Background:Chronic hyperuricemia is associated with complications such as gout and uric acid nephropathy,but uric acid also exhibits biological activities(e.g.,antioxidant effects,potential neuroprotective properties ...Background:Chronic hyperuricemia is associated with complications such as gout and uric acid nephropathy,but uric acid also exhibits biological activities(e.g.,antioxidant effects,potential neuroprotective properties against neurodegenerative diseases).Nonhuman primates are ideal models for studying neurodegenerative diseases;however,existing nonhuman primate hyperuricemia models cannot sustain long-term elevated serum uric acid levels,nor recapitulate the impaired uric acid excretion observed in clinical hyperuricemic patients.Methods:First,we detected uricase expression in cynomolgus monkeys and compared it with that in mice.Then,we established a cynomolgus monkey hyperuricemia model by administering a mixture of potassium oxonate,hydrochlorothiazide,and adenine via fruits and vegetables.We further analyzed the regulatory effects of this model on uric acid metabolism(synthesis,degradation,and excretion)and the expression of uric acid transporter genes in the intestine and kidney.Results:Cynomolgus monkeys express functional uricase,but at a lower level than mice.The established model maintained stable,long-term hyperuricemia by three mechanisms:increasing intestinal and renal uric acid excretion load,inhibiting hepatic uric acid degradation,and promoting uric acid synthesis.Additionally,the model downregulated the expression of intestinal/renal uric acid-secreting transporter genes,while upregulating uric acid-reabsorbing transporter genes.Conclusions:This novel cynomolgus monkey hyperuricemia model provides a new tool for investigating the association between hyperuricemia and neurodegenerative diseases,and will help clarify the mechanism by which serum uric acid influences cognitive function.展开更多
Targeted genome editing technology has been widely used in biomedical studies. The CRISPR- associated RNA-guided endonuclease Cas9 has become a versatile genome editing tool. The CRISPR/Cas9 system is useful for study...Targeted genome editing technology has been widely used in biomedical studies. The CRISPR- associated RNA-guided endonuclease Cas9 has become a versatile genome editing tool. The CRISPR/Cas9 system is useful for studying gene function through efficient knock-out, knock-in or chromatin modification of the targeted gene loci in various cell types and organisms. It can be applied in a number of fields, such as genetic breeding, disease treatment and gene functional investigation In this review, we introduce the most recent developments and applications, the challenges, and future directions of Cas9 in generating disease animal model. Derived from the CRISPR adaptive immune system of bacteria, the development trend of Cas9 will inevitably fuel the vital applications from basic research to biotechnology and bio- medicine.展开更多
DEAR EDITOR Centenarians are a typical longevity model characterized by delayed onset of morbidity in age-related diseases such as cancer, cardiovascular disease, dementia, and stroke （Andersen et al, 2012）. Though ...DEAR EDITOR Centenarians are a typical longevity model characterized by delayed onset of morbidity in age-related diseases such as cancer, cardiovascular disease, dementia, and stroke （Andersen et al, 2012）. Though there may be a number of underlying mechanisms behind this longevity, curiously it seems that the survival advantage persists in their offspring （Terry et al, 2003）, suggesting a potentially important role for genetic factors. Previous studies suggested that the heritability of human longevity may be ~25% （Herskind et al, 1996; Mcgue et al, 1993）, whicih is consistent with other studies on model organisms that identified several longevity-related genes, such as age-l, daf-2, daf-16, and sir-2 （Friedman ＆ Johnson, 1988; Kenyon et al, 1993; Lin et al, 1997; Tissenbaum ＆ Guarente, 2001）. Likewise, several studies have reported the existence of many mutations related to human longevity （Holstege et al, 2014; Sebastiani et al, 2012）.展开更多
基金The Yunnan“Xingdian Talent Program”Yunling Scholar Project,(Grant No.CA24129L025A)National Natural Science Foundation of China,Grant/Award Number:32160157 and 82160564Major Science and Technology Project of Yunnan Province(Grant No.202202AG050008)。
文摘Background:Chronic hyperuricemia is associated with complications such as gout and uric acid nephropathy,but uric acid also exhibits biological activities(e.g.,antioxidant effects,potential neuroprotective properties against neurodegenerative diseases).Nonhuman primates are ideal models for studying neurodegenerative diseases;however,existing nonhuman primate hyperuricemia models cannot sustain long-term elevated serum uric acid levels,nor recapitulate the impaired uric acid excretion observed in clinical hyperuricemic patients.Methods:First,we detected uricase expression in cynomolgus monkeys and compared it with that in mice.Then,we established a cynomolgus monkey hyperuricemia model by administering a mixture of potassium oxonate,hydrochlorothiazide,and adenine via fruits and vegetables.We further analyzed the regulatory effects of this model on uric acid metabolism(synthesis,degradation,and excretion)and the expression of uric acid transporter genes in the intestine and kidney.Results:Cynomolgus monkeys express functional uricase,but at a lower level than mice.The established model maintained stable,long-term hyperuricemia by three mechanisms:increasing intestinal and renal uric acid excretion load,inhibiting hepatic uric acid degradation,and promoting uric acid synthesis.Additionally,the model downregulated the expression of intestinal/renal uric acid-secreting transporter genes,while upregulating uric acid-reabsorbing transporter genes.Conclusions:This novel cynomolgus monkey hyperuricemia model provides a new tool for investigating the association between hyperuricemia and neurodegenerative diseases,and will help clarify the mechanism by which serum uric acid influences cognitive function.
基金partially supported by the National Natural Science Foundation of China(81202110,81120108019,U1132605 and 81325016)
文摘Targeted genome editing technology has been widely used in biomedical studies. The CRISPR- associated RNA-guided endonuclease Cas9 has become a versatile genome editing tool. The CRISPR/Cas9 system is useful for studying gene function through efficient knock-out, knock-in or chromatin modification of the targeted gene loci in various cell types and organisms. It can be applied in a number of fields, such as genetic breeding, disease treatment and gene functional investigation In this review, we introduce the most recent developments and applications, the challenges, and future directions of Cas9 in generating disease animal model. Derived from the CRISPR adaptive immune system of bacteria, the development trend of Cas9 will inevitably fuel the vital applications from basic research to biotechnology and bio- medicine.
基金supported by grants from the Yunnan Applied Basic Research Project（2013FB069）
文摘DEAR EDITOR Centenarians are a typical longevity model characterized by delayed onset of morbidity in age-related diseases such as cancer, cardiovascular disease, dementia, and stroke （Andersen et al, 2012）. Though there may be a number of underlying mechanisms behind this longevity, curiously it seems that the survival advantage persists in their offspring （Terry et al, 2003）, suggesting a potentially important role for genetic factors. Previous studies suggested that the heritability of human longevity may be ~25% （Herskind et al, 1996; Mcgue et al, 1993）, whicih is consistent with other studies on model organisms that identified several longevity-related genes, such as age-l, daf-2, daf-16, and sir-2 （Friedman ＆ Johnson, 1988; Kenyon et al, 1993; Lin et al, 1997; Tissenbaum ＆ Guarente, 2001）. Likewise, several studies have reported the existence of many mutations related to human longevity （Holstege et al, 2014; Sebastiani et al, 2012）.
