Abstract Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Con- ventional antidepressants take at least several weeks to achieve a therapeutic response and this la...Abstract Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Con- ventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hin- dered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N- methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast- acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concem. In this review, we focus on the limitations of ketamine, including neurotoicity, cognitive dysfunction, adverse events associated with mental status, psy- chotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associ- ated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine （esketamine） and R-ketamine, are also discussed. R-ketamine has greater antidepressantactions than S-ketamine, without ketamine-related side- effects. Future treatment strategies should consider using R- ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term keta- mine use.展开更多
Blood glucose lowering assay proved that [B16Ala]insulin and [B26Ala]insulin exhibit potency of acute blood glucose lowering in normal pigs, which demonstrates that they are fast- acting insulin. Single-chain precurso...Blood glucose lowering assay proved that [B16Ala]insulin and [B26Ala]insulin exhibit potency of acute blood glucose lowering in normal pigs, which demonstrates that they are fast- acting insulin. Single-chain precursor of [B16Ala]insulin and [B26Ala]insulin is [B16Ala]PIP and [B26Ala]PIP, respectively, which are suitable for gene expression. Secretory expression level of the precursors in methylotrophic yeast Pichia pastoris was quite high, 650 mg/L and 130 mg/L, respectively. In vivo biological assay showed that the two fast-acting insulins have full or nearly full biological activity. So both [B16Ala]insulin and [B26Ala]insulin can be well developed as fast-acting insulin for clinic use.展开更多
Major depressive disorder(MDD)is a disabling and highly prevalent mood disorder as well as a common cause of suicide.Chronic stress,inflammation,and intestinal dysbiosis have all been shown to play crucial roles in th...Major depressive disorder(MDD)is a disabling and highly prevalent mood disorder as well as a common cause of suicide.Chronic stress,inflammation,and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD.Although conventional antidepressants are widely used in the clinic,they can take weeks to months to produce therapeutic effects.The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD.However,the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use.Therefore,agmatine,an endogenous glutamatergic modulator,has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway,similar to ketamine.However,recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota,which have been shown to play a crucial role in the pathophysiology of MDD,may also participate in the antidepressant-like effects of both ketamine and agmatine.This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies.Considering the anti-inflammatory properties of agmatine,it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state.Moreover,the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.展开更多
基金supported by the National Natural Science Foundation of China(81371489)the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development.AMED
文摘Abstract Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Con- ventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hin- dered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N- methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast- acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concem. In this review, we focus on the limitations of ketamine, including neurotoicity, cognitive dysfunction, adverse events associated with mental status, psy- chotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associ- ated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine （esketamine） and R-ketamine, are also discussed. R-ketamine has greater antidepressantactions than S-ketamine, without ketamine-related side- effects. Future treatment strategies should consider using R- ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term keta- mine use.
文摘Blood glucose lowering assay proved that [B16Ala]insulin and [B26Ala]insulin exhibit potency of acute blood glucose lowering in normal pigs, which demonstrates that they are fast- acting insulin. Single-chain precursor of [B16Ala]insulin and [B26Ala]insulin is [B16Ala]PIP and [B26Ala]PIP, respectively, which are suitable for gene expression. Secretory expression level of the precursors in methylotrophic yeast Pichia pastoris was quite high, 650 mg/L and 130 mg/L, respectively. In vivo biological assay showed that the two fast-acting insulins have full or nearly full biological activity. So both [B16Ala]insulin and [B26Ala]insulin can be well developed as fast-acting insulin for clinic use.
基金Supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico,No.310113/2017-2the CNPq Research Productivity Fellowship.
文摘Major depressive disorder(MDD)is a disabling and highly prevalent mood disorder as well as a common cause of suicide.Chronic stress,inflammation,and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD.Although conventional antidepressants are widely used in the clinic,they can take weeks to months to produce therapeutic effects.The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD.However,the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use.Therefore,agmatine,an endogenous glutamatergic modulator,has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway,similar to ketamine.However,recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota,which have been shown to play a crucial role in the pathophysiology of MDD,may also participate in the antidepressant-like effects of both ketamine and agmatine.This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies.Considering the anti-inflammatory properties of agmatine,it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state.Moreover,the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.
