Traditionally, Centella asiatica leaf extracts are used to treat neurodegenerative diseases in India. Centella asiatica is reportedly used to enhance memory and treat dementia, but its promoting effect on neural stem cell differentiation has not been studied yet. In the present study, we investigated whether or not Centella asiatica leaf extracts act on neuronal precursor cells and neuronal cell lines to induce neuronal differentiation, neurite outgrowth, and neuroprotection. The neurogenesis-promoting potential of Centella asiatica leaf extracts was determined by differentiation assay on neural stem cells isolated from mouse embryos and PC12 cell lines. To understand the contribution of specific neural cell types towards increase after Centella asiatica treatment, neural stem cells were differentiated into various neural subtypes and checked by Western blotting using neural cell lineage-specific antibody markers. Neuroprotective activity of Centella asiatica was analyzed in PC12 cells exposed to 100 μM of H2O2. Cell growth was analyzed by MTT assay while cell death was analyzed by Western blotting detection of apoptosis-related proteins. Cells treated with Centella asiatica had significantly longer primary and secondary neurites as well as a higher number of neurites per cell compared to control cells. Expression levels of TUBBIII, TH, NF, and BDNF increased upon Centella asiatica treatment, suggesting that Centella asiatica has a neurogenesis-promoting effect. Centella asiatica also inhibited oxidative stress-induced neural cell damage through regulation of apoptosis- and cell cycle-related proteins. Thus, leaf extracts of Centella asiatica might promote neurogenesis, neuroregeneration, and neuroprotection in the context of neurodegenerative diseases.
Human natural killer (NK) cells are major players in innate immune response. The functions of these cells as a scavenger of cancer cells are enhanced by cytokines such as interleukin-2 (IL-2), which play an important role in immune response in both tumors and virally infected cells. Liver cancer has a high incidence rate and is a major cause of death in Korea. We provide evidence that human NK cells inhibit tumor growth of the hepatocellular carcinoma cell line SNU-354. NK cells were cultured with human IL-2 for 14 days, yielding an enriched NK cell population containing 35% CD8+ cells, 6% CD4+ cells, and 51% CD16+ /CD56+ cells. Intravenous injection of NK cells at doses from 2.5 to 10 million cells/mouse was administered once per week in a nude mouse model that retains human liver tumor induced by implantation of SNU-354 cells. The results showed that human NK cells were recruited within tumor tissue and inhibited SNU-354 tumor growth by 32%, 58%, and 65%. The current data suggest the potential for use of NK cell-based immunotherapy for treatment of human liver cancer.
Cytokines are known to function as regulatory molecules that can be produced by virtually every nucleated cell type in the body, including lymphocytes, monocytes/macrophages, epithelial cells, fibroblasts, and many others. Cytokines include lymphocyte-derived factors (lymphokines), monocyte-derived factors (monokines), hematopoietic factors (colony-stimulating factors), connective tissue/ growth factors, and chemotactic chemokines. Cytokines released in response to infection can affect tumor development in different ways. When exposed to infectious agents, cytokines are secreted by sentinel cells, such as macrophages and dendritic cells. These cytokines include interleukin 1 (IL-1) and tumor necrosis factor-α, as well as others, such as IL-6, IL-12, and IL-18. When released in sufficient quantities, these molecules can cause inflammation. Chronic inflammation is highly associated with tumor initiation, promotion, and progression. In this article, we review the roles and mechanisms of cytokines in tumor development.
The objective of this study was to determine the effect of macrophages on growth of human colon cancer cells. The results showed that co-culture of colon cancer cells with macrophages inhibited the growth of colon cancer cells (HCT116 and SW620) depending on the number of macrophages, RAW 264.7 cells, and activated THP-1 cells accompanied by down regulation of pSTAT3 in cancer cells. We also found that expression and release of cancer cell growth inhibitory cytokines, IL-1 receptor antagonist (IL-1ra) and IL-10, was increased in macrophages. Blocking of the STAT3 pathway with specific inhibitor and siRNA of STAT3 abolished the growth of colon cancer cells and expression of IL-1ra and IL-10. In addition, neutralization of IL-1ra and IL-10 with antibodies resulted in reversal of macrophage-induced inhibition of cancer cell growth. These data showed that IL-1ra and IL-10 released from macrophages inhibit growth of colon cancer cells through inhibition of the STAT3 pathway.
Chronic inflammatory diseases such as Crohn′s disease and ulcerative colitis are associated with increased risk of colon adenocarcinoma. Apoptic induction of colon cancer cells by cytokines and death receptors is an important anti-cancer therapy. We observed that co-administration of TNFα and IFNγ in human colon cancer cell line, HCT116, resulted in cell death and expression of IL-32. Cleavage forms of caspase-3, caspase-9, and PARP were increased in TNFα / IFNγ-treated HCT116. mRNA expression of death receptors, including TNFR1 and Fas were not changed and NO generation was not induced by combination of TNFα and IFNγ. However, mRNA expression of IL-32α, β, and γ was increased in TNFα / IFNγ-treated HCT116. To determine the effect of IL-32 in HCT116 cell apoptosis by TNFα / IFNγ stimulation, IL-32 siRNA-transfected HCT116 cells were cultured with TNFα / IFNγ and cell proliferation was measured. IL-32 siRNA induced slight recovery of cell viability of TNFα / IFNγ-stimulated HCT116. These results suggest that IL-32 is not directly related to apoptosis of HCT116 by TNFα / IFNγ stimulation. However, IL-32 expression by TNFα or TNFα / IFNγ in a colon cancer cell line is very interesting because of the unknown effect of IL-32 in colon cancer. Our study will contribute to development of studies for IL-32 function in human colon cancer and anti-cancer therapies using cytokines.
The Maillard Reaction Products (MRPs) such as Glucose-tyrosine (Glu-Tyr) and Xylose-arginine (Xyl-Arg) have antioxidant, antimutagenic, and antibacterial effects. However, to date, still little is known about the other biological effects of the MRPs. In this study, we investigated whether the fructose-tyrosine MRP, 2,4-bis(p-hydroxyphenyl)-2-butenal (Fru-Tyr), could modulate cell cycle progression and NF-κB activity, and thereby induce apoptotic cell death of colon cancer cells. Treatment with different concentrations (10-40 μg/ ml) of Fru-Tyr for 24 h inhibited colon cancer cell (SW620 and HCT116) growth followed by induction of G2/M phase cell cycle arrest and apoptosis in a dose-dependent manner. We also found that Fru-Tyr suppressed tumor necrosis factor-alpha (TNF-α)-induced NF-κB transcriptional activity. Moreover, Fru-Tyr induced the expression of apoptotic gene, cleaved caspse-3. These results suggest that Fru-Tyr inhibited colon cancer cell growth through induction of G2/M phase cell cycle arrest and apoptotic cell death by modulating of NF-κB.