YS. p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway.

PLR and NLR measurements can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

Postinfluenza pneumococcal pneumonia is a common cause of death in humans. However, the role of IL-27 in the pathogenesis of secondary pneumococcal pneumonia after influenza is unknown. We now report that influenza infection induced pulmonary IL-27 production in a type I IFN-α/β receptor (IFNAR) signalling-dependent manner, which sensitized mice to secondary pneumococcal infection downstream of IFNAR pathway. Mice deficient in IL-27 receptor were resistant to secondary pneumococcal infection and generated more IL-17A-producing γδ T cells but not αβ T cells, thereby leading to enhanced neutrophil response during the early phase of host defence. IL-27 treatment could suppress the development of IL-17A-producing γδ T cells activated by Streptococcus pneumoniae and dendritic cells. This suppressive activity of IL-27 on γδ T cells was dependent on transcription factor STAT1. Finally, neutralization of IL-27 or administration of IL-17A restored the role of γδ T cells in combating secondary pneumococcal infection. Our study defines what we believe to be a novel role of IL-27 in impairing host innate immunity against pneumococcal infection.

BackgroundThe efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remain largely elusive.MethodsCell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs motility was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tubular formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA.ResultsAnlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tubular formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect.ConclusionAnlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.

The poor outcome of cancer gene therapy in clinical trials relates in part to insufficient gene delivery to tumor sites. Mesenchymal stem cells (MSCs) represent a new tool for the delivery of therapeutic agents to tumor cells. This study used an orthotopic nude mice model of hepatocellular carcinoma (HCC) to evaluate the potential of genetically modified human MSCs (hMSCs), to function as an effective delivery vehicle for therapeutic genes. hMSCs derived from the bone marrow were efficiently engineered to express human pigment epithelium-derived factor (PEDF) by lentiviral transduction, then tested in vitro for high-level expression and bioactivity of the transgenic protein. The preferential homing of hMSCs toward HCC was confirmed by in vitro and in vivo migration assays. in vivo efficacy experiments showed that intravenous (i.v.) injection of PEDF-expressing hMSCs significantly suppressed both the growth of primary liver tumors and the development of pulmonary metastases. Moreover, hMSCs-based PEDF gene delivery moderately increased the systemic levels of human PEDF. Immunohistochemistry of primary liver tumors demonstrated lower microvessel density in mice treated with hMSCs-PEDF than in control mice. This is the first study to show the potential of hMSCs as an effective delivery vehicle for therapeutic genes in the treatment of HCC.

BackgroundGestational diabetes mellitus (GDM) is common all over the world. GDM women are with inflammatory and metabolisms abnormalities. However, few studies have focused on the association of IL-65–72C/G and TNF-α-857C/T single nucleotide polymorphisms (SNPs), inflammatory biomarkers, and metabolic indexes in women with GDM, especially in the Inner Mongolia population. The aim of this study was to investigate the associations of IL-65–72C/G and TNF-α-857C/T SNPs, and inflammation and metabolic biomarkers in women with GDM pregnancies.Material/MethodsBlood samples and placentas from 140 women with GDM and 140 women with healthy pregnancies were collected. Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) and MassARRAY-IPLEX were performed to analyze IL-65–72C/G and TNF-α-857C/T SNPs. Enzyme linked immunosorbent assay (ELISA) was performed to analyze inflammatory biomarkers and adipokines.ResultsDistribution frequency of TNF-α-857CT (OR=3.316, 95% CI=1.092–8.304, p=0.025) in women with GDM pregnancies were obviously higher than that in women with healthy pregnancies. Women with GDM were of older maternal age, had higher BMI, were more nulliparous, and had T2DM and GDM history, compared to women with healthy pregnancies (p<0.05). Inflammatory biomarkers in serum (hs-CRP, IL-6, IL-8, IL-6/IL-10 ratio) and placental (NF-κB, IL-6, IL-8, IL-6/IL-10 ratio, IL-1β, TNF-α) were significantly different (p<0.05) between women with GDM and women with healthy pregnancies. Differences were found for serum FBG, FINS, HOMA-IR, and HOMA-β, and placental IRS-1, IRS-2, leptin, adiponectin, visfatin, RBP-4, chemerin, nesfatin-1, FATP-4, EL, LPL, FABP-1, FABP-3, FABP-4, and FABP-5.ConclusionsTNF-α-857C/T SNP, hs-CRP, IL-6, IL-8, and IL-6/IL-10 were associated with GDM in women from Inner Mongolia, as was serious inflammation and disordered lipid and glucose metabolisms.

Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related mortalities worldwide. Platelets play an important and multifaceted role in cancer progression. Elevated mean platelet volume (MPV) detected in peripheral blood has been identified in various types of cancer. In the present study, we investigated the application value of MPV in early diagnostic and prognostic prediction in patients with resectable gastric cancer. In total, 168 patients with resectable gastric cancer were included and separated into the gastric cancer and healthy control groups according to median pre-operatic MPV value (MPV low, <10.51 or MPV high, ≥10.51). The results showed that the pre-operatic MPV level was significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operatic MPV level correlated with improved clinicopathological features, including decreased depth of invasion, less lymphonodus metastasis and early tumor stage. The Kaplan-Meier plots showed that the patients with higher pre-operatic MPV had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant decrease in the MPV level. The patients whose MPV level decreased following surgery had an improved OS. Multivariate Cox regression analysis revealed that the depth of invasion, lymphonodus metastasis, American Joint Committee on Cancer (AJCC) stage, and changes in MPV following surgery were prognostic factors affecting OS, and the AJCC stage and pre-operatic MPV were prognostic factors affecting DFS. In conclusion, MPV measurement can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

The aim of the study was to investigate the application value of neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) in the prediction of chemotherapy response and prognosis in patients with advanced gastric cancer. In total, 120 patients with unresectable gastric cancer were included and separated into two groups according to the median values of NLR or PLR (NLR low: <4.62 or NLR high: ≥4.62 and PLR low: <235 or PLR high: ≥235, respectively). Low baseline NLR level correlated with improved clinicopathological characteristics, including smaller tumor size, well differentiation and less metastasis. Low baseline PLR level also associated with less metastasis. Patients with a low baseline level of NLR or PLR had an improved response to chemotherapy. Patients with a higher baseline NLR and PLR had decreased progression-free survival (PFS) and overall survival (OS) ratios. Alterations in the NLR and PLR levels were associated with therapeutic efficacy and prognosis. The patients who remained in or switched to the low NLR level subgroup subsequent to first-line chemotherapy had an improved response and improved OS ratios, compared to the patients remaining in or switching to the high NLR level group. Similar results were observed when the PLR level was investigated. In conclusion, baseline NLR and PLR measurements, as well as changes of NLR and PLR following chemotherapy can predict the prognostic results in patients with unresectable gastric cancer.