ISSN / EISSN : 23523964 / 23523964
Current Publisher: Elsevier BV (10.1016)
Total articles ≅ 2,913
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EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102920
Research in Context Evidence before this studyDysregulation of regenerative program following AP injury would cause exocrine insufficiency or recurrent / chronic pancreatitis. Infiltrating leukocytes, particular macrophages, determine the extent of ADM formation. Added value of this studyWe demonstrated dynamic transcriptome profile and function of pancreatic macrophages during pancreas repair/ regeneration post AP injury. Furthermore, IL4RA signaling mediated M2 polarization during ADM stage, limiting the extent of ADM formation. Macrophage-derived PI3K-AKT signaling facilitates inflammation resolution during acinar re-differentiation. Implications of all the available evidenceOur findings pave the way for the development of macrophage-based therapies to enhance the efficiency of regenerative process, providing a novel strategy for pancreatic disease treatment.
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102919
Research in context Evidence before this studyPerineuronal nets are reticular formations of extracellular matrix that scaffold neuronal synapses, with direct involvement in neuronal plasticity and memory. The Alzheimer's disease brain is characterized by the presence of extracellular Aβ plaques, which elicit a microglia-evoked inflammatory response that is implicated in mediating subsequent synaptic and neuronal loss. However, the fate of perineuronal nets in the Alzheimer's disease brain is unclear, as well as the roles that microglia may play in regulating them. Added value of this studyIn this study, we explore the relationships between microglia, perineuronal nets, and amyloid plaques in Alzheimer's disease model and human brains through immunohistochemical analysis. We find that perineuronal nets are extensively lost in disease and identify the presence of aggrecan, a critical net component, in human dense-core plaques. We also observe close spatial association between morphologically altered perineuronal nets and disease microglia, which contain inclusions of perineuronal net material consistent with phagocytic uptake. Finally, we test the hypothesis that microglia directly contribute to perineuronal net loss via their pharmacological depletion with colony-stimulating factor 1 receptor (CSF1R) inhibitor treatment, and find that microglial depletion prevents the loss of perineuronal nets in Alzheimer's disease. Implications of all the available evidenceOur data suggest that perineuronal net loss is a salient phenotype of the Alzheimer's disease model and human brain, and a recurring phenotype in the context of neurodegeneration overall. These results add to a growing body of research underscoring the increasingly central role microglia are believed to play in Alzheimer's disease pathogenesis by demonstrating that microglia mediate the disease-related loss of perineuronal nets. As perineuronal nets are implicated in neuronal health and function, protecting cells against neurotoxins (e.g. Aβ1–42, oxidative stress) in addition to modulating neuronal activity and the synaptic landscape, the microglia-mediated loss of these structures likely plays an important role in disease outcome. Interestingly, we also show here as before that the depletion of microglia enhances basal perineuronal net levels in healthy adult mice, thereby suggesting that microglia regulate net formation in health as well as disease.
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102887
AP-2-associated protein kinase
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102925
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102921
Microbial biofilms, i.e. communities of microorganisms embedded in a complex matrix mainly composed by macromolecules of bacterial origin, play a significant role in several chronic and relapsing infections. A major hurdle in treating biofilm-mediated infections, including those formed on the surface of medical devices, is that bacterial cells are physiologically much more resistant to both antibacterials and host innate and adaptive immune mechanisms [1Del Pozo J.L Biofilm-related disease.Expert Rev Anti Infect Ther. 2018; 16: 51-65Crossref PubMed Scopus (44) Google Scholar]. Astoundingly, the U.S. National Institutes of Health estimates biofilms account for 80% of human microbial infections [2Magana M. Sereti C. Ioannidis A. et al.Options and limitations in clinical investigation of bacterial biofilms.Clin Microbiol Rev. 2018; 31 (e00084-16)Crossref PubMed Scopus (33) Google Scholar]. This translates to roughly 2 million cases per year, with an estimated 268,000 deaths and a cost of $18 billion, which often requires extreme measures, such as the replacement or the removal of implanted devices or debridement of infected wounds [3Rumbaugh K.P. Sauer K Biofilm dispersion.Nat Rev Microbiol. 2020; Crossref PubMed Scopus (2) Google Scholar,4Omar A. Wright J.B. Schultz G. Burrell R. Nadworny P Microbial biofilms and chronic wounds.Microorganisms. 2017; 5: 9Crossref Google Scholar]. Therefore, identification of novel strategies to treat or prevent biofilm-mediated infections is an urgent clinical need. In this optic, strategies that disperse bacteria from an established biofilm, or that prevent its formation by active host immunization (e. g. anti-biofilm vaccines), are now considered promising approaches.
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102913
Research in context Evidence before this studyAccumulating evidence has demonstrated that intestinal dysbiosis is implicated in several autoimmune diseases, including RA. Overrepresentation of Prevotellaceae, particularly Prevotella copri and underrepresentation of the Clostridium cluster XIVa including Lachnospiraceae, which are major butyrate producers, are found in new-onset untreated RA (NORA) patients. Butyrate administration via drinking water, which is mostly absorbed in the upper small intestine, suppresses the development of autoimmune arthritis models in mice. Follicular regulatory T (TFR) cells play critical roles in the regulation of autoimmune diseases, including RA. The abundance of TFR cells is negatively correlated with disease activity in patients with RA. Added value of this studyHere, we report that intestinal microbiota-derived butyrate serves as an environmental cue to induce the differentiation of functional TFR cells in the gut-associated lymphoid tissue (GALT). Intestinal microbiota plays an essential role in both the initiation and suppression of autoimmune arthritis by modifying the immune system in the GALT. We observed that immunization with collagen caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of collagen-induced arthritis, indicating that GALTs enhance the autoimmune response to circulating autoantigens. However, butyrate mitigated these pathological events by increasing TFR cells. We newly developed an in vitro CXCR5+Bcl-6+Foxp3+ TFR (iTFR) cell-inducing culture system, and confirmed that butyrate facilitates the differentiation of TFR cells directly. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the TFR-cell marker genes. The adoptive transfer of the butyrate-treated T cells significantly reduced collagen-specific autoantibody production and thus ameliorated the symptoms of arthritis. Considering that butyrate production is affected in RA patients, this metabolite may play a key role in RA prevention. Implications of all the available evidenceOur data and methods provide the basis for future studies allowing further mechanistic dissection of TFR cell differentiation. Administration of butyrate-producing bacteria or functional food to subjects genetically susceptible to RA could have therapeutic potential to prevent the disease onset or the development of following disease symptoms. Our findings provide a molecular basis for new prophylaxis and treatment approaches for systemic autoimmune disorders by targeting the intestinal environment and autoimmune responses in GALT.
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102897
BackgroundGene therapy has held promises for treating specific genetic diseases. However, the key to clinical application depends on effective gene delivery.MethodsUsing a large animal model, we developed two pharmaceutical formulations for gene delivery in the pigs' vagina, which were made up of poly (β-amino ester) (PBAE)-plasmid polyplex nanoparticles (NPs) based two gel materials, modified montmorillonite (mMMT) and hectorite (HTT).FindingsBy conducting flow cytometry of the cervical cells, we found that PBAE-GFP-NPs-mMMT gel was more efficient than PBAE-GFP-NPs-HTT gel in delivering exogenous DNA intravaginally. Next, we designed specific CRISPR/SpCas9 sgRNAs targeting porcine endogenous retroviruses (PERVs) and evaluated the genome editing efficacy in vivo. We discovered that PERV copy number in vaginal epithelium could be significantly reduced by the local delivery of the PBAE-SpCas9/sgRNA NPs-mMMT gel. Comparable genome editing results were also obtained by high-fidelity version of SpCas9, SpCas9-HF1 and eSpCas9, in the mMMT gel. Further, we confirmed that the expression of topically delivered SpCas9 was limited to the vagina/cervix and did not diffuse to nearby organs, which was relatively safe with low toxicity.InterpretationOur data suggested that the PBAE-NPs mMMT vaginal gel is an effective preparation for local gene therapy, yielding insights into novel therapeutic approaches to sexually transmitted disease in the genital tract.FundingThis work was supported by the National Science and Technology Major Project of the Ministry of science and technology of China (No. 2018ZX10301402); the National Natural Science Foundation of China (81761148025, 81871473 and 81402158); Guangzhou Science and Technology Programme (No. 201704020093); National Ten Thousand Plan-Young Top Talents of China, Fundamental Research Funds for the Central Universities (17ykzd15 and 19ykyjs07); Three Big Constructions—Supercomputing Application Cultivation Projects sponsored by National Supercomputer Center In Guangzhou; the National Research FFoundation (NRF) South Africa under BRICS Multilateral Joint Call for Proposals; grant 17–54–80078 from the Russian Foundation for Basic Research.
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102888
In parallel with the ongoing epidemics of obesity, diabetes and metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), characterized by excess hepatic lipid accumulation in the absence of other causes such as alcohol consumption, is rapidly becoming the most common etiology of chronic liver disease. It is estimatted that NAFLD affects 25% of the general population worldwide and 85–98% of morbidly obese patients[1Paik J.M. Golabi P. Younossi Y. Mishra A. Younossi Z.M Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of nonalcoholic fatty liver disease.Hepatology. 2020; Crossref Google Scholar]. Non-alcoholic steatohepatitis (NASH), a histological subtype of NAFLD, has a potentially progressive course leading to liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation, which affects around 1.5–6.5% of the general population[2Castera L. Friedrich-Rust M. Loomba R Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.Gastroenterology. 2019; 156 (1264-81 e4)Summary Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. The underlying mechanisms, diagnosis and thrapeutic targets of NAFLD/NASH have attracted extensive attentions. However, despite decades of research, effective therapy for NAFLD/NASH is still lacking.
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102877
Research in context Evidence before this studyWe have searched MEDLINE (via PubMed) for articles published in any language between Jan 1, 1974, and Jan 1, 2020 using the search terms (“Barrett esophagus” [MeSH Terms] AND “Biomarkers” [MeSH Terms] AND “Methylation” [MeSH Terms]) and identified 54 research papers.Widespread DNA methylation changes are observed in Barrett's esophagus carcinogenesis. Several methylation markers have been found accurate in discriminating Barrett's epithelium from normal glandular mucosa in endoscopic biopsies, esophageal brushings, and samples obtained by non-endoscopic cell-collection devices such as the Cytosponge™ and EsophaCap™. For example, our group have previously shown that a methylation panel consisting of four genes (TFPI2, TWIST1, ZNF345, ZNF569) applied to Cytosponge™ samples can diagnose Barrett's epithelium (intestinal metaplasia with goblet cells) with an area under the ROC curve (AUC) ranging from 78·7% to 87·7%. Moreover, a different four-gene methylation panel (SLC22A18, PIGR, GJA12 and RIN2) was found useful in stratifying patients into three risk groups with potential clinical utility. So far, none of the methylation markers have been investigated as a test to assess response to endoscopic treatment of Barrett's esophagus, such as radiofrequency ablation (RFA). Added value of this studyIn this study we demonstrate that three methylation markers genes (ZNF345, TFP12, ZNF569) accurately differentiate Barrett's epithelium from normal gastroesophageal junction samples with an area under the ROC curves of 95·1% (95%CI 91·1% - 99·1%). Moreover, the mean methylation score (“Meth-score”) measured at the gastroesophageal junction after completion of the RFA treatment significantly correlates with the amount of residual Barrett's phenotype measured by number of glands with intestinal metaplasia (IM-Score) and the intensity of the TFF3 staining (rho=66·0% and 75·6%, respectively; P<·001). Lastly, we show that patients with widespread IM at the gastroesophageal junction during the follow-up that received re-treatment with RFA have a 7·6-fold reduction in the methylation levels. Implications of all the available evidenceOur data suggest that this methylation panel can objectively quantify the degree of response following radiofrequency ablation for Barrett's esophagus. Given the subjectivity in the histologic assessment for intestinal metaplasia, this novel biomarker panel on clinical biopsies can measure the amount residual disease and inform clinical management.
EBioMedicine, Volume 58; doi:10.1016/j.ebiom.2020.102902
Research in context Evidence before this studyA number of groups have investigated the efficacy of anticancer drugs in free form in zebrafish embryos xenotransplanted with human or mice cancer cells. In most cases, the drugs were added to the fish bathing water, making it difficult to control the effective dose that enters the fish. For cancer chemotherapy, intravenously injected nano-sized carriers containing drugs represent a rapidly developing strategy. Until now, only a few studies have addressed the therapy of intravenously injected nanoparticles in tumour-bearing zebrafish embryos. Added value of this studyHere, we introduce the zebrafish for visualizing and evaluating the efficacy of anti-cancer drug loaded nanoparticles. We injected cancer cells into the neural tube, a transplantation site which is better suited for tumour development and for light and electron microscopy imaging. In this system we followed the fate of intravenously injected nanoparticles. Our results reveal the zebrafish embryo to be a rapid and powerful screening tool to assess key parameters of nanoparticles aimed for cancer therapy namely: the toxicity, the localization and the treatment. Implication of the available evidenceOur study opens the way for assessing the efficacy of drug-loaded nanoparticles on xenotransplants of patient-derived cancer cells. For this purpose the zebrafish embryo is unique in allowing an assessment in only 10 days and therefore seems to be very attractive for rapid analysis to select the most powerful formulations for pre-clinical characterization.