Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cachexia is a common manifestation of late stage malignancy and is characterized by anemia, anorexia, muscle wasting, loss of adipose tissue, and fatigue. Although cachexia is disabling and can diminish the life expectancy of cancer patients, there are still no effective therapies for this condition. We have examined the feasibility of using a myogenic plasmid to express growth hormone-releasing hormone (GHRH) in severely debilitated companion dogs with naturally occurring tumors. At a median of 16 days after intramuscular delivery of the plasmid, serum concentrations of insulin-like growth factor I (IGF-I), a measure of GHRH activity, were increased in 12 of 16 dogs (P < 0.01). These increases ranged from 21 to 120% (median, 49%) of the pretreatment values and were generally sustained or higher on the final evaluation. Anemia resolved posttreatment, as indicated by significant increases in mean red blood cell count, hematocrit, and hemoglobin concentrations, and there was also a significant rise in the percentage of circulating lymphocytes. Treated dogs maintained their weights over the 56-day study and did not show any adverse effects from the GHRH gene transfer. We conclude that intramuscular injection of a GHRH-expressing plasmid is both safe and capable of stimulating the release of growth hormone and IGF-I in large animals. The observed anabolic responses to a single dose of this therapy might be beneficial in patients with cancer-associated anemia and cachexia.
Mol Ther 2002 Dec
PMID:Effects of plasmid-mediated growth hormone-releasing hormone in severely debilitated dogs with cancer. 1249 79

Inhibin and activin are members of the transforming growth factor beta (TGF-beta) family of ligands produced and secreted primarily by the gonads and adrenals. Inhibin-null (INH(-/-)) mice develop gonadal tumors and-when gonadectomized-adrenocortical carcinoma. The mechanisms leading to adrenal tumorigenesis have been proposed to involve the lack of a gonadal factor and/or a compensatory increase in gonadotropins. In order to achieve elevation of gonadotropins without the concomitant loss of a gonadal hormone, we crossed INH(-/-) mice with a transgenic mouse strain that has chronically elevated luteinizing hormone (LH) levels (LH-CTP). Compound INH(-/-)-LH-CTP mice die within 6 weeks of age from severe cancer cachexia induced by large, activin-secreting ovarian tumors. Unexpectedly, INH(-/-)-LH-CTP mice not only fail to develop adrenal tumors but have smaller adrenals, with a regressed x zone, indicating that elevated LH levels are not sufficient to induce adrenal tumor formation. However, following gonadectomy, INH(-/-)-LH-CTP mice develop large, sex steroid-producing adrenal tumors that arise from the x zone, indicating a growth-promoting effect of high levels of LH on the adrenal cortex in the absence of ovarian tumors. In addition, in vivo and in vitro data indicate that activin induces apoptosis specifically in the adrenal x zone. The restricted expression of activin receptor subunits and Smad2 in cells of the adrenal x zone, together with the elevated activin levels in INH(-/-)-LH-CTP mice, supports the conclusion that activin inhibits adrenal tumor growth by inducing x-zone regression.
Mol Cell Biol 2003 Jun
PMID:Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice. 1274 96

Advanced Viral Research Corp is developing reticulose, a nontoxic peptide nucleic acid preparation, for the potential treatment of viral infection. The compound is undergoing phase II clinical trials for the potential topical treatment of human papillomavirus infection in the US. Reticulose has also been investigated in clinical studies for the treatment of HIV infection in Barbados. Additionally, the drug is being investigated for the potential treatment of adenovirus infection, and is being evaluated in adjuvant arthritis models by the Weizmann Institute of Science. Investigations into the use of reticulose to reduce the toxic effects of cancer treatment are underway in Israel. Phase I trials in patients with cachexia associated with HIV, lymphoma and solid tumor, have also been initiated in Israel.
Curr Opin Mol Ther 2003 Apr
PMID:Technology evaluation: reticulose, advanced viral research. 1277 10

This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.
J Mol Med (Berl) 2003 Oct
PMID:Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. 1292 88

A highly malignant transplantable rat lymphosarcoma was studied to determine the involvement of hepatic adrenergic receptors in the development of the hypoglycemia of cancer cachexia. Following inoculation of Fischer 344 rats with lymphosarcoma cells, rats were examined at 2 and 4 weeks, at the pre-cachexic stage; 6 weeks, at the transitional stage; and 7 weeks, at the cachexic hypoglycemic stage of lymphosarcoma progression. Death occurred by the 8th week. Blood glucose levels in lymphosarcoma-bearing rats relative to control rats were: unaffected at week 2; significantly reduced 8% at weeks 4 and 6; and reduced 24% at week 7. Alpha1 adrenergic receptor binding to plasma membranes isolated from the livers of lymphosarcoma-bearing rats was: 114, 89, 67 and 30% of control at weeks 2, 4, 6, and 7, respectively. Kinetic analysis indicated that the lymphosarcoma-induced decrease at week 7 was due to a decrease in numbers of receptors with no change in affinity: B(max)(control): 1411.1 fmol/mg: Kd(control): 0.44 nm; B(max)(lympho): 345.5 fmol/mg; Kd(lympho): 0.50 nm. Alpha2 adrenergic receptor binding to plasma membranes isolated from the livers of lymphosarcoma-bearing rats was: 130, 137, 243 and 212% of control at weeks 2,4, 6, and 7, respectively. The pattern of changes in hepatic alpha1, alpha2 and beta adrenergic receptors at week 6 was comparable to that of 17 day fetal liver: a decrease in alpha1 and beta and an increase in alpha2. Hepatic adrenergic receptor changes occurred in the absence of liver damage and were not due to contamination of the liver plasma membrane fractions with lymphosarcoma cells. Plasma insulin levels displayed modest (10-15%), but not statistically significant, increases post-inoculation after week 4. Plasma glucagon levels fluctuated post-inoculation until week 7 where they were significantly increased: 202% of control. Plasma T3 and T4 levels displayed an early and steady decline after lymphosarcoma inoculation: T3: unchanged at week 2 and significantly decreased 14, 44 and 50% at weeks 4, 6 and 7, respectively. T4 increased 20% at week 1; decreased 9% at week 4 and significantly decreased thereafter: 55 and 49% at weeks 6 and 7, respectively. We propose that the development of the hypoglycemia of cancer cachexia in this lymphosarcoma model is due primarily to an early and progressive thyroid hormone dependent decrease in the number of hepatic alpha1 adrenergic receptors, compounded by an increase and decrease, respectively, in the hepatic beta and alpha2 adrenergic receptors.
Mol Cell Biochem 2003 Aug
PMID:Lymphosarcoma-induced alterations in hepatic adrenergic receptors: implications to the hypoglycemia of cancer cachexia. 1296 55

In recent years many efforts of researchers and clinicians were made to improve our knowledge of cachexia syndrome. Not only cancer, but also many chronic or end-stage diseases such as AIDS, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, tuberculosis and Crohn's disease are associated with cachexia, a condition of abnormally low weight, weakness, and general bodily decline which deteriorates quality of life and reduces the prognosis of the patients who suffer from it. In the present editorial we will focus cachexia related on cancer and provide some insight into this prognosis-limiting syndrome.
Mol Cancer 2003 Nov 05
PMID:Cancer cachexia. 1461 83

To investigate the interrelationship of inhibin alpha and growth differentiation factor 9 (GDF9) during early folliculogenesis, we generated mice lacking both inhibin alpha and GDF9. Our findings on these Inha Gdf9 double-mutant mice are as follows: 1). females develop ovarian tumors and a cachexia-like wasting syndrome, resembling mice lacking inhibin alpha alone. This indicates that the granulosa cells are competent to proliferate despite the lack of GDF9; 2). follicular development progresses to multiple-layer follicle stages before tumorigenesis. This demonstrates that the up-regulation of inhibin alpha in the Gdf9 knockout ovary directly prevents the proliferation of the granulosa cells at the primary follicle stage, an effect that is released in the absence of inhibin alpha; 3). a morphological theca forms around the preantral follicles with no detectable selective theca markers [i.e. 17alpha-hydroxylase (Cyp17), LH receptor (Lhr), and Kit]. These results indicate that the theca recruitment can occur independently of GDF9, but the differentiation of thecal cells is blocked; and 4). inhibin/activin subunits betaA, betaB, and Kit ligand (Kitl) mRNA are highly up-regulated, suggesting that the increased activins and KITL play functional roles in early folliculogenesis. Thus, GDF9 appears to function indirectly to regulate early granulosa cell proliferation and theca recruitment in vivo.
Mol Endocrinol 2004 Jun
PMID:Interrelationship of growth differentiation factor 9 and inhibin in early folliculogenesis and ovarian tumorigenesis in mice. 1501 37

Tumor necrosis factor (TNF) was originally described as a molecule with antitumor properties released by macrophages stimulated with bacterial products. Almost at the same time that TNF was cloned, it was found to be identical to cachectin, a mediator of cachexia. After the finding of this second aspect of TNF action, several studies demonstrated its role as a pro-inflammatory cytokine. These studies led to the use of anti-TNF molecules in rheumatoid arthritis and Crohn's disease. The various strategies used to inhibit TNF are summarized.
Methods Mol Med 2004
PMID:Tumor necrosis factor as a pharmacological target. 1506 28

BACKGROUND: Eosinophilic gastritis is related to eosinophilic gastroenteritis, varying only in regards to the extent of disease and small bowel involvement. Common symptoms reported are similar to our patient's including: abdominal pain, epigastric pain, anorexia, bloating, weight loss, diarrhea, ankle edema, dysphagia, melaena and postprandial nausea and vomiting. Microscopic features of eosinophilic infiltration usually occur in the lamina propria or submucosa with perivascular aggregates. The disease is likely mediated by eosinophils activated by various cytokines and chemokines. Therapy centers around the use of immunosuppressive agents and dietary therapy if food allergy is a factor. CASE PRESENTATION: The patient is a 31 year old Caucasian female with a past medical history significant for ulcerative colitis. She presented with recurrent bouts of vomiting, abdominal pain and chest discomfort of 11 months duration. The bouts of vomiting had been reoccurring every 7-10 days, with each episode lasting for 1-3 days. This was associated with extreme weakness and cachexia. Gastric biopsies revealed intense eosinophilic infiltration. The patient responded to glucocorticoids and azathioprine. The differential diagnosis and molecular pathogenesis of eosinophilic gastritis as well as the molecular effects of glucocorticoids in eosinophilic disorders are discussed. CONCLUSIONS: The patient responded to a combination of glucocorticosteroids and azathioprine with decreased eosinophilia and symptoms. It is likely that eosinophil-active cytokines such as interleukin-3 (IL-3), granulocyte macrophage colony stimulating factor (GM-CSF) and IL-5 play pivotal roles in this disease. Chemokines such as eotaxin may be involved in eosinophil recruitment. These mediators are downregulated or inhibited by the use of immunosuppressive medications.
Clin Mol Allergy 2004 May 14
PMID:Eosinophilia in a patient with cyclical vomiting: a case report. 1514 61

Overexpression of the proto-oncogene c-ski in mice results in the development of a hypertrophic phenotype, characterized by increases in body and muscle weights. It has been previously shown in our laboratories that down-regulation of muscle protein breakdown associated with reduced expression of genes pertaining to different proteolytic systems likely account for this hypertrophic pattern. The aim of the present study was to evaluate the resistance of c-ski transgenic mice to catabolic stimuli such as those induced by the growth of the Lewis lung carcinoma. The tumor elicited a loss of body weight either in transgenic or in non-transgenic animals, although it was less pronounced in the former. The mass of gastrocnemius, tibialis and extensor digitorum longus (EDL) muscles were significantly reduced in non-transgenic tumor-bearing mice. Despite the anabolic setting displayed by the transgenic animals, the EDL only is completely protected against wasting. Indeed, gastrocnemius, tibialis and soleus show a reduction in weight, the latter two being significantly more depleted when compared to the non-transgenic tumor bearers. Similarly, the perigenital white adipose tissue presented a reduced mass which was more marked in the transgenic group. The quantitation of gene expression for ubiquitin, E2, C8 and calpain in the EDL showed marked differences between the transgenic and the non-transgenic groups of tumor hosts. As expected from previous results, in the latter group most of the transcripts examined increased with respect to controls as a consequence of tumor growth; by contrast, in the transgenic tumor hosts there was a significant reduction of ubiquitin, E2, C8 subunit, and calpain mRNA levels in comparison with the transgenic tumor-free animals. These results show that c-ski hyperexpression prevents tumor-induced muscle wasting in the EDL muscle, likely by impairing the state of activation of different proteolytic systems. However, the lack of effectiveness in the other muscles examined suggests that the achievement of a significant interference with the development of cachexia at the molecular level is not an easy task and probably should be designed taking into consideration more than one target.
Int J Mol Med 2004 Oct
PMID:Effect of c-ski overexpression on the development of cachexia in mice bearing the Lewis lung carcinoma. 1537 7


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