Renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and senescence. It has long been believed ...that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney diseases. In response to injury, tubular epithelial cells undergo changes and function as inflammatory and fibrogenic cells, with the consequent production of various bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the tubular epithelium also aggravate immune responses. Necroinflammation, an autoamplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, tubular cells also play an active role in progressive renal injury via emerging mechanisms associated with a partial epithelial-mesenchymal transition, cell-cycle arrest at both G1/S and G2/M check points, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives inflammation and fibrosis is necessary for the development of therapeutics to halt the progression of chronic kidney disease.
Tubulointerstitial inflammation is a common characteristic of acute and chronic kidney injury. However, the mechanism by which the initial injury of tubular epithelial cells (TECs) drives ...interstitial inflammation remains unclear. This paper aims to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation. Global microRNA(miRNA) expression profiling of renal exosomes was examined in a LPS induced acute kidney injury (AKI) mouse model and miR-19b-3p was identified as the miRNA that was most notably increased in TEC-derived exosomes compared to controls. Similar results were also found in an adriamycin (ADR) induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-κB/SOCS-1. A dual-luciferase reporter assay confirmed that SOCS-1 was the direct target of miR-19b-3p. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptively transferred of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and were correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy. Thus, our studies demonstrated that exosomal miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation. The exosome/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.
Along with finite differences and finite elements, spectral methods are one of the three main methodologies for solving partial differential equations on computers. This book provides a detailed ...presentation of basic spectral algorithms, as well as a systematical presentation of basic convergence theory and error analysis for spectral methods. Readers of this book will be exposed to a unified framework for designing and analyzing spectral algorithms for a variety of problems, including in particular high-order differential equations and problems in unbounded domains. The book contains a large number of figures which are designed to illustrate various concepts stressed in the book. A set of basic matlab codes has been made available online to help the readers to develop their own spectral codes for their specific applications.
Extracellular vesicles (EVs) are released to maintain cellular homeostasis as well as to mediate cell communication by spreading protective or injury signals to neighbour or remote cells. In kidney, ...increasing evidence support that EVs are signalling vesicles for different segments of tubules, intra‐glomerular, glomerular‐tubule and tubule‐interstitial communication. EVs released by kidney resident and infiltrating cells can be isolated from urine and were found to be promising biomarkers for kidney disease, reflecting deterioration of renal function and histological change. We have here summarized the recent progress about the functional role of EVs in kidney disease as well as challenges and future directions involved.
Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. ...Hydroxychloroquine (HCQ), a well-known anti-malarial drug, is commonly used in clinical practice for its anti-inflammatory actions. However, little is known about its role in renal ischemia/reperfusion (I/R) injury. In the current study, mice were subjected to I/R injury and HCQ was administered for seven days by gavage prior to surgery. In parallel, HK-2 human renal proximal tubule cells were prophylactically treated with HCQ and then were exposed to hypoxia/reoxygenation (H/R). The results showed that HCQ significantly attenuated renal dysfunction evidenced by blunted decreases in serum creatinine and kidney injury molecular-1 expression and the improvement of HK-2 cell viability. Additionally, HCQ markedly reduced macrophage and neutrophil infiltration, pro-inflammatory cytokine production, and NLRP3 inflammasome activation. Mechanistic studies showed that HCQ could inhibit the priming of the NLRP3 inflammasome by down-regulating I/R or H/R-induced NF-κB signaling. Moreover, HCQ reduced cathepsin (CTS) B, CTSD and CTSL activity, and their redistribution from lysosomes to cytoplasm. CTSB and CTSL (not CTSD) were implicated in I/R triggered NLRP3 inflammasome activation. Notably, we found that HCQ attenuated renal injury through downregulation of CTSB and CTSL-mediated NLRP3 inflammasome activation. This study provides new insights into the anti-inflammatory effect of HCQ in the treatment of AKI.
Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the
biodistribution of MSC-exos in ischemic AKI has not ...been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown.
Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated
and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair.
imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both
and
. Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice.
MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.
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The controlled carbonization of polymers is one of the most important polymer reactions. It represents the conversion process of polymeric precursors into carbonaceous materials in a ...“controlled” manner. In this review, we summarize the research progress on the controlled carbonization of (waste) polymers in preparing functional carbon materials with well-defined microstructures, fabricating advanced polymer composites with enhanced flame retardancy, and converting waste polymers into high value-added nanocarbon materials. The carbonization mechanisms of polymers with different compositions and chain structures are highlighted. How to match the degradation reaction of polymers with the carbonization reaction of the degradation products is addressed to improve the carbonization efficiency and optimize the growth of carbon materials. The applications of (waste) polymer-derived carbon materials in electrochemical energy storage and environmental remediation are reviewed. Current existing limitations and future perspectives are also given.
Extracellular vesicles (EVs) are nanosized, membrane‐bound vesicles released from different cells. Recent studies have revealed that EVs may participate in renal tissue damage and regeneration ...through mediating inter‐nephron communication. Thus, the potential use of EVs as therapeutic vector has gained considerable interest. In this review, we will discuss the basic characteristics of EVs and its role in nephron cellular communication. Then, the application of EVs as therapeutic vector based on its natural content or as carriers of drug, in acute and chronic kidney injury, was discussed. Finally, perspectives and challenges of EVs in therapy of kidney disease were described.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors, initially developed as a novel class of anti-hyperglycaemic drugs, have been shown to significantly improve metabolic indicators and protect the ...kidneys and heart of patients with or without type 2 diabetes mellitus. The possible mechanisms mediating these unexpected cardiorenal benefits are being extensively investigated because they cannot solely be attributed to improvements in glycaemic control. Notably, emerging data indicate that metabolic reprogramming is involved in the progression of cardiorenal metabolic diseases. SGLT2 inhibitors reprogram systemic metabolism to a fasting-like metabolic paradigm, involving the metabolic switch from carbohydrates to other energetic substrates and regulation of the related nutrient-sensing pathways, which might explain some of their cardiorenal protective effects. In this review, we will focus on the current understanding of cardiorenal protection by SGLT2 inhibitors, specifically its relevance to metabolic reprogramming.
Social and organizational innovations are one of the most effective ways to gain social collaboration for effective, rapid, and coordinated interventions. An analysis of the relationship among ...organizational performance (OP), social innovations (SI) and organizational innovation (OI) in social organizations (SOs) is little discussed in the literature and much less with main component analysis. This paper is an effort to provide some empirical evidences about social and organizational innovations that social organizations in China have implemented to address the social issues of the society. A survey of Chinese SO's is conducted during beginning two months of 2022 in provinces of Jiangsu, Guangdong and Zhejiang to attain the statistics and assessing the insights of the executives of the SOs participating in this study with respect to organizational performance, social and organizational innovations. The technique used to select the sample is a non-probabilistic sampling and multiple linear regression model is applied to determine the partial impact of organizational innovations and social innovations on the organizational performance. The grouping of the variables is carried out through main components analysis. The empirical findings of the study highlight that Chinese SOs are innovative because they adopt management strategies to address the social issues associated with their institutional mission. There are four groups of derived components from organizational and social innovations based on the empirical evidence: SO's innovative activities to modify the environment; inside innovative measures to enhance SO's performance; innovative activities of SO's to enhance their relationships with outside actors; innovative measures to improve the management of SOs related to their mission and institutional projects. The findings of this study offer an efficient solution to government and policy makers for involving SOs in terms of planning of social development in China. The social and organizational innovations are very necessary to overcome the social issues so government should encourage the establishment and sustainability of social organizations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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