Are endothelium-derived hyperpolarizing and contracting factors isoprostanes?

The endothelium releases many vasoactive substances, including prostacyclin, nitric oxide and endothelin, in addition to several other factors about which little is known. The latter are referred to as 'endothelium-derived hyperpolarizing factors' (EDHFs) and 'endothelium-derived contracting factors' (EDCFs). Although there is much debate about the identities of EDHFs and EDCFs, a prevailing hypothesis is that they are cyclooxygenase-independent metabolites of arachidonic acid and many researchers associate them with free radicals. These properties are shared with isoprostanes. In this article, I compare the properties of EDHFs and EDCFs with those of the isoprostanes and propose novel experiments that might identify isoprostanes as candidate molecules for EDHFs and EDCFs.     

Does the C-type natriuretic peptide have prognostic value in chagas disease and other dilated cardiomyopathies?

Atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) are powerful neurohormonal indicators of left-ventricular function and prognosis in heart failure (HF). Chagas disease (CD) caused by the protozoan Trypanosoma cruzi remains a major cause of HF in Latin America. We assessed whether the plasma concentration of the third natriuretic peptide, C-type natriuretic peptide (CNP), also has diagnostic and prognostic properties in patients with CD or other dilated cardiomyopathies (DCM). Blood samples were obtained from 66 patients with CD, 50 patients with DCM from other causes, and 30 gender- and age-matched healthy subjects. Patients were subdivided according to the New York Heart Association (NYHA) class. The CNP concentration was determined by radioimmunoassay (Immundiagnostik, Bensheim, Germany). The main duration of follow-up was 31.4 months (range 13 to 54 months); 19 patients had died and 11 patients received a heart transplant. CNP concentrations were only significantly altered in patients with DCM or CD of the NYHA classes III and IV (P < 0.05). The Pearson correlation of echocardiographic data with CNP revealed an association only with the left-ventricular end systolic volume (P = 0.03) in patients with DCM. Furthermore, CNP did not predict mortality or the necessity for heart transplant. Our data are the first to demonstrate the raised levels of the third natriuretic peptide CNP in CD and other DCM. Whereas ANP and BNP have a high predictive value for mortality in both diseases, CNP is without any predictive potency.     

Candida albicans cellular internalization: a new pathogenic factor?

The preliminary results of a study to show the possibility that Candida albicans can internalize into epithelial cells are reported. The study was performed on buccal, vaginal and HeLa cells. Buccal and vaginal cells, at a concentration of 5×10⁴ cells/ml and HeLa monolayers were incubated for 2, 3 and 4 h with 10⁵ colony forming units of a Candida albicans isolate. After incubation, non-internalised yeasts were eliminated and samples were processed for examination by Scanning Electron Microscopy. Results suggest that receptor-mediated endocytosis could be involved in the pathogenesis of recurrent oral and vaginal infections. This phenomenon could represent an interesting experimental model to testing drug interference in the development of therapeutic strategies against C. albicans infections.     

Heparin affin regulatory peptide: a new target for tumour therapy?

Heparin affin regulatory peptide (HARP), also known as pleiotrophin or heparin-binding growth-associated molecule, is an 18-kDa growth factor that has a high affinity for heparin. It constitutes with midkine and retinoic acid heparin-binding protein, a family of structurally related heparin-binding growth factors. A growing body of evidence indicates that HARP is involved in the control of cellular proliferation, migration and differentiation and plays a significant role in tumor growth and angiogenesis. HARP has a well described role in physiological as well as tumor angiogenesis, and is detected in various carcinomas, such as human breast and prostate cancer, neuroblastomas, gliomas, benign meningiomas, small cell lung cancer and mammary tumors, exhibiting a proto-oncogene function. It is also constitutively expressed in tumour cell lines and is involved in tumour growth and metastasis. Therefore, HARP appears to be a potential new target for the treatment or/and diagnosis of several types of cancer.     

Fertilization promoting peptide (FPP): a new peptide of importance in male fertility?

Infertility in men is currently increasing and, if this trend continues, may become a major problem in the 21st Century. This review describes the discovery and potential physiological role of a novel peptide, fertilization promoting peptide (FPP). This peptide is structurally similar to thyrotrophin-releasing hormone (TRH) and is found in high concentrations in the prostate gland and semen of mammals. Substantial amounts are also present in the anterior lobe of the pituitary gland. Physiological concentrations of FPP cause a marked increase in the fertilising ability of mouse epididymal spermatozoa as assessed by in vitro fertilisation and the chlortetracycline (CTC) fluorescence assay. In the future, FPP may provide a new therapy for some cases of unexplained male infertility.     

Brain natriuretic peptide: Disease marker or more in cardiovascular medicine?

Brain natriuretic peptide (BNP) is predominantly a cardiac ventricular hormone that promotes natriuresis and diuresis, inhibits the renin-angiotensin-aldosterone axis, and is a vasodilator. Plasma BNP levels are raised in essential hypertension, and more so in left ventricular (LV) hypertrophy and heart failure. Plasma BNP levels are also elevated in ischemic heart disease. Attempts have been made to use plasma BNP levels as a marker of LV dysfunction, but these have shown that plasma BNP levels are probably not sensitive enough to replace echocardiography in the diagnosis of LV dysfunction. Pericardial BNP or N-BNP may be more suitable markers of LV dysfunction. Plasma BNP levels are also elevated in right ventricular dysfunction, pregnancy-induced hypertension, aortic stenosis, age, subarachnoid hemorrhage, cardiac allograft rejection and cavopulmonary connection, and BNP may have an important pathophysiological role in some or all of these conditions. Clinical trials have demonstrated the natriuretic, diuretic and vasodilator effects, as well as inhibitory effects on renin and aldosterone of infused synthetic human BNP (nesiritide) in healthy humans. BNP infusion improves LV function in patients with congestive heart failure via a vasodilating and a prominent natriuretic effect. BNP infusion is useful for the treatment of decompensated congestive heart failure requiring hospitalization. The clinical potential of BNP is limited as it is a peptide and requires infusion. Drugs that modify the effects of BNP are furthering our understanding of the pathophysiological role and clinical potential of BNP. Increasing the effects of BNP may be a useful therapeutic approach in heart failure involving LV dysfunction. The levels of plasma BNP are increased by beta-blockers, cardiac glycosides and vasopeptidase inhibitors, and this may contribute to the usefulness of these agents in heart failure. (c) 2001 Prous Science. All rights reserved.     

The role of atrial natriuretic peptide in alcohol withdrawal: a peripheral indicator and central modulator?

Changes in fluid and electrolyte homeostasis may accompany and are likely to modify the clinical symptoms of alcohol-withdrawal reactions. It was of obvious theoretical and practical interest therefore to investigate the changes in the secretion of hormones, which regulate the fluid and electrolyte homeostasis (atrial natriuretic peptide, aldosterone and plasma renin activity) during alcohol withdrawal in chronic alcoholic patients. In a phase of severe withdrawal, there were increased plasma renin activity and aldosterone levels observed. In a phase of partial recovery, on the other hand, the elevated plasma renin activity and aldosterone levels were back to the normal range. In 60% of the patients, delirium tremens was gradually developing during the observation period. In these patients, an elevated level of atrial natriuretic peptide was observed at the time of hospital admission, i.e. days before the actual onset of delirium tremens. It is concluded that the disturbed volume homeostasis and the consequently altered plasma atrial natriuretic peptide secretion might be associated with, and therefore used as an indicator of the onset of delirium tremens. To study the role of central nervous atrial natriuretic peptide, mice were rendered tolerant to and dependent on alcohol with an alcohol-liquid diet for 14 days. Five hours after withdrawal from alcohol, withdrawal hyperexcitability symptoms were analyzed. Intracerebroventricular (i.c.v.) injection of atrial natriuretic peptide attenuated, whereas that of an antiserum against atrial natriuretic peptide intensified the severity of handling-induced convulsions. N-methyl-D-aspartate induced behavioral seizures in a dose-dependent manner, whose effect was more intensive during the alcohol-withdrawal period than in alcohol-naive animals. I.c.v. injections of atrial natriuretic peptide dose-dependently inhibited, whereas that of antiserum against atrial natriuretic peptide potentiated the seizure-inducing effect of N-methyl-D-aspartate in alcohol-dependent mice. Although tentatively, it is concluded that peripheral secretion of atrial natriuretic peptide may be an indicator, whereas central nervous atrial natriuretic peptide a neuropeptide modulator of alcohol-withdrawal symptomatology.     

B-cell activating factor (BAFF) — a new factor linking immunity to diet?

B cell activation factor (BAFF) is a recently discovered member of the TNF ligand superfamily secreted by adipocytes, previously linked to autoimmune and lymphoproliferative disease. The aim of this study was to investigate the relationship between BAFF plasma levels and the non-modified, usual dietary composition as well as obesity-related anthropometric parameters in a cohort of 58 obese and non-obese Central-European Caucasian individuals. We found that BAFF had an independent predictive role for percentage of body fat; moreover, BAFF levels were correlated with waist and hip circumference. BAFF plasma levels were also significantly correlated with investigated dietary composition based on the 7-day food records, as the BAFF levels correlated with the percentage of energy derived from the carbohydrates and with energy derived from the dietary fat. Our results suggest that BAFF may play a role in linking the immune status and metabolic response to diet.     

Antipsychotic drugs: a new risk factor for osteoporosis in young women with schizophrenia?

Schizophrenic illness is associated with high rates of osteoporosis, the etiology of which remains obscure, but which may be at least partly explained by the prolactin-raising properties of antipsychotic medication. Conventional antipsychotics all cause hyperprolactinemia, whereas a limited number of atypical antipsychotic drugs do not. To investigate this further, we designed a cross-sectional comparison study between groups taking either prolactin-raising or prolactin-sparing antipsychotic medication. Participants were required to be premenopausal women with a diagnosis of schizophrenia, and to have received exclusively either prolactin-raising (n = 26), or olanzapine (n = 12) antipsychotic medication. Half of the subjects in the prolactin-raising group were being treated with conventional (n = 13), and half with newer "atypical," antipsychotic drugs (n = 13). Subjects had lumbar spine and hip bone mineral density (BMD) evaluated by a dual-energy x-ray absorptiometer (DEXA) scan. A blood sample was taken to measure prolactin and sex hormone axis measures. The results demonstrated that the group taking prolactin-raising medication had higher rates of bone pathology, compared with the olanzapine group. High prolactin levels were related to measures of hypogonadism and low BMD values. Within the prolactin-raising group, those taking newer atypical compounds had higher levels of prolactin, lower levels of sex hormones, and lower BMD values than the group taking conventional antipsychotic medication. These findings suggest that the high rates of osteoporosis associated with schizophrenia may result from hypogonadism secondary to antipsychotic-induced hyperprolactinemia, and that the prolactin-raising profile of antipsychotic drugs should be considered when choosing an antipsychotic drug.     

Thalidomide: a new anticancer drug?

Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.     

B‐type natriuretic peptide and heart failure: what can we learn from clinical trials?

The B‐type natriuretic peptide (BNP) may favour natriuresis and diuresis, making it an ideal drug to aid in diuresing a fluid‐overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these has resulted in a better outcome. The current challenge for BNP research in acute HF lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP as well as a better integration of basic and clinical science.     

Tumor necrosis factor: renaissance as a cancer therapeutic?

Since the discovery of tumor necrosis factor (TNF)-alpha, researchers have pursued many approaches to harness the potency of TNF-alpha and TNF superfamily members to treat human cancers. Several ligands of the TNF superfamily, including TNF-alpha, lymphotoxin, FAS ligand (FasL), and APO2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) have been tested in various stages of clinical research for their anti-tumor efficacy. Moreover, several antibodies to TNF receptor (TNFR) superfamily members are now being explored as cancer therapeutics. Due to the toxicity associated with delivering TNF-alpha systemically at clinically relevant doses, more targeted methods are now seen as a likely alternative to provide a localized therapeutically effective dose of TNF-alpha. In this review we revisit historical attempts to use TNF-alpha to treat human cancer, and put this into the context of more recent targeted strategies to circumvent TNF-alpha's systemic toxicity. We will attempt to integrate the results of pre-clinical and clinical trials with a concise synopsis of the TNF-alpha signaling network, with the goal of reconciling our understanding of how the cell biology and tumor biology mechanistically relate.