Acinar Cell-Derived Extracellular Vesicle MiRNA-183-5p Aggravates Acute Pancreatitis by Promoting M1 Macrophage Polarization Through Downregulation of FoxO1.

Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage in vivo. Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis. Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.

Comprehensive Analysis of Necroptosis in Pancreatic Cancer for Appealing its Implications in Prognosis, Immunotherapy, and Chemotherapy Responses.

Objective: Necroptosis represents a new target for cancer immunotherapy and is considered a form of cell death that overcomes apoptosis resistance and enhances tumor immunogenicity. Herein, we aimed to determine necroptosis subtypes and investigate the roles of necroptosis in pancreatic cancer therapy. Methods: Based on the expression of prognostic necroptosis genes in pancreatic cancer samples from TCGA and ICGC cohorts, a consensus clustering approach was implemented for robustly identifying necroptosis subtypes. Immunogenic features were evaluated according to immune cell infiltrations, immune checkpoints, HLA molecules, and cancer-immunity cycle. The sensitivity to chemotherapy agents was estimated using the pRRophetic package. A necroptosis-relevant risk model was developed with a multivariate Cox regression analysis. Results: Five necroptosis subtypes were determined for pancreatic cancer (C1∼C5) with diverse prognosis, immunogenic features, and chemosensitivity. In particular, C4 and C5 presented favorable prognosis and weakened immunogenicity; C2 had high immunogenicity; C1 had undesirable prognosis and high genetic mutations. C5 was the most sensitive to known chemotherapy agents (cisplatin, gemcitabine, docetaxel, and paclitaxel), while C4 displayed resistance to aforementioned agents. The necroptosis-relevant risk model could accurately predict prognosis, immunogenicity, and chemosensitivity. Conclusion: Our findings provided a conceptual framework for comprehending necroptosis in pancreatic cancer biology. Future work is required for evaluating its relevance in the design of combined therapeutic regimens and guiding the best choice for immuno- and chemotherapy.

ATG7-enhanced impaired autophagy exacerbates acute pancreatitis by promoting regulated necrosis via the miR-30b-5p/CAMKII pathway.

The present study was performed to explore whether and how impaired autophagy could modulate calcium/calmodulin-dependent protein kinase II (CAMKII)-regulated necrosis in the pathogenesis of acute pancreatitis (AP). Wistar rats and AR42J cells were used for AP modeling. When indicated, genetic regulation of CAMKII or ATG7 was performed prior to AP induction. AP-related necrotic injury was positively regulated by the incubation level of CAMKII. ATG7 positively modulated the level of CAMKII and necrosis following AP induction, indicating that there might be a connection between impaired autophagy and CAMKII-regulated necrosis in the pathogenesis of AP. microRNA (miR)-30b-5p was predicted and then verified as the upstream regulator of CAMKII mRNA in our setting of AP. Given that the level of miR-30b-5p was negatively correlated with the incubation levels of ATG7 after AP induction, a rescue experiment was performed and indicated that the miR-30b-5p mimic compromised ATG7 overexpression-induced upregulation of CAMKII-regulated necrosis after AP induction. In conclusion, our results indicate that ATG7-enhanced impaired autophagy exacerbates AP by promoting regulated necrosis via the miR-30b-5p/CAMKII pathway.

lncRNA FGD5­AS1 promotes breast cancer progression by regulating the hsa­miR­195­5p/NUAK2 axis.

Breast cancer is the second most prevalent cancer in women worldwide. Long non­coding RNAs (lncRNAs) have been identified as important regulators of tumorigenesis and tumor metastasis. lncRNA FGD5­AS1 has been previously reported as a carcinogenic gene, however its role in breast cancer has yet to be investigated. The present study aimed to understand the function of lncRNA FGD5­AS1 in breast cancer and examine the underlying molecular mechanisms. Sample tissues for downstream gene expression profiling were collected from patients with breast cancer (n=23). The effect of FGD5­AS1 overexpression on cell viability, invasion and migration has been studied in breast cancer cells (MDA­MB­231). Changes in glycolysis were monitored by comparing glucose consumption, lactate production and ATP levels. Using StarBase and TargetScan databases a putative interaction between FGD5­AS1, miR­195­5p and SNF1­like kinase 2 (NUAK2) was predicted in silico. Expression levels of FGD5­AS1, has­miR­195­5p and NUAK2 were validated by reverse transcription­quantitative PCR and interactions were validated using dual­luciferase reporter assays and RNA pull­down. High expression of lncRNA FGD5­AS1 was detected in breast cancer tissue samples and disease model cell lines. Silencing of FGD5­AS1 led to decreased cell proliferation, migration and invasion. It was identified that at a molecular level FGD5­AS1 serves as a sponge of miR­195­5p and alters the expression of its downstream target gene NUAK2. In breast cancer lncRNA FGD5­AS1 serve a key role in glycolysis and tumor progression via the miR­195­5p/NUAK2 axis. The findings of the present study indicated FGD5­AS1 as a candidate target for intervention in patients with breast cancer.

Beyond Crystal Engineering: Significant Enhancement of C2H2/CO2 Separation by Constructing Composite Material.

Different from the established crystal engineering method for enhancing gas-separation performance, we demonstrate herein a distinct approach. In contrast to the pristine MOF (metal-organic framework) material, the C2H2/CO2 separation ability for the resultant Ag NPs (nanoparticle)@Fe2O3@MOF composite material, estimated from breakthrough calculations, is greatly enhanced by 2 times, and further magnified up to 3 times under visible light irradiation.

Reversible photo/thermoswitchable dual-color fluorescence through single-crystal-to-single-crystal transformation.

Reversible photo/thermoswitchable dual-color green-to-blue fluorescence is reported here, which is mainly due to a single-crystal-to-single-crystal (SCSC) transformation of the chromophore from a supramolecular aggregation to a covalently bonded polymer.

Photoswitching adsorption selectivity in a diarylethene-azobenzene MOF.

The first MOF (metal-organic framework) built on both diarylethene and azobenzene photochromic units is reported here and displays distinct photoresponses for different guest molecules, thus creating an easy-to-use pathway to modulate the adsorption selectivity of MOF materials.

MOF catalysis of Fe(II)-to-Fe(III) reaction for an ultrafast and one-step generation of the Fe2O3@MOF composite and uranium(vi) reduction by iron(ii) under ambient conditions.

Herein, we demonstrate that Zn-MOF-74 enables the ultrafast and one-step generation of the Fe2O3@MOF composite once Zn-MOF-74 contacts with FeSO4 solution. This unique reaction can be further applied in catalysis of U(vi) reduction by Fe(ii) under ambient conditions. The results provide a highly renovated strategy for U(vi) reduction by Fe(ii) just under ambient conditions, which completely subvert all established methods about U(vi) reduction by Fe(ii) in which O2- and CO2-free conditions are absolutely required.