Binding efficacy of aminobenzoic acid derivatives with DNA duplex: drug binding sites and DNA structure and dynamics.

Communicated by Ramaswamy H. Sarma.

Biomolecular study and conjugation of two para-aminobenzoic acid derivatives with serum proteins: drug binding efficacy and protein structural analysis.

Two aminobenzoic acid derivatives DAB-0 and DAB-1 showed distinct biological properties on murine bladder cancer (BCa) cell line MB49-I. In contrast to DAB-1, DAB-0 does not possess any anti-inflammatory activity and is less toxic. Furthermore, DAB-0 does not interfere with INFγ-induced STAT1 activation and TNFα-induced IκB phosphorylation, while DAB-1 does. In order to rationalize these results, the binding efficacy of DAB-0 and DAB-1 with serum proteins such a human serum albumin (HSA), bovine serum albumin (BSA) and beta-lactoglobulin (ß-LG) was investigated in aqueous solution at physiological pH. Multiple spectroscopic methods and thermodynamic analysis were used to determine the binding efficacy of DAB-0 and DAB-1 with serum proteins. Drug-protein conjugation was observed via through ionic contacts. DAB-1 forms stronger adducts than DAB-0, while ß-LG shows more affinity with the order of stability ß-LG > BSA > HSA. The stronger complexation of DAB-1 with serum proteins might account for its biological potential and transport in the blood. The binding efficacy ranged from 40 to 60%. Major alterations of protein secondary structures were detected upon drug complexation. Serum proteins are capable of delivering DAB-1 in vitro.Communicated by Ramaswamy H. Sarma.

Influence of the base-line determination on work efficiency during submaximal cycling.

AIM: The purpose of this study was to compare work efficiency values (WE = work accomplished/energy expenditure above exercising with 0 load) among different unloaded base-line correction techniques for different power outputs. METHODS: Twelve healthy men performed 6 5-min steady-state exercises of 0 (unloaded), 40, 80, 120, 160 and 200 W at a pedalling rate of 90 rpm on a cycle ergometer. Three different unloaded base-line corrections were used for WE calculation: an actual measurement of VO(2) corresponding to the unloaded pedalling exercise, the y-intercept value of the linear regression between VO(2) and power output and the y-intercept value of the curvilinear VO(2)-power regression. RESULTS: The present study demonstrated that WE was significantly higher when determined using the actual measurement of the unloaded VO(2) than y-intercept values of the linear (p<0.001) and curvilinear (p<0.05) VO(2)-power regressions. WE based on theoretical determinations (linear vs curvilinear regressions) were not significantly different. The power output significantly affected all WE index, with higher WE being measured when the power output was low and lower WE when power output was high. CONCLUSION: The high WE values determined using the actual VO(2) measurement could be explained by (i) the additional energy expended to stabilise the body in addition to the energy expenditure of moving the lower limbs without power production and by (ii) the difficulty to experimentally reproduce the unloaded condition. The large range of WE values measured in the present study is due to differences in the procedures used to determine the unloaded VO(2) (and thus differences in unloaded VO(2) values) as well as differences in the cycling intensities.

Kinin receptors in pain and inflammation.

Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B(1) and B(2). Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg(9)-kinins). The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1 beta and tumor necrosis factor-alpha. This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response. The B(1) receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B(1) receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B(1) receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B(1) receptor deserves to be investigated further.

Pharmacological characterization of the cardiovascular responses elicited by kinin B(1) and B(2) receptor agonists in the spinal cord of streptozotocin-diabetic rats.

Kinin receptor agonists and antagonists at the B(1) and B(2) receptors were injected intrathecally (i.t., at T-9 spinal cord level) to conscious unrestrained rats and their effects on mean arterial pressure (MAP) and heart rate (HR) were compared in streptozotocin (STZ)-diabetic rats (65 mg kg(-1) STZ, i.p. 3 weeks earlier) and aged-matched control rats. The B(1) receptor agonist, des-Arg(9)-Bradykinin (BK) (3.2 - 32.5 nmol), evoked dose-dependent increases in MAP and tachycardia during the first 10 min post-injection in STZ-diabetic rats only. The cardiovascular response to 6.5 nmol des-Arg(9)-BK was reversibly blocked by the prior i.t. injection of antagonists for the B(1) receptor ([des-Arg(10)]-Hoe 140, 650 pmol or [Leu(8)]-des-Arg(9)-BK, 65 nmol) and B(2) receptor (Hoe 140, 81 pmol or FR173657, 81 pmol) or by indomethacin (5 mg kg(-1), i.a.). The i.t. injection of BK (8.1 - 810 pmol) induced dose-dependent increases in MAP which were accompanied either by tachycardiac (STZ-diabetic rats) or bradycardiac (control rats) responses. The pressor response to BK was significantly greater in STZ-diabetic rats. The cardiovascular response to 81 pmol BK was reversibly blocked by 81 pmol Hoe 140 or 81 pmol FR173657 but not by B(1) receptor antagonists nor by indomethacin in STZ-diabetic rats. The data suggest that the activation of kinin B(1) receptor in the spinal cord of STZ-diabetic rats leads to cardiovascular changes through a prostaglandin mediated mechanism. Thus, this study affords an accessible model for studying the expression, the pharmacology and physiopathology of the B(1) receptor in the central nervous system.

[Short-term psychotherapy]. / Les psychothérapies brèves.

Short-term psychotherapy is characterized by a reduction in the number of interviews as compared with the conventional methods and by more limited therapeutic objectives. It is still based on psychoanalysis, but the setting and problematics are different. Interviews take place face to face and include a so-called focalization. The results, on the whole, are interesting. Short-term psychotherapy constitutes a more expeditious approach making the best possible use of available resources.