Herbal medicine IMOD suppresses LPS-induced production of proinflammatory cytokines in human dendritic cells

Traditional medicines that stimulate or modulate the immune system can be used as innovative approaches to treat immunological diseases. The herbal medicine IMOD has been shown to strongly modulate immune responses in several animal studies as well as in clinical trials. However, little is known about the mechanisms of IMOD to modulate immunity. Here we have investigated whether IMOD modulates the immunological function of human dendritic cells (DCs). IMOD alone did not induce DC maturation nor production of cytokines. Notably, IMOD decreased the production of pro-inflammatory cytokines IL-6, IL-12 p70 and TNFα by LPS-activated DCs at both mRNA and protein levels in a dose dependent manner. In contrast, treatment with IMOD did not affect LPS induced-production of the anti-inflammatory cytokine IL-10. Furthermore, IMOD inhibited T cell activation/proliferation by LPS-treated DCs and skewed T-cells responses towards the T helper type 2 polarization. These data strongly indicate that IMOD has a potent immunomodulatory ability that affects TLR signaling and thereby modulates DC function. Insight into the immunomodulatory effect of herbal medicine IMOD may provide innovative strategies to affect the immune system and to help combat various disease

The role of 5 -nucleotidases and deoxynucleoside kinases in responses to nucleoside analogues

The efficacy of nucleoside analogues (NAs) in treating several hematological malignancies, solid tumors and viral infections is limited primarily by side-effects and the development of drug resistance. The aims of the present thesis were to elucidate mechanism(s) involved in tissue-specific toxicity associated with NA therapy, as well as the mechanisms underlying resistance to these drugs. The mRNA levels and activities of different cytosolic and mitochondrial deoxynucleoside kinases (dNKs) and 5'-nucleotidases (5'- NTs) exhibit a distinct pattern for each of a variety of mouse tissues. Heart and skeletal muscle, as well as adipose tissue demonstrate low levels of both the anabolic and catabolic enzymes, which may explain at least some of the adverse side-effects of NA treatment. A novel approach based on high-performance liquid chromatography (HPLC) revealed that each of 14 different mouse and rat tissues exhibits a unique profile of dNK and 5'NT activities, with 2-3-fold species differences for certain of these tissues. These observations have important implications for the choice of an animal model for characterization of NA toxicity. The cytotoxicity of gemcitabine (a cytidine-containing NA employed clinically to treat patients with cancer) towards human leukemia and melanoma cell lines rendered deficient in either deoxycytidine kinase (dCK) or deoxyguanosine kinase (dGK) with siRNA was compared to the corresponding toxicity towards cells that express these enzymes. Both types of deficient cells were more sensitive to gemcitabine, suggesting that, at least in this system, the toxicity of this drug is not correlated to the levels of activating enzymes. The activites of various 5'-NTs in peripheral blood cells isolated from CLL patients show considreble inter-individual variation. Degradation of the phosphorylated forms of cladribine and fludarabine, two important anti-leukemic NAs, was characterized in these cells. Significant correlations between the rate of cladribine monophosphate degradation and the activity of cytosolic 5'-nucleotidase 1 (CN1), as well as between the rate of fludarabine monophosphate degradation and the activity of cytosolic 5'-nucleotidase 2 (CN2) were observed. This investigation provides new insights regarding the patterns of expression of anabolic and catabolic enzymes that hopefully can be used to improve NA therapy in the future

Biochemical Alteration Induced by Cadmium and Lead in Common Carp via an Experimental Food Chain

Background: Evaluation on the toxicity of two mainly contaminant heavy metals, cadmium (Cd) and lead (Pb) through the food chain was the aim of this study. Methods: A total number of 270 healthy common carp (4±1.14 g) in April, 2015 transported to the Khatam Alanbia University of Technology, Behbahan, Iran. Fishes were divided into three groups and transferred to the 20 L aquaria each containing 30 juveniles. The first group (control) fed by metal-free Artemia fransiscan anauplii throughout the experiment. The second and third groups were feeding by Cd and Pb (1.5 mg/L free ion) contaminated nauplia, respectively. The experimental study was carried out for three weeks and sampling was done in 4th, 7th, 14th and 21st days. Finally, the alterations in plasma biochemical responses were determined. Results: Alanine aminotransferase and aspartate aminotransferase activities increased in response to feeding Pb-contaminated nauplia. Creatine phosphokinase activity showed significant increase in fourth day about both Cd and Pb and at the end of experiment only in Cd treatment (P<0.05). Cholesterol and triglyceride were increased significantly only for Pb (P<0.05). Plasma glucose and creatinine levels increased by both heavy metals compared to the control but glucose just remained high only for Pb at the end of the experiment. Total protein, albumin and globulin were significantly declined in both metal contaminated groups (P<0.05). Conclusion: It seems Pb had a greater toxicity than Cd through the food chain and it may be due to its more trophic transfer than Cd