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1.
Int J Mol Sci ; 21(19)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003561

RESUMO

In diabetes mellitus, hyperglycemia promotes the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) to enhance medial vascular calcification, a common complication strongly associated with cardiovascular disease and mortality. The mechanisms involved are, however, still poorly understood. Therefore, the present study explored the potential role of serum- and glucocorticoid-inducible kinase 1 (SGK1) during vascular calcification promoted by hyperglycemic conditions. Exposure to high-glucose conditions up-regulated the SGK1 expression in primary human aortic VSMCs. High glucose increased osteogenic marker expression and activity and, thus, promoted the osteogenic transdifferentiation of VSMCs, effects significantly suppressed by additional treatment with the SGK1 inhibitor EMD638683. Moreover, high glucose augmented the mineralization of VSMCs in the presence of calcification medium, effects again significantly reduced by SGK1 inhibition. Similarly, SGK1 knockdown blunted the high glucose-induced osteogenic transdifferentiation of VSMCs. The osteoinductive signaling promoted by high glucose required SGK1-dependent NF-kB activation. In addition, advanced glycation end products (AGEs) increased the SGK1 expression in VSMCs, and SGK1 inhibition was able to interfere with AGEs-induced osteogenic signaling. In conclusion, SGK1 is up-regulated and mediates, at least partly, the osteogenic transdifferentiation and calcification of VSMCs during hyperglycemic conditions. Thus, SGK1 inhibition may reduce the development of vascular calcification promoted by hyperglycemia in diabetes.

2.
J Leukoc Biol ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33070368

RESUMO

Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent α and a constitutive ß subunit. The stability of HIF-1α and HIF-2α is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1α and HIF-2α modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1α enables efficient infection defense by myeloid cells. HIF-2α delays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders.

3.
Scand J Trauma Resusc Emerg Med ; 28(1): 96, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32972428

RESUMO

OBJECTIVE: Optimal management of out of hospital circulatory arrest (OHCA) remains challenging, in particular in patients who do not develop rapid return of spontaneous circulation (ROSC). Extracorporeal cardiopulmonary resuscitation (eCPR) can be a life-saving bridging procedure. However its requirements and feasibility of implementation in patients with OHCA, appropriate inclusion criteria and achievable outcomes remain poorly defined. DESIGN: Prospective cohort study. SETTING: Tertiary referral university hospital center. PATIENTS: Here we report on characteristics, course and outcomes on the first consecutive 254 patients admitted between August 2014 and December 2017. INTERVENTION: eCPR program for OHCA. MESUREMENTS AND MAIN RESULTS: A structured clinical pathway was designed and implemented as 24/7 eCPR service at the Charité in Berlin. In total, 254 patients were transferred with ongoing CPR, including automated chest compression, of which 30 showed or developed ROSC after admission. Following hospital admission predefined in- and exclusion criteria for eCPR were checked; in the remaining 224, 126 were considered as eligible for eCPR. State of the art postresuscitation therapy was applied and prognostication of neurological outcome was performed according to a standardized protocol. Eighteen patients survived, with a good neurological outcome (cerebral performance category (CPC) 1 or 2) in 15 patients. Compared to non-survivors survivors had significantly shorter time between collaps and start of eCPR (58 min (IQR 12-85) vs. 90 min (IQR 74-114), p = 0.01), lower lactate levels on admission (95 mg/dL (IQR 44-130) vs. 143 mg/dL (IQR 111-178), p <  0.05), and less severe acidosis on admission (pH 7.2 (IQR 7.15-7.4) vs. 7.0 (IQR6.9-7.2), p <  0.05). Binary logistic regression analysis identified latency to eCPR and low pH as independent predictors for mortality. CONCLUSION: An eCPR program can be life-saving for a subset of individuals with refractory circulatory arrest, with time to initiation of eCPR being a main determinant of survival.

7.
BMC Nephrol ; 21(1): 354, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32819287

RESUMO

BACKGROUND: In de novo kidney transplant recipients (KTR) treatment with belatacept has been established as a comparable option as maintenance immunosuppression, preferably as a strategy to convert from calcineurin inhibitor (CNI)- to belatacept-based immunosuppression. Switch to belatacept demonstrated improved renal function in patients with CNI-induced nephrotoxicity, but risk of transplant rejection and the development of donor-specific antibodies (DSA) are still a matter of debate. Only few data are available in patients at increased immunological risk and late after transplantation. METHODS: We analyzed 30 long-term KTR (including 2 combined pancreas-KTR) converted from CNI to belatacept > 60 months after transplantation with moderate to severe graft dysfunction (GFR ≤ 45 mL/min). Biopsies were classified according to the Banff 2015 criteria. Group differences were assessed in a univariate analysis using Mann Whitney U or Chi square test, respectively. Multivariate analysis of risk factors for treatment failure was performed using a binary logistic regression model including significant predictors from univariate analysis. Fifty-six KTR matched for donor and recipient characteristics were used as a control cohort remaining under CNI-treatment. RESULTS: Patient survival in belatacept cohort at 12/24 months was 96.7%/90%, overall graft survival was 76.7 and 60.0%, while graft survival censored for death was 79.3%/66.7%. In patients with functioning grafts, median GFR improved from 22.5 mL/min to 24.5 mL/min at 24 months. Positivity for DSA at conversion was 46.7%. From univariate analysis of risk factors for graft loss, GFR < 25 mL/min (p = 0.042) and Banff microvascular inflammation (MVI) sum score ≥ 2 (p = 0.023) at conversion were significant at 24 months. In the analysis of risk factors for treatment failure, a MVI sum score ≥ 2 was significant univariately (p = 0.023) and in a bivariate (p = 0.037) logistic regression at 12 months. DSA-positivity was neither associated with graft loss nor treatment failure. The control cohort had comparable graft survival outcomes at 24 months, albeit without increase of mean GFR in patients with functioning grafts (ΔGFR of - 3.6 ± 8.5 mL/min). CONCLUSION: Rescue therapy with conversion to belatacept is feasible in patients with worsening renal function, even many years after transplantation. The benefit in patients with MVI and severe GFR impairment remains to be investigated.

8.
Genome Med ; 12(1): 74, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32825847

RESUMO

BACKGROUND: The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts. METHODS: We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline. RESULTS: R21X carriers (frequency 0.016-0.021) showed significantly lower mean Lp(a) concentrations (- 11.7 mg/dL [- 15.5; - 7.82], p = 3.39e-32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D' = 0.958, R2 = 0.281). D' was very high in all 1000G populations (0.986-0.996), although rs41272114 frequency varies considerably (0-0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping. CONCLUSIONS: We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.

14.
Curr Opin Rheumatol ; 32(5): 449-457, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32675717

RESUMO

PURPOSE OF REVIEW: The current review highlights recent insights into direct antiviral effects by antimalarials against severe acute respiratory syndrome (SARS)-CoV-2 and other viruses and their potential indirect effects on the host by avoiding exaggerated immune responses (reduced cytokine release, Toll-like receptor response, antigen presentation related to lysosomal processing). RECENT FINDINGS: Currently, there is a large debate on the use of antimalarials for prophylaxis and treatment of SARS-CoV-2-induced disease based on preclinical in-vitro data, small case series and extrapolation from earlier studies of their effect on intracellular pathogens, including many viruses. Hydroxychloroquine (HCQ) or chloroquine have not demonstrated robust efficacy in prior randomized controlled studies against several other viruses. In-vitro data indicate a reduced viral replication of SARS-CoV-2. Especially immunomodulatory effects of antimalarials might also contribute to a clinical efficacy. For SARS-CoV-2 various large studies will provide answers as to whether antimalarials have a place in prophylaxis or treatment of the acute virus infection with SARS-CoV-2 but compelling data are missing so far. SUMMARY: In-vitro data provide a theoretical framework for an efficacy of antimalarials in SARS-CoV-2-induced disease but clinical proof is currently missing.


Assuntos
Antimaláricos/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Cloroquina/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Pandemias
18.
Kidney Int ; 98(2): 488-497, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641227

RESUMO

Telomere length is known to be inversely associated with aging and has been proposed as a marker for aging-related diseases. Telomere attrition can be accelerated by oxidative stress and inflammation, both commonly present in patients with chronic kidney disease. Here, we investigated whether relative telomere length is associated with mortality in a large cohort of patients with chronic kidney disease stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. Relative telomere length was quantified in peripheral blood by a quantitative PCR method in 4,955 patients from the GCKD study, an ongoing prospective observational cohort. Complete four-year follow-up was available from 4,926 patients in whom we recorded 354 deaths. Relative telomere length was a strong and independent predictor of all-cause mortality. Each decrease of 0.1 relative telomere length unit was highly associated with a 14% increased risk of death (hazard ratio1.14 [95% confidence interval 1.06-1.22]) in a model adjusted for age, sex, baseline eGFR, urine albumin/creatinine ratio, diabetes mellitus, prevalent cardiovascular disease, LDL-cholesterol, HDL-cholesterol, smoking, body mass index, systolic and diastolic blood pressure, C-reactive protein and serum albumin. This translated to a 75% higher risk for those in the lowest compared to the highest quartile of relative telomere length. The association was mainly driven by 117 cardiovascular deaths (1.20 [1.05-1.35]) as well as 67 deaths due to infections (1.27 [1.07-1.50]). Thus, our findings support an association of shorter telomere length with all-cause mortality, cardiovascular mortality and death due to infections in patients with moderate chronic kidney disease.

19.
J Am Soc Nephrol ; 31(9): 1987-1995, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32660969

RESUMO

BACKGROUND: A state of oxalate homeostasis is maintained in patients with healthy kidney function. However, as GFR declines, plasma oxalate (Pox) concentrations start to rise. Several groups of researchers have described augmentation of oxalate secretion in the colon in models of CKD, but the oxalate transporters remain unidentified. The oxalate transporter Slc26a6 is a candidate for contributing to the extrarenal clearance of oxalate via the gut in CKD. METHODS: Feeding a diet high in soluble oxalate or weekly injections of aristolochic acid induced CKD in age- and sex-matched wild-type and Slc26a6 -/- mice. qPCR, immunohistochemistry, and western blot analysis assessed intestinal Slc26a6 expression. An oxalate oxidase assay measured fecal and Pox concentrations. RESULTS: Fecal oxalate excretion was enhanced in wild-type mice with CKD. This increase was abrogated in Slc26a6 -/- mice associated with a significant elevation in plasma oxalate concentration. Slc26a6 mRNA and protein expression were greatly increased in the intestine of mice with CKD. Raising Pox without inducing kidney injury did not alter intestinal Slc26a6 expression, suggesting that changes associated with CKD regulate transporter expression rather than elevations in Pox. CONCLUSIONS: Slc26a6-mediated enteric oxalate secretion is critical in decreasing the body burden of oxalate in murine CKD models. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance.

20.
Infection ; 2020 Jun 13.
Artigo em Inglês | MEDLINE | ID: covidwho-597401

RESUMO

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).

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