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Biomedical subjects

N Franceschini

Publications and source records attributed to N Franceschini.

At least 37 records · Page 2Linked to original sources
PubMed1998

Can non-steroidal anti-inflammatory drugs act as metalloproteinase modulators? An in-vitro study of inhibition of collagenase activity.

The in-vitro effects of some non-steroidal anti-inflammatory drugs and some analgesic drugs on collagenase activity were studied by use of a self-quenched fluorogenic esapeptide as substrate. The increased fluorescence signal arising as a result of peptide cleavage by collagenase was recorded and related to the inhibitory potency of the drugs. The effective concentrations in collagenase modulation were also correlated with the levels of the drugs in the plasma and synovial fluids of patients receiving therapeutic doses. Six of the tested drugs, nimesulide, piroxicam, tolmetin, meloxicam, sulindac and sodium meclofenamate, inhibited enzyme activity with IC50 values (concentrations resulting in 50% inhibition) ranging from 1.9 to 28.2 microM and Ki (apparent inhibition constant) ranging from 0.83 to 21.8 microM. Much of the activity was restored after dialysis of the enzyme-drug complex, demonstrating the reversibility of the effect. Although these results indicate that some anti-inflammatory drugs could modulate enzymatic activity involved in the degradation of the extracellular matrix, their possible pharmacological involvement as collagenase inhibitors in collagen degradative diseases remains to be assessed by clinical studies.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Ceftazidime and aztreonam resistance in Providencia stuartii: characterization of a natural TEM-derived extended-spectrum beta-lactamase, TEM-60.

A plasmid-encoded beta-lactamase produced from a clinical strain of Providencia stuartii has been purified and characterized. The gene coding for the beta-lactamase was cloned and sequenced. It appears to be a new natural TEM-derived enzyme, named TEM-60. Point mutations (Q39K, L51P, E104K, and R164S) are present with respect to the TEM-1 enzyme; the mutation L51P has never been previously reported, with the exception of the chromosomally encoded extended-spectrum beta-lactamase PER-1. Kinetic parameters relative to penicillins, cephalosporins, and monobactams other than mechanism-based inactivators were related to the in vitro susceptibility phenotype.

Anti-Bacterial Agents↗
PubMed1997

Non-inducible, mainly cell-associated beta-lactamase from Nocardia asteroides strain 108.

The beta-lactamase of the soil-borne strain 108 (parental strain) of Nocardia asteroides is a non-inducible enzyme mainly associated with the cells; it can be efficiently extracted by ultrasonication and SDS treatment. Crude enzyme preparations showed penicillinase and cephalosporinase activity. The kinetics of beta-lactamase production and in-vitro susceptibility to combinations of beta-lactam antibiotics plus beta-lactamase inhibitors have been studied in two stable overproducer mutants (A14 and B1) obtained by mutagenization of the parental strain with nitrosoguanidine. The cell-associated enzyme increased with bacterial growth in parental and mutant strains and was particularly abundant in stationary phase cells. The beta-lactamase inhibitors sulbactam and clavulanic acid decreased MIC values of penicillins more efficiently in the parental strain than in mutants, thus indicating some involvement of the enzyme in the resistance of N. asteroides strain 108 to beta-lactam antibiotics.

Amoxicillin↗
PubMed1997

Characterization of a new TEM-derived beta-lactamase produced in a Serratia marcescens strain.

A natural TEM variant beta-lactamase was isolated from an epidemic strain of Serratia marcescens. Nucleotide gene sequencing revealed multiple point mutations located in the 42-to-44 tripeptide and positions 145 to 146, 178, and 238. In addition, a glutamic acid 212 deletion was also found. The purified enzyme was studied from a kinetic point of view, revealing the highest catalytic efficiency (k[cat]/Km) values for ceftazidime and aztreonam compared with the TEM-1 prototype enzyme. The in vitro resistance correlated with kinetic parameters, and the enzyme also mediated resistance to some penicillins and an ampicillin-clavulanic acid combination. The mutational and kinetic changes are discussed in relation to the three-dimensional crystallographic structure of the wild-type TEM-1 enzyme.

Amino Acid Sequence↗
PubMed1997

Sensitivity of Aeromonas hydrophila carbapenemase to delta3-cephems: comparative study with other metallo-beta-lactamases.

Ceftriaxone and ceftriaxone S-oxide behaved as inactivators against the metallo-beta-lactamase of Aeromonas hydrophila AE036 and as substrates for the zinc beta-lactamase produced by Bacillus cereus (569/H/9) and Stenotrophomonas maltophilia ULA 511. Moreover, RO 09-1428, a catechol-cephalosporin, was not recognized by the A. hydrophila enzyme. Panipenem, cephalosporin C, cephalosporin C-gamma-lactone, and loracarbef were substrates for the three studied beta-lactamases.

Aeromonas hydrophila↗
PubMed1997

Heparin decreases blood pressure and response to exogenous endothelin but does not protect against chronic experimental cyclosporine nephropathy.

Cyclosporine nephrotoxicity is caused by renal arteriolar vasoconstriction and tubulointerstitial fibrosis. Endothelin has been proposed as a major mediator of these phenomena. Heparin inhibits vascular smooth muscle cell proliferation and lowers blood pressure by regulating endogenous endothelin 1 production. In a model of chronic cyclosporine nephrotoxicity in the rat, animals were treated with cyclosporine alone, cyclosporine plus heparin, and heparin alone for 28 days. Independent experiments determined that these doses of heparin resulted in a marked decrease in responsivity to exogenous endothelin. Despite this, there were no beneficial effects on renal structure or function in this animal model of chronic cyclosporine nephrotoxicity. Thus, the role of endothelin in the pathogenesis of the chronic tubulointerstitial changes and arteriolopathy in this model is probably minor.

Animals↗
PubMed1996

Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model.

Rapamycin (RAPA) acts synergistically with cyclosporine (CsA) to achieve powerful immunosuppression in several animal models of organ transplantation and autoimmune disease. If these drugs are to be used together, they should not enhance toxicity. Thus, we examined the effects of combining CsA and RAPA on renal structure and function in a rat model of chronic CSA nephropathy. Rats were given placebo, CSA (2, 4, and 8 mg/kg), RAPA (0.01 and 0.1 mg/kg), or CsA+RAPA for 28 days while on a low-salt diet. RAPA at a subtherapeutic dose of 0.1 mg/kg worsened glucose metabolism and potentiated chronic nephrotoxicity induced by CsA at 8 mg/kg in terms of both renal function and structural injury. Since hyperglycemia is known to accelerate fibrotic processes, the impairment of glucose metabolism may play a role in tubulointerstitial fibrosis (plasma glucose vs. tubulointerstitial fibrosis, r=0.72, n=18, P<0.001). RAPA had to be given at a dose 10-fold lower (0.01 mg/kg) and CsA at a dose 4-fold lower (2 mg/kg) than the dose required for complete immunosuppression to minimize nephrotoxicity. Although the CsA+RAPA combination acts synergistically on immunosuppression, the combination at the subtherapeutic dose of each drug may be synergistically nephrotoxic, perhaps due to hyperglycemia. Clinical combinations of CsA and RAPA must be tested carefully for chronic nephrotoxicity.

Animals↗
PubMed1996

Inhibition studies of S-adenosylhomocysteine hydrolase purified from Acinetobacter calcoaceticus ULA-501.

Adenosine analogs previously reported as reversible inhibitors of mammalian S-adenosylhomocysteine hydrolase (SAHase) have been found to exert similar effects on Acinetobacter calcoaceticus ULA-501 enzyme. In addition, two metal coordination compounds, cis-platinum diammine dichloride (cis-DDP) and its trans isomer (trans-DDP), the former well known for its employment in anticancer chemotherapy, were assayed on both bacterial and mammalian SAHases. In our conditions, trans-DDP appeared to be the strongest inhibitor toward both SAHases. Finally, treatment of the bacterial enzyme with a mixture of ATP-Mg acetate and KC1 caused only a slight reversible inhibition, in contrast to the complete inactivation exerted on the mammalian SAHase.

2-Chloroadenosine↗
PubMed1996

Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy.

The pathogenesis of fibrosis in chronic cyclosporine (CsA) nephropathy remains unknown. Since TGF-beta 1 plays a key role in the fibrogenesis of a number of renal diseases, we studied a salt-depleted rat model of chronic CsA nephropathy which shows similarity to the structural and functional lesions described in patients. Pair fed rats were treated with either CsA (15 mg/kg/day s.c.) or an equivalent dose of olive oil and sacrificed at 7 and 28 days. Characteristic histologic changes of proximal tubular injury, tubulointerstitial fibrosis and arteriolopathy developed in CsA-treated rats at day 28. They were accompanied by physiologic changes of increased serum creatinine, decreased creatinine clearance, increased enzymuria and decreased concentrating ability. CsA-treated rats showed a progressive increase in mRNA expression of TGF-beta 1 and matrix proteins at days 7 and 28. Most of the changes were in the tubulointerstitial and vascular compartments by immunofluorescence with a predominant involvement of the medulla as compared to cortex. The mRNA expression of plasminogen activator inhibitor, a protease inhibitor stimulated by TGF-beta 1, followed TGF-beta 1 and matrix proteins, suggesting that the fibrosis of chronic CsA nephropathy likely involves the dual action of TGF-beta on matrix deposition and degradation.

Animals↗
PubMed1996

Overproduction and purification of the Aeromonas hydrophila CphA metallo-beta-lactamase expressed in Escherichia coli.

The Aeromonas hydrophila CphA metallo-beta-lactamase was overexpressed in a soluble secreted form in Escherichia coli using a T7 RNA polymerase-based expression system, and a simple protocol based on a single cation-exchange chromatographic step was developed, which is suitable for rapid purification of the overexpressed enzyme from E. coli lysates. A yield of up to 30 micrograms of purified enzyme per milliliter of culture was obtained. The purified enzyme preparation showed properties identical to those previously reported in the literature.

Aeromonas hydrophila↗
PubMed1995

Antigenic properties and immunoelectron microscopic localization of Mycobacterium fortuitum beta-lactamase.

Mycobacterium fortuitum is a fast-growing Mycobacterium species which produces a beta-lactamase involved in the intrinsic resistance of the microorganism to beta-lactam antibiotics. An anti-beta-lactamase serum against the purified enzyme was raised in rabbits. Antibody binding was specific for native beta-lactamase, and enzyme activity was partially inhibited by the serum; furthermore, cross-reactions with denatured class A beta-lactamases were observed. This serum was used as a probe in immunogold labeling for the localization of the cell-bound beta-lactamase in both the low-level producer ATCC 19542 (parental strain) and the overproducer mutant D316. By the combination of preembedding immunogold labeling and replica technique, it was shown that the beta-lactamase was uniformly distributed on the whole external cell surface, where it appeared to be associated with a Tween 80-removable capsule-like material. Compared with the parental strain, a much higher level of expression of surface enzyme was observed in strain D316. Surface labeling was more intense in the stationary phase of growth than in exponentially growing cells. The data obtained are interpreted in the context of the intrinsic resistance of M. fortuitum to beta-lactam antibiotics.

Antigens, Bacterial↗
PubMed1995

Interactions of biapenem with active-site serine and metallo-beta-lactamases.

Biapenem, formerly LJC 10,627 or L-627, a carbapenem antibiotic, was studied in its interactions with 12 beta-lactamases belonging to the four molecular classes proposed by R. P. Ambler (Philos. Trans. R. Soc. Lond. Biol. Sci. 289:321-331, 1980). Kinetic parameters were determined. Biapenem was readily inactivated by metallo-beta-lactamases but behaved as a transient inhibitor of the active-site serine enzymes tested, although with different acylation efficiency values. Class A and class D beta-lactamases were unable to confer in vitro resistance toward this carbapenem antibiotic. Surprisingly, the same situation was found in the case of class B enzymes from Aeromonas hydrophila AE036 and Bacillus cereus 5/B/6 when expressed in Escherichia coli strains.

Binding Sites↗
PubMed1995

Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin.

Low-salt-diet, cyclosporine (CsA; 15 mg/kg per day)-treated rats develop striped interstitial fibrosis, arteriolar hyalinosis, and azotemia similar to the chronic nephropathy observed in humans. To examine the role of angiotensin II in this model, rats on a low-salt diet were given CsA, CsA and the angiotensin II receptor Type I antagonist Losartan (10 mg/kg per day), CsA and hydralazine/furosemide, or vehicle. At Day 35, CsA-treated rats had tubular injury, arteriolopathy of the afferent arteriole, increased expression of the monocyte-macrophage adhesive protein osteopontin, interstitial macrophage infiltration, increased interstitial transforming growth factor-beta expression, and interstitial fibrosis. This study provides new insight in both pathogenic and therapeutic aspects of CsA nephropathy. The pathogenesis of CsA nephropathy involves the expression of osteopontin by tubular epithelial cells, the level of which closely correlates with the degree of macrophage infiltration and interstitial fibrosis in all groups (r = 0.79 and 0.74, respectively; P < 0.001). Therapeutic conclusions can be drawn from the observation that both losartan and hydralazine/furosemide reduced osteopontin expression, macrophage infiltration, transforming growth factor-beta expression, and interstitial fibrosis, but did not prevent the decrease in GFR. Treatment with losartan, but not with hydralazine and furosemide, markedly reduced arteriolopathy. It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA. In contrast, the interstitial fibrosis mediated by CsA can be partially prevented by both an angiotensin II Type I receptor antagonist or by hydralazine and furosemide. This suggests that the interstitial fibrosis can be dissociated from the vascular effects of CsA. The beneficial effects of lowering blood pressure or vasodilation per se may be difficult to distinguish from the specific effects of angiotensin II receptor blockade.

Angiotensin II↗
PubMed1994

Activity of antimicrobial drugs evaluated by agar dilution and radiometric methods against strains of Nocardia asteroides isolated in Italy from immunocompromised patients.

Benzylpenicillin, amoxicillin, amoxicillin plus clavulanic acid, cephalothin, cephaloridine, cefotaxime, imipenem, erythromycin, clarithromycin, azithromycin, amikacin, ciprofloxacin and trimethoprim-sulfamethoxazole were tested in vitro by the agar dilution method against eleven strains of Nocardia asteroides isolated both from AIDS and other immunocompromised patients. Imipenem, amikacin and trimethoprim-sulfamethoxazole were shown to be the most active drugs with minimum inhibitory concentrations (MIC) values nearly always lower than concentrations achievable in blood. Ciprofloxacin, cephaloridine and cefotaxime were moderately active, while the remaining drugs were totally ineffective. When susceptibility was assessed by the radiometric method the MIC90 values were uniformly lower than those in the agar method, possibly due to lower inactivation of drugs during incubation. The two methods showed a good correlation only for imipenem, amikacin and ciprofloxacin. The results obtained by the radiometric method seem to indicate that, as for mycobacteria, this method may also give a more accurate evaluation of the antimicrobial susceptibility of Nocardiae.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Use of the chromosomal class A beta-lactamase of Mycobacterium fortuitum D316 to study potentially poor substrates and inhibitory beta-lactam compounds.

Sixteen different compounds usually considered beta-lactamase stable or representing potential beta-lactam inhibitors and inactivators were tested against the beta-lactamase produced by Mycobacterium fortuitum. The compounds exhibiting the most interesting properties were BRL42715, which was by far the best inactivator, and CGP31608 and ceftazidime, which were not recognized by the enzyme. These compounds thus exhibited adequate properties for fighting mycobacterial infections. Although cloxacillin, dicloxacillin, cefoxitin, and CP65207-2 exhibited poor inhibitory efficiency against the enzyme, they were also rather poor substrates and might be considered potential antimycobacterial agents. By contrast, CGP31523A and ceftamet were good substrates.

Anti-Bacterial Agents↗
PubMed1994

Fine needle aspirative biopsy of the liver in HBsAG-positive patients with end-stage renal failure.

HBsAg-positive patients with end-stage renal failure have a high prevalence of asymptomatic chronic hepatitis. In order to determine the usefulness of hepatic cytology in the diagnosis of liver disease, the findings of hepatic needle core biopsy (NCB) and fine needle aspirative biopsy (FNAB) were compared in 15 HBsAg-positive uremic patients. The patients, aged 42 +/- 12 years, 14 males, were on hemodialysis for periods ranging from 13 to 105 months. The NCB was processed by standard histologic and immunohistochemical techniques and FNAB by the conventional technique, using the total corrected increment score (TCI). Plasma samples were collected for evaluation of hepatic function and for viral serologic tests. In 15 patients a diagnosis was made by NCB: normal, 7 cases; chronic persistent hepatitis, 4 cases; and chronic active hepatitis, 4 cases. When the patients were allocated into two groups according to the severity of the liver histologic findings [group I--minor changes (normal+chronic persistent hepatitis), 11 patients; group II--major changes (chronic active hepatitis), 4 patients], statistically higher values were found in the major changes group for alanine aminotransferase (49 +/- 33 vs. 24 +/- 11, p = 0.04), gamma-glutamyl transpeptidase [148 +/- 53 vs. 38 +/- 28, p < (minor) 0.02] and TCI (3.7 +/- 1.2 vs. 2.5 +/- 0.8, p = 0.04). In conclusion, liver FNAB can be useful as a screening procedure for the identification of liver histologic changes (minor or major) in uremic HBsAG-positive patients.

Adult↗
PubMed1994

Nephrotoxicity of immunosuppressive drugs.

Drugs used to modify the immune response in solid organ transplantation or autoimmune disease may cause dose-related nephrotoxicity. Cyclosporine, FK506, cyclosporine G, and rapamycin have all been studied experimentally and to a more limited extent in patients. This paper summarizes this literature using data from clinically relevant animal models.

Acute Kidney Injury↗