Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives.

Liver fibrosis is the pathological deposition of extracellular matrix rich in fibrillar collagen within the hepatocytes in response to chronic liver injury due to various causes. As the condition advances, it can progress to cirrhosis, the late stages of which are irreversible. Multiple pathophysiological mechanisms and cell types are responsible for the progression of liver fibrosis and cirrhosis.

The Role of Sphingolipids in Regulating Vascular Permeability in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease that causes scarring and fibrotic transformation of the lung parenchyma, resulting in the progressive loss of respiratory function and, often, death. Current treatments that target profibrotic factors can slow the rate of progression but are unable to ultimately stop it. In the past decade, many studies have shown that increased vascular permeability may be both a predictive and perpetuating factor in fibrogenesis.

Atomic force microscopy reveals involvement of the cell envelope in biomechanical properties of sickle erythrocytes.

Background: Intracellular hemoglobin polymerization has been supposed to be the major determinant for the elevated rigidity/stiffness of sickle erythrocytes from sickle cell anemia (SCA) patients. However, the contribution of the cell envelope remains unclear.

Results: In this study, using atomic force microscopy (AFM), we compared the normal and sickled erythrocyte surfaces for stiffness and topography.

Mixed and nonvaccine high risk HPV types are associated with higher mortality in Black women with cervical cancer.

We studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were < 55 years of age.

Airway Resistance Caused by Sphingomyelin Synthase 2 Insufficiency in Response to Cigarette Smoke.

Sphingomyelin synthase is responsible for the production of sphingomyelin (SGM), the second most abundant phospholipid in mammalian plasma, from ceramide, a major sphingolipid. Knowledge of the effects of cigarette smoke on SGM production is limited. In the present study, we examined the effect of chronic cigarette smoke on sphingomyelin synthase (SGMS) activity and evaluated how the deficiency of , one of the two isoforms of mammalian SGMS, impacts pulmonary function.

Sepsis-Associated Encephalopathy: The Blood-Brain Barrier and the Sphingolipid Rheostat.

Sepsis is not only a significant cause of mortality worldwide but has particularly devastating effects on the central nervous system of survivors. It is therefore crucial to understand the molecular structure, physiology, and events involved in the pathogenesis of sepsis-associated encephalopathy, so that potential therapeutic advances can be achieved. A key determinant to the development of this type of encephalopathy is morphological and functional modification of the blood-brain barrier (BBB), whose function is to protect the CNS from pathogens and toxic threats.

Dysregulation of ubiquitin-proteasome pathway and apolipoprotein A metabolism in sickle cell disease-related pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a major complication of sickle cell disease (SCD). Low levels of apolipoprotein A1 (Apo-A1) have been implicated in the development of PAH in SCD. We speculate that lower levels of Apo-A1 are related to dysregulation of the ubiquitin-proteasome pathway (UPP).

Electrotonic suppression of early afterdepolarizations in the neonatal rat ventricular myocyte monolayer.

Pathologies that result in early afterdepolarizations (EADs) are a known trigger for tachyarrhythmias, but the conditions that cause surrounding tissue to conduct or suppress EADs are poorly understood. Here we introduce a cell culture model of EAD propagation consisting of monolayers of cultured neonatal rat ventricular myocytes treated with anthopleurin-A (AP-A). AP-A-treated monolayers display a cycle length dependent prolongation of action potential duration (245 ms untreated, vs.

Characterization of Trypanosoma cruzi infectivity, proliferation, and cytokine patterns in gut and pancreatic epithelial cells maintained in vitro.

Trypanosoma cruzi infects all nucleated cells in both humans and experimental animals. As a prelude to our studies of T. cruzi pathogenesis in the gastrointestinal system, we have initiated in vitro cultures of gut (Caco-2 and HT-29) and pancreatic (Panc-1) epithelial cells.

Uric Acid as a potential biomarker of pulmonary arterial hypertension in patients with sickle cell disease.

Serum uric acid (UA) is emerging as a strong and independent marker for pulmonary arterial hypertension (PAH). PAH is well recognized as a life threatening complication of sickle cell disease (SCD). However, the association between UA and PAH in SCD is unknown.

Sphingosine kinase 1 deficiency exacerbates LPS-induced neuroinflammation.

The pathogenesis of inflammation in the central nervous system (CNS), which contributes to numerous neurodegenerative diseases and results in encephalopathy and neuroinflammation, is poorly understood. Sphingolipid metabolism plays a crucial role in maintaining cellular processes in the CNS, and thus mediates the various pathological consequences of inflammation. For a better understanding of the role of sphingosine kinase activation during neuroinflammation, we developed a bacterial lipopolysaccharide (LPS)-induced brain injury model.

Characterization of altered patterns of endothelial progenitor cells in sickle cell disease related pulmonary arterial hypertension.

Endothelial dysfunction plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH) in sickle cell disease (SCD). A variety of evidence suggests that circulating endothelial progenitor cells (EPCs) play an integral role in vascular repair. We hypothesized that SCD patients with PAH are deficient in EPCs, potentially contributing to endothelial dysfunction and disease progression.

Role of sphingomyelin synthesis in pulmonary endothelial cell cytoskeletal activation and endotoxin-induced lung injury.

Sphingomyelin (SM), a major sphingolipid in the lipid raft microdomains of the cell membrane, is synthesized by plasma membrane-bound sphingomyelin synthase 2 (SMS2). SMS2 is required for the maintenance of plasma membrane microdomain fluidity and receptor-mediated responses to inflammation in macrophages. However, the exact mechanism of SMS2 activation in endothelial barrier disruption and lung injury is not fully understood.

Sphingomyelin synthase 2 (SMS2) deficiency attenuates LPS-induced lung injury.

Sphingomyelin synthase (SMS) catalyzes the synthesis of sphingomyelin (SM) and is required for maintenance of plasma membrane microdomain fluidity. Of the two isoforms of mammalian SMS, SMS1 is mostly present in the trans-Golgi apparatus, whereas SMS2 is predominantly found at the plasma membrane. SMS2 has a role in receptor mediated response to inflammation in macrophages, however, the role of SMS2 in vascular permeability, pulmonary edema, and lung injury have not been investigated.

Sphingosine kinase-1 (SphK-1) regulates Mycobacterium smegmatis infection in macrophages.

Sphingosine kinase-1 is known to mediate Mycobacterium smegmatis induced inflammatory responses in macrophages, but its role in controlling infection has not been reported to date. We aimed to unravel the significance of SphK-1 in controlling M. smegmatis infection in RAW 264.

Congenital heart block: identification of autoantibody binding site on the extracellular loop (domain I, S5-S6) of alpha(1D) L-type Ca channel.

Congenital heart block (CHB) is an autoimmune disease associated with autoantibodies against intracellular ribonucleoproteins SSB/La and SSA/Ro. The hallmark of CHB is complete atrioventricular block. We have recently established that anti-SSA/Ro -SSB/La autoantibodies inhibit alpha(1D) L-type Ca current, I(Ca-L), and cross-react with the alpha(1D) Ca channel protein.

Silencing of Cav1.2 gene in neonatal cardiomyocytes by lentiviral delivered shRNA.

Cav1.2 (alpha1C) and Cav1.3 (alpha1D) L-type Ca channels are co-expressed in the heart.

Sphingomyelin synthase 2 is one of the determinants for plasma and liver sphingomyelin levels in mice.

Background: It has been proposed that plasma sphingomyelin (SM) plays a very important role in plasma lipoprotein metabolism and atherosclerosis. Sphingomyelin synthase (SMS) is the last enzyme for SM de novo biosynthesis. Two SMS genes, SMS1 and SMS2, have been cloned and characterized.

Differential regulation of sphingosine kinases 1 and 2 in lung injury.

Two mammalian sphingosine kinase (SphK) isoforms, SphK1 and SphK2, possess identical kinase domains but have distinct kinetic properties and subcellular localizations, suggesting each has one or more specific roles in sphingosine-1-phosphate (S1P) generation. Although both kinases use sphingosine as a substrate to generate S1P, the mechanisms controlling SphK activation and subsequent S1P generation during lung injury are not fully understood. In this study, we established a murine lung injury model to investigate LPS-induced lung injury in SphK1 knockout (SphK1(-/-)) and wild-type (WT) mice.

Phosphorylation of the consensus sites of protein kinase A on alpha1D L-type calcium channel.

The novel alpha(1D) L-type Ca(2+) channel is expressed in supraventricular tissue and has been implicated in the pacemaker activity of the heart and in atrial fibrillation. We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Here we sought to identify the phosphorylated PKA consensus sites on the alpha(1) subunit of the alpha(1D) Ca(2+) channel by generating GST fusion proteins of the intracellular loops, N terminus, proximal and distal C termini of the alpha(1) subunit of alpha(1D) Ca(2+) channel.

Thrombin induced secretion of macrophage migration inhibitory factor (MIF) and its effect on nuclear signaling in endothelium.

The procoagulant thrombin stimulates endothelial cells (EC) to undergo rapid cytoskeleton changes via signaling pathways that induce multiple phenotypic changes, including alterations in permeability, vasomotor tone, adhesion molecule synthesis, and leukocyte trafficking. We studied a novel role of thrombin's action on the endothelium that results in MIF secretion, which is linked to myosin light chain (MLC) and extracellular signal-regulated kinase (ERK(1/2))-dependent nuclear signaling. In bovine pulmonary artery EC (BPAEC), thrombin treatment induced intracellular MLC phosphorylation within 15 min, followed by a significant increase in MIF secretion within 30 min.

Pancreatitis-associated protein 2 modulates inflammatory responses in macrophages.

Pancreatitis-associated proteins (PAP) are stress-induced secretory proteins that are implicated in immunoregulation. Previous studies have demonstrated that PAP is up-regulated in acute pancreatitis and that gene knockdown of PAP correlated with worsening severity of pancreatitis, suggesting a protective effect for PAP. In the present study, we investigated the effect of PAP2 in the regulation of macrophage physiology.

Sphingomyelin synthase 2 deficiency attenuates NFkappaB activation.

Background: NFkappaB has long been regarded as a proatherogenic factor, mainly because of its regulation of many of the proinflammatory genes linked to atherosclerosis. Metabolism of sphingomyelin (SM) has been suggested to affect NFkappaB activation, but the mechanism is largely unknown. SMS2 regulates SM levels in cell plasma membrane and lipid rafts and has a potential to regulate NFkappaB activation.

Small-interference RNA gene knockdown of pancreatitis-associated proteins in rat acute pancreatitis.

Objectives: Pancreatitis-associated proteins (PAPs) are induced in acute pancreatitis and antisense-mediated gene knockdown of PAP decreased PAP gene expression and worsened pancreatitis. Here, we investigated the effect of a more stable inhibition of PAP using small-interference RNA gene knockdown in vitro and in an in vivo model of experimental pancreatitis.

Methods: Pancreatitis-associated protein-specific siRNA was administered to AR42J cell cultures or rats induced with pancreatitis.