Aberrant activation of the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(PKB,Akt)-mammalian target of rapamycin(mTOR) pathway is commonly observed in human cancer and is critical for cell survival, proliferation and differentiation.A variety of small molecule inhibitors targeting PI3K-Akt-mTOR pathway are under clinical studies.This review will summarize the recent studies in terms of the PI3K-Akt-mTOR signaling pathway and cancer,research progress of the antitumor activity possessed by PI3K-Akt-mTOR inhibitors,as well as the recent research in the related field conducted by our group.

Objective:To explore the effects of serum triglyceride (STAG) level within 48 hours after hospitalization on the complications of acute pancreatitis (AP).Methods:From January 2012 to June 2016, 1 006 hospitalized patients diagnosed with AP at the Third People′s Hospital of Chengdu were collected. According to the STAG level within 48 hours after hospitalization, AP patients were divided into normal to mild hypertriglyceridemia (HTG) group(STAG <2.3 mmol/L, 877 cases), moderate HTG group(STAG: 2.3 to <8.5 mmol/L, 82 cases) and severe HTG group (≥8.5 mmol/L, 47 cases). The general clinical data and the incidence of local complications of AP including acute necrotizing pancreatitis, pancreatic necrosis, acute peripancreatic fluid collection (APFC) and acute necrotic collection (ANC) and AP-associated gastrointestinal abnormal changes were compared in the three groups. The severity of the complications of AP was scored by modified-magnetic resonance severity index (M-MRSI). Wilcoxon rank sum test and chi-square test were used for statistical analysis, and multivariate logistic regression analysis was used to analyze the correlation between STAG level and persistent organ failure (POF).Results:Compared with that of the normal to mild HTG group and moderate HTG group, the age of the patients of the severe HTG group was the youngest (52 years old, 19 to 82 years old and 47 years old, 21 to 62 years old vs. 35 years old, 18 to 43 years old), the proportion of male was the highest (46.3%, 406/877 and 64.6%, 53/82 vs. 85.1%, 40/47), and the differences were statistically significant( Z=3.943, 2.841, χ2=26.912, 6.224, all P<0.017). The proportion of body mass index (BMI)≥30 kg/m 2 in severe HTG group was higher than that in normal to mild HTG group (38.3%, 18/47 vs. 20.2%, 177/877), and the difference was statistically significant ( χ2=8.792, P=0.003). The proportions of patients with history of diabetes and severe alcohol intake of moderate HTG group and severe HTG group were all higher than those of normal to mild HTG group (31.7%, 26/82 and 29.8%, 14/47 vs. 15.4%, 135/877; 37.8%, 31/82 and 46.8%, 22/47 vs. 9.6%, 84/877), and the differences were statistically significant ( χ2=14.286, 6.833, 56.613 and 60.844, all P<0.017). Compared with those of the normal to mild HTG group and moderate HTG group, the incidences of pancreatic necrosis, APFC, and the M-MRSI score of the severe HTG group were all the highest (8.2%, 72/877 and 15.9%, 13/82 vs. 38.3%, 18/47; 17.8%, 156/877 and 36.6%, 30/82 vs. 59.6%, 28/47; 2, 0 to 10 and 3, 0 to 10 vs. 5, 0 to 10), and the differences were statistically significant( χ2=45.936, 8.244, 48.842 and 6.381, Z=2.711 and 3.049, all P<0.017). The incidence rates of acute necrotizing pancreatitis and ANC of moderate HTG group and severe HTG group were all higher than those of normal to mild HTG group(28.0%, 23/82 and 48.9%, 23/47 vs. 13.3%, 117/877; 26.8%, 22/82 and 42.6%, 20/47 vs. 13.3%, 117/877), and the differences were statistically significant ( χ2=13.011, 43.965, 11.008 and 30.144, all P<0.017). The incidence rate of POF of severe HTG group was higher than those of normal to mild HTG group and moderate HTG group (46.8%, 22/47 vs.14.8%, 130/877 and 24.4%, 20/82), and the differences were statistically significant ( χ2=33.205 and 6.838, both P<0.017). The results of multivariate logistic regression analysis showed that age ≥ 60 years old (odds ratio ( OR)=1.84, 95% confidence interval ( CI) 1.26 to 3.03), BMI≥30 kg/m 2 ( OR=2.41, 95% CI 1.61 to 3.77), alcohol intake ( OR=3.81, 95% CI 2.09 to 5.47), moderate HTG( OR=1.89, 95% CI 1.78 to 5.23) and severe HTG ( OR=3.65, 95% CI 1.98 to 6.49) were independent risk factors of POF(all P<0.05). Conclusion:The STAG level is related to the complications of AP, and moderate HTG and severe HTG(STAG ≥2.3 mmol/L) are independently associated with the risk of POF.

OBJECTIVES: To investigate the effect of borneol on cutaneous toxicity of gilteritinib and to explore possible compounds that can intervene with the cutaneous toxicity. METHODS: C57BL/6J male mice were given gilteritinib by continuous gavage for 28 d and the damage to keratinocytes in the skin tissues was observed with hematoxylin and eosin (HE) staining, TUNEL assay and immunohistochemistry. Human keratinocytes HaCaT were treated with gilteritinib, and cell death and morphological changes were examined by SRB staining and microscopy; apoptosis of HaCaT cells was examined by Western blotting, flow cytometry with propidium iodide/AnnexinⅤ double staining and immunofluorescence; the accumulation of cellular reactive oxygen species (ROS) was examined by flow cytometry with DCFH-DA. Compounds that can effectively intervene the cutaneous toxicity of gilteritinib were screened from a natural compound library using SRB method, and the intervention effect of borneol on gilteritinib cutaneous toxicity was further investigated in HaCaT cells and C57BL/6J male mice. RESULTS: In vivo studies showed pathological changes in the skin with apoptosis of keratinocytes in the stratum spinosum and stratum granulosum in the modeling group. Invitro studies showed apoptosis of HaCaT cells, significant up-regulation of cleaved poly (ADP-ribose) polymerase (c-PARP) and gamma-H2A histone family member X (γ-H2AX) levels, and increased accumulation of ROS in gilteritinib-modeled skin keratinocytes compared with controls. Screening of the natural compound library revealed that borneol showed excellent intervention effects on the death of HaCaT cells. In vitro, cell apoptosis was significantly reduced in the borneol+gilteritinib group compared to the gilteritinib control group. The levels of c-PARP, γ-H2AX and ROS in cells were significantly decreased. In vivo, borneol alleviated gilteritinib-induced skin pathological changes and skin cell apoptosis in mice. CONCLUSIONS Gilteritinib induces keratinocytes apoptosis by causing intracellular ROS accumulation, resulting in cutaneous toxicity. Borneol can ameliorate the cutaneous toxicity of gilteritinib by reducing the accumulation of ROS and apoptosis of keratinocytes in the skin tissue.
Male ; Humans ; Animals ; Mice ; Reactive Oxygen Species/metabolism* ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology* ; Mice, Inbred C57BL ; Apoptosis ; Poly(ADP-ribose) Polymerases/metabolism*

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure. Recently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3K/AKT in fibrotic processes is increasingly prominent, with PI3K/AKT inhibitors currently under clinical evaluation in IPF. Therefore, PI3K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic-associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both and . Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.