Nanoparticle-mediated drug delivery is recognized as a promising option for targeted treatment of atherosclerosis. In this paper, the Eulerian-Lagrangian technique is adopted to simulate the delivery of drug-loaded na...Nanoparticle-mediated drug delivery is recognized as a promising option for targeted treatment of atherosclerosis. In this paper, the Eulerian-Lagrangian technique is adopted to simulate the delivery of drug-loaded nanoparticles to patient-specific atherosclerotic plaque with the aid of an external magnetic field. Plaques and vascular walls are introduced as porous media formulated by the Darcy-Forchheimer model in this targeted transport process. The results demonstrate that the delivery efficiency of particles to atherosclerosis depends on the external magnetic field, such as configuration and intensity, in which the configuration angle of the current wire is a key factor and the double current wires have advantages over the single current wire. Meanwhile, the delivery efficiency gradually decreases as the distance between the plaque cap and the current wire increases. Further, although augmenting the current or magnetic susceptibility can generally improve the delivery efficiency of nanoparticles, this increase is not apparent when small-sized nanoparticles are employed as drug transport particles. The results obtained can potentially serve as the guideline to optimize regimens for the targeted therapy of atherosclerosis.展开更多
Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predic...Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.展开更多
Atherosclerosis is a severe cardiovascular disease followed by the accumulation of atherosclerotic plaques within the lumen of blood vessels resulting in reduced blood flow thus initiating a series of events.Conventio...Atherosclerosis is a severe cardiovascular disease followed by the accumulation of atherosclerotic plaques within the lumen of blood vessels resulting in reduced blood flow thus initiating a series of events.Conventional therapies for atherosclerosis encounter multiple chal-lenges,especially difficulty in precisely concentrating in certain affected regions and the potential for unwanted side effects.Consequently,scientists are focused on developing nanoformulations for atherosclerosis diagnosis and therapy.Peptide-based nanomedi-cines improve conventional therapies by offering improved structural and therapeutic stability and enabling target-specific delivery.Their inherent biocompatibility and biodegradability additionally render them desirable materials intended for in vivo use.This review manu-script aims to provide an in-depth overview of peptide-based nano-medicines for atherosclerosis,focusing on targeted cells like endothelial cells,macrophages,and monocytes and their interaction with different plaque components.Moreover,the manuscript also highlights the latest progress in multimodal techniques and provides a comprehensive overview of limitations associated with their practical implementation.展开更多
Atherosclerosis(AS)has emerged as one of the prevalent arterial vascular diseases characterized by plaque and inflammation,primarily causing disability and mortality globally.Drug therapy remains the main treatment fo...Atherosclerosis(AS)has emerged as one of the prevalent arterial vascular diseases characterized by plaque and inflammation,primarily causing disability and mortality globally.Drug therapy remains the main treatment for AS.However,a series of obstacles hinder effective drug delivery.Nature,from natural micro-/nano-structural biological particles like natural cells and extracellular vesicles to the distinctions between the normal and pathological microenvironment,offers compelling solutions for efficient drug delivery.Nature-inspired nanocarriers of synthetic stimulus-responsive materials and natural components,such as lipids,proteins and membrane structures,have emerged as promising candidates for fulfilling drug delivery needs.These nanocarriers offer several advantages,including prolonged blood circulation,targeted plaque delivery,targeted specific cells delivery and controlled drug release at the action site.In this review,we discuss the nature-inspired nanocarriers which leverage the natural properties of cells or the microenvironment to improve atherosclerotic drug therapy.Finally,we provide an overview of the challenges and opportunities of applying these innovative nature-inspired nanocarriers.展开更多
Atherosclerosis is a chronic inflammatory vascular disease and a leading cause of death worldwide.Macrophages play an important role in inflammatory responses,cell-cell communications,plaque growth and plaque rupture ...Atherosclerosis is a chronic inflammatory vascular disease and a leading cause of death worldwide.Macrophages play an important role in inflammatory responses,cell-cell communications,plaque growth and plaque rupture in atherosclerotic lesions.Here,we review the sources,functions and complex phenotypes of macrophages in the progression of atherosclerosis,and discuss the recent approaches in modulating macrophage phenotype and autophagy for atherosclerosis treatment.We then focus on the drug delivery strategies that target macrophages or use macrophage membrane-coated particles to deliver therapeutics to the lesion sites.These biomaterial-based approaches that target,modulate or engineer macrophages have broad applications for disease therapies and tissue regeneration.展开更多
Atherosclerosis(AS)is a leading cause of the life-threatening cardiovascular disease(CVD),creating an urgent need for efficient,biocompatible therapeutics for diagnosis and treatment.Biomimetic nanomedicines(b NMs)are...Atherosclerosis(AS)is a leading cause of the life-threatening cardiovascular disease(CVD),creating an urgent need for efficient,biocompatible therapeutics for diagnosis and treatment.Biomimetic nanomedicines(b NMs)are moving closer to fulfilling this need,pushing back the frontier of nano-based drug delivery systems design.This review seeks to outline how these nanomedicines(NMs)might work to diagnose and treat atherosclerosis,to trace the trajectory of their development to date and in the coming years,and to provide a foundation for further discussion about atherosclerotic theranostics.展开更多
BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease ...BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.AIM To investigate potential triggers of drug-induced colitis(DiC).METHODS We conducted a retrospective,observational case control study.Patients were assigned to DiC or one of two age-and gender-matched control groups(noninflammatory controls and inflammatory colitis of another cause)based on histopathological findings.Histopathology was reassessed in a subset of patients(28 DiC with atherosclerosis,DiC without atherosclerosis and ischaemic colitis each)for validation purposes.Medical history was collected from the electronic database and patient records.Statistical analysis included chi-squared test,t-test,logistic and multivariate regression models.RESULTS Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa(7%of all screened colonoscopic biopsy samples);a total of 633 patients were included equally matched throughout the three groups(291 males,mean age:62.1±16.1 years).In the univariate analysis,DiC was associated with diuretics,dihydropyridines,glycosides,ASS,platelet aggregation inhibitors,nonsteroidal anti-inflammatory drugs(NSAIDs),statins and fibrates,and with atherosclerosis,particularly coronary heart disease,and hyperlipoproteinaemia.Echocardiographic parameters did not show substantial differences.In the multivariate analysis only fibrates[odds ratio(OR)=9.1],NSAIDs(OR=6.7)and atherosclerosis(OR=2.1)proved to be associated with DiC.Both DiC reassessment groups presented milder inflammation than ischaemic colitis.The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.CONCLUSION Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC.Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.展开更多
Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, th...Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment response, and low toxicity, stimuli-responsive nano-based drug delivery systems(NDDSs) have been a promising approach in AS treatments. Herein, we will systematically summarize the recent advances in stimuli-responsive NDDSs for AS treatment, including internal stimuli(reactive oxygen species, enzyme, shear stress, and pH) and external stimuli(light, ultrasound, and magnetism) responsive NDDSs. Besides, we will also summarize in detail the classification of stimuli-responsive NDDSs for AS, such as organic NDDSs(e.g., lipid-based and polymer-based nanomaterials), inorganic NDDSs(e.g., metal-based nanoparticles and nonmetallic nanomaterials), and composite multifunctional NDDSs. Finally, the critical challenges and prospects of this field will also be proposed and discussed.展开更多
The key initiating process in atherogenesis is the subendothelial cholesterol retention, which is both necessary and sufficient to provoke lesion initiation. Retention of cholesterol transported by low density lipopro...The key initiating process in atherogenesis is the subendothelial cholesterol retention, which is both necessary and sufficient to provoke lesion initiation. Retention of cholesterol transported by low density lipoprotien (LDL) in subendothelial cells of arterial wall, is an absolute requirement for lesion development. This allows us to consider intracellular cholesterol retention as a novel target for anti-atherosclerotic therapy. In this case, the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review summarizes the results of our basic studies shedding light on the mechanisms of intracellular cholesterol retention. We describe our cellular models to search for anti-atherosclerotic agents and demonstrate the use of these models for the development of anti-atherosclerotic drugs. We use natural products as the basis of anti-atherosclerotic drugs because anti-atherosclerotic therapy should be long-term or even lifelong. Using cellular models and natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured subendothelial aortic cells. We have developed drugs that reduce intracellular cholesterol retention, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with Allicor or Inflaminat caused regression of carotid atherosclerosis in asymptomatic men. Karinat prevented the development of new atherosclerotic plaques in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinics. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.展开更多
Cholesterol-core nanoparticles （LDE） have been shown to be recognized by low-density lipoprotein receptors （LDLR） after administration; therefore, LDE is an ideal vehicle to deliver drug with targeting property. P...Cholesterol-core nanoparticles （LDE） have been shown to be recognized by low-density lipoprotein receptors （LDLR） after administration; therefore, LDE is an ideal vehicle to deliver drug with targeting property. Paclitaxel, when incorporated into LDE, promotes atherosclerosis regression with reduced drug toxicity in rabbits through LDLR. Here, we tested whether LDE-paclitaxel could still be effective in reducing diet-induced atherosclerosis in a mouse model without LDLR. Nineteen LDLR knockout male mice were fed 1% cholesterol for 12 weeks. Then, 12 animals received 4-weekly intraperitoneal LDE-paclitaxel （4 mg/kg） while 7 controls received saline solution. On week 12 and 16, in vivo MR/of the aortic roots was performed. Aorta macroscopy was made after euthanasia. Reduction ofatherosclerotic lesions was observed. LDE-paclitaxel treatment resulted in reduction of wall area （14%） and stenosis （22%） by MR/and 33% by macroscopy. Thus, LDE-paclitaxel may produce pharmacological effects through LDE uptake by mechanisms other than LDLR.展开更多
Accumulation of cholesterol in arterial cells, intracellular cholesterol retention, may be responsible for all major manifestations of atherosclerosis on a cellular level. Previously we have shown that intracellular c...Accumulation of cholesterol in arterial cells, intracellular cholesterol retention, may be responsible for all major manifestations of atherosclerosis on a cellular level. Previously we have shown that intracellular cholesterol retention is the principal event in the genesis of atherosclerotic lesions. This allows us to consider cellular retention of cholesterol as a novel target for anti-atherosclerotic therapy. In this case the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review describes our approach based on the use of cultured human arterial cells for the development of direct anti-atherosclerotic therapy. We use natural products as the basis of promising drugs for anti-atherosclerotic therapy. Using natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured cells. Our knowledge of the mechanisms of atherosclerosis is the foundation on which we have developed drugs that have a direct anti-atherosclerotic effect, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with allicor or inflaminat has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic men. Karinat prevents the development of carotid atherosclerosis in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinical practice. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.展开更多
基金Project supported by the National Natural Science Foundation of China(Nos.11772046 and 81870345)。
文摘Nanoparticle-mediated drug delivery is recognized as a promising option for targeted treatment of atherosclerosis. In this paper, the Eulerian-Lagrangian technique is adopted to simulate the delivery of drug-loaded nanoparticles to patient-specific atherosclerotic plaque with the aid of an external magnetic field. Plaques and vascular walls are introduced as porous media formulated by the Darcy-Forchheimer model in this targeted transport process. The results demonstrate that the delivery efficiency of particles to atherosclerosis depends on the external magnetic field, such as configuration and intensity, in which the configuration angle of the current wire is a key factor and the double current wires have advantages over the single current wire. Meanwhile, the delivery efficiency gradually decreases as the distance between the plaque cap and the current wire increases. Further, although augmenting the current or magnetic susceptibility can generally improve the delivery efficiency of nanoparticles, this increase is not apparent when small-sized nanoparticles are employed as drug transport particles. The results obtained can potentially serve as the guideline to optimize regimens for the targeted therapy of atherosclerosis.
文摘Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.
文摘Atherosclerosis is a severe cardiovascular disease followed by the accumulation of atherosclerotic plaques within the lumen of blood vessels resulting in reduced blood flow thus initiating a series of events.Conventional therapies for atherosclerosis encounter multiple chal-lenges,especially difficulty in precisely concentrating in certain affected regions and the potential for unwanted side effects.Consequently,scientists are focused on developing nanoformulations for atherosclerosis diagnosis and therapy.Peptide-based nanomedi-cines improve conventional therapies by offering improved structural and therapeutic stability and enabling target-specific delivery.Their inherent biocompatibility and biodegradability additionally render them desirable materials intended for in vivo use.This review manu-script aims to provide an in-depth overview of peptide-based nano-medicines for atherosclerosis,focusing on targeted cells like endothelial cells,macrophages,and monocytes and their interaction with different plaque components.Moreover,the manuscript also highlights the latest progress in multimodal techniques and provides a comprehensive overview of limitations associated with their practical implementation.
基金supported by the National Natural Science Foundation of China(NSFC 32071323 and 32271410)Program for Innovative Research Team in Science and Technology in Fujian Province University,Scientific Research Funds of Huaqiao University(22BS125).
文摘Atherosclerosis(AS)has emerged as one of the prevalent arterial vascular diseases characterized by plaque and inflammation,primarily causing disability and mortality globally.Drug therapy remains the main treatment for AS.However,a series of obstacles hinder effective drug delivery.Nature,from natural micro-/nano-structural biological particles like natural cells and extracellular vesicles to the distinctions between the normal and pathological microenvironment,offers compelling solutions for efficient drug delivery.Nature-inspired nanocarriers of synthetic stimulus-responsive materials and natural components,such as lipids,proteins and membrane structures,have emerged as promising candidates for fulfilling drug delivery needs.These nanocarriers offer several advantages,including prolonged blood circulation,targeted plaque delivery,targeted specific cells delivery and controlled drug release at the action site.In this review,we discuss the nature-inspired nanocarriers which leverage the natural properties of cells or the microenvironment to improve atherosclerotic drug therapy.Finally,we provide an overview of the challenges and opportunities of applying these innovative nature-inspired nanocarriers.
基金supported by grants from the National Institute of Health(R01HL149940 to S.L.)the National Natural Science Foundation of China(11932014 and 31971239 to X.L.).
文摘Atherosclerosis is a chronic inflammatory vascular disease and a leading cause of death worldwide.Macrophages play an important role in inflammatory responses,cell-cell communications,plaque growth and plaque rupture in atherosclerotic lesions.Here,we review the sources,functions and complex phenotypes of macrophages in the progression of atherosclerosis,and discuss the recent approaches in modulating macrophage phenotype and autophagy for atherosclerosis treatment.We then focus on the drug delivery strategies that target macrophages or use macrophage membrane-coated particles to deliver therapeutics to the lesion sites.These biomaterial-based approaches that target,modulate or engineer macrophages have broad applications for disease therapies and tissue regeneration.
基金partially supported by grants from the National Natural Science Foundation of China (No.31971302,China)the Natural Science Foundation of Guangdong Province of China (No.2019A1515011597,China)+2 种基金the talent young scientist supporting program of China Association for Science and Technologythe Educational Commission of Guangdong Province of China Key Project (No.2020ZDZX2001,China)the joint grant between Guangzhou City and College (No.202102010106,China)。
文摘Atherosclerosis(AS)is a leading cause of the life-threatening cardiovascular disease(CVD),creating an urgent need for efficient,biocompatible therapeutics for diagnosis and treatment.Biomimetic nanomedicines(b NMs)are moving closer to fulfilling this need,pushing back the frontier of nano-based drug delivery systems design.This review seeks to outline how these nanomedicines(NMs)might work to diagnose and treat atherosclerosis,to trace the trajectory of their development to date and in the coming years,and to provide a foundation for further discussion about atherosclerotic theranostics.
文摘BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.AIM To investigate potential triggers of drug-induced colitis(DiC).METHODS We conducted a retrospective,observational case control study.Patients were assigned to DiC or one of two age-and gender-matched control groups(noninflammatory controls and inflammatory colitis of another cause)based on histopathological findings.Histopathology was reassessed in a subset of patients(28 DiC with atherosclerosis,DiC without atherosclerosis and ischaemic colitis each)for validation purposes.Medical history was collected from the electronic database and patient records.Statistical analysis included chi-squared test,t-test,logistic and multivariate regression models.RESULTS Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa(7%of all screened colonoscopic biopsy samples);a total of 633 patients were included equally matched throughout the three groups(291 males,mean age:62.1±16.1 years).In the univariate analysis,DiC was associated with diuretics,dihydropyridines,glycosides,ASS,platelet aggregation inhibitors,nonsteroidal anti-inflammatory drugs(NSAIDs),statins and fibrates,and with atherosclerosis,particularly coronary heart disease,and hyperlipoproteinaemia.Echocardiographic parameters did not show substantial differences.In the multivariate analysis only fibrates[odds ratio(OR)=9.1],NSAIDs(OR=6.7)and atherosclerosis(OR=2.1)proved to be associated with DiC.Both DiC reassessment groups presented milder inflammation than ischaemic colitis.The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.CONCLUSION Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC.Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.
基金financial support from the Young Elite Scientists Sponsorship Program by Tianjin (No. 0701320001)Major Special Project of Tianjin (No. 0402080005)+1 种基金Program for Excellent Innovative Talents in Universities of Hebei Province (No. BJ2021019)Vietnam National University,Ho Chi Minh City (VNU-HCM,NCM2020-28-01)。
文摘Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment response, and low toxicity, stimuli-responsive nano-based drug delivery systems(NDDSs) have been a promising approach in AS treatments. Herein, we will systematically summarize the recent advances in stimuli-responsive NDDSs for AS treatment, including internal stimuli(reactive oxygen species, enzyme, shear stress, and pH) and external stimuli(light, ultrasound, and magnetism) responsive NDDSs. Besides, we will also summarize in detail the classification of stimuli-responsive NDDSs for AS, such as organic NDDSs(e.g., lipid-based and polymer-based nanomaterials), inorganic NDDSs(e.g., metal-based nanoparticles and nonmetallic nanomaterials), and composite multifunctional NDDSs. Finally, the critical challenges and prospects of this field will also be proposed and discussed.
文摘The key initiating process in atherogenesis is the subendothelial cholesterol retention, which is both necessary and sufficient to provoke lesion initiation. Retention of cholesterol transported by low density lipoprotien (LDL) in subendothelial cells of arterial wall, is an absolute requirement for lesion development. This allows us to consider intracellular cholesterol retention as a novel target for anti-atherosclerotic therapy. In this case, the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review summarizes the results of our basic studies shedding light on the mechanisms of intracellular cholesterol retention. We describe our cellular models to search for anti-atherosclerotic agents and demonstrate the use of these models for the development of anti-atherosclerotic drugs. We use natural products as the basis of anti-atherosclerotic drugs because anti-atherosclerotic therapy should be long-term or even lifelong. Using cellular models and natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured subendothelial aortic cells. We have developed drugs that reduce intracellular cholesterol retention, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with Allicor or Inflaminat caused regression of carotid atherosclerosis in asymptomatic men. Karinat prevented the development of new atherosclerotic plaques in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinics. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.
基金provided by a grant from Boston University,United States,Fundacao de Amparo à Pesquisa do Estado de Sao Paulo(FAPESP),Sao PauloConselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Brasília,Brazila scholarship from Coordena??o de Aperfeicoamento de Pessoal de Nível Superior-CAPES
文摘Cholesterol-core nanoparticles （LDE） have been shown to be recognized by low-density lipoprotein receptors （LDLR） after administration; therefore, LDE is an ideal vehicle to deliver drug with targeting property. Paclitaxel, when incorporated into LDE, promotes atherosclerosis regression with reduced drug toxicity in rabbits through LDLR. Here, we tested whether LDE-paclitaxel could still be effective in reducing diet-induced atherosclerosis in a mouse model without LDLR. Nineteen LDLR knockout male mice were fed 1% cholesterol for 12 weeks. Then, 12 animals received 4-weekly intraperitoneal LDE-paclitaxel （4 mg/kg） while 7 controls received saline solution. On week 12 and 16, in vivo MR/of the aortic roots was performed. Aorta macroscopy was made after euthanasia. Reduction ofatherosclerotic lesions was observed. LDE-paclitaxel treatment resulted in reduction of wall area （14%） and stenosis （22%） by MR/and 33% by macroscopy. Thus, LDE-paclitaxel may produce pharmacological effects through LDE uptake by mechanisms other than LDLR.
文摘Accumulation of cholesterol in arterial cells, intracellular cholesterol retention, may be responsible for all major manifestations of atherosclerosis on a cellular level. Previously we have shown that intracellular cholesterol retention is the principal event in the genesis of atherosclerotic lesions. This allows us to consider cellular retention of cholesterol as a novel target for anti-atherosclerotic therapy. In this case the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review describes our approach based on the use of cultured human arterial cells for the development of direct anti-atherosclerotic therapy. We use natural products as the basis of promising drugs for anti-atherosclerotic therapy. Using natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured cells. Our knowledge of the mechanisms of atherosclerosis is the foundation on which we have developed drugs that have a direct anti-atherosclerotic effect, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with allicor or inflaminat has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic men. Karinat prevents the development of carotid atherosclerosis in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinical practice. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.
