Novel chemotherapeutic agent FX-9 activates NF-κB signaling and induces G1 phase arrest by activating CDKN1A in a human prostate cancer cell line.

Background: The aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells. In contrast, decreased cytotoxic effects against non-neoplastic blood cells, chondrocytes, and fibroblasts were observed. However, the actual FX-9 molecular mode of action is currently not fully understood.

Evaluation of combination protocols of the chemotherapeutic agent FX-9 with azacitidine, dichloroacetic acid, doxorubicin or carboplatin on prostate carcinoma cell lines.

The isoquinolinamine FX-9 is a novel potential chemotherapeutic agent showing antiproliferative effects against hematologic and prostate cancer cell lines such as B- and T-acute lymphoblastic leukemia and prostate cancer (PC) of different species. Interestingly, FX-9 shows no hemolytic activity and low toxicity in benign adherent cells. The detailed FX-9 molecular mode of action is currently not fully understood.

Isoquinolinamine FX-9 Exhibits Anti-Mitotic Activity in Human and Canine Prostate Carcinoma Cell Lines.

Current therapies are insufficient for metastatic prostate cancer (PCa) in men and dogs. As human castrate-resistant PCa shares several characteristics with the canine disease, comparative evaluation of novel therapeutic agents is of considerable value for both species. Novel isoquinolinamine FX-9 exhibits antiproliferative activity in acute lymphoblastic leukemia cell lines but has not been tested yet on any solid neoplasia type.

Density Propagator for Many-Body Localization: Finite-Size Effects, Transient Subdiffusion, and Exponential Decay.

We investigate charge relaxation in quantum wires of spinless disordered fermions (t-V model). Our observable is the time-dependent density propagator Π_{ϵ}(x,t), calculated in windows of different energy density ϵ of the many-body Hamiltonian and at different disorder strengths W, not exceeding the critical value W_{c}. The width Δx_{ϵ}(t) of Π_{ϵ}(x,t) exhibits a behavior dlnΔx_{ϵ}(t)/dlnt=β_{ϵ}(t), where the exponent function β_{ϵ}(t)≲1/2 is seen to depend strongly on L at all investigated parameter combinations.

Chronic cough associated with interferon/ribavirin therapy for hepatitis C.

What Is Known And Objective: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy.

Treatment of chronic hepatitis C with interferon alfa-n3: a multicenter, randomized, open-label trial.

We studied the antiviral effectiveness and safety of interferon alfa-n3, a natural alpha interferon which contains multiple interferon species, in the treatment of previously untreated patients with chronic hepatitis C. Seventy-seven patients were randomized to receive either 1.0, 2.

Gastric vascular ectases.

Gastric vascular ectases are being increasingly recognized as a significant source of acute and chronic upper gastrointestinal bleeding. Upper gastrointestinal endoscopy has not only facilitated the identification of gastric vascular ectases but has also revolutionized their therapy. This article reviews recent developments with reference to the epidemiology, diagnosis, pathogenesis, and therapy of gastric vascular ectases.

A role for cytokines as regulators of hepatic fibrogenesis.

It is evident that hepatic fibrogenesis is a complex process involving a cascade of cytokines which interact to enhance the expression of ECM. Cytokines involved early in this cascade may serve as proinflammatory agents or as stimulators of macrophage and Ito cell activation and proliferation, while those cytokines involved later in this process may be directly fibrogenic. Furthermore, we speculate that a balance between profibrogenic and antifibrogenic cytokines normally exists but in the presence of hepatic insults, a relative super-abundance of the fibrogenic factors promotes the development of liver fibrosis.

Increased transforming growth factor-beta 1 gene expression in human liver disease.

We recently demonstrated that transforming growth factor-beta 1 stimulates collagen synthesis in hepatic cells in vitro, and that the synthesis of this cytokine is markedly increased in two rodent models of hepatic fibrosis. In the present study, we investigated the association of transforming growth factor-beta 1 (TFG-beta 1) gene expression in human liver disease. Sixteen patients with active liver disease had percutaneous liver biopsies performed for diagnostic purposes.

The effects of hepatic fibrosis on Ito cell gene expression.

While Ito cells appear to be a major source of increased matrix synthesis during hepatic fibrogenesis, the cellular changes that occur in these cells during liver fibrosis have not been well delineated. In this study we examined Ito cell gene expression in isolated cells from normal rats, and rats with carbon tetrachloride-induced fibrosis, in order to better define the changes occurring in these cells during this pathologic process. Specifically, we addressed three questions: (1) which matrix genes are over expressed in Ito cells in fibrotic liver; (2) do these cells increase their expression of the fibrogenic cytokine transforming growth factor-beta 1 (TGF-beta 1); and (3) do Ito cells change their phenotype during hepatic fibrogenesis as reflected by alterations in the expression of their intermediate filament genes? Northern hybridization analysis revealed that Ito cells isolated from fibrotic livers had significant increases in mRNA levels of types I, III and IV procollagen compared to normal cells, while no increases were found in hepatocytes, and Kupffer/endothelial cells had only an increase in type I procollagen mRNA.

Ito cell expression of a nuclear retinoic acid receptor.

Although it has been suggested that retinoids regulate Ito cell proliferation and collagen synthesis, little is known about the ability of Ito cells to respond to retinoids in vivo. Because retinoids may mediate their molecular effects through nuclear receptors, Ito cells were examined for the presence of one of these receptors, nuclear retinoic acid receptor-beta. The modulation of nuclear retinoic acid receptor-beta expression was also studied during cell culture and hepatic fibrogenesis.

Regulation of gene expression by insulin and tumor necrosis factor alpha in 3T3-L1 cells. Modulation of the transcription of genes encoding acyl-CoA synthetase and stearoyl-CoA desaturase-1.

Insulin and tumor necrosis factor alpha (TNF alpha) produce potent and opposing physiological signals in adipocytes. However, genes that are co-regulated by the hormone and cytokine during and after adipocyte differentiation have not been characterized. Using 3T3-L1 cells, we have studied the regulation of the expression of genes encoding acyl-CoA synthetase (ACS), and stearoyl CoA desaturase-1 (SCD-1), two enzymes that play key roles in the metabolism of long chain fatty acids.

Amplification of the metallothionein-1 and metallothionein-2 genes in copper-resistant hepatoma cells.

The molecular basis for increased metallothionein concentrations in copper-resistant hepatoma cells was examined. The copper-resistant cell line HAC600, which is maintained in 600 microns copper, had increased steady-state mRNA levels for both the metallothionein-1 (MT-1) and the metallothionein-2 (MT-2) genes. Levels of mRNA were increased 11-fold for MT-1 and 15-fold for MT-2, with no significant change in alpha-tubulin mRNA content.

Ito-cell gene expression and collagen regulation.

Ito cells are perisinusoidal cells thought to be a major source of collagen in normal and fibrotic livers. These cells appear to have features similar to several cell types but when cultured assume a fibroblast-like morphology. In this study we evaluated the phenotype of both freshly isolated and cultured Ito cells by examining their gene expression.

Albumin and collagen gene regulation in alcohol- and virus-induced human liver disease.

Common features of chronic alcoholic liver disease are progressive hypoalbuminemia and a spectrum of liver fibrosis. The molecular mechanisms that account for these effects are still the subject of controversy. Therefore, in the present study we evaluated albumin and collagen gene expression in livers of alcohol abusers and patients with virus-induced liver disease.

Gamma-interferon treatment inhibits collagen deposition in murine schistosomiasis.

Since interferons have been shown to affect the synthesis of matrix proteins such as collagen in several in vitro systems, the potential role of gamma-interferon in inhibiting hepatic fibrosis was investigated. Hepatic cells, consisting primarily of hepatocytes, were treated with recombinant gamma-interferon for 24 hr. Northern blot hybridization showed that gamma-interferon treatment caused a profound decrease in pro-alpha 2(I)collagen mRNA levels but an increase in beta-actin mRNA content.

In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis.

Despite extensive efforts, little progress has been made in identifying the factors that induce hepatic fibrosis. Transforming growth factor-beta (TGF-beta) has been shown to enhance collagen production, therefore its role in hepatic fibrosis was investigated. Treatment of cultured hepatic cells with TGF-beta 1 increased type I procollagen mRNA levels 13-fold due to post-transcriptional gene regulation.

Regulation of collagen gene expression in 3T3-L1 cells. Effects of adipocyte differentiation and tumor necrosis factor alpha.

An early feature in the development of adipocytes from fibroblast-like precursor cells is the biogenesis of an extracellular basement membrane (Napolitano, 1963; Kuri-Harcuch et al., 1984). Interactions between components of the basement membrane (e.

Expression of tumor necrosis factor-alpha and transforming growth factor-beta 1 in acute liver injury.

Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta 1) have a number of in vitro functions that could be important in vivo in acute liver injury and repair. Therefore, we investigated these two cytokines in acute liver damage. Northern blots of RNA isolated from rats sacrificed at various time intervals after a single oral dose of CCl4 revealed that TNF-alpha mRNA levels were elevated within 6 hr of CCl4 administration and returned to control values by 24-32 hr.

Collagen chain mRNAs in isolated heart cells from young and adult rats.

Collagen is the predominant component of the extracellular matrix of the heart, where it is organized in a hierarchy of structures. To establish the cellular origin of the various collagen types, type I-procollagen alpha 2 chain and types III and IV collagen mRNAs were examined in preparations of myocytes and non-myocyte heart cells freshly isolated from rats 1 to 6 months old. The cardiomyocytes appeared morphologically intact and functionally competent.

Glucose, insulin and glucagon response to intravenous glucose load in patients on chronic hemodialysis.

We examined the theory that patients with chronic renal failure exhibit glucose intolerance that is not completely corrected by dialysis. I.v.