Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronide

A series of 6-beta-arylamidomorphines was synthesized and biologically evaluated. Various aryl substituents were introduced into the arylamidomorphines to examine substituent structure-activity relationships. Competition binding assays showed that compounds 10a-h bound to the mu opioid receptor with high affinity (0.2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat.     

Biophysical studies of the c-MYC NHE III1 promoter: model quadruplex interactions with a cationic porphyrin

Regulation of the structural equilibrium of G-quadruplex-forming sequences located in the promoter regions of oncogenes by the binding of small molecules has shown potential as a new avenue for cancer chemotherapy. In this study, microcalorimetry (isothermal titration calorimetry and differential scanning calorimetry), electronic spectroscopy (ultraviolet-visible and circular dichroism), and molecular modeling were used to probe the complex interactions between a cationic porphryin mesotetra (N-methyl-4-pyridyl) porphine (TMPyP4) and the c-MYC PU 27-mer quadruplex. The stoichiometry at saturation is 4:1 mol of TMPyP4/c-MYC PU 27-mer G-quadruplex as determined by isothermal titration calorimetry, circular dichroism, and ultraviolet-visible spectroscopy. The four independent TMPyP4 binding sites fall into one of two modes. The two binding modes are different with respect to affinity, enthalpy change, and entropy change for formation of the 1:1 and 2:1, or 3:1 and 4:1 complexes. Binding of TMPyP4, at or near physiologic ionic strength ([K(+)] = 0.13 M), is described by a "two-independent-sites model." The two highest-affinity sites exhibit a K(1) of 1.6 x 10(7) M(-1) and the two lowest-affinity sites exhibit a K(2) of 4.2 x 10(5) M(-1). Dissection of the free-energy change into the enthalpy- and entropy-change contributions for the two modes is consistent with both "intercalative" and "exterior" binding mechanisms. An additional complexity is that there may be as many as six possible conformational quadruplex isomers based on the sequence. Differential scanning calorimetry experiments demonstrated two distinct melting events (T(m)1 = 74.7 degrees C and T(m)2 = 91.2 degrees C) resulting from a mixture of at least two conformers for the c-MYC PU 27-mer in solution.     

Evaluation of the <Emphasis Type="Italic">OPTC</Emphasis> gene in primary open angle glaucoma: functional significance of a silent change

Background  

We investigated the molecular basis of primary open-angle glaucoma (POAG) using Opticin (OPTC) as a candidate gene on the basis of its expression in the trabecular meshwork cells involved in the disease pathogenesis. Two hundred POAG patients and 100 controls were enrolled in this study. The coding sequence of OPTC was amplified by PCR from genomic DNA of POAG patients, followed by SSCP, DHPLC and DNA sequencing. Subsequent bioinformatic analysis, site-directed mutagenesis, quantitative RT-PCR and western blot experiments were performed to address the functional significance of a 'silent' change in the OPTC coding region while screening for mutations in POAG patients.     

Vitamin D Binding Protein Genotype Is Associated with Serum 25-Hydroxyvitamin D and PTH Concentrations,as Well as Bone Health in Children and Adolescents in Finland

Vitamin D binding protein (DBP)/group-specific component (Gc), correlates positively with serum vitamin D metabolites, and phenotype influences serum 25-hydroxyvitamin D (S-25(OH)D) concentration. The protein isoform has been associated with decreased bone mineral density (BMD) and increased fracture risk. We examined the role of GC genotypes in S-25(OH)D status and BMD in 231 Finnish children and adolescents aged 7−19 yr. BMD was measured with DXA from lumbar spine (LS), total hip, and whole body, and for 175 subjects, radial volumetric BMD was measured with pQCT. Background characteristic and total dietary intakes of vitamin D and calcium were collected. The concentrations of 25(OH)D, parathyroid hormone (PTH), calcium and other markers of calcium homeostasis were determined from blood and urine. Genotyping was based on single-nucleotide polymorphism (rs4588) in the GC gene. The genotype distribution was: GC 1/1 68%, GC 1/2 26% and GC 2/2 6%. A significant difference emerged in 25(OH)D and PTH concentrations between the genotypes, (p = 0.001 and 0.028 respectively, ANCOVA). There was also a linear trend in: Gc 2/2 had the lowest 25(OH)D and PTH concentrations (p = 0.025 and 0.012, respectively). Total hip bone mineral content was associated with GC genotype (BMC) (p = 0.05, ANCOVA) in boys. In regression analysis, after adjusting for relevant covariates, GC genotype was associated with LS BMC and strength and strain index (SSI) Z-score in both genders, and LS BMD in boys. In conclusion, the present study demonstrates the association between GC genotypes and S-25(OH)D and PTH concentrations. The results show the influence of DBP genetic variation on bone mass accrual in adolescence.     

Evolution of Transdisciplinarity and Ecosystem Health at the University of Newcastle,New South Wales,Australia

Antipodean pioneers of transdisciplinary (TD) thinking at the University of Newcastle, Glenn Albrecht and Nick Higginbotham have applied this perspective to contexts of human health globally and to the development of health social science as an emerging TD field. Nick Higginbotham has successfully championed the cause of TD thinking in international networks such as The International Clinical Epidemiology Network (INCLEN) and the International Forum for Social Sciences (IFSSEH). Glenn Albrecht has connected the Newcastle variety of TD thinking to its independently created doppelganger in the form of TD Ecosystem Health as pioneered by David Rapport in Canada. The convergence of TD thinking and Ecosystem Health at Newcastle has promoted a new curriculum in both undergraduate and postgraduate health and environmental sciences courses. Furthermore, TD research teams have been created and pursue investigations of both health and environmental problems. A successful national conference on transdisciplinary approaches to ecosystem health in Australia was held at Newcastle in April 2003. This article details the history of the evolution and synthesis of transdisciplinarity, ecosystem health, and ecohealth at the University of Newcastle, Australia, over a period from 1988 to the present.     

Cloning and sequencing of the medium-chain S-acyl fatty acid synthetase thioester hydrolase cDNA from rat mammary gland.

Catecholamines and Ca2+ mediate an increase in reactive-thiol status of phosphofructokinase, associated with an increase in activation of the enzyme. A correlation was observed between the number of reactive thiols and activation (r = 0.878; P less than 0.001) for 14 different treatments, with approx. 1 group per 85,000-Mr subunit becoming available over the range from the lowest to the highest state of activation.     

Histopathology, blood chemistry, and physiological status of normal and moribund striped bass (Morone saxatilis) involved in summer mortality ('die-off') in the Sacramento-San Joaquin Delta of California

Summer mortality ('die-off') is common in striped bass, Morone saxatilis (Walbaum), in the San Francisco Bay-Delta region. Tissue and blood samples of moribund and healthy striped bass collected during the summers of 1986–1988 were analysed. Sixteen moribund and 25 healthy reference fish from the Carquinez Strait area and eight fish caught in the Pacific Ocean were studied. Moribund fish plasma was invariably yellow-orange; most of the moribund fish had discoloured livers with haemorrhagic regions, and approximately one-third had haemorrhagic intestines. Piasma levels of aspartale aminotransferase, uric acid, alkaline phosphatase and cortisol were significantly higher than in reference fish from Carquinez Strait and the Pacific Ocean, whereas cholesterol, sodium, chloride, triiodothyronine and glucose levels were significantly lower. Hepatic heavy metal concentrations and bacterial content were similar in moribund and reference fish. Gill Na.⁺, K⁺ -ATPase activity was significantly lower in moribund fish. Liver, kidney, intestine, and thyroid follicles of moribund fish displayed various histopathological changes, and corticosteroidogenic (interrenal) tissue could not be identified positively in moribund fish. These findings are discussed in relation to recent work on the chemical burdens (industrial and agricultural hydrocarbons) found in livers from some of the fish examined in this study.     

Elevated light and nutrients alter the nutritional quality of stream periphyton

相似文献