Tanshinone Ⅱ-A Attenuates and Stabilizes Atherosclerotic Plaques in Apolipoprotein E Knockout Mice Fed with High Cholesterol Diet

Objective TanshinoneⅡ-A(Tan),a bioactive diterpene isolated fromSalvia miltiorrhiza Bunge(Danshen),possesses anti-oxidant and anti-in-flammatory activities.The present study investigated whether Tan can reduce and stabilize atherosclerotic plaques in Apolipoprotein E knockout(ApoE-/-) mice maintained on a high cholesterol diet(HCD).Methods and Results Six week-old mice challenged with HCD were ran-domly assigned to 4 groups: C57BL/6J,ApoE-/-,ApoE-/-+30 mg/kg.d Tan and ApoE-/-+10 mg/kg.d Tan.After 16 weeks of inter-vention,Tan treated mice showed decreased atherosclerotic lesion size in the aortic sinus and face aorta.Furthermore,immunohistochemical a-nalysis revealed that Tan rendered the lesion composition a more stable phenotype as evidenced by reduced necrotic cores,decreased macrophageinfiltration,increased smooth muscle cell and collagen content.Tan also significantly reduced in situ superoxide anion production,aortic expres-sion of NF-κB,and matrix metalloproteinase-9(MMP-9).In vitro treatment of RAW264.7 macrophages with Tan significantly suppressed oxi-dized LDL-induced reactive oxygen species production,pro-inflammatory cytokine(IL-6,TNF-α,MCP-1) expression,and MMP-9 activity.Conclusions Tan attenuates the development of atherosclerotic lesions and promotes plaque stability in ApoE-/-mice by reducing vascular oxi-dative stress and inflammatory responses.Our findings highlightTan as a potential therapeutic agentto preventatherosclerotic cardiovascular dis-eases.

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries.Preclinical studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease models.Of clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia stroke.Here,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy.We highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and others.Finally,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

Targeting protein modifications in metabolic diseases:molecular mechanisms and targeted therapies

The ever-increasing prevalence of noncommunicable diseases(NCDs)represents a major public health burden worldwide.The most common form of NCD is metabolic diseases,which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications.A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum.Protein posttranslational modification(PTM)is an important term that refers to biochemical modification of specific amino acid residues in target proteins,which immensely increases the functional diversity of the proteome.The range of PTMs includes phosphorylation,acetylation,methylation,ubiquitination,SUMOylation,neddylation,glycosylation,palmitoylation,myristoylation,prenylation,cholesterylation,glutathionylation,S-nitrosylation,sulfhydration,citrullination,ADPribosylation,and several novel PTMs.Here,we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences,including diabetes,obesity,fatty liver diseases,hyperlipidemia,and atherosclerosis.Building upon this framework,we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications,showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials,and offer future perspectives.Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.

ASGR1:an emerging therapeutic target in hypercholesterolemia

In a recent study published in Nature,Wang et al.1 discovered that inhibition of asialoglycoprotein receptor 1(ASGR1)increased cholesterol efflux and thus lowered blood cholesterol and reduced atherosclerosis.This study offers an emerging new therapeutic target in hypercholesterolemia and its comorbidities and complications(such as fatty liver and atherosclerosis),which are major threats to public health.

Natural products,PGC-1α,and Duchenne muscular dystrophy

Peroxisome proliferator-activated receptorγ(PPARγ)is a transcriptional coactivator that binds to a diverse range of transcription factors.PPARγcoactivator 1(PGC-1)coactivators possess an extensive range of biological effects in different tissues,and play a key part in the regulation of the oxidative metabolism,consequently modulating the production of reactive oxygen species,autophagy,and mitochondrial biogenesis.Owing to these findings,a large body of studies,aiming to establish the role of PGC-1 in the neuromuscular system,has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases.Among these,some evidence has shown that various signaling pathways linked to PGC-1αare deregulated in muscular dystrophy,leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species(ROS)production.In the light of these results,any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies.PGC-1αis influenced by different patho-physiological/pharmacological stimuli.Natural products have been reported to display modulatory effects on PPARγactivation with fewer side effects in comparison to synthetic drugs.Taken together,this review summarizes the current knowledge on Duchenne muscular dystrophy,focusing on the potential effects of natural compounds,acting as regulators of PGC-1α.

Regulation of cholesterol homeostasis in health and diseases:from mechanisms to targeted therapeutics

Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases,such as cardiovascular diseases(CVD),neurodegenerative diseases and cancers,particularly the CVD in which the accumulation of lipids(mainly the cholesteryl esters)within macrophage/foam cells underneath the endothelial layer drives the formation of atherosclerotic lesions eventually.More and more studies have shown that lowering cholesterol level,especially low-density lipoprotein cholesterol level,protects cardiovascular system and prevents cardiovascular events effectively.Maintaining cholesterol homeostasis is determined by cholesterol biosynthesis,uptake,efflux,transport,storage,utilization,and/or excretion.All the processes should be precisely controlled by the multiple regulatory pathways.Based on the regulation of cholesterol homeostasis,many interventions have been developed to lower cholesterol by inhibiting cholesterol biosynthesis and uptake or enhancing cholesterol utilization and excretion.Herein,we summarize the historical review and research events,the current understandings of the molecular pathways playing key roles in regulating cholesterol homeostasis,and the cholesterol-lowering interventions in clinics or in preclinical studies as well as new cholesterol-lowering targets and their clinical advances.More importantly,we review and discuss the benefits of those interventions for the treatment of multiple diseases including atherosclerotic cardiovascular diseases,obesity,diabetes,nonalcoholic fatty liver disease,cancer,neurodegenerative diseases,osteoporosis and virus infection.

The zinc finger transcription factor,KLF2,protects against COVID-19 associated endothelial dysfunction

Coronavirus disease 2019(COVID-19)is regarded as an endothelial disease(endothelialitis)with its patho-mechanism being incompletely understood.Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries.Thus,pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications.The objective of the present study is to evaluate whether kruppel-like factor 2(KLF2),a master regulator of vascular homeostasis,represents a therapeutic target for C0VID-19-induced endothelial dysfunction.Here,we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules,ICAM1 and VCAM1.IL-1β and TNF-α;two cytokines elevated in cytokine release syndrome in COVID-19 patients,decreased KLF2 gene expression.Pharmacologic(atorvastatin and tannic acid)and genetic(adenoviral overexpression)approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion.Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function(vasodilation,antiinflammation,antioxidant status,anti-thrombosis/-coagulation,anti-fibrosis,and reduced angiogenesis).Finally,knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion.Collectively,the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.