Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in ...Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.展开更多
Stroke is characterised by high mortality and disability rate in China.This study aimed to explore the temporal trends in years of life lost(YLL)and loss of life expectancy due to stroke and its subtypes in urban and ...Stroke is characterised by high mortality and disability rate in China.This study aimed to explore the temporal trends in years of life lost(YLL)and loss of life expectancy due to stroke and its subtypes in urban and rural areas in China during 2005-2020.Data were obtained from China National Mortality Surveillance System.Abbreviated life and stroke-eliminated life tables were generated to calculate loss of life expectancy.The YLL and loss of life expectancy due to stroke in urban and rural areas at both national and provincial level during 2005-2020 were estimated.In China,the age-standardised YLL rate due to stroke and its subtypes were higher in rural areas than in urban areas.The YLL rate due to stroke showed a downward trend in both urban and rural residents from 2005 to 2020,decreased by 39.9%and 21.5%,respectively.Loss of life expectancy caused by stroke decreased from 1.75 years to 1.70 years from 2005 to 2020.During which,loss of life expectancy due to intracerebral haemorrhage(ICH)decreased from 0.94 years to 0.65 years,while that of ischaemic stroke(IS)increased from 0.62 years to 0.86 years.A slightly upward trend was observed in loss of life expectancy caused by subarachnoid haemorrhage(SAH),from 0.05 years to 0.06 years.Loss of life expectancy due to ICH and SAH was always higher in rural areas than in urban areas,whereas that of IS was higher in urban areas than in rural areas.Rural males suffered the greatest loss of life expectancy due to ICH and SAH,while the highest loss of life expectancy caused by IS was found in urban females.Furthermore,Heilongjiang(2.25 years),Tibet(2.17 years)and Jilin(2.16 years)were found to have the highest loss of life expectancy caused by stroke in 2020.Loss of life expectancy caused by ICH and SAH was higher in western China,while the disease burden of IS was heavier in northeast China.Stroke remains a major public health problem in China,although the age-standardised YLL rate and loss of life expectancy due to stroke decreased.Evidence-based strategies should be conducted to reduce the premature death burden caused by stroke and prolong life expectancy in Chinese population.展开更多
The matrix-degrading metalloproteinases （MMPs）, particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas. In the present study, the oncogenic role of MMP-9 in malignant gliom...The matrix-degrading metalloproteinases （MMPs）, particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas. In the present study, the oncogenic role of MMP-9 in malignant glioma cells was investigated via antisense RNA blockade in vitro and in vivo. TJ905 malignant glioma cells were transfected with pcDNA3.0 vector expressing antisense MMP-9 RNA （pcDNA-AS-MMP9）, which significantly decreased MMP-9 expression, and cell proliferation was assessed. For in vivo studies, U251 cells, a human malignant glioma cell line, were implanted subcutaneously into 4-to 6-week-old BALB/c nude mice. The mice bearing well-established U251 gliomas were treated with intratumoral pcDNA-AS-MMP9-Lipofectamine complex （AS-MMP-9-treated group）, subcutaneous injection of endostatin （endostatin-treated group）, or both （combined therapy group）. Mice treated with pcDNA （empty vector）-Lipofectamine served as the control group. Four or eight weeks later, the volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity were assayed. We demonstrate that pcDNA-AS-MMP9 significantly decreased MMP-9 expression and inhibited glioma cell proliferation. Volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity in the antisense-MMP-9-treated and therapeutic alliance groups were significantly lower than those in the control group. The results suggest that MMP-9 not only promotes malignant glioma cell invasiveness, but also affects tumor cell proliferation. Blocking the expression of MMP-9 with antisense RNA substantially suppresses the malignant phenotype of glioma cells, and thus can be used as an effective therapeutic strategy for malignant gliomas.展开更多
基金supported by the National Natural Science Foundation of China(81970202,81903609,U21A20339)the Natural Science Foundation of Heilongjiang Province,China(LH2022H002)+1 种基金the Outstanding Young Talent Research Fund of College of Pharmacy,Harbin Medical University(2019-JQ-02)2021(the second batch)Research Funds for affiliated research institutes in Heilongjiang Province(CZKYF2021-2-C013).
文摘Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.
基金the National Key Research and Development Program of China(2018YFC1315301).
文摘Stroke is characterised by high mortality and disability rate in China.This study aimed to explore the temporal trends in years of life lost(YLL)and loss of life expectancy due to stroke and its subtypes in urban and rural areas in China during 2005-2020.Data were obtained from China National Mortality Surveillance System.Abbreviated life and stroke-eliminated life tables were generated to calculate loss of life expectancy.The YLL and loss of life expectancy due to stroke in urban and rural areas at both national and provincial level during 2005-2020 were estimated.In China,the age-standardised YLL rate due to stroke and its subtypes were higher in rural areas than in urban areas.The YLL rate due to stroke showed a downward trend in both urban and rural residents from 2005 to 2020,decreased by 39.9%and 21.5%,respectively.Loss of life expectancy caused by stroke decreased from 1.75 years to 1.70 years from 2005 to 2020.During which,loss of life expectancy due to intracerebral haemorrhage(ICH)decreased from 0.94 years to 0.65 years,while that of ischaemic stroke(IS)increased from 0.62 years to 0.86 years.A slightly upward trend was observed in loss of life expectancy caused by subarachnoid haemorrhage(SAH),from 0.05 years to 0.06 years.Loss of life expectancy due to ICH and SAH was always higher in rural areas than in urban areas,whereas that of IS was higher in urban areas than in rural areas.Rural males suffered the greatest loss of life expectancy due to ICH and SAH,while the highest loss of life expectancy caused by IS was found in urban females.Furthermore,Heilongjiang(2.25 years),Tibet(2.17 years)and Jilin(2.16 years)were found to have the highest loss of life expectancy caused by stroke in 2020.Loss of life expectancy caused by ICH and SAH was higher in western China,while the disease burden of IS was heavier in northeast China.Stroke remains a major public health problem in China,although the age-standardised YLL rate and loss of life expectancy due to stroke decreased.Evidence-based strategies should be conducted to reduce the premature death burden caused by stroke and prolong life expectancy in Chinese population.
基金supported by the National Natural Science Foundation of China(30770827,31170864and81100887)National Basic Research Development Program of China(973Program,2010CB529405)+5 种基金Key Laboratory Project of Tianjin Municipality for Science and Technology(10SYSYJC28800)Major Program of Research on Applied Fundamentals and Frontier Technologies(10JCZDJC19400)Key Program of Higher Education of Tianjin Municipality for Science and Technology(2004ZD06,20060202)Program for New Century Excellent Talents in University of China(NCET-11-1067)Key Project of Natural Science Foundation of Tianjin Municipality,China(12JCZDJC24200)Key Project for Science and Technology of Ministry of Education,China(212005)
文摘The matrix-degrading metalloproteinases （MMPs）, particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas. In the present study, the oncogenic role of MMP-9 in malignant glioma cells was investigated via antisense RNA blockade in vitro and in vivo. TJ905 malignant glioma cells were transfected with pcDNA3.0 vector expressing antisense MMP-9 RNA （pcDNA-AS-MMP9）, which significantly decreased MMP-9 expression, and cell proliferation was assessed. For in vivo studies, U251 cells, a human malignant glioma cell line, were implanted subcutaneously into 4-to 6-week-old BALB/c nude mice. The mice bearing well-established U251 gliomas were treated with intratumoral pcDNA-AS-MMP9-Lipofectamine complex （AS-MMP-9-treated group）, subcutaneous injection of endostatin （endostatin-treated group）, or both （combined therapy group）. Mice treated with pcDNA （empty vector）-Lipofectamine served as the control group. Four or eight weeks later, the volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity were assayed. We demonstrate that pcDNA-AS-MMP9 significantly decreased MMP-9 expression and inhibited glioma cell proliferation. Volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity in the antisense-MMP-9-treated and therapeutic alliance groups were significantly lower than those in the control group. The results suggest that MMP-9 not only promotes malignant glioma cell invasiveness, but also affects tumor cell proliferation. Blocking the expression of MMP-9 with antisense RNA substantially suppresses the malignant phenotype of glioma cells, and thus can be used as an effective therapeutic strategy for malignant gliomas.
