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C Tonello

Publications and source records attributed to C Tonello.

35 records · Page 2Linked to original sources
PubMed1997

Tumor necrosis factor-alpha induces apoptosis in rat brown adipocytes.

Accumulating evidence demonstrates that adipose tissue is a major site of tumor necrosis factor-alpha (TNF-alpha) gene expression, which is markedly high in obese animals and may contribute to obesity-linked insulin resistance. We now report that recombinant murine TNF-alpha triggers the apoptotic degeneration of brown adipocytes differentiated in culture. Moreover, noradrenaline, which has been described as having trophic effects on brown fat and accelerating the differentiation of brown adipocytes, is capable of dose-dependently preventing the TNF-alpha-induced apoptosis of brown fat cells. Since obesity is characterized by greatly increased TNF-alpha production and reduced catecholaminergic activity, apoptosis was studied in the brown fat of genetically obese animals. In situ DNA fragmentation analysis revealed a larger number of apoptotic cells in the brown fat of obese (fa/fa) than in that of lean (+/+) Zucker rats. The exposure of obese rats to low temperatures for 7 days, which increases the sympathetic activity of brown adipose tissue, significantly reduces the number of apoptotic brown adipocytes. We hypothesize that TNF-alpha may play a significant role in the control of brown fat homeostasis.

Journal Article↗
PubMed1997

Inducible nitric oxide synthase in rat brown adipocytes: implications for blood flow to brown adipose tissue.

Exposure of rat brown adipocytes differentiated in culture to norepinephrine (NE) results in the production of nitrites (NO2-), the breakdown product of nitric oxide (NO). This production, which is blocked by actinomycin D1 is directly related to the duration of exposure to and dose of NE. Cytosol from NE-treated brown fat cells, but not from untreated cultures, catalyzed the Ca(2+)-independent conversion of L-arginine to L-citrulline, which could be significantly blocked by the specific nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester. Reverse transcriptase-PCR demonstrates that the addition of NE; selective beta 1-, beta 2-, or beta 3-adrenergic receptor agonists; or agents increasing cAMP production, such as forskolin, to brown adipocytes stimulates inducible NOS (iNOS) messenger RNA, which is present within 4 h after exposure. That iNOS is synthesized in brown fat cells is confirmed by immunoblotting using an antibody to the iNOS of mouse macrophages, Finally, in both brown adipose tissue (BAT) and brown adipocyte preparations from animals exposed to low temperature, iNOS messenger RNA and protein were expressed, and NOS activity was detectable; these findings were unlikely for room temperature-acclimated rats. We conclude that brown fat cells can express an inducible form of NOS similar to the iNOS of macrophages, and that its production is directly dependent on sympathetic activity in physiological conditions. NO generated by stimulation of iNOS in brown adipocytes may represent an important mechanism to modulate different BAT functions, among which is vasodilation of the BAT microcirculation.

Adipocytes↗
PubMed1996

Expression of nerve growth factor in brown adipose tissue: implications for thermogenesis and obesity.

The presence of nerve growth factor (NGF) and the ability of adrenergic stimulation to affect the rate of its synthesis in mouse, rat, and human brown adipose tissue (BAT) were investigated. Addition of conditioned medium, obtained from preconfluent and confluent brown adipocytes, to PC12 cells induced typical morphological changes similar to those due to NGF itself. Anti-NGF antibodies blocked this action. Moreover, NGF mRNA was detected by RT-PCR both in BAT and in brown adipocyte preparations. That NGF is synthesized in and released from brown fat cells was confirmed by immunoblotting. When the animals were exposed to low temperatures, NGF production declined. The effect of cold exposure could be mimicked by the addition of norepinephrine (NE) at day 4 or 8 (preconfluent and confluent cells, respectively). NE depletion obtained by reserpine injection induced a drastic increase of BAT NGF production. In both rat and human BAT, immunohistochemistry identified distinct anatomical structures that express the low affinity neurotropin receptor, termed p75NGFR. BAT production of NGF was higher in genetically obese rats and mice than in their lean counterparts, a difference that becomes more evident with age. Prolonged exposure to low temperature significantly decreased the BAT NGF synthesis also in obese animals. We conclude that NGF is synthesized in and released from brown fat cells, its production being inversely dependent on sympathetic activity, in both physiological and pathophysiological conditions, and increased in genetic animal models of obesity.

Adipose Tissue, Brown↗
PubMed1996

Functional studies of the first selective beta 3-adrenergic receptor antagonist SR 59230A in rat brown adipocytes.

The SS-enantiomer 3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahy dronaphth-1-ylaminol]-(2S)-2-propanol oxalate (SR 59230A) is proposed to be the first beta 3-adrenergic receptor antagonist. The present work shows that SR 59230A, unlike its inactive RR-enantiomer (SR 59483), antagonized a typical beta 3-adrenergic response in vitro, i.e., SR 58611A, the ethyl-[(7s)-7-[[(2R)-2-(3- chlorophenyl)-2-hydroxethyl]amino]-5,6,7,8-tetrahydronaphth- 2- yl]oxyacetate hydrochloride- or (-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one (CGP 12177)-stimulated synthesis of cAMP in rat brown adipose tissue membranes, with pKB values of 8.87 +/- 0.12 and 8.20 +/- 0.15. In addition, SR 59230A had no antagonistic effect on forskolin-induced cAMP accumulation in rat interscapular brown adipose tissue. SR 59230A, in contrast to the selective beta 1- and beta 2-adrenoceptor antagonists (+/-)[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]- 3-[4(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2 propanol and erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan- 2-ol-hydrochloride did not counteract the cAMP production induced by (-)-isoprenaline or norepinephrine (NE) in rat brain areas rich in beta 1- or beta 2-adrenoceptors, such as frontal cortex and cerebellum. Moreover, in proliferating brown fat cells, in which the beta 1-adrenoceptor is the only beta-adrenergic subtype coupled to cAMP production, SR 59230A did not modify the production of cAMP induced by NE, whereas CGP 12177 did. In confluent brown fat cells, in which the beta 3-adrenoceptor is the functional beta-adrenergic subtype coupled to adenylyl cyclase, SR 59230A antagonized the NE-induced cAMP accumulation and glycerol release without affecting their basal values, whereas CGP 12177, which per se stimulated cAMP accumulation and glycerol release, did not change the NE-induced increase of either parameter. Finally, SR 59230A concentration-dependently counteracted the NE-stimulated synthesis of uncoupling protein gene in confluent brown fat cells, which is considered mainly a result of selective stimulation of beta 3-adrenoceptors. These results provide evidence that the new selective beta 3-adrenoceptor antagonist can contribute considerably to functional characterization of the beta 3-adrenoceptors.

Actins↗
PubMed1995

Rat frontal cortex beta 1-adrenoceptors are activated by the beta 3-adrenoceptor agonists SR 58611A and SR 58878A but not by BRL 37344 or ICI 215,001.

SR 58611A, a selective agonist of gut and brown adipose tissue beta 3-adrenoceptors (beta 3 ARs), has been reported to have antidepressant-like activity in rodents, by indicating brain beta 3ARs as the sites of this property. SR 58611A and its acid metabolite SR 58878A, as opposed to BRL 37344, ICI 215,001, and CGP 12177, increased cyclic AMP levels in rat frontal cortex. ICI 215,001, differently from BRL 37344, at concentrations in the millimolar range antagonized norepinephrine- or (-)-isoproterenol-stimulated adenylyl cyclase partially. The increase of cyclic AMP levels induced by SR 58878A was blocked selectively by beta 1AR antagonist CGP 20712A but not by beta 2AR antagonist ICI 118,551. In addition, PCR analysis did not reveal beta 3AR mRNA, and no specific beta 3AR binding sites were detected by [3H]CGP 12177 in rat frontal cortex. When down-regulation of the beta 1AR ligand binding and mRNA levels had been induced in frontal cortex by chronic administration of imipramine, SR 58878A as well as norepinephrine and (-)-isoproterenol inceased the cyclic AMP production less markedly. Our findings indicate that beta 3ARs are absent in the adult rat frontal cortex, and that various beta 3AR agonists differently affect the frontal cortex beta 1ARs, indicating that SR 58611A may exert its putative antidepressant effect acting on the frontal cortex beta 1ARS.

Adipose Tissue, Brown↗
PubMed1994

SR 58611A: a novel thermogenic beta-adrenoceptor agonist.

N(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R )-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride (SR 58611A) increased cyclic AMP levels in membrane homogenates from rat interscapular brown adipose tissue with an EC50 of 20 +/- 2 nM. Substitution of GTP with the GDP analog, guanosine-5'-O[thiodiphosphate], in the incubation medium suppressed the stimulation of adenylyl cyclase activity by SR 58611A. This compound also stimulated glycerol release from the brown fat cells, with an EC50 of 11 +/- 0.4 nM. Only at doses higher than 10 microM did the non-selective beta-adrenoceptor antagonists, propranolol and alprenolol, as well as the selective beta 1- and beta 2-adrenoceptor antagonists, (+-)-[2-(3-carbamoyl-4-hydroxy-phenoxy)- ethylamino]-3-[4(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2 propanol (CGP 20712A) and erythro-(+-)-1-(7-methylindan-4-yloxy)-3-iso-propylamino butan-2-ol-hydrochloride (ICI 118,551), antagonize the SR 58611A-induced stimulation of both adenylyl cyclase activity and lipid metabolism. Since, at high doses, all these beta-adrenoceptor antagonists lack selectivity for beta 1- or beta 2-adrenoceptors, these results suggest that the beta-adrenoceptor agonist, SR 58611A, activates thermogenesis by acting on brown fat cell beta 3-adrenoceptors. This implies that this compound might be useful for treatment of obesity.

Adenylyl Cyclases↗
PubMed1993

Neurochemical and behavioral evidence that Ro 41-9067 is a selective presynaptic dopamine receptor agonist.

(-)-2,3,4a,5,6,10b-Hexahydro-7-hydroxy-2-methylbenzo(f)-quinoline 4(1H)-ethanol (Ro 41-9067) was compared with apomorphine, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine (B-HT 920), lisuride and other dopamine (DA) receptor agonists in a series of tests designed to characterize its pharmacological activity on DA receptors. In vitro binding studies indicated that Ro 41-9067 bound selectively to DA D2 vs. D1 receptors. It also had a moderate affinity for serotonin1A and alpha-2 adrenergic receptors. Ro 41-9067 exhibited a marked agonistic component for the presynaptic DA autoreceptors. Indeed, it caused a dose-related reduction in locomotor activity over a wide dose range and prolonged periods of observation without stimulating locomotor activity, reflecting postsynaptic DA receptor activation, even at the highest doses. Ro 41-9067 inhibited the gamma-butyrolactone-induced increase in I-dopa accumulation in the rat striatum, an effect sensitive to haloperiodol. Ro 41-9067 inhibited K(+)-induced [3H]DA release and significantly reduced the striatal contents of the DA metabolites, dihydroxyphenilacetic acid and homovanillic acid. Furthermore, the compound counteracted stereotyped behavior and locomotor stimulation induced by amphetamine. Finally, Ro 41-9067 did not appear to act on postsynaptic D2 receptors because it, similarly to B-HT 920 but differently from bromocriptine, quinpirole and lisuride, did not change basal or forskolin-stimulated adenylate cyclase activity. Only at very high concentrations Ro 41-9067 increased adenylate cyclase activity, this effect being due to a D1 agonistic component.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗
PubMed1992

Tolerance to hypoactivity and sensitization to hyperactivity after chronic treatment with a presynaptic dose of lisuride in rats.

We studied the adaptive changes of the locomotor effects of lisuride, a selective agonist for dopamine (DA) D2 receptors, and the functional state of D1 and D2 receptors after repeated administration of lisuride at a dose supposed to act preferentially on DA autoreceptors. Rats were treated daily with saline or lisuride, at a dose that causes a significant reduction in locomotor activity when given to naive rats (25 micrograms/kg i.p.), for 33 days and the effect of different challenging doses of the drug on locomotor activity was measured at different times during and after the treatment. The functional state of D1 and D2 DA receptors was evaluated by measuring SKF 82526-stimulated and LY 171555-inhibited adenylate cyclase (AC) activity in the caudatus/putamen, nucleus accumbens and substantia nigra and naive and chronically treated rats. There was a progressive decline in the ability of lisuride to decrease locomotor activity in rats given daily injections of lisuride, and there was a marked reduction in the threshold dose of lisuride for causing hypermotility. The functional state of DA receptors, positively or negatively linked to AC activity, was not modified by the treatment. The most suitable explanation of the reported adaptive behavioral changes is a down-regulation of DA autoreceptors after chronic treatment with presynaptic doses of lisuride.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Biochemical and functional identification of a novel dopamine receptor subtype in rat brown adipose tissue. Its role in modulating sympathetic stimulation-induced thermogenesis.

Various dopamine (DA) agonists including propylnorapomorphine, lisuride, bromocriptine, apomorphine and quinpirole were found to reduce adenylate cyclase activity in rat brown adipose tissue homogenates. These inhibitory effects were antagonized, with a very low stereoselectivity, by DA receptor antagonists with the following rank order of potency: haloperidol > (+)-butaclamol > or = (-)-butaclamol >> clozapine > or = (-)-sulpiride > or = (+)-sulpiride > or = eticlopride, but not by the alpha-2 adrenoceptor antagonists, phenoxybenzamine and yohimbine or the serotonin receptor antagonists, ketanserin and metergoline. The selective D1 agonist, fenoldopam, was completely inactive in modifying the basal enzyme activity. DA as well as various DA agonists (lisuride > propylnorapomorphine > bromocriptine > apomorphine > quinpirole) dose-dependently reduced the stimulation of adenylate cyclase activity induced either by forskolin or by the beta adrenoceptor agonist, (-)-isoproterenol. Similar results were obtained also in dispersed brown adipocytes. We also found that DA and various DA receptor agonists induced a significant decrease of beta adrenoceptor-stimulated glycerol and nonesterified fatty acids release from brown adipocytes. This effect was selectively antagonized by haloperidol and butaclamol. Thus, the receptors present on the BAT membranes appear to be dopaminergic in nature although they differ from the classical D2 receptor for the following: 1) the low affinity for the most selective D2, D3 and D4 receptor agonist and antagonist (quinpirole, sulpiride and clozapine); 2) the absence of stereoselectivity for various DA antagonists (butaclamol and sulpiride); and 3) the lack of detectable mRNA encoding D2 or D3 DA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1987

Influence of meal ingestion time on pharmacokinetics of orally administered levodopa in parkinsonian patients.

The influence of meal ingestion time on rate and extent of oral levodopa absorption was evaluated in a group of 17 patients, after administration of their usual second daily dose of levodopa plus carbidopa (Sinemet 10:1) or benserazide (Madopar 4:1). Standard meals were consumed by the patients after they had fasted 15-17 h, on one occasion 30 min before ingestion of the levodopa "study dose" and, at another time, 2 h after ingestion of the same dose. This study dose, ranging from 50 to 250 mg levodopa, was given to the patients at 11 a.m., 4 h after their first morning dose. Time to peak plasma levodopa concentration increased threefold (from 45 +/- 23 to 134 +/- 76 min, p less than 0.001), when levodopa was administered after meals. Area under the 6-h plasma concentration-time curve for levodopa was decreased in 10 subjects, unchanged in three and higher in four after ingestion of meals, the latter finding probably resulting from an erratic absorption even at fasting. On the whole, levodopa absorption proved significantly lower (p less than 0.01), on the average 15%. Similarly, peak plasma levodopa concentrations were lower in 12 patients, unchanged in two, and higher in three, with an overall significant decrease (p less than 0.001) of 30% on the average. The data confirm the importance of meal ingestion time in relation to levodopa dose as a determinant of drug absorption.

Aged↗
PubMedDate not supplied

[Extended resection in locally advanced colon cancer].

Colorectal malignant tumors with a mono o multivisceral involvement have a poor prognosis and surgery is the only treatment with a hope to be curative. Aggressive surgical management of locally advanced colo-rectal cancer seems to be justified by good oncological results. At the Institute of Clinica Chirurgica of the University of Trieste 58 extended resections were performed for advanced tumors of colon and rectum. The specific morbidity rate was 24% for standard and 24.1% for extended resections. Operative morality was 15.2%; hystological specimen confirmed in 31 cases neoplastic infiltration of contigous structures. The 5 year survival rate was 38.5% in right colonic tumors and 53.3% in left colonic tumors. The literature favors an aggressive approach when the tumor adhesions are suspected. The excision of adjacent organs, whether or not they are microscopically involved by the tumor, is necessary to avoid leaving potentially curable disease The authors, analyzing their results, have also reported good results by management including resection of the colon and contigous organs if involved. Palliative therapy must be performed only if liver metastases are detected or in those cases when primary resection is not thecnically feable or in patients not able to tolerate the procedure.

Aged↗
PubMedDate not supplied

[Surgical therapy of right colon cancer].

The debate about the management of frequent advanced right colon cancer is still opened: the opportunity of extended resections when the surrounding organs or tissues are infiltrated, the lymphadenectomy extension and its role, the possibility of identifying prognostic factors that could be useful to decide adjuvant therapy, the definition of the role of laparoscopy. Considering these problems, we have reviewed a series of 159 operations performed by the Institute of Clinical Surgery of the University of Trieste from 1980. 112 of these operations had a curative goal. The reconstruction of intestinal continuity was carried out manually in 28 cases and with mechanical stapler in 78. As far as the curative resection are concerned, in 89 of them an extended lymphadenectomy was performed (D3), while in 18 cases the lymphadenectomy was limited to the lymph nodes of first and second level due to the general bed conditions of the patient. 27 of the curative exeresis were performed in patients with T4 tumor infiltrating the nearby tissues. Referring to Dukes' classification, 8 were included in stage A, 59 in stage B and 40 in stage C, while as far as the depth of wall infiltration is concerned 2 were categorized as T1, 9 as T2, 69 as T3 and 27 as T4. The overall operative mortality was of 5 patients, the overall morbidity of 14%, that specific of 4.6%. The final incidence of local recurrences was 13.8% for Dukes A cancers, 10.9% for Dukes B and 120.5% for Dukes C (p = 0.0614). Half of the recurrences (50%) occurred in patients with a cancer infiltrating the nearby tissues. The 5 year survival rate for patients with Dukes A lesions was 100%, for patients with Dukes B lesions 73.4% and for Dukes C 52.3% (p = 0.00510). With Cox' multivariate analysis only the stage disease, T and grading showed a significative correlation with the survival rate. Our experience, therefore, suggests the execution of an exeresis with lymphadenectomy D3 in each cases where the local site of the lesion and the general conditions of the patients allow it and an extended exeresis where possible from a technical point of view and when the lymph nodes are involved.

Adult↗
PubMedDate not supplied

[DNA ploidy and cell kinetics in cancer of the rectum].

The pathological assessment of rectal cancer remained essentially unchanged for 50 years and it is based mainly on Dukes' classification and histological granding. Alternative methods of classifications have also been developed but, actually, Dukes'taging is the most important prognostic factor. The limit of Dukes' classification is the incomplete discrimination between high risk and low risk patients into the same stages. The measurements of cellular DNA content by flow cytometry is emerging as a prognostic aid in many human tumours. Authors analyze on the basis of their experience on 116 curative operations for the cancer of the rectum, the relationship between tumour's features, CEA, symptoms, recurrences, survival, type of operation and DNA flow cytometry. In 100 cases they studied the percentage of cells in "s" phase. (SPF). Samples of flow-cytometry were prepared using paraffin-embedded tumour blocks. The authors didn't find any statistically significant relation among pathological features, staging, ploidy and SPF. Recurrences rate was 16.6% in diploid tumours and 23% in no diploid (p = 0.3). In SPF < 25% it was 18.2% (p = 0.5). 5-year survival was worse in aneuploid patients (p = 0.06). Using Cox' multivariate regression analysis, ploidy has not independent prognostic significance. In conclusion authors consider ploidy a prognostic factor in rectal cancer, but not independent. However, authors conclude that flow cytometry could help in early staging of the disease, especially in preoperative diagnosis. Flow cytometry has a prognostic significance with informations on tumoral biology and could contribute to select patients for adjuvant therapy or different surgical techniques.

Adult↗
PubMedDate not supplied

Differential relevance of beta-adrenoceptor subtypes in modulating the rat brown adipocytes function.

The potencies and intrinsic activities on cyclic AMP accumulation and lipolysis of various selective beta 3-adrenoceptor agonists were studied in brown adipocytes and compared to those of the nonselective, (-)-isoprenaline, and conventional beta 1- (dobutamine) and beta 2-adrenoceptor (salbutamol) agonists. (-)-Isoprenaline, dobutamine and salbutamol were more potent stimulants of lipolysis than of cyclic AMP accumulation, while the selective beta 3-adrenoceptor agonists had similar potencies for these two functions. Apparent pA2 values of the selective beta 1-(CGP20712A) and beta 2-adrenoceptor (ICI118551) antagonist for inhibition of adenylyl cyclase stimulation by (-)-isoprenaline and the beta 3-adrenoceptor agonists, BRL37344, SR58611A, and ICI215001, indicated that (-)-isoprenaline can stimulate the enzyme through a relevant beta 1-adrenergic component, while the other drugs activate the enzyme mainly by acting on the beta 3-adrenoceptors. On the contrary, antagonism of the lipolysis yielded apparent pA2 values for CGP20712A and ICI118551, suggesting that (-)-isoprenaline, like all the beta 3-adrenoceptor agonists, stimulated the brown adipose tissue lipid metabolism mainly through an action on beta 3-adrenoceptors.

Adipocytes↗
PubMedDate not supplied

[Evaluation of the surgical risk and preparation to major surgical intervention in geriatric surgery].

BACKGROUND: The progress in surgery, anaesthesia, pre and postoperative care improves the number of old patients undergoing major surgery. The preoperative physiologic assessment is very important to identify patients who are at higher risk group and to plan the therapeutical strategics. METHODS: This study has been carried out on 849 patients aged 70 years and over who underwent major surgery; biliary tract surgery in 314 cases, colorectal in 279, gastroesophageal in 144, vascular in 48, jejunal in 32, pulmonary in 13, pancreatic in 11, hepatic in 8. 158 patients underwent urgency surgery. Mortality and morbidity index are related to the age of the patients, the urgency of the treatment, the time required for the operation, the preoperative physiologic assessment. RESULTS: The overall mortality rate was 13.7%: 84 patients died for cardiovascular complications and 32 for pulmonary complications. Mortality rate was 6% after elective surgical treatment and 48% in urgency. The urgency influences considerably the mortality in the group over 80 years than in younger (p < 0.01). The difference in mortality after elective surgery was less significative (p < 0.06). The time required for the operation doesn't influence the mortality rate. CONCLUSION: The authors emphasize that the preoperative physiologic assessment to identify patients at higher risk and an accurate preoperative care may reduce the mortality rate also in patients over 80 years undergoing major surgery. In urgency, when the patients cannot undergo a preoperative assessment and care, the postoperative mortality is higher in the group over 80 years than in younger.

Age Factors↗