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Journal of Personalized Medicine May 2024Chest pain is a prevalent reason for emergency room referrals and presents diagnostic challenges. The physician must carefully differentiate between cardiac and...
BACKGROUND
Chest pain is a prevalent reason for emergency room referrals and presents diagnostic challenges. The physician must carefully differentiate between cardiac and noncardiac causes, including various vascular and extracardiovascular conditions. However, it is crucial not to overlook serious conditions such as acute coronary syndrome (ACS). Diagnosis of acute myocardial infarction (AMI) and early discharge management become difficult when traditional clinical criteria, ECG, and troponin values are insufficient. Recently, the focus has shifted to a "multi-marker" approach to improve diagnostic accuracy and prognosis in patients with chest pain.
METHODS
This observational, prospective, single-center study involved, with informed consent, 360 patients presenting to the emergency department with typical chest pain and included a control group of 120 healthy subjects. In addition to routine examinations, including tests for hsTnI (Siemens TNIH kit), according to the 0-1 h algorithm, biochemical markers sST2 (tumorigenicity suppression-2) and suPAR (soluble urokinase plasminogen activator receptor) were also evaluated for each patient. A 12-month follow-up was conducted to monitor outcomes and adverse events.
RESULTS
We identified two groups of patients: a positive one (112 patients) with high levels of hsTnI, sST2 > 24.19 ng/mL, and suPAR > 2.9 ng/mL, diagnosed with ACS; and a negative one (136 patients) with low levels of hsTnI, suPAR < 2.9 ng/mL, and sST2 < 24.19 ng/mL. During the 12-month follow-up, no adverse events were observed in the negative group. In the intermediate group, patients with hsTnI between 6 ng/L and the ischemic limit, sST2 > 29.1 ng/mL and suPAR > 2.9 ng/mL, showed the highest probability of adverse events during follow-up, while those with sST2 < 24.19 ng/mL and suPAR < 2.9 ng/mL had a better outcome with no adverse events at 12 months.
CONCLUSION
Our data suggest that sST2 and suPAR, together with hsTnI, may be useful in the prognosis of cardiovascular patients with ACS, providing additional information on endothelial damage. These biomarkers could guide the clinical decision on further diagnostic investigations. In addition, suPAR and sST2 emerge as promising for event prediction in patients with chest pain. Their integration into the standard approach in PS could facilitate more efficient patient management, allowing safe release or timely admission based on individual risk.
PubMed: 38929785
DOI: 10.3390/jpm14060564 -
Biomedicines Jun 2024Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several...
Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on HT mechanisms are still unknown. In our study, we use the models of photothrombosis (PT)-induced brain ischemia and oxygen-glucose deprivation (OGD) to investigate the effect of Li on tPA-induced changes in brain and endothelial cell cultures. We found that tPA did not affect lesion volume or exacerbate neurological deficits but disrupted the blood-brain barrier. We demonstrate that poststroke treatment with Li improves neurological status and increases blood-brain barrier integrity after thrombolytic therapy. Under conditions of OGD, tPA treatment increased MMP-2/9 levels in endothelial cells, and preincubation with LiCl abolished this MMP activation. Moreover, we observed the effect of Li on glycolysis in tPA-treated endothelial cells, which we hypothesized to have an effect on MMP expression.
PubMed: 38927532
DOI: 10.3390/biomedicines12061325 -
Biomedicines May 2024Obesity is a chronic inflammatory disorder that increases the risk of cardiovascular diseases (CVDs). Given the high CVD mortality rate among individuals with obesity,...
BACKGROUND
Obesity is a chronic inflammatory disorder that increases the risk of cardiovascular diseases (CVDs). Given the high CVD mortality rate among individuals with obesity, early screening should be considered. Plasminogen activator inhibitor (PAI-1), a cytokine that links obesity and CVDs, represents a promising biomarker. However, PAI-1 is not part of the clinical routine due to its high cost. Therefore, it is necessary to find good predictors that would allow an indirect assessment of PAI-1.
METHODS
This study enrolled 47 women with severe obesity (SO). The obtained anthropometric measurements included weight, height, neck (NC), waist (WC), and hip circumference (HC). Blood samples were collected to analyse glucose and lipid profiles, C-reactive protein, liver markers, adiponectin, and PAI-1 (determined by ELISA immunoassay). Homeostasis model assessment-adiponectin (HOMA-AD), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), triglyceride-glucose index (TyG), and atherogenic index of plasma (AIP) were calculated. The women were grouped according to PAI-1 levels. The data were analysed using IBM SPSS Statistics, version 21. The significance level for the analysis was set at 5%.
RESULTS
Women with SO who have higher levels of PAI-1 have lower values of high-density lipoprotein cholesterol (HDL) ( = 0.037) and QUICKI (0.020) and higher values of HOMA-AD (0.046) and HOMA-IR (0.037). HOMA-IR was demonstrated to be a good predictor of PAI-1 in this sample (B = 0.2791; = 0.017).
CONCLUSIONS
HOMA-IR could be used as a predictor of PAI-1 levels, pointing out the relevance of assessing glycaemic parameters for the prevention of CVDs in women with SO.
PubMed: 38927429
DOI: 10.3390/biomedicines12061222 -
Biomedicines May 2024Plasminogen activator inhibitor-1 (PAI-1) has a significant role in fibrinolysis, atherogenesis, cellular senescence, and chronic inflammation. OSA (obstructive sleep...
Plasminogen activator inhibitor-1 (PAI-1) has a significant role in fibrinolysis, atherogenesis, cellular senescence, and chronic inflammation. OSA (obstructive sleep apnea) leads to increased PAI-1 levels and the development of cardiovascular disease (CVD). The aim of this study was to determine the effects of CPAP therapy on coagulation parameters and PAI-1 in patients with severe OSA. This prospective, controlled study enrolled 57 patients who were newly diagnosed with severe OSA, 37 of whom had had good CPAP adherence after 6 months of therapy (usage of the device for at least 4 h per night), and their data were analyzed. The analysis showed a statistically significant increase in D-dimer values before CPAP therapy (415 (316.5-537.5)) vs. after therapy (499 (327-652)), = 0.0282, and a decrease in fibrinogen values (3.665 ± 0.752 before CPAP therapy vs. 3.365 ± 0.771 after therapy, = 0.0075)). PAI-1 concentration values before and after CPAP therapy did not differ significantly (17.35 ± 7.01 ng/mL before CPAP therapy vs. 17.42 ± 6.99 ng/mL after therapy, = 0.9367). This study shows a tendency for fibrinolytic capacity to improve in patients with OSA after CPAP therapy, although PAI-1 levels did not differ significantly.
PubMed: 38927404
DOI: 10.3390/biomedicines12061197 -
Biomedicines May 2024The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR... (Review)
Review
The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.
PubMed: 38927374
DOI: 10.3390/biomedicines12061167 -
Tropical Medicine and Infectious Disease May 2024, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with...
, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood-brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by infection. We investigated pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after . The study evaluates the critical role of Cav-1 regulation through the TLR4/MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in -induced meningoencephalitis.
PubMed: 38922036
DOI: 10.3390/tropicalmed9060124 -
Cells Jun 2024Mesenchymal stem cells (MSCs) of placental origin hold great promise in tissue engineering and regenerative medicine for diseases affecting cartilage and bone. However,...
Mesenchymal stem cells (MSCs) of placental origin hold great promise in tissue engineering and regenerative medicine for diseases affecting cartilage and bone. However, their utility has been limited by their tendency to undergo premature senescence and phenotypic drift into adipocytes. This study aimed to explore the potential involvement of a specific subset of aging and antiaging genes by measuring their expression prior to and following in vitro-induced differentiation of placental MSCs into chondrocytes and osteoblasts as opposed to adipocytes. The targeted genes of interest included the various transcript variants (lamin A, lamin C, and lamin A∆10), sirtuin 7 (SIRT7), and SM22α, along with the classic aging markers plasminogen activator inhibitor 1 (PAI-1), p53, and p16. MSCs were isolated from the decidua basalis of human term placentas, expanded, and then analyzed for phenotypic properties by flow cytometry and evaluated for colony-forming efficiency. The cells were then induced to differentiate in vitro into chondrocytes, osteocytes, and adipocytes following established protocols. The mRNA expression of the targeted genes was measured by RT-qPCR in the undifferentiated cells and those fully differentiated into the three cellular lineages. Compared to undifferentiated cells, the differentiated chondrocytes demonstrated decreased expression of SIRT7, along with decreased PAI-1, lamin A, and SM22α expression, but the expression of p16 and p53 increased, suggesting their tendency to undergo premature senescence. Interestingly, the cells maintained the expression of lamin C, which indicates that it is the primary lamin variant influencing the mechanoelastic properties of the differentiated cells. Notably, the expression of all targeted genes did not differ from the undifferentiated cells following osteogenic differentiation. On the other hand, the differentiation of the cells into adipocytes was associated with decreased expression of lamin A and PAI-1. The distinct patterns of expression of aging and antiaging genes following in vitro-induced differentiation of MSCs into chondrocytes, osteocytes, and adipocytes potentially reflect specific roles for these genes during and following differentiation in the fully functional cells. Understanding these roles and the network of signaling molecules involved can open opportunities to improve the handling and utility of MSCs as cellular precursors for the treatment of cartilage and bone diseases.
Topics: Humans; Mesenchymal Stem Cells; Female; Placenta; Cell Differentiation; Chondrogenesis; Pregnancy; Osteogenesis; Biomarkers; Cellular Senescence; Chondrocytes; Aging; Lamin Type A
PubMed: 38920652
DOI: 10.3390/cells13121022 -
BioRxiv : the Preprint Server For... Jun 2024Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively...
Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively impacting their translational relevance. Here we aimed to develop a minimally invasive thrombotic stroke model through magnetic particle delivery that does not require craniotomy, is amenable to reperfusion therapy, can be combined with in vivo imaging modalities, and can be performed in awake mice. We found that the model results in reproducible cortical infarcts within the middle cerebral artery (MCA) with cytologic and immune changes similar to that observed with more invasive distal MCA occlusion models. Importantly, the injury produced by the model was ameliorated by tissue plasminogen activator (tPA) administration. We also show that MCA occlusion in awake animals results in bigger ischemic lesions independent of day/night cycle. Magnetic particle delivery had no overt effects on physiologic parameters and systemic immune biomarkers. In conclusion, we developed a novel stroke model in mice that fulfills many requirements for modeling human stroke.
PubMed: 38915621
DOI: 10.1101/2024.06.10.598243 -
PLoS Pathogens Jun 2024COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS- CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly...
COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS- CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly understood, largely due to the lack of suitable animal models that recapitulate key clinical and pathological symptoms. Here, we fully characterized AC70 line of human ACE2 transgenic (AC70 hACE2 Tg) mice for SARS-CoV-2 infection. We noted that this model is highly permissive to SARS-CoV-2 with values of 50% lethal dose and infectious dose as ~ 3 and ~ 0.5 TCID50 of SARS-CoV-2, respectively. Mice infected with 105 TCID50 of SARS-CoV-2 rapidly succumbed to infection with 100% mortality within 5 days. Lung and brain were the prime tissues harboring high viral titers, accompanied by histopathology. However, viral RNA and inflammatory mediators could be detectable in other organs, suggesting the nature of a systemic infection. Lethal challenge of AC70 hACE2 Tg mice caused acute onset of leukopenia, lymphopenia, along with an increased neutrophil-to-lymphocyte ratio (NLR). Importantly, infected animals recapitulated key features of COVID-19-associated coagulopathy. SARS-CoV-2 could induce the release of circulating neutrophil extracellular traps (NETs), along with activated platelet/endothelium marker. Immunohistochemical staining with anti-platelet factor-4 (PF4) antibody revealed profound platelet aggregates especially within blocked veins of the lungs. We showed that acute SARS-CoV-2 infection triggered a hypercoagulable state coexisting with ill-regulated fibrinolysis. Finally, we highlighted the potential role of Annexin A2 (ANXA2) in fibrinolytic failure. ANXA2 is a calcium-dependent phospholipid-binding protein that forms a heterotertrameric complexes localized at the extracellular membranes with two S100A10 small molecules acting as a co-receptor for tissue-plasminogen activator (t-PA), tightly involved in cell surface fibrinolysis. Thus, our results revealing elevated IgG type anti-ANXA2 antibody production, downregulated de novo ANXA2/S100A10 synthesis, and reduced ANXA2/S100A10 association in infected mice, this protein might serve as druggable targets for development of antithrombotic and/or anti-fibrinolytic agents to attenuate pathogenesis of COVID-19.
PubMed: 38913740
DOI: 10.1371/journal.ppat.1011777 -
Cureus May 2024A hemodialysis tunneled catheter is one option for vascular access used with hemodialysis patients; however, catheter complications such as thrombosis are still...
INTRODUCTION
A hemodialysis tunneled catheter is one option for vascular access used with hemodialysis patients; however, catheter complications such as thrombosis are still inevitable. To prevent thrombosis formation, a catheter-locking solution is instilled between dialysis sessions. Heparin is used as a default locking solution in our Hemodialysis Care Project centers, while a recombinant tissue plasminogen activator (rt-PA) such as alteplase is used to treat suspected catheter thrombosis. This study aimed to identify the clinical factors, catheter brands, and hemodialysis variables that influence the choice of use for alteplase versus heparin, for those patients with tunneled catheters, and reduce overprescribing of high-alert medication alteplase.
METHODS
A retrospective medical chart review study was conducted involving 230 patients with tunneled catheters; the first group of 133 patients used alteplase regularly three times a week, while the second group of 97 patients completed at least one year using the same catheter access with heparin lock only.
RESULTS
Multivariate logistic regression and logistic regression analysis showed a significant association (p < 0.05) between different variables. Results suggest that overweight and hyperlipidemia patients are more likely to use alteplase. Patients using brand-name catheters such as Hemostar/Vas-cath (BD, Franklin Lakes, NJ) are less likely to use heparin than those using Medcomp catheters (Medcomp, Yuma, AZ). In addition, patients having a history of angioplasty would be less likely to have heparin than no angioplasty. Moreover, if the patient's fluid removal were equal to or less than 2 kg, they would be more likely to use heparin and vice versa.
CONCLUSION
The study postulates that identified variables affect whether alteplase or heparin is used in hemodialysis tunneled catheters, and may be useful to increase awareness, improve practices, or judiciously control the use of alteplase within Saudi Arabia and globally.
PubMed: 38910780
DOI: 10.7759/cureus.60817