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Biomedical subjects

J M Argilés

Publications and source records attributed to J M Argilés.

At least 37 records · Page 2Linked to original sources
PubMed2000

LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha.

The deleterious effects of lipopolysaccharide (LPS) during endotoxic shock are associated with the secretion of tumor necrosis factor (TNF) and the production of nitric oxide (NO), both predominantly released by tissue macrophages. We analyzed the mechanism by which LPS induces apoptosis in bone marrow-derived macrophages (BMDM). LPS-induced apoptosis reached a plateau at about 6 hours of stimulation, whereas the production of NO by the inducible NO-synthase (iNOS) required between 12 and 24 hours. Furthermore, LPS-induced early apoptosis was only moderately reduced in the presence of an inhibitor of iNOS or when using macrophages from iNOS -/-mice. In contrast, early apoptosis was paralleled by the rapid secretion of TNF and was almost absent in macrophages from mice deficient for one (p55) or both (p55 and p75) TNF-receptors. During the late phase of apoptosis (12-24 hours) NO significantly contributed to the death of macrophages even in the absence of TNF-receptor signaling. NO-mediated cell death, but not apoptosis induced by TNF, correlated with the induction of p53 and Bax genes. Thus, LPS-induced apoptosis results from 2 independent mechanisms: first and predominantly, through the autocrine secretion of TNF-alpha (early apoptotic events), and second, through the production of NO (late phase of apoptosis). (Blood. 2000;95:3823-3831)

Animals↗
PubMed2000

Calpain-3 gene expression is decreased during experimental cancer cachexia.

The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the protein hypercatabolism associated with cancer cachexia. The present study was aimed at investigating if the calpain-3 gene expression in skeletal muscle was affected by tumor growth. The results presented clearly show that calpain-3 gene expression is considerably reduced in experimental cancer cachexia, while there is a reciprocal change in the expression of the ubiquitin-dependent proteolytic system and in the ubiquitous m-calpain. The results, observed during cancer cachexia, suggest a potential counterregulatory role of calpain-3 in muscle proteolysis.

Animals↗
PubMed2000

DNA fragmentation occurs in skeletal muscle during tumor growth: A link with cancer cachexia?

In two different experimental models of cancer cachexia, the rat Yoshida AH-130 ascites hepatoma and the mouse Lewis lung carcinoma, the implantation of the tumor caused a loss of body weight which was associated with a reduction in the weight of different skeletal muscles, as well as with their protein content. The decrease in protein content was accompanied by a reduction in DNA content. Interestingly, the protein/DNA ratio was unchanged in the skeletal muscle of the tumor-bearing animals as compared with the non-tumor-bearing controls. Analysis of DNA fragmentation in skeletal muscle clearly showed enhanced laddering in the skeletal muscle of tumor-bearing animals, suggesting an apoptotic phenomenon. Interestingly, the degree of laddering (total DNA fragmented) increased with tumor burden. These results suggest that DNA fragmentation may be a primary event in cancer-associated cachexia.

Animals↗
PubMed2000

Branched-chain amino acids inhibit proteolysis in rat skeletal muscle: mechanisms involved.

Incubation of isolated rat soleus and EDL muscles in the presence of 10 mM leucine resulted in a decreased proteolytic rate as measured by the release of tyrosine into the incubation medium. The effect of this branched-chain amino acid (BCAA) is associated with a decreased activity of the lysosomal proteases and a decreased expression of the genes of the ATP-ubiquitin-dependent proteolysis (ubiquitin and C8). Incubation of muscles in the presence of actinomycin D revealed that the effects of the amino acid can be accounted for by an inhibition of the transcription rate. The presence of leucine did not influence the gene expression of other nonlysosomal (m-calpain) and lysosomal (cathepsin B) proteolytic systems. It is concluded that the well-known effect of BCAA on muscle proteolysis is mediated, in the short term, by the inhibition of lysosomal proteolysis. In a longer period, based on the inhibition of gene transcription observed, an involvement of the ATP-dependent proteolytic system is also likely to occur.

Adenosine Triphosphate↗
PubMed2000

Short-term effects of leptin on skeletal muscle protein metabolism in the rat.

We have examined the short-term effects of leptin on protein metabolism in the rat. Indeed, an intravenous leptin administration (100 microg/kg body weight), which resulted in no changes in circulating insulin in the time interval studied, induced a decrease in the incorporation of (14)C-leucine to (14)C-skeletal muscle protein. No changes were observed in relation to muscle protein degradation (either measured in vivo following isotope preloading or in vitro as tyrosine released into the incubation medium) and gene expression associated with the different proteolytic systems (cathepsin B, m-calpain and ubiquitin-proteasome system). The effects of leptin on amino acid incorporation into muscle protein do not seem to be direct because incubation of isolated EDL muscles in the presence of 10 microg/ml of leptin did not modify either the protein incorporation or the oxidation of (14)C-leucine. It may, therefore, be suggested that leptin is able to influence protein synthesis in skeletal muscle through the action of an unknown mediator.

Journal Article↗
PubMed2000

Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats.

Tissue protein hypercatabolism (TPH) is an important feature in cancer cachexia, particularly with regard to the skeletal muscle. The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle wasting, primarily due to TPH. The present study was aimed at investigating if IL-15, which is known to favour muscle fibre hypertrophy, could antagonize the enhanced muscle protein breakdown in this cancer cachexia model. Indeed, IL-15 treatment partly inhibited skeletal muscle wasting in AH-130-bearing rats by decreasing (8-fold) protein degradative rates (as measured by 14C-bicarbonate pre-loading of muscle proteins) to values even lower than those observed in non-tumour-bearing animals. These alterations in protein breakdown rates were associated with an inhibition of the ATP-ubiquitin-dependent proteolytic pathway (35% and 41% for 2.4 and 1.2 kb ubiquitin mRNA, and 57% for the C8 proteasome subunit, respectively). The cytokine did not modify the plasma levels of corticosterone and insulin in the tumour hosts. The present data give new insights into the mechanisms by which IL-15 exerts its preventive effect on muscle protein wasting and seem to warrant the implementation of experimental protocols involving the use of the cytokine in the treatment of pathological states characterized by TPH, particularly in skeletal muscle, such as in the present model of cancer cachexia.

Animals↗
PubMed2000

Does the mechanism responsible for TNF-mediated insulin resistance involve the proteasome?

Recent studies have demonstrated that in many pathological states there is an overproduction of tumour necrosis factor-alpha (TNF). Interestingly, TNF also seems to be responsible for the insulin resistance associated with these pathological states, since decreases the tyrosine kinase activity of the insulin receptor. Our group has demonstrated that TNF is able to activate the proteasome-mediated ubiquitin-dependent proteolysis. Since this proteolytic system is involved in the control of receptor-associated tyrosine kinase activity (i.e. insulin receptor), it is postulated here that the mechanism of TNF-induced insulin resistance is mediated by the activation of the proteasomic, ubiquitin-dependent proteolysis.

Cysteine Endopeptidases↗
PubMed2000

Lipids: A key role in multidrug resistance? (Review).

Among tumoral resistances, multidrug resistance (MDR) is characterized as cross-resistance to a variety of structurally and functionally unrelated drugs such as vinca alkaloids, colchicine, and anthracyclines. Decreased drug cellular influx and increased cellular ability for drug extrusion are the main mechanisms involved in MDR. Two plasma membrane proteins, p-glycoprotein (p-gp) and the multidrug resistance-associated protein (MRP), act as ATP-dependent cellular efflux. Furthermore, protein kinase C (PKC) is also central to MDR. The present study reviews the role of cholesterol and other lipids in the reduction of drug influx and drug binding to cellular membranes. The study also examines the effect of lipid composition on p-gp activity. Concerning the role of PKC in MDR, two phospholipases involved in diacylglycerol (DG) production increase in MDR cells. These are phosphatidylinositol-4, 5-bisphosphate-specific phospholipase C and phosphatidylethanolamine-specific phospholipase D. A positive feedback mechanism for DG production which includes these phospholipases, a phosphatidylcholine-specific phospholipase C and a phosphatidylcholine-specific phospholipase A2 has also been suggested. The hypothesis of exocytic involvement in MDR is reviewed, and some lipid changes found in MDR cells are interpreted according to those fusogenic properties normally involved in exocytic transport. Also, the possible role of lipid mediators, such as phosphatidic acid and platelet-activating factor, is examined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

The divergent effects of tumour necrosis factor-alpha on skeletal muscle: implications in wasting.

Tumour necrosis factor-alpha (TNF) is a pleiotropic cytokine that can have effects on many cell types, including skeletal muscle, the most abundant tissue (representing almost 45% of body weight), where many effects of this cytokine have been described. Thus, TNF receptors have been described in muscle tissue, and different investigations have revealed effects of the cytokine on membrane potential, glucose uptake and metabolism, amino acid transport and protein turnover. However, the results found are relatively divergent, therefore the main aim of the present review has been to clarify and reconcile some of the most contradictory studies concerning the effects of TNF on metabolism in skeletal muscle.

Amino Acids↗
PubMed1999

Leptin and tumor growth in rats.

We have examined the role of leptin in tumor-induced anorexia in 2 different tumor models. In rats bearing the Yoshida AH-130 ascites hepatoma, the reduction in food intake becomes important from day 6 after tumor inoculation. Interestingly, at day 4, when the animals do not show any anorectic behavior, circulating leptin levels were already reduced. Indeed, in all the tumor-bearing groups studied the levels of leptin were lower than in control animals. Moreover, the changes in the circulating levels paralleled changes in adipose tissue leptin mRNA expression, even at early stages following tumor inoculation when neither food intake nor fat stores were modified by the presence of a tumor. Interestingly, 7-day pair-fed controls showed changes similar to those present in tumor-bearing rats. These results agree with previous observations relating fasting to decreased leptin expression. Similar results were observed in another tumor model, the mouse Lewis lung carcinoma; i.e., at day 8 after tumor inoculation (when the animals did not show anorexia) both the circulating levels and the adipose leptin mRNA expression were also reduced. Our results suggest that experimental cancer-induced anorexia is not related to leptin changes.

Adipose Tissue↗
PubMed1999

Tumour necrosis factor, a key role in obesity?

Tumour necrosis factor-alpha (TNF) is a pleiotropic cytokine involved in many metabolic responses in both normal and pathophysiological states. In spite of the fact that this cytokine (also known as "cachectin") has been related to many of the metabolic abnormalities associated with cachexia, recent studies suggest that TNF may also have a central role in obesity modulating energy expenditure, fat deposition and insulin resistance. This review deals with the role of TNF in the control of fat mass and obesity.

Adipose Tissue↗
PubMed1999

Resveratrol, a natural product present in wine, decreases tumour growth in a rat tumour model.

Resveratrol administration to rats inoculated with a fast growing tumour (the Yoshida AH-130 ascites hepatoma) caused a very significant decrease (25%) in the tumour cell content. The effects of this diphenol were associated with an increase in the number of cells in the G2/M cell cycle phase. Interestingly, flow cytometric analysis of the tumour cell population revealed the existence of an aneuploid peak (representing 28% of total), which suggests that resveratrol causes apoptosis in the tumour cell population resulting in a decreased cell number.

Animals↗
PubMed1999

The role of cytokines in cancer cachexia.

A large number of observations point towards cytokines, polypeptides released mainly by immune cells, as the molecules responsible for the metabolic derangements associated with cancer-bearing states. Indeed, these alterations lead to a pathological state known as cancer cachexia which is, unfortunately, one of the worst effects of malignancy, accounting for nearly a third of cancer deaths. It is characterized by weight loss together with anorexia, weakness, anemia, and asthenia. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient and have effects on the efficiency of the anticancer treatment, resulting in a considerably decreased survival time. At the metabolic level, cachexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores. The cachectic patient, in addition to having practically no adipose tissue, is basically subject to an important muscle wastage manifested as an excessive nitrogen loss. The metabolic changes are partially mediated by alterations in circulating hormone concentrations (insulin, glucagon, and glucocorticoids in particular) or in their effectiveness. The present study reviews the involvement of different cytokines in the metabolic and physiological alterations associated with tumor burden and cachexia. Among these cytokines, some can be considered as procachectic (such as tumor necrosis factor-alpha), while others having opposite effects can be named as anticachectic cytokines. It is the balance between these two cytokine types that finally seems to have a key role in cancer cachexia.

Cachexia↗
PubMed1999

Leptin administration to lactating rats is unable to induce changes in lipid metabolism in white adipose tissue or mammary gland.

During lactation in the rat, despite hyperphagia, there are no changes in either the plasma levels or the gene expression of leptin. Removal of the litter, however, results in an important increase in the circulating concentration of leptin. Administration of leptin to lactating rats resulted in no changes in the in vivo lipogenic rate and lipoprotein lipase (LPL) activity in either adipose tissue or mammary gland, although there was an increase in insulin levels as a consequence of leptin administration. Conversely, litter removal resulted in an important decrease of LPL activity and lipogenic rate in the mammary gland while an increase in these parameters took place in adipose tissue. It is concluded that leptin is not the signal responsible for the changes in lipid metabolism that take place both in adipose tissue and mammary gland following litter removal.

Adipose Tissue↗
PubMed1999

Mechanism for the increased skeletal muscle protein degradation in the obese Zucker rat.

Obese (fa/fa) Zucker rats showed a decreased protein content in skeletal muscle compared with their lean counterparts. This was associated with both a decrease in the fractional rate of protein synthesis and an enhanced fractional rate of protein degradation in skeletal muscle, as studied by pre-loading body proteins with (14)C-bicarbonate. The increased protein degradation could be the result of the clearly enhanced expression for several transcripts of the ubiquitin genes in skeletal muscle. The results suggest that the increased protein degradation in the skeletal muscle of the obese animals may be due to increased activity of the ubiquitin-dependent proteolytic system.

Journal Article↗
PubMed1999

Tumour growth and nitrogen metabolism in the host (Review).

Tumour growth is frequently associated with massive loss of body weight and negative nitrogen balance leading to cachexia, one of the worst features of malignancy accounting for nearly two thirds of cancer deaths. At the metabolic level, cachexia is associated with depletion of body lipid stores as well as loss of skeletal muscle protein, which is manifested as an excessive nitrogen loss. The present study reviews the modulations of nitrogen metabolism in tumour-bearing conditions. In addition, the role of different mediators (such as cytokines) in the development of protein wasting is discussed. Particular emphasis has been given to tumour necrosis factor-alpha (TNF-alpha) which seems to have a key role in mediating changes related to nitrogen metabolism in the tumour-bearing host.

Animals↗