18ß-glycyrrhetinic acid suppresses Lewis lung cancer growth through protecting immune cells from ferroptosis.

PURPOSE: 18ß-glycyrrhetinic acid (GA), the main metabolite of glycyrrhizic acid extracted from the root of licorice, has been reported to possess anti-cancer and immunomodulatory activity, but the mechanisms are not well understood. Recent studies have shown that ferroptosis of immune cells is involved in tumor-associated immune suppression. The purpose of this study was to investigate whether the enhanced immune response via inhibiting immune cell ferroptosis contributed to the anticancer effect of 18ß-GA. METHODS: Lewis Lung carcinoma mouse model and Murine CD8 + T cell culture model were used to examine the changes of immune response and ferroptosis of immune cells. RESULTS: We found that 18ß-GA was effective against lung cancer accompanied by enhanced activation of tumor-infiltrating CD8+ T cells in Lewis Lung carcinoma mouse model. Furthermore, we demonstrated that the boosted immune response by GA was attributed to its ability to inhibit arachidonic acid (AA)-mediated CD8+ T ferroptosis via suppressing CD36 expression. CONCLUSION: The findings of the present study unraveled a novel mechanism underlying the anti-cancer and immunomodulatory activity of 18ß-GA and support that 18ß-GA holds potential to be used as an immune enhancer for lung cancer prevention or treatment.

Delta-tocotrienol disrupts PD-L1 glycosylation and reverses PD-L1-mediated immune suppression.

PD-L1-mediated immune escape plays an important role in cancer development and progression. Targeting PD-L1 is consider to be an attractive approach for cancer treatment. PD-L1 is a heavily N-linked glycosylated protein, and the glycosylation of PD-L1 is essential for its ability to interact with its receptor PD-1 to mediate immune suppression. In the present study, we demonstrated for the first time that delta-tocotrienol (δ-T3) not any of the other forms of vitamin E was able to disrupt PD-L1 glycosylation mechanistically associated with the suppression of TCF4-STT3a/STT3b axis. The inhibition of PD-L1 glycosylation by δ-T3 resulted in the decrease of PD-L1 expression and its exosomal secretion, leading to the reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. The findings of the present study provide a novel mechanistic interpretation for the superior anticancer activity of δ-T3 among 8 isomers of the vitamin E.

Inhibition of PD-L1-mediated tumor-promoting signaling is involved in the anti-cancer activity of ß-tocotrienol.

Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is commonly overexpressed on the surface of many tumor types including lung and prostate cancer. PD-L1 can exert cancer-promoting activity through either suppressing T cell-mediated immune response or activating tumor-intrinsic signaling. Here, we demonstrated that ß-tocotrienol (ß-T3), an isomer of vitamin E, effectively inhibited PD-L1 expression both in vitro and in vivo, which was mechanistically associated inactivating JAK2/STAT3 pathway. Down-regulating PD-L1 expression by ß-T3 led to enhanced immune response and inactivation of PD-L1-induced tumor-intrinsic signaling, which in turn contributed to its anticancer activity. This study uncovered a novel mechanism involved in the anticancer effect of ß-T3.

Involvement of PD-L1-mediated tumor-intrinsic signaling and immune suppression in tumorigenic effect of α-tocopherol.

Numerous studies have shown that the different isoforms vitamin E have distinct activity on carcinogenesis. α-Tocopherol (α-T), the most abundant vitamin E in certain types of food and animal tissues, has demonstrated a cancer-promoting effect in a number of human clinical trials and pre-clinical studies, whereas the γ- and δ- forms of Tocopherols and Tocotrienols have exhibited significant anticancer effect in various pre-clinical studies. However, the mechanisms underlying the tumorigenic effect of α-T have not yet been fully understood. In the present study, we found that α-T was able to activate programmed death-ligand 1 (PD-L1)-mediated tumor-intrinsic signaling and immune suppression via JAK/STAT3-dependent transcriptional and ERK-dependent post-transcriptional mechanism. In line with PD-L1 induction, α-T treatment increased cancer cell viability in vitro and promoted tumor growth in LLC xenograft mouse model. The findings of the present study for the first time provided evidence that PD-L1-mediated tumor-intrinsic and immune escape mechanism contributed to the tumorigenic effect of α-T.

Trimethylamine N-oxide exacerbates acetaminophen-induced liver injury by interfering with macrophage-mediated liver regeneration.

Acetaminophen (APAP)-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Trimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota and is relatively high in the circulation of the elderly, individuals with diabetes, and heart disease. Herein, we showed that TMAO exacerbates APAP hepatotoxicity. It is possible that delayed liver repair and regeneration that resulted from reduced macrophage accumulation was responsible for this combined hepatotoxicity. Moreover, matrix metalloproteinase 12 (Mmp12), expressed predominantly by macrophages, were reduced by TMAO in vitro and in vivo. This led to the inhibition of macrophage migration and a subsequent decrease in the recruitment of proresolving macrophages to the necrosis area. Furthermore, the administration of recombinant Mmp12 mitigated the enhanced hepatotoxicity in mice cotreated with TMAO and APAP. Overall, this study indicates that TMAO exacerbates APAP-induced hepatotoxicity by hindering macrophage-mediated liver repair, which might stem from the inhibition of Mmp12. These findings imply that liver damage in patients with high levels of circulating TMAO may be more severe in AILI and should exercise caution when treating with NAC.

PD-L1 positively regulates MET phosphorylation through inhibiting PTP1B.

Increasing bodies of evidence support the involvement of tumor-intrinsic action in PD-L1-mediated cancer progression. However, the mechanisms underlying the tumor-intrinsic function of PD-L1 are less well understood. In the present study, we found a positive correlation between PD-L1 expression and MET phosphorylation in lung cancer and melanoma cell lines. PD-L1 inhibition led to a decrease in MET phosphorylation, while PD-L1 induction by IFN-γ resulted in a PD-L1-dependent increase of MET phosphorylation both in vitro and in vivo. The results indicated that MET phosphorylation can be positively regulated by PD-L1. Furthermore, we identified PTP1B as a mediator contributing to the regulation of MET phosphorylation by PD-L1. In agreement with the induction of MET phosphorylation by PD-L1, inhibition of PD-L1 caused reduced phosphorylation of ERKs, a known downstream kinase of MET, and inhibited cell proliferation. Collectively, the present study demonstrated for the first time that the MET pathway, as a downstream of PD-L1, contributed to its tumor-intrinsic effect, and provided a novel mechanistic explanation for the tumor-intrinsic function of PD-L1 and a rationale for the combination of immunotherapy and MET-targeted therapy in cancer treatment.

Apple phlorizin attenuates oxidative stress in Drosophila melanogaster.

Apple phlorizin has a lot of applications owing to its antioxidant and hepatoprotective properties. This study explored the antioxidant effects and life span-prolonging activity of apple phlorizin in Drosophila melanogaster. Treatment with apple phlorizin was found to significantly extend the life span and ameliorate the age-related decline of locomotor function. This life span-extending activity was associated with the increased activity of superoxide dismutase, catalase, mRNA expression of glutamate-cysteine ligase catalytic subunit, cap-n-collar (cnc, homologue of mammalian Nrf2 gene), Keap1, and deacetylase sir2, as well as the downregulation of methuselah. Computational analysis suggested phlorizin could work as a Nrf2 activator and exert its biological activities by interfering with the Keap1 and Nrf2 binding. Therefore, it was concluded that the antioxidant and anti-aging effects of phlorizin might, at least in part, be mediated through the cooperation with the endogenous stress defense system. PRACTICAL APPLICATIONS: Phlorizin, from apple peel, has been used as a nutrient for over 100 years. To date, despite extensive research on phlorizin, a report on its effect on the antioxidant system in fruit flies is yet lacking. This report demonstrates that phlorizin can exert a protective effect on antioxidant issues and prolong life in fruit flies, which is valuable in the rational utilization of phlorizin in functional foods.