Objective:To determine the active components of Eupolyphaga sinensis Walker(Tu Bie Chong)and explore the mechanisms underlying its fracture-healing ability.Methods: A modified Einhorn method was used to develop a rat ...Objective:To determine the active components of Eupolyphaga sinensis Walker(Tu Bie Chong)and explore the mechanisms underlying its fracture-healing ability.Methods: A modified Einhorn method was used to develop a rat tibial fracture model.Progression of bone healing was assessed using radiological methods.Safranin O/fast green and CD31 immunohistochemical staining were performed to evaluate the growth of bone cells and angiogenesis at the fracture site.Methylthiazoletetrazolium blue and wound healing assays were used to analyze cell viability and migration.The Transwell assay was used to explore the invasion capacity of the cells.Tubule formation assays were used to assess the angiogenesis capacity of human vascular endothelial cells(HUVECs).qRT-PCR was used to evaluate the changes in gene transcription levels.Results: Tu Bie Chong fraction 3(TF3)significantly shortened the fracture healing time in model rats.X-ray results showed that on day 14,fracture healing in the TF3 treatment group was significantly better than that in the control group(P=.0086).Tissue staining showed that cartilage growth and the number of H-shaped blood vessels at the fracture site of the TF3 treatment group were better than those of the control group.In vitro,TF3 significantly promoted the proliferation and wound healing of MC3T3-E1s and HUVECs(all P<.01).Transwell assays showed that TF3 promoted the migration of HUVECs,but inhibited the migration of MC3T3-E1 cells.Tubule formation experiments confirmed that TF3 markedly promoted the ability of vascular endothelial cells to form microtubules.Gene expression analysis revealed that TF3 significantly promoted the expression of VEGFA,SPOCD1,NGF,and NGFR in HUVECs.In MC3T3-E1 cells,the transcript levels of RUNX2 and COL2A1 were significantly elevated following TF3 treatment.Conclusion: TF3 promotes fracture healing by promoting bone regeneration associated with the RUNX2 pathway and angiogenesis associated with the VEGFA pathway.展开更多
Although the endothelium has a number of important functions, the term endothelial dysfunction is commonly used to describe impairment in its vasodilatory capacity. There have been numerous studies evaluating the rela...Although the endothelium has a number of important functions, the term endothelial dysfunction is commonly used to describe impairment in its vasodilatory capacity. There have been numerous studies evaluating the relationship between endothelial dysfunction and cardiovascular disease, however assessment of endothelial function is perhaps still primarily thought of as a research tool and has not reached widespread clinical acceptance. In this review we explore the relationship between endothelial dysfunction and cardiovascular disease, its prognostic significance, methods of pharmacological reversal of endothelial dysfunction, and ask the question, is reversal of endothelial dysfunction still an attractive target in modern cardiology?展开更多
Hypertension is a multifactorial condition which makes the development of treatment approaches difficult. The vast majority of patients are treated with lifestyle measures either alone or in combination with antihyper...Hypertension is a multifactorial condition which makes the development of treatment approaches difficult. The vast majority of patients are treated with lifestyle measures either alone or in combination with antihypertensive drugs, and this approach is largely successful in controlling blood pressure. However, for a subgroup of patients, control of blood pressure remains resistant to this approach and therefore the development of new strategies is im- perative. The sympathetic nervous system has been known to be implicated in hypertension for many decades, and evidence from studies in the past has revealed the benefit of reducing sympathetic nerve activity in the control of blood pressure albeit with severe side effects. Recent technological advances have allowed for specific targeting of the renal sympathetic nerves by catheter ablation. The Symplicity HTN-1 and HTN-2 trials have provided strong evidence for renal denervation giving rise to considerable blood pressure reductions in treatment-resistant hyper- tensives and, due to the high incidence of hypertension worldwide, this carries the promise of further reducing the global burden of hypertension and its attendant complications. Here we review the evidence for renal denervation in the management of hypertension.展开更多
Circadian rhythm protects neurons：Although the master clock entrains the whole body rhythm,peripheral tissues also express core clock transcription factors Clock and Bmal1,which regulate expression of clock genes inc...Circadian rhythm protects neurons：Although the master clock entrains the whole body rhythm,peripheral tissues also express core clock transcription factors Clock and Bmal1,which regulate expression of clock genes including Period（Per）and Cryptochrome（Cry）proteins.Complexes of Per and Cry proteins repress Bmal1-and Clock-mediated transcription forming a negative feedback loop,which regulates nearly a 24 hours self-sustained rhythm including energy metabolism.展开更多
Aims: The aims of the study were to assess the degree of knowledge and adherence to the recommended safe practice for driving and the risk of road traffic accidents among people with diabetes mellitus in Armenia. Meth...Aims: The aims of the study were to assess the degree of knowledge and adherence to the recommended safe practice for driving and the risk of road traffic accidents among people with diabetes mellitus in Armenia. Methods: A total of 628 respondents, including 200 drivers, out of 641 consecutive attendees at six diabetes clinics, participated in the survey. A modified British questionnaire on driving and diabetes was used to obtain the relevant data. The information from all 103 drivers treated with insulin and 73 taking sulfonylureas was reviewed. Results: The study revealed that of 176 insulin and sulfonylurea-treated drivers, 161 (91.5%) had never received any advice about safe driving practices. Among the drivers, 156 (88.6%) never measured their blood glucose before, or during driving. The survey revealed that 86 (51.2%) of 168 patients had a history of at least one motor vehicle accident within the previous 5 years. The average road traffic accident rate per person/year was 0.21. Conclusions: The study revealed a lack of knowledge among drivers with diabetes treated with insulin or sulfonylureas concerning recommended safe practices for driving. This was associated with significant hypoglycemia while driving and an elevated rate of road traffic accidents.展开更多
Left sided valvular heart disease poses major impact on life and lifestyle.Medical therapy merely palliates chronic severe valve disease and once symptoms or haemodynamic sequelae appear,life expectancy is markedly tr...Left sided valvular heart disease poses major impact on life and lifestyle.Medical therapy merely palliates chronic severe valve disease and once symptoms or haemodynamic sequelae appear,life expectancy is markedly truncated.In this article,we review the mechanisms of valve pathology,latest evidence in the quest for pharmacological options,means by which to predict deterioration,and standard and novel treatment options.展开更多
Background Heme-oxygenase 1 （HO-1） is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide （CO） and may have significant anti-inflammatory function. The HO-1 gene promoter r...Background Heme-oxygenase 1 （HO-1） is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide （CO） and may have significant anti-inflammatory function. The HO-1 gene promoter region shows microsatellite polymorphism with different （GT）n repeats, reported to differently induce gene expression, with the short allele associated with higher gene expression. We measured the acute inflammatory response using coronary artery bypass surgery （CABG） as a well-characterized and uniform stimulus and examined the correlation between levels of IL-6, C-reactive protein （CRP） and fibrinogen and their relationship to HO-1 genotype. Methods Two hundred and seventy-five consecutive patients undergoing CABG were genotyped for the HO-1 promoter polymorphism using PCR and automated DNA capillary sequencer. IL-6, CRP and fibrinogen were measured at baseline and 6, 24, 48, 72, 96 and 120 hours after CABG. Results Complete IL-6, CRP and fibrinogen measures were available in 220 patients. Before surgery IL-6 levels showed a strong correlation with CRP and fibrinogen （ r = 0. 48, P 〈 0. 0001 ; r = 0. 41, P 〈 0. 0001 respectively）, with a significant correlation between CRP and fibrinogen （r=0. 61, P 〈 0. 0001 ）. All three acute phase reactants showed a significant increase after CABG. After surgery, peak IL-6 was strongly correlated with peak CRP （r=0. 34, P =0.0009） but not with peak fibrinogen （r=0. 15, P =0. 13 ）, while peak CRP and peak fibrinogen were significantly correlated （r = 0. 15, P 〈 0. 0001 ）. HO-1 allelic repeats ranged from 22- 42, with （GT）25 and （GT）32 being the two most common alleles, and subsequently divided into three groups according to previous published work： 〈 30 （GT） n were designated as S （short） , 30 - 37 （GT） n as M （middle） and long repeats with 〉 37 （GT） n as L （long） ; allele frequency 0. 35, 0. 58 and 0.07 respectively. Baseline CRP differed by genotype： those carrying at least one long allele having higher CRP than those with no long allele （3.76 ＋-0. 79 vs. 2. 07 ＋-0. 17, P =0. 013）. Conversely, those carrying at least one short allele had higher fibrinogen levels than those with no short allele （3.83 ＋-0. 79 vs. 3.51 ＋- 0. 88, P = 0. 006）. Conclusions There is a strong correlation between the measured acute phase reactants both at baseline and after the inflammatory response to CABG in patients with coronary disease. There was an association between the HO-1 microsatellite polymorphism and CRP and fibrinogen levels at baseline but there was no similar association following CABG. This may indicate that HO-1 is associated with chronic atherosclerotic inflammatory processes rather than acute.展开更多
Everincreasing ambient ozone(O3)pollution in China has been exacerbating cardiopulmonary premature deaths.However,the urban-rural exposure inequity has seldom been explored.Here,we assess populationcale 03 exposure an...Everincreasing ambient ozone(O3)pollution in China has been exacerbating cardiopulmonary premature deaths.However,the urban-rural exposure inequity has seldom been explored.Here,we assess populationcale 03 exposure and mortality burdens between 1990 and 2019 based on integrated pollution tracking and epidemiological evidence.We find Chinese population have been suffering from climbing 03 exposure by 4.3±2.8 ppb per decade as a result of rapid urbanization and growing prosperity of socioeconomic activities.Rural residents are broadly exposed to 9.8±4.1 ppb higher ambient O3 than the adjacent urban citizens,and thus urbaniza-tion-oriented migration compromises the exposure-associated mortality on total population.Cardiopulmonary excess premature deaths attributable to longterm 03 exposure,373,500(95%uncertainty interval[U]:240,600-510,900)in 2019,is underestimated in previous studies due to ignorance of cardiovascular causes.Future 03 pollution policy should focus more on rural population who are facing an aggravating threat of mortality risks to ameliorate environmental health injustice.展开更多
RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues.Injectable hydrogels are one potentially simple and dire...RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues.Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers.Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine^(■)3.0,a lipid nonviral transfection vector,for local and sustained release.PEGylation of fibrin allowed for controlled release of small interfering RNA(siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin in vitro and in vivo.A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days.Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth.Thus,the increased efficacy observed here for the combination of a lipid nanoparticle,the only type of nonviral vector approved for the clinic,with fibrin,might allow for more rapid translation of injectable hydrogel-based RNA interference.展开更多
基金supported by“the Fundamental Research Funds for the Central Universities”(2020-JYB-ZDGG-054)“Beijing university of Chinese medicine XINAO Award Fund”(2019)Beijing University of Chinese Medicine Scientific Research and Development Fund(2170072220002).
文摘Objective:To determine the active components of Eupolyphaga sinensis Walker(Tu Bie Chong)and explore the mechanisms underlying its fracture-healing ability.Methods: A modified Einhorn method was used to develop a rat tibial fracture model.Progression of bone healing was assessed using radiological methods.Safranin O/fast green and CD31 immunohistochemical staining were performed to evaluate the growth of bone cells and angiogenesis at the fracture site.Methylthiazoletetrazolium blue and wound healing assays were used to analyze cell viability and migration.The Transwell assay was used to explore the invasion capacity of the cells.Tubule formation assays were used to assess the angiogenesis capacity of human vascular endothelial cells(HUVECs).qRT-PCR was used to evaluate the changes in gene transcription levels.Results: Tu Bie Chong fraction 3(TF3)significantly shortened the fracture healing time in model rats.X-ray results showed that on day 14,fracture healing in the TF3 treatment group was significantly better than that in the control group(P=.0086).Tissue staining showed that cartilage growth and the number of H-shaped blood vessels at the fracture site of the TF3 treatment group were better than those of the control group.In vitro,TF3 significantly promoted the proliferation and wound healing of MC3T3-E1s and HUVECs(all P<.01).Transwell assays showed that TF3 promoted the migration of HUVECs,but inhibited the migration of MC3T3-E1 cells.Tubule formation experiments confirmed that TF3 markedly promoted the ability of vascular endothelial cells to form microtubules.Gene expression analysis revealed that TF3 significantly promoted the expression of VEGFA,SPOCD1,NGF,and NGFR in HUVECs.In MC3T3-E1 cells,the transcript levels of RUNX2 and COL2A1 were significantly elevated following TF3 treatment.Conclusion: TF3 promotes fracture healing by promoting bone regeneration associated with the RUNX2 pathway and angiogenesis associated with the VEGFA pathway.
文摘Although the endothelium has a number of important functions, the term endothelial dysfunction is commonly used to describe impairment in its vasodilatory capacity. There have been numerous studies evaluating the relationship between endothelial dysfunction and cardiovascular disease, however assessment of endothelial function is perhaps still primarily thought of as a research tool and has not reached widespread clinical acceptance. In this review we explore the relationship between endothelial dysfunction and cardiovascular disease, its prognostic significance, methods of pharmacological reversal of endothelial dysfunction, and ask the question, is reversal of endothelial dysfunction still an attractive target in modern cardiology?
文摘Hypertension is a multifactorial condition which makes the development of treatment approaches difficult. The vast majority of patients are treated with lifestyle measures either alone or in combination with antihypertensive drugs, and this approach is largely successful in controlling blood pressure. However, for a subgroup of patients, control of blood pressure remains resistant to this approach and therefore the development of new strategies is im- perative. The sympathetic nervous system has been known to be implicated in hypertension for many decades, and evidence from studies in the past has revealed the benefit of reducing sympathetic nerve activity in the control of blood pressure albeit with severe side effects. Recent technological advances have allowed for specific targeting of the renal sympathetic nerves by catheter ablation. The Symplicity HTN-1 and HTN-2 trials have provided strong evidence for renal denervation giving rise to considerable blood pressure reductions in treatment-resistant hyper- tensives and, due to the high incidence of hypertension worldwide, this carries the promise of further reducing the global burden of hypertension and its attendant complications. Here we review the evidence for renal denervation in the management of hypertension.
基金support of JSPS KAKENHI Grant Number 21500386 (TI)British Heart Foundation (GEM, FS/15/31298 FS/16/67/32548)
文摘Circadian rhythm protects neurons：Although the master clock entrains the whole body rhythm,peripheral tissues also express core clock transcription factors Clock and Bmal1,which regulate expression of clock genes including Period（Per）and Cryptochrome（Cry）proteins.Complexes of Per and Cry proteins repress Bmal1-and Clock-mediated transcription forming a negative feedback loop,which regulates nearly a 24 hours self-sustained rhythm including energy metabolism.
文摘Aims: The aims of the study were to assess the degree of knowledge and adherence to the recommended safe practice for driving and the risk of road traffic accidents among people with diabetes mellitus in Armenia. Methods: A total of 628 respondents, including 200 drivers, out of 641 consecutive attendees at six diabetes clinics, participated in the survey. A modified British questionnaire on driving and diabetes was used to obtain the relevant data. The information from all 103 drivers treated with insulin and 73 taking sulfonylureas was reviewed. Results: The study revealed that of 176 insulin and sulfonylurea-treated drivers, 161 (91.5%) had never received any advice about safe driving practices. Among the drivers, 156 (88.6%) never measured their blood glucose before, or during driving. The survey revealed that 86 (51.2%) of 168 patients had a history of at least one motor vehicle accident within the previous 5 years. The average road traffic accident rate per person/year was 0.21. Conclusions: The study revealed a lack of knowledge among drivers with diabetes treated with insulin or sulfonylureas concerning recommended safe practices for driving. This was associated with significant hypoglycemia while driving and an elevated rate of road traffic accidents.
文摘Left sided valvular heart disease poses major impact on life and lifestyle.Medical therapy merely palliates chronic severe valve disease and once symptoms or haemodynamic sequelae appear,life expectancy is markedly truncated.In this article,we review the mechanisms of valve pathology,latest evidence in the quest for pharmacological options,means by which to predict deterioration,and standard and novel treatment options.
文摘Background Heme-oxygenase 1 （HO-1） is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide （CO） and may have significant anti-inflammatory function. The HO-1 gene promoter region shows microsatellite polymorphism with different （GT）n repeats, reported to differently induce gene expression, with the short allele associated with higher gene expression. We measured the acute inflammatory response using coronary artery bypass surgery （CABG） as a well-characterized and uniform stimulus and examined the correlation between levels of IL-6, C-reactive protein （CRP） and fibrinogen and their relationship to HO-1 genotype. Methods Two hundred and seventy-five consecutive patients undergoing CABG were genotyped for the HO-1 promoter polymorphism using PCR and automated DNA capillary sequencer. IL-6, CRP and fibrinogen were measured at baseline and 6, 24, 48, 72, 96 and 120 hours after CABG. Results Complete IL-6, CRP and fibrinogen measures were available in 220 patients. Before surgery IL-6 levels showed a strong correlation with CRP and fibrinogen （ r = 0. 48, P 〈 0. 0001 ; r = 0. 41, P 〈 0. 0001 respectively）, with a significant correlation between CRP and fibrinogen （r=0. 61, P 〈 0. 0001 ）. All three acute phase reactants showed a significant increase after CABG. After surgery, peak IL-6 was strongly correlated with peak CRP （r=0. 34, P =0.0009） but not with peak fibrinogen （r=0. 15, P =0. 13 ）, while peak CRP and peak fibrinogen were significantly correlated （r = 0. 15, P 〈 0. 0001 ）. HO-1 allelic repeats ranged from 22- 42, with （GT）25 and （GT）32 being the two most common alleles, and subsequently divided into three groups according to previous published work： 〈 30 （GT） n were designated as S （short） , 30 - 37 （GT） n as M （middle） and long repeats with 〉 37 （GT） n as L （long） ; allele frequency 0. 35, 0. 58 and 0.07 respectively. Baseline CRP differed by genotype： those carrying at least one long allele having higher CRP than those with no long allele （3.76 ＋-0. 79 vs. 2. 07 ＋-0. 17, P =0. 013）. Conversely, those carrying at least one short allele had higher fibrinogen levels than those with no short allele （3.83 ＋-0. 79 vs. 3.51 ＋- 0. 88, P = 0. 006）. Conclusions There is a strong correlation between the measured acute phase reactants both at baseline and after the inflammatory response to CABG in patients with coronary disease. There was an association between the HO-1 microsatellite polymorphism and CRP and fibrinogen levels at baseline but there was no similar association following CABG. This may indicate that HO-1 is associated with chronic atherosclerotic inflammatory processes rather than acute.
基金UK Natural Environment Research Council(NERC)UK Na tional Centre for Atmospheric Science(NCAS),Australian Research Council(DP210102076)+8 种基金Australian National Health and Medical Research Council(APP2000581)H.Z.S andM.W.receive funding from the Engineering and Physical Sciences Research Council(EPSRC)via the UK Research and Innovation(UKRI)Centre for Doctoral Training in Application of Artificial Itelligence to the study of Environmental Risks(AI4ER,EP/S022961/1)HZ.S.also gives thanks for generous support from the US Fulbright Pro-gram.P.Y.is supported by China Scholarship Council(no.201906210065)Z.S.acknow-edges support from the UKRI NERC Cambridge Climate,Life and Earth Doctoral Training Partnership(C-CL EAR DTP,NE/S007164/1)M.M.C.is sponsored by the Croucher Founda-tion and Cambridge Commonwealth,European and Intemational Trust funding through a Croucher Cambridge Intemational ScholarshipH.L.is supported by the National NaturalSci ence Foundation of China(no.42061130213)Royal Society of the United Kingdom through the Newton Advanced Fllowship(NAF/R1/201166)A.TA.acknowledges funding from NERC(NE/P016383/1)through the Met Office UKRI Clean Air Program.Y.G.is supported by a Career Development Fellowship of the Australian Natinal Health and Med-|cal Research Council(APP1163693)Special appreciation is extended to Prof.Xiao Lu(School of Atmospheric Sciences,Sun Yat sen University)for his insightful discussion on the quality control of TOAR and CNEMC observations,and Prof.Aiyu Liu(Department of Sociology,Peking University)for her trenchant research perspectives on China's urbanization,to improve this curent interdiscilinary research.
文摘Everincreasing ambient ozone(O3)pollution in China has been exacerbating cardiopulmonary premature deaths.However,the urban-rural exposure inequity has seldom been explored.Here,we assess populationcale 03 exposure and mortality burdens between 1990 and 2019 based on integrated pollution tracking and epidemiological evidence.We find Chinese population have been suffering from climbing 03 exposure by 4.3±2.8 ppb per decade as a result of rapid urbanization and growing prosperity of socioeconomic activities.Rural residents are broadly exposed to 9.8±4.1 ppb higher ambient O3 than the adjacent urban citizens,and thus urbaniza-tion-oriented migration compromises the exposure-associated mortality on total population.Cardiopulmonary excess premature deaths attributable to longterm 03 exposure,373,500(95%uncertainty interval[U]:240,600-510,900)in 2019,is underestimated in previous studies due to ignorance of cardiovascular causes.Future 03 pollution policy should focus more on rural population who are facing an aggravating threat of mortality risks to ameliorate environmental health injustice.
基金supported by the National Research Foundation of South Africa(93550)International Centre for Genetic Engineering and Biotechnology(CRP/ZAF14-01)the South African Medical Research Council(416007).
文摘RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues.Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers.Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine^(■)3.0,a lipid nonviral transfection vector,for local and sustained release.PEGylation of fibrin allowed for controlled release of small interfering RNA(siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin in vitro and in vivo.A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days.Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth.Thus,the increased efficacy observed here for the combination of a lipid nanoparticle,the only type of nonviral vector approved for the clinic,with fibrin,might allow for more rapid translation of injectable hydrogel-based RNA interference.
基金关于作者（Contributors） ：All authors contributed to writing and revising this article, and they all approved the final manuscript. RM is the guarantor.资助（Funding） ：The National Collaborating Centre for Primary Care was commissioned and funded by the National Institute for Health and Clinical Excellence to write this summary..
