Prevention of nonalcoholic steatohepatitis in rats by two manganese-salen complexes

Nonalcoholic steatohepatitis [NASH], a progressive stage of nonalcoholic fatty liver disease [NAFLD], is characterized by steatosis with inflammation. Investigations have suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. To provide further insights into beneficial effects of antioxidants in NASH prevention, we employed two manganese-superoxide dismutase/catalase mimetics, manganese N,N-bis[salicyldene] ethylene diamine chloride [EUK-8] and manganese-3-methoxy N,N-bis[salicyldene] ethylenediamine chloride [EUK-134], as two salen representatives and vitamin C as the standard antioxidant Experimental NASH was induced in Male N-Mary rats by feeding a methionine/choline-deficient [MCD] diet to rats for 10 weeks. The rats [n = 5, 30 mg/kg/day] were randomly assigned to receive vitamin C, EUK-8, EUK-134 or vehicle orally Administration of salens together with the MCD diet reduced the serum aminotransferases, glutathione transferase and alkaline phosphatase, cholesterol, and LDL contents. In addition, the EUK-8 and EUK-134 improved NASH pathological features in liver of MCD-fed rats. EUK-8 and EUK-134 supplementation reduces NASH-induced abnormalities, pointing out that antioxidant strategy could be beneficial for prevention of NASH

Antioxidant and free radical scavenging potential of yakuchinone B derivatives in reduction of lipofuscin formation using H[2]O[2]-treated neuroblastoma cells

The progressive accumulation of misfolded and aggregated proteins in neurons is an accepted mechanism in aging. Overproduction of reactive oxygen species [ROS], referred to as oxidative stress, is currently believed to play a pivotal role in this process. Lipofuscin as a histological index of aging results from cross-links between oxidized proteins and lipids. Therefore, to attenuate lipofuscin formation, it would be logical to use exogenous natural or synthetic antioxidants. Yakuchinone B [1-[4'-hydroxy-3'-methoxyphenyl]-7-phenylhept-1-en- 3-one] is a component of Alpinia oxyphylla seeds with established antioxidant activity. To evaluate the neuroprotective roles of yakuchinone B [JC6] and its structural analogues [JC1-JC5], the free radical scavenging capabilities of yakuchinone B derivatives were studied in terms of cell viability, apoptosis, cells ROS content, catalase [CAT] and superoxide dismutase [SOD] activity and the intracellular lipofuscin content in SK-N-MC cells exposed to H[2]O[2]. The level of MDA [malondialdehyde], as an index of lipid peroxidation and acid phosphatase activity were also measured. Our results indicated that derivatives especially JC4, JC5 and JC6 decreased the extent of apoptosis and ROS level, while they increased the activities of SOD and CAT in drug-pretreated cells as compared to H[2]O[2]-treated cells. A clear relationship between the structure and antioxidant activities of these compounds was established. In addition, JC4, JC5 and JC6 were capable of down-regulating the formation of MDA and lipofuscin. Our results indicated that free radicals play significant roles in lipofuscin formation and cellular aging which can be attenuated by yakuchinone B derivatives

G1 phase arrest and apoptosis induction in human thyroid cancer cell line thr.C1.PI33 by 3-hydrogenkwadaphnin isolated from dendrostellera lessertii

Dendrostellera lessertii [Thymelaeaceae] is a toxic plant that grows in parts of Iran. The antiproliferative properties of its crude methanol extract and one of its active components, 3-hydrogenkwadaphnin [3-HK], have been established using several cancer cell lines. In a further attempt to determine the mode of action, two groups of synchronously growing cells were treated with a single dose of 3-HK [3.5 nM] and/or a single dose of the crude extract [equivalent to 0.36 mg plant powder]. Every 8 hours, the percentages of cells within G1, S, and G2-M phases were determined by flow cytometric [FCM] analysis; electron microscopic pictures were taken after fixation with 2% glutaraldehyde. Twelve hours after treatments, apoptotic cell death was confirmed by the observation of marked morphological changes of the plasma membrane as microvillar disappearance and the appearance of apoptotic bodies in the treated cells. FCM analyses revealed that the G1 phase arrest was under the influence of the pure substance. The results confirmed the previously drawn conclusion that the raw material and the pure substance from D. lessertii exert their anti-tumor effects through cell cycle arrest at G1 phase and diversion of cell fate toward programmed cell death

T-cell tolerance following bacterial glutamic acid decarboxylase [GAD] feeding in streptozotocin-induced diabetes

Autoimmune type 1 diabetes mellitus is caused by T-cell mediated immune destruction of the insulin-producing a-cell in pancreatic islets of Langerhans. Specificity of the auto-antibodies and of the auto-reactive T-cells has been investigated, in which several auto-antigens were proposed. To determine whether glutamic acid decarboxylase [GAD] feeding would induce oral tolerance of either T-cell or B-cell compartment in streptozotocin [STZ] diabetic rats. Rats in the experimental group were fed 2 mg/kg of GAD [extracted from Escherichia coli] 14 days before intra-peritoneal injections of streptozotocin [30 mg/kg body weight for 5 consecutive days]. Two control groups were considered: diabetic control group, which underwent STZ injections without receiving GAD, and normal control group. Systemic response was compared between the three groups. T-cells response was assessed by a proliferation assay of spleen cells and those of the B-cells by enzyme-linked immunosorbent assay [ELISA] for anti-GAD specific antibodies in serum. Compared with the diabetic control group, a significant reduction was observed only in the proliferative response of spleen cells, but not in the level of anti-GAD antibody. GAD feeding induces systemic T-cell tolerance in STZ-induced diabetes

anti-metastatic potency of gnidilatimonoein, from daphne mucronata, compared to two glycosylation inhibitors: castanospermine and tunicamycin

It is well known that the modification of oligosaccharide moieties of the cell surface glycoproteins modulates the adhesion and metastatic potential of several cancerous cell lines. Based on this knowledge, the anti-metastatic property of Daphne mucronata crude extract and one of its newly characterized active component, Gnidilatimonoein, were evaluated in wehi-164 cells by measuring their adhesion to fibronectin coated plates, relative to Castanospermine and Tunicamycin treated cells.Twenty four hours after treatment of the cells with the plant crude extract [equivalent to 0.54 mg of the plant leaves powder/ml], Gnidilatimonoein [0.94 nM], Castanospermine [2.6 micro M] and/or Tunicamycin [2.4 micro M], their attachment to fibronectin-coated wells were depressed, by 24%, 30%, 26% and 58%, respectively. This data may classify the new anticancer compound, Gnidilatimonoein, as a strong glycosylation inhibitor

effect of gnidilatimonoein from daphne mucronata, on the adhesive property of human platelets

The adhesive interaction between tumor cells and the host cells or the extracellular matrix plays a crucial role in tumor metastasis. To evaluate the mediation of cell adhesion by Daphne mucronata, an anti-cancer medicinal plant in Iranian folk medicine, the adhesion of thrombin activated human platelets to the cultured monocytes or HL-60 cells was investigated under the effect of the plant extract [0.54 mg/ml] or one of its purified components [gnidilatimonoein, 0.94 micro M]. Treatment of the platelets with the plant extract or the active component, for various time intervals, followed by their activation by thrombin resulted in 80-90% reduction in the number of monocytes with more than 10 attached platelets. Similarly, under almost all identical conditions, the adhesion of the activated platelets to HL-60 cells was decreased by 90%. The adhesion of thrombin activated human platelets to the plant treated HL-60 cells was also reduced significantly [by 95%]. These data clearly indicate that Daphne mucronata is capable of mediating tumor metastasis through effecting cell adhesion properties of the cells

Anti - tumor activity and cell cycle arrest of a new diterpene ester from daphne mucronata using K562 cells

In our search for new anticancer medicinal plants, the antiproliferative activity of the methanol extract of Daphne mucronata [Thymelaeaceae] was evaluated using human myelogenous leukemia K562 cells. The cells responded to plant treatments in a dose dependent manner and the IC50 of the crude extract [equivalent to 1 g of plant leaves powder per ml] and the purified active component were found to be 42 micro l and 1.3 micro M, respectively. The antiproliferative activity of the plant was also evaluated using flow cytometry technique. The results indicated that the crude extract and the active purified component are capable of arresting the cells in G1 phase of the cell progression cycle. This data may provide a mechanism for the antiproliferative action of the plant

Prevention of experimental autoimmune vitiligo by oral administration of mushroom tyrosinase

Experimental autoimmune vitiligo was induced by the intradermal injection of the purified mushroom tyrosinase emulsified in Complete Freund's Adjuvant [CFA] in female C57BL/6 mice. The onset of vitiligo was characterized by hair hypopigmentation and total melanocyte depletion in the basal layer of the epidermis. Oral administration of semipurified mushroom tyrosinase prevented experimental autoimmune vitiligo [EAV]. Suppression of clinical and histological disease was observed when animals received mushroom tyrosinase. A decrease in lymphocyte proliferation, delayed type hypersensitivity responses, increase in humoral immunity of the mice may all suggest that the suppression of the disease is correlated with cellular immune responses suppression. Based on our data, it may be concluded that the oral administration of the mushroom tyrosinase may have practical implications in vitiligo