Human lung is a major target organ for all inhaled drugs, environmental toxicants and carcinogens. Recent hypotheses suggesting a role for environmental toxicants in the pathogenesis of lung diseases, such as lung cancer and chronic obstructive pulmonary disease have stimulated interest in research on the xenobiotic metabolizing capability of the lung. Many of the compounds associated with these diseases require enzymatic activation to exert their deleterious effects on pulmonary cells. Interindividual differences in in situ activation and inactivation of xenobiotics may contribute to the risk of developing of lung diseases associated with these compounds. The major xenobiotic metabolizing enzymes, including both phase I and phase II enzymes, have been detected in animal and human lung tissues. Although the lung cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes share many common features with those present in other tissues such as liver, kidney and gut, there are some distinctive differences. It is evident from the studies carried out to date CYP1A1, 1B1, 2A13, 2F1, 2S1 and 4B1 are preferentially expressed in the lung together with CYP2E1 and 3A5. This review provides a detailed picture of major xenobiotic-metabolizing phase I (CYPs, epoxide hydrolases, flavin monooxygenases, etc.) and phase II enzymes (conjugation enzymes, including several transferases) expressed in human lung. The roles of individual metabolizing enzymes and their genetic polymorphisms are also discussed.
Described herein are the discovery and structure-activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen bonding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further development as oral anti-HBV infection agent.
Advanced glycation end products (AGEs) have been reported to cause neurodegeneration, senile plaque formation and spatial learning and memory deficits. There is much evidence describing the beneficial effects of aminoguanidine (AG) on the central nervous system; AG is able to inhibit the receptor for AGEs and beta-amyloid (Aβ) deposition in the brain, thus preventing cognitive decline and neurodegeneration. In this study, we investigated whether AG protects against ovariectomy-induced neuronal deficits and Aβ deposition in rats. Animals in the ovariectomy group (OVX) group, and those in the OVX+AG group were treated with AG (100 mg/kg/day) for 8 weeks. Learning and memory were evaluated using the electric Y maze. AGE and Aβ1-40 biochemical assessments were performed using enzyme-linked immunosorbent assay (ELISA) kits. Furthermore, evaluations of brain amyloid precursor protein 695 (APP695) mRNA expression by RT-PCR and AGE expression by immunohistochemistry were carried out. Ovariectomized rats exhibited memory impairment and Aβ production disorder with upregulated APP695 mRNA and AGE expression levels. AG pretreatment relieved the ovariectomy-induced learning and memory disorder and significantly ameliorated the Aβ production disturbance and AGE generation.Additionally, pathological changes in morphology were also significantly recovered. Our data reveal that AG plays a potentially neuroprotective role against ovariectomy-induced learning and cognitive impairment and Aβ production disorder.
This represented in Heilongjiang province is in the transition of the forestry ecological construction, hope to push on through the forest resources property rights reform system, strengthen the management of forest resources in science rising strength, the basis of timber production vigorously carrying out reforestation, eventually built provincial forest resources comprehensive monitoring center. And through these measure not only solve preventing sand soil and water loss, such problems, but also finish converting cropland to forest and wildlife reserves of construction, finally realizes the protection of natural forest resources, establish comparatively perfect forestry ecological system.
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