Apigenin ameliorates imiquimod-induced psoriasis in C57BL/6J mice by inactivating STAT3 and NF-κB

Psoriasis is a chronic autoimmune disease featured by patches on the skin.It is caused by malfunction of immune cells and keratinocytes with inflammation as one of its key features.Apigenin(API)is a natural flavonoid with anti-inflammatory and immunoregulatory properties.Therefore,we speculated that API can ameliorate psoriasis,and determined its effect on the development of psoriasis by using imiquimod(IMQ)-induced psoriasis mouse model.Our results showed that API attenuated IMQ-induced phenotypic changes,such as erythema,scaling and epidermal thickening,and improved splenic hyperplasia.Abnormal differentiation of immune cells was restored in API-treated mice.Mechanistically,we revealed that API is a key regulator of signal transducer activator of transcription 3(STAT3).API regulated immune responses by reducing interleukin-23(IL-23)/STAT3/IL-17A axis.Moreover,it suppressed IMQ-caused cell hyperproliferation by inactivating STAT3 through regulation of extracellular signal-regulated kinase 1/2 and nuclear factor-κB(NF-κB)pathway.Furthermore,API reduced expression of inflammatory cytokines through inactivation of NF-κB.Taken together,our study demonstrates that API can ameliorate psoriasis and may be considered as a strategy for psoriasis treatment.

Combination of XianGui capsule and LCZ696 inhibits doxorubicin- induced heart failure in mice

Objective:We used doxorubicin(DOX)-induced heart failure mouse model to investigate the therapeutic effect and involved mechanism of XianGui capsule(XG)combined with Sacubitril Valsartan Sodium tablets(LCZ696)on heart failure.Methods:C57BL/6 mice were divided into control(Ctrl)group,DOX group,XG group,LCZ696 group and combination(XL)group.After the administration,mice heart functions,blood pressure,and serum cardiac injury markers were detected.Heart sections were conducted with HE,Sirius Red and immunohistochemical staining.The heart tissues were collected for the determination of protein or mRNA expression of anti oxidative,fibrosis,inflammation and apoptosis-related genes by Western Blot and qRT-PCR.Results:XG,LCZ696 or XG plus LCZ696 can significantly improve the heart functions of mice,reduce the expression of cardiac injury markers,and inhibit myocardial fibrosis.Mechanically,XG,LCZ696 or their co treatment antagonized myocardial apoptosis,increase forkhead box O3a,superoxide dismutase 2(SOD2)protein,SOD1,catalase mRNA expressions and inhibited the protein and mRNA levels of toll-like 4,nuclear factorkB,and inflammatory cytokines.Conclusion:XG,LCZ696 or XG plus LCZ696 decreases DOX-induced cardiomyocytes apoptosis by reducing inflammatory factors and enhancing expression of antioxidant enzymes,thereby alleviating the development of heart failure.

Dendrobium huoshanense improves doxorubicin-induced heart failure in C57BL/6 mice

Objective:To investigate the therapeutic effect of Shihu(Dendrobium huoshanense,DH)on doxorubicin(DOX)-induced heart failure in mice and the involved mechanisms.Methods:Male C57BL/6 mice were randomly divided into 3 groups:Control(Ctrl)group,DOX group and DH group.Chronic heart failure was induced by intraperitoneal injection of doxorubicin solution.Mice in DH group were fed normal chow containing DH powder for 4 weeks.After 4-week treatment,electrocardiograms were measured.At the end of experiment,serum and heart sample were collected for determination of indicators for heart failure indicators.The heart tissues were conducted HE,Masson,Sirius red staining and TUNEL staining to determine cardiac tissue morphology,fibrosis,collagen content and apoptosis,respectively.mRNA and protein expression were determined by qRT-PCR and Western blot,respectively.Results:DH reduced the DOX-induced serum biomarkers(creatine kinase,aspartate aminotransferase and lactate dehydrogenase)of heart damage and reduced heart fibrosis.Mechanically,DH inhibited myocardial apoptosis,decreased interleukin 6 and tumor necrosis factoralevels,but increased superoxide dismutase 2 expression.Conclusion:DH alleviates DOX-induced chronic heart failure by inhibiting inflammatory pathway and enhancing anti-oxidative enzymes.Our study provides the potential of DH for heart failure treatment.

Compound Danshen Dripping Pill inhibits hypercholesterolemia/atherosclerosis-induced heart failure in ApoE and LDLR dual deficient mice via multiple mechanisms

Heart failure is the leading cause of death worldwide.Compound Danshen Dripping Pill(CDDP)or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China.However,the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown.We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E(ApoE)and LDL receptor(LDLR)dual deficient(ApoE^(–/–)LDLR^(–/–))mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure.CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis.Mechanistically,both Wnt and lysine-specific demethylase 4A(KDM4A)pathways were significantly activated in mice with heart injury.Conversely,CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors.While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity.In addition,CDDP attenuated simvastatin-induced myolysis in skeletal muscle.Taken together,our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

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.

DanHong Injection inhibits the development of primary abdominal aortic aneurysms in apoE knockout mice

Clinical observations indicate that DanHong Injection(DHI)can increase blood flow and reduce various syndromes in patients with cardiovascular disease.However,it still needs to define the function of DHI and the involved mechanisms in details,such as the protective effect on the development of primary abdominal aortic aneurysms(AAAs).In this study,we determined whether DHI is able to inhibit AAA in apoE knockout(apoE-/-)mice.Thirty apoE-/-male mice on high-fat diet(0.5%cholesterol,21%fat)were randomly divided into two groups and received i.p.injection of saline(100 lL/day)and DHI(100 lL/day),respectively,for 16 weeks.At the end of experiment,we determined the development of atherosclerosis in en face aorta and aneurysms,pathological morphology of arterial wall,and serum lipid levels.We also determined the expression of monocyte chemoattractant protein-1(MCP-1),MMP-2,and MMP-9mRNA in aortic wall using real-time RT-PCR.Our results indicated that high-fat diet induced the development of AAAs in apoE-/-mice,but the induction was totally blocked by DHI(P\0.01).The result of staining of abdominal aortic cross sections showed that DHI maintained the collagen content in arterial wall,thereby preventing the animals from the development of AAA.Although DHI had little effect on serum total-and LDLcholesterol levels,it reduced the expression of MCP-1,MMP-2,and MMP-9 mRNA in aortic wall(P\0.01).Taken together,our study suggests that DHI can inhibit the high-fat diet-induced AAA formation.The inhibitory effects may be related to the maintenance of the collagen content and inhibition of expression of AAA-related genes.Our study may suggest a new application of DHI in clinics.