Variants of the arachidonate 5-1ipoxygenase-activating protein （ALOX5AP） gene have been suggested to play an important role in the pathogenesis of atherosclerosis and ischemic stroke. This study was aimed to explore...Variants of the arachidonate 5-1ipoxygenase-activating protein （ALOX5AP） gene have been suggested to play an important role in the pathogenesis of atherosclerosis and ischemic stroke. This study was aimed to explore the association of ALOX5AP variants with ischemic stroke risk in Han Chinese of eastern China. A total of 690 ischemic stroke cases and 767 controls were recruited. The subjects were further subtyped according to the Trial of Org 10172 in Acute Stroke Treatment （TOAST） criteria. On the basis of that, two polymorphisms of the ALOX5AP gene （rs10507391 and rs12429692） were determined by TaqMan genotyping assay. In addition, plasma leukotriene B4 （LTB4） levels were analyzed in these subjects. There was no evidence of association between the two variants of ALOX5AP and the risk of ischemic stroke or its TOAST-subtypes. Haplotype analysis and stratification analysis according to sex, age, body mass index, hypertension, and diabetes also showed negative association. Analysis of LTB4 levels in a subset of cases and controls revealed that LTB4 levels were significantly higher in ischemic stroke cases than in the controls （70.06± 14.75 ng/L vs 57.34±10.93 ng/L; P = 0.000） and carriers of the T allele of the rs10507391 variant were associated with higher plasma LTB4 levels （P = 0.000）. The present study suggests there is no association of the two polymorphisms in the ALOX5AP gene with ischemic stroke risk in Han Chinese of eastern China.展开更多
BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have bee...BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.展开更多
Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the int...Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function(LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia(FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.展开更多
Background: Global Covid-19 pandemic has led to remarkable scientific achievements resulting in the development and rapid implementation of vaccines towards the original wild-type SARS-CoV-2 virus. Most Covid-19 vacci...Background: Global Covid-19 pandemic has led to remarkable scientific achievements resulting in the development and rapid implementation of vaccines towards the original wild-type SARS-CoV-2 virus. Most Covid-19 vaccines are targeted to only one protein (the Spike protein) on the virus. SARS-CoV-2 that causes Covid-19 naturally undergoes multiple mutations over time. Such mutations can be inconsequential or have dire consequences. The lack of effectiveness of current vaccines towards mutated variants of Covid-19 is of major concern. The objective of this study is to describe an optimal solvent system that creates, via delipidation, a non-synthetic, host-derived or nonhost-derived modified viral particle that has its lipid envelope removed, exposing hidden undenatured proteins from within the virus, that generate a positive immunologic response when administered into a host, thereby providing a vaccine that offers strong and broad protection against the virus. Methods: Lipid removal from viruses by specific procedures renders the exposure of hidden proteins. Protection by antibodies to all of the virus’ protein types has shown to be far superior to protection by antibodies that are created by a single protein type. Results: Published studies with the Hepatitis virus, Pestivirus and HIV virus have reported the wide range of applications with this delipidation approach resulting in effectively long-term and broad protection vaccines. Conclusion: Mutations are rendering existing vaccines less effective. New approaches to obtain a more permanent vaccine that minimizes the effects of mutation are obtainable by delipidation of the viral particle and thereby creating vaccines that are more permanent with broad protection.展开更多
Glial cell line-derived neurotrophic factor(GDNF) plays a critical role in neuronal survival and function. GDNF has two major splice variants in the brain,α-pro-GDNF and β-pro-GDNF, and both isoforms have strong neu...Glial cell line-derived neurotrophic factor(GDNF) plays a critical role in neuronal survival and function. GDNF has two major splice variants in the brain,α-pro-GDNF and β-pro-GDNF, and both isoforms have strong neuroprotective effects on dopamine neurons. However, the expression of the GDNF splice variants in dopaminergic neurons in the brain remains unclear. Therefore, in this study, we investigated the mRNA and protein expression of α-and β-pro-GDNF in the mouse brain by real-time quantitative polymerase chain reaction, using splice variant-specific primers, and western blot analysis. At the mRNA level,β-pro-GDNF expression was significantly greater than that of α-pro-GDNF in the mouse brain. In contrast, at the protein level,α-pro-GDNF expression was markedly greater than that of β-pro-GDNF. To clarify the mechanism underlying this inverse relationship in mRNA and protein expression levels of the GDNF splice variants, we analyzed the expression of sorting protein-related receptor with A-type repeats(SorLA) by real-time quantitative polymerase chain reaction. At the mRNA level, SorLA was positively associated with β-pro-GDNF expression, but not with α-pro-GDNF expression. This suggests that the differential expression of α-and β-pro-GDNF in the mouse brain is related to SorLA expression. As a sorting protein, SorLA could contribute to the inverse relationship among the mRNA and protein levels of the GDNF isoforms. This study was approved by the Animal Ethics Committee of Xuzhou Medical University, China on July 14, 2016.展开更多
基金supported by a grant from the Health Bureau of Jiangsu Province (No. H201005)
文摘Variants of the arachidonate 5-1ipoxygenase-activating protein （ALOX5AP） gene have been suggested to play an important role in the pathogenesis of atherosclerosis and ischemic stroke. This study was aimed to explore the association of ALOX5AP variants with ischemic stroke risk in Han Chinese of eastern China. A total of 690 ischemic stroke cases and 767 controls were recruited. The subjects were further subtyped according to the Trial of Org 10172 in Acute Stroke Treatment （TOAST） criteria. On the basis of that, two polymorphisms of the ALOX5AP gene （rs10507391 and rs12429692） were determined by TaqMan genotyping assay. In addition, plasma leukotriene B4 （LTB4） levels were analyzed in these subjects. There was no evidence of association between the two variants of ALOX5AP and the risk of ischemic stroke or its TOAST-subtypes. Haplotype analysis and stratification analysis according to sex, age, body mass index, hypertension, and diabetes also showed negative association. Analysis of LTB4 levels in a subset of cases and controls revealed that LTB4 levels were significantly higher in ischemic stroke cases than in the controls （70.06± 14.75 ng/L vs 57.34±10.93 ng/L; P = 0.000） and carriers of the T allele of the rs10507391 variant were associated with higher plasma LTB4 levels （P = 0.000）. The present study suggests there is no association of the two polymorphisms in the ALOX5AP gene with ischemic stroke risk in Han Chinese of eastern China.
基金Supported by Sanming Project of Medicine in Shenzhen of China,No.SZSM201612074
文摘BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.
文摘Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function(LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia(FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.
文摘Background: Global Covid-19 pandemic has led to remarkable scientific achievements resulting in the development and rapid implementation of vaccines towards the original wild-type SARS-CoV-2 virus. Most Covid-19 vaccines are targeted to only one protein (the Spike protein) on the virus. SARS-CoV-2 that causes Covid-19 naturally undergoes multiple mutations over time. Such mutations can be inconsequential or have dire consequences. The lack of effectiveness of current vaccines towards mutated variants of Covid-19 is of major concern. The objective of this study is to describe an optimal solvent system that creates, via delipidation, a non-synthetic, host-derived or nonhost-derived modified viral particle that has its lipid envelope removed, exposing hidden undenatured proteins from within the virus, that generate a positive immunologic response when administered into a host, thereby providing a vaccine that offers strong and broad protection against the virus. Methods: Lipid removal from viruses by specific procedures renders the exposure of hidden proteins. Protection by antibodies to all of the virus’ protein types has shown to be far superior to protection by antibodies that are created by a single protein type. Results: Published studies with the Hepatitis virus, Pestivirus and HIV virus have reported the wide range of applications with this delipidation approach resulting in effectively long-term and broad protection vaccines. Conclusion: Mutations are rendering existing vaccines less effective. New approaches to obtain a more permanent vaccine that minimizes the effects of mutation are obtainable by delipidation of the viral particle and thereby creating vaccines that are more permanent with broad protection.
基金supported by the National Natural Science Foundation of China,No.81772688(to DSG)the Postdoctoral Science Foundation of Jiangsu Province of China,No.1202119C(to HL)
文摘Glial cell line-derived neurotrophic factor(GDNF) plays a critical role in neuronal survival and function. GDNF has two major splice variants in the brain,α-pro-GDNF and β-pro-GDNF, and both isoforms have strong neuroprotective effects on dopamine neurons. However, the expression of the GDNF splice variants in dopaminergic neurons in the brain remains unclear. Therefore, in this study, we investigated the mRNA and protein expression of α-and β-pro-GDNF in the mouse brain by real-time quantitative polymerase chain reaction, using splice variant-specific primers, and western blot analysis. At the mRNA level,β-pro-GDNF expression was significantly greater than that of α-pro-GDNF in the mouse brain. In contrast, at the protein level,α-pro-GDNF expression was markedly greater than that of β-pro-GDNF. To clarify the mechanism underlying this inverse relationship in mRNA and protein expression levels of the GDNF splice variants, we analyzed the expression of sorting protein-related receptor with A-type repeats(SorLA) by real-time quantitative polymerase chain reaction. At the mRNA level, SorLA was positively associated with β-pro-GDNF expression, but not with α-pro-GDNF expression. This suggests that the differential expression of α-and β-pro-GDNF in the mouse brain is related to SorLA expression. As a sorting protein, SorLA could contribute to the inverse relationship among the mRNA and protein levels of the GDNF isoforms. This study was approved by the Animal Ethics Committee of Xuzhou Medical University, China on July 14, 2016.
