RESUMEN
Clinical use of intraoperative auto-transfusion requires the removal of platelets and plasma proteins due to pump-based suction and water-soluble anticoagulant administration, which causes dilutional coagulopathy. Herein, we develop a carboxylated and sulfonated heparin-mimetic polymer-modified sponge with spontaneous blood adsorption and instantaneous anticoagulation. We find that intrinsic coagulation factors, especially XI, are inactivated by adsorption to the sponge surface, while inactivation of thrombin in the sponge-treated plasma effectively inhibits the common coagulation pathway. We show whole blood auto-transfusion in trauma-induced hemorrhage, benefiting from the multiple inhibitory effects of the sponge on coagulation enzymes and calcium depletion. We demonstrate that the transfusion of collected blood favors faster recovery of hemostasis compared to traditional heparinized blood in a rabbit model. Our work not only develops a safe and convenient approach for whole blood auto-transfusion, but also provides the mechanism of action of self-anticoagulant heparin-mimetic polymer-modified surfaces.
Asunto(s)
Anticoagulantes , Trastornos de la Coagulación Sanguínea , Animales , Conejos , Anticoagulantes/farmacología , Factores de Coagulación Sanguínea/metabolismo , Hemostasis , Heparina/farmacología , Hemorragia/etiología , Polímeros/farmacologíaRESUMEN
Vascular calcification is commonly observed in chronic kidney disease. The mechanism of how the calcification signal from endothelial cells is transmitted to vascular smooth muscle cells (VSMCs) remains unknown. The aim of the present study was to investigate whether exosomes from HUVECs (HUVECExos) could regulate VSMC calcification and its potential signaling pathway. HUVECExos were isolated from HUVECs under no phosphorus (NP) and high phosphorus (HP) conditions. Alizarin Red S staining and calcium (Ca) content analysis were carried out to detect calcification in VSMCs. Proteomics analysis was carried out to detect the differential expression of exosomal proteins. Protein and mRNA levels were measured by western blot analysis and reverse transcriptionquantitative PCR (RTqPCR). Exosomes derived from HPHUVECs promoted the calcification of VSMCs, as assessed by Alizarin Red S staining, alkaline phosphatase activity assays, Ca content measurements and the increased expression of runtrelated transcription factor 2 and osteopontin. Proteomic analysis detected the upregulation of STAT1 in HPexosomes from HUVECs (HUVECExos) compared with NPHUVECExos, which was also confirmed by western blot analysis and RTqPCR. Inhibition of STAT1 expression in VSMCs using fludarabine or knockdown of STAT1 expression using small interfering RNA alleviated the calcification of VSMCs. Furthermore, lithium chloride (Wnt activator) reversed the protective effect of STAT1 inhibition on VSMC calcification, while Dickkopf1 (Wnt inhibitor) exerted the opposite effect, suggesting that activation of the Wnt/ßcatenin signaling pathway was involved in STAT1mediated VSMC calcification. In conclusion, the present results indicated that exosomal STAT1 derived from HPtreated HUVECs could promote VSMC calcification, and activation of the Wnt/ßcatenin pathway may be a potential mechanism of the VSMC calcification promoted by exosomes.
Asunto(s)
Músculo Liso Vascular , Calcificación Vascular , Humanos , Músculo Liso Vascular/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Osteopontina/metabolismo , Células Endoteliales/metabolismo , Calcio/metabolismo , Fósforo/metabolismo , Fosfatasa Alcalina/metabolismo , Proteómica , ARN Interferente Pequeño/metabolismo , Cloruro de Litio/farmacología , Miocitos del Músculo Liso/metabolismo , Calcificación Vascular/metabolismo , ARN Mensajero/metabolismo , Células CultivadasRESUMEN
BACKGROUND: Although many molecular studies have tried to explore the relationship between vitamin D metabolism and kidney function, the association between 25-hydroxyvitamin D [25(OH)D] and kidney function is still controversial. Previous studies reported that low vitamin D status and decreased kidney function were associated with insulin resistance (IR). However, neither of them was confirmed by large population-based studies. This study evaluated the associations between 25(OH)D and kidney function and the associations between both of them and IR among adults in the United States of America (USA). METHODS: We analyzed 36,523 adults from the National Health and Nutrition Examination Survey (NHANES) (2001-2014). Kidney function was assessed by the estimated glomerular filtration rate (eGFR), and IR was assessed by homeostasis model assessment (HOMA-IR). All data were survey-weighted, and corresponding linear regression models were performed to examine the associations. RESULTS: The mean serum 25(OH)D levels were found to be increased in participants with decreased kidney function (eGFR <90 ml/min/1.73 m2), and each unit of decreased serum 25(OH)D concentrations predicted 0.453 ml/min/1.73 m2 (95% CI: 0.426 to 0.480, p < 0.0001) higher eGFR. In addition, each unit of decreased eGFR was associated with 0.007 higher HOMA-IR, while each unit of decreased 25(OH)D concentrations led to 0.025 higher HOMA-IR. CONCLUSIONS: Serum 25-hydroxyvitamin D concentrations were negatively associated with kidney function. IR appears in the early stage of kidney dysfunction, and both serum 25(OH)D concentrations and kidney function are negatively associated with IR. Clinicians should maintain appropriate serum 25(OH)D concentrations and doses of vitamin D supplements for different populations. The underlying mechanism of these associations still needs more research, especially the negative association between serum 25(OH)D concentrations and kidney function.
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Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication in patients experiencing end-stage renal disease (ESRD). It includes abnormalities in bone and mineral metabolism and vascular calcification. Hyperphosphatemia is a major risk factor leading to morbidity and mortality in patients with chronic kidney disease. Increased mortality has been observed in patients with ESRD, with serum phosphorus levels of >5.5 mg/dL. Therefore, control of hyperphosphatemia is a major therapeutic goal in the prevention and treatment of CKD-MBD. The treatment of hyperphosphatemia includes decreasing intestinal phosphorus load and increasing renal phosphorus removal. Decreasing the intestinal load of phosphorus plays a major role in the prevention and treatment of CKD-MBD. Among the dietary sources of phosphorus, some of the commonly prescribed medications have also been reported to contain phosphorus. However, drugs are often ignored even though they act as a potential source of phosphorus. Similarly, although proteins are the major source of dietary phosphorus, reducing protein intake can increase mortality in patients with CKD. Recently, the importance of phosphorus/protein ratio in food have been reported to be a sensitive marker for controlling dietary intake of phosphorus. This review summarizes the progress in the research on phosphate content in drugs as an excipient and the various aspects of dietary management of hyperphosphatemia in patients with CKD, with special emphasis on dietary restriction of phosphorus with low dietary phosphate/protein ratio.