fecal-microbiota-transplantation-detection-prevalence-iga-coated

Fecal Microbiota Transplantation and Detection of Prevalence of IgA-Coated Bacteria in the Gut

Gut microbiota exert pleiotropic roles in human health and disease. Fecal microbiota transplantation (FMT) is an effective method to investigate the ...

Sichuan University

Epidermal growth factor receptor (EGFR) has been recently implicated in pathological tissue remodelling and sustained remodelling processes can lead to pathological outcomes, such as cardiac hypertrophy in heart failure. Dilated cardiomyopathy (DCM) is the most common form of heart muscle disease, comprising 60% of the cases of identified cardiomyopathy. This study aimed to evaluate the association between the EGFR gene polymorphisms and DCM in a Chinese population.

Epidermal growth factor receptor gene polymorphisms, R497K, but not (CA)n repeat, is associated with dilated cardiomyopathy.

Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy.

Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway.

Nesprins-1 and -2 are highly expressed in skeletal and cardiac muscle and together with SUN (Sad1p/UNC84)-domain containing proteins and lamin A/C form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) bridging complex at the nuclear envelope (NE). Mutations in nesprin-1/2 have previously been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). In this study, three novel rare variants (R8272Q, S8381C and N8406K) in the C-terminus of the SYNE1 gene (nesprin-1) were identified in seven DCM patients by mutation screening. Expression of these mutants caused nuclear morphology defects and reduced lamin A/C and SUN2 staining at the NE. GST pull-down indicated that nesprin-1/lamin/SUN interactions were disrupted. Nesprin-1 mutations were also associated with augmented activation of the ERK pathway in vitro and in hearts in vivo. During C2C12 muscle cell differentiation, nesprin-1 levels are increased concomitantly with kinesin light chain (KLC-1/2) and immunoprecipitation and GST pull-down showed that these proteins interacted via a recently identified LEWD domain in the C-terminus of nesprin-1. Expression of nesprin-1 mutants in C2C12 cells caused defects in myoblast differentiation and fusion associated with dysregulation of myogenic transcription factors and disruption of the nesprin-1 and KLC-1/2 interaction at the outer nuclear membrane. Expression of nesprin-1α2 WT and mutants in zebrafish embryos caused heart developmental defects that varied in severity. These findings support a role for nesprin-1 in myogenesis and muscle disease, and uncover a novel mechanism whereby disruption of the LINC complex may contribute to the pathogenesis of DCM.

Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis.

The aim of the present study was to investigate the influence of a high-fat diet (HFD) on hematopoietic system recovery under stress condition caused by 5-fluorouracil (5-Fu) and to evaluate the alleviating benefit of proliferator-activated receptor γ (PPAR-γ) inhibition on aggravation of 5-Fu-induced toxicity under HFD. Survival rates of HFD or normal diet (ND) mice were monitored after 5-Fu injection. Hematopoietic stem cells (HSCs) and the progenitor cells in bone marrow were detected at various time points after 5-Fu administration by flow cytometry. Genes expressed in stem cell and platelet proliferation was tested by reverse transcription polymerase chain reaction. The blood cell profile and coagulation function were determined with an ADVIA 120 hematology system and rotational thromboelastometry, respectively. None of HFD mice remained alive after 5-Fu injection, whereas 87.4% of ND mice survived. HFD accelerated 5-Fu-induced myelosuppression and cytopenia in the circulation, reflected by the worse recovery of HSCs and myeloid progenitor cells. In HFD mice, the number of platelets significantly decreased, and the Vcam-1/Vla-4 signal pathway was downregulated in bone marrow. Meanwhile, mice receiving HFD exhibited dysfunction of blood coagulation with increased clotting formation time. However, pretreatment of HFD mice with bisphenol A diglycidyl ether (BADGE), the PPAR-γ antagonist, reversed the acute lethal toxicity and bone marrow suppression of 5-Fu and accelerated the recovery of HSCs and platelets. In the light of these results, HFD could exacerbate 5-Fu-induced bone marrow toxicity and cytopenia. BADGE treatment offers a potential strategy to alleviate the aggravated hematopoiesis under an HFD.

High fat diet-induced obesity exacerbates hematopoiesis deficiency and cytopenia caused by 5-fluorouracil via peroxisome proliferator-activated receptor γ.

Nesprins (nuclear envelope spectrin repeat proteins) are multi-isomeric scaffolding proteins. Nesprin-1 and -2 are highly expressed in skeletal and cardiac muscles and together with SUN (Sad1p/UNC84) domain-containing proteins form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex at the nuclear envelope in association with lamin A/C and emerin. Mutations in nesprin-1/2 have been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). Several lines of evidence indicate that compromised LINC complex function is the critical step leading to muscle disease. Here, we review recent advances in our understanding of the functions of nesprin-1/2 in the LINC complex and mechanistic insights into how mutations in nesprin-1/2 lead to nesprin-related muscle diseases, in particular DCM and EDMD.

Nesprin-1/2: roles in nuclear envelope organisation, myogenesis and muscle disease.

Nesprins (nuclear envelope spectrin repeat proteins) are a family of multi-isomeric scaffolding proteins. Nesprins form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) complex with SUN (Sad1p/UNC84) domain-containing proteins at the nuclear envelope, in association with lamin A/C and emerin, linking the nucleoskeleton to the cytoskeleton. The LINC complex serves as both a physical linker between the nuclear lamina and the cytoskeleton and a mechanosensor. The LINC complex has a broad range of functions and is involved in maintaining nuclear architecture, nuclear positioning and migration, and also modulating gene expression. Over 80 disease-related variants have been identified in - (nesprin-1/2) genes, which result in muscular or central nervous system disorders including autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and autosomal recessive cerebellar ataxia type 1. To date, 17 different nesprin mouse lines have been established to mimic these nesprin-related human diseases, which have provided valuable insights into the roles of nesprin and its scaffold LINC complex in a tissue-specific manner. In this review, we summarise the existing nesprin mouse models, compare their phenotypes and discuss the potential mechanisms underlying nesprin-associated diseases.

Mouse models of nesprin-related diseases.

Acute respiratory distress syndrome threatens public health with high morbidity and mortality due to ineffective intervention whereby lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice provides a research model. The seeds of Euphorbia lathyris L. have a long history of usage in Traditional Chinese Medicine. Euphorbia factors L1-L11, extracted from this herb, have been reported to have anti-inflammation and anti-cancer effects. Here, we report the preventive and therapeutic potential of Euphorbia factor L2 (EFL2) on LPS-induced ALI in mice, where EFL2 attenuated pathological alterations in the lung and improved survival. Significant suppression of the recruitment and transmigration of inflammatory cells, specifically neutrophils, by 40 mg/kg of EFL2 was observed. EFL2 exerted potent anti-inflammatory effects by decreasing the levels of interleukin-1β (IL-1 β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF- α), interleukin-8 (IL-8) and myeloperoxidase (MPO) in the lung and bronchioalveolar lavage fluid. Consistent with the findings in vivo, EFL2 also showed robust inhibitory effects on the production of IL-1 β, IL-6, TNF- α and IL-8 released from LPS-stimulated RAW264.7 cells in vitro. Interestingly, this effect appeared to be mediated by EFL2's inhibition of NF-κB signaling activation, but not the MAPK pathway. Not only phosphorylation of IKK α/β and IκBα was down-regulated, p65 translocation and its DNA-binding activity were also significantly suppressed by EFL2. Moreover, overexpression of p65 reversed the inhibitory effect of EFL2 in LPS-induced NF-κB activation and cytokines production. The observed anti-inflammatory bioactivity of EFL2 indicates its potential as a drug development candidate, particularly for LPS-mediated disorders of inflammation.

Euphorbia factor L2 alleviates lipopolysaccharide-induced acute lung injury and inflammation in mice through the suppression of NF-κB activation.

To summarize and investigate the comparative efficacy and safety of targeted disease-modifying antirheumatic drugs (DMARDs) for active psoriatic arthritis (PsA).

Comparative efficacy and safety of targeted DMARDs for active psoriatic arthritis during induction therapy: A systematic review and network meta-analysis.

Oral microbial dysbiosis is known to increase susceptibility of an individual to develop rheumatoid arthritis (RA). Individuals at-risk of RA may undergo different phases of disease progression. In this study, we aim to investigate whether and whereby the oral microbiome communities alter prior to symptoms of RA. Seventy-nine saliva samples were collected from 29 high-risk individuals, who were positive for anti-citrullinated protein antibodies (ACPA) and have no clinical arthritis, 27 RA patients and 23 healthy controls (HCs). The salivary microbiome was examined using 16S ribosomal RNA gene sequencing. Alpha and beta diversity analysis and the linear discriminant analysis were applied to examine the bacterial diversity, community structure and discriminatory taxa between three groups, respectively. The correlation between salivary bacteria and autoantibodies were analyzed. In the "pre-clinical" stages, salivary microbial diversity was significantly reduced comparing to RA patients and HCs. In contrast to HCs, like RA patients, individuals at high-risk for RA showed a reduction in the abundance of genus  and the species , but an expansion of _6. Unexpectedly, the relative abundance of , reported as opportunistic pathogens for RA development, was significantly decreased in high-risk individuals. Additionally, we identified four genera in the saliva from high-risk individuals positively correlated with serum ACPA titers, and the other two genera inversely displayed. In summary, we observed a characteristic compositional change of salivary microbes in individuals at high-risk for RA, suggesting that oral microbiota dysbiosis occurs in the "pre-clinical" stage of RA and are correlated with systemic autoimmune features.

Qiuping Zhang

Department of Rheumatology and Immunology,
West China Hospital,
Department of Rheumatology and Immunology, West China Hospital

Sichuan University

Fecal Microbiota Transplantation and Detection of Prevalence of IgA-Coated Bacteria in the Gut

Qiuping Zhang

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Rheumatology and Immunology,West China Hospital,Department of Rheumatology and Immunology, West China Hospital

Sichuan University

Fecal Microbiota Transplantation and Detection of Prevalence of IgA-Coated Bacteria in the Gut

Department of Rheumatology and Immunology,
West China Hospital,
Department of Rheumatology and Immunology, West China Hospital