Search PubMed⌕ Search

Biomedical subjects

S L Friedman

Publications and source records attributed to S L Friedman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Resistance to p53-mediated growth arrest and apoptosis in Hep 3B hepatoma cells.

Mutations in the tumor suppressor p53 are a common event in hepatocellular carcinoma (HCC). Because HCCs typically occur in livers with chronic injury and impaired function, we have explored the role of wild-type p53 in regulating the growth and differentiation of Hep 3B hepatoma cells, a p53-negative line derived from a liver cancer. Stable Hep 3B cell lines were generated in which inducible p53 was introduced using either a temperature-sensitive mutant (p53val135) or a tamoxifen-regulated p53-estrogen receptor chimera (p53-mERtm-pBabepuro). In both cell lines, induction of transcriptionally active p53 was confirmed by assessing several p53 targets: Mdm2 protein, p21waf1 mRNA and protein, and the cyclin G promoter. Despite marked induction of p21waf1, cells with active p53 failed to undergo growth arrest, which is probably due to the presence of a non-functional retinoblastoma protein (pRb) in these cells. Apoptosis also was not observed, even after prolonged (48 h) serum starvation or exposure to cisplatinum. Lack of apoptosis was correlated with unchanged bax mRNA levels following p53 induction. Additionally, albumin mRNA levels remained unchanged, and there was no change in basal transactivation of a reporter containing the promoter of the haptoglobin gene, encoding an acute phase protein. This suggests that growth arrest may be required to promote liver-specific gene expression. Overall, our data demonstrate that introduction of transcriptionally active p53 does not alter the malignant, dedifferentiated phenotype of Hep 3B hepatoma cells. Hence, not all cancer cells are equally responsive to the re-activation of wild-type 53. The ability of a cancer cell to undergo p53-mediated phenotypic alterations may depend on the retention of functional downstream effector pathways.

Apoptosis↗
PubMed1997

Molecular mechanisms of hepatic fibrosis and principles of therapy.

Tremendous insights into the understanding of hepatic fibrosis have taken place over the past ten years. Foremost among these is the recognition that hepatic stellate cells (formerly known as lipocytes, Ito cells, or fat-storing cells) play a central role based on their ability to undergo activation following liver injury of any cause. Stellate cell activation is a broad phenotypic response, characterized by distinct functional changes in proliferation, contractility, fibrogenesis, cytokine secretion, and matrix degradation. Insights gained into the molecular regulation of hepatic stellate cell activation will lead to new, targeted approaches to hepatic fibrosis in the future, and could lead to reduced morbidity and mortality in patients with chronic liver injury.

Animals↗
PubMed1997

Scarring in alcoholic liver disease: new insights and emerging therapies.

Like other organs, the liver responds to injury (e.g., from chronic alcohol ingestion) with scar formation (i.e., fibrosis). Specialized cells known as stellate cells play a major role in the development of liver fibrosis. Normally these cells serve as important storage depots for vitamin A, but during alcoholic injury, a collection of cellular and molecular mediators cause stellate cells to undergo a process of activation that results in dramatic changes in their structure and function. Activated stellate cells then become primary producers of scar tissue. In turn, accumulated scar provokes a series of events that contributes to deteriorated liver function. An improved understanding of the factors that trigger stellate cell activation has led to new therapeutic approaches for reversing or preventing liver fibrosis more effectively.

Animals↗
PubMed1996

Practical classification for the use of nonsteroidal anti-inflammatory drugs.

The podiatric physician is faced with a multitude of nonsteroidal anti-inflammatory drugs from which to choose. Podiatric physicians are overwhelmed with advertisements in the literature, outlining the safety and efficacy of one or another of these medications. This article will categorize the nonsteroidal anti-inflammatory drugs to aid in their selection.

Animals↗
PubMed1995

An imaging filter for biological applications.

A recently developed post-column imaging filter optimized for biological electron microscopy is described. The filter uses a single magnetic prism, four strong quadrupole lenses and five sextupole lenses to form images and spectra free of all important aberrations and distortions of first and second order. The performance of the filter is illustrated with practical applications. It is shown that the filter offers several important advantages over currently existing in-column filters, particularly in the areas of imaging at low magnifications, attainable collection efficiency, energy resolution, and general spectroscopic operation.

Animals↗
PubMed1995

Hepatic lipocytes: a major target for endothelin-1.

Lipocytes are the predominant target for ET-1 within the normal and fibrotic liver. ET-1-induced contraction of lipocytes becomes prominent in liver injury. In this setting, ET-1 may have an autocrine role in regulating sinusoidal flow, in association with eicosanoids and other endothelium derived factors such as nitric oxide (NO). In more advanced fibrosis, ET-1 may participate in contraction of collagen bands causing distortion of the lobular structure. A direct role of ET-1 in the activation of lipocytes is still hypothetical but could represent additional effects of ET-1 in various stages of liver fibrogenesis via paracrine and/or autocrine routes.

Adipocytes↗
PubMed1994

Modulation of transforming growth factor beta receptors of rat lipocytes during the hepatic wound healing response. Enhanced binding and reduced gene expression accompany cellular activation in culture and in vivo.

Activation of lipocytes, characterized by increased proliferation and fibrogenesis, is a central feature of the hepatic wound healing response. We have examined whether modulation of receptors for transforming growth factor beta (TGF-beta) contributes to the fibrogenic behavior of activated lipocytes. Isolated lipocytes were maintained in a quiescent state by culturing the cells in suspension, where they displayed minimal specific binding for TGF-beta 1 and only a small amount of type III (betaglycan) receptor by affinity labeling. In contrast, lipocytes activated by growth on uncoated plastic displayed saturable binding of TGF-beta 1 (Kd = 28 pM, 7,730 receptors/cell), and receptors types I, II, and III. Binding activity in quiescent and activated cells correlated with responsiveness to TGF-beta 1; TGF-beta 1 induced cellular fibronectin mRNA expression only in activated and not quiescent cells. Despite the absence of binding in quiescent cells, type II receptor was detectable by immunoblot. By RNase protection assay, mRNAs for receptor types II and III were greater in quiescent than activated cells. In freshly isolated lipocytes from animals with liver injury caused by the administration of carbon tetrachloride, a rapid but transient increase in mRNA for receptor types I (approximately 3.2-fold), II (approximately 1.5-fold), and III (approximately 3-fold) was observed with peaks at 12 h for type I receptor, 1 h for type II receptor, and 6 h for type III receptor; mRNA induction was followed by down-regulation for all receptors. The modest changes in mRNAs compared with marked alterations in binding activity during mesenchymal cell activation suggest that TGF-beta receptors may be regulated in vivo in part by a post-translational mechanism.

Adipocytes↗
PubMed1994

Cellular sources of glutathione S-transferase P in primary cultured rat hepatocytes: localization by in situ hybridization.

Hepatocytes in vivo express Alpha and Mu but not Pi forms of glutathione S-transferase (GST). GST P (a fetal Pi form) appears in rat hepatocytes after 2 days in primary culture, which suggests that hepatocytes may undergo dedifferentiation [Abramovitz, Ishigaki and Listowsky (1989) Hepatology 9, 235-239]. However, in this and other studies, primary rat hepatocyte cultures were shown by immunohistochemistry to contain significant numbers of lipocytes (Ito cells). Freshly isolated lipocytes contained GST activity when assayed with chlorodinitrobenzene (680 nmol/min per mg), and expression of Alpha, Mu and Pi forms of GST was detected by Western-blot analysis. Expression of GST P persisted during culture of the lipocytes. In situ hybridization of the cultured cells was performed to define whether hepatocytes, lipocytes or both expressed the enzyme. Lipocytes in culture contained abundant GST P transcripts. Hepatocytes contained no GST P transcripts after 12 h in culture, and after 24 h, only a few hepatocytes expressed this enzyme. After 48 h in culture all hepatocytes contained GST P transcripts, and the number of transcripts continued to increase up until 72 h. Therefore, in freshly isolated preparations of hepatocytes and early in hepatocyte culture, measurable levels of GST P protein or message appeared to reflect the presence of lipocytes. After 48 h in culture almost all of the GST P reflected expression by the hepatocytes. Lipocytes constitutively expressed Alpha-, Mu- and Pi-class GSTs and had significant intracellular levels of GSH (5.2 nmol/mg of protein). Lipocytes are capable therefore of detoxifying a number of injurious compounds.

Adipocytes↗
PubMed1994

Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture.

A consistent response to liver injury is the activation of resident mesenchymal cells known as lipocytes (Ito, fat-storing cells) into a proliferating cell type. In cultured lipocytes, platelet-derived growth factor (PDGF) is the most potent proliferative cytokine, but requires the activation-dependent expression of its receptor protein (Friedman, S. L., and M. J. P. Arthur. 1989. J. Clin. Invest. 84:1780-1785); the role of PDGF receptor (PDGFR) in liver injury is unknown. We have examined PDGFR gene expression in freshly isolated lipocytes during liver injury and correlated these findings with a culture model of cellular activation. Whereas lipocytes from normal rats had no detectable transcript for the beta-PDGFR subunit, this mRNA was induced within 1 h after a dose of carbon tetrachloride (CCl4). In contrast, alpha subunit mRNA was detected in normal cells, but was unchanged after liver injury. Similar results were observed in lipocytes from bile duct-obstructed rats, although beta-PDGFR induction was less marked. By immunoblot, induction of beta-PDGFR protein in lipocytes isolated from CCl4-treated animals correlated with mRNA increases. In contrast to lipocytes, endothelial cells from normal liver expressed low levels of alpha- and beta-receptor subunit mRNA, which did not increase with injury. Using a beta-PDGFR antibody, receptor protein could be identified within fibrotic septa in CCl4-treated animals in regions where cells expressed proliferating cell nuclear antigen (PCNA). In cultured lipocytes activated by growth on uncoated plastic, beta-PDGFR transcripts appeared within 3 d after plating, which coincided with the onset of cellular proliferation. In contrast, quiescent cells in suspension culture had no detectable beta-PDGFR mRNA. These results indicate that beta-PDGF receptor induction by lipocytes is an early event during hepatic injury in vivo and in primary culture.

Adipocytes↗
PubMed1993

The change in ulnar variance with grip.

The effect of grip on ulnar variance was evaluated in 66 symptom-free wrists of 53 volunteers. Zero-rotation posteroanterior x-ray films were taken of each wrist before and after exertion of a grip force measured with a Jamar dynamometer. The volunteers were randomly divided into two groups. Group I subjects (35 wrists) were asked to exert a constant grip force of 11.3 kg. Group II subjects (31 wrists) were asked to exert a maximum grip effort, which resulted in a mean grip force of 30 kg (range, 22.8 kg to 53.6 kg). Group I demonstrated a mean increase in ulnar variance of 1.27 mm and group II showed a mean increase of 1.95 mm. The minimum increase in ulnar variance observed was 0.25 mm. The changes observed were statistically significant. The results confirm that a relative increase in ulnar variance occurs with grip. There may be an etiologic role for daily activities that involve repetitive grip and forearm rotation in development of the ulnar impaction syndrome.

Adolescent↗
PubMed1993

Retinol release by activated rat hepatic lipocytes: regulation by Kupffer cell-conditioned medium and PDGF.

In normal liver, lipocytes are the principal reservoir for retinoids, which are stored as retinyl esters. In liver injury, lipocytes activate into myofibroblast-like cells, which lack retinoid. We examined mechanisms of retinoid loss using a culture model in which lipocyte activation is provoked by exposure to Kupffer cell-conditioned medium (KCM) (S.L. Friedman and M. J. P. Arthur, J. Clin. Invest. 84: 1780-1785, 1989). In lipocytes exposed to KCM, there was approximately 11-fold more retinol in medium than in untreated cells, without release of retinyl esters. Both bile salt-dependent and -independent retinyl ester hydrolase was entirely intracellular, suggesting that the increase in retinol was due to intracellular hydrolysis; activity of bile salt-independent hydrolase was increased in KCM-treated lipocytes. Release of retinol was serum dependent and inhibited 40% by antibodies to platelet-derived growth factor (PDGF). The addition of 10 nM PDGF to serum-free KCM also induced retinol release. Lipocyte expression of mRNAs for cellular retinol-binding protein, retinoic acid receptor (RAR)-alpha, and RAR-beta was unchanged after exposure to KCM. In summary, activation of cultured lipocytes by KCM is accompanied by serum- and PDGF-dependent release of retinol; a similar mechanism may underlie retinoid loss by activated lipocytes in vivo.

Adipose Tissue↗