Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro1,8naphthyridine group as a ...potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
Recent reports suggest that combinations of prebiotics and probiotics may be protective against colorectal cancer. We examined in rats the effects of probiotic bacteria, resistant starch (RS), and ...their interaction on luminal and epithelial events of relevance to the development of colorectal cancer. Lyophilized cultures (1 × 1010 cfu/g) of Lactobacillus acidophilus and/or Bifidobacterium lactis were added at a concentration of 1% by weight to a semipurified diet containing either low-RS (no supplemented RS) or moderate-RS (10% Hi-maize®) and fed to male Sprague-Dawley rats for 4 wk. Experimental end-points included cecal bacterial enumeration, fecal and cecal pH, SCFA levels, cell proliferation, and the acute apoptotic response to a genotoxic carcinogen (AARGC; measured 6 h after a single azoxymethane injection). A significant interaction between dietary RS and supplemental bacteria was observed for the AARGC in the colon and fecal pH (P < 0.01). Rats fed the moderate-RS diet in combination with B. lactis had a significantly greater AARGC in the colon than those fed that diet without B. lactis. Fecal pH was elevated in the moderate-RS fed rats supplemented with bacteria. The moderate-RS diet increased cell proliferation and crypt column height (P < 0.001) compared with the low-RS diet. SCFA levels and numbers of bifidobacteria and lactobacilli species were also increased (P < 0.001) by the moderate-RS diet, whereas pH levels and total coliforms were lowered (P < 0.001). The synbiotic combination of RS and B. lactis significantly facilitated the apoptotic response to a genotoxic carcinogen in the distal colon of rats. It appears likely that ingested RS acts as a metabolic substrate, thus creating the right conditions for B. lactis to exert its proapoptotic action. Because the synbiotic combination of these agents facilitates the apoptotic response to DNA damage by a cancer initiator in the colon of rats, it warrants further study for its capacity to protect against colorectal cancer.
The insulin‐like growth factor binding protein‐1 (IGFBP‐1) gene is highly expressed in fetal, perinatal, and regenerating liver. Up‐regulation is transcriptionally mediated in regenerating liver and ...occurs in the first few minutes to hours after partial hepatectomy. In transgenic mice a 970‐bp region from −776 to +151 of the IGFBP‐1 promoter was sufficient for tissue‐specific and induced expression of the gene in fetal and hepatectomized livers. However weak and/or poorly regulated expression in some transgenic lines suggested the existence of other regulatory regions. Here, genomic clones containing large regions 5′ of the mouse IGFBP‐1 gene sequence were isolated, subcloned, and sequenced. Deoxyribonuclease I (DNaseI) hypersensitivity analyses identified clusters of tissue‐specific nuclease‐sensitive sites in the promoter region, −100 to −300, −2,300, −3,100, and −5,000 along with other weak sites. After partial hepatectomy, enhanced sensitivity and/or novel sites were detected in the −100/−300, −5,000, and −3,100 regions, the promoter region remaining the most hypersensitive. A subset of these sites was present in fetal and perinatal livers. Novel tissue‐specific sites that interacted with C/EBP and hepatic nuclear factor 3 (HNF3) transcription factors were identified in the −3,100 region. A hepatectomy‐induced DNA binding complex containing the transcription factor USF1 was identified within the −100 to −300 region of the promoter. These results suggested that a complex array of tissue‐specific and hepatic proliferation‐induced transcription factors combine to regulate both the proximal promoter and more distal regulatory elements of the
IGFBP‐1 gene.
3(S)-(6-methoxypyridin-3-yl)-3-2-oxo-3-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propylimidazolidin-1-ylpropionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) ...receptor. This compound has an excellent in vitro profile (IC(50) = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.
Modification of the potent fibrinogen receptor (αIIbβ3) antagonist 1 generated compounds with high affinity for the vitronectin receptor αvβ3. Sequential modification of the basic N-terminus of 1 led ...to the identification of the 5,6,7,8-tetrahydro1,8naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor αvβ3. The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to αvβ3 is also reported.
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, α
vβ
3. The use of the 5,6,7,8-tetrahydro1,8naphthyridine group as a potency-enhancing ...N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in α
IIbβ
3 antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor α
vβ
3. The use of the 5,6,7,8-tetrahydro1,8naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in α
IIbβ
3 antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor.
La plupart des patients atteints d’atrophie multisystématisée (AMS), développent des troubles du comportement en sommeil paradoxal (TCSP). Nous avons récemment démontré que le syndrome parkinsonien ...était amélioré pendant les TCSP au cours de la maladie de Parkinson (MP).
Nous avons recherché si cette amélioration existe aussi dans la MSA alors que ce syndrome parkinsonien est moins dopasensible.
Nous avons interrogé 49 patients atteints d’AMS, et 49 patients atteints de MP appariés en âge et en sexe ainsi que leurs 98 partenaires de lit sur la présence de TCSP et sur la qualité de mouvement pendant les TCSP par rapport à la veille. Nous avons réalisé un enregistrement video- polysomnographique chez 22 patients atteints d’AMS et 19 de MP.
Nous avons retrouvé des TCSP, à l’interrogatoire, chez 43/49 patients (88 %) atteints d’AMS. Parmi les 31 conjoints qui étaient capables de juger la qualité des mouvements de leur partenaire, 81 % d’entre eux rapportaient une amélioration de cette qualité. Celle- ci comprenait une amélioration du mouvement (73 % des patients ; plus rapides, 67 % ; plus forts, 52 % ; et plus souples, 26 %), une amélioration de la parole (59 % des patients ; plus forte, 55 % ; plus intelligible, 17 % ; et mieux articulée, 36 %), et une disparition de l’amimie (50 % des patients). Chez 7 patients, l’enregistrement vidéo a confirmé l’amélioration du mouvement. Ces mouvements étaient « hachés » mais pas parkinsoniens ni cérébelleux.
Le syndrome parkinsonien est donc amélioré pendant les TCSP dans l’AMS malgré sa faible dopa- sensibilité Il est donc probable que l’amélioration du mouvement pendant les TCSP soit donc indépendante d’une restauration de la transmission dopaminergique.
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