Lactobacillus rhamnosus HN001 facilitates the efficacy of dual PI3K/mTOR inhibition prolonging cardiac transplant survival and enhancing antitumor effect.

Solid organ transplantation is a crucial treatment for patients who have reached the end stage of heart, lung, kidney, or liver failure. However, the likelihood of developing cancer post-transplantation increases. Additionally, primary malignant tumors remain a major obstacle to the long-term survival of transplanted organs. Therefore, it is essential to investigate effective therapies that can boost the immune system's ability to combat cancer and prevent allograft rejection. We established a mouse orthotopic liver tumor model and conducted allogeneic heterotopic heart transplantation. Various treatments were administered, and survival curves were generated using the Kaplan-Meier method. We also collected graft samples and measured inflammatory cytokine levels in the serum using an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. We administered a combination therapy of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 to primary liver cancer model mice with cardiac allografts. Consistent with our prior findings, L. rhamnosus HN001 alleviated the intestinal flora imbalance caused by BEZ235. Our previous research confirmed that the combination of BEZ235 and L. rhamnosus HN001 significantly prolonged cardiac transplant survival. IMPORTANCE: We observed that the combination of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 notably prolonged cardiac transplant survival while also inhibiting the progression of primary liver cancer. The combination therapy was efficacious in treating antitumor immunity and allograft rejection, as demonstrated by the efficacy results. We also found that this phenomenon was accompanied by the regulation of inflammatory IL-6 expression. Our study presents a novel and effective therapeutic approach to address antitumor immunity and prevent allograft rejection.

Targeting SIRT1 synergistically improves the antitumor effect of JQ-1 in hepatocellular carcinoma.

Bromodomain and extraterminal domain protein inhibitors have shown therapeutic promise in hepatocellular carcinoma. However, resistance to bromodomain and extraterminal domain protein inhibitors has emerged in preclinical trials, presenting an immense clinical challenge, and the mechanisms are unclear. In this study, we found that overexpression of SIRT1 induced by JQ-1, a bromodomain and extraterminal domain protein inhibitor, may confer resistance to JQ-1 in hepatocellular carcinoma. SIRT1 protein expression was higher in hepatocellular carcinoma tissues than in normal tissues, and this phenotype was correlated with a poor prognosis. Cotreatment with JQ-1 and the SIRT1 inhibitor EX527 synergistically suppressed proliferation and blocked cell cycle progression in hepatocellular carcinoma cells. Combined administration of JQ-1 and EX527 successfully reduced the tumor burden in vivo. In addition, JQ-1 mediated AMPK/p-AMPK axis activation to upregulate SIRT1 protein expression and enhanced autophagy to inhibit cell apoptosis. Activation of AMPK could alleviate the antitumor effect of the combination of JQ-1 and EX527 on hepatocellular carcinoma cells. Furthermore, inhibition of SIRT1 further enhanced the antitumor effect of JQ-1 by blocking protective autophagy in hepatocellular carcinoma. Our study proposes a novel and efficacious therapeutic strategy of a BET inhibitor combined with a SIRT1 inhibitor for hepatocellular carcinoma.

Cardiomyocytic cyclic GMP-AMP synthase is critical for the induction of experimental cardiac graft rejection.

OBJECTIVE: During cardiac transplantation, cellular injury and DNA damage can result in the accumulation of cytosolic double-stranded DNA (dsDNA), which can activate the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling pathway and thus induce multiple proinflammatory responses. However, the role of the cGAS-STING pathway in cardiac transplantation remains unclear. This study explored the role of cardiomyocytic cGAS in mouse heart transplantation during the ischemia/reperfusion and rejection processes. METHODS AND RESULTS: Cytosolic dsDNA accumulation and cGAS-STING signaling pathway component upregulation were observed in the grafts posttransplantation. The use of cGAS-deficient donor tissues led to significantly prolonged graft survival. The underlying mechanisms involved decreased expression and phosphorylation of downstream proteins, including TANK binding kinase 1 and nuclear factor κB. In parallel, notably diminished expression levels of various proinflammatory cytokines were observed. Accordingly, substantially decreased proportions of macrophages (CD11b+F4/80+) and CD8+ T cells were observed in the spleen. The activation of CD8+ T cells (CD8+CD69+) within the graft and the proportion of effector memory (CD44highCD62Llow) lymphocytes in the spleen were notably decreased. Treatment with the cGAS inhibitor Ru.521 led to significantly prolonged graft survival. CONCLUSIONS: Cardiomyocytic cGAS plays a critical role by sensing cytosolic dsDNA during cardiac transplantation and could serve as a potential therapeutic target to prevent graft rejection.