微生物次级代谢产物生物合成基因簇与药物创新

微生物产生众多结构和生物活性多样的次级代谢产物，其生物合成基因簇的克隆是药物创新和产量提高的必要前提。迄今为止已有超过150种生物合成基因簇通过各种方式被克隆，并被用于组合生物合成、体外糖类随机化、代谢工程的定向改造。我们研究室已经克隆并测定了氨基糖苷类井冈霉索／有效霉索、多烯类抗生素FR-008／克念菌索、聚醚类南昌霉索、聚酮类梅岭霉索、杂合聚酮一多肽类略唑霉索等生物合成基因簇。深入的基因功能分析揭示了他们独特的生物合成途径和调节机理，为正在进行的组合生物合成结构改造和代谢工程产量提高奠定了基础。     

Discontinued drugs in 2006: renal,endocrine and metabolic drugs

This perspective summarizes key compounds from the endocrine and metabolic area that were discontinued from clinical development during the calendar year 2006. This is a continuation in a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates covered in this summary were being developed for the treatment of diabetes and obesity, as well as for reproductive and urogenital health issues.     

Discontinued drugs in 2006: renal, endocrine and metabolic drugs

This perspective summarizes key compounds from the endocrine and metabolic area that were discontinued from clinical development during the calendar year 2006. This is a continuation in a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates covered in this summary were being developed for the treatment of diabetes and obesity, as well as for reproductive and urogenital health issues.     

Glucocorticoids differentially regulate the innate immune responses of TLR4 and the cytosolic DNA sensing pathway

Glucocorticoids (GCs) are widely used to treat the chronic inflammatory disorders because of their powerful anti-inflammatory properties; however, their effects on macrophage-mediated immune responses are not completely understood. In the present study, we found that GCs decreased LPS-mediated TBK1 activation and the expression of IFN-β, RANTES and CXCL-10; however, poly(dA:dT)-induced TBK1 activity and cytokine expression were not affected by GCs treatment. Furthermore, GCs decreased the expression of key autophagy-related genes (ATGs), including ATG5, ATG7 and ATG12, and inhibited autophagy in macrophages after LPS stimulation. However, GCs had no effect on poly(dA:dT)-mediated autophagy and ATG expression in macrophages. Collectively, this study demonstrates that GCs inhibit the TLR4-mediated innate immune response, but do not affect the cytosolic DNA sensing pathway. This provides new insights into the immunomodulatory mechanisms of GCs in macrophages, which may provide useful information for the clinical use of GCs in treating chronic inflammatory disorders.     

Antimalarial drugs and drug targets specific to fatty acid metabolic pathway of Plasmodium falciparum

Plasmodium falciparum, a causitive agent of malaria, is the third most prevalent factor for mortility in the world. Falciparum malaria is an example of evolutionary and balancing selection. Because of mutation and natural selection, the parasite has developed resistance to most of the existing drugs. Under such circumstances, there is a growing need to develop new molecular targets in P. falciparum. A four membrane bound organelles called apicoplast, very much similar to that of chloroplast of plants, have been found in parasite. Therefore, the proteins involved in metabolic pathways of apicoplasts are important drug targets. Among the pathways in apicoplast, fatty acid biosynthetic pathway is the most important metabolic pathway in P. falciparum. Several studies have explored the role of different proteins involved in this pathway and antimalarial compounds against this target. In this review, we have studied the role of different proteins in fatty acid metabolism and designing, synthesis and evaluation of compounds against the targets identified in fatty acid metabolic pathway.     

Interactions of membrane stabilizing drugs affecting human erythrocytes in vitro

Chlorpromazine, diazepam, propranolol and practolol protect human erythrocytes against hypotonic hemolysis in vitro. Half-maximal protection was obtained with 4 × 10^?6 moles/1 chlorpromazine, 2 × 10^?4 moles/1 propranolol, 2 × 10^?4 moles/1 diazepam and 4 × 10^?4 moles/1 practolol.The interaction between pairs of these four membrane stabilizing agents wasexamined by obtaining dose-response curves for each of them alone as well as in the presence of a constant concentration of one of the others. The maximal antihemolytic effect was not increased by any of the combinations tested, and the dose-response curves for the combined effect conformed to theoretical curves for the combined effect of two drugs acting by the same mechanism.     

Discontinued drug in 2007: renal, endocrine and metabolic drugs

This perspective is the first part of an annual series of papers discussing drugs dropped from clinical development in the previous year. Specifically, this paper focuses on the 14 renal, endocrine and metabolic drugs discontinued in 2007. The candidates covered in this summary were being developed for treatment of diabetes, obesity, reproductive and urogenital health issues, and growth hormone deficiency. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I - III clinical trials.     

Discontinued drug in 2007: renal,endocrine and metabolic drugs

This perspective is the first part of an annual series of papers discussing drugs dropped from clinical development in the previous year. Specifically, this paper focuses on the 14 renal, endocrine and metabolic drugs discontinued in 2007. The candidates covered in this summary were being developed for treatment of diabetes, obesity, reproductive and urogenital health issues, and growth hormone deficiency. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I – III clinical trials.     

Elucidation of the metabolic pathway of S-equol in rat,monkey and man

S-equol is a selective estrogen receptor β (ERβ) agonist which is produced in certain individuals after ingestion of its precursor daidzein, an isoflavone present in soy. S-equol is thought to provide certain health benefits, including reduced menopausal symptoms. The metabolic profile of S-equol was determined in vivo in Sprague–Dawley rats and cynomolgus monkeys, and in vitro using hepatocytes from rat, monkey, and human. High resolution MS fragmentation patterns indicated that the major metabolite of S-equol in rat plasma and urine was the 4′-glucuronide conjugate, with lesser amounts of unconjugated S-equol, the 7-sulfate conjugate, and the 4′-glucuronide-7-sulfate diconjugate. Monkeys also showed extensive metabolism, with the major species in plasma being the 4′-glucuronide and the 7-sulfate-4′-glucuronide diconjugate; urine contained primarily the 4′-glucuronide, as seen in the rat. In vitro metabolism by hepatocytes was extensive and similar in all species, with fragmentation patterns also indicating that the 4′-glucuronide was the major metabolite. No oxidative metabolites of [¹⁴C] S-equol were detected in either in vivo or in vitro studies. These findings show that glucuronidation is the primary pathway for the metabolism of S-equol in rat, monkey and man, and that all metabolic routes of S-equol observed in vitro were also observed in vivo.     

Discontinued drugs in 2008: endocrine and metabolic

This perspective summarizes key compounds from the endocrine and metabolic area that were discontinued during the calendar year 2008. This is a continuation in a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates covered in this summary were being developed for the treatment of diabetes, diabetic complications, anti-atherosclerosis and obesity.     

Discontinued drugs in 2005: endocrine and metabolic

This perspective describes the compounds from the endocrine and metabolic area that were discontinued during the calendar year 2005. This is a continuation of a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates for this summary were being developed in the areas of treatment of diabetes and diabetes complications, as well as reproductive and urogenital heath issues.     

Discontinued drugs in 2005: endocrine and metabolic

This perspective describes the compounds from the endocrine and metabolic area that were discontinued during the calendar year 2005. This is a continuation of a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates for this summary were being developed in the areas of treatment of diabetes and diabetes complications, as well as reproductive and urogenital health issues.     

Stimulus-controlled delivery of drugs and genes

Macromolecular and colloidal systems used for the systemic delivery of drugs and genes promise to improve the way we treat and prevent numerous diseases. New generations of drug and gene delivery systems (DGDS) are being designed to enhance further efficiency by using a range of endogenous and external stimuli. This review focuses on three qualitatively distinct ways a stimulus can improve the efficiency of DGDS; namely, by selectively triggering release of the therapeutic agent from the DGDS, by modulating physical properties of DGDS and by favourably altering physiological properties of tissues to enhance DGDS transport. Recent developments in these areas are discussed to illustrate the potential of stimulus-controlled DGDS in the development of new generations of therapeutics.     

Stimulus-controlled delivery of drugs and genes

Macromolecular and colloidal systems used for the systemic delivery of drugs and genes promise to improve the way we treat and prevent numerous diseases. New generations of drug and gene delivery systems (DGDS) are being designed to enhance further efficiency by using a range of endogenous and external stimuli. This review focuses on three qualitatively distinct ways a stimulus can improve the efficiency of DGDS; namely, by selectively triggering release of the therapeutic agent from the DGDS, by modulating physical properties of DGDS and by favourably altering physiological properties of tissues to enhance DGDS transport. Recent developments in these areas are discussed to illustrate the potential of stimulus-controlled DGDS in the development of new generations of therapeutics.