Abstract Acute kidney injury (AKI) has considerably high morbidity and mortality but we do not have proper treatment for it. There is an urgent need to develop new prevention or treatment methods. Gut microbiota has a close connection with renal diseases and has become the new therapy target for AKI. In this study, we found the oral administration of the probiotic Limosilactobacillus reuteri had a prevention effect on the AKI induced by lipopolysaccharide (LPS). It reduced serum concentration of creatinine and urea nitrogen and protected the renal cells from necrosis and apoptosis. Meanwhile, L. reuteri improved the gut barrier function, which is destroyed in AKI, and modulated the gut microbiota and relevant metabolites. Compared with the LPS group, L. reuteri increased the proportion of Proteobacteria and reduced the proportion of Firmicutes, changing the overall structure of the gut microbiota. It also influenced the fecal metabolites and changed the metabolite pathways, such as tyrosine metabolism, pentose and glucuronate interconversions, galactose metabolism, purine metabolism, and insulin resistance. These results showed that L. reuteri is a potential therapy for AKI as it helps in sustaining the gut barrier integrity and modulating gut microbiota and related metabolites.
Neuropathic pain (NPP) is a common clinical disease symptom, its mechanism is complicated, and there is no good treatment method. Therefore, the exploration of the pathological mechanism and treatment methods of NPP has attracted the attention of many researchers. A large number of studies have shown that P2X7 receptor (P2X7R) plays a key role in the development of NPP. High expression of P2X7R can induce pain. In this study, neural stem cells (NSC) and microencapsulated neural stem cells (MC-NSC) were transplanted into the site of chronic sciatic nerve injury, and behavioral methods were used to detect changes in pain. Expression levels of P2X7R proteins and mRNA were detected by using in situ hybridization, RT-PCR and western-blotting. ELISA method was used to detect the changes of the pro-inflammatory factors IL-6, IL-1β, IL-10 and TNF-a in rat serum. Western-blotting was used to detect p-ERK1/2, p-p38 and ERK1/2 protein expression in dorsal root ganglia (DRG), To explore the effect of NSC and MC-NSC on the treatment of NPP. and compare the difference between the two. The results showed that after chronic constriction injury (CCI), mechanical withdrawal thresholds (MWT) and thermal withdrawal latency (TWL) of rats were significantly reduced, the expression levels of P2X7R, p-ERK1/2 and p-p38 in DRG were significantly increased, and IL-6, IL-1β, IL-10 and TNF-a concentrations were significantly increased in serum of rats. After transplantation of NSC and MC-NSC, it was found that expression levels of P2X7R, p-ERK1/2 and p-p38 in DRG were significantly reduced, and IL-6, IL-1β, IL-10 and TNF-a concentrations also significantly decreased in serum, and MWT and TWL of rats increased significantly. Importantly, compared with NSC transplantation, transplantation of MC-NSC could better reduce the expression levels of P2X7R, p-ERK1/2 and p-p38, decrease IL-6, IL-1β, IL-10 and TNF- a concentrations, and inhibit mechanical allodynia in rats. But total ERK1/2 protein expression level remains unchanged. Therefore, our conclusion is that MC-NSC can better reduce the expression level of P2X7R and inhibit NPP, which may become another potential treatment method for treatment of NPP.Funding Statement: These studies were supported by grants from the National Natural Science Foundation of China (81760418 and 81260190), the Natural Science Foundation of Jiangxi Province (20181BBG70015 and 20181BAB205061).Declaration of Interests: The authors stated that there is no conflict of interest in this paper.Ethics Approval Statement: All protocols were approved by the Animal Care and Ethics Committee, China.
Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is an orphan disease without proven therapies, we rescued it with human amnion-derived mesenchymal stem cells (hAMSCs). In a discovery cohort of 10 uremic patients and 3 CUA patients, plasma proteomic analysis showed core differentially expressed proteins (DEPs) Thrombospondin 1 (THBS1) and Latent transforming growth factor (TGF)-β binding protein 1 (LTBP1) decreased significantly after 3 days of hAMSC treatment. Single-cell transcriptome sequencing of peripheral blood mononuclear cells (PBMCs) indicated megakaryocytes were the source of THBS1 in CUA patient. Same as the discovery cohort, plasma THBS1 and TGF-β1 levels were increased in seven CUA patients compared to the uremic group (n=20), as measured by enzyme-linked immunosorbent assay (ELISA) in the validation cohort. They can be inhibited after hAMSC treatment and increased as the frequency of therapy decreased. THBS1 and its receptor, CD47, were increased in the CUA skin. THBS1 and TGF-β1 are biomarker candidates for calciphylaxis.
A novel and reusable electrochemiluminescence biosensor was developed based on tetrahedral DNA (TDN) signal amplification for ultrasensitive detection of miRNA-27a. The flowered nickel-iron layered double hydroxide@AuNPs (NiFe-LDH@AuNPs) composites increase the amount of hairpin DNA fixed on the electrode. When miRNA is present, TDN-Ru(bpy)32+ acts as an ECL probe, forming a stable sandwich structure with miRNA-27a and hairpin DNA through base complementation pairing, thus achieving miRNA detection. This biosensor has the characteristics of high sensitivity, excellent selectivity, and good reproducibility.
Objective: Podocyte Infolding Glomerulopathy (PIG) is a described pathologic entity characterized by diffuse podocyte infolding into the Glomerular Basement Membrane (GBM) associated with ultra structurally demonstrable microspherular aggregates.The objective of this study was to report the clinical characteristics of two PIG patients and to investigate the pathological changes of nephrotic syndrome caused by immune disease, which may be the abnormal morphology of podocytes entrapment into the glomerular basement membrane.This pathological change is closely related to the immune disease, but is not related to the prognosis. Conclusion:Characteristic clustering of these microparticles near the invaginated tips of podocyte foot processes in the GBM was observed on transmission electron microscopy.The clinical, light microscopic, and diagnostic electron microscopic features of this condition are highlighted in this report in an attempt to contribute some insights into the possible pathogenetic mechanisms of this obscure entity.PIG is closely associated with immune diseases, which may be a transient phenomenon caused by immune disorders.
Abstract Esophageal cancer is one of the malignant tumors in the digestive system. Because the early symptoms of esophageal cancer are occult and lack effective screening of specific molecular markers of esophageal cancer, most patients are in the middle or advanced stage at the time of treatment, and the 5-year survival rate is low. This study aimed to find molecular biomarkers of clinical value in the development and diagnosis of esophageal cancer. The factors affecting esophageal cancer were identified by clinical factor analysis and tissue transcriptome sequencing of 180 cases of esophageal cancer in Jiangsu, China. The results of the Chi-square test and correlation analysis demonstrated that: a). relative expression of KRT17 was higher in esophageal cancer with diabetes ( P = 0.036); b). expression of KRT17 correlated with blood glucose levels ( r = 0.186, P = 0.013) and tumor size ( r = -0.197, P = 0.009) in esophageal cancer patients; c). and expression of COL1A1 correlated with age ( r = -0.148, P = 0.047) and blood glucose levels ( r = 0.212, P = 0.004) in esophageal cancer patients; d). Experimental results of QRT-RCR: KRT17 and COL1A1 genes were highly expressed in esophageal cancer, respectively ( P < 0.05); when the two genes were used as a combination test, the positive detection rate of esophageal cancer was 90.6%, ROC curve, specificity, and sensitivity had greater power, and KRT17 and COL1A1 genes had the potential to be biomarkers for the diagnosis of esophageal cancer.
BACKGROUND: Post-transcriptional regulation of mRNA induced by microRNA is known crucial in tumor occurrence, progression, and metastasis. This study aims at identifying significant miRNA-mRNA axes for stomach adenocarcinomas (STAD). METHOD: RNA expression profiles were collected from The Cancer Genome Atlas (TCGA) and GEO database for screening differently expressed RNAs and miRNAs (DE-miRNAs/DE-mRNAs). Functional enrichment analysis was conducted with Hiplot and DAVID-mirPath. Connectivity MAP was applied in compounds prediction. MiRNA-mRNA axes were forecasted by TarBase and MiRTarBase. Real-time reverse transcription polymerase chain reaction (RT-qPCR) of stomach specimen verified these miRNA-mRNA pairs. Diagnosis efficacy of miRNA-mRNA interactions was measured by Receiver operation characteristic curve and Decision Curve Analysis. Clinical and survival analysis were also carried out. CIBERSORT and ESTIMATE was employed for immune microenvironment measurement. RESULT: Totally 228 DE-mRNAs (105 upregulated and 123 downregulated) and 38 DE-miRNAs (22 upregulated and 16 downregulated) were considered significant. TarBase and MiRTarBase identified 18 miRNA-mRNA pairs, 12 of which were verified in RT-qPCR. The network of miR-301a-3p/ELL2 and miR-1-3p/ANXA2 were established and verified in external validation. The model containing all 4 signatures showed better diagnosis ability. Via interacting with M0 macrophage and resting mast cell, these miRNA-mRNA axes may influence tumor microenvironment. CONCLUSION: This study established a miRNA-mRNA network via bioinformatic analysis and experiment validation for STAD.
Families that contain multiple siblings affected with childhood-onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole-exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus.
Methods
Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional SLE patients. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively.
Results
The two familial ultra-rare, predicted loss-of-function (LOF) SAT1 variants exhibited X-linked recessive Mendelian inheritance in two unrelated African-American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous female Sat1p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leukocyte infiltration, proteinuria and elevated expression of type I interferon inducible genes. SAT1 is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3+CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3+CD4+ T cells correlated with decreased plasma levels of spermine in treatment naïve, incipient SLE patients.
Conclusions
We identified two novel SAT1 loss-of-function variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism, and identified SAT1 LOF variants as new monogenic causes for SLE.
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