Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of a...Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.展开更多
ffeStun6. ObjeCtif Dens cette dtude nons avons ewilue l' effet de l' insuline sur ba Proliferation cellulaire, liberationd' oxide nitrique et l' expression gdrktique de synthase d' oxide nitrique d...ffeStun6. ObjeCtif Dens cette dtude nons avons ewilue l' effet de l' insuline sur ba Proliferation cellulaire, liberationd' oxide nitrique et l' expression gdrktique de synthase d' oxide nitrique dens la cellule endotheliale aortique bovine. methIn mitogdthe est evalude per la ndthae M7T. In Production de NO dans ie alga en culture est determine per la reactionGness. In technique quantitative RT/PCR est utility pour quantifier ie niveau de sWthase d' oxide nitrique mRNA dens la cellule endotheliale aortique...展开更多
Hepatic ischemia-reperfusion injury(HIRI)is a major clinical cause of morbidity and mortality in liver surgery and transplantation.Many studies have found that nitric oxide(NO)plays an important role in the HIRI and i...Hepatic ischemia-reperfusion injury(HIRI)is a major clinical cause of morbidity and mortality in liver surgery and transplantation.Many studies have found that nitric oxide(NO)plays an important role in the HIRI and its increase or decrease can affect the progression and outcome of HIRI.However,the role of NO in HIRI is controversial and complicated.NO derived by endothelial NO synthase(eNOS)shows a protective role in HIRI,while excessive NO derived by inducible NO synthase(iNOS)accelerates inflammation and increases oxidative stress,further aggravating HIRI.Nevertheless,the overexpression of eNOS may exacerbate HIRI and iNOS-derived NO in some cases reduces HIRI.Here we review the new progress in the understanding of the roles of NO during HIRI:(1)NO possesses different roles in HIRI by increasing NO bioavailability,down-regulating leukotriene C4 synthase,inhibiting the activation of the nuclear factorκB(NFκB)pathway,enhancing cell autophagy,and reducing inflammatory cytokines and reactive oxygen species(ROS).And NO has both protective and deleterious effects by regulating apoptotic factors;(2)eNOS promotes NO production and suppresses its own overexpression,exerting a hepatoprotective effect reversely.Its activation is regulated by the PI3K/Akt and KLF2/AMPK pathways;and(3)iNOS derived NO mainly has deteriorating effects on HIRI,while it may have a protective function under some conditions.Their expression should reach a balance to reduce the adverse side and make NO protective in the treatment of HIRI.Thus,it can be inferred that NO modulating drugs may be a new direction in the treatment of HIRI or may be used as an adjunct to mitigate HIRI for the purpose of protecting the liver.展开更多
With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic...With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.展开更多
Genetic polymorphism has a vital role in the pathogenesis and development of myocardial infarction(MI).Single nucleotide polymorphism at any one of the amino acid sequences can result in a diseased state.A single gene...Genetic polymorphism has a vital role in the pathogenesis and development of myocardial infarction(MI).Single nucleotide polymorphism at any one of the amino acid sequences can result in a diseased state.A single gene can exhibit genetic polymorphism at more than one position giving rise to different variants.Genetic polymorphism of angiotensinogen(AGT)M235T,AGT T174M,and angiotensin-1-converting enzyme(ACE)I/D,endothelial nitric oxide synthase(eNOS),and methylenetetrahydrofolate reductase(MTHFR)can be a risk factor for MI.However,it is important to study the prevalence of genetic polymorphisms of these genes among different populations.MI is influenced by genetic polymorphism of various genes,including AGT,ACE,eNOS,MTHFR,etc.However,the association of genetic polymorphism of these genes varies among different populations,but different ethnic groups could show contradictory results.These genes have shown a positive association with risks of MI in some populations,whereas the results have not been consistent with every ethnic group.In this article,we have summarized the genetic variations in the aforementioned genes and their association with MI.展开更多
Objective:To investigate the effects of Δ^(9)-tetrahydrocannabinol,the principal psychoactive compound of Cannabis sativa,and cannabinol,a Δ^(9)-tetrahydrocannabinol degradative product,on human non-small cell lung ...Objective:To investigate the effects of Δ^(9)-tetrahydrocannabinol,the principal psychoactive compound of Cannabis sativa,and cannabinol,a Δ^(9)-tetrahydrocannabinol degradative product,on human non-small cell lung cancer cells.Methods:Δ^(9)-Tetrahydrocannabinol and cannabinol were tested for anticancer activity in human non-small cell lung cancer(A549)cells.The effects on cell proliferation,apoptosis,and phosphorylation profiles were examined.The effects of Δ^(9)-tetrahydrocannabinol and cannabinol on tumor growth were also investigated using a xenograft nude mouse model.Apoptosis and targeted phosphorylation were verified by immunohistochemistry.Results:Δ^(9)-Tetrahydrocannabinol and cannabinol significantly inhibited cell proliferation and increased the number of apoptotic cells in a concentration-dependent manner.The Δ^(9)-tetrahydrocannabinol-and cannabinol-treated cells had lower levels of phosphorylated protein kinase B[AKT(S473)],glycogen synthase kinase 3 alpha/beta,and endothelial nitric oxide synthase compared to the controls.The study of xenograft mice revealed that tumors treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly smaller than those of the control mice.The tumor progression rates in mice treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly slower than in the control group.Conclusions:These findings indicate that Δ^(9)-tetrahydrocannabinol and cannabinol inhibit lung cancer cell growth by inhibiting AKT and its signaling pathways,which include glycogen synthase kinase 3 alpha/beta and endothelial nitric oxide synthase.展开更多
Objective:To investigate the frequency of-786T>C variant in endothelial nitric oxide synthase(eNOS)gene promoter in Iranian women with recurrent pregnancy loss.Methods:Blood samples were obtained from 100 unrelated...Objective:To investigate the frequency of-786T>C variant in endothelial nitric oxide synthase(eNOS)gene promoter in Iranian women with recurrent pregnancy loss.Methods:Blood samples were obtained from 100 unrelated women affected by recurrent pregnancy loss and 100 unaffected women as the controls.Genomic DNA was extracted and-786T>C polymorphism in eNOS gene promoter was investigated by PCR-RFLP method.Statistical analyses and Hardy-Weinberg equilibrium in the groups of patients and controls were performed by Chi-square test and SPSS standard software(Version 21).Results:The frequency of homozygous TT was 40%in cases and 46%in the control group;the frequency of CC was 7%in cases and 5%in the control group;frequency heterozygote TC was 53%in cases and 49%in the control group.Genotype frequencies between the two groups showed no significant differences(P>0.05).Conclusions:The-786T>C polymorphism is not more frequent in recurrent pregnancy loss in this population.展开更多
Background:Reversibility of pulmonary hypertension(PH)is closely related to the treatment options for and prognosis of children with congenital heart disease.Objective:We combined patient-specific clinical features in...Background:Reversibility of pulmonary hypertension(PH)is closely related to the treatment options for and prognosis of children with congenital heart disease.Objective:We combined patient-specific clinical features including diagnosis,age and echocardiographic results,and biomarkers of pulmonary vascular dysfunction to explore the noninvasive methods that can be used to accurately evaluate the reversibility of pulmonary hypertension in congenital heart disease(PH-CHD).Methods:Based on the preoperative systolic pulmonary arterial pressure(sPAP),70 CHD patients were divided into normal,PH-CHD suspected,and confirmed groups.Additionally,biomarkers of circulating endothelial cells(CECs),endothelin-1(ET-1),and endothelial nitric oxide synthase(eNOS)were detected.Patients were categorized into reversible(RPH)and irreversible(IRPH)groups according to the sPAP 6 months after surgery.Risk stratification was performed according to the clinical features and biomarkers.Results:CECs and ET-1 levels in the confirmed group were significantly higher.eNOS was higher in the confirmed and suspected groups than that in the normal group.CECs in the IRPH group were significantly higher compared to the RPH group.No such intergroup differences were observed with respect to ET-1 and eNOS levels.The ROC curve showed that the risk stratification was of high diagnostic value to evaluate reversibility.Conclusion:The CECs,eNOS,and ET-1 were closely related with PH-CHD.CECs and risk stratification have high practical value in assessing the reversibility of PH-CHD.展开更多
Several mechanisms may explain how exercise training mechanistically confers protection against coronavirus disease 2019(COVID-19).Here we propose two new perspectives through which cardiorespiratory fitness may prote...Several mechanisms may explain how exercise training mechanistically confers protection against coronavirus disease 2019(COVID-19).Here we propose two new perspectives through which cardiorespiratory fitness may protect against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2).Physical exercise-activated adenosine monophosphate(AMP)-activated protein kinase(AMPK)signaling induces endothelial nitric oxide(NO)synthase(eNOS),increases NO bio-availability,and inhibits palmitoylation,leading to specific and immediate SARS-CoV-2 protection.AMPK signaling also induces angiotensin 1-7 release and enhances eNOS activation thus further mediating cardio-and renoprotection.Irisin,a myokine released from skeletal muscles during aerobic exercise,also participates in the AMPK/Akt-eNOS/NO pathway,protects mitochondrial functions in endothelial cells,and antagonizes renin angiotensin system proinflammatory action leading to reductions in genes associated with severe COVID-19 outcomes.Collectively,all the above findings point to the fact that increased AMPK and irisin activity through exercise training greatly benefits molecular processes that mediate specific,immediate,and delayed SARS-CoV-2 protection.Maintaining regular physical activity levels is a safe and affordable lifestyle strategy against the current and future pandemics and may also mitigate against obesity and cardiometabolic disease syndemics.Move more because a moving target is harder to kill.展开更多
We previously demonstrated that normal high-density lipoprotein(nHDL)can promote angiogenesis,whereas HDL from patients with coronary artery disease(d HDL)is dysfunctional and impairs angiogenesis.Autophagy plays a cr...We previously demonstrated that normal high-density lipoprotein(nHDL)can promote angiogenesis,whereas HDL from patients with coronary artery disease(d HDL)is dysfunctional and impairs angiogenesis.Autophagy plays a critical role in angiogenesis,and HDL regulates autophagy.However,it is unclear whether n HDL and d HDL regulate angiogenesis by affecting autophagy.Endothelial cells(ECs)were treated with n HDL and d HDL with or without an autophagy inhibitor.Autophagy,endothelial nitric oxide synthase(e NOS)expression,miRNA expression,nitric oxide(NO)production,superoxide anion(O2^(·-))generation,EC migration,and tube formation were evaluated.n HDL suppressed the expression of miR-181a-5p,which promotes autophagy and the expression of e NOS,resulting in NO production and the inhibition of O2^(·-)generation,and ultimately increasing in EC migration and tube formation.d HDL showed opposite effects compared to n HDL and ultimately inhibited EC migration and tube formation.We found that autophagy-related protein 5(ATG5)was a direct target of miR-181a-5p.ATG5 silencing or miR-181a-5p mimic inhibited n HDL-induced autophagy,e NOS expression,NO production,EC migration,tube formation,and enhanced O2^(·-)generation,whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of d HDL.ATG5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null(LDLr^(-/-))mice when compared to C57BL/6 mice.ATG5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr^(-/-)mice.Taken together,nHDL was able to stimulate autophagy by suppressing miR-181a-5p,subsequently increasing e NOS expression,which generated NO and promoted angiogenesis.In contrast,d HDL inhibited angiogenesis,at least partially,by increasing miR-181a-5p expression,which decreased autophagy and e NOS expression,resulting in a decrease in NO production and an increase in O2^(·-)generation.Our findings reveal a novel mechanism by which HDL affects angiogenesis by regulating autophagy and provide a therapeutic target for d HDL-impaired angiogenesis.展开更多
The objective of this study was to investigate the effects of resistin on insulin signaling in human umbilical vein endothelial cells(HUVECs).HUVECs were incubated with recombinant human resistin(0–100 ng/mL)for 24 h...The objective of this study was to investigate the effects of resistin on insulin signaling in human umbilical vein endothelial cells(HUVECs).HUVECs were incubated with recombinant human resistin(0–100 ng/mL)for 24 h.Akt and endothelial nitric oxide synthase(eNOS)phosphorylation levels of endothelial cells under basal or insulin stimulated conditions were measured by Western blot.Nitric oxide(NO)production of HUVECs was also detected.The results showed that resistin could significantly inhibit Akt and eNOS phos-phorylation and NO production in endothelial cells under insulin stimulated conditions(P<0.05 vs control).But under basal conditions,treatment with resistin could result in a decrease in eNOS phosphorylation(P<0.05 vs control)but had no effect on NO production and Akt phosphorylation levels.Thesefindings suggested that resistin exerted an inhibitory effect on NO production by inhibiting insulin signaling and eNOS phosphorylation in endothelial cells.展开更多
Mesenchymal stem cells(MSCs)secrete various cytokines with angiogenic and neuroprotective effects.This study aimed to assess the effects of human umbilical cord Wharton’s jelly-derived MSCs(hWJ-MSCs)on diabetes-relat...Mesenchymal stem cells(MSCs)secrete various cytokines with angiogenic and neuroprotective effects.This study aimed to assess the effects of human umbilical cord Wharton’s jelly-derived MSCs(hWJ-MSCs)on diabetes-related intracavernosal pressure(ICP)impairment in rats.hWJ-MSCs were isolated from human umbilical cord Wharton’s jelly and transplanted into the corpus cavernosum of streptozotocin(STZ)-induced diabetic rats by unilateral injection.The erectile function was evaluated at 4 weeks,as well as the expression levels of vascular endothelial growth factor(VEGF),basic fibroblast growth factor(bFGF),endothelial nitric oxide synthase(eNOS),and insulin-like growth factor 1(IGF1).STZ-induced diabetic rats showed impaired ICP,which was significantly improved by hWJ-MSC treatment.VEGF,eNOS,IGF1,and bFGF expression levels were higher in hWJ-MSC injection sites than those in control ones in STZ-induced diabetic rats.These results suggest that hWJ-MSC transplantation might improve diabetic erectile dysfunction through increased production of paracrine growth factors,highlighting a novel potential therapeutic option for erectile dysfunction.展开更多
Sickle cell disease has been shown to demonstrate extensive variability in disease severity among and between individuals,the variability highlighted by differing genetic haplotypes.Despite the abundance of reports of...Sickle cell disease has been shown to demonstrate extensive variability in disease severity among and between individuals,the variability highlighted by differing genetic haplotypes.Despite the abundance of reports of functional significance due to polymorphisms of endothelial nitric oxide synthase(eNOS)and endothelin-1(ET-1)genes,the role of these polymorphisms in mediating sickle cell disease pathophysiology among African Americans is presently unclear.To deconvolute their potential significance among African Americans with sickle cell disease,we examined the genetic diversity and haplotype frequency of eNOS and ET-1 polymorphisms in disease(n Z 331)and control(n Z 379)groups,with a polymerase echain reaction restriction fragment length polymorphism assay.We report that genotypic and allelic frequencies of eNOS variants are not significantly different between groups.eNOS homozygote mutants,which had been shown to have clinical significance elsewhere,showed no statistical significance in our study.On the other hand,and contrary to previous report among Africans with sickle cell disease,the endothelin-1 homozygous mutant variant showed significant difference in genotypic(p Z 2.84E-12)and allelic frequencies(p Z 2.20E-16)between groups.The most common haplotype is the combination of T786C homozygote wildtype variant with homozygote mutant variants of G5665T(ET-1)and Glu298Asp(eNOS).These results show that endothelin-1(rs5370)polymorphism,rather than endothelial nitric oxide synthase polymorphism might play a significant role in disease severity or individual clinical outcomes among African Americans with sickle cell disease.This would have profound implications for designing and/or advancing personalized care for sickle cell patients and relieving disease complications.展开更多
基金supported by the Natural Nature Science Foundation of China,Nos.82030071,81874004the Science and Technology Major Project of Changsha,No.kh2103008(all to JZH).
文摘Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.
文摘ffeStun6. ObjeCtif Dens cette dtude nons avons ewilue l' effet de l' insuline sur ba Proliferation cellulaire, liberationd' oxide nitrique et l' expression gdrktique de synthase d' oxide nitrique dens la cellule endotheliale aortique bovine. methIn mitogdthe est evalude per la ndthae M7T. In Production de NO dans ie alga en culture est determine per la reactionGness. In technique quantitative RT/PCR est utility pour quantifier ie niveau de sWthase d' oxide nitrique mRNA dens la cellule endotheliale aortique...
文摘Hepatic ischemia-reperfusion injury(HIRI)is a major clinical cause of morbidity and mortality in liver surgery and transplantation.Many studies have found that nitric oxide(NO)plays an important role in the HIRI and its increase or decrease can affect the progression and outcome of HIRI.However,the role of NO in HIRI is controversial and complicated.NO derived by endothelial NO synthase(eNOS)shows a protective role in HIRI,while excessive NO derived by inducible NO synthase(iNOS)accelerates inflammation and increases oxidative stress,further aggravating HIRI.Nevertheless,the overexpression of eNOS may exacerbate HIRI and iNOS-derived NO in some cases reduces HIRI.Here we review the new progress in the understanding of the roles of NO during HIRI:(1)NO possesses different roles in HIRI by increasing NO bioavailability,down-regulating leukotriene C4 synthase,inhibiting the activation of the nuclear factorκB(NFκB)pathway,enhancing cell autophagy,and reducing inflammatory cytokines and reactive oxygen species(ROS).And NO has both protective and deleterious effects by regulating apoptotic factors;(2)eNOS promotes NO production and suppresses its own overexpression,exerting a hepatoprotective effect reversely.Its activation is regulated by the PI3K/Akt and KLF2/AMPK pathways;and(3)iNOS derived NO mainly has deteriorating effects on HIRI,while it may have a protective function under some conditions.Their expression should reach a balance to reduce the adverse side and make NO protective in the treatment of HIRI.Thus,it can be inferred that NO modulating drugs may be a new direction in the treatment of HIRI or may be used as an adjunct to mitigate HIRI for the purpose of protecting the liver.
基金supported by the National Key R&D Program of China,No.2019YFE0121200(to LQZ)the National Natural Science Foundation of China,Nos.82325017(to LQZ),82030032(to LQZ),82261138555(to DL)+2 种基金the Natural Science Foundation of Hubei Province,No.2022CFA004(to LQZ)the Natural Science Foundation of Jiangxi Province,No.20224BAB206040(to XZ)Research Project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province,No.RZYB202201(to XZ).
文摘With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.
基金the support of the Research Center for Advanced Materials Science(RCAMS)at King Khalid University Abha,Saudi Arabia,through Grant(KKU/RCAMS/22).
文摘Genetic polymorphism has a vital role in the pathogenesis and development of myocardial infarction(MI).Single nucleotide polymorphism at any one of the amino acid sequences can result in a diseased state.A single gene can exhibit genetic polymorphism at more than one position giving rise to different variants.Genetic polymorphism of angiotensinogen(AGT)M235T,AGT T174M,and angiotensin-1-converting enzyme(ACE)I/D,endothelial nitric oxide synthase(eNOS),and methylenetetrahydrofolate reductase(MTHFR)can be a risk factor for MI.However,it is important to study the prevalence of genetic polymorphisms of these genes among different populations.MI is influenced by genetic polymorphism of various genes,including AGT,ACE,eNOS,MTHFR,etc.However,the association of genetic polymorphism of these genes varies among different populations,but different ethnic groups could show contradictory results.These genes have shown a positive association with risks of MI in some populations,whereas the results have not been consistent with every ethnic group.In this article,we have summarized the genetic variations in the aforementioned genes and their association with MI.
基金the Research Institute,Rangsit University(grant number 103/2561,2018)and by the College of Pharmacy,Rangsit University.
文摘Objective:To investigate the effects of Δ^(9)-tetrahydrocannabinol,the principal psychoactive compound of Cannabis sativa,and cannabinol,a Δ^(9)-tetrahydrocannabinol degradative product,on human non-small cell lung cancer cells.Methods:Δ^(9)-Tetrahydrocannabinol and cannabinol were tested for anticancer activity in human non-small cell lung cancer(A549)cells.The effects on cell proliferation,apoptosis,and phosphorylation profiles were examined.The effects of Δ^(9)-tetrahydrocannabinol and cannabinol on tumor growth were also investigated using a xenograft nude mouse model.Apoptosis and targeted phosphorylation were verified by immunohistochemistry.Results:Δ^(9)-Tetrahydrocannabinol and cannabinol significantly inhibited cell proliferation and increased the number of apoptotic cells in a concentration-dependent manner.The Δ^(9)-tetrahydrocannabinol-and cannabinol-treated cells had lower levels of phosphorylated protein kinase B[AKT(S473)],glycogen synthase kinase 3 alpha/beta,and endothelial nitric oxide synthase compared to the controls.The study of xenograft mice revealed that tumors treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly smaller than those of the control mice.The tumor progression rates in mice treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly slower than in the control group.Conclusions:These findings indicate that Δ^(9)-tetrahydrocannabinol and cannabinol inhibit lung cancer cell growth by inhibiting AKT and its signaling pathways,which include glycogen synthase kinase 3 alpha/beta and endothelial nitric oxide synthase.
文摘Objective:To investigate the frequency of-786T>C variant in endothelial nitric oxide synthase(eNOS)gene promoter in Iranian women with recurrent pregnancy loss.Methods:Blood samples were obtained from 100 unrelated women affected by recurrent pregnancy loss and 100 unaffected women as the controls.Genomic DNA was extracted and-786T>C polymorphism in eNOS gene promoter was investigated by PCR-RFLP method.Statistical analyses and Hardy-Weinberg equilibrium in the groups of patients and controls were performed by Chi-square test and SPSS standard software(Version 21).Results:The frequency of homozygous TT was 40%in cases and 46%in the control group;the frequency of CC was 7%in cases and 5%in the control group;frequency heterozygote TC was 53%in cases and 49%in the control group.Genotype frequencies between the two groups showed no significant differences(P>0.05).Conclusions:The-786T>C polymorphism is not more frequent in recurrent pregnancy loss in this population.
基金We thank the support of National Nature Science Foundation of China(81771934)Shanghai Jiao Tong University Medical and Engineering Intersection Fund(YG2019ZDA03).
文摘Background:Reversibility of pulmonary hypertension(PH)is closely related to the treatment options for and prognosis of children with congenital heart disease.Objective:We combined patient-specific clinical features including diagnosis,age and echocardiographic results,and biomarkers of pulmonary vascular dysfunction to explore the noninvasive methods that can be used to accurately evaluate the reversibility of pulmonary hypertension in congenital heart disease(PH-CHD).Methods:Based on the preoperative systolic pulmonary arterial pressure(sPAP),70 CHD patients were divided into normal,PH-CHD suspected,and confirmed groups.Additionally,biomarkers of circulating endothelial cells(CECs),endothelin-1(ET-1),and endothelial nitric oxide synthase(eNOS)were detected.Patients were categorized into reversible(RPH)and irreversible(IRPH)groups according to the sPAP 6 months after surgery.Risk stratification was performed according to the clinical features and biomarkers.Results:CECs and ET-1 levels in the confirmed group were significantly higher.eNOS was higher in the confirmed and suspected groups than that in the normal group.CECs in the IRPH group were significantly higher compared to the RPH group.No such intergroup differences were observed with respect to ET-1 and eNOS levels.The ROC curve showed that the risk stratification was of high diagnostic value to evaluate reversibility.Conclusion:The CECs,eNOS,and ET-1 were closely related with PH-CHD.CECs and risk stratification have high practical value in assessing the reversibility of PH-CHD.
文摘Several mechanisms may explain how exercise training mechanistically confers protection against coronavirus disease 2019(COVID-19).Here we propose two new perspectives through which cardiorespiratory fitness may protect against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2).Physical exercise-activated adenosine monophosphate(AMP)-activated protein kinase(AMPK)signaling induces endothelial nitric oxide(NO)synthase(eNOS),increases NO bio-availability,and inhibits palmitoylation,leading to specific and immediate SARS-CoV-2 protection.AMPK signaling also induces angiotensin 1-7 release and enhances eNOS activation thus further mediating cardio-and renoprotection.Irisin,a myokine released from skeletal muscles during aerobic exercise,also participates in the AMPK/Akt-eNOS/NO pathway,protects mitochondrial functions in endothelial cells,and antagonizes renin angiotensin system proinflammatory action leading to reductions in genes associated with severe COVID-19 outcomes.Collectively,all the above findings point to the fact that increased AMPK and irisin activity through exercise training greatly benefits molecular processes that mediate specific,immediate,and delayed SARS-CoV-2 protection.Maintaining regular physical activity levels is a safe and affordable lifestyle strategy against the current and future pandemics and may also mitigate against obesity and cardiometabolic disease syndemics.Move more because a moving target is harder to kill.
基金supported by the National Natural Science Foundation of China(81830013,82100424,92268202,81970363)the National Key Research and Development Program of China(2021YFA0805100)+4 种基金Guangdong Basic and Applied Basic Research Foundation(2019B1515120092)Science and Technology Planning Project of GuangzhouChina(202103000016)the Sun Yat-sen University Clinical Research 5010 Program(2014002)Program of National Key Clinical Specialties。
文摘We previously demonstrated that normal high-density lipoprotein(nHDL)can promote angiogenesis,whereas HDL from patients with coronary artery disease(d HDL)is dysfunctional and impairs angiogenesis.Autophagy plays a critical role in angiogenesis,and HDL regulates autophagy.However,it is unclear whether n HDL and d HDL regulate angiogenesis by affecting autophagy.Endothelial cells(ECs)were treated with n HDL and d HDL with or without an autophagy inhibitor.Autophagy,endothelial nitric oxide synthase(e NOS)expression,miRNA expression,nitric oxide(NO)production,superoxide anion(O2^(·-))generation,EC migration,and tube formation were evaluated.n HDL suppressed the expression of miR-181a-5p,which promotes autophagy and the expression of e NOS,resulting in NO production and the inhibition of O2^(·-)generation,and ultimately increasing in EC migration and tube formation.d HDL showed opposite effects compared to n HDL and ultimately inhibited EC migration and tube formation.We found that autophagy-related protein 5(ATG5)was a direct target of miR-181a-5p.ATG5 silencing or miR-181a-5p mimic inhibited n HDL-induced autophagy,e NOS expression,NO production,EC migration,tube formation,and enhanced O2^(·-)generation,whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of d HDL.ATG5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null(LDLr^(-/-))mice when compared to C57BL/6 mice.ATG5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr^(-/-)mice.Taken together,nHDL was able to stimulate autophagy by suppressing miR-181a-5p,subsequently increasing e NOS expression,which generated NO and promoted angiogenesis.In contrast,d HDL inhibited angiogenesis,at least partially,by increasing miR-181a-5p expression,which decreased autophagy and e NOS expression,resulting in a decrease in NO production and an increase in O2^(·-)generation.Our findings reveal a novel mechanism by which HDL affects angiogenesis by regulating autophagy and provide a therapeutic target for d HDL-impaired angiogenesis.
基金supported by the National Natural Science Foundation of China(Grant No.30570886).
文摘The objective of this study was to investigate the effects of resistin on insulin signaling in human umbilical vein endothelial cells(HUVECs).HUVECs were incubated with recombinant human resistin(0–100 ng/mL)for 24 h.Akt and endothelial nitric oxide synthase(eNOS)phosphorylation levels of endothelial cells under basal or insulin stimulated conditions were measured by Western blot.Nitric oxide(NO)production of HUVECs was also detected.The results showed that resistin could significantly inhibit Akt and eNOS phos-phorylation and NO production in endothelial cells under insulin stimulated conditions(P<0.05 vs control).But under basal conditions,treatment with resistin could result in a decrease in eNOS phosphorylation(P<0.05 vs control)but had no effect on NO production and Akt phosphorylation levels.Thesefindings suggested that resistin exerted an inhibitory effect on NO production by inhibiting insulin signaling and eNOS phosphorylation in endothelial cells.
基金This study was supported by the National Natural Science Foundation of China(No.81400683).
文摘Mesenchymal stem cells(MSCs)secrete various cytokines with angiogenic and neuroprotective effects.This study aimed to assess the effects of human umbilical cord Wharton’s jelly-derived MSCs(hWJ-MSCs)on diabetes-related intracavernosal pressure(ICP)impairment in rats.hWJ-MSCs were isolated from human umbilical cord Wharton’s jelly and transplanted into the corpus cavernosum of streptozotocin(STZ)-induced diabetic rats by unilateral injection.The erectile function was evaluated at 4 weeks,as well as the expression levels of vascular endothelial growth factor(VEGF),basic fibroblast growth factor(bFGF),endothelial nitric oxide synthase(eNOS),and insulin-like growth factor 1(IGF1).STZ-induced diabetic rats showed impaired ICP,which was significantly improved by hWJ-MSC treatment.VEGF,eNOS,IGF1,and bFGF expression levels were higher in hWJ-MSC injection sites than those in control ones in STZ-induced diabetic rats.These results suggest that hWJ-MSC transplantation might improve diabetic erectile dysfunction through increased production of paracrine growth factors,highlighting a novel potential therapeutic option for erectile dysfunction.
基金We are grateful to Betty Pace and Joann Moulds who graciously provided us with the genomic DNA samples.We acknowledge the assistance of Yi Li,Shanxi University,China with data analysis.This project was supported by a Research Laboratory Support and Faculty Development Award,College of Health Sciences and Technology,Rochester Institute of Technology(BNT).An ABRCMS Travel Award(KGN)to present this work at the Annual Biomedical Research Conference for Minority Students,Seattle WA November 12e15,2015 is acknowledged.
文摘Sickle cell disease has been shown to demonstrate extensive variability in disease severity among and between individuals,the variability highlighted by differing genetic haplotypes.Despite the abundance of reports of functional significance due to polymorphisms of endothelial nitric oxide synthase(eNOS)and endothelin-1(ET-1)genes,the role of these polymorphisms in mediating sickle cell disease pathophysiology among African Americans is presently unclear.To deconvolute their potential significance among African Americans with sickle cell disease,we examined the genetic diversity and haplotype frequency of eNOS and ET-1 polymorphisms in disease(n Z 331)and control(n Z 379)groups,with a polymerase echain reaction restriction fragment length polymorphism assay.We report that genotypic and allelic frequencies of eNOS variants are not significantly different between groups.eNOS homozygote mutants,which had been shown to have clinical significance elsewhere,showed no statistical significance in our study.On the other hand,and contrary to previous report among Africans with sickle cell disease,the endothelin-1 homozygous mutant variant showed significant difference in genotypic(p Z 2.84E-12)and allelic frequencies(p Z 2.20E-16)between groups.The most common haplotype is the combination of T786C homozygote wildtype variant with homozygote mutant variants of G5665T(ET-1)and Glu298Asp(eNOS).These results show that endothelin-1(rs5370)polymorphism,rather than endothelial nitric oxide synthase polymorphism might play a significant role in disease severity or individual clinical outcomes among African Americans with sickle cell disease.This would have profound implications for designing and/or advancing personalized care for sickle cell patients and relieving disease complications.
