ABSTRACT
ArtinM is a d-mannose-binding lectin found in the seeds of Artocarpus heterophyllus (jackfruit) that interacts with N-glycans, that is associated with receptors on the surface of phagocytic cells and induces the production of inflammatory mediators. Some of them are especially important because they may be required for antitumor immune response. This study aimed to evaluate the effect of ArtinM on hepatocellular preneoplastic foci. Wistar rats received 50 mg/kg of diethyl-nitrosamine (DEN) intraperitoneal weekly for 12 weeks. From the 14th week, the treated animals received 50 µg/kg of ArtinM subcutaneous every 2 weeks until the 18th week, whereas control animals were injected with vehicle alone. Preneoplastic-related factors were estimated using histological, western blotting and RT-PCR analysis. In comparison to the groups exposed to DEN, the ArtinM-treated rats showed diminution of preneoplastic foci, decreased expression of proliferating cell nuclear antigen (PCNA), increased number of nuclear p21 and p27 stained cells, augmented number of apoptotic cells, increased expression of p53, p42/44 MAPK and p21 proteins, reduced cyclin D1 (CCND1) protein levels and increased expression of TNFα and IFNγ genes. No difference was observed in interleukin 12 (IL12) protein levels. These findings indicate that ArtinM may provide protection against hepatocarcinogenesis as a result of the induction of cell-cycle blockage and pro-apoptotic mechanisms.
Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Liver Neoplasms/prevention & control , Mannose-Binding Lectin/pharmacology , Precancerous Conditions/prevention & control , Animals , Apoptosis/genetics , Apoptosis Regulatory Proteins/metabolism , Artocarpus/chemistry , Blotting, Western , Cell Proliferation/genetics , Cyclin D1/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Interferon-gamma/genetics , Interleukin-12/genetics , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Male , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phytotherapy , Precancerous Conditions/genetics , Precancerous Conditions/metabolism , Proliferating Cell Nuclear Antigen/metabolism , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/geneticsABSTRACT
To investigate the relationship between NF-kappaB activation and hepatic stellate cell (HSC) apoptosis in hepatosplenic schistosomiasis, hepatic biopsies from patients with Schistosoma mansoni-induced periportal fibrosis, hepatitis C virus-induced cirrhosis, and normal liver were submitted to alpha-smooth muscle actin (alpha-SMA) and NF-kappaB p65 immunohistochemistry, as well as to NF-kappaB Southwestern histochemistry and TUNEL assay. The numbers of alpha-SMA-positive cells and NF-kappaB- and NF-kappaB p65-positive HSC nuclei were reduced in schistosomal fibrosis relative to liver cirrhosis. In addition, increased HSC NF-kappaB p65 and TUNEL labeling was observed in schistosomiasis when compared to cirrhosis.These results suggest a possible relationship between the slight activation of the NF-kappaB complex and the increase of apoptotic HSC number in schistosome-induced fibrosis, taking place to a reduced HSC number in schistosomiasis in relation to liver cirrhosis. Therefore, the NF-kappaB pathway may constitute an important down-regulatory mechanism in the pathogenesis of human schistosomiasis mansoni, although further studies are needed to refine the understanding of this process.
