients suffering from xeroderma pigmentosum complementation-A disease. Similarly, immunohistochemical analysis revealed that Silymarin did not reduce the number of UVB-induced sunburn/apoptotic cells in the skin of NER-deficient mice, but reduced the number of sunburn cells in their wild-type counterparts. Together, these results suggest that Silymarin exert the capacity to reduce UV radiation-induced DNA damage and, thus, prevent the harmful effects of UV radiation on the genomic stability of epidermal cells.
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Silymarin induces apoptosis primarily through a p53 dependent pathway involving bcl 2 bax cytochrome c release and caspase activation
Molecular Cancer Therapeutics, 2005Co-Authors: Santosh K Katiyar, Manjeshwar S BaligaAbstract:Silymarin, a plant flavonoid, has been shown to inhibit skin carcinogenesis in mice. However, the mechanism responsible for the anti-skin carcinogenic effects of Silymarin is not clearly understood. Here, we report that treatment of JB6 C141 cells (preneoplastic epidermal keratinocytes) and p53+/+ fibroblasts with Silymarin and silibinin (a major constituent of Silymarin) resulted in a dose-dependent inhibition of cell viability and induction of apoptosis in an identical manner. Silymarin-induced apoptosis was determined by fluorescence staining (8–64% apoptosis) and flow cytometry (12–76% apoptosis). The Silymarin-induced apoptosis was primarily p53 dependent because apoptosis occurred to a much greater extent in the cells expressing wild-type p53 (p53+/+, 9–61%) than in p53-deficient cells (p53−/−, 6–20%). The induction of apoptosis in JB6 C141 cells was associated with increased expression of the tumor suppressor protein, p53, and its phosphorylation at Ser15. The constitutive expression of antiapoptotic proteins Bcl-2 and Bcl-xl were decreased after Silymarin treatment, whereas the expression of the proapoptotic protein Bax was increased. There was a shift in Bax/Bcl-2 ratio in favor of apoptotic signal in Silymarin-treated cells, which resulted in increased levels of cytochrome c release, apoptotic protease-activating factor-1, and cleaved caspase-3 and poly(ADP-ribose) polymerase in JB6 C141 cells. The shift in Bax/Bcl-2 ratio was more prominent in p53+/+ fibroblasts than in p53−/− cells. Silymarin-induced apoptosis was blocked by the caspase inhibitor (Z-VAD-FMK) in JB6 C141 cells which suggested the role of caspase activation in the induction of apoptosis. These observations show that Silymarin-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3.
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treatment of Silymarin a plant flavonoid prevents ultraviolet light induced immune suppression and oxidative stress in mouse skin
International Journal of Oncology, 2002Co-Authors: Santosh K KatiyarAbstract:It is well documented that ultraviolet (UV) light-induced immune suppression and oxidative stress play an important role in the induction of skin cancers. Earlier, we have shown that topical treatment of Silymarin, a plant flavonoid from milk thistle (Silybum marianum L. Gaertn.), to mouse skin prevents photocarcinogenesis, but the preventive mechanism of photocarcinogenesis in vivo animal system by Silymarin is not well defined and understood. To define the mechanism of prevention, we employed immunostaining, analytical assays and ELISA which revealed that topical treatment of Silymarin (1 mg/cm 2 skin area) to C3H/HeN mice inhibits UVB (90 mJ/ cm 2 )-induced suppression of contact hypersensitivity (CHS) response to contact sensitizer dinitrofluorobenzene. Prevention of UVB-induced suppression of CHS by Silymarin was found to be associated with the inhibition of infiltrating leukocytes, particularly CDT11b + cell type, and myeloperoxidase activity (50-71%). Silymarin treatment also resulted in significant reduction of UVB-induced immunosuppressive cytokine interleukin-10 producing cells and its production (58-72%, p<0.001). Topical treatment of Silymarin also resulted in significant reduction of the number of UVB-induced H 2 O 2 producing cells and inducible nitric oxide synthase expressing cells concomitant with decrease in H 2 O 2 (58-65%, p<0.001) and nitric oxide (65-68%, p<0.001) production. Together, these data suggest that prevention of UVB-induced immunosuppression and oxidative stress by Silymarin may be associated with the prevention of photocarcinogenesis in mice. The data obtained from this study also suggest: i) phase-I clinical trial of Silymarin in high skin cancer risk human population and ii) development of sunscreen containing Silymarin as an antioxidant (chemopreventive agent) or Silymarin can be supplemented in skin care products.
Akio Inui - One of the best experts on this subject based on the ideXlab platform.
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Silymarin induces insulin resistance through an increase of phosphatase and tensin homolog in wistar rats
PLOS ONE, 2014Co-Authors: Kaichun Cheng, Jueitang Cheng, Akihiro Asakawa, Yingxiao Li, Hsienhui Chung, Haruka Amitani, Takatoshi Ueki, Akio InuiAbstract:Background and aims Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of Silymarin on the development of insulin resistance remains unknown. Methods Wistar rats fed fructose-rich chow or normal chow were administered oral Silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection. Results Oral administration of Silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with Silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in L6 cells reversed Silymarin-induced impaired insulin signaling and glucose uptake. Conclusions Silymarin has the ability to disrupt insulin signaling through increased PTEN expression. Therefore, Silymarin should be used carefully in type-2 diabetic patients.
