Glioma, especially glioblastoma, is pathologically characterized by high aggressiveness, which largely contributed to the ineffectiveness of current therapies. It has been recently reported that intrinsic PD-L1 can regulate tumor malignancy, whereas underlying mechanisms remain mostly unclear. Here, we report a novel mechanism by which PD-L1 promotes glioma cell infiltration. In orthotopic glioma models, PD-L1 expression was up-regulated predominantly in glioma cells in the infiltrating front. For PD-L1-overexpressed glioma cells, PI3K/Akt and actin regulations were among the top six most altered signaling pathways as detected by RNA-sequencing. PD-L1 significantly activated Akt/F-actin signaling while suppressed autophagic signaling upon cell starvation. Mechanistically, PD-L1 preferentially bound to Akt among various PI3K/Akt signaling proteins. Serial truncation identified the interaction between the 128-237aa fragment of PD-L1 and the 112-480aa fragment of Akt, which facilitates the membrane translocation/activation of Akt, and was unaffected by Perifosin (specific p-Akt inhibitor targeting Akt PH-domain). Taken together, our data indicate that in glioma cells, PD-L1 is induced to prevent autophagic cytoskeleton collapse via Akt binding/activation, facilitating glioma cell invasion upon starvation stress.

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The current study aimed to explore the antitumor effect of β-caryophyllene (BCP) on two different cell lines of T24 and 5637 human bladder cancer (BC) cells and its potential molecular mechanisms in inhibition of STAT-3/mTOR/AKT signaling pathways and the inductive process of apoptosis mechanism. The results indicated that BCP showed significant cytotoxicity in BC T24 and 5637 cells in a doseand time-dependent manner, and IC 50 values were 40 µg/ml in the BC cells T24 and 5637. Reactive oxygen species (ROS) synthesis and apoptosis induction were significantly developed, but the mitochondrial membrane potential (Δψm) decreased on BCP treatment as detected by the fluorescence method. Moreover, cell migration was markedly reduced in BCP and Bax, Bcl-2 mRNA expression was modified. Finally, it was found that the STAT-3, mTOR, and AKT protein expressions were suppressed via inhibition of cytotoxicity in T24 and 5637 cells. Therefore, we finally concluded that BCP is an effective treatment against BC T24 and 5637 cells, and it has great chemotherapeutic potential for further bladder carcinoma treatment.

Meta-analyses of randomised controlled trials (RCTs) report that polyphenol-rich diets can modulate a range of cardiometabolic biomarkers, with increasing evidence that inter-individual factors (e.g. age, BMI, or ethnicity) contribute toward the variability in the response to the bioactive (1,2). This systematic review and meta-analysis assessed the effect of flavanols from cocoa, apple and tea on fasting insulin and HOMA-IR and explored the role of inter-individual variability. PubMed and Web of Science databases were searched from inception to October 2017 (PROSPERO reg. CRD42016033878). The effect of flavanols supplementation on insulin and HOMA-IR was estimated using a random effects meta-analysis model and reported as standardised mean difference (SMD) and 95%CI. Subgroup analyses (Q tests; multivariate meta-regression) focused on baseline BMI, gender, age, and geographical location to explore the role of inter-individual variability. Out of 1409 studies identified, 31 RCTs were included for insulin (n = 1792) and 21 RCTs for HOMA-IR (n = 1152). Low heterogeneity was found between studies (insulin I 2 = 0%, p = 0.98; HOMA-IR I 2 = 5.9%, p = 0.38) with evidence of low publication bias. Flavanol-rich interventions (2-26 weeks; 88 to 1344 mg flavanols/day) decreased both insulin (SMD −0.25, 95% CI −0.33; −0.16) and HOMA-IR (SMD −0.26; 95% CI −0.36, −0.16). Results were consistent across subgroups (Q tests) with lack of effect in subgroups with BMI<25 or male subjects only; multivariate meta-regression showed that baseline BMI (overweight versus lean, coef. −1.07; 95% CI −2.03, −0.08; p = 0.03) and study location (Asia versus other sites, coef. 0.94; 95% CI 0.03,1.84; p = 0.04) impacted on the effect on HOMA-IR significantly. There was no impact of age, gender, baseline BMI or geographical location on the effect on insulin. Flavanols from tea, apple and cocoa were effective in modulating insulin and HOMA-IR. Inter-individual variability in the response was limited in contrast to previous studies (1,2). This could be partly explained by the small number of trials reporting data for specific subgroups, and the broad range of doses and duration tested among the studies.