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Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a 'preeclampsia-like syndrome'. However, the mechanisms underpinning SARS-CoV-2-induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS-CoV-2 infection. Methods: We utilised whole-transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS-CoV-2 in the third trimester of their pregnancy (n = 7) and those collected prior to the start of the coronavirus disease 2019 (COVID-19) pandemic (n = 9). Results: Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified SARS-CoV-2 to promote signatures associated with hypoxia and placental dysfunction. Notably, genes associated with vasodilation (NOS3), oxidative stress (GDF15, CRH) and preeclampsia (FLT1, EGFR, KISS1, PAPPA2) were enriched with SARS-CoV-2. Pathways related to increased nutrient uptake, vascular tension, hypertension and inflammation were also enriched in SARS-CoV-2 samples compared to uninfected controls. Conclusions: Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS-CoV-2 infection.
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BACKGROUND: Galectin-3 (Gal-3) is a biomarker involved in a wide range of diseases including cardiac remodeling following acute myocardial infarction (AMI). Identification of prognostic markers in patients with AMI can guide strategies towards improved survival and quality of life. METHODS: Our study included 59 patients with AMI and a preserved ejection fraction. We determined the Gal-3 plasma concentration within 24 h of chest pain onset from the aortic root, femoral/radial artery, coronary sinus and cubital vein. Major adverse cardiovascular events (MACEs) were evaluated at six months follow-up. RESULTS: MACE at six months post-AMI was recorded in 20 patients (34%). The Gal-3 plasma concentration from the aortic root and the femoral/radial artery were independent predictors of MACE at six months follow-up after the first AMI (OR 1.228; 95%CI: 1.011-1.491; p = 0.038; OR 3.438; 95%CI: 1.275-9.265; p = 0.015). ROC analysis identifies the Gal-3 plasma concentration from the aortic root as a better predictor of MACE or death (cut-off ≥ 10.86 ng/mL; AUC 0.858; 95%CI: 0.744-0.973; p < 0.001) than Gal-3 plasma concentration from the femoral/radial artery (cut-off ≥ 10.18 ng/mL; AUC 0.742; 95%CI: 0.596-0.888; p = 0.006). CONCLUSION: the Gal-3 plasma concentration in patients with AMI determined during coronary angiography, especially from the aortic root, within 24 h after chest pain onset is a valuable biomarker of prognosis at six months follow-up.
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Preeclampsia is a heterogeneous and multiorgan cardiovascular disorder of pregnancy. Here, we report the development of a novel strip-based lateral flow assay (LFA) using lanthanide-doped upconversion nanoparticles conjugated to antibodies targeting two different biomarkers for detection of preeclampsia. We first measured circulating plasma FKBPL and CD44 protein concentrations from individuals with early-onset preeclampsia (EOPE), using ELISA. We confirmed that the CD44/FKBPL ratio is reduced in EOPE with a good diagnostic potential. Using our rapid LFA prototypes, we achieved an improved lower limit of detection: 10â pg ml-1 for FKBPL and 15â pg ml-1 for CD44, which is more than one order lower than the standard ELISA method. Using clinical samples, a cut-off value of 1.24 for CD44/FKBPL ratio provided positive predictive value of 100 % and the negative predictive value of 91 %. Our LFA shows promise as a rapid and highly sensitive point-of-care test for preeclampsia.
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Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Sensibilidade e Especificidade , Testes Imediatos , Biomarcadores/análise , Proteínas de Ligação a TacrolimoRESUMO
Cardiovascular disease (CVD) is a leading cause of mortality worldwide, with cigarette smoking being a major preventable risk factor. Smoking cessation can be difficult due to the addictive nature of nicotine and the withdrawal symptoms following cessation. Electronic cigarettes (e-Cigs) have emerged as an alternative smoking cessation device, which has been increasingly used by non-smokers; however, the cardiovascular effects surrounding the use of e-Cigs remains unclear. This study aimed to investigate the effects of e-Cig aerosol condensate (EAC) (0 mg and 18 mg nicotine) in vitro on human coronary artery endothelial cells (HCAEC) and in vivo on the cardiovascular system using a mouse model of 'e-vaping'. In vitro results show a decrease in cell viability of HCAEC when exposed to EAC either directly or after exposure to conditioned lung cell media (p < 0.05 vs. control). Reactive oxygen species were increased in HCAEC when exposed to EAC directly or after exposure to conditioned lung cell media (p < 0.0001 vs. control). ICAM-1 protein expression levels were increased after exposure to conditioned lung cell media (18 mg vs. control, p < 0.01). Ex vivo results show an increase in the mRNA levels of anti-angiogenic marker, FKBPL (p < 0.05 vs. sham), and endothelial cell adhesion molecule involved in barrier function, ICAM-1 (p < 0.05 vs. sham) in murine hearts following exposure to electronic cigarette aerosol treatment containing a higher amount of nicotine. Immunohistochemistry also revealed an upregulation of FKBPL and ICAM-1 protein expression levels. This study showed that despite e-Cigs being widely used for tobacco smoking cessation, these can negatively impact endothelial cell health with a potential to lead to the development of cardiovascular disease.
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Doenças Cardiovasculares , Sistemas Eletrônicos de Liberação de Nicotina , Animais , Camundongos , Humanos , Nicotina/efeitos adversos , Molécula 1 de Adesão Intercelular , Células Endoteliais , Doenças Cardiovasculares/etiologia , Aerossóis , Proteínas de Ligação a TacrolimoRESUMO
Background: Implantation of insulin-secreting cells has been trialed as a treatment for Type 1 diabetes mellitus; however, the host immunogenic response limits their effectiveness. Methodology: The authors developed a core-shell nanostructure of upconversion nanoparticle-mesoporous silica for controlled local delivery of an immunomodulatory agent, MCC950, using near-infrared light and validated it in in vitro models of fibrosis. Results: The individual components of the nanosystem did not affect the proliferation of insulin-secreting cells, unlike fibroblast proliferation (p < 0.01). The nanosystem is effective at releasing MCC950 and preventing fibroblast differentiation (p < 0.01), inflammation (IL-6 expression; p < 0.05) and monocyte adhesion (p < 0.01). Conclusion: This MCC950-loaded nanomedicine system could be used in the future together with insulin-secreting cell implants to increase their longevity as a curative treatment for Type 1 diabetes mellitus.
This work describes a new drug-delivery system that can release an immunomodulatory drug in a controlled manner and prevent fibrosis, which is part of the immune response when a foreign body is implanted. This system can be particularly useful for insulin-secreting cell implants, used to replace multiple daily injections of insulin and improve the quality of life of people with Type 1 diabetes mellitus. By preventing the immune response that leads to fibrosis, the longevity of these cellular implants can be extended without the need for frequent replacement procedures. This innovative nanosystem can release the required amount of immunomodulatory drug, which could be stimulated with the use of special light, hence showing the ability for local and extended delivery. This type of system has the potential to reduce the side effects associated with oral daily administration of immunomodulatory agents in people with Type 1 diabetes mellitus.
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Diabetes Mellitus Tipo 1 , Nanopartículas , Nanoestruturas , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Nanoestruturas/químicaRESUMO
Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are critical mediators of angiogenesis and inflammation. Thus, in this study, we investigated-for the first time-FKBPL's role in the pathogenesis and as a biomarker of HFpEF. In vitro models of cardiac hypertrophy following exposure to a hypertensive stimulus, angiotensin-II (Ang-II, 100 nM), and/or AD-01 (100 nM), for 24 and 48 h were employed as well as human plasma samples from people with different forms of HFpEF and controls. Whilst the FKBPL peptide mimetic, AD-01, induced cardiomyocyte hypertrophy in a similar manner to Ang-II (p < 0.0001), when AD-01 and Ang-II were combined together, this process was abrogated (p < 0.01-0.0001). This mechanism appears to involve a negative feedback loop related to FKBPL (p < 0.05). In human plasma samples, FKBPL concentration was increased in HFpEF compared to controls (p < 0.01); however, similar to NT-proBNP and Gal-3, it was unable to stratify between different forms of HFpEF: acute HFpEF, chronic HFpEF and hypertrophic cardiomyopathy (HCM). FKBPL may be explored for its biomarker and therapeutic target potential in HFpEF.
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Insuficiência Cardíaca , Hipertensão , Humanos , Insuficiência Cardíaca/diagnóstico , Volume Sistólico , Proteínas de Ligação a Tacrolimo/uso terapêutico , Biomarcadores , Proteínas de Ciclo Celular , Fragmentos de PeptídeosRESUMO
AIMS: The aim of this scoping review is to evaluate the current biomarkers used in the assessment of adverse cardiac remodelling in people with diabetes mellitus (DM) and in the diagnosis and prognosis of subsequent cardiovascular disease. We aim to discuss the biomarkers' pathophysiological roles as a reflection of the cardiac remodelling mechanisms in the presence of DM. METHODS: We performed the literature search to include studies from 2003 to 2021 using the following databases: MEDLINE, Scopus, Web of Science, PubMed, and Cochrane library. Articles that met our inclusion criteria were screened and appraised before being included in this review. The PRISMA guidelines for Scoping Reviews were followed. RESULTS: Our literature search identified a total of 43 eligible articles, which were included in this scoping review. We identified 15 different biomarkers, each described by at least two studies, that were used to determine signs of cardiac remodelling in cardiovascular disease (CVD) and people with DM. NT-proBNP was identified as the most frequently employed biomarker in this context; however, we also identified emerging biomarkers including hs-CRP, hs-cTnT, and Galectin-3. CONCLUSION: There is a complex relationship between DM and cardiovascular health, where more research is needed. Current biomarkers reflective of adverse cardiac remodelling in DM are often used to diagnose other CVDs, such as NT-proBNP for heart failure. Hence there is a need for identification of specific biomarkers that can detect early signs of cardiac remodelling in the presence of DM. Further research into these biomarkers and mechanisms can deepen our understanding of their role in DM-associated CVD and lead to better preventative therapies.
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Doenças Cardiovasculares , Diabetes Mellitus , Humanos , Prognóstico , Remodelação Ventricular , BiomarcadoresRESUMO
2',3,3,5'-Tetramethyl-4'-nitro-2'H-1,3'-bipyrazole (TMNB) is a novel bipyrazole compound with unknown therapeutic potential in diabetes mellitus. This study aims to investigate the anti-diabetic effects of TMNB in a high-fat diet and streptozotocin-(HFD/STZ)-induced rat model of type 2 diabetes mellitus (T2D). Rats were fed HFD, followed by a single low dose of STZ (40 mg/kg). HFD/STZ diabetic rats were treated orally with TMNB (10 mg/kg) or (200 mg/kg) metformin for 10 days before terminating the experiment and collecting plasma, soleus muscle, adipose tissue, and liver for further downstream analysis. TMNB reduced the elevated levels of serum glucose in diabetic rats compared to the vehicle control group (p < 0.001). TMNB abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control rats (p < 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in the diabetic rats treated with TMNB compared to the vehicle controls. The skeletal muscle and adipose tissue protein contents of GLUT4 and AMPK were upregulated following treatment with TMNB (p < 0.001, < 0.01, respectively). TMNB was able to upregulate GLUT2 and AMPK protein expression in liver (p < 0.001, < 0.001, respectively). LDL, triglyceride, and cholesterol were reduced in diabetic rats treated with TMNB compared to the vehicle controls (p < 0.001, 0.01, respectively). TMNB reduced MDA and IL-6 levels (p < 0.001), and increased GSH level (p < 0.05) in diabetic rats compared to the vehicle controls. Conclusion: TMNB ameliorates insulin resistance, oxidative stress, and inflammation in a T2D model. TMNB could represent a promising therapeutic agent to treat T2D.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Ratos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Diabetes Mellitus Experimental/metabolismo , Proteínas Quinases Ativadas por AMP , Metformina/farmacologia , Metformina/uso terapêuticoRESUMO
Preeclampsia is a pregnancy-specific cardiovascular disorder, involving significant maternal endothelial dysfunction. Although inappropriate placentation due to aberrant angiogenesis, inflammation and shallow trophoblast invasion are the root causes of preeclampsia, pathogenic mechanisms are poorly understood, particularly in early pregnancy. Here, we first confirm the abnormal expression of important vascular and inflammatory proteins, FK506-binding protein-like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissues from women with preeclampsia and normotensive controls. We then employ a three-dimensional microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signaling in inflammatory conditions. In human samples, both circulating (n = 17 controls; n = 30 preeclampsia) and placental (n ≥ 6) FKBPL and Gal-3 levels were increased in preeclampsia compared to controls (plasma: FKBPL, p < 0.0001; Gal-3, p < 0.01; placenta: FKBPL, p < 0.05; Gal-3, p < 0.01), indicative of vascular dysfunction in preeclampsia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel endothelial vascular networks. Inflammatory cytokine tumour necrosis factor-α (10 ng/mL) modulates both FKBPL and Gal-3 signaling in conjunction with trophoblast migration and impairs vascular network formation (p < 0.005). Our placenta-on-a-chip recapitulates aspects of inappropriate placental development and vascular dysfunction in preeclampsia.
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Placenta , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Placenta/metabolismo , Galectina 3/genética , Galectina 3/metabolismo , Trofoblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas de Ciclo Celular/metabolismo , Dispositivos Lab-On-A-Chip , Proteínas de Ligação a Tacrolimo/metabolismoRESUMO
Type 1 diabetes (T1D) is a chronic, lifelong metabolic disease. It is characterised by the autoimmune-mediated loss of insulin-producing pancreatic ß cells in the islets of Langerhans (ß-islets), resulting in disrupted glucose homeostasis. Administration of exogenous insulin is the most common management method for T1D, but this requires lifelong reliance on insulin injections and invasive blood glucose monitoring. Replacement therapies with beta cells are being developed as an advanced curative treatment for T1D. Unfortunately, this approach is limited by the lack of donated pancreatic tissue, the difficulties in beta cell isolation and viability maintenance, the longevity of the transplanted cells in vivo, and consequently high costs. Emerging approaches to address these limitations are under intensive investigations, including the production of insulin-producing beta cells from various stem cells, and the development of bioengineered devices including nanotechnologies for improving islet transplantation efficacy without the need for recipients taking toxic anti-rejection drugs. These emerging approaches present promising prospects, while the challenges with the new techniques need to be tackled for ultimately clinical treatment of T1D. This review discussed the benefits and limitations of the cell-based therapies for beta cell replacement as potential curative treatment for T1D, and the applications of bioengineered devices including nanotechnology to overcome the challenges associated with beta cell transplantation.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Humanos , Diabetes Mellitus Tipo 1/terapia , Automonitorização da Glicemia , Glicemia , Células Secretoras de Insulina/metabolismo , Insulina/metabolismoRESUMO
Immunophilins are a family of proteins encompassing FK506-binding proteins (FKBPs) and cyclophilins (Cyps). FKBPs and Cyps exert peptidyl-prolyl cis-trans isomerase (PPIase) activity, which facilitates diverse protein folding assembly, or disassembly. In addition, they bind to immunosuppressant medications where FKBPs bind to tacrolimus (FK506) and rapamycin, whereas cyclophilins bind to cyclosporin. Some large immunophilins have domains other than PPIase referred to as tetratricopeptide (TPR) domain, which is involved in heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp 70) chaperone interaction. The TPR domain confers immunophilins' pleotropic actions to mediate various physiological and biochemical processes. So far, immunophilins have been implicated to play an important role in pathophysiology of inflammation, cancer and neurodegenerative disorders. However, their importance in the development of fibrosis has not yet been elucidated. In this review we focus on the pivotal functional and mechanistic roles of different immunophilins in fibrosis establishment affecting various organs. The vast majority of the studies reported that cyclophilin A, FKBP12 and FKBP10 likely induce organ fibrosis through the calcineurin or TGF-ß pathways. FKBP51 demonstrated a role in myelofibrosis development through calcineurin-dependant pathway, STAT5 or NF-κB pathways. Inhibition of these specific immunophilins has been shown to decrease the extent of fibrosis suggesting that immunophilins could be a novel promising therapeutic target to prevent or reverse fibrosis.
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Ciclofilinas , Tacrolimo , Tacrolimo/farmacologia , Calcineurina/metabolismo , Peptidilprolil Isomerase/metabolismo , Chaperonas Moleculares/metabolismo , Dobramento de ProteínaRESUMO
Preeclampsia is still the leading cause of morbidity and mortality in pregnancy without a cure. There are two phenotypes of preeclampsia, early-onset (EOPE) and late-onset (LOPE) with poorly defined pathogenic differences. This study aimed to facilitate better understanding of the mechanisms of pathophysiology of EOPE and LOPE, and identify specific biomarkers or therapeutic targets. In this study, we conducted an untargeted, label-free quantitative proteomic analyses of plasma samples from pregnant women with EOPE (n = 17) and LOPE (n = 11), and age, BMI-matched normotensive controls (n = 18). Targeted proteomics approach was also employed to validate a subset of proteins (n = 17). In total, there were 26 and 20 differentially abundant proteins between EOPE or LOPE, and normotensive controls, respectively. A series of angiogenic and inflammatory proteins, including insulin-like growth factor-binding protein 4 (IGFBP4; EOPE: FDR = 0.0030 and LOPE: FDR = 0.00396) and inter-alpha-trypsin inhibitor heavy chain H2-4 (ITIH2-4), were significantly altered in abundance in both phenotypes. Through validation we confirmed that ITIH2 was perturbed only in LOPE (p = 0.005) whereas ITIH3 and ITIH4 were perturbed in both phenotypes (p < 0.05). Overall, lipid metabolism/transport proteins associated with atherosclerosis were highly abundant in LOPE, however, ECM proteins had a more pronounced role in EOPE. The complement cascade and binding and uptake of ligands by scavenger receptors, pathways, were associated with both EOPE and LOPE.
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Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/metabolismo , Proteoma , Proteômica , BiomarcadoresRESUMO
Background and Objectives: FK506 binding protein like (FKBPL) is a member of the immunophilin family, with anti-angiogenic effects capable of inhibiting the migration of endothelial cells and blood vessel formation. Its role as an inhibitor of tumor growth and angiogenesis has previously been shown in studies with breast and ovarian cancer. The role of FKBPL in angiogenesis, growth, and carcinogenesis of endometrioid endometrial carcinoma (EEC) is still largely unknown. The aim of this study was to examine the expression of FKBPL in EEC and benign endometrial hyperplasia (BEH) and its correlation with the expression of vascular endothelial factor-A (VEGF-A) and estrogen receptor alpha (ERα). Materials and Methods: Specimens from 89 patients with EEC and 40 patients with BEH, as well as histological, clinical, and demographic data, were obtained from the Clinical Hospital Centre Zemun, Belgrade, Serbia over a 10-year period (2010−2020). Immunohistochemical staining of the tissue was performed for FKBPL, VEGF-A, and ERα. Slides were analyzed blind by two pathologists, who measured the intensity of FKBPL and VEGF-A expression and used the Allred score to determine the level of ERα expression. Results: Immunohistochemical analysis showed moderate to high intensity of FKBPL expression in 97.5% (n = 39) of samples of BEH, and low or no expression in 93.3% (n = 83) of cases of EEC. FKBPL staining showed a high positive predictive value (98.8%) and a high negative predictive value for malignant diagnosis (86.7%). The difference in FKBPL expression between EEC and BEH was statistically significant (p < 0.001), showing a decrease in intensity and loss of expression in malignant tissues of the endometrium. FKBPL expression was positively correlated with ERα expression (intensity, percentage and high Allred score values) and negatively correlated with the expression of VEGF-A (p < 0.05 for all). Conclusions: FKBPL protein expression demonstrated a significant decrease in FKBPL in EEC in comparison to BEH tissue, with a high predictive value for malignancy. FKBPL might be emerging as a significant protein with antiangiogenic and antineoplastic effects, showing great promise for the diagnostic and therapeutic applications of its therapeutic derivatives in gynecological oncology.
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Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Humanos , Receptor alfa de Estrogênio/metabolismo , Células Endoteliais/metabolismo , Fator A de Crescimento do Endotélio Vascular , Carcinoma Endometrioide/patologia , Fatores de Transcrição , Proteínas de Ciclo Celular , Proteínas de Ligação a Tacrolimo , Neovascularização Patológica , Neoplasias do Endométrio/patologiaRESUMO
Heart failure with preserved ejection fraction (HFpEF) accounts for around 50% of all heart failure cases. It is a heterogeneous condition with poorly understood pathogenesis. Here, we aimed to identify unique pathogenic mechanisms in acute and chronic HFpEF and hypertrophic cardiomyopathy (HCM). We performed unbiased, comprehensive proteomic analyses of plasma samples from gender- and BMI-matched patients with acute HFpEF (n = 8), chronic HFpEF (n = 9) and HCM (n = 14) using liquid chromatography-mass spectrometry. Distinct molecular signatures were observed in different HFpEF forms. Clusters of biomarkers differentially abundant between HFpEF forms were predominantly associated with microvascular inflammation. New candidate protein markers were also identified, including leucine-rich alpha-2-glycoprotein 1 (LRG1), serum amyloid A1 (SAA1) and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Our study is the first to apply systematic, quantitative proteomic screening of plasma samples from patients with different subtypes of HFpEF and identify candidate biomarkers for improved management of acute and chronic HFpEF and HCM.
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Insuficiência Cardíaca , Humanos , Volume Sistólico , Proteômica , Leucina , Biomarcadores/metabolismo , Fenótipo , GlicoproteínasRESUMO
BACKGROUND: Preeclampsia is a multifactorial cardiovascular disorder of pregnancy. If left untreated, it can lead to severe maternal and fetal outcomes. Hence, timely diagnosis and management of preeclampsia are extremely important. Biomarkers of oxidative stress are associated with the pathogenesis of preeclampsia and therefore could be indicative of evolving preeclampsia and utilized for timely diagnosis. In this study, we conducted a systematic review and meta-analysis to determine the most reliable oxidative stress biomarkers in preeclampsia, based on their diagnostic sensitivities and specificities as well as their positive and negative predictive values. METHODS: A systematic search using PubMed, ScienceDirect, ResearchGate, and PLOS databases (1900 to March 2021) identified nine relevant studies including a total of 343 women with preeclampsia and 354 normotensive controls. RESULTS: Ischemia-modified albumin (IMA), uric acid (UA), and malondialdehyde (MDA) were associated with 3.38 (95% CI 2.23, 4.53), 3.05 (95% CI 2.39, 3.71), and 2.37 (95% CI 1.03, 3.70) odds ratios for preeclampsia diagnosis, respectively. The IMA showed the most promising diagnostic potential with the positive predictive ratio (PPV) of 0.852 (95% CI 0.728, 0.929) and negative predictive ratio (NPV) of 0.811 (95% CI 0.683, 0.890) for preeclampsia. Minor between-study heterogeneity was reported for these biomarkers (Higgins' I2 = 0-15.879%). CONCLUSIONS: This systematic review and meta-analysis identified IMA, UA, and MDA as the most promising oxidative stress biomarkers associated with established preeclampsia. IMA as a biomarker of tissue damage exhibited the best diagnostic test accuracy. Thus, these oxidative stress biomarkers should be further explored in larger cohorts for preeclampsia diagnosis.
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Pré-Eclâmpsia , Biomarcadores , Feminino , Humanos , Estresse Oxidativo , Pré-Eclâmpsia/diagnóstico , Gravidez , Albumina Sérica , Ácido ÚricoRESUMO
Preeclampsia is a cardiovascular pregnancy complication characterised by new onset hypertension and organ damage or intrauterine growth restriction. It is one of the leading causes of maternal and fetal mortality in pregnancy globally. Short of pre-term delivery of the fetus and placenta, treatment options are limited. Consequently, preeclampsia leads to increased cardiovascular disease risk in both mothers and offspring later in life. Here we aim to examine the impact of the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia on the maternal cardiovascular system, placental and fetal heart metabolism. The surgical RUPP model was induced in pregnant rats by applying silver clips around the aorta and uterine arteries on gestational day 14, resulting in ~ 40% uterine blood flow reduction. The experiment was terminated on gestational day 19 and metabolomic profile of placentae, maternal and fetal hearts analysed using high-resolution 1H NMR spectroscopy. Impairment of uterine perfusion in RUPP rats caused placental and cardiac hypoxia and a series of metabolic adaptations: altered energetics, carbohydrate, lipid and amino acid metabolism of placentae and maternal hearts. Comparatively, the fetal metabolic phenotype was mildly affected. Nevertheless, long-term effects of these changes in both mothers and the offspring should be investigated further in the future.
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Hipóxia/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Útero/irrigação sanguínea , Animais , Pressão Sanguínea/fisiologia , Simulação por Computador , Modelos Animais de Doenças , Feminino , Coração Fetal/metabolismo , Humanos , Hipóxia/fisiopatologia , Metabolômica , Modelos Biológicos , Placenta/irrigação sanguínea , Circulação Placentária/fisiologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Útero/fisiologiaRESUMO
The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has had a dramatic negative impact on public health and economies worldwide. Recent studies on COVID-19 complications and mortality rates suggest that there is a higher prevalence in cardiovascular diseases (CVD) patients. Past investigations on the associations between pre-existing CVDs and susceptibility to coronavirus infections including SARS-CoV and the Middle East Respiratory Syndrome coronavirus (MERS-CoV), have demonstrated similar results. However, the underlying mechanisms are poorly understood. This has impeded adequate risk stratification and treatment strategies for CVD patients with SARS-CoV-2 infections. Generally, dysregulation of the expression of angiotensin-converting enzyme (ACE) and the counter regulator, angiotensin-converting enzyme 2 (ACE2) is a hallmark of cardiovascular risk and CVD. ACE2 is the main host receptor for SARS-CoV-2. Although further studies are required, dysfunction of ACE2 after virus binding and dysregulation of the renin-angiotensin-aldosterone system (RAAS) signaling may worsen the outcomes of people affected by COVID-19 and with preexisting CVD. Here, we review the current knowledge and outline the gaps related to the relationship between CVD and COVID-19 with a focus on the RAAS. Improved understanding of the mechanisms regulating viral entry and the role of RAAS may direct future research with the potential to improve the prevention and management of COVID-19.
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COVID-19/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19/complicações , Doenças Cardiovasculares/complicações , Humanos , Receptores de Coronavírus/metabolismo , Fatores de Risco , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Drug-delivery vehicles have garnered immense interest in recent years due to unparalleled progress made in material science and nanomedicine. However, the development of stimuli-responsive devices with controllable drug-release systems (DRSs) is still in its nascent stage. In this paper, we designed a two-way controlled drug-release system that can be promoted and prolonged, using the external stimulation of near-infrared light (NIR) and protein coating. A hierarchical nanostructure was fabricated using upconversion nanoparticles (UCNPs)-mesoporous silica as the core-shell structure with protein lysozyme coating. The mesoporous silica shell provides abundant pores for the loading of drug molecules and a specific type of photosensitive molecules. The morphology and the physical properties of the nanostructures were thoroughly characterized. The results exhibited the uniform core-shell nanostructures of ~four UCNPs encapsulated in one mesoporous silica nanoparticle. The core-shell nanoparticles were in the spherical shape with an average size of 200 nm, average surface area of 446.54 m2/g, and pore size of 4.6 nm. Using doxorubicin (DOX), a chemotherapy agent as the drug model, we demonstrated that a novel DRS with capacity of smart modulation to promote or inhibit the drug release under NIR light and protein coating, respectively. Further, we demonstrated the therapeutic effect of the designed DRSs using breast cancer cells. The reported novel controlled DRS with dual functionality could have a promising potential for chemotherapy treatment of solid cancers.