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Dive into the research topics where Michele Chiesi is active.

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Featured researches published by Michele Chiesi.


Circulation Research | 1992

Alpha B-crystallin in cardiac tissue. Association with actin and desmin filaments.

F Bennardini; A Wrzosek; Michele Chiesi

alpha B-Crystallin is a 20-kd peptide highly homologous to the small heat-shock proteins. This protein forms soluble homomultimeric complexes (M(r), 300-700 kd) and is very abundant in cardiac muscle cells. In vitro experiments (affinity column chromatography and binding studies with isolated proteins) have shown that alpha B-crystallin interacts directly with actin and, in particular, with desmin filaments. The immunocytochemical localization of alpha B-crystallin within the cardiomyocytes showed that the protein is distributed exclusively in the central region of the I bands (Z lines), where desmin is localized. In vitro studies have further shown that the binding affinity of alpha B-crystallin to actin and desmin filaments increases considerably at slightly acidic pH (6.5) or after a heat treatment (45 degrees C). Moreover, alpha B-crystallin was found to prevent effectively the tendency of actin filaments to form aggregates (i.e., paracrystals) at acidic pH. These in vitro data suggest a protective role of alpha B-crystallin during stress conditions such as ischemia of the heart. Crystallin could prevent the aggregation of filaments, which might occur during the acidification of the cytosol and lead eventually to irreversible structural damage.


FEBS Letters | 1996

Regulation of ob gene mRNA levels in cultured adipocytes.

Juerg Rentsch; Michele Chiesi

mRNA levels of the ob gene product, leptin, were investigated by quantitative competitive RT‐PCR in a mouse cell line (3T3‐L1) which can be induced to differentiate into adipocytes. During conversion to fat cells, the level of leptin mRNA increased several‐fold and in parallel to that for typical adipocyte markers like lipoprotein lipase, adipsin and glycerophosphate dehydrogenase. Leptin transcription, however, did not correlate with the size of the adipocytes measured as total triglycerides. On the other hand, mRNA levels for leptin in fully differentiated adipocytes were increased 2–3 fold by insulin. In contrast, free fatty acids exerted a concentration‐dependent inhibition of leptin transcription while the corticosteroid dexamethasone and an elevation of intracellular cAMP displayed only marginal inhibitory effects on leptin mRNA levels.


Journal of Clinical Investigation | 1998

FOOD INTAKE IN FREE-FEEDING AND ENERGY-DEPRIVED LEAN RATS IS MEDIATED BY THE NEUROPEPTIDE Y5 RECEPTOR

Leoluca Criscione; Pascal Rigollier; C Batzl-Hartmann; H Rüeger; A Stricker-Krongrad; P Wyss; L Brunner; Steven Whitebread; Yasuchika Yamaguchi; C Gerald; R O Heurich; Mary W. Walker; Michele Chiesi; Walter Schilling; K G Hofbauer; N Levens

The new neuropeptide Y (NPY) Y5 receptor antagonist CGP 71683A displayed high affinity for the cloned rat NPY Y5 subtype, but > 1, 000-fold lower affinity for the cloned rat NPY Y1, Y2, and Y4 subtypes. In LMTK cells transfected with the human NPY Y5 receptor, CGP 71683A was without intrinsic activity and antagonized NPY-induced Ca2+ transients. CGP 71683A was given intraperitoneally (dose range 1-100 mg/kg) to a series of animal models of high hypothalamic NPY levels. In lean satiated rats CGP 71683A significantly antagonized the increase in food intake induced by intracerebroventricular injection of NPY. In 24-h fasted and streptozotocin diabetic rats CGP 71683A dose-dependently inhibited food intake. During the dark phase, CGP 71683A dose-dependently inhibited food intake in free-feeding lean rats without affecting the normal pattern of food intake or inducing taste aversion. In free-feeding lean rats, intraperitoneal administration of CGP 71683A for 28 d inhibited food intake dose-dependently with a maximum reduction observed on days 3 and 4. Despite the return of food intake to control levels, body weight and the peripheral fat mass remained significantly reduced. The data demonstrate that the NPY Y5 receptor subtype plays a role in NPY-induced food intake, but also suggest that, with chronic blockade, counterregulatory mechanisms are induced to restore appetite.


FEBS Letters | 1999

Recombinant human uncoupling protein-3 increases thermogenesis in yeast cells

W. Hinz; B. Faller; S. Grüninger; P. Gazzotti; Michele Chiesi

The long form of human uncoupling protein‐3 (hUCP3L) is highly homologous to thermogenin (UCP1), the uncoupling protein of brown fat mitochondria, but is expressed predominantly in skeletal muscle. Its putative role is to regulate the coupling efficiency of oxidative phosphorylation and thus thermogenesis in skeletal muscle, a major thermogenic tissue in higher mammals. To study the functional relevance of hUCP3L, the protein was expressed in yeast cells under the control of the galactose promoter. Expression of hUCP3L induced a series of phenotype changes in the yeast cells. The cellular growth and the mitochondrial membrane potential were both diminished. The portion of cellular respiration coupled to oxidative phosphorylation decreased from 57% to 11% (P<0.001) and the cellular heat production, as measured by direct microcalorimetry, was increased by 33.3±3.2% (P<0.001) after induction of UCP3L. These observations demonstrate for the first time the intrinsic thermogenic properties of hUCP3L in intact cells.


Trends in Pharmacological Sciences | 2001

Pharmacotherapy of obesity : targets and perspectives

Michele Chiesi; Christine Huppertz; Karl G. Hofbauer

The search for anti-obesity agents has become one of the most exciting areas in drug discovery. Subsequent to an enormous increase in the number of possible molecular targets, the focus has shifted from target identification to target validation. Because important biological functions such as the regulation of energy intake and expenditure are controlled by complex systems, an improved understanding of pathophysiology is a prerequisite for the selection of successful development candidates for the treatment of obesity. Although most of the information on the regulation of energy balance has been obtained from rodents, various monogenic forms of human obesity provide clinical proof of concept for some of these mechanisms. However, it is still not known which are the most promising clinical approaches to lowering body weight and subsequently reducing morbidity and mortality.


Biochemical Pharmacology | 1995

Inhibition of constitutive endothelial nosynthase activity by tannin and quercetin

Michele Chiesi; Roland Schwaller

The effect of natural polyphenols on three isoforms of NO-synthase was investigated. Among the compounds tested, tannin was the most potent, inhibiting endothelial constitutive NO synthase (eNOS) with an IC50 of 2.2 microM. Other NOS isoforms (i.e. neuronal constitutive NOS and smooth muscle inducible NOS) were also inhibited but at much higher concentrations (selectivity ratio of approx. 20-30). Quercetin was also an effective but less potent inhibitor of eNOS (IC50 = 220 microM). The kinetics of tannin inhibition were investigated to gather information on the mechanism of action. Tannin did not interfere with the interaction of the enzyme with the co-substrates L-arginine and NADPH nor with the cofactor tetrahydrobiopterin. The inhibition level was also independent of free Ca2+ concentration as well as of the presence of high exogenous calmodulin concentrations.


Molecular and Cellular Biochemistry | 1990

Cardiac alpha-crystallin

Stefano Longoni; Sari Lattonen; Gillian Rosemary Bullock; Michele Chiesi

SummaryA major component of the soluble fraction of rat heart is a homopolymer (Mr about 400–650 k) of a small protein (Mr about 20 k). This cardiac protein, which is highly homologous to alpha-B-crystallin, was isolated in its native state and visualized by electron microscopy. A homogeneous population of globular particles with an average diameter of about 14-16 nM could be seen using either negative staining or rotary shadowing procedures. The structures were globular in nature with a central depression (torus-like structures). Polyclonal antibodies, raised against the cardiac crystallin, were used for the immunocytochemical localization of the macromolecular complexes. Using fluorescent secondary antibodies, a clear and sharp striation of fixed and permeabilized rat heart myocytes could be observed, similar to that observed with anti-desmin antibodies and characteristic for the central region of the I-band. Cardiac crystallin was not found associated with F-actin in preparations of rat heart myofibrils. On the other hand, it was a major contaminant of cardiac desmin preparations. These observations suggest that cardiac crystallin is involved in the organization of cytoskeletal filaments of the Z-lines.


Cell Calcium | 1992

Effect of thapsigargin on cardiac muscle cells

A Wrzosek; H Schneider; Stephan Grueninger; Michele Chiesi

The effect of thapsigargin on the activity of various enzymes involved in the Ca(2+)-homeostasis of cardiac muscle and on the contractile activity of isolated cardiomyocytes was investigated. Thapsigargin was found to be a potent and specific inhibitor of the Ca(2+)-pump of striated muscle SR (IC50 in the low nanomolar range). A strong reduction of the Vmax of the Ca(2+)-pump was observed while the Km (Ca2+) was only slightly affected. Reduction of the Vmax was caused by the inability of the ATPase to form the Ca(2+)-dependent acylphosphate intermediate. Thapsigargin did not change the passive permeability characteristics nor the function of the Ca(2+)-release channels of the cisternal compartments of the SR. In addition, no significant effects of thapsigargin on other ATPases, such as the Ca(2+)-ATPase and the Na+/K(+)-ATPase of the plasma membrane as well as the actomyosin ATPase could be detected. The contractile activity of paced adult rat cardiomyocytes was completely abolished by 300 nM thapsigargin. At lower concentrations the drug prolonged considerably the contraction-relaxation cycle, in particular the relaxation phase. The intracellular Ca(2+)-transients elicited by electrical stimulation (as measured by the changes in Fluo-3 fluorescence) decreased in parallel and the time needed to lower free Ca2+ down to the resting level increased. In conclusion, the results indicate that selective inhibition of the Ca(2+)-pump of the SR by thapsigargin accounts for the functional degeneration of myocytes treated with the drug.


Bioorganic & Medicinal Chemistry Letters | 2000

Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists.

Heinrich Rueeger; Pascal Rigollier; Yasuchika Yamaguchi; Tibur Schmidlin; Walter Schilling; Leoluca Criscione; Steven Whitebread; Michele Chiesi; Mary W. Walker; Dale Dhanoa; Imadul Islam; Jack Zhang; Charles Gluchowski

The design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identification of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 affinity. The synthesis and SAR towards CGP71683A is described.


FEBS Letters | 1999

Properties of the human long and short isoforms of the uncoupling protein-3 expressed in yeast cells

W. Hinz; S. Grüninger; A. De Pover; Michele Chiesi

Two splice variants of the human uncoupling protein‐3 (UCP3L and UCP3S) are highly expressed in skeletal muscle. The properties of UCP3L and S have been compared to those of UCP1 in a heterologous yeast expression system under the control of the galactose promoter. Both UCP3 isoforms were found to strongly impair the coupling efficiency of respiring cells thus resulting in increased thermogenesis. The uncoupling properties of both UCP3L and S could be clearly demonstrated also in isolated yeast mitochondria both in terms of coupled respiration and in the capacity to polarize the inner membrane in conditions of limited substrate availability. Contrary to what was observed with mitochondria containing UCP1, millimolar GDP and ATP had little if any effect on the uncoupling activity of UCP3. A very marked uncoupling of whole cells and isolated mitochondria was observed at very low expression levels of UCP3S indicating that the short isoform is more active than the long one.

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Thomas Vorherr

École Polytechnique Fédérale de Lausanne

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