Medullary sponge kidney with IgA nephropathy: a case report and literature review.

BACKGROUND: Medullary sponge kidney (MSK)is rare in association with glomerulonephritis. We report a patient with medullary sponge kidney, and the kidney biopsy revealed a diagnosis of IgA nephropathy. CASE PRESENTATION: A 27-year-old female presented with hematuria and proteinuria, and imaging studies indicated the presence of medullary spongy kidney. With appropriate preparation, a kidney biopsy was performed. Considering the patient's clinical and pathological characteristics, the final diagnosis was determined to be medullary sponge kidney associated by IgA nephropathy. The combination of corticosteroids and angiotensin receptor blockers (ARBs) proved to be significantly effective in reducing proteinuria in the current case. To the best of our knowledge, this is the first reported case that demonstrates the coexistence of MSK and IgA nephropathy. CONCLUSIONS: Administering precise therapy based on renal pathology can potentially enhance outcomes for patients with renal conditions, necessitating the need for clinicians to be vigilant about differential diagnosis in order to reduce the rates of missed diagnoses and misdiagnosis.

Association of Lung Ultrasound B-Lines with Left Ventricular Diastolic Function in Clinically Euvolemic Haemodialysis Patients.

INTRODUCTION: Left ventricular diastolic dysfunction (LVDD) frequently occurs in haemodialysis patients and is associated with adverse outcomes. Lung ultrasound (LUS) has been recently proposed for the quantification of extravascular lung water through assessment of B-lines. LUS findings and their relationship with LVDD in clinically euvolemic haemodialysis patients were investigated in this study. METHODS: Echocardiography and LUS examinations were performed on each patient. Multivariate linear regression and forward stepwise logistic regression were performed to determine the relationship between B-lines and LVDD. A receiver operating characteristic (ROC) curve with area under the curve (AUC) was calculated to determine the accuracy of B-lines for evaluating LVDD. RESULTS: A total of 119 patients were enrolled. The number of B-lines was statistically related to echocardiographic parameters (LAVI, LVEDVI, E/A, and E/e') of diastolic function, while the relationship between B-lines and LVEF disappeared after adjusting for potential confounding factors. Additionally, compared with the mild B-line group (B-lines: <14), the moderate (B-lines: 14-30) and severe B-line groups (B-lines: >30) were associated with an increased risk of LVDD (OR 24.344, 95% CI 4.854-122.084, p < 0.001, and OR 94.552, 95% CI 9.617-929.022, p < 0.001, respectively). Furthermore, the AUC of the ROC curve for B-lines predicting LVDD was 0.845, and the cut-off of B-lines was 14.5 (sensitivity 64.91%, specificity 93.55%). CONCLUSION: LUS B-lines were closely associated with left ventricular diastolic function in clinically euvolemic haemodialysis patients. Moreover, our findings suggested a B-line ≥14.5 as a reliable cut-off value for identifying patients with LVDD. LUS B-lines may be used as a novel indicator for evaluating LVDD.

Risk Prediction Models for Invasive Mechanical Ventilation in Patients with Autoimmune Encephalitis: A Retrospective Cohort Study.

Methods: A multivariate predictive nomogram model was developed using the risk factors identified by LASSO regression and assessed by receiver operator characteristics (ROC) curve, calibration curve, and decision curve analysis. Results: The risk factors predictive of severe respiratory failure were male gender, impaired hepatic function, elevated intracranial pressure, and higher neuron-specific enolase. The final nomogram achieved an AUC of 0.770. After validation by bootstrapping, a concordance index of 0.748 was achieved. Conclusions: Our nomogram accurately predicted the risk of developing respiratory failure needing IMV in AE patients and provide clinicians with a simple and effective tool to guide treatment interventions in the AE patients.

Network pharmacology and molecular docking of endogenous active metabolites in diabetic kidney disease.

OBJECTIVES: Network pharmacology and molecular docking were used to predict endogenous active metabolites with protective effects in diabetic kidney disease (DKD). METHODS: We utilized metabolomics to screen differentially expressed metabolites in kidney tissues of mice with type 2 DKD and predicted potential targets using relevant databases. The interaction network between endogenous active metabolites and target proteins was established by integrating differentially expressed metabolites and proteins associated with DKD identified through proteomics. Gene ontology (GO) and signaling pathway enrichment analysis were performed. The biological functions of the active candidate metabolites and their effects on downstream pathways were also verified. RESULTS: Metabolomics revealed 130 differentially expressed metabolites. Through co-expression network analysis coupled with the investigation of differentially expressed proteins in proteomics, 2-hydroxyphenylpropionylglycine (2-HPG) emerged as a key regulator of DKD. 2-HPG was found to modulate the progression of DKD by regulating the conformation and activity of synaptophysin 1 (SYNJ1), with a correlation coefficient of 0.974. In vivo experiments revealed that SYNJ1 expression was significantly downregulated in the Macroalbuminuria Group compared to the Control Group and negatively correlated with proteinuria (r = -0.7137), indicating its important role in DKD progression. Immunofluorescence demonstrated that treatment with 2-HPG restores the expression of the foot process marker protein Wilms tumor-1 (WT-1) in podocytes injured by high glucose levels. Western blot and polymerase chain reaction support the involvement of SYNJ1 in this process. CONCLUSIONS: This study demonstrated the significance of the 2-HPG/SYNJ1 signaling axis in safeguarding the foot process of podocytes in DKD.

The protective mechanism of Dehydromiltirone in diabetic kidney disease is revealed through network pharmacology and experimental validation.

Background: Salvia miltiorrhiza (SM) is an effective traditional Chinese medicine for treating DKD, but the exact mechanism is elusive. In this study, we aimed to investigate and confirm the method underlying the action of the active components of SM in the treatment of DKD. Methods: Renal tissue transcriptomics and network pharmacology of DKD patients was performed to identify the active components of SM and the disease targets of DKD. Next, the point of convergence among these three groups was studied. Potential candidate genes were identified and analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The component-target networks were modelled and visualized with Cytoscape. In addition, docking studies were performed to validate our potential target predictions. Lastly, in vitro and in vivo experiments were performed to understand the role of Dehydromiltirone (DHT), the active component of SM, in the phenotypic switching of mesangial cells. Results: Transcriptomics of DKD patients' renal tissues screened 4,864 differentially expressed genes. Eighty-nine active components of SM and 161 common targets were found. Functional enrichment analysis indicated that 161 genes were enriched in apoptosis, the PI3K-AKT signaling pathway, and the AGE-RAGE signaling pathway in diabetes complications. Molecular docking and molecular dynamic simulations show that DHT can bind to functional PIK3CA pockets, thereby becoming a possible inhibitor of PIK3CA. In vitro study demonstrated that DHT reduced the expression of phenotypic switching markers α-SMA, Col-I, and FN in HMCs by downregulating the over-activation of the PI3K-AKT signaling pathway through the inhibition of PIK3CA. Furthermore, the DKD mouse model confirmed that DHT could reduce proteinuria and improve glomerular hypertrophy in vivo. Conclusion: DHT was identified as the key active component of SM, and its therapeutic effect on DKD was achieved by inhibiting the phenotypic switching of mesangial cells via the PIK3CA signaling pathway.

Ursolic Acid Ameliorated Neuronal Damage by Restoring Microglia-Activated MMP/TIMP Imbalance in vitro.

Purpose: The oxygen and glucose deprivation-reoxygenation (OGDR) model is widely used to evaluate ischemic stroke and cerebral ischemia-reperfusion (I/R) injury in vitro. Excessively activated microglia produce pro-inflammatory mediators such as matrix metalloproteinases [MMPs] and their specific inhibitors, tissue inhibitors of metalloproteinases [TIMPs], causing neuronal damage. Ursolic acid (UA) acts as a neuroprotective agent in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model keeping the MMP/TIMP balance with underlying mechanisms unclear. Our study used OGDR model to determine whether and how UA reduces neuronal damage by reversing MMP/TIMP imbalance caused by microglia in I/R injury in vitro. Methods: SH-SY5Y cells were first cultured with 95% N2 and 5% CO2 and then cultivated regularly for OGDR model. Cell viability was tested for a proper UA dose. We established a co-culture system with SH-SY5Y cells and microglia-conditioned medium (MCM) stimulated by lipopolysaccharide (LPS) and interferon-gamma (IFNγ). MMP9 and TIMP1 levels were measured with ELISA assay to confirm the UA effect. We added recombinant MMP9 (rMMP9) and TIMP1 neutralizing antibody (anti-TIMP1) for reconfirmation. Transmission electron microscopy was used to observe cell morphology, and flow cytometry and Annexin V-FITC and PI labeling for apoptotic conditions. We further measured the calcium fluorescence intensity in SH-SY5Y cells. Results: The MCM significantly reduced cell viability of SH-SY5Y cells after OGDR (p<0.01), which was restored by UA (0.25 µM) (p<0.05), whereas lactate dehydrogenase activity, intraneuronal Ca2+ concentration, and apoptosis-related indexes were showed significant improvement after UA treatment (p<0.01). UA corrected the MMP/TIMP imbalance by decreasing MMP9 expression and increasing TIMP1 expression in the co-culture system (p<0.01) and the effects of UA on SH-SY5Y cells were mitigated by the administration of rMMP9 and anti-TIMP1 (p<0.01). Conclusion: We demonstrated that UA inhibited microglia-induced neuronal cell death in an OGDR model of ischemic reperfusion injury by stabilizing the MMP9/TIMP1 imbalance.

Phase-Field Study of Exchange Coupling in Co-Pt Nonstandard Nanochessboards.

The Co-Pt binary system can form a two-phase nanochessboard structure comprising regularly aligned nanorods of magnetically hard tetragonal L10 phase and magnetically soft cubic L12 phase. This Co-Pt nanochessboard, being an exchange-coupled magnetic nanocomposite, exhibits a strong effect on magnetic domains and coercivity. While the ideal nanochessboard structure has tiles with equal edge lengths (a = b), the non-ideal or nonstandard nanochessboard structure has tiles with unequal edge lengths (a ≠ b). In this study, we employed phase-field modeling and computer simulation to systematically investigate the exchange coupling effect on magnetic properties in nonstandard nanochessboards. The simulations reveal that coercivity is dependent on the length scale, with magnetic hardening occurring below the critical exchange length, followed by magnetic softening above the critical exchange length, similar to the standard nanochessboards. Moreover, the presence of unequal edge lengths induces an anisotropic exchange coupling and shifts the coercivity peak with the length scale.

Association between HMGB1 genetic variants and ischemic stroke susceptibility, onset age, and recurrence risk among Chinese Han individuals.

OBJECTIVES: Ischemic stroke has long been a global health threat. Genetic factors, a looming risk for ischemic stroke, remain unexplored. The high-mobility group box 1 (HMGB1) protein showed a connection with the occurrence and development of ischemic stroke. This study was conducted to find whether frequent HMGB1 polymorphisms (rs1045411, rs1412125, and rs2249825) play a role in ischemic stroke susceptibility and recurrence risk. METHODS: Our study was carried out in a Chinese Han population with a sample size of 871 patients and 858 age-matched healthy controls. Tag single nucleotide polymorphisms (tagSNPs) were selected by conventional protocols and DNA was extracted for genotype analysis after the participants had signed an informed consent. Comprehensive statistical analyses were conducted. RESULTS: It was found that the C allele of the HMGB1 rs1412125 (OR = 1.263, 95% CI = 1.075-1.483, P = 0.004) and HMGB1 rs2249825 (adjusted OR = 2.464, 95% CI = 1.215-4.996, P = 0.012) variants was associated with a high risk of ischemic stroke, with the male subgroup carrying the TT allele of the HMGB1 rs1045411 variant tended to suffer more from the disease (adjusted OR = 3.600, 95% CI = 1.272-10.193, P = 0.016). A haplotype study also showed significant results (OR = 1.554, 95% CI = 1.246-1.938, P = 0.001). The rs1412125 polymorphism was highly associated with the chance of recurrence but not with the onset age (TC vs. TT: P = 0.034; CC vs. TT: P < 0.001). Cox regression analysis and stratified analysis were carried out with notable conclusions. CONCLUSIONS: Our study provided evidence for the association between HMGB1 polymorphisms and ischemic stroke susceptibility and recurrence, indicating that HMGB1 gene variants may be potential markers for first and secondary stroke prevention.

SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4.

BACKGROUND: Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms. METHODS: Mouse unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-ß stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis. RESULTS: We observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-ß stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p < 0.001) in mouse kidneys was observed after renal injection which was assessed by LC-MS/MS. We further showed that intrarenal administration of SDMA attenuated renal fibrosis in UIRI induced mouse fibrotic kidneys. Through RNA sequencing analysis, we found that the expression of STAT4 was reduced by SDMA in UUO kidneys, which was further confirmed by quantitative PCR and Western blotting analysis in mouse fibrotic kidneys and renal cells. Inhibition of STAT4 by berbamine dihydrochloride (0.3 mg/ml or 3.3 mg/ml) or siRNA reduced the expression of pro-fibrotic markers in TGF-ß stimulated HK2 cells. Furthermore, blockage of STAT4 attenuated the anti-fibrotic effect of SDMA in TGF-ß stimulated HK2 cells. Conversely, overexpression of STAT4 reversed the anti-fibrotic effect of SDMA in TGF-ß stimulated HK2 cells. CONCLUSION: Taken together, our study indicates that renal SDMA ameliorates renal tubulointerstitial fibrosis through inhibition of STAT4.

Genetic polymorphisms of pri-let-7f, gene-environment and gene-gene interactions, and associations with ischemic stroke risk in Liaoning Province.

OBJECTIVE: The incidence of stroke has been rising annually and investigations into traditional risk factors have led to increased attention on genetic factors. In this study, we focused on the pri-let-7f gene, and investigated the association between pri-let-7f gene polymorphisms and ischemic stroke (IS). METHODS: This case-control study included 1803 patients and 1456 healthy controls of Han ethnicity living in Liaoning Province. We carried out genotyping analysis of two loci, pri-let-7f-1 rs10739971 and pri-let-7f-2 rs17276588, and performed statistical analysis controlling for confounding factors by logistic regression. RESULTS: The A alleles and AA genotypes of both loci were significantly associated with an increased risk of IS. Variant genotypes of rs17276588 may also increase the risk of IS in females with alcohol intake. Gene-gene interaction analysis showed combined effects of mutations in both these single nucleotide polymorphisms (SNPs). CONCLUSIONS: This study demonstrated an association between pri-let-7f SNPs and IS, providing potential latent biomarkers for the risk of IS. However, more detailed studies are needed to clarify these results.

Enhanced volatile fatty acid production from waste activated sludge by urea hydrogen peroxide: performance and mechanisms.

Anaerobic acidogenesis of waste activated sludge (WAS) presents significant potential for resource recovery and waste treatment. However, the slow hydrolysis of WAS limits the efficiency of this approach. In this study, we applied urea hydrogen peroxide (UHP) pretreatment to enhance WAS hydrolysis and investigated the effects of operating parameters on volatile fatty acid (VFA) production and the associated mechanisms. Results demonstrated that UHP significantly improved WAS hydrolysis and VFA production, with a three-fold increase in soluble chemical oxygen demand (SCOD) compared to the control group. UHP dosage emerged as the most critical factor for VFA production, with the maximum VFA concentration increasing from 1127.6 to 8800.9 mg COD per L as UHP dosage ranged from 0 to 6 mmol g-1 VSS (Volatile suspended solids). At an optimal UHP dosage of 4 mmol g-1 VSS, both the unit oxidant promotion efficiency (ΔVFAs/ΔUHP) and the maximum VFA concentration reached relatively high levels, at 35.3 mg COD per mmol and 7527.3 mg COD per L, respectively. UHP pretreatment generated alkaline conditions, H2O2, ·OH and free ammonia, which collectively disrupted the extracellular polymeric substances (EPS) structure, transforming unextractable EPS into extractable forms and promoting the release of organic matter during both the pretreatment and fermentation stages. Excitation-emission matrix (EEM) analysis revealed that UHP increased the concentration of easily utilizable organic matter, providing more substrates for acidogenic bacteria and enhancing VFA production. Furthermore, weak alkaline conditions and high free ammonia concentrations in the UHP group facilitated VFA accumulation by preventing rapid acidification and suppressing methanogen activity. This study offers valuable insights into the potential of UHP pretreatment for enhancing WAS hydrolysis and VFA production, with promising applications in wastewater treatment and resource recovery.

Ursolic acid promotes microglial polarization toward the M2 phenotype via PPARγ regulation of MMP2 transcription.

Microglia, which are the primary inflammatory cells of the brain, can undergo phenotypic switching between M1 and M2 polarization, which have opposing effects on inflammation. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor family of ligand-inducible transcription factors, and PPARγ is known to regulate M2 macrophage polarization. Previous studies have shown that the natural pentacyclic triterpenoid ursolic acid (3ß-hydroxy-urs-12-en-28-oic acid; UA) influences microglial activation. Additionally, UA increases tissue inhibitor matrix metalloproteinase 1 (TIMP1), while greatly reducing the release of matrix metalloproteinase 2 (MMP2) and MMP9 in a PPARγ-dependent manner. Here, we examined the anti-inflammatory properties of UA by observing how well it promotes the phenotypic transition of lipopolysaccharide (LPS) and interferon gamma (IFNγ)-activated BV2 microglia from M1 to M2 polarization. To determine if PPARγ is involved in the underlying molecular pathway, we treated rats with UA and the PPARγ inhibitor BADGE. We also investigated the mechanisms by which PPARγ controls transcription from the MMP2 promoter. The in-vitro experiments showed that UA shifted LPS/IFNγ-activated BV2 microglia from the M1 to the M2 phenotype, which was associated with a reduction in the neurotoxic factors MMP2 and MMP9, and an increase in the anti-inflammatory factor TIMP1. Co-treatment with increased MMP2 and MMP9 synthesis while decreasing TIMP1 release, indicating that UA has anti-inflammatory effects on LPS/IFNγ-activated BV2 cells via activation of PPARγ. Next, we found that PPARγ directly influences MMP2 transcriptional activity by identifying the crucial peroxisome proliferator response element (PPRE) among five potential PPREs in the MMP2 promoter. These results suggest that UA has a protective anti-inflammatory effect against neuroinflammatory toxicity, which is exerted by direct activation of PPARγ and selectively modulates microglial polarization and suppresses MMP2 formation.

Investigating the effect of dehydromiltirone on septic AKI using a network pharmacology method, molecular docking, and experimental validation.

Acute kidney injury (AKI) is a severe and frequent complication of sepsis that occurs in intensive care units with inflammation and rapid decline in renal function as the main pathological features. Systemic inflammation, microvascular dysfunction, and tubule injury are the main causes of sepsis-induced AKI (SI-AKI). The high prevalence and death rate from SI-AKI is a great challenge for clinical treatment worldwide. However, in addition to hemodialysis, there is no effective drug to improve renal tissue damage and alleviate the decline in kidney function. We conducted a network pharmacological analysis of Salvia miltiorrhiza (SM), a traditional Chinese medicine, which is widely used for the treatment of kidney disease. Then, we combined molecular docking and a dynamics simulation to screen for the active monomer dehydromiltirone (DHT) that has therapeutic effects on SI-AKI and investigated its potential mechanism of action through experimental validation. The components and targets of SM were obtained by searching the database, and 32 overlapping genes were screened by intersection analysis with AKI targets. GO and KEGG data showed that the functions of a common gene were closely related to oxidative stress, mitochondrial function, and apoptosis. The molecular docking results combined with molecular dynamics simulations provide evidence for a binding model between DHT and cyclooxygenase-2 (COX2), both of which are mainly driven by van der Waals interactions and a hydrophobic effect. In vivo, we found that mice pretreated with an intraperitoneal injection of DHT (20 mg/kg/d) for 3 days ameliorated CLP surgery-induced renal function loss and renal tissue damage and inhibited inflammatory mediators IL-6, IL-1ß, TNF-α, and MCP-1 production. In vitro, the DHT pretreatment decreased LPS-induced expression of COX2, inhibited cell death and oxidative stress, alleviated mitochondrial dysfunction, and restrained apoptosis in HK-2 cells. Our research indicates that the renal preventive effect of DHT is related to maintaining mitochondrial dynamic balance, restoring mitochondrial oxidative phosphorylation, and inhibiting cell apoptosis. The findings in this study provide a theoretical basis and a novel method for the clinical therapy of SI-AKI.

Multi-centre, prospective randomized comparison of three different substrate ablation strategies for persistent atrial fibrillation.

AIMS: The optimal strategy for persistent atrial fibrillation (PerAF) is poorly defined. We conducted a multicentre, randomized, prospective trial to compare the outcomes of different ablation strategies for PerAF. METHODS AND RESULTS: We enrolled 450 patients and randomly assigned them in a 1:1:1 ratio to undergo pulmonary vein isolation and subsequently undergo the following three different ablation strategies: anatomical guided ablation (ANAT group, n = 150), electrogram guided ablation (EGM group, n = 150), and extensive electro-anatomical guided ablation (EXT group, n = 150). The primary endpoint was freedom from atrial fibrillation (AF) lasting longer than 30 s at 12 months after a single ablation procedure. After 12 months of follow-up, 72% (108) of patients in the EXT group were free from AF recurrence, as compared with the 64% (96) in the EGM group (P = 0.116), and 54% (81) in the ANAT group (P = 0.002). The EXT group showed less AF/atrial tachycardia recurrence than the EGM group (60% vs. 50%, P = 0.064) and the ANAT group (60% vs. 37.3%, P < 0.001). The EXT group showed the highest rate of AF termination (66.7%), followed by 56.7% in the EGM group, and 20.7% in the ANAT group. The AF termination signified less AF recurrence at 12 months compared to patients without AF termination (30.1% vs. 42.7%, P = 0.008). Safety endpoints did not differ significantly between the three groups (P = 0.924). CONCLUSIONS: Electro-anatomical guided ablation achieved the most favourable outcomes among the three ablation strategies. The AF termination is a reliable ablation endpoint.

Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk.

OBJECTIVE: Accumulating evidence has shown that aberrant alternative splicing events are closely associated with the onset and development of cancer. However, whether genetic variants-associated alternative splicing is linked to risk of endometrial cancer remains largely uncertain. METHODS: We identified single nucleotide polymorphisms (SNPs) locates in the splicing number trait locus (sQTL) of endometrial cancer using the CancerSplicing QTL database. In parallel with bioinformatics analysis, we conducted a case-control study comprising 2,000 cases and 2,013 controls to assess the association between identified SNP which possesses mRNA splicing function and endometrial cancer susceptibility. Furthermore, we used the Kaplan-Meier Plotter, The Human Protein Atlas, SPNR, and Spliceman2 databases for sQTL and differential gene expression analyses to identify the genetic variant which most potentially influence the risk of endometrial cancer through alternative splicing to reveal the potential mechanism by which candidate SNPs regulate the risk of endometrial cancer. RESULTS: The results indicated that SNP rs7128029 A

Genetic variants in the promoters of let-7 are associated with the risk and age at onset of ischemic stroke: A case control study.

PURPOSE: Let-7 family members serve as crucial regulatory molecules in the pathogenesis of ischemic stroke. We predicted that genetic variations in the let-7 family's promoters may be linked to the risk of ischemic stroke. The connection of rs10877887 and rs13293512 in the let-7 family promoters with liability to ischemic stroke was explored in this study. PATIENTS AND METHODS: Clinical data and peripheral blood samples were collected from 914 ischemic stroke patients and 836 controls in this case-control study. All statistical analyses were carried out using SPSS. RESULTS: Our analysis results reveal that the rs10877887 TC+CC genotype in the dominant model is associated with a lower risk of ischemic stroke than the TT genotype. Individuals with heterozygous TC or homozygous CC genotypes in the male population showed higher odds of ischemic stroke than those with the wild TT genotype in rs13293512 analysis. Furthermore, there existed a multiplicative interaction between the rs10877887 C allele and the rs13293512 T allele. In the presence of the rs13293512 T allele, the effect of the rs10877887 C allele on ischemic stroke risk was increased. Similarly, in the presence of the rs10877887 C allele, the outcome of the rs13293512 T allele on ischemic stroke risk was elevated. In addition, the rs13293512 CC genotype seemed to lead to an earlier onset of ischemic stroke. CONCLUSION: Our findings indicated that these two SNPs might have a joint role in IS and could potentially act as risk markers. Detecting let-7 promoter polymorphisms could raise awareness of the risk of IS, which directed individuals with risk alleles to have regular checks at an appropriate frequency to avoid developing the disease.

Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus.

Although extracellular DNA is known to form immune complexes (ICs) with autoantibodies in systemic lupus erythematosus (SLE), the mechanisms leading to the release of DNA from cells remain poorly characterized. Here, we show that the pore-forming protein, gasdermin D (GSDMD), is required for nuclear DNA and mitochondrial DNA (mtDNA) release from neutrophils and lytic cell death following ex vivo stimulation with serum from patients with SLE and IFN-γ. Mechanistically, the activation of FcγR downregulated Serpinb1 following ex vivo stimulation with serum from patients with SLE, leading to spontaneous activation of both caspase-1/caspase-11 and cleavage of GSDMD into GSDMD-N. Furthermore, mtDNA oxidization promoted GSDMD-N oligomerization and cell death. In addition, GSDMD, but not peptidyl arginine deiminase 4 is necessary for extracellular mtDNA release from low-density granulocytes from SLE patients or healthy human neutrophils following incubation with ICs. Using the pristane-induced lupus model, we show that disease severity is significantly reduced in mice with neutrophil-specific Gsdmd deficiency or following treatment with the GSDMD inhibitor, disulfiram. Altogether, our study highlights an important role for oxidized mtDNA in inducing GSDMD oligomerization and pore formation. These findings also suggest that GSDMD might represent a possible therapeutic target in SLE.

Glutamate ionotropic receptor NMDA type subunit 1: A novel potential protein target of dapagliflozin against renal interstitial fibrosis.

Renal interstitial fibrosis (RIF) is the final pathway for chronic kidney diseases (CKD) to end-stage renal disease, with no ideal therapy at present. Previous studies indicated that sodium glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin had the effect of anti-RIF, but the mechanism remains elusive and the renal protective effect could not be fully explained by singly targeting SGLT2. In this study, we aimed to explore the mechanism of dapagliflozin against RIF and identify novel potential targets. Firstly, dapagliflozin treatment improved pro-fibrotic indicators in unilateral ureteral obstruction mice and transforming growth factor beta 1 induced human proximal tubular epithelial cells. Then, transcriptomics and bioinformatics analysis were performed, and results revealed that dapagliflozin against RIF by regulating inflammation and oxidative stress related signals. Subsequently, targets prediction and analysis demonstrated that glutamate ionotropic receptor NMDA type subunit 1 (GRIN1) was a novel potential target of dapagliflozin, which was related to inflammation and oxidative stress related signals. Moreover, molecular dynamics simulation revealed that dapagliflozin could stably bind to GRIN1 protein and change its spatial conformation. Furthermore, human renal samples and Nephroseq data were used for GRIN1 expression evaluation, and the results showed that GRIN1 expression were increased in renal tissues of CKD and RIF patients than controls. Additionally, further studies demonstrated that dapagliflozin could reduce intracellular calcium influx in renal tubular cells, which depended on regulating GRIN1 protein but not gene. In conclusion, GRIN1 is probably a novel target of dapagliflozin against RIF.

Genetic variation within the pri-let-7f-2 in the X chromosome predicting stroke risk in a Chinese Han population from Liaoning, China: From a case-control study to a new predictive nomogram.

Background and objectives: Stroke is the most common cause of disability and the second cause of death worldwide. Therefore, there is a need to identify patients at risk of developing stroke. This case-control study aimed to create and verify a gender-specific genetic signature-based nomogram to facilitate the prediction of ischemic stroke (IS) risk using only easily available clinical variables. Materials and methods: A total of 1,803 IS patients and 1,456 healthy controls from the Liaoning province in China (Han population) were included which randomly divided into training cohort (70%) and validation cohort (30%) using the sample function in R software. The distribution of the pri-let-7f-2 rs17276588 variant genotype was analyzed. Following genotyping analysis, statistical analysis was used to identify relevant features. The features identified from the multivariate logistic regression, the least absolute shrinkage and selection operator (LASSO) regression, and univariate regression were used to create a multivariate prediction nomogram model. A calibration curve was used to determine the discrimination accuracy of the model in the training and validation cohorts. External validity was also performed. Results: The genotyping analysis identified the A allele as a potential risk factor for IS in both men and women. The nomogram identified the rs17276588 variant genotype and several clinical parameters, including age, diabetes mellitus, body mass index (BMI), hypertension, history of alcohol use, history of smoking, and hyperlipidemia as risk factors for developing IS. The calibration curves for the male and female models showed good consistency and applicability. Conclusion: The pri-let-7f-2 rs17276588 variant genotype is highly linked to the incidence of IS in the northern Chinese Han population. The nomogram we devised, which combines genetic fingerprints and clinical data, has a lot of promise for predicting the risk of IS within the Chinese Han population.

TREM2 improves neurological dysfunction and attenuates neuroinflammation, TLR signaling and neuronal apoptosis in the acute phase of intracerebral hemorrhage.

Neuroinflammation contributes to secondary brain injury following intracerebral hemorrhage (ICH). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effect by suppressing neuroinflammatory response in experimental ischemic stroke. This study aimed to clarify the neuroprotective role of TREM2 and potential underlying mechanism in a mouse model of ICH and in vitro. Adeno-associated virus (AAV) and green fluorescent protein-lentivirus (GFP-LV) strategies were employed to enhance TREM2 expression in the C57/BL6 mice and BV2 cells, respectively. The adult male C57/BL6 mice were subjected to ICH by administration of collagenase-IV in 1 month after the AAV particles injection. An in vitro ICH model was performed with oxygen hemoglobin in BV2 cells. Toll-like receptor 4 (TLR4) antagonist TAK242 was applied at 6 h following ICH. Neurological function, TREM2, pro-inflammatory cytokines, brain water content and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were evaluated at 24 h following ICH. TLR4, NF-κB and mitogen-activated protein kinases (MAPK) signaling pathways were also determined by Western blot analysis at the same time point. The levels of TREM2 were increased at 12 h, peaked at 24 h and recovered on 7d following ICH. TREM2 overexpression ameliorated ICH induced neurological dysfunction, inhibited neuroinflammation, and attenuated apoptosis and brain edema. Further mechanistic study revealed that TREM2 overexpression inhibited TLR4 activation and NF-κB and MAPK signaling pathways. ICH increased the percentage of TUNEL-positive cells, which was markedly decreased by TREM2 overexpression. A similar improvement was also observed by the administration of TAK242 following ICH. TREM2 improves neurological dysfunction and attenuates neuroinflammation and neuronal apoptosis in the acute phase of ICH, which is, at least in part, mediated by negatively regulating TLR4 signaling pathway. These findings highlight TREM2 as a potential target for early brain injury following ICH.