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Background:Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease. So far, there is no specific treatment for this disease. Some therapeutic drugs have shown certain effects. However, they also increase the risk of infection and malignant tumors in patients. Therefore, exploring novel medicine with good therapeutic effects and few side effects is urgently needed. Total glucosides of paeony (TGP) is the main active ingredient of white peony. Clinical studies have shown that TGP had certain curative effects in the treatment of rheumatoid arthritis, systemic lupus erythematosus and SS. However, the mechanisms of the beneficial effects of TGP on SS remain to be elucidated.Objectives:We aim to explore the relationship between the therapeutic effects of TGP in the treatment of SS and NLRP3 inflammasome activation in submandibular gland (SG) cells.Methods:Female non-obese diabetic (NOD) mice were selected as the model of SS. TGP was administered intragastrically every day for 4 weeks in NOD mice. The SS-like symptoms and pathological changes of the SG of mice were analyzed. The activation of NLRP3 inflammasome in SG was detected. The SG cells with activation of NLRP3 inflammasome were treated with or without TGP. Then, NLRP3 inflammasome activation was assessed.Results:Compared with control mice, NOD mice showed SS-like symptoms and lymphocyte infiltration in SG, and the expression of NLRP3 inflammasome in SG was significantly increased. The SS-like symptoms were alleviated, and lymphocyte infiltration in SG was reduced, and the level of NLRP3 inflammasome in SG mice was decreased after TGP treatment (Figure 1). TGP also significantly inhibit the activation of NLRP3 inflammasome of SG cells in vitro (Figure 2).Conclusion:In summary, our findings indicated that SG cells showed excessive NLRP3 inflammasome activation, other than an injured target in SS. We demonstrated that TGP alleviated the symptoms of experimental Sjögren’s syndrome. Our data highlight that the beneficial effects of TGP on SS is related to limit overactivation of NLRP3 inflammasome of SG. These findings not only reveal the new mechanism of TGP in the treatment of SS, but also provide new evidence for the further application of TGP in the treatment of SS.Figure 1.TGP reduced NLRP3 inflammasome activation in the submandibular gland of NOD miceREFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background: T lymphocyte infiltration has been detected in glioma, although its significance remains unclear. The purpose of the present study was to explore the prognostic value of CD4 + and CD8 + tumour-infiltrating lymphocytes (TILs) in glioma, and the prognostic value of infiltrating Forkhead box protein 3 (FoxP3 + ) regulatory T cells were also investigated. Methods: CD4 + , FoxP3 + and CD8 + TILs were assessed by immunohistochemical staining of tissue microarray cores from 284 gliomas. Kaplan–Meier analysis and Cox proportional hazards models were used to examine the survival function of these TILs in 90 glioblastoma patients. Results: The number of CD8 + TILs was inversely correlated with tumour grade ( P =0.025), whereas the number of CD4 + TILs was positively correlated with tumour grade ( P =0.002). FoxP3 + TILs were only observed in glioblastomas, but not in low-grade astrocytomas or oligodendroglial tumours. Among patients with glioblastoma, none of CD4 + TILs, FoxP3 + TILs and CD8 + TILs alone was significantly associated with patient prognosis. However, the presence of high CD4 + and low CD8 + TIL levels was an independent predictor of poor progress-free survival (multivariate hazard ratio (HR) 1.618, 95% confidence interval (CI) 1.245–2.101, P <0.001) and poor overall survival (multivariate HR 1.508, 95% CI 1.162–1.956, P =0.002). Moreover, pseudoprogression was more often found in patients with high CD4 + TILs and high CD8 + TILs. Conclusions: The combination of CD4 + and CD8 + TILs is a predictor of clinical outcome in glioblastoma patients, and a high level of CD4 + TILs combined with low CD8 + TILs was associated with unfavourable prognosis.

The Three‐Georges Dam holds many records in the history of engineering. While the dam has produced benefits in terms of flood control, hydropower generation and increased navigation capacity of the Yangtze River, serious questions have been raised concerning its impact on both upstream and downstream ecosystems. It has been suggested that the dam operation intensifies the extremes of wet and dry conditions in the downstream Poyang Lake, and affects adversely important local wetlands. A floodgate has been proposed to maintain the lake water level by controlling the flow between the Poyang Lake and Yangtze River. Using extensive hydrological data and generalized linear statistical models, we demonstrated that the dam operation induces major changes in the downstream river discharge near the dam, including an average “water loss”. The analysis also revealed considerable effects on the Poyang Lake water level, particularly a reduced level over the dry period from late summer to autumn. However, the dam impact needs to be further assessed based on long‐term monitoring of the lake ecosystem, covering a wide range of parameters related to hydrological and hydraulic characteristics of the lake, water quality, geomorphological characteristics, aquatic biota and their habitat, wetland vegetation and associated fauna. Key Points The 3GD induces major changes in the downstream river discharge near the dam The 3GD causes considerable effects on the Poyang Lake water level The lake behavior is controlled by local factors modulated by the dam

MicroRNAs (miRNAs) are a family of 19–24 nucleotide non-coding RNAs with posttranscriptional regulatory functions. The involvement of miRNAs in normal hematopoiesis implies that deregulated miRNAs might contribute to leukemogenesis. To date, although certain miRNAs have been established a clear oncogenic role in hematological malignancies, other individual miRNAs potentially involved in human leukemogenesis still remain elusive. In this report, we showed that miR-142-3p was upregulated in human T-leukemic cell lines and primary T-leukemic cells isolated from T-cell acute lymphoblastic leukemia (T-ALL) patients and its expressive levels were correlated with patients’ prognosis. Such an oncogenic role of miR-142-3p could be explained by its targeting cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and glucocorticoid receptor alpha (GRα). High levels of miR-142-3p resulted in low levels of cAMP and weak activity of PKA, thus relieving the inhibitory effect of PKA on T-leukemic cell proliferation. Meanwhile, miR-142-3p decreased GRα protein expression by directly targeting the 3′-untranslational region of GRα mRNA, leading to glucocorticoid resistance. Transfection of the miR-142-3p inhibitor effectively converted glucocorticoid resistance, because of the resultant increase of GRα expression and PKA activity. These findings suggest that miR-142-3p is critical in T-cell leukemogenesis and may serve as a potential therapeutic target in T-ALL patients.

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.

Disease can act as a driving force in shaping genetic makeup across populations, even species, if the impacts influence a particularly sensitive part of their life cycles. White-nose disease is caused by a fungal pathogen infecting bats during hibernation. The mycosis has caused massive population declines of susceptible species in North America, particularly in the genus Myotis . However, Myotis bats appear to tolerate infection in Eurasia, where the fungal pathogen has co-evolved with its bat hosts for an extended period of time. Therefore, with susceptible and tolerant populations, the fungal disease provides a unique opportunity to tease apart factors contributing to tolerance at a genomic level to and gain an understanding of the evolution of non-harmful in host-parasite interactions. To investigate if the fungal disease has caused adaptation on a genomic level in Eurasian bat species, we adopted both whole-genome sequencing approaches and a literature search to compile a set of 300 genes from which to investigate signals of positive selection in genomes of 11 Eurasian bats at the codon-level. Our results indicate significant positive selection in 38 genes, many of which have a marked role in responses to infection. Our findings suggest that white-nose syndrome may have applied a significant selective pressure on Eurasian Myotis -bats in the past, which can contribute their survival in co-existence with the pathogen. Our findings provide an insight on the selective pressure pathogens afflict on their hosts using methodology that can be adapted to other host-pathogen study systems.

Exosomes are carriers of pro-tumorigenic factors that participate in glioblastoma (GBM) progression, and many fusion genes are strong driver mutations in neoplasia and are involved in tumorigenesis. However, the ability of fusion genes to be transduced by exosomes is unknown. We characterized exosomes from GBM cells harbouring and not harbouring PTPRZ1–MET fusion (ZM fusion). We also determined the effect of the exosomes from ZM fusion cells (ZM exosomes) on pro-oncogenic secretions and showed that ZM exosomes are internalized by the recipient cells. In addition, we studied the effect of ZM exosome-mediated intercellular communication in the GBM microenvironment. MET proto-oncogene expression was higher in ZM exosomes. Moreover, phosphorylated MET was detected only in ZM exosomes and not in exosomes released by non-ZM fusion GBM cells. ZM exosomes transferred to non-ZM fusion GBM cells and normal human astrocytes altered gene expression and induced epithelial–mesenchymal transition. The uptake of ZM exosomes also induced an exosome-dependent phenotype defined by GBM cell migration and invasion, neurosphere growth and angiogenesis. In addition, ZM exosomes conferred temozolomide resistance to the GBM cells, and exosome-derived ZM fusion network proteins targeted multiple pro-oncogenic effectors in recipient cells within the GBM microenvironment. Our findings show that exosomes mediate the aggressive character of GBM and demonstrate the role of ZM fusion in the exacerbation of this effect. These findings have possible implications for the foundation of gene fusion-based therapy for managing GBM.

Growing research is devoted to the development of plant-derived products as new therapeutic drugs to reduce side effects. Plant-derived exosome-like nanoparticles (ELNs) have shown promising potential in the treatment of colitis. As a proof of concept, the efficacy of ELNs from edible (ZbELNs) in protecting macrophages from inflammation was determined by in vitro experiments. Moreover, we assess the therapeutic effect of ZbELNs to colitis in a mouse model. ZbELNs were found to have an ideal particle size (160.0 nm) and contain a large number of lipids, some functional proteins or metabolites, and many small RNA molecules. The in vitro experiment results revealed that ZbELN pretreatment increased cell vitality and decreased the levels of pro-inflammatory cytokines. Furthermore, the in vivo experiments indicated that oral administration of ZbELNs can significantly reduce disease activity index, increase colon length, and inhibit colon wall thickening, thereby alleviating acute colitis in dextran sulfate sodium-induced model mice. In addition, ZbELN treatment can reduce the degree of histological damage in the colon and suppress pro-inflammatory cytokines levels in mice serum. Notably, miRNA-1 and miRNA-21 in ZbELNs showed similar therapeutic effects on macrophage inflammation. These findings suggest that ZbELNs are a novel natural nanomedicine with promising therapeutic potential for the treatment of colonic diseases.

Wounds occur when skin integrity is broken and the skin is damaged. With progressive changes in the disease spectrum, the acute wounds caused by mechanical trauma have been become less common, while chronic wounds triggered with aging, diabetes and infection have become more frequent. Chronic wounds now affect more than 6 million people in the United States, amounting to 10 billion dollars in annual expenditure. However, the treatment of chronic wounds is associated with numerous challenges. Traditional remedies for chronic wounds include skin grafting, flap transplantation, negative-pressure wound therapy, and gauze dressing, all of which can cause tissue damage or activity limitations. Nanobiotechnology--which comprises a diverse array of technologies derived from engineering, chemistry, and biology--is now being applied in biomedical practice. Here, we review the design, application, and clinical trials for nanotechnology-based therapies for chronic wound healing, highlighting the clinical potential of nanobiotechnology in such treatments. By summarizing previous nanobiotechnology studies, we lay the foundation for future wound care via a nanotech-based multifunctional smart system. Keywords: nanobiotechnology, chronic wound healing, scaffold systems, cell-carrying systems, stimuli-responsive systems

Increasing evidence has shown the aberrant expression of inflammasome-related proteins in Alzheimer’s disease (AD) brain; these proteins, including NLRP1 inflammasome, are implicated in the execution of inflammatory response and pyroptotic death. Although current data are associated NLRP1 genetic variants with AD, the involvement of NLRP1 inflammasome in AD pathogenesis is still unknown. Using APPswe/PS1dE9 transgenic mice, we found that cerebral NLRP1 levels were upregulated. Our in vitro studies further showed that increased NLRP1-mediated caspase-1-dependent ‘pyroptosis’ in cultured cortical neurons in response to amyloid- β . Moreover, we employed direct in vivo infusion of non-viral small-interfering RNA to knockdown NLRP1 or caspase-1 in APPswe/PS1dE9 brain, and discovered that these NLRP1 or caspase-1 deficiency mice resulted in significantly reduced neuronal pyroptosis and reversed cognitive impairments. Taken together, our findings indicate an important role for NLRP1/caspase-1 signaling in AD progression, and point to the modulation of NLRP1 inflammasome as a promising strategy for AD therapy.