Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4

Abstract

Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent.

Polysaccharides from pectinase digests of green tea enhances host immune defence through toll-like receptor 4

“…The binding of polysaccharides to TLR4 is a critical event in immune activation (Tewari et al, 2017). iNOS and TNF-α signalling pathway is activated by TLR4 and transduced via mitogen-activated protein kinases MAPKs (ERK, p38 and JNK), NFκB as well as a Janus tyrosine kinase (JAK) and signal transducers and activators of transcription (STATs) (Chang, Kim, Lee, Park, & Kim, 2015;Zhou et al, 2015). PPGT was found to increase the phosphorylation of ERK, JNK, p38, IKK, and STAT-1 in a dose-dependent manner.…”

“…RAW264.7 (1 × 10 5 cells/well) were incubated in a 96-well plate with 10, 30, or 100 μg/mL PPGT for 24 h. NO was measured by determining the concentration of nitrite, its stable oxidative metabolite, using a microplate assay according to a previously described method (Chang et al, 2015).…”

Follistatin‐like protein 1 contributes to dendritic cell and T‐lymphocyte activation in nasopharyngeal carcinoma patients by altering nuclear factor κb and Jun N‐terminal kinase expression

“…Moreover, NF‐κb up‐regulation enhances T‐cell immunity . MFE can increase NK cell and cytotoxic T‐lymphocyte activity by activating NF‐κb to generate IFN‐γ . Medicines can also suppress NF‐κb to inhibit the immune response, which leads to carcinoma cell escape .…”

“…43 MFE can increase NK cell and cytotoxic T-lymphocyte activity by activating NF-κb to generate IFN-γ. 44 Medicines can also suppress NF-κb to inhibit the immune response, which leads to carcinoma cell escape. 45 Our results indicated that the addition of FSTL1 downregulated JNK expression, thereby enhancing immune activity ( Figures 4C and 4E).…”

An immunological perspective for preventing cancer with berries

“…Morus alba L. (white mulberry), found in Asia, has been traditionally used in Korea [55]. When orally given to BALB/c mice bearing CT26 colon tumors for 3 weeks, M. alba L. fruit extract (MFE) at a dose of 300 mg/kg of body weight, which was equivalent to 24.3 mg/kg human body weight, has been shown to significantly enhance the anti-tumor activity when in combination with 5-fluorouracil, and strongly promote NK cell activity, cytotoxic T lymphocyte activity, and IFN-γ production in spleen [55].…”