Protective effects of silymarin on testis histopathology,oxidative stress indicators,antioxidant defence enzymes and serum testosterone in cadmium‐treated mice

Cadmium is known as an oxidative stress‐inducing factor. Silymarin extracted from Silybum marianum is regarded as a potent antioxidant. The present study investigated the preventing effects of silymarin on cadmium chloride‐induced toxicity in terms of testis histopathology and serum testosterone level as well as oxidative stress indicators in mice. In addition, the activities of antioxidant defence enzymes was evaluated. Adult male mice were divided into four groups (n = 6 in each group): (a) control; (b) cadmium chloride; (c) silymarin + cadmium chloride and (d) Silymarin. In this study, cadmium chloride significantly decreased the diameter and wall thickness of the seminiferous tubule, diameter of the spermatogonia nucleus and serum testosterone levels compared to the control group. Furthermore, in mice treated with this pollutant, a significant increase in malondialdehyde was observed while ferric reducing antioxidant power level, and the activity of catalase, superoxide dismutase and glutathione peroxidase were significantly reduced in the testis. In the silymarin + cadmium chloride group, silymarin could significantly reverse the toxic effects of cadmium chloride. The findings of this study showed that silymarin, as a potent antioxidant, can compensate the adverse effects of cadmium chloride on testis histopathology, testosterone level, oxidative stress indicators and antioxidant defence enzymes in mice.     

Topical Silymarin Administration for Prevention of Capecitabine‐Induced Hand–Foot Syndrome: A Randomized,Double‐Blinded,Placebo‐Controlled Clinical Trial

Hand–foot syndrome (HFS) is a frequent dose‐limiting adverse reaction of capecitabine in patient with gastrointestinal cancers. Silymarin is a polyphenolic flavonoid extracted from the Silybum marianum that exhibits strong antioxidant and antiinflammatory activities. In this study, we evaluated silymarin efficacy in prevention of capecitabine‐induced HFS in patients with gastrointestinal cancers, as the first human study. During this pilot, randomized, double‐blinded, placebo‐controlled clinical trial, the effect of silymarin gel 1%, which is applied on the palms and soles twice daily starting at the first day of chemotherapy for 9 weeks, on HFS occurrence was assessed. Forty patients fulfilled the inclusion criteria assigned to the silymarin or placebo group. World Health Organization HFS grading scale scores were recorded at baseline and every 3 weeks during these 9 weeks. The median WHO HFS scores were significantly lower in silymarin group at the end of the 9^th week (p < 0.05). The scores increased significantly in both placebo and silymarin groups during chemotherapy, but there was a delay for HFS development and progression in silymarin group. Prophylactic administration of silymarin topical formulation could significantly reduce the severity of capecitabine‐induced HFS and delays its occurrence in patients with gastrointestinal cancer after 9 weeks of application. Copyright © 2017 John Wiley & Sons, Ltd.     

Effects of Silymarin on Diabetes Mellitus Complications: A Review

Diabetes mellitus is a common metabolic disorder that is caused by a deficit in the production of (type 1) or response to (type 2) insulin. Diabetes mellitus is characterized by a state of chronic hyperglycemia and such symptoms as weight loss, thirst, polyuria, and blurred vision. These disturbances represent one of the major causes of morbidity and mortality nowadays, despite available treatments, such as insulin, insulin secretagogues, insulin sensitizers, and oral hypoglycemic agents. However, many efforts have been made to discover new drugs for diabetes treatment, including medicinal plant extracts. Silymarin is a powder extract of the seeds from Silybum marianum, a plant from the Asteraceae family. The major active ingredients include four isomers: silybin, isosilybin, silychristin, and silydianin. Silymarin is indicated for the treatment of hepatic disorders, such as cirrhosis, chronic hepatitis, and gallstones. Moreover, several studies of other pathologies, including diabetes, sepsis, osteoporosis, arthritis, hypercholesterolemia, cancer, viral infections, and Alzheimer's and Parkinson's diseases, have tested the effects of silymarin and reported promising results. This article reviews data from clinical, in vivo, and in vitro studies on the use of silymarin, with a focus on the complications of diabetes, including nephropathy, neuropathy, healing delays, oxidative stress, hepatotoxicity, and cardiomyopathy. Copyright © 2017 John Wiley & Sons, Ltd.     

Impact of silymarin on cadmium-induced apoptosis in human spermatozoa

Oxidative stress-induced apoptosis in spermatozoa may lead to male infertility. Environmental pollutants and heavy metals such as cadmium cause harmful effects on the reproductive system and sperm parameters through the induction of oxidative stress. Silymarin, as a potent antioxidant, is able to inhibit oxidative stress. This study was performed to investigate the protective effects of silymarin on cadmium-induced toxicity in human spermatozoa. Sperm samples were divided into the following five groups: (a) spermatozoa at 0 min, (b) spermatozoa in the control group, (c) spermatozoa treated with cadmium chloride (20 μM), (d) spermatozoa treated with silymarin (2 μM)+ cadmium chloride (20 μM) and (e) spermatozoa treated with silymarin (2 μM). Sperm parameters related to apoptosis, such as DNA fragmentation, nucleus diameter, mitochondrial membrane potential (MMP) and expression of caspase-3, were evaluated in all groups. After 180 min, spermatozoa treated with cadmium chloride showed a significant decrease in nucleus diameter and MMP but a significant increase in DNA fragmentation; however, caspase-3 expression remained unchanged. At this time point, silymarin in the silymarin + cadmium chloride group could significantly reverse the adverse effects of cadmium chloride on these parameters.Silymarn could partly compensate for the caspase-independent apoptosis in the spermatozoa. Therefore, oxidative stress could be a consequence for cadmium toxicity.     

Impact of aluminium toxicity on vital human sperm parameters—Protective effects of silymarin

Aluminium is an environmental pollutant which induces oxidative stress, while silymarin is a potent antioxidant. This study was conducted to investigate the possible protective effects of silymarin on adverse effects of aluminium chloride on vital sperm parameters as well as its effects on oxidative stress markers in human spermatozoa. Human spermatozoa were divided into 5 groups as follows: (a) spermatozoa at 0 hr; (b) spermatozoa at 180 min (control); (c) spermatozoa treated with aluminium chloride; (d) spermatozoa treated with silymarin + aluminium chloride; and (e) spermatozoa treated with silymarin. The sperm samples were used to assess sperm vital parameters such as acrosome and plasma membrane integrity, viability, mitochondrial membrane potential (MMP) and motility as well as sperm malondialdehyde (MDA) level and the total antioxidant capacity. The percentage of acrosome and plasma membrane integrity, viability, MMP, motility and the total antioxidant capacity of spermatozoa treated with aluminium chloride significantly decreased compared with control group, while the level of MDA significantly increased compared with the control group. In the silymarin + aluminium chloride group, silymarin could significantly compensate the adverse effects of aluminium chloride on these parameters. Administration of silymarin alone significantly increased the percentage of acrosome and plasma membrane integrity, viability, motility and total antioxidant capacity, while significantly reduced MDA levels compared with the control group. Aluminium chloride by inducing oxidative stress exerts disastrous effects on the vital parameters of human spermatozoa and silymarin, as a potent antioxidant, could reverse the effects of aluminium chloride on these parameters.     

Cisplatin nephrotoxicity and protection by milk thistle extract in rats

The protective effect of methanolic extract of milk thistle seeds and silymarin against cisplatin-induced renal toxicity in male rats after a single intraperitoneal injection of 3 mg kg cisplatin were studied. Over 5 days, cisplatin-treated rats showed tubular necrosis and elevation in blood urea nitrogen (BUN) and serum creatinine (Scr). Pretreatment of animals with silymarin (50 mg kg) or extract (0.6 g kg) 2 h before cisplatin prevented the tubular damage. Rats treated with silymarin or extract 2 h after cisplatin had BUN and Scr significantly lower than those receiving cisplatin, but mild to moderate necrosis was observed. These results suggested that milk thistle may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplatin to limit renal injury.     

Recent advances in plant hepatoprotectives: a chemical and biological profile of some important leads

Medicinal plants have been traditionally used for treating liver diseases since centuries. Several leads from plant sources have been found as potential hepatoprotective agents with diverse chemical structures. Although, a big list of hepatoprotective phytomolecules was reported in the scientific literature, only a few were potent against various types of liver damages. Of which, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside, phyllanthin, hypophyllanthin, and glycyrrhizin have largely attracted the scientific community. This review focuses discussion on the chemistry, biological activity, mode of action, toxicity, and future prospects of these leads.     

Protective effects of silymarin on epirubicin-induced mucosal barrier injury of the gastrointestinal tract

Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the protective effects of silymarin on epirubicin-induced mucosal barrier injury in CD-1 mice. Immunohistochemical activity of both pro-apoptotic Bax and anti-apoptotic Bcl-2 markers, together with p53, cyt-P450 expression and DNA damage analysis on stomach, small intestine and colon were evaluated. Our results indicated stronger expression for cyt P450 in all analyzed gastrointestinal tissues of Epi group, which demonstrate intense drug detoxification. Bax immunopositivity was intense in the absorptive enterocytes and lamina connective cells of the small intestine, surface epithelial cells of the stomach and also in the colonic epithelium and lamina concomitant with a decreased Bcl-2 expression in all analyzed tissues. Epirubicin-induced gastrointestinal damage was verified by a goblet cell count and morphology analysis on histopathological sections stained for mucins. In all analyzed tissues, Bax immunopositivity has been withdrawn by highest dose of silymarin concomitant with reversal of Bcl-2 intensity at a level comparable with control. p53 expression was found in all analyzed tissues and decreased by high dose of silymarin. Also, DNA internucleosomal fragmentation was observed in the Epi groups for all analyzed tissues was almost suppressed at 100?mg/kg Sy co-treatment. Histological aspect and goblet cell count were restored at a highest dose of Sy for both small and large intestine. In conclusion, our findings suggest that silymarin may prevent cellular damage of epirubicin-induced toxicity and was effective in reducing the severity indicators of gastrointestinal mucositis in mice.     

Silymarin attenuates paraquat‐induced lung injury via Nrf2‐mediated pathway in vivo and in vitro

The present study aims to investigate the impacts and mechanisms of silymarin on paraquat (PQ)‐induced lung injury in vivo and in vitro. In in vivo experiments, a total of 32 male Sprague‐Dawley (SD) rats were randomly divided into four groups. The rats were killed on day 3. Histopathological changes in lung tissue were examined using HE and Masson's trichrome staining. Biomarkers of neutrophil activation, pulmonary oedema, pulmonary fibrosis, lung permeability and oxidative stress were detected. Several proinflammatory mediators and antioxidant related proteins were measured. In in vitro experiments, A549 cells were transfected with Nrf2 special siRNA to investigate the roles of Nrf2. The results show that silymarin administration abated PQ‐induced lung histopathologic changes, decreased inflammatory cell infiltration and lung wet weight/dry weight (W/D) ratio, suppressed myeloperoxidase (MPO) activity and nitric oxide (NO)/inducible nitric oxide synthases (iNOS) expression, downregulated hydroxyproline (HYP) levels, reduced total protein concentration and proinflammatory mediator release, and improved oxidative stress (malondialdehyde, MDA; superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GSH‐Px) in lung tissue and serum. Meanwhile, treatment with silymarin upregulated the levels of nuclear factor‐erythroid‐2‐related factor 2 (Nrf2), heme oxygenase‐1 (HO‐1) and NAD(P)H:quinone oxidoreductase‐1(NQO1). However, the addition of Nrf2 siRNA reduced the expression of Nrf2‐mediated antioxidant protein HO‐1 and thus reversed the protective effects of silymarin against oxidative stress and inflammatory response. These results suggest that silymarin may exert protective effects against PQ‐induced lung injury. Its mechanisms were associated with the Nrf2‐mediated pathway. Therefore, silymarin may be a potential therapeutic drug for lung injury.     

Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from A Pilot,Randomized, Double‐Blinded,Placebo‐Controlled Clinical Trial

Despite several introduced preventive modalities, cisplatin nephrotoxicity remains a clinical problem. Some in vitro and in vivo studies have addressed the protective effects of silymarin against cisplatin nephrotoxicity. This study evaluated the effects of silymarin administration on cisplatin nephrotoxicity as the first human study. During this pilot, randomized, double‐blinded, placebo‐controlled clinical trial, the effect of oral silymarin 420 mg daily in three divided doses starting 24–48 h before the initiation of cisplatin infusion and continuing to the end of three 21‐day cisplatin‐containing chemotherapy courses on cisplatin‐induced renal electrolytes wasting and kidney function were assessed. Cisplatin‐associated acute kidney injury (AKI) occurred in 8% of the patients. Urine neutrophil gelatinase‐associated lipocalin to urine creatinine ratio (NGAL/Cr) and urinary magnesium and potassium wasting increased significantly after cisplatin infusion in both groups. Significant positive correlation was found between cumulative dose of cisplatin and urine NGAL/Cr after three courses of cisplatin infusion. Incidence of AKI and the magnitude of urinary magnesium and potassium wasting did not differ between silymarin and placebo groups. No adverse reaction was reported by silymarin administration. Prophylactic administration of conventional form of silymarin tablets could not prevent cisplatin‐induced urine electrolyte wasting or renal function impairment. Copyright © 2015 John Wiley & Sons, Ltd.