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PubMed1996

The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice.

The role of cell-mediated cytotoxicity in the complex pathophysiology of graft-versus-host disease (GVHD) has remained poorly defined for several decades. We transplanted T cells from Fas-ligand (FasL)-defective and perforin-deficient mutant donor mice into lethally irradiated MHC-matched allogeneic recipient mice to characterize the role of cell-mediated cytotoxicity in GVHD. Although recipients of allogeneic FasL-defective donor T cells underwent severe GVHD-associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perforin-deficient allogeneic donor T cells developed signs of acute GVHD, but the time of onset was significantly delayed. These findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage.

Animals↗

PubMed1997

Decrease in phosphocreatine level in skeletal muscle of SIV-infected rhesus macaques correlates with decrease in intracellular glutathione.

Loss of skeletal muscle tissue (cachexia) is one of the hallmarks of HIV infection. It has been found (1) that creatine kinase, i.e., an enzyme of pivotal importance in muscular mitochondrial energy metabolism, is inhibited by oxidative glutathiolation, and (2) that reduced glutathione (GSH) is decreased in skeletal muscle of SIV-infected rhesus monkeys. We, therefore, have studied the phosphocreatine (P-Cr) levels. Muscle tissue from SIV-infected macaques showed significantly decreased P-Cr but normal creatine (Cr), ATP, and ADP when compared with uninfected macaques. Individual P-Cr levels were significantly correlated with GSH. Our findings may explain the dysregulation of energy metabolism in cachexia.

Animals↗

PubMed1997

Whole body metabolic responses to brain trauma in the rat.

Increases in metabolic rate reported in head-injured patients can contribute to increases in respiratory demand, raised body temperature, and host body wasting (cachexia). The objective of the present study was to quantify the metabolic responses to brain trauma in the rat and investigate the underlying mechanisms. Lateral fluid-percussion (FP) injury (applied cortical pressure 1.6-1.8 atm) in the rat resulted in consistent and reproducible cortical brain lesions (44 +/- 6 mm3). Body weight and food intake were reduced significantly 24 h after brain trauma compared to sham-operated (7 and 49%,p < 0.01) and control animals (14 and 65%,p < 0.001), respectively. Resting oxygen consumption (V(O2), measured at 24 degrees C) was increased significantly, by 9-16% above sham-operated, and 14-26% above control animals for 2-7 h after brain trauma (p < 0.05), but V(O2) was not raised thereafter (24-72 h) and colonic temperature was not changed. Raising the ambient temperature from 24 degrees C to 28 degrees C significantly reduced the hypermetabolism of brain-injured rats compared to sham-operated controls. Injection of the beta-adrenoceptor antagonist propranolol (10 mg/kg, i.p.) completely abolished the rise in metabolic rate of brain-injured rats, and reduced significantly the rise in metabolic rate of the sham-operated animals (26%, p < 0.01 and 11%, p < 0.05; respectively). Systemic injection of the cyclo-oxygenase inhibitor indomethacin (1 mg/kg, i.p.) significantly attenuated (by 11%,p < 0.01), but did not completely abolish the hypermetabolism of brain-injured animals. Lateral FP injury in the rat causes a significant cachexia. Weight loss is due to hypophagia, and an increase in energy expenditure, which is mediated by sympathetic activation of thermogenesis and in part by prostaglandins.

Animals↗

PubMed2005

Plasma arginine concentrations are reduced in cancer patients: evidence for arginine deficiency?

BACKGROUND: The disturbances leading to cancer cachexia remain to be unraveled. Preliminary evidence suggests that arginine availability in cancer is reduced. However, no valid data are available on plasma arginine concentrations in cancer patients. OBJECTIVE: We aimed to determine whether there is evidence for disturbed arginine metabolism in cancer. DESIGN: We measured plasma arginine concentrations postabsorptively in patients with various types of tumors, hypothesizing that arginine concentrations would be lower than those in age- and sex-matched control subjects. Patients with localized tumors with a range of metabolic implications were studied: breast cancer (no weight loss), colonic cancer (sometimes weight loss), and pancreatic cancer (usually weight loss). Plasma amino acid concentrations were measured by HPLC. RESULTS: Plasma arginine concentrations were lower in patients with cancer (breast cancer: 80 +/- 3 compared with 103 +/- 9 micromol/L; colonic cancer: 80 +/- 3 compared with 96 +/- 7 micromol/L; pancreatic cancer: 76 +/- 5 compared with 99 +/- 7 micromol/L; P < 0.05 versus respective age- and sex-matched control subjects), irrespective of tumor type, weight loss, tumor stage, or body mass index (correlations with P > 0.05). CONCLUSIONS: Malignant tumors associated with various degrees of metabolic derangements are all associated with decreased plasma arginine concentrations, even without weight loss. This suggests that decreased arginine availability is a specific feature of the presence of cancer. These disturbances in arginine metabolism could contribute to the cascade of metabolic events leading to cancer cachexia.

Adult↗

PubMed1999

Special considerations in design of trials with elderly subjects: unexplained weight loss, body composition and energy expenditure.

Wasting and cachexia are significant problems in the elderly that increase mortality and morbidity. It is presently unclear as to the physiological mechanism underlying unexplained weight loss. We examine heart failure as a physiological model to demonstrate the importance of measuring several physiological outcome variables that have increased our understanding of wasting and cachexia in the elderly. These include the assessment of: energy expenditure, body composition, physical activity and exercise tolerance. We review recent data that has assessed energy expenditure in free-living heart failure patients using stable isotope methodology (doubly labeled water). Preliminary results show low levels of daily energy expenditure in heart failure patients due to extremely low levels of physical activity. Thus, a "hypermetabolic state" in free-living heart failure patients is not supported by these findings. The low level of physical activity is likely a consequence of their reduced exercise capacity and contributes to their skeletal muscle atrophy. This concept is support by the relationship between peak VO2 and muscle mass (r = 0.92; P < 0.01), as measured from dual energy x-ray absorptiometry. An understanding of the physiological factors influencing energy dysregulation and low exercise capacity may help guide future therapeutic interventions to restore energy balance and increase functional independence in patients with chronic heart failure.

Aged↗

PubMed1998

Current concepts in pancreatic cancer: symposium summary.

This recent symposium featured speakers from several clinical and research disciplines. Among the findings: peptic ulcer disease is a significant predisposing risk factor (odds ratio = 3.9) for pancreatic cancer; as many as 50% of all intraductal papillary mucinous neoplasms are associated with invasive adenocarcinomas; alteration of gene expression via methylation of a gene promotor region constitutes a potentially reversible method of tumor suppressor gene inactivation; > 400 transcriptional alterations of gene expression have been identified for pancreatic cancer; some common molecular markers such as p53 and HER-2/neu may be related to morphologic alterations of in situ neoplasia and to transcriptional alterations of gene expression rather than mutational events; epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), and related molecules may modulate gene transcription via "autocrine" or "paracrine" mechanisms; several cytokines, amylin (islet amyloid polypeptide), and other cachexia factors are responsible for paraneoplastic peripheral insulin resistance, ineffective utilization of glucose, and profound cachexia. In the clinical diagnostic arena: the World Health Organization established a standard nomenclature for intraductal papillary mucinous neoplasms, mucinous cystic tumors, intraductal mucinous hyperplasias, and solid pseudopapillary tumors; focal glandular differentiation may be commonly identified within pancreatic endocrine neoplasms (islet cell tumors) while not necessarily implying an unfavorable prognosis typical of ductal adenocarcinomas; positron emission tomography scanning may be used for evaluation of early tumor response to novel chemotherapeutic regimens; helical computed tomography (CT) is the state of the art in preoperative imaging for pancreatic cancer; neoadjuvant 5-fluorouracil (5-FU)-based chemoradiation in 39 "resectable" patients provided a median survival of 19 months, actuarial 4-year survival of 19%, and improved local tumor control; gemcitabine has shown promise in alleviating tumor-related symptoms with a significantly better "clinical benefit response" than single agent 5-FU (23.8 vs. 4.8%, p = 0.0022) based on change in pain intensity, daily analgesic consumption, performance status, and weight; a significant survival advantage was demonstrated in patients treated with conventional therapies whose tumors expressed p21WAF-1, an important inhibitor of cell cycle progression and downstream molecule of p53 and TGF-beta; a p21-adenovirus (rAD-p21) gene therapy resulted in significant growth inhibition of pancreatic cancer cell lines in tissue culture, and development of a successful SCID mouse-human pancreatic adenocarcinoma xenograft model provided an animal model for preclinical trials of rAD-p21.

Antineoplastic Agents↗

PubMed2002

Biochemical mechanisms of cellular catabolism.

PURPOSE OF REVIEW: To provide an in-depth analysis of current developments concerning biochemical mechanisms of cellular catabolism. There have been a number of important developments in this area over the past 12 months, particularly with respect to protein catabolism. RECENT FINDINGS: Protein degradation in a range of catabolic conditions is mediated primarily through the ubiquitin-proteasome proteolytic pathway. Glucocorticoids have been suggested to activate this system in sepsis, while in cancer cachexia a tumour-produced sulphated glycoprotein, proteolysis-inducing factor, induces protein catabolism in skeletal muscle by increasing expression of proteasome subunits and the ubiquitin carrier protein, E2(14k). Apoptosis may also be important in the loss of muscle protein during the early stage of cachexia. Induction of proteasome expression by glucocorticoids appears to be a direct result of the downregulation of the activity of nuclear factor kappaB, while proteolysis-inducing factor acts through 15-hydroxyeicosatetraenoic acid as an intracellular transducer. SUMMARY: Formation of 15-hydroxyeicosatetraenoic acid is inhibited by eicosapentaenoic acid, which has been shown to attenuate the development of weight loss in patients with pancreatic cancer. When eicosapentaenoic acid is combined with an energy dense nutritional supplement, there is an increase in body weight of cachectic cancer patients through an increase in lean body mass. Eicosapentaenoic acid also prevents protein catabolism and activation of the ubiquitin-proteasome proteolytic pathway during acute starvation in mice, suggesting a similar pathway is involved. Thus eicosapentaenoic acid may be effective in the treatment of protein catabolism in conditions other than cancer.

Adipose Tissue↗

PubMed2004

Pathogenesis and consequences of HIV-associated wasting.

Weight loss is a negative prognostic indicator in patients infected with HIV. Mortality rates rise measurably with as little as 3-5% weight loss over 6 months. The sensitivity of this measure is at least partly due to the correlation between weight loss and a metabolic cachexia that has been observed with other infections, trauma, and some cancers. However, the cachexia in patients with HIV, commonly termed wasting, may also be due to, or exacerbated by, reduced caloric intake, gastrointestinal dysfunction, or metabolic abnormalities independent of abnormal energy expenditure. In patients with HIV wasting, therapies should be directed both at reversing the underlying source of protein energy malnutrition and at other factors that may be contributing to weight loss.

Antiretroviral Therapy, Highly Active↗

PubMed2003

Increased muscle proteasome activity correlates with disease severity in gastric cancer patients.

OBJECTIVE: To investigate the state of activation of the ATP-ubiquitin-dependent proteolytic system in the skeletal muscle of gastric cancer patients. SUMMARY BACKGROUND DATA: Muscle wasting in experimental cancer cachexia is frequently associated with hyperactivation of the ATP-dependent ubiquitin-proteasome proteolytic system. Increased muscle ubiquitin mRNA levels have been previously shown in gastric cancer patients, suggesting that this proteolytic system might be modulated also in human cancer. METHODS: Biopsies of the rectus abdominis muscle were obtained intraoperatively from 23 gastric cancer patients and 14 subjects undergoing surgery for benign abdominal diseases, and muscle ubiquitin mRNA expression and proteasome proteolytic activities were assessed. RESULTS: Muscle ubiquitin mRNA was hyperexpressed in gastric cancer patients compared to controls. In parallel, three proteasome proteolytic activities (CTL, chymotrypsin-like; TL, trypsin-like; PGP, peptidyl-glutamyl-peptidase) significantly increased in gastric cancer patients with respect to controls. Advanced tumor stage, poor nutritional status, and age more than 50 years were associated with significantly higher CTL activity but had no influence on TL and PGP activity. CONCLUSIONS: These results confirm the involvement of the ubiquitin-proteasome proteolytic system in the pathogenesis of muscle protein hypercatabolism in cancer cachexia. The observation that perturbations of this pathway in gastric cancer patients occur even before clinical evidence of body wasting supports the thinking that specific pharmacologic and metabolic approaches aimed at counteracting the upregulation of this pathway should be undertaken as early as cancer is diagnosed.

Biopsy↗

PubMed1993

Chronic administration of transforming growth factor-beta suppresses erythropoietin-dependent erythropoiesis and induces tumour necrosis factor in vivo.

Transforming growth factor beta is a known inhibitor of the proliferation and differentiation of early haematopoietic progenitors but has no effect on mature erythroid cells in vitro. Mice injected with rhTGF beta 1 exhibited severe and progressive suppression of erythropoiesis manifested by a decline of reticulocyte count, marrow erythroblasts and marrow and spleen CFU-E, which could be prevented by administration of erythropoietin. This suppression of erythropoiesis was associated with the appearance of tumour necrosis factor in the blood, development of pronounced cachexia and depression of serum erythropoietin levels. TGF beta induces TNF in vivo that leads to cachexia, decrease of serum erythropoietin levels and suppression of erythropoietin dependent erythropoiesis.

Animals↗

PubMed1975

The growth hormone response to insulin induced hypoglycaemia in anorexia nervosa and control underweight or normal subjects.

Hypoglycaemic stimulation of growth hormone (GH) secretion has been measured in 12 anorexia nervosa patients, 11 adolescents approximately matched for weight and age, 14 underweight adults with no history of anorexia nervosa and 27 normal patients. The results showed a high proportion of blunted growth hormone responses among the anorexia nervosa patients as compared to normal subjects, underweight adolescents or adults. In the group of underweight adults, diminshed growth hormone responses were most frequently seen in patients with depressive illness. The complex pathogenesis of the diminshed growth hormone response in anorexia nervosa involves many factors; undernutrition itself, possible hypothalamic insufficiency related to the psychopathological background and other endocrine abnormalities like hypogonadism, relative hypercorticism and hypothyroidism. The interference of the nutritional, psychological and endocrine factors could not be dissociated in our investigation or from the review of the literature on this subject. It is suggested that hypothalamic insufficiency plays a prominent role in the growth hormone hyporesponsiveness in anorexia nervosa. Although diminished, the stimulated growth hormone response remains higher in anorexia nervosa than in true hypopituitarism. This phenomenon coupled to a preserved or even increased suprarenal function enables one to differentiate cachexia resulting from anorexia nervosa and hypopituitarism leading eventually to cachexia.

Adolescent↗

PubMedDate not supplied

Alterations in carbohydrate metabolism in canine lymphoma.

Following an overnight fast, blood samples were obtained from 14 dogs with previously untreated lymphoma before and 5, 15, 30, 45, 60, and 90 minutes following an intravenous challenge with 500 mg/kg dextrose. Samples were assayed for glucose, lactate, and insulin concentrations and compared statistically with ten control dogs of similar weight and age undergoing an identical dextrose challenge. Dogs with lymphoma had similar glucose tolerance curves when compared with controls. Lactate concentrations were significantly higher (P less than 0.001) at baseline and all time periods of the glucose tolerance test in dogs with lymphoma when compared with controls. Rise in lactate concentrations over baseline levels in the first 30 minutes of the glucose tolerance test were significantly higher in dogs with lymphoma (P = 0.011). Insulin concentrations were significantly higher (P less than 0.001) at baseline and at the 5-, 45-, 60-, and 90-minute time periods of the glucose tolerance test in dogs with lymphoma. Rise in insulin concentrations over baseline in the first 5 minutes of the glucose tolerance test were also significantly greater in dogs with lymphoma (P = 0.021). These results indicate carbohydrate metabolism is altered in dogs with lymphoma. Many of these alterations parallel those observed in human patients suffering from cancer cachexia making canine lymphoma a potential model for further study of the pathogenesis and therapy of cancer cachexia.

Animals↗

PubMedDate not supplied

Alterations in lipoprotein profiles in dogs with lymphoma.

After a 12-hour fast, blood samples were obtained from 31 dogs with previously untreated lymphoma. Blood samples were also collected from 16 of these dogs after up to 5 treatments with doxorubicin (30 mg/m2 intravenously every 3 weeks). All 16 dogs underwent complete remission. Five dogs were re-evaluated after relapse and after overt signs of cancer cachexia had become clinically apparent. Samples were assayed for 8 quantitative parameters: total cholesterol (T-CH) and total triglyceride (T-TG) concentrations, and the concentration of cholesterol and triglyceride in each of the three major lipoprotein fractions, very-low-density lipoprotein (LDL-CH and LDL-TG), and high-density lipoprotein (HDL-CH and HDL-TG). The results were compared with those from 20 healthy control dogs of similar weight and age before and 3 weeks after being given one dose of doxorubicin (30 mg/m2 intravenously). The administration of doxorubicin to control dogs resulted in a significant (P < .05) decrease in T-CH, LDL-CH, and HDL-CH, as well as a significant increase in VLDL-TG and HDL-TG. When compared with untreated controls, untreated dogs with lymphoma had significantly higher concentrations of VLDL-CH, T-TG, VLDL-TG, LDL-TG, and HDL-TG, and significantly lower concentrations of HDL-CH. HDL-TG and VLDL-TG concentrations from dogs with lymphoma were significantly increased above pretreatment values after relapse and development of overt signs of cancer cachexia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis.

The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.

Animals↗

PubMed2004

Inhibition of cyclooxygenase-2 by celecoxib reverses tumor-induced wasting.

There have been a number of reports suggesting inhibition of prostaglandin production may impact tumor-mediated wasting and levels of associated humoral factors such as hypercalcemia. These reductions were achieved using traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which are often contraindicated in cancer patients. This is especially true during chemotherapeutic regimens due to concerns of bleeding from gastrointestinal and hematopoietic toxicities associated with inhibition of the housekeeping cyclooxygenase enzyme COX-1. Here, we report that celecoxib, one of the new class of selective COX-2 inhibitors, has the potential to reverse tumor-mediated wasting and associated humoral factors such as interleukin (IL)-6 and hypercalcemia in preclinical models of cachexia. Tumor bearing mice in late stage cachexia regained weight within days of the start of celecoxib treatment. Two models were tested. The first was the Colon 26 (Col26) syngeneic murine model that induces high levels of circulating IL-6 and hypercalcemia. The second was the human head and neck 1483 HNSCC xenograft model, which is less inflammatory and produces less prostaglandin than Col26. Despite the observation that no significant impact on tumor growth was observed between vehicle and celecoxib-treated animals over the course of the studies, celecoxib rapidly reversed weight loss in both cachectic models. With the added safety of celecoxib over traditional NSAIDs, these results suggest a possible therapeutic use for celecoxib for treating tumor-mediated wasting.

Animals↗

PubMed2002

Treatment with megestrol acetate improves human immunodeficiency virus-associated immune thrombocytopenia.

Splenic macrophage Fc gamma receptors participate in the pathophysiology of immune cytopenias, and in such disorders, the beneficial effects of glucocorticoids are in part mediated by decreased expression of macrophage Fc gamma receptors. In the animal model, progesterones, like glucocorticoids, inhibit expression of these receptors. Megestrol acetate (MA) is a progesterone frequently used for treating human immunodeficiency virus (HIV)-associated anorexia-cachexia. Twenty-eight patients with HIV-associated thrombocytopenia with shortened platelet survival and increased platelet-associated immunoglobulin G (IgG) who were being treated with MA for anorexia-cachexia were prospectively studied for a 6-month period to assess the potential role of progesterones in the treatment of immune thrombocytopenia. Treatment with MA for non-consecutive periods of 2 months and 1 month significantly increased platelet count and platelet survival without significant alteration of platelet-associated immunoglobulin levels. Of the 28 patients studied, 22 presented a complete response, 19 presented a complete response 1 month after finishing the MA treatment regimen, and 12 remained in complete response for a further month. Expression of Fc gamma receptors (Fc gamma RI and Fc gamma RII) by peripheral blood monocytes and the in vitro recognition of IgG-sensitized cells by monocytes were significantly decreased by the MA treatment. Decreased expression and functioning of these receptors significantly correlated with platelet counts and survival times, but no relationship was found with platelet-associated immunoglobulin, circulating immune complexes, body mass index, plasma HIV load, or CD4 lymphocyte levels. These results suggest that treatment with progesterones, like MA, may be an alternative therapy for immune cytopenias, with few side effects.

Adult↗

PubMed1998

First identification of autochthonous Cryptococcus neoformans var. gattii isloated from goats with predominantly severe pulmonary disease in Spain.

Cryptococcus neoformans var. gattii is associated with Eucalyptus trees growing in various tropical and subtropical regions of the world. The identification of 13 autochthonous strains of C. neoformans var. gattii in Spain is reported. These strains were isolated from lung (10 samples), liver (1 sample), and brain (2 samples) tissue specimens from six goats suffering from predominantly severe pulmonary disease that were autopsied. The animals were members of five different herds of goats grazing in rural areas of the province of Cáceres (Extremadura, Spain). Between 1990 and 1994, there were five outbreaks, in which between 2.5 and 12% of the goats were affected. Although respiratory symptoms (pneumonia) associated with cachexia were the predominant clinical picture in all outbreaks, brain and liver involvement was also documented in three of the five outbreaks. Biotyping was performed by culturing the isolates on L-canavanine-glycine-bromothymol blue medium and testing them for the assimilation of D-proline and D-tryptophan. Serotyping by agglutination tests confirmed the characterization of all strains as C. neoformans var. gattii serotype B. This is the first confirmation of the presence of this variety in Spain, with a peculiar ability to produce severe pulmonary and systemic disease in normal goats, particularly in the form of outbreaks of pneumonia in association with cachexia.

Agglutination Tests↗

PubMed2005

NF-kappa B-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release.

Muscle wasting (cachexia) is a consequence of chronic diseases, such as cancer, and is associated with degradation of muscle proteins such as MyoD. The cytokines tumor necrosis factor alpha and gamma interferon induce muscle degeneration by activating the transcription factor NF-kappaB and its target genes. Here, we show that a downstream target of NF-kappaB is the nitric oxide (NO) synthase gene (iNos) and suggest that NO production stimulates MyoD mRNA loss. In fact, although cytokine treatment of iNos(-/-) mice activated NF-kappaB, it did not trigger MyoD mRNA degeneration, demonstrating that NF-kappaB-mediated muscle wasting requires an active iNOS-NO pathway. The induced expression of iNOS by cytokines relies on both transcriptional activation via NF-kappaB and increased mRNA stability via the RNA-binding protein HuR. Moreover, we show that HuR regulates iNOS expression in an AMP-activated protein kinase (AMPK)-dependent manner. Furthermore, AMPK activation results in HuR nuclear sequestration, inhibition of iNOS synthesis, and reduction in cytokine-induced MyoD loss. These results define iNOS and HuR as critical players in cytokine-induced cachexia, establishing them as potential therapeutic targets.

Animals↗