BackgroundProfound chemoresistance remains an intractable obstacle in pancreatic cancer treatment. Pancreatic cancer stem cells (CSCs) and the ubiquitous hypoxic niche have been proposed to account for drug resistance. However, the mechanism involved requires further exploration. This study investigated whether the hypoxic niche enhances gemcitabine-induced stemness and acquired resistance in pancreatic cancer cells by activating the AKT/Notch1 signaling cascade. The therapeutic effects of blockading this signaling cascade on gemcitabine-enriched CSCs were also investigated.MethodsThe expression levels of CSC-associated markers Bmi1 and Sox2 as well as those of proteins involved in AKT/Notch1 signaling were measured by Western blot analysis. The expression level of the pancreatic CSC marker CD24 was measured by flow cytometry. Change in gemcitabine sensitivity was evaluated by the MTT assay. The ability of sphere formation was tested by the sphere-forming assay in stem cell medium. The ability of migration and invasion was detected by the transwell migration/invasion assay. A mouse xenograft model of pancreatic cancer was established to determine the effect of Notch1 inhibition on the killing effect of gemcitabine in vivo. The ability of metastasis was investigated by an in vivo lung metastasis assay.ResultsGemcitabine promoted pancreatic cancer cell stemness and associated malignant phenotypes such as enhanced migration, invasion, metastasis, and chemoresistance. The AKT/Notch1 signaling cascade was activated after gemcitabine treatment and mediated this process. Blockading this pathway enhanced the killing effect of gemcitabine in vivo. However, supplementation with hypoxia treatment synergistically enhanced the AKT/Notch1 signaling pathway and collaboratively promoted gemcitabine-induced stemness.ConclusionsThese findings demonstrate a novel mechanism of acquired gemcitabine resistance in pancreatic cancer cells through induction of stemness, which was mediated by the activation of AKT/Notch1 signaling and synergistically aggravated by the ubiquitous hypoxic niche. Our results might provide new insights for identifying potential targets for reversing chemoresistance in patients with pancreatic cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0972-3) contains supplementary material, which is available to authorized users.
Background. Resveratrol (RSV), one of the SIRT1 agonists, has the ability of alleviating severe acute pancreatitis (SAP); however, the concrete protective mechanism remains unknown. It is noteworthy that microcirculation disturbance plays a vital role in SAP, and the SIRT1/FOX1 axis can regulate microcirculation. Therefore, this study is aimed at ascertaining what is the underlying mechanism of the protective effect of RSV on SAP, and whether it is associated with alleviating microcirculation disturbance by regulating the SIRT1/FOX1 axis. Method. The model of SAP was induced by retrograde injection of sodium taurodeoxycholate into the bile duct of the rats. The pancreatic wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α ratios; microcirculatory function; and SIRT1 activity were examined. ELISA was used to examine the serum level of lipase, amylase, hemorheology, ET, NO, TXB2, and 6-keto-PGF1α and the content of SIRT1, VEGF, Ang I, and Ang II in the pancreas. RT-PCR was used to examine the mRNA level of VEGF, Ang I, and Ang II. Western blotting was used to detect SIRT1, FOXO1, and acetyl-FOXO1. Immunoprecipitation was used to examine the interaction of SIRT1 and FOXO1. Results. Resveratrol can significantly decrease the expression of lipase, amylase, acetyl-FOXO1, VEGF, Ang II, ET, NO, TXB2, and 6-keto-PGF1α and the ratio of wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α by improving microcirculatory dysfunction and blood viscosity in SAP. Moreover, resveratrol can also promote the interaction of SIRT1 and FOXO1 and increase SIRT1 activity and the expression of SIRT1 and Ang I. The SIRT1 inhibitor, Sirtinol (EX527), obliviously reversed the effects of RSV on SAP. Conclusion. Resveratrol can protect rats against SAP, and its protective mechanism is associated with suppressing microcirculation disturbance through activating SIRT1-FOXO1 axis.
CAR-T cell therapy has demonstrated encouraging therapeutic effects when treating haematological malignancies. 1,2 Two CAR-T treatments targeting CD19 have been launched successfully. 3,4 CAR-T targeting the B-cell maturation antigen (BCMA) has also shown positive therapeutic effects in clinical trials. [5][6][7] However, CAR-T cell therapy has not yet had similar results in solid tumours. [8][9][10] Solid tumours have a more complex immunosuppressive microenvironment and there are many immunosuppressive cells and cytokines which inhibit the activation and survival of CAR-T cells within the tumour. 11,12 The dense extracellular matrix (ECM) also prevents CAR-T cells from infiltrating into solid tumours and can affect CAR-T cell activity. 13,14 During cultivation, additional cytokines, such as IL7 and IL15, can promote the effective proliferation and maintenance of the memory phenotype of CAR-T cells. 15,16 However, adding extra IL-7 during cultivation has no effect in vivo. It is difficult for T cells, including CAR-T cells, to penetrate the extracellular matrix and thus infiltrate the tumour. 13,14 Reports suggest that recombinant hyaluronidase rHPH20
Tartary buckwheat is a nutritious pseudo-cereal crop that is resistant to abiotic stresses, such as drought. However, the buckwheat’s mechanisms for responding to drought stress remains unknown. We investigated the changes in physiology and gene expression under drought stress, which was simulated by treatment with polyethylene glycol (PEG). Five physiological indexes, namely MDA content, H2O2 content, CAT activity, SOD activity, and POD activity, were measured over time after 20% PEG treatment. All indexes showed dramatic changes in response to drought stress. A total of 1,190 differentially expressed genes (DEGs) were identified using RNA-seq and the most predominant were related to a number of stress-response genes and late embryogenesis abundant (LEA) proteins. DEGs were gathered into six clusters and were found to be involved in the ABA biosynthesis and signal pathway based on hierarchical clustering and GO and KEGG pathway enrichment. Transcription factors, such as NAC and bZIP, also took part in the response to drought stress. We determined an ABA-dependent and ABA-independent pathway in the regulation of drought stress in Tartary buckwheat. To the best of our knowledge, this is the first transcriptome analysis of drought stress in Tartary buckwheat, and our results provide a comprehensive gene regulatory network of this crop in response to drought stress.
Some individuals develop prediabetes and/or diabetes following acute pancreatitis (AP). AP-induced beta-cell injury and the limited regenerative capacity of beta cells might account for pancreatic endocrine insufficiency. Previously, we found that only a few pancreatic cytokeratin 5 positive (Krt5+) cells differentiated into beta cells in the murine AP model, which was insufficient to maintain glucose homeostasis. Notch signaling determines pancreatic progenitor differentiation in pancreas development. This study aimed to examine whether Notch signaling inhibition could promote pancreatic Krt5+ cell differentiation into beta cells and improve glucose homeostasis following AP. Pancreatic tissues from patients with acute necrotizing pancreatitis (ANP) were used to evaluate beta-cell injury, Krt5+ cell activation and differentiation, and Notch activity. The murine AP model was induced by cerulein, and the effect of Notch inhibition on Krt5+ cell differentiation was evaluated both in vivo and in vitro. The results demonstrated beta-cell loss in ANP patients and AP mice. Krt5+ cells were activated in ANP pancreases along with persistently elevated Notch activity, which resulted in the formation of massive duct-like structures. AP mice that received Notch inhibitor showed that impaired glucose tolerance was reversed 7 and 15 days following AP, and increased numbers of newborn small islets due to increased differentiation of Krt5+ cells to beta cells to some extent. In addition, Krt5+ cells isolated from AP mice showed increased differentiation to beta cells by Notch inhibition. Collectively, these findings suggest that beta-cell loss contributes to pancreatic endocrine insufficiency following AP, and inhibition of Notch activity promotes pancreatic Krt5+ cell differentiation to beta cells and improves glucose homeostasis. The findings from this study may shed light on the potential treatment of prediabetes/diabetes following AP.
Plant NAC transcription factors play vital roles in diverse biological processes, especially in response to stress. However, only a limited number of the FtNAC genes have been cloned and functionally analyzed in Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn.), which is a coarse grain crop that is highly resistant to abiotic stress. Here, we identified seven Tartary buckwheat FtNAC genes, namely FtNAC11, FtNAC12, FtNAC26, FtNAC28, FtNAC65, FtNAC70, and FtNAC78. Multiple-sequence alignments revealed that all of them contained the conserved NAM domain, which consisted of the A, B, C, D, and E subdomains. Seven NAC proteins were classified into six subgroups based on phylogenetic analyses. Cis-acting regulatory elements analyses (CARE) indicated that there were numerous CAREs related to biotic and abiotic responses and hormone responses in the promoters of FtNAC genes. qRT-PCR showed that they were tissue-specifically expressed and could be induced by four out of six treatments, namely PEG, NaCl, cold, MeJA, ABA, and GA, implying that they were abiotic and hormone responsive. Among these, FtNAC70 was the most strongly induced gene and could be induced by all six treatments. Meanwhile, FtNAC70-overexpressed Arabidopsis showed more resistance to salt and drought. The identification, phylogenetics, expression, and functional study of seven stress-responsive FtNAC genes laid a foundation for further research on the molecular mechanism of abiotic stress regulated by NAC TFs in Tartary buckwheat.
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