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Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together, our data indicate that ablation of tissue-resident macrophages represents an important strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.
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Cisplatino , Macrófagos , Ototoxicidad , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Ratones , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & control , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/patología , Cóclea/efectos de los fármacos , Cóclea/metabolismo , Cóclea/patología , Ratones Endogámicos C57BL , Aminopiridinas , PirrolesRESUMEN
Drug-induced kidney injury (DIKI) refers to kidney damage resulting from the administration of medications. The aim of this project was to identify reliable urinary microRNA (miRNAs) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. This study quantified a panel of six miRNAs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) across multiple time points using urinary samples from a previous investigation evaluating effects of a nephrotoxicant in cynomolgus monkeys. Exosome-associated miRNA exhibited distinctive trends when compared to miRNAs quantified in whole urine, which may reflect a different urinary excretion mechanism of miRNAs than those released passively into the urine. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials. Also, these findings can potentially be translated into other non-clinical species or human for the detection of DIKI.
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Biomarcadores , Macaca fascicularis , MicroARNs , Animales , MicroARNs/orina , MicroARNs/genética , Biomarcadores/orina , Masculino , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Exosomas/genéticaRESUMEN
BACKGROUND: Continuous loss of muscle mass and strength are the consequences of the ageing process, which increase the risk of falls among older people. Falls can lead to severe consequences such as bone fractures and hampered physical and psychological well-being. Regular exercise is the key to reversing muscle atrophy and relieving sarcopenia. However, the frailty of older people and the recent COVID-19 pandemic may affect their confidence to leave home to attend classes in the community. A feasible and effective alternative should be explored. METHODS: The primary objective is to evaluate the effectiveness of tele-exercise (TE) in relation to physical functioning and exercise adherence among community-dwelling older people at risk of falls in comparison with a community-based group (CB). The secondary objective includes evaluating older people's experience with tele-exercise, emphasizing their psychological welfare, social well-being, and acceptance of the telehealth approach. The design, conduct, and report follow the SPIRIT guidelines (Standard Protocol Items: recommended items to address in a Clinical Trial Protocol and Related Documents). Older people will be recruited from 10 local community centres in Hong Kong and randomly allocated into two groups. All participants will attend the exercise training 3 days per week for 3 months but the mode of delivery will differ, either online as the tele-exercise group (TE) or face-to-face as the community-based group (CB). The outcome measures include muscle strength, physical function, exercise adherence and dropout rate, psychological and social well-being will be assessed at the baseline, and the 3rd, 6th and 12th month. Some participants will be invited to attend focus group interviews to evaluate their overall experience of the tele-exercise training. DISCUSSION: Tele-exercise reduces the barriers to exercise, such as time constraints, inaccessibility to facilities, and the fear of frail older people leaving their homes. Promoting an online home-based exercise programme for older people can encourage them to engage in regular physical activity and increase their exercise adherence even when remaining at home. The use of telehealth can potentially result in savings in cost and time. The final findings will provide insights on delivering exercise via telehealth to older people and propose an exercise delivery and maintenance model for future practice. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( https://www.chictr.org.cn/hvshowprojectEN.html?id=219002&v=1.1 ), registration number: ChiCTR2200063370. Registered on 5 September 2022.
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Sarcopenia , Telemedicina , Humanos , Anciano , Sarcopenia/prevención & control , Accidentes por Caídas/prevención & control , Pandemias/prevención & control , Ejercicio Físico , Terapia por Ejercicio/métodos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Cisplatin is a widely used and highly effective anti-cancer drug with significant side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced ototoxicity and nephrotoxicity, we used PLX3397, an FDA-approved inhibitor of the colony-stimulating factor 1 receptor (CSF1R), to eliminate tissue-resident macrophages during the course of cisplatin administration. Mice treated with cisplatin alone (cisplatin/vehicle) had significant hearing loss (ototoxicity) as well as kidney injury (nephrotoxicity). Macrophage ablation using PLX3397 resulted in significantly reduced hearing loss measured by auditory brainstem responses (ABR) and distortion-product otoacoustic emissions (DPOAE). Sensory hair cells in the cochlea were protected against cisplatin-induced death in mice treated with PLX3397. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis as well as reduced plasma blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together our data indicate that ablation of tissue-resident macrophages represents a novel strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.
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Sepsis pathogenesis is complex and heterogeneous; hence, a precision-medicine strategy is needed. Acute kidney injury (AKI) following sepsis portends higher mortality. Overproduction of mitochondrial ROS (mtROS) is a potential mediator of sepsis and sepsis-induced AKI. BAM15, a chemical uncoupler, dissipates mitochondrial proton gradients without generating mtROS. We injected BAM15 into mice at 0, 6, or 12 hours after cecal ligation and puncture (CLP), and these mice were treated with fluids and antibiotics. BAM15 reduced mortality, even after 12 hours, when mice were ill, and BAM15 reduced kidney damage and splenic apoptosis. Serial plasma and urinary mitochondrial DNA (mtDNA) levels increased after CLP and decreased after BAM15 administration (at 0 or 6 hours). In vitro septic serum proportionately increased mtROS overproduction and mtDNA release from kidney tubule cells, which BAM15 prevented. BAM15 decreased neutrophil apoptosis and mtDNA release; neutrophil depletion counteracted BAM15 benefits. Further, mtDNA injection in vivo replicated inflammation and kidney injury, which was prevented by BAM15. A large dose of exogenous mtDNA reversed protection by BAM15. We conclude that BAM15 is an effective preventive and therapeutic candidate in experimental sepsis and that BAM15 and mtDNA, a potential drug-companion diagnostic/drug-efficacy pair for clinical sepsis, are mechanistically linked via mtROS.
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Lesión Renal Aguda , Sepsis , Ratones , Animales , ADN Mitocondrial/genética , Neutrófilos/patología , Riñón/patología , Lesión Renal Aguda/patología , Sepsis/genética , Ratones Endogámicos C57BLRESUMEN
Multirotor Unmanned Air Systems (UAS) represent a significant improvement in capability for Synthetic Aperture Radar (SAR) imaging when compared to traditional, fixed-wing, platforms. In particular, a swarm of UAS can generate significant measurement diversity through variation of spatial and frequency collections across an array of sensors. In such imaging schemes, the image formation step is challenging due to strong extended sidelobe; however, were this to be effectively managed, a dramatic increase in image quality is theoretically possible. Since 2015, QinetiQ have developed the RIBI system, which uses multiple UAS to perform short-range multistatic collections, and this requires novel near-field processing to mitigate the high sidelobes observed and form actionable imagery. This paper applies a number of algorithms to assess image reconstruction of simulated near-field multistatic SAR with an aim to suppress sidelobes observed in the RIBI system, investigating techniques including traditional SAR processing, regularised linear regression, compressive sensing. In these simulations presented, Elastic net, Orthogonal Matched Pursuit, and Iterative Hard Thresholding all show the ability to suppress sidelobes while preserving accuracy of scatterer RCS. This has also lead to a novel processing approach for reconstructing SAR images based on the observed Elastic net and Iterative Hard Thresholding performance, mitigating weaknesses to generate an improved combined approach. The relative strengths and weaknesses of the algorithms are discussed, as well as their application to more complex real-world imagery.
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Compresión de Datos , Radar , Procesamiento de Imagen Asistido por Computador/métodos , Algoritmos , Diagnóstico por ImagenRESUMEN
Inflammation is an important factor in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). The role of interleukin (IL)-18 in this progression has not been examined. We aimed to clarify whether and how IL-18 limits this progression. In a folic acid induced renal injury mouse model, we studied the time course of kidney injury and renal IL-18 expression. In wild-type mice following injection, renal IL-18 expression increased. In parallel, we characterized other processes, including at day 2, renal tubular necroptosis assessed by receptor-interacting serine/threonine-protein kinase1 (RIPK1) and RIPK3; at day 14, transdifferentiation (assessed by transforming growth factor ß1, vimentin and E-cadherin); and at day 30, fibrosis (assessed by collagen 1). In IL-18 knockout mice given folate, compared to wild-type mice, tubular damage and necroptosis, transdifferentiation, and renal fibrosis were attenuated. Importantly, IL-18 deletion decreased numbers of renal M1 macrophages and M1 macrophage cytokine levels at day 14, and reduced M2 macrophages numbers and macrophage cytokine expression at day 30. In HK-2 cells, IL-18 knockdown attenuated necroptosis, transdifferentiating and fibrosis.In patients with tubulointerstitial nephritis, IL-18 protein expression was increased on renal biopsies using immunohistochemistry. We conclude that genetic IL-18 deficiency ameliorates renal tubular damage, necroptosis, cell transdifferentiation, and fibrosis. The renoprotective role of IL-18 deletion in the progression from AKI to fibrosis may be mediated by reducing a switch in predominance from M1 to profibrotic M2 macrophages during the process of kidney repair.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Ratones , Animales , Interleucina-18/genética , Interleucina-18/metabolismo , Ratones Endogámicos C57BL , Lesión Renal Aguda/metabolismo , Riñón/patología , Insuficiencia Renal Crónica/metabolismo , FibrosisRESUMEN
Sepsis, a life-threatening organ dysfunction, results from dysregulated host responses to infection and still has a high incidence and mortality. Although administration of vasopressors to treat septic shock is standard of care, the benefits are not well established. We evaluated the effect of continuous intravenous norepinephrine infusion in a septic cecal ligation and puncture (CLP) mouse model, evaluating systemic hemodynamics and body temperature post-hoc. CLP surgery significantly decreased mean arterial blood pressure (MAP), heart rate, and body temperature within six hours. Continuous norepinephrine infusion (NE+, n = 12) started at the time of CLP surgery significantly increased MAP at 24 and 30 hours and heart rate at 6, 18, 24, and 30 hours after CLP vs CLP alone (NE-, n = 12). However, addition of norepinephrine did not improve survival rate (NE+ n = 34, NE- n = 31). Early (6 hours or earlier, when the animal became visibly sick) MAP did not predict 7-day mortality. However, heart rates at 3 and at 6 hours after CLP/norepinephrine (NE+) were highly predictive of mortality, as also been found in one clinical study. We conclude that limited hemodynamic support can be provided in a mouse sepsis model. We propose that heart rate can be used to stratify severity of illness in rodent preclinical studies of sepsis therapeutics.
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Sepsis , Choque Séptico , Animales , Modelos Animales de Enfermedad , Hemodinámica , Ratones , Norepinefrina/uso terapéutico , Choque Séptico/complicaciones , Choque Séptico/tratamiento farmacológicoRESUMEN
The population of biological species in the ecosystem is known sensitive to the periodic fluctuations of seasonal change, food resources and climatic conditions. Research in the ecological management discipline conventionally models the behavior of such dynamic systems through specific impulsive response functions, but the results of such research are applicable only when the environments conform exactly to the conditions as defined by the specific response functions that have been implemented for specific scenarios. This means that the application of previous work may be somewhat limited. Moreover, the intra and inter competitions among species have been seldom studied for modelling the prey-predator ecosystem. To fill in the gaps this paper models the delicate balance of two-prey and one-predator system by addressing three main areas of: â °) instead of using the specific impulse response this work models the ecosystem through a more general response function; â ±) to include the effects due to the competition between species and â ²) the system is subjected to the influences of seasonal factors. The seasonal factor has been implemented here in terms of periodic functions to represent the growth rates of predators. The sufficient condition for the local and global asymptotic stability of the prey-free periodic solution and the permanence of the system have been subsequently obtained by using the Comparison techniques and the Floquet theorems. Finally, the correctness of developed theories is verified by numerical simulation, and the corresponding biological explanation is given.
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Ecosistema , Conducta Predatoria , Animales , Simulación por Computador , Cadena Alimentaria , Modelos Biológicos , Dinámica Poblacional , Conducta Predatoria/fisiologíaRESUMEN
Preclinical models of human disease provide powerful tools for therapeutic discovery but have limitations. This problem is especially apparent in the field of acute kidney injury (AKI), in which clinical trial failures have been attributed to inaccurate modelling performed largely in rodents. Multidisciplinary efforts such as the Kidney Precision Medicine Project are now starting to identify molecular subtypes of human AKI. In addition, over the past decade, there have been developments in human pluripotent stem cell-derived kidney organoids as well as zebrafish, rodent and large animal models of AKI. These organoid and AKI models are being deployed at different stages of preclinical therapeutic development. However, the traditionally siloed, preclinical investigator-driven approaches that have been used to evaluate AKI therapeutics to date rarely account for the limitations of the model systems used and have given rise to false expectations of clinical efficacy in patients with different AKI pathophysiologies. To address this problem, there is a need to develop more flexible and integrated approaches, involving teams of investigators with expertise in a range of different model systems, working closely with clinical investigators, to develop robust preclinical evidence to support more focused interventions in patients with AKI.
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Lesión Renal Aguda , Investigación Biomédica Traslacional , Lesión Renal Aguda/terapia , Animales , Femenino , Humanos , Riñón , Masculino , Modelos Teóricos , Pez CebraRESUMEN
Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI-deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates the understanding of SR-BI's role in endotoxemia/sepsis, calling for the use of alternative models. In this study, using human SR-BI (hSR-BI) and hSR-BII transgenic mice, we found that SR-BI and, to a lesser extent, its splicing variant SR-BII protect against LPS-induced lung damage. At 20 h after intratracheal LPS instillation, the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice than in wild-type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content and lung tissue neutrophil infiltration found in wild-type mice were associated with markedly (2 to 3 times) increased proinflammatory cytokine production compared to these parameters in transgenic mice following LPS administration. The markedly lower endotoxin levels detected in BALF of transgenic versus wild-type mice and the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 h after the i.t. LPS injection suggest that hSR-BI- and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.
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Lesión Pulmonar Aguda/metabolismo , Proteínas de Membrana de los Lisosomas/metabolismo , Receptores Depuradores/metabolismo , Receptores Depuradores de Clase B/metabolismo , Células A549 , Lesión Pulmonar Aguda/inducido químicamente , Animales , Líquido del Lavado Bronquioalveolar , Línea Celular Tumoral , Citocinas/metabolismo , Modelos Animales de Enfermedad , Endotoxemia/metabolismo , Humanos , Inflamación/inmunología , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neutrófilos/metabolismo , Sepsis/metabolismoRESUMEN
Urine is commonly used for clinical diagnosis and biomedical research. The discovery of extracellular vesicles (EV) in urine opened a new fast-growing scientific field. In the last decade urinary extracellular vesicles (uEVs) were shown to mirror molecular processes as well as physiological and pathological conditions in kidney, urothelial and prostate tissue. Therefore, several methods to isolate and characterize uEVs have been developed. However, methodological aspects of EV separation and analysis, including normalization of results, need further optimization and standardization to foster scientific advances in uEV research and a subsequent successful translation into clinical practice. This position paper is written by the Urine Task Force of the Rigor and Standardization Subcommittee of ISEV consisting of nephrologists, urologists, cardiologists and biologists with active experience in uEV research. Our aim is to present the state of the art and identify challenges and gaps in current uEV-based analyses for clinical applications. Finally, recommendations for improved rigor, reproducibility and interoperability in uEV research are provided in order to facilitate advances in the field.
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Biomarcadores/orina , Vesículas Extracelulares/fisiología , Sistema Urinario/patología , Comités Consultivos , Líquidos Corporales/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Humanos , Riñón , Estándares de Referencia , Reproducibilidad de los Resultados , Sociedades , OrinaRESUMEN
MicroRNAs (miRNAs) are small non-coding RNA that regulate the expression of messenger RNA and are implicated in almost all cellular processes. Importantly, miRNAs can be released extracellularly and are stable in these matrices where they may serve as indicators of organ or cell-specific toxicity, disease, and biological status. There has thus been great enthusiasm for developing miRNAs as biomarkers of adverse outcomes for scientific, regulatory, and clinical purposes. Despite advances in measurement capabilities for miRNAs, miRNAs are still not routinely employed as noninvasive biomarkers. This is in part due to the lack of standard approaches for sample preparation and miRNA measurement and uncertainty in their biological interpretation. Members of the microRNA Biomarkers Workgroup within the Health and Environmental Sciences Institute's (HESI) Committee on Emerging Systems Toxicology for the Assessment of Risk (eSTAR) are a consortium of private- and public-sector scientists dedicated to developing miRNAs as applied biomarkers. Here, we explore major impediments to routine acceptance and use of miRNA biomarkers and case examples of successes and deficiencies in development. Finally, we provide insight on miRNA measurement, collection, and analysis tools to provide solid footing for addressing knowledge gaps toward routine biomarker use.
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Biomarcadores , MicroARNs , Toxicología , HumanosRESUMEN
INTRODUCTIONThe clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories.METHODSWe conducted a multicenter prospective cohort study to enroll patients with COVID-19 and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses were performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza.RESULTSWe found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and D-dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9-specific antagonist.CONCLUSIONcfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19-induced tissue injury.FUNDINGIntramural Targeted Anti-COVID-19 grant, NIH.
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COVID-19 , Ácidos Nucleicos Libres de Células , Insuficiencia Multiorgánica , Especificidad de Órganos/genética , SARS-CoV-2 , Biomarcadores/análisis , Biomarcadores/sangre , COVID-19/sangre , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/mortalidad , Ácidos Nucleicos Libres de Células/análisis , Ácidos Nucleicos Libres de Células/sangre , Estudios de Cohortes , Metilación de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/sangre , Insuficiencia Multiorgánica/diagnóstico , Insuficiencia Multiorgánica/etiología , Evaluación de Resultado en la Atención de Salud , Pronóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidad , Índice de Severidad de la Enfermedad , Estados Unidos/epidemiologíaRESUMEN
We investigated whether microRNA-150 (miR-150)-based RNA interference (RNAi) ameliorates tubular injury and tubulointerstitial fibrosis. Mice injected with folic acid developed tubulointerstitial fibrosis at day 30. miR-150 levels were increased at day 7 and peaked at day 30. At day 30, protein levels of α-smooth muscle actin, fibronectin (FN), and collagen 1 (COL-1) were increased, while suppressor of cytokine signal 1 (SOCS1) was decreased. Kidneys manifested increased macrophage numbers and increased expression of potential mediators: interferon-γ, interleukin-6, and tumor necrosis factor-α. Locked nucleic acid-anti-miR-150, started prior to or after tubular injury and administered twice weekly for 4 weeks, reversed renal inflammation and fibrosis. In HK-2 cells, co-culture with macrophages increased miR-150 expression and decreased SOCS1. Janus kinase (JAK) and signal transducer and activators of transcription (STAT) pathway-related proteins p-JAK1, p-JAK2, p-STAT1, p-STAT3, and pro-fibrotic genes encoding α-smooth muscle actin, FN, and COL-1 were all upregulated. The miR-150 antagonist reversed these transcriptional changes. Lastly, in renal biopsies from patients with chronic interstitial fibrosis, renal miR-150, and pro-fibrotic gene expression and macrophage numbers were increased, while SOCS1 expression was decreased. In conclusion, miR-150-based RNAi is as a potential novel therapeutic agent for tubulointerstitial fibrosis, suppressing the SOCS1/JAK/STAT pathway and reducing macrophage influx.
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This paper illustrates a simple yet effective spectroscopic technique for the prediction of soil organic matter (SOM) from moist soil through the synchronous 2D correlation spectroscopy (2D-COS) analysis. In the moist soil system, the strong overlap between the water absorption peaks and the SOM characteristic features in the visible-near infrared (Vis-NIR) spectral region have long been recognised as one of the main factors that causes significant errors in the prediction of the SOM content. The aim of the paper is to illustrate how the tangling effects due to the moisture and the SOM can be unveiled under 2D-COS through a sequential correlogram analysis of the two perturbation variables (i.e., the moisture and the SOM) independently. The main outcome from the 2D-COS analysis is the discovery of SOM-related bands at the 597 nm, 1646 nm and 2138 nm, together with the predominant water absorbance feature at the 1934 nm and the relatively less important ones at 1447 nm and 2210 nm. This information is then utilised to build partial least square regression (PLSR) models for the prediction of the SOM content. The experiment has shown that by discarding noisy bands adjacent to the SOM features, and the removal of the water absorption bands, the determination coefficient of prediction (Rp2) and the ratio of prediction to deviation (RPD) for the prediction of SOM from moist soil have achieved Rp2 = 0.92 and the RPD = 3.19, both of which are about 5% better than that of using all bands for building the PLSR model. The very high RPD (=3.19) obtained in this study may suggest that the 2D-COS technique is effective for the analysis of complex system like the prediction of SOM from moist soil.
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OBJECTIVES: The furosemide stress test measures the volume of urine produced after a furosemide challenge. Furosemide stress test has previously demonstrated sensitive and specific prediction of progression to Kidney Disease: Improving Global Outcomes guideline defined acute kidney injury stage III in the ICU. Furosemide is actively excreted into the nephron lumen where it inhibits the sodium-potassium-chloride cotransporter, causing diuresis. We hypothesize that furosemide excretion is a more direct measure of tubule health than diuresis. DESIGN: We developed a furosemide excretion stress test to evaluate this hypothesis in a murine model of septic-acute kidney injury. SETTING: Basic science laboratory. SUBJECTS: Male and female 8-week old CD-1 mice. INTERVENTIONS: Sepsis was induced by cecal ligation and puncture in male and female mice. Furosemide stress test/furosemide excretion stress test started 42 hours post-cecal ligation and puncture with a 1 mg/kg furosemide bolus and urine was collected for 12 hours. The mice were then euthanized or monitored until 7 days post-cecal ligation and puncture. In another cohort, mice were treated with vasopressin, which decreases urine volume. Furosemide concentration was determined by high performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Urine production during the 12-hour collection varied from 0.08 to 2.62 mL. Both urine production (furosemide stress test) and furosemide excretion (furosemide excretion stress test) predicted mortality (area under the receiver operating characteristic curve = 0.925 and 0.916) and time of death (R 2 = 0.26 and 0.74). Male and female mice demonstrated consistent results. Following vasopressin treatment, furosemide stress test specificity fell to 33% (p = 0.016) but furosemide excretion stress test specificity was maintained. CONCLUSIONS: The furosemide stress test and furosemide excretion stress test performed similarly in predicting mortality; however, furosemide excretion stress test was superior in predicting time to death and maintained performance when challenged with vasopressin treatment in a mouse sepsis model.
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OBJECTIVES: Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants. METHODS: Lupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function. RESULTS: MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody . CONCLUSIONS: These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.
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Trampas Extracelulares/inmunología , Enfermedades Renales/metabolismo , Lupus Eritematoso Sistémico/inmunología , Mitocondrias/metabolismo , Compuestos Organofosforados/farmacología , Ubiquinona/análogos & derivados , Animales , Autoanticuerpos/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Interferón Tipo I/inmunología , Riñón/metabolismo , Riñón/fisiopatología , Enfermedades Renales/fisiopatología , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Ratones , Ratones Endogámicos MRL lpr , Neutrófilos/inmunología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/inmunología , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Ubiquinona/farmacologíaRESUMEN
OBJECTIVE: A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematosus (SLE). Idebenone is a coenzyme Q10 synthetic quinone analog and an antioxidant that has been used in humans to treat diverse diseases in which mitochondrial function is impaired. This study was undertaken to assess whether idebenone ameliorates lupus in murine models. METHODS: Idebenone was administered orally to MRL/lpr mice at 2 different doses (1 gm/kg or 1.5 gm/kg idebenone-containing diet) for 8 weeks. At peak disease activity, clinical, immunologic, and metabolic parameters were analyzed and compared to those in untreated mice (n = 10 per treatment group). Results were confirmed in the lupus-prone NZM2328 mouse model. RESULTS: In MRL/lpr mice, idebenone-treated mice showed a significant reduction in mortality incidence (P < 0.01 versus untreated mice), and the treatment attenuated several disease features, including glomerular inflammation and fibrosis (each P < 0.05 versus untreated mice), and improved renal function in association with decreased renal expression of interleukin-17A (IL-17A) and mature IL-18. Levels of splenic proinflammatory cytokines and inflammasome-related genes were significantly decreased (at least P < 0.05 and some with higher significance) in mice treated with idebenone, while no obvious drug toxicity was observed. Idebenone inhibited neutrophil extracellular trap formation in neutrophils from lupus-prone mice (P < 0.05) and human patients with SLE. Idebenone also improved mitochondrial metabolism (30% increase in basal respiration and ATP production), reduced the extent of heart lipid peroxidation (by one-half that of untreated mice), and significantly improved endothelium-dependent vasorelaxation (P < 0.001). NZM2328 mice exposed to idebenone also displayed improvements in renal and systemic inflammation, reducing the kidney pathology score (P < 0.05), IgG/C3 deposition (P < 0.05), and the gene expression of interferon, proinflammatory, and inflammasome-related genes (at least P < 0.05 and some with higher significance). CONCLUSION: Idebenone ameliorates murine lupus disease activity and the severity of organ damage, supporting the hypothesis that agents that modulate mitochondrial biologic processes may have a therapeutic role in human SLE.