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Calcific aortic valve disease (CAVD) is an aging related disease characterized by inflammation and fibrocalcific remodeling. IL-17A is a key cytokine associated with pathophysiology of inflammatory and fibrotic disease. Previous studies showed accumulation of IL-17A-producing T helper lymphocytes in human calcified aortic valves and significantly elevated IL-17RA expression in calcified valves. However, the role of IL-17A signaling in the initiation and development of CAVD is still unclear. In this study, by analyzing public transcriptome databases, we found that IL-17A-IL-17RA signaling is activated in calcified valves. Gene expression analysis revealed significantly increased IL-17A, IL-17RA, and RUNX2 expression in calcified human aortic valves compared to in non-calcified valves, and the expression of IL-17A and IL-17RA were positively correlated with RUNX2 expression. A 5/6 nephrectomy was performed in Apoe-/- (Apoe knockout) mice to establish a CAVD mouse model. IL-17A-neutralizing antibodies significantly reduced valve calcium deposition and decreased expression of RUNX2 in aortic valves. Immunofluorescence staining of human aortic valves and qRT-PCR analysis of primary aortic valve cells revealed abundant expression of IL-17RA in valvular endothelial cells (VECs). RNA sequencing indicated that IL-17A promoted the activation of inflammatory signaling pathways in VECs. Furthermore, qRT-PCR and cytometric bead array analysis confirmed that IL-17A promoted the expression or secretion of inflammatory cytokines IL-6 and IL-1ß, chemokines CXCL2 and CXCL8, and fibrosis-related gene COL16A1. Our findings indicate that elevated IL-17A in CAVD may promote valve inflammation, fibrosis, and calcification by inducing endothelial activation and inflammation. Targeting IL-17A-IL-17RA signaling may be a potential therapeutic strategy for CAVD.
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Estenose da Valva Aórtica , Valva Aórtica , Humanos , Camundongos , Animais , Valva Aórtica/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Células Endoteliais/metabolismo , Interleucina-17/metabolismo , Estenose da Valva Aórtica/genética , Citocinas/metabolismo , Inflamação/patologia , Fibrose , Apolipoproteínas E/metabolismo , Células CultivadasRESUMO
Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes. Currently, the prevalence and mortality of DKD are increasing annually. However, with no effective drugs to prevent its occurrence and development, the primary therapeutic option is to control blood sugar and blood pressure. Therefore, new and effective drugs/methods are imperative to prevent the development of DKD in patients with diabetes. Mesenchymal stem cells (MSCs) with multi-differentiation potential and paracrine function have received extensive attention as a new treatment option for DKD. However, their role and mechanism in the treatment of DKD remain unclear, and clinical applications are still being explored. Given this, we here provide an unbiased review of recent advances in MSCs for the treatment of DKD in the last decade from the perspectives of the pathogenesis of DKD, biological characteristics of MSCs, and different molecular and signaling pathways. Furthermore, we summarize information on combination therapy strategies using MSCs. Finally, we discuss the challenges and prospects for clinical application.
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Diabetes Mellitus , Nefropatias Diabéticas , Células-Tronco Mesenquimais , Nefropatias Diabéticas/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Transdução de SinaisRESUMO
Primary membranous nephropathy (PMN) is a common cause of adult nephrotic syndrome, most commonly associated with autoantibodies against M-type phospholipase A2 receptor (PLA2R). Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a rare disorder characterized by asthma, eosinophilia, and multiorgan vasculitis. Here, we report the case of an adult who presented with typical nephrotic syndrome. Renal biopsy revealed PLA2R-positive PMN without crescents. He had a history of asthma, eczema, and eosinophilia, and testing revealed positive serological proteinase 3 (PR3) and antineutrophil cytoplasmic antibody (ANCA). Further skin and bone marrow biopsy revealed histologic eosinophilic infiltration, and a diagnosis of EGPA was made. The renal biopsy revealed a few eosinophils in glomerular capillary lumen and tubulointerstitial. Treatment with a glucocorticoid and cyclophosphamide was initiated. At 32 months after completing therapy, the patient was in complete clinical remission, and the PR3-ANCA result was negative.
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Síndrome de Churg-Strauss/complicações , Glomerulonefrite Membranosa/complicações , Mieloblastina/análise , Receptores da Fosfolipase A2/análise , Anticorpos Anticitoplasma de Neutrófilos/análise , Síndrome de Churg-Strauss/tratamento farmacológico , Síndrome de Churg-Strauss/enzimologia , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Introduction: We aimed to investigate the relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression levels, lupus nephritis (LN) disease activity, and the degree of renal injury (based on the estimated glomerular filtration rate [eGFR]) in patients with LN. Methods: We selected 40 healthy control participants and 102 patients with LN who were treated in the Second Hospital of Jilin University, China, for inclusion in this study. Patients with LN were classified into LN with high-eGFR and LN with low-eGFR groups. Nrf2 protein levels were measured in the serum and renal tissues of the participants in both groups to assess the correlation between Nrf2 protein levels and different LN disease states. Results: There was a significantly positive correlation between serum Nrf2 protein levels, the degree of renal injury, and systemic lupus erythematosus disease activity index (SLEDAI) scores in patients with LN. Nrf2 protein levels were higher in the LN with high-eGFR group than in the healthy control and LN with low-eGFR groups. In follow-up patients in the LN high eGFR group, Nrf2 protein levels decreased significantly after remission of disease activity. Conclusion: Nrf2 protein expression has a dual role in patients with LN. Nrf2 protein levels not only correlate with disease activity in patients with LN, but also with the degree of kidney injury. Before implementing targeted therapy for Nrf2, evaluating both Nrf2 protein expression and the disease state in patients with LN is necessary to better identify and place each patient in an appropriate patient group.
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Nefrite Lúpica , Fator 2 Relacionado a NF-E2 , Insuficiência Renal , Humanos , Biomarcadores/sangue , Rim/patologia , Nefrite Lúpica/sangue , Nefrite Lúpica/patologia , Fator 2 Relacionado a NF-E2/sangue , Insuficiência Renal/sangue , Insuficiência Renal/patologiaRESUMO
Calcific aortic valve stenosis (CAVS) is characterized by increasing inflammation and progressive calcification in the aortic valve leaflets and is a major cause of death in the aging population. This study aimed to identify the inflammatory proteins involved in CAVS and provide potential therapeutic targets. We investigated the observational and causal associations of 92 inflammatory proteins, which were measured using affinity-based proteomic assays. Firstly, the case-control cohort identified differential proteins associated with the occurrence and progression of CAVS. Subsequently, we delved into exploring the causal impacts of these associated proteins through Mendelian randomization. This involved utilizing genetic instruments derived from cis-protein quantitative loci identified in genome-wide association studies, encompassing a cohort of over 400,000 individuals. Finally, we investigated the gene transcription and protein expression levels of inflammatory proteins by single-cell and immunohistochemistry analysis. Multivariate logistic regression and spearman's correlation analysis showed that five proteins showed a significant positive correlation with disease severity. Mendelian randomization showed that elevated levels of two proteins, namely, matrix metallopeptidase-1 (MMP1) and sirtuin 2 (SIRT2), were associated with an increased risk of CAVS. Immunohistochemistry and single-cell transcriptomes showed that expression levels of MMP1 and SIRT2 at the tissue and cell levels were significantly higher in calcified valves than in non-calcified control valves. These findings indicate that MMP1 and SIRT2 are causally related to CAVS and open up the possibility for identifying novel therapeutic targets.
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Estenose da Valva Aórtica , Valva Aórtica , Valva Aórtica/patologia , Biomarcadores , Calcinose , Mediadores da Inflamação , Metaloproteinase 1 da Matriz , Análise da Randomização Mendeliana , Proteômica , Humanos , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Calcinose/genética , Calcinose/metabolismo , Calcinose/sangue , Calcinose/patologia , Valva Aórtica/metabolismo , Masculino , Feminino , Idoso , Estudos de Casos e Controles , Biomarcadores/sangue , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/sangue , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Idoso de 80 Anos ou mais , Predisposição Genética para Doença , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/análise , FenótipoRESUMO
Obesity-related glomerulopathy, which is an obesity-triggered kidney damage, has become a significant threat to human health. Several studies have recently highlighted the critical role of inflammation in obesity-related glomerulopathy development. Additionally, excess adipose tissue and adipocytes in patients with obesity produce various inflammatory factors that cause systemic low-grade inflammation with consequent damage to vascular endothelial cells, exacerbating glomerular injury. Therefore, we conducted a comprehensive review of obesity-related glomerulopathy and addressed the critical role of obesity-induced chronic inflammation in obesity-related glomerulopathy pathogenesis and progression, which leads to tubular damage and proteinuria, ultimately impairing renal function. The relationship between obesity and obesity-related glomerulopathy is facilitated by a network of various inflammation-associated cells (including macrophages, lymphocytes, and mast cells) and a series of inflammatory mediators (such as tumor necrosis factor α, interleukin 6, leptin, adiponectin, resistin, chemokines, adhesion molecules, and plasminogen activator inhibitor 1) and their inflammatory pathways. Furthermore, we discuss a recently discovered relationship between micronutrients and obesity-related glomerulopathy inflammation and the important role of micronutrients in the body's anti-inflammatory response. Therefore, assessing these inflammatory molecules and pathways will provide a strong theoretical basis for developing therapeutic strategies based on anti-inflammatory effects to prevent or delay the onset of kidney injury.
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Inflamação , Obesidade , Humanos , Obesidade/complicações , Inflamação/complicações , Inflamação/patologia , Animais , Nefropatias/etiologia , Nefropatias/patologia , Nefropatias/imunologia , Mediadores da Inflamação/metabolismo , Glomérulos Renais/patologiaRESUMO
OBJECTIVE: Periodontitis is a complex and multifactorial disease and it is challenging to decipher its underlying causes and mechanisms. This study attempted to explore potential circulating proteins in connection to periodontitis through proteome-wide Mendelian randomisation (MR). METHODS: We analysed 1722 circulating proteins to identify prospective drug targets for tackling periodontitis, using the genomic dataset from the FinnGen study. Two-sample MR was conducted to evaluate the bidirectional relationship between circulating proteins and periodontitis risk. A dataset from the UK Biobank was used to validate the findings. Single-cell analysis was performed to assess the cellular expression of the identified proteins within gingival tissues. RESULTS: MR analyses found that genetically predicted circulating levels of von Willebrand factor A domain-containing 1 (von Willebrand factor A domain containing 1 [VWA1], odds ratios: 0.94, 95% CI 0.92-0.97, P = 1.28 × 10-5) were inversely associated with periodontitis. In contrast, the level of growth differentiation factor 15 (growth differentiation factor 15 [GDF15], odds ratios: 1.05, 95% CI 1.02-1.07, P = 2.12 × 10-5) might be associated with an increased risk of periodontitis. Single-cell analysis indicated that VWA1 was primarily expressed in endothelial cells of healthy gingival tissues, while the main source of GDF15 was not derived from periodontal cells. CONCLUSIONS: The present study suggests that certain plasma proteins like VWA1 and GDF15 may be potentially indicative of the risk and susceptibility to periodontitis. These proteins could possibly be the potential therapeutic targets for treating periodontitis, and further investigation is highly warranted.
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An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell- or fibroblast-specific knockout of Igf1r, the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl2-induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.
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Aneurisma da Aorta Abdominal , Modelos Animais de Doenças , Fator de Crescimento Insulin-Like I , Receptor IGF Tipo 1 , Animais , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Humanos , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/prevenção & controle , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Suínos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , RatosRESUMO
Palmd-deficient mice of advanced age manifest increased aortic valve peak velocity, thickened aortic valve leaflets, and excessive extracellular matrix deposition, which are key features of calcific aortic valve disease. PALMD is predominantly expressed in endothelial cells of aortic valves, and PALMD-silenced valvular endothelial cells are prone to oscillatory shear stress-induced endothelial-to-mesenchymal transition. Mechanistically, PALMD is associated with TNFAIP3 interaction protein 1, a binding protein of TNFAIP3 and IKBKG in NF-κB signaling. Loss of PALMD impairs TNFAIP3-dependent deubiquitinating activity and promotes the ubiquitination of IKBKG and subsequent NF-κB activation. Adeno-associated virus-mediated PALMD overexpression ameliorates aortic valvular remodeling in mice with calcific aortic valve disease, indicating protection.
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OBJECTIVE: We investigated the correlation between zinc levels and Nrf2 expression and potential effects on the clinicopathology of patients with diabetic nephropathy (DN). METHODS: We selected 30 patients with DN, diagnosed via renal biopsy at our hospital from March 2018 to November 2019, and enrolled 30 healthy individuals from a medical examination center as the control group. Patients with DN were divided into normal-zinc and low-zinc groups. We detected the levels of zinc, copper, and Nrf2 mRNA in their serum, and collected the clinical and pathological data of DN patients. RESULTS: Serum zinc level and Nrf2 mRNA expression were significantly decreased in patients with DN compared to those of healthy people (P < 0.05). Of the 30 patients, 16 had low zinc (53.3%) and 14 had normal zinc levels (46.7%). There was no significant difference in the blood Nrf2 mRNA expression between the two groups (P > 0.05). However, the expression of Nrf2 in the kidney tissue of the low-zinc group was significantly lower compared to the normal-zinc group (P < 0.05). Diastolic blood pressure and copper levels were significantly higher in the low-zinc group (P < 0.05). In contrast, body mass index, red blood cell count, Hb level, and the ratio of zinc to copper were significantly lower in the low-zinc group (P < 0.05). The pathological classifications of the low-zinc group were more severe (P < 0.05). CONCLUSION: Patients with DN were more likely to have zinc deficiency and lower expression of Nrf2. Additionally, DN patients with zinc deficiency were prone to have more severe clinical and pathological manifestations.
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Diabetes Mellitus , Nefropatias Diabéticas , Fator 2 Relacionado a NF-E2/genética , Cobre , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro , ZincoRESUMO
Mitochondria are essential for eukaryotic cell activity and function, and their dysfunction is associated with the development and progression of renal diseases. In recent years, there has been a rapid development in mitochondria-targeting pharmacological strategies as mitochondrial biogenesis, morphology, and function, as well as dynamic changes in mitochondria, have been studied in disease states. Mitochondria-targeting drugs include nicotinamide mononucleotide, which supplements the NAD+ pool; mitochondria-targeted protective compounds, such as MitoQ; the antioxidant coenzyme, Q10; and cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. However, traditional drugs targeting mitochondria have limited clinical applications due to their inability to be effectively absorbed by mitochondria in vivo and their high toxicity. Recently, SS-31, a mitochondria-targeting antioxidant, has received significant research attention as it decreases mitochondrial reactive oxygen species production and prevents mitochondrial depolarization, mitochondrial permeability transition pore formation, and Ca2+-induced mitochondrial swelling, and has no effects on normal mitochondria. At present, few studies have evaluated the effects of SS-31 against renal diseases, and the mechanism underlying its action is unclear. In this review, we first discuss the pharmacokinetics of SS-31 and the possible mechanisms underlying its protective effects against renal diseases. Then, we analyze its renal disease-improving effects in various experimental models, including animal and cell models, and summarize the clinical evidence of its benefits in renal disease treatment. Finally, the potential mechanism underlying the action of SS-31 against renal diseases is explored to lay a foundation for future preclinical studies and for the evaluation of its clinical applications.
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Nefropatias , Poro de Transição de Permeabilidade Mitocondrial , Animais , Antioxidantes/farmacologia , Nefropatias/tratamento farmacológico , Mitocôndrias , Peptídeos/farmacologia , Espécies Reativas de Oxigênio/farmacologiaRESUMO
Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes and is the leading cause of end-stage renal disease (ESRD). Persistent proteinuria is an important feature of DKD, which is caused by the destruction of the glomerular filtration barrier (GFB). Glomerular endothelial cells (GECs) and podocytes are important components of the GFB, and their damage can be observed in the early stages of DKD. Recently, studies have found that crosstalk between cells directly affects DKD progression, which has prospective research significance. However, the pathways involved are complex and largely unexplored. Here, we review the literature on cellular crosstalk of GECs and podocytes in the context of DKD, and highlight specific gaps in the field to propose future research directions. Elucidating the intricates of such complex processes will help to further understand the pathogenesis of DKD and develop better prevention and treatment options.
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Fibrillin 1 (Fbn1) mutation causes Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. The mechanisms for extracellular matrix (ECM) homeostasis disruption in MFS TAA are unclear. Here, we found ECM-related gene secreted phosphoprotein 1 (Spp1) increased in Fbn1C1041G/+ mice using transcriptome sequencing and a distinct fibroblast subcluster with Spp1 as the strongest marker was identified with analysis of the MFS mouse aortic single-cell sequencing dataset. Immunostaining confirmed elevated Spp1 in adventitial fibroblasts, and Spp1 might regulate fibroblast and smooth muscle cell (SMC) communication primarily through Itga8/Itgb1. Then, we observed Spp1 reduced contractile genes Acta2 and Tagln expression in SMCs and increased collagen expression in fibroblasts, which might contribute to TAA development. Finally, we also found elevated SPP1 plasma level was associated with an increased risk of TAA in patients. Therefore, SPP1 may serve as a biomarker and therapeutic target for TAA.
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Aneurisma da Aorta Torácica , Aneurisma Aórtico , Síndrome de Marfan , Camundongos , Animais , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Aneurisma Aórtico/genética , Aneurisma da Aorta Torácica/genética , Matriz Extracelular/metabolismo , Fibroblastos/metabolismoRESUMO
Lupus nephritis (LN) is a significant cause of various acute and chronic renal diseases, which can eventually lead to end-stage renal disease. The pathogenic mechanisms of LN are characterized by abnormal activation of the immune responses, increased cytokine production, and dysregulation of inflammatory signaling pathways. LN treatment is an important issue in the prevention and treatment of systemic lupus erythematosus. Mesenchymal stem cells (MSCs) have the advantages of immunomodulation, anti-inflammation, and anti-proliferation. These unique properties make MSCs a strong candidate for cell therapy of autoimmune diseases. MSCs can suppress the proliferation of innate and adaptive immune cells, such as natural killer cells (NKs), dendritic cells (DCs), T cells, and B cells. Furthermore, MSCs suppress the functions of various immune cells, such as the cytotoxicity of T cells and NKs, maturation and antibody secretion of B cells, maturation and antigen presentation of DCs, and inhibition of cytokine secretion, such as interleukins (ILs), tumor necrosis factor (TNF), and interferons (IFNs) by a variety of immune cells. MSCs can exert immunomodulatory effects in LN through these immune functions to suppress autoimmunity, improve renal pathology, and restore kidney function in lupus mice and LN patients. Herein, we review the role of immune cells and cytokines in the pathogenesis of LN and the mechanisms involved, as well as the progress of research on the immunomodulatory role of MSCs in LN.
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Nefrite Lúpica , Células-Tronco Mesenquimais , Animais , Citocinas/metabolismo , Humanos , Imunidade , Imunomodulação , Células-Tronco Mesenquimais/metabolismo , CamundongosRESUMO
Background: Mitral valve surgery (MVS) is an effective treatment for mitral valve diseases. There is a lack of reliable personalized risk prediction models for mortality in patients undergoing mitral valve surgery. Our aim was to develop a risk stratification system to predict all-cause mortality in patients after mitral valve surgery. Methods: Different machine learning models for the prediction of all-cause mortality were trained on a derivation cohort of 1,883 patients undergoing mitral valve surgery [split into a training cohort (70%) and internal validation cohort (30%)] to predict all-cause mortality. Forty-five clinical variables routinely evaluated at discharge were used to train the models. The best performance model (PRIME score) was tested in an externally validated cohort of 220 patients undergoing mitral valve surgery. The model performance was evaluated according to the area under the curve (AUC). Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were compared with existing risk strategies. Results: After a median follow-up of 2 years, there were 133 (7.063%) deaths in the derivation cohort and 17 (7.727%) deaths in the validation cohort. The PRIME score showed an AUC of 0.902 (95% confidence interval [CI], 0.849-0.956) in the internal validation cohort and 0.873 (95% CI: 0.769-0.977) in the external validation cohort. In the external validation cohort, the performance of the PRIME score was significantly improved compared with that of the existing EuroSCORE II (NRI = 0.550, [95% CI 0.001-1.099], P = 0.049, IDI = 0.485, [95% CI 0.230-0.741], P < 0.001). Conclusion: Machine learning-based model (the PRIME score) that integrate clinical, demographic, imaging, and laboratory features demonstrated superior performance for the prediction of mortality patients after mitral valve surgery compared with the traditional risk model EuroSCORE II. Clinical Trial Registration: [http://www.clinicaltrials.gov], identifier [NCT05141292].
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Renal fibrosis, a characteristic of all chronic kidney diseases, lacks effective therapeutic drugs currently. Pirfenidone (PFD), a small molecule drug with good oral bioavailability, is widely used in idiopathic pulmonary fibrosis and exerts anti-fibrotic, anti-inflammatory, antioxidant, and anti-apoptotic effects. These effects have been attributed to the suppression of cell growth factors (in particular, but not exclusively, transforming growth factor-ß) and the epithelial-mesenchymal transition, as well as the possible down-regulation of pro-inflammatory mediators (such as tumour necrosis factor-α), the protection of mitochondrial function, and the regulation of inflammatory cells. Considering the activation of similar anti-fibrotic pathways in lung and kidney disease and the broad activity of PFD, this drug has improved the treatment of the renal fibrotic disease. In this review, we briefly summarize the pharmacokinetics and safety of PFD as well as the mechanisms of PFD focusing on kidney disease. We summarize the effects of PFD on renal function and pathological alterations based on animal experiments, as well as changes in growth factors based on both animal and renal cell experiments. Moreover, given the activation of similar profibrotic pathways in pulmonary diseases and other disorders, we reviewed in-depth the possible signalling pathways targeted by PFD to attenuate renal fibrosis and protect renal function. Finally, we provide an overview of the current clinical trials of PFD for the treatment of renal fibrosis.
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PiridonasRESUMO
INTRODUCTION: In 2018, a renal risk score of antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) based on estimated glomerular filtration rate (eGFR), normal glomeruli, and tubular atrophy/interstitial fibrosis (TA/IF) was proposed to predict renal outcomes. We aimed to evaluate this renal risk score in a myeloperoxidase (MPO)-ANCA predominant population in Northeast China. METHODS: We retrospectively analyzed the clinicopathologic data of 65 patients biopsy-proven from a Chinese medical center. Each patient was assessed by eGFR, normal glomeruli, and TA/IF, and the renal outcome was evaluated using the renal risk score. RESULTS: In our study, 95.4% of patients were ANCA positive (78.5% MPO-ANCA positive and 16.9% proteinase 3-ANCA positive). The average follow-up period was 14.3 months. Thirty-four patients (52.3%) reached end-stage renal disease (ESRD). Based on the renal risk score, 8 (12.3%), 31 (47.7%), and 26 (40%) patients were divided into the low-risk, medium-risk, and high-risk groups, respectively. Kaplan-Meier survival curves revealed the high-risk group had worse renal outcomes than the low-risk group (p<0.01) and the medium-risk group (p<0.01), but the renal outcome did not differ between the low-risk and medium-risk groups (p>0.017). Similar results were obtained by the competitive survival analysis. The AUC for 3-year overall ESRD predictions was 0.845. In the regression analysis, the renal risk score was a favorable predictor for the development of ESRD (HR 3.13, 95%CI 1.58-6.19, p=0.001). CONCLUSION: The renal risk score is a preferred index that can predict ESRD in Chinese AAGN patients, especially in the high-risk group with worse renal outcomes. Key Points ⢠The eGFR and percentage of normal glomeruli were valuable predictors of renal outcome, whereas TA/IF was not. ⢠We confirmed the renal risk score is a preferred index that can predict ESRD in Chinese AAGN patients. ⢠Based on the renal risk score, the high-risk group had worse renal outcomes than the low-risk group and the medium-risk group.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos , China/epidemiologia , Glomerulonefrite/epidemiologia , Humanos , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Mesenchymal stem cells (MSCs) have a therapeutic effect on diabetic nephropathy (DN) but the underlying mechanism remains unclear. This study was conducted to investigate whether human umbilical cord-MSCs (hUCMSCs) can induce oxidative damage and apoptosis by activating Nrf2. METHODS: We used a type 2 diabetic rat model and a high-glucose and fat-stimulated human glomerular mesangial cell (hGMC) model. Western blotting, RT-qPCR, and TUNEL staining were performed on animal tissues and cultured cells. Nuclear expression of Nrf2 was detected in the renal tissue. Furthermore, Nrf2 siRNA was used to examine the effects of hUCMSCs on hGMCs. Finally, the effect of hUCMSCs on the Nrf2 upstream signalling pathway was investigated. RESULTS: After treatment with hUCMSCs, Nrf2 showed increased expression and nuclear translocation. After Nrf2-specific knockout in hGMCs, the protective effect of hUCMSCs on apoptosis induced by high-glucose and fat conditions was reduced. Activation of the PI3K signalling pathway may be helpful for ameliorating DN using hUCMSCs. CONCLUSIONS: hUCMSCs attenuated renal oxidative damage and apoptosis in type 2 diabetes mellitus and Nrf2 activation is one of the important mechanisms of this effect. hUCMSCs show potential as drug targets for DN.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Células-Tronco Mesenquimais , Animais , Apoptose , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Humanos , Células-Tronco Mesenquimais/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos , Cordão Umbilical/metabolismoRESUMO
OBJECTIVES: We sought to determine the optimal antithrombotic therapy after transcatheter aortic valve replacement. METHODS: Related scientific databases were searched until December 2018. We conducted a pairwise and a network meta-analysis within a frequentist framework, measuring 30-day bleeding, stroke and all-cause mortality. The surface under the cumulative ranking (SUCRA) curve was estimated to rank the therapies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was performed. The protocol was registered with PROSPERO (CRD42018111163). RESULTS: Eight studies comprising 2173 patients were analysed. The risk of 30-day bleeding was higher for dual antiplatelet therapy (DAPT) than single antiplatelet therapy (SAPT) [odds ratio (OR) 1.90 (1.10-3.28); P = 0.02], whereas there was no difference in the risk of 30-day stroke [OR 1.27 (0.38-4.20); P = 0.69] and mortality [OR 1.46 (0.67-3.22); P = 0.34] between DAPT and SAPT. In the network meta-analysis, DAPT + oral anticoagulant (OAC) increased the risk of 30-day bleeding compared with SAPT [OR 6.21 (1.74-22.17); P = 0.005], DAPT [OR 3.27 (1.04-10.32); P = 0.043], SAPT + OAC [OR 4.87 (2.51-9.45); P < 0.001] and OAC [OR 14.4 (1.3-154.7); P = 0.028]. Additionally, patients receiving DAPT + OAC had the highest risks for 30-day bleeding (SUCRA 1.0%). OAC seemed to be superior to SAPT and DAPT in terms of 30-day bleeding (SUCRA OAC: 86.3%, SAPT: 72.3%, DAPT: 32.3%) and stroke (SUCRA 54.2%, 47.4%, 40.5%), but not mortality (SUCRA 69.6%, 74.1%, 43.4%). CONCLUSIONS: There is a trend towards less bleeding with the application of SAPT, but no mortality benefit with the application of DAPT is shown. The comparison of SAPT, DAPT and OAC shows that OAC may improve the balance between stroke and bleeding, which can reduce the risk of mortality. In addition, the application of DAPT + OAC was ranked the worst amongst all treatment modalities and should be avoided due to an increased risk of bleeding. CLINICAL TRIAL REGISTRATION NUMBER: PROSPERO (International Prospective Register of Systematic Reviews, CRD42018111163).
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Substituição da Valva Aórtica Transcateter , Humanos , Valva Aórtica/cirurgia , Quimioterapia Combinada , Fibrinolíticos/efeitos adversos , Metanálise em Rede , Inibidores da Agregação Plaquetária/efeitos adversos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: To compare the effect of etomidate versus propofol infusion on hemodynamic profiles, spontaneous breathing, and corneal reflex during the induction of anesthesia. METHODS: Adult patients (n=80) were randomized to receive etomidate (Group E, n=40) or propofol (Group P, n=40) infusion during anesthesia induction. Throughout induction, mean blood pressure and heart rate were monitored. Time to loss of consciousness (LOC), bispectral index (BIS), existence of spontaneous breathing, and corneal reflex at LOC were recorded. RESULTS: Fewer changes in hemodynamic profile occurred in Group E compared with Group P during induction of anesthesia. The mean time to LOC was shorter with etomidate than propofol (129.5 s vs 189.5 s, P<0.0001). BIS was lower in Group E compared with Group P at LOC (46.3 vs 52.9, P=0.0141). More patients exhibited spontaneous breathing in Group E compared with Group P at LOC (80% vs 17.5%, P<0.0001). Similarly, more patients maintained corneal reflex in Group E compared with Group P (34 patients vs 4 patients, P<0.0001). The incidence of etomidate-induced myoclonus was 17.5%. CONCLUSION: Compared with propofol infusion, etomidate infusion during anesthesia induction had fewer effects on the hemodynamic profile of patients. Among patients who received etomidate, the BIS value was lower at LOC, and more patients displayed spontaneous breathing and corneal reflex. TRIAL REGISTRY NUMBER: China Clinical Research Information Service, ChiCTR-IOR-17011050.