Therapeutic effects of proanthocyanidins on the pathogenesis of periodontitis--an overview

Periodontitis is a bacterially induced chronic inflammatory disease that destroys the connective tissue and bone that support teeth. Bacteria initiates periodontitis and destruction of the alveolar bone and periodontal connective tissue is clearly observed. But, the events occuring between these two points of time remain obscure and this study focusses on these aspects. The proanthocyanidins (PC) have variable pharmacological and nutraceutical benefits including improvement of ischemic cardiovascular disease, prevention of atherosclerosis and antiarthritic, anticancer and antimicrobial activities. The benefits associated with the antioxidant activity of PC have been evaluated both in vivo and in vitro. But, reports on the ameliorative effects of PC on oral diseases and specifically on periodontitis are very few. Hence, a novel attempt is made to review the possible protective effects of PC and its mechanism of action in periodontitis and also to show whether PC could be developed as a therapeutic agent for periodontitis.     

Inhibitory effect of the flavonoid silymarin on the erythrocyte hemolysis induced by phenylhydrazine

The flavonoid silymarin, which is used as a therapeutical agent in the treatment of liver diseases, can inhibit the hemolysis and lipid peroxidation induced by phenylhydrazine on erythrocytes obtained from rats treated with the flavonoid. This effect is ascribed to the antioxidant properties as a free radical scavenger exhibited by the flavonoid. Silymarin failed to inhibit the glutathione depletion induced by phenylhydrazine on erythrocytes. It is proposed that the flavonoid acts at the membrane level of the cell avoiding the lipid peroxidative and fluidizing effect of phenylhydrazine.     

Photodynamic activity of cercosporin on plant tissues

Abstract Cercosporin, excited by incandescent light in the presence of oxygen, induced a loss of ions from the plant tissues tested. Silymarin, BHA (2(3)-tert-butyl-4-hydroxyanisole) and EDTA were effective in lowering the activity of cercosporin. Circumstantial evidence suggests that the toxic effect may be mediated by the singlet oxygen and free radical formation which induces a lipoperoxidative degradation of the polyunsaturated fatty acids of cell membranes.     

Silymarin and neurodegenerative diseases: Therapeutic potential and basic molecular mechanisms

BackgroundNeurodegenerative diseases (NDDs) are primarily characterized by selective neuronal loss in the brain. Alzheimer's disease as the most common NDDs and the most prevalent cause of dementia is characterized by Amyloid-beta deposition, which leads to cognitive and memory impairment. Parkinson's disease is a progressive neurodegenerative disease characterized by the dramatic death of dopaminergic neuronal cells, especially in the SNc and caused alpha-synuclein accumulation in the neurons. Silymarin, an extract from seeds of Silybum marianum, administered mostly for liver disorders and also had anti-oxidant and anti-carcinogenic activities.PurposeThe present comprehensive review summarizes the beneficial effects of Silymarin in-vivo and in-vitro and even in animal models for these NDDs.MethodsA diagram model for systematic review is utilized for this search. The research is conducted in the following databases: PubMed, Web of Science, Scopus, and Science Direct. Results: Based on the inclusion criteria, 83 studies were selected and discussed in this review.ConclusionLastly, we review the latest experimental evidences supporting the potential effects of Silymarin, as a neuroprotective agent in NDDs.     

Silymarin BIO-C, an extract from Silybum marianum fruits, induces hyperprolactinemia in intact female rats

Breastfeeding is widely acknowledged to have important health benefits for infants and mothers. Milk thistle (Silybum marianum fruits) has been recently proposed to be used by nursing mothers for stimulating milk production; however, the mode of action of this herbal drug is still unknown. In this paper, we have evaluated the effect of a micronized standardized extract of S. marianum (Silymarin BIO-C^®=Piùlatte^®) on the serum levels of prolactin in female rats. A 14-day treatment with Silymarin BIO-C^® (25–200 mg/kg, given orally) increased, in a dose dependent manner, the serum prolactin levels. Moreover, after a 66-day discontinuation of Silymarin BIO-C^® treatment, prolactin levels were still significantly elevated although we observed a trend to decrease that was counteracted by a further 7-day treatment with Silymarin BIO-C^®. Bromocriptine, a dopamine D₂ receptor agonist, (1–10 mg/kg, os) significantly and in a dose dependent manner, reduced the serum prolactin levels; bromocriptine, at the dose of 1 mg/kg, significantly reduced the high serum prolactin levels induced by Silymarin BIO-C^®. In conclusion, we have shown that an extract from S. marianum fruits significantly increases circulating prolactin levels in female rats; this effect seems to involve, at least in part, dopamine D₂ receptors.     

Investigation of in vitro and in vivo antioxidant potential of secoisolariciresinol diglucoside

The present study was designed to evaluate the in vitro and in vivo ameliorative antioxidant potential of secoisolariciresinol diglucoside (SDG). In vitro antioxidant activity of synthetic SDG was carried out using DPPH, reducing power potency, and DNA protection assays. Wistar albino rats weighing 180–220 g were used for in vivo studies and liver damage was induced in the experimental animals by a single intraperitoneal (I.P.) injection of CCl₄ (2 g/kg b.w.). Intoxicated animals were treated orally with synthetic SDG at (12.5 and 25 mg/kg b.w.) and Silymarin (25 mg/kg) for 14 consecutive days. The levels of catalase (CAT), superoxide dismutase (SOD), peroxidase (POX), and lipid peroxidase (LPO) were measured in liver and kidney homogenates. The synthetic SDG exerts high in vitro antioxidant potency as it could scavenge DPPH at a IC₅₀ value of 78.9 μg/ml and has dose-dependent reducing power potency and protected DNA at 0.5 mg/ml concentration. Oral administration of synthetic SDG at 12.5 and 25 mg/kg b.w. showed significant protection compared to Silymarin (25 mg/kg) and the activities of CAT, SOD, and POX were markedly increased (P < 0.05), whereas LPO significantly decreased (P < 0.001) in a dose-dependent manner in liver and kidney in both pre- and post-treatment groups when compared to toxin-treated group. The results of in vitro and in vivo investigations revealed that synthetic SDG at 25 mg/kg b.w. is associated with beneficial changes in hepatic enzyme activities and thereby plays a key role in the prevention of oxidative damage in immunologic system.     

Silymarin inhibits TNF-alpha-induced expression of adhesion molecules in human umbilical vein endothelial cells

Silymarin is known to have an anti-atherosclerotic activity, but the mechanism responsible for it remains unclear. Here, we demonstrate a possible mechanism involved in the anti-atherosclerotic activity of silymarin. Silymarin inhibited THP-1 cell adhesion to human umbilical vein endothelial cells (HUVECs). Silymarin also suppressed the TNF-alpha-induced protein and mRNA expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in HUVECs. Moreover, silymarin suppressed the TNF-alpha-induced DNA binding of NF-kappaB/Rel in HUVECs. Taken together, these results demonstrate that silymarin exerts an anti-atherosclerotic activity, at least in part, by inhibiting the expression of adhesion molecules.     

Anti-inflammatory, antiarthritic and analgesic activity of a herbal formulation (DRF/AY/4012)

Anti-inflammatory, antiarthritic and analgesic effect of a herbal product (DRF/AY/4012) was evaluated in animal models. Herbal product treatment induced a dose dependent anti-inflammatory activity in acute inflammatory models (carrageenin and egg-albumin induced rat hind paw edema). It also elicited promising anti-inflammatory activity in chronic inflammatory models (cotton pellet granuloma and Freund's adjuvant induced polyarthritis in rats). Further, the product inhibited the increased level of serum lysosomal enzyme activity viz. serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase and the lipid peroxidation in liver. In Freund's adjuvant induced polyarthritis, herbal product reduced the increased level of hydroxy proline, hexosamine and total protein content in edematous tissue. The product also exhibited mild to moderate analgesic activity in acetic acid induced writhing in mice. The LD50 value of the herbal product was more than 16 gm/kg by oral route in mice. The product has distinct advantages over the existing agents and deserves further developmental studies.     

Erythrocyte defects precede the onset of CCl4-induced liver cirrhosis. Protection by silymarin.

The time-course of some alterations produced in erythrocytes during the onset of CCl4-induced liver cirrhosis was studied in rats. Erythrocyte membranes were isolated to measure Na+, K+ and Ca+2-ATPase activities. Membrane lipid composition was determined to calculate the cholesterol/phospholipid ratio and serum samples were used to measure lipoperoxidation. The results demonstrated that as CCl4 treatment progressed, serum lipoperoxidation and membrane cholesterol/phospholipid ratio increased while ATPase activities decreased. ATPase activities in red blood cells of cirrhotic rats were 50% below normal values but those determined in cells of animals treated simultaneously with CCl4 + silymarin were significantly improved. Silymarin co-treatment also preserved the normal cholesterol/phospholipid ratio in the membranes. Our results suggest that the measure of ATPase activities in erythrocytes membranes could be a simple, safe and useful early marker of liver damage and also valuable to test the effectiveness of a given drug therapy.     

Protective Effects of Pterostilbene against Acetaminophen‐Induced Hepatotoxicity in Rats

The present study was undertaken to evaluate the protective effect of pterostilbene against acetaminophen‐induced hepatotoxicity. Silymarin was used as a standard hepatoprotective agent. A single dose of acetaminophen (800 mg/kg i.p.), injected to male rats, caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, total cholesterol, triglycerides, tumor necrosis factor alpha, and hepatic contents of malondialdehyde, nitric oxide, caspase‐3, hydroxyproline, with significant decreases in serum HDL‐cholesterol, total proteins, albumin, and hepatic activities of reduced glutathione, superoxide dismutase and catalase as compared with the control group. On the other hand, administration of each of pterostilbene (50 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) for 15 days before acetaminophen ameliorated liver function and oxidative stress parameters. Histopathological evidence confirmed the protection offered by pterostilbene from the tissue damage caused by acetaminophen. In conclusion, pterostilbene possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti‐inflammatory, and antiapoptotic actions.     

Protective effect of gallic acid isolated from Peltiphyllum peltatum against sodium fluoride-induced oxidative stress in rat’s kidney

In the present study, the nephroprotective effect of gallic acid isolated from Peltiphyllum peltatum was examined in sodium fluoride (NaF) treated rats. Nephrotoxicity was induced by 1-week intoxication of NaF at 600 ppm through drinking water. The levels of thiobarbituric acid reactive substances, reduced glutathione as well as activities of superoxide dismutase and catalase in renal tissues homogenates were determined. The serum biochemical markers of renal injuries including creatinine, serum urea, blood urea nitrogen, uric acid levels as well as the levels of phosphate and calcium were also assessed. Intoxication with NaF caused a significant increase in the levels of thiobarbituric acid reactive substances (46 % versus to control) and reduced the glutathione concentration (47 %) and the activities of superoxide dismutase (46 %) and catalase (41 %) in renal tissues homogenates. NaF intoxication also induced significant alterations in the kidney biochemical markers increasing the levels of urea, uric acid, blood urea nitrogen, creatinine, and phosphate and decreasing the levels of calcium. Daily administration of gallic acid (20 mg/kg) for 1 week before NaF intoxication brought the antioxidant–oxidant balance similar to the NaF-untreated group. Silymarin, used a standard antioxidant agent, also showed a nephroprotective activity. We concluded that NaF caused nephrotoxicity and oxidative stress in renal tissues and daily administration of gallic acid for 1 week prior to intoxication inhibited toxicity and oxidative stress.     

Silybin and silymarin--new effects and applications

This article aims to review critically literature published mainly within this millennium on the new and emerging applications of silymarin, the polyphenolic fraction from the seeds of Silybum marianum and its main component silybin. Silymarin and silybin used so far mostly as hepatoprotectants were shown to have other interesting activities as e.g., anticancer and canceroprotective. These activities were demonstrated in a large variety of illnesses of different organs as e.g., prostate, lungs, CNS, kidneys, pancreas and others. Besides the cytoprotective activity of silybin mediated by its antioxidative and radical-scavenging properties also new activities based on the specific receptor interaction were discovered--e.g., inhibition and modulation of drug transporters, P-glycoproteins, estrogenic receptors, nuclear receptors and some others. New derivatives of silybin open new ways to its therapeutic applications. Pharmacology dealing with optically pure silybin diastereomers may suggest new mechanisms of its action.     

In vitro antioxidant activity of silymarin

Silymarin, a known standardized extract obtained from seeds of Silybum marianum is widely used in treatment of several diseases of varying origin. In the present paper, we clarified the antioxidant activity of silymarin by employing various in vitro antioxidant assay such as 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH(.)) scavenging, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging activity, total antioxidant activity determination by ferric thiocyanate, total reducing ability determination by Fe3+ - Fe2+ transformation method and Cuprac assay, superoxide anion radical scavenging by riboflavin/methionine/illuminate system, hydrogen peroxide scavenging and ferrous ions (Fe2+) chelating activities. Silymarin inhibited 82.7% lipid peroxidation of linoleic acid emulsion at 30 microg/mL concentration; butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), alpha-tocopherol and trolox indicated inhibition of 83.3, 82.1, 68.1 and 81.3% on peroxidation of linoleic acid emulsion at the same concentration, respectively. In addition, silymarin had an effective DPPH(.) scavenging, ABTS(.)+ scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, ferric ions (Fe3+) reducing power by Fe3+-Fe2+ transformation, cupric ions (Cu2+) reducing ability by Cuprac method, and ferrous ions (Fe2+) chelating activities. Also, BHA, BHT, alpha-tocopherol and trolox, were used as the reference antioxidant and radical scavenger compounds. Moreover, this study, which clarifies antioxidant mechanism of silymarin, brings new information on the antioxidant properties of silymarin. According to the present study, silymarin had effective in vitro antioxidant and radical scavenging activity. It could be used in the pharmacological and food industry because of its antioxidant properties.     

Silymarin inhibited proliferation and induced apoptosis in hepatic cancer cells

Objectives:  The aim of this study was to investigate mechanisms involved in the growth inhibitory effect of silymarin, in humanhepatocellular carcinoma.
Materials and Methods:  The human hepatocellular carcinoma cell line HepG2 was utilized and the MTT assay was performed to study the antiproliferative effect of silymarin. Dual staining was undertaken for ethidium bromide/acridine orange, propidium iodide staining and DNA fragmentation studies were executed to confirm the presence of apoptosis. Cell-cycle analysis was revealed by flow cytometry and mitochondrial transmembrane potential was measured by uptake of the mitochondrial-specific lipophilic cationic dye rhodamine 123. Western blotting analysis for cytochrome c, p53, Bax, Bcl-2, APAF-1, caspase-3, survivin, β-catenin, cyclin D1, c-Myc and PCNA was carried out.
Results:  Silymarin inhibited population growth of the hepatocellular carcinoma cells in a dose-dependent manner, and the percentage of apoptotic cells was increased after treatment with 50 and 75 µg/ml silymarin for 24 h. Silymarin treatment increased the proportion of cells with reduced DNA content (sub-G₀/G₁ or A₀ peak), indicative of apoptosis with loss of cells in the G₁ phase. Silymarin also decreased mitochondrial transmembrane potential of the cells, thereby increasing levels of cytosolic cytochrome c while up-regulating expression of pro-apoptotic proteins (such as p53, Bax, APAF-1 and caspase-3) with concomitant decrease in anti-apoptotic proteins (Bcl-2 and survivin) and proliferation-associated proteins (β-catenin, cyclin D1, c-Myc and PCNA).
Conclusions:  Our results demonstrate that silymarin treatment inhibited proliferation and induced apoptosis in the human hepatocellular carcinoma cell line HepG2.     

The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats

Background/objective

This study was designed to evaluate the potential chemopreventive activities of Ginkgo biloba extract (EGb) and Silybum marianum extract (silymarin) against hepatocarcinogenesis induced by N-nitrosodiethylamine (NDEA) in rats.

Methods

Rats were divided into 6 groups. Group 1 served as normal control rats. Group 2 animals were intragastrically administrated NDEA at a dose of 10 mg/kg five times a week for 12 weeks to induce hepatocellular carcinoma (HCC). Groups 3 and 4 animals were pretreated with silymarin and EGb respectively. Groups 5 and 6 animals were posttreated with silymarin and EGb respectively. The investigated parameters in serum are alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT) and vascular endothelial growth factor (VEGF). The investigated parameters in liver tissue are malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and comet assay parameters.

Results

In NDEA group, MDA level was elevated with subsequent decrease in GSH level and SOD, GPx and GR activities. In addition, NDEA group revealed a significant increase in serum ALT, AST and GGT activities and VEGF level. Furthermore, NDEA administrated animals showed a marked increase in comet assay parameters. These biochemical alterations induced by NDEA were confirmed by the histopathological examination of rat livers intoxicated with NDEA that showed an obvious cellular damage and well differentiated HCC. In contrast, silymarin+NDEA treated groups (3&;5) and EGb+NDEA treated groups (4&;6) showed a significant decrease in MDA level and a significant increase in GSH content and SOD, GPx and GR activities compared to NDEA group. Silymarin and EGb also beneficially down-regulated the increase in serum ALT, AST, GGT activities and VEGF level induced by NDEA. In addition, silymarin and EGb significantly decreased comet assay parameters. Histopathological examination of rat livers treated with either silymarin or EGb exhibited an improvement in the liver architecture compared to NDEA group.

Conclusions

The obtained findings suggested that silymarin and EGb may have beneficial chemopreventive roles against hepatocarcinogenesis through their antioxidant, antiangiogenic and antigenotoxic activities.     

Tuning the Au(I)-mediated inhibition of cathepsin B through ligand substitutions

It has been over 80 years since the antiarthritic properties of gold(I) complexes were first recognized. However, a detailed understanding of their mechanism of action has been slow to develop. One likely biological target of gold(I) is the cathepsin family of lysosomal cysteine proteases, enzymes involved in the inflammation and joint destruction that are hallmarks of rheumatoid arthritis (RA). We have previously shown that analogs of auranofin, a clinically available antiarthritic drug, inhibit cathepsin B. In this study, the extent to which the steric and electronic properties of the phosphine ligand can be modified to obtain enhanced potency against cathepsin B is investigated.     

香水莲花总提取物对小鼠急性酒精肝损伤的实验研究

目的:观察香水莲花提取物对酒精所致小鼠急性化学损伤的保护作用。方法:雄性昆明种小鼠70只,随机分为正常对照组、急性酒精肝损伤模型组、水飞蓟素阳性对照组(46.7 mg/kg)以及香水莲花低、中、高剂量组(120、180、240 mg/kg)共6组,检测肝组织甘油三酯(TG)、丙二醛(MDA)和还原型谷胱甘肽(GSH)含量,称量体重和肝脏重量。结果:香水莲花总提取物能够抑制急性酒精肝损伤小鼠肝组织的TG、MDA含量升高(P0.05),增加GSH含量(P0.05)。结论:香水莲花总提取物对急性酒精肝损伤有明显的保护作用。     

Silymarin alleviates hepatic oxidative stress and protects against metabolic disorders in high-fat diet-fed mice

Silymarin is a potent antioxidant medicine and has been widely used for the treatment of liver diseases over 30 years. Recent studies suggest that silymarin may benefit patients with glucose intolerance. However, the mechanism underlying the action of silymarin is not clarified. The aim of this work was to assess the impact of silymarin on glucose intolerance in high-fat diet (HFD)-fed mice, and explore the potential therapeutic mechanisms. C57BL/6 mice were fed with HFD for 12 weeks, randomized, and treated orally with vehicle saline or silymarin (30?mg/kg) daily for 30 days. We found that silymarin significantly improved HFD-induced body weight gain, glucose intolerance, and insulin resistance in mice. Silymarin treatment reduced HFD-increased oxidative stress indicators (reactive oxygen species, lipid peroxidation, protein oxidation) and restored HFD-down-regulated activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in the plasma and/or liver of the HFD-fed mice. Furthermore, silymarin decreased HFD-up-regulated hepatic NADPH oxidase expression and NF-κB activation in mice. Additionally, silymarin treatment mitigated HFD-increased plasma IL-1β, TNF-α levels, and HFD-enhanced hepatic NO, TLR4, and iNOS expression in mice. These novel data indicate that silymarin has potent anti-diabetic actions through alleviating oxidative stress and inflammatory response, partially by inhibiting hepatic NADPH oxidase expression and the NF-κB signaling.