Identification of novel probiotic strains is of great interest in the field of functional foods. Specific strains of heat-killed bacteria have been reported to exert immunomodulatory effects. Herein, we investigated the immune-stimulatory function of heat-killed Lactobacillus plantarum KCTC 13314BP (LBP). Treatment with LBP significantly increased the production of TNF-α and IL-6 by macrophages. More importantly, LBP was able to enhance the phagocytic activity of macrophages against bacterial particles. Activation of p38, JNK, ERK, NF-κB, and STAT3 was involved in the immunomodulatory function of LBP. LBP treatment significantly increased production of TNF-α by bone marrow-derived macrophages and splenocytes, further confirming the immunostimulatory effect of LBP in primary immune cells. Interestingly, the immunomodulatory effects of LBP were much stronger than those of Lactobacillus rhamnosus GG, a well-known probiotic strain. These results indicate that LBP can be a promising immune-enhancing functional food agent.

Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.

Removal of sugar moieties from ginsenosides has been proposed to increase their biological effects in various disease models. In order to identify strains that can increase aglycone contents, we performed a screening using bacteria isolated from the feces of infants focusing on acid tolerance and β-glucosidase activity. We isolated 565 bacteria and selected Bifidobacterium animalis subsp. lactis LT 19-2 (LT 19-2), which exhibited the highest β-glucosidase activity with strong acid tolerance. As red ginseng (RG) has been known to exert immunomodulatory functions, we fermented RG using LT 19-2 (FRG) and investigated whether this could alter the aglycone profile of ginsenosides and improve its immunomodulatory effect. FRG increased macrophage activity more potently compared to RG, demonstrated by higher TNF-α and IL-6 production. More importantly, the FRG treatment stimulated the proliferation of mouse splenocytes and increased TNF-α levels in bone marrow-derived macrophages, confirming that the enhanced immunomodulatory function can be recapitulated in primary immune cells. Examination of the molecular mechanism revealed that F-RG could induce phosphorylations of ERK, p38, JNK, and NF-κB. Analysis of the ginsenoside composition showed a decrease in Rb1, Re, Rc, and Rb3, accompanied by an increase in Rd, Rh1, F2, and Rg3, the corresponding aglycone metabolites, in FRG compared to RG. Collectively, LT 19-2 maybe used as a probiotic strain to improve the bioactivity of functional foods through modifying the aglycone/glycoside profile.

There is an increasing interest in using inactivated probiotics to modulate the host immune system and protect against pathogens. As the immunomodulatory function of heat-killed Lactobacillus brevis KCTC 12777BP (LBB) and its mechanism is unclear, we investigated the effect of LBB on immune response based on the hypothesis that LBB might exert stimulatory effects on immunity. In the current study, we demonstrate that administration of LBB can exert immune-stimulatory effects and promote clearance of foreign matters through enhancing phagocytosis. Treatment with LBB induced the production of TNF-α, IL-6, and nitric oxide in macrophages. Importantly, LBB directly increased the phagocytic activity of macrophages against bacterial particles. LBB was able to promote the production of TNF-α in bone marrow-derived macrophages and splenocytes and also increase the proliferation rate of splenocytes, suggesting that the immune-stimulating activity of LBB can be observed in primary immune cells. Investigation into the molecular mechanism responsible revealed that LBB upregulates TAK1 activity and its downstream ERK, p38, and JNK signaling pathways. To further confirm the immunomodulatory capability of LBB in vivo, we orally administered LBB to mice and assessed the effect on primary splenocytes. Splenocytes isolated from LBB-treated mice exhibited higher TNF-α expression and proliferative capacity. These results show that heat-killed L. brevis, a wildly consumed probiotic, may provide protection against pathogens through enhancing host immunity.

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