Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture After Myocardial Infarction.

Background: Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial.

Cardiac Expression of Factor X Mediates Cardiac Hypertrophy and Fibrosis in Pressure Overload.

Activated factor X is a key component of the coagulation cascade, but whether it directly regulates pathological cardiac remodeling is unclear. In mice subjected to pressure overload stress, cardiac factor X mRNA expression and activity increased concurrently with cardiac hypertrophy, fibrosis, inflammation and diastolic dysfunction, and responses blocked with a low coagulation-independent dose of rivaroxaban. In vitro, neurohormone stressors increased activated factor X expression in both cardiac myocytes and fibroblasts, resulting in activated factor X-mediated activation of protease-activated receptors and pro-hypertrophic and -fibrotic responses, respectively.

Inflammatory Serine Proteases Play a Critical Role in the Early Pathogenesis of Diabetic Cardiomyopathy.

Background/aims: Diabetic cardiomyopathy (DCM) is characterized by structural and functional alterations that can lead to heart failure. Several mechanisms are known to be involved in the pathogenesis of DCM, however, the molecular mechanism that links inflammation to DCM is incompletely understood. To learn about this mechanism, we investigated the role of inflammatory serine proteases (ISPs) during the development of DCM.

Intracardiac administration of neutrophil protease cathepsin G activates noncanonical inflammasome pathway and promotes inflammation and pathological remodeling in non-injured heart.

Background: Inflammatory serine proteases (ISPs) play an important role in cardiac repair after injury through hydrolysis of dead cells and extracellular matrix (ECM) debris. Evidence also suggests an important role of ISPs in the coordination of the inflammatory response. However, the effect of ISPs on inflammation is obfuscated by the confounding factors associated with cell death and inflammatory cell infiltration induced after cardiac injury.

Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models.

End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM.

[Intussusception followed by intestinal obstruction in adults].

Aim: To evaluate the effectiveness of complex preoperative diagnostics and medication of intussusception followed by intestinal obstruction in adults with the choice of surgical repair and analysis of the outcomes depending on the causes of intussusception.

Material And Methods: 15 intussusception patients aged 19 - 86 years were enrolled. Mean age was 52.

Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury.

Early reperfusion of ischemic cardiac tissue increases inflammatory cell infiltration which contributes to cardiomyocyte death and loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Neutrophil- and mast cell-derived proteases, cathepsin G (Cat.G) and chymase, are released early after IR, but their function is complicated by potentially redundant actions and targets.

Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth.

Platelet-derived microparticles (PMPs) are associated with enhancement of metastasis and poor cancer outcomes. Circulating PMPs transfer platelet microRNAs (miRNAs) to vascular cells. Solid tumor vasculature is highly permeable, allowing the possibility of PMP-tumor cell interaction.

Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury.

Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice.

Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy.

Background: Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis.

Objectives: This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy.

c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia.

Background: The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia.

Beta1-adrenergic receptors promote focal adhesion signaling downregulation and myocyte apoptosis in acute volume overload.

Numerous studies demonstrated increased expression of extracellular matrix (ECM) proteins and activation of focal adhesion (FA) signaling pathways in models of pressure overload-induced cardiac hypertrophy. However, little is known about FA signaling in response to volume overload where cardiac hypertrophy is associated with ECM loss. This study examines the role of beta1-adrenergic receptors (β(1)-ARs) in FA signaling changes and myocyte apoptosis induced during acute hemodynamic stress of volume overload.

c-Cbl ubiquitin ligase regulates focal adhesion protein turnover and myofibril degeneration induced by neutrophil protease cathepsin G.

The neutrophil-derived serine protease, cathepsin G (Cat.G), has been shown to induce myocyte detachment and apoptosis by anoikis through down-regulation of focal adhesion (FA) signaling. However, the mechanisms that control FA protein stability and turnover in myocytes are not well understood.

Increasing cardiac contractility after myocardial infarction exacerbates cardiac injury and pump dysfunction.

Rationale: Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined and are the focus of this study.

Objectives: We developed a mouse model in which we could prevent depressed myocyte contractility after MI and used it to test the idea that preventing depression of myocyte Ca(2+)-handling defects could avert post-MI cardiac pump dysfunction.

Pleiotropic effects of neutrophils on myocyte apoptosis and left ventricular remodeling during early volume overload.

Most of the available evidence on the role of neutrophils on pathological cardiac remodeling has been pertained after acute myocardial infarction. However, whether neutrophils directly contribute to the pathogenesis of cardiac remodeling after events other than acute myocardial infarction remains unknown. Here we show that acute eccentric hypertrophy induced by aorto-caval fistula (ACF) in the rats induced an increase in the inflammatory response characterized by activation of the STAT pathway and increased infiltration of neutrophils in the myocardium.

Pro- and antioxidants in the central lymph in experimental chronic toxic hepatitis.

Using rat model of chronic toxic hepatitis we showed the involvement of the lymph system in the formation of the response to toxic liver damage consisting in deposition of LPO products in the central lymph and active involvement of antioxidants in their neutralization with redistribution of ceruloplasmin into lymph vessels against the background of reduced a-tocopherol content in the central lymph.

[Diagnostic potential of chronoaximetric electrodiagnostics in the assessment of denervation-induced defects of m. soleus in patients with diabetic neuropathy].

The study was designed to elucidate the informative value of chronaximetry for the quantitative assessment of denervation-induced defects of m. soleus in patients with diabetic neuropathy. Conditions are clarified under which chronaximetric measurements disagree with the position of the IT hyperbola; this discrepancy lowers substantially the informative value of these characteristics as a measure of the degree of manifestation of diabetic neuropathy.

Sympathetic activation causes focal adhesion signaling alteration in early compensated volume overload attributable to isolated mitral regurgitation in the dog.

We reported that left ventricular (LV) dilatation after 4 weeks of isolated mitral regurgitation (MR) in the dogs is marked by extracellular matrix loss and an increase in adrenergic drive. Given that extracellular matrix proteins and their receptor integrins influence beta-adrenergic receptor (beta-AR) responses in vitro, we tested whether beta1-AR activation modulates focal adhesion (FA) signaling and LV remodeling in these same dogs with isolated MR. Normal dogs were compared with dogs with MR of a 4-week duration and with MR dogs treated with beta(1)-AR blockade (beta(1)-RB) (extended-release metoprolol succinate, 100 mg QD) that was started 24 hours after MR induction.

Role of protein-tyrosine phosphatase SHP2 in focal adhesion kinase down-regulation during neutrophil cathepsin G-induced cardiomyocytes anoikis.

Inflammatory cells and their proteases contribute to tissue reparation at site of inflammation. Although beneficial at early stages, excessive inflammatory reaction leads to cell death and tissue damage. Cathepsin G (Cat.

[The clinical and pharmacokinetic features of lymphotropic therapy in patients with new-onset pulmonary tuberculosis].

Regional lymphotropic therapy used in complex treatment of patients with new-onset pulmonary tuberculosis enhances its efficiency. It is well tolerated by patients and easy-to-use. The pharmacokinetic feature of isoniazid during its lymphotropic administration is its shorter elimination half-life, decreased total clearance, and a larger area under the pharmacokinetic curve.

Hepatoprotective properties of aqueous extract from Pentaphylloides fruticosa during chronic toxic hepatitis.

Hepatoprotective properties of Pentaphylloides fruticosa L. aqueous extract were studied using rat model of chronic toxic hepatitis. The preparation normalized alanine aminotransferase activity and bilirubin concentration in the plasma.

[Effects of the enterosorbent SUMS-1 on isoniazid pharmacokinetics and lipid peroxidation in patients with pulmonary tuberculosis and drug-induced hepatic lesions].

The use of the enterosorbent SUMS-1 in the combined therapy for pulmonary tuberculosis patients with drug-induced toxic hepatic lesion arrests the clinical and laboratory manifestations of endotoxicosis, removes antibiotic intolerance, increases the elimination rate of isoniazid, and reduces its distribution scope, the area beneath the kinetic curve being unchanged. The plasma concentrations of primary products and after-products of lipid peroxidation products during enterosorbent therapy decline and the levels of ceruloplasmin and alpha-tocopherol remain unchanged.

[The effect of acute hypoxia on antipyrine and isoniazid pharmacokinetics in rats with different resistances to oxygen deficiency].

Experiments in rats with different sensitivity to hypobaric hypoxia established bimodal distribution of antipyrine and isoniazide half-lives. Moreover, the low-sensitive rats were rapid acetylators and slow oxidizers, but the high-sensitive ones vice versa. The slowing down of antipyrine and isoniazide metabolism is supposed to be the most rational reaction of oxygen-dependent systems to the lack of oxygen in tissues.