Evaluation of the intracellular lipid-lowering effect of polyphenols extract from highland barley in HepG2 cells

Active ingredients from highland barley have received considerable attention as natural products for developing treatments and dietary supplements against obesity.In practical application,the research of food combinations is more significant than a specific food component.This study investigated the lipid-lowering effect of highland barley polyphenols via lipase assay in vitro and HepG2 cells induced by oleic acid(OA).Five indexes,triglyceride(TG),total cholesterol(T-CHO),low density lipoprotein-cholesterol(LDL-C),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),were used to evaluate the lipidlowering effect of highland barley extract.We also preliminary studied the lipid-lowering mechanism by Realtime fluorescent quantitative polymerase chain reaction(q PCR).The results indicated that highland barley extract contains many components with lipid-lowering effects,such as hyperoside and scoparone.In vitro,the lipase assay showed an 18.4%lipase inhibition rate when the additive contents of highland barley extract were 100μg/m L.The intracellular lipid-lowering effect of highland barley extract was examined using 0.25 mmol/L OA-induced HepG2 cells.The results showed that intracellular TG,LDL-C,and T-CHO content decreased by 34.4%,51.2%,and 18.4%,respectively.ALT and AST decreased by 51.6%and 20.7%compared with the untreated hyperlipidemic HepG2 cells.q PCR results showed that highland barley polyphenols could up-regulation the expression of lipid metabolism-related genes such as PPARγand Fabp4.

Lipids,lipid-lowering drug and sepsis:a Mendelian randomization study

lipid-lowering interventions on the disease.Methods:Two-sample Mendelian randomization analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,triglycerides,apolipoprotein B and apolipoprotein A-I levels with risks for sepsis,and those of low-density lipoprotein cholesterol(HMGCR,PCSK9,NPC1L1),triglycerides(LPL,ANGPTL3,APOC3)and high-density lipoprotein cholesterol(CETP),apolipoprotein A-I(CETP),apolipoprotein B(HMGCR,PCSK9,NPC1L1,LPL,APOC3)with sepsis.Results:HMGCR-mediated low-density lipoprotein cholesterol and apolipoprotein B were associated with an increased risk of sepsis,with an odds ratio value of 1.4(95%confidence interval(CI):1.06-1.84,P=0.017)and 1.41(95%CI:1.01-1.98,P=0.046).CETP-mediated high-density lipoprotein cholesterol and apolipoprotein A-I were associated with a reduced risk of sepsis,with an odds ratio of 0.87(95%CI:0.82-0.92,P<0.01)respectively and 0.84(95%CI:0.78-0.9,P<0.01).Sensitivity analysis showed that the results were robust.Conclusion:HMG-CoA reductase inhibitors and CETP inhibitors may contribute to the prevention and treatment of sepsis.

Lipid-lowering effect of Oroxylum indicum(L.)Kurz extract in hyperlipidemic mice

Objective:To investigate the effect of Oroxylum indicum fruit extract on high-fat diet-induced hyperlipidemic mice.Methods:The phytochemical composition of Oroxylum indicum fruit extract was determined by liquid chromatographymass spectrometry/mass spectrometry(LC-MS/MS)and gas chromatography-mass spectrometry.Forty-two male mice were used.The mice were divided into six groups:normal control,high-fat diet control,simvastatin treatment(20 mg/kg BW/day),and Oroxylum indicum fruit extract(100,200,300 mg/kg BW/day)treatment groups.Food intake,body weight,serum parameters,lipid profile,and histopathological lesions of the kidney,liver,and epididymal fat were observed.Results:LC-MS/MS results revealed four major components of Oroxylum indicum fruit extract:luteolin,apigenin,baicalein,and oroxylin A.Twenty-seven volatile oils were identified from Oroxylum indicum fruit extract.Daily oral administration of Oroxylum indicum fruit extract at 100 to 300 mg/kg BW/day significantly reduced the body weight,total cholesterol,triglyceride,and low-density lipoprotein cholesterol level(P<0.05),whereas high-density lipoprotein cholesterol was higher than the high-fat diet control group.Treatment with 300 mg/kg BW/day Oroxylum indicum fruit extract reduced the pathological lesion and prevented fat accumulation in the kidney and liver.Conclusions:Oroxylum indicum fruit extract has hypolipidemic effect in hyperlipidemic mice,and the active ingredients of Oroxylum indicum fruit extract,both flavonoids and volatile oils,should be further explored as an antihyperlipidemic agent.

Effects of lipid-lowering agents on diabetic retinopathy: a Meta-analysis and systematic review

AIM：To clarify this controversy and to provide evidence for application of lipid lowering agents in treatment of diabetic retinopathy（DR）.METHODS：We searched the databases of Pub Med,Embase and Cochrane Library Central Register of Controlled Trials（CENTRAL）and abstracts from main annual meetings up to January 1,2017.Google scholar and Clinical Trials.gov were also searched for unpublished relevant studies.We included randomized controlled trials（RCTs）that studied lipid-lowering agents in type 1 or type 2 diabetes in this Meta-analysis.The primary endpoint was the progression of DR,and the secondary endpoints included vision loss,development of diabetic macular edema（DME）and aggravation of hard exudates.The pooled odds ratios（OR）with corresponding 95%confidence intervals（95%CIs）were calculated.RESULTS：After systemic and manual literature search by two independent investigators,we included 8 RCTs from 7 published articles with 13 454 participants in this Meta-analysis.The results revealed that lipid-lowering drugs were associated with reduced risk in DR progression[OR=0.77（95%CI：0.62,0.96）,P=0.02].Lipid-lowering agents might have protective effect on DME compared to placebo,although the difference was not statistically significant[OR=0.60（95%CI：0.34,1.08）,P=0.09].However,no significant differences in the worsening of vision acuity[OR=0.96（95%CI：0.81,1.14）,P=0.64]and hard exudates[OR=0.50（95%CI：0.15,1.74）,P=0.28]were found between the lipidlowering drugs and the placebo groups.CONCLUSION：In DR patients,lipid-lowering agents show a protective effect on DR progression and might be associated with reduced risk in the development of DME.However,lipid-lowering agents have no effects on vision loss and hard exudates aggravation.Further clinical trials in larger scale are required to confirm the conclusion of this study and thus justify the use of intensive control lipids with anti-lipid agents at the early stages of DR.

Characteristic chemical profile of Juhe Fang extract with lipid-lowering properties

Objective:The objective of this study was to verify the lipid-lowering effect of Juhe Fang extract(JHFE)and to determine its characteristic chemical profile in vitro and in vivo.Methods:A hyperlipidemia model was established by feeding mice a high-fat diet(HFD).After treatment for 30 days,serum total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C)and low-density lipoprotein cholesterol(LDL-C)levels were measured with an automatic biochemistry analyzer.The components from JHFE obtained from in vivo and in vitro experiments were investigated using an UPLC-Q Exactive-Orbitrap MS/MS.Results:The TC,TG,and LDL-C in the serum significantly decreased and the HDL-C significantly increased after JHFE treatment.A total of 95 compounds from JHEF including 15 phenolic acids(PA),4 phenylethanoid glycosides(PG),24 flavonoids(F),14 triterpenoids(T),10 diterpenoid glycosides(D),18 alkaloids(A)and 10 others(O)were identified.Trigonelline was discovered for the first time in a herbal medicine of Juhe Fang.Furthermore,68 compounds were identified in vivo including 28 prototype compounds and 40 metabolites.The metabolic characteristics of these components were revealed including identification of new metabolites of 4-hydroxyphenyl ethyl-8-O-[a-L-arabinopyranosyl-(1/6)]-b-D-glucopyranoside(PEG)and lirinidine.A total of 43 components from JHFE were absorbed and/or metabolized.The contribution rate of each type of chemical component from JHFE to its lipidlowering effect from high to low were A,F,PG,PA,D and T.Conclusion:The results of this study showed that JHFE demonstrated a significant lipid-lowering effect in a high-fat diet(HFD)-induced hyperlipidemia mouse model.Specific types of PA,PG,F,D,T and A formed the pharmaceutical architecture of the lipid-lowering effect of JHFE.This study should prove useful for clarifying the components responsible for the lipid-lowering effect of JHFE and provide a basis for precision quality control research.

Intensive lipid-lowering therapy,time to think beyond low-density lipoprotein cholesterol

Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering therapies using ezetimibe and more recently proprotein convertase subtilisin kexin 9 inhibitors have further improved clinical outcomes.Unselective application of these treatments is undesirable and unaffordable and,therefore,has been guided by LDL-c level.Nonetheless,the residual risk in the post-statin era is markedly heterogeneous,including thrombosis and inflammation risks.Moreover,the lipoprotein related risk is increasingly recognised to be related to other non-LDL-c markers such as Lp(a).Emerging data show that intensive lipid-lowering therapy produce larger absolute risk reduction in patients with polyvascular disease,post coronary artery bypass graft and diabetes.Notably,these clinical entities share similar phenotype of large burden of atherosclerotic plaques.Novel plaque imaging may aid decision making by identifying patients with propensity to develop lipid rich plagues at multi-vascular sites.Those patients may be suitable candidates for intensive lipid lowering treatment.

(+)/(-)-Gerbeloid A,a pair of unprecedented coumarin-based polycyclic meroterpenoid enantiomers from Gerbera piloselloides:Structural elucidation,semi-synthesis,and lipid-lowering activity

A pair of coumarin-based polycyclic meroterpenoid enantiomers(+)/(-)-gerbeloid A[(+)-1a and(-)-1b]were isolated from the medicinal plant Gerbera piloselloides,which have a unique caged oxatricyclo[4.2.2.0^(3,8)]decene scaffold.Their planar and three-dimensional structures were exhaustively characterized by comprehensive spectroscopic data and X-ray diffraction analysis.Guided by the hypothetical biosynthetic pathway,the biomimetic synthesis of racemic 1 was achieved using 4-hydroxy-5-methylcoumarin and citral as the starting material via oxa-6πelectrocyclization and intramolecular[2+2]photocycloaddition.Subsequently,the results of the biological activity assay demonstrated that both(+)-1a and(-)-1b exhibited potent lipid-lowering effects in 3T3-L1 adipocytes and the high-fat diet zebrafish model.Notably,the lipid-lowering activity of(+)-1a is better than that of(-)-1b at the same concentration,and molecular mechanism study has shown that(+)-1a and(-)-1b impairs adipocyte differentiation and stimulate lipolysis by regulating C/EBPα/PPARγsignaling and Perilipin signaling in vitro and in vivo.Our findings provide a promising drug model molecule for the treatment of obesity.

Influences of Lactiplantibacillus plantarum and Saccharomyces cerevisiae fermentation on the nutritional components,flavor property and lipid-lowering effect of highland barley

Highland barley is a well-known cereal in Qinghai-Tibet Plateau area with high nutritional value,which has been reported to be a health-promoting grain for the obesity and the diabetes.Fermentation by certain microbiota can improve the flavor property and nutritional characteristics.In the present study,Lactiplantibacillus plantarum and Saccharomyces cerevisiae were singly or jointly applied to ferment highland barley,and the profile of volatile substances and lipid-lowering effects of the respective extracts were analyzed.Results indicated that either L.plantarum or S.cerevisiae or co-fermentation could consume the polysaccharides of highland barley to provide energy,and dramatically increase the contents of total protein and polyphenol.Gas chromatography-mass spectrometry(GC-MS)analysis revealed that the presence of S.cerevisiae was critical for production of the pleasant flavors,especially for the ethyl ester substances including hexadecanoic acid ethyl,hexanoic acid ethyl ester and so on.Meanwhile,we found that fermented highland barley extracts by L.plantarum exhibited stronger lipid-lowering effects in Caenorhabditis elegans than that by S.cerevisiae,while the co-fermentation not only emitted pleasant odors but also exerted high hypolipidemic function.In all,co-fermentation by L.plantarum and S.cerevisiae was proposed to be a promising processing to improve the flavor and functional properties of highland barley.

Novel benzamido derivatives as PTP1B inhibitors with anti-hyperglycemic and lipid-lowering efficacy

Based on a non-competitive and selective PTP1 B inhibitor reported by us previously, thirtynine benzamido derivatives were designed and synthesized as novel PTP1 B inhibitors. Among them,twelve compounds exhibited IC_(50) values at micromolar level against human recombinant PTP1 B, and most of them exhibited significant selectivity to PTP1 B over TC-PTP and CD45. Further evaluation of the most potent compound 27 on high-fat diet(HFD)-induced insulin-resistant(IR) obese mice indicated that27 could modulate glucose metabolism and ameliorate dyslipidemia simultaneously.& 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Pyridocarbazole alkaloids from Ochrosia borbonica: lipid-lowering agents inhibit the cell proliferation and adipogenesis of 3T3-L1 adipocyte via intercalating into supercoiled DNA

Bioassay-guided fractionation of an ethanolic extract of Ochrosia borbonica led to the isolation of two known pyridocarbazole alkaloids,ellipticine(1)and 9-methoxyellipticine(2),and six known monoterpenoid indole alkaloids(3-8).Lipid-lowering assay in 3 T3-L1 cell model revealed that 1 and 2 could significantly inhibit the lipid droplet formation(EC50(28)0.41 and 0.92μmol·L^–1,respectively)and lower triglyceride levels by 50%-60%at the concentration of 1μmol·L^–1,being more potent than the positive drug luteolin(EC50(28)2.63μmol·L–^1).A mechanistic study indicated that 1 and 2 could intercalate into supercoiled DNA,which consequently inhibited the mitotic clonal expansion of 3 T3-L1 cells at the early differentiation phase,leading to the retardance of following adipogenesis and lipogenesis.These findings suggest that 1 and 2 may serve as promising leads for further d evelopment of anti-obesity drugs.

An overview of Pu-erh tea and its health-promoting effects of lipid-lowering and anti-obesity

As a dark tea,Pu-erh tea(PET)is produced from sun-dried leaves of Camellia sinensis var.assamica mainly in Yunnan Province of China.Many microorganisms are involved in the fermentation of PET.Among them,Aspergillus niger is most important.It is believed that the longer the preservation period,the better is the quality and taste of PET,which is commercially available as loose,compressed or instant tea leaves.Chemical components of PET include flavones,flavanols,flavonols,phenolic acids,alkaloids and methylxanthines.In this overview,the lipid-lowering and anti-obesity effects of PET were discussed based on animal models and human trials,and our study provided some insights into possible mechanisms of bioactive compounds,such as theabrownin,catechins,lovastatin and gallic acid.Other bioactivities of PET and some information on Fuzhuan brick tea were also included.Sources of information cited were from Google Scholar,Pub Med,Pub Med Central,Science Direct,J-Stage,Pub Chem,Directory of Open Access Journals(DOAJ),and China National Knowledge Infrastructure(CNKI).

Is medical management useful in Moyamoya disease?

Moyamoya disease(MMD),characterized by progressive internal carotid artery stenosis and collateral vessel formation,prompts cerebral perfusion complications and is stratified into idiopathic and Moyamoya syndrome subtypes.A multifa-ceted approach toward MMD management addresses cerebral infarctions through revascularization surgery and adjunctive medical therapy,while also navigating risks such as intracranial hemorrhage and cerebral infarction resulting from arte-rial stenosis and fragile collateral vessels.Addressing antithrombotic management reveals a potential role for treatments like antiplatelet agents and anticoagulants,despite the ambiguous contribution of thrombosis to MMD-related infarctions and the critical balance between preventing ischemic events and averting hemo-rrhagic complications.Transcranial doppler has proven useful in thromboembolic detection,despite persisting challenges concerning the efficacy and safety of an-tithrombotic treatments.Furthermore,antihypertensive interventions aim to ma-nage blood pressure meticulously,especially during intracerebral hemorrhage,with recommendations and protocols varying based on the patient’s hypertension status.Additionally,lipid-lowering therapeutic strategies,particularly employing statins,are appraised for their possible beneficial role in MMD management,even as comprehensive data from disease-specific clinical trials remains elusive.Com-prehensive guidelines and protocols to navigate the multifaceted therapeutic ave-nues for MMD,while maintaining a delicate balance between efficacy and safety,warrant further meticulous research and development.This protocol manuscript seeks to elucidate the various aspects and challenges imbued in managing and navigating through the complex landscape of MMD treatment.

脉平片药效学研究

目的观察脉平片抗血栓、降脂、耐缺氧的药理作用。方法通过测定脉平片对实验性大鼠血栓模型血栓形成时间的影响,观察其抗血栓作用;建立大鼠高脂血症病理模型,观察脉平片的降脂作用;通过小鼠耐缺氧实验,观察脉平片的耐缺氧作用。结果脉平片3个剂量组均能够延长小鼠凝血时间,明显延长血浆凝血酶原时间、凝血酶原消耗时间及白陶土部分凝血活酶时间;脉平片高剂量组能够明显降低血清总胆固醇及三酰甘油含量,提高高密度脂蛋白胆固醇含量;脉平片3个剂量组常压下均能够提高小鼠低氧条件下的生存能力。结论脉平片有较好的抗凝、降脂及耐缺氧作用。

Influences of blood lipids on the occurrence and prognosis of hemorrhagic transformation after acute cerebral infarction: a case-control study of 732 patients

Background: To study the influence of blood lipid levels on hemorrhagic transformation(HT) and prognosis after acute cerebral infarction(ACI).Methods: Patients with ACI within 72 h of symptoms onset between January 1 st, 2015, and December 31 st, 2016, were retrospectively analyzed. Patients were divided into group A(without HT) and group B(HT). The outcomes were assessed after 3 months of disease onset using the modified Rankin Scale(m RS). An m RS score of 0–2 points indicated excellent prognosis, and an m RS score of 3–6 points indicated poor prognosis.Results: A total of 732 patients conformed to the inclusion criteria, including 628 in group A and 104 in group B. The incidence of HT was 14.2%, and the median onset time was 2 d(interquartile range, 1–7 d). The percentages of patients with large infarct size and cortex involvement in group B were 80.8% and 79.8%, respectively, which were both significantly higher than those in group A(28.7 and 33.4%, respectively). The incidence rate of atrial fibrillation(AF) in group B was significantly higher than that in group A(39.4% vs. 13.9%, P<0.001). The adjusted multivariate analysis results showed that large infarct size, cortex involvement and AF were independent risk factors of HT, while total cholesterol(TC) was a protective factor of HT(OR=0.359, 95% CI 0.136–0.944, P=0.038). With every 1 mmol/L reduction in normal TC levels, the risk of HT increased by 64.1%. The mortality and morbidity at 3 months in group B(21.2% and 76.7%, respectively) were both significantly higher than those in group A(8.0% and 42.8%, respectively). The adjusted multivariate analysis results showed that large infarct size(OR=12.178, 95% CI 5.390–27.516, P<0.001) was an independent risk factor of long-term unfavorable outcomes, whereas low-density lipoprotein cholesterol(LDL-C) was a protective factor(OR=0.538, 95% CI 0.300–0.964, P=0.037). With every 1 mmol/L reduction in normal LDL-C levels, the risk of an unfavorable outcome increased by 46.2%. Major therapies, including intravenous recombinant human tissue plasminogen activator(r TPA), intensive lipid-lowering statins and anti-platelets, were not significantly related to either HT or long-term, post-ACI poor prognosis.Conclusions: For patients with large infarct sizes, especially those with cortex involvement, AF, or lower levels of TC, the risk of HT might increase after ACI. The risk of a long-term unfavorable outcome in these patients might increase with a reduction in LDL-C.

Protective effect of lemongrass oil against dexamethasone induced hyperlipidemia in rats:possible role of decreased lecithin cholesterol acetyl transferase activity

Objective:To evaluate the anti-hyperlipidemic activity of lemongrass oil against in dexamethasone induced hyperlipidemia in rats.Methods:Administration of dexamethasone was given at 10 mg/kg,sc.to the adult rats for 8 d induces hyperlipidemia characterized by marked increase in serum cholesterol and triglyceride levels along with increase in atherogenic index.Results:Lemongrass oil(100 and 200 mg/kg,po.) treatment has showed significant inhibition against dexamethasone hyperlipidemia by maintaining the serum levels of cholesterol, triglycerides and atherogenic index near to the normal levels and the antihyperlipidemic effect of the lemongross oil was comparable with atorvastatin 10 mg/kg,po.The possible mechanism may be associated with decrease in lecithin cholesterol acetyl transferase(LCAT) activity.Conclusions:These results suggested that Lemon gross oil possess significant antihyperlipidemic activity.

Editorial on hemoglobin A1c, blood pressure, and lowdensity lipoprotein cholesterol goals in diabetics

The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considered in adults with short duration of diabetes, long life expectancy, and no significant cardiovascular disease if this can be achieved without significant hypoglycemia or other adverse effects of treatment. A hemoglobin A1c level less than 8.0% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced macrovascular and microvascular complications, extensive comorbidities, and long-standing diabetes in whom the hemoglobin A1c goal is difficult to attain despite multiple glucoselowering drugs including insulin. The ADA 2013 guidelines recommend that the systolic blood pressure in most diabetics with hypertension should be reduced to less than 140 mmHg. These guidelines also recommend use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in the treatment of hypertension in diabetics unless they are pregnant. Diabetics at high risk for cardiovascular events should have theirserum low-density lipoprotein (LDL) cholesterol lowered to less than 70 mg/dL with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to less than 100 mg/dL. Combination therapy of a statin with either a fibrate or niacin has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not recommended. Hypertriglyceridemia should be treated with dietary and lifestyle changes. Severe hypertriglyceridemia should be treated with drug therapy to reduce the risk of acute pancreatitis.

The inhibitory effects of Yigan Jiangzhi formula on hepatic metastasis of colorectal cancer

Background:To observe the inhibitory effects of Yigan Jiangzhi formula(liver-supplementing lipid-lowering formula,YGJZF)on hepatic metastasis of colorectal cancer.Methods:The hepatic metastasis BALB-c mice model of colorectal cancer was established by injecting HCT-116 cell suspension following splenectomy.Next,we randomly divided BALB-c mice into 5 groups,which were blank group,model group(tumor only),traditional Chinese medicine group(YGJZF),western medicine group(capecitabine),combined group(YGJZF and capecitabine),respectively.After 14 days treatment,the effects of different treatments were evaluated the serological indicators were evaluated,including the levels of alanine transaminase,aspartate transaminase,triglyceride,total cholesterol and vascular endothelial growth factor(VEGF)by ELISA.Results:Except the blank group,the other groups showed diffuse hepatic metastasis.Compared with the model group,the total number and weight of the metastatic tumors as well as serological indicators in medicine-given groups were sharply reduced(P<0.05 for all)the combined group had better effects.The serum levels of these indicators showed no statistical difference among each medicine-given group(P>0.05),but the combined group has a remarkable decrease of all the indicators than in western medicine group.Conclusion:YGJZF not only can inhibit the hepatic metastasis of colorectal cancer in BALB-c mice,but also affect the levels of hepatic enzymes and lipids.Meanwhile,it can reduce the expression of VEGF.All these results indicate that YGJZF,which lowers down lipids and protects hepatic functions,has the potential to block VEGF pathway,contributing to the inhibition of hepatic metastasis.

Chlorajaponins A—Q,Lindenane-Related Sesquiterpenoid Dimers from Chloranthus japonicus and Their Biological Activities

Seventeen undescribed lindenane-related sesquiterpenoid dimers,chlorajaponins A—Q(1—17),and 13 reported analogs(18—30)were isolated from Chloranthus japonicus Sieb.Compound 1 possesses an unprecedented 3/5/7/5/5/6/5/3 fused octacyclic scaffold,featuring a 6(5→4)-abeo-lindenane monomer,while 2 exhibits a 3/5/6/6/5/6/5/3 fused octacyclic scaffold.Their structures were determined through a combination of spectroscopic analyses and X-ray crystallography.Compounds 1,2,and 18 demonstrated significant inhibitory effects on lipid accumulation and effectively reduced the levels of triglycerides and total cholesterol,as well as the levels of aspartate aminotransferase and alanine aminotransferase in a HepG2 cell model.In addition,compounds 1,2,and 18 significantly suppressed the protein expression of the fatty acid synthase(FASN)and the sterol regulatory element-binding protein 1(SREBP1).Moreover,the anti-inflammatory assay showed that compounds 19—22 and 25 inhibited the NO production induced by lipopolysaccharide in RAW 264.7 macrophages with IC50 values of 7.89±0.44,6.25±0.46,2.98±0.29,10.77±0.60,and 3.60±0.28μmol/L.

Design,synthesis,and biological evaluation of novel tetrahydroprotoberberine derivatives(THPBs) as proprotein convertase subtilisin/kexin type 9(PCSK9)modulators for the treatment of hyperlipidemia

Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol(LDL-C).A novel series of tetrahydroprotoberberine derivatives(THPBs)were designed,synthesized,and evaluated as PCSK9 modulators for the treatment of hyperlipidemia.Among them,eight compounds exhibited excellent activities in downregulatinghepatic PCSK9 expression better than berberine in HepG2 cells.In addition,five compounds 15,18,22,(R)-22,and(S)-22 showed better performance in the low-density lipoprotein,labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethyl-indocarbocyanine perchlorate(Dil-LDL)uptake assay,compared with berberine at the same concentration.Compound 22,selected for in vivo evaluation,demonstrated significant reductions of total cholesterol(TC)and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile.Further exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells.Additional results of human ether-ago-go related gene(hERG)inhibition assay indicated the potential druggability for compound 22,which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.

Rationale, Criteria, and Impact of Identifying Extreme Risk in Patients with Atherosclerotic Cardiovascular Disease

Assessment of the overall risk of atherosclerotic cardiovascular disease(ASCVD)is the first step in managing dyslipidemia and is an important reference for the target and intensity of treatment.Recently,different guidelines and consensuses on the management of this condition have successively recommended further risk stratification among patients with ASCVD,and a new“extreme risk”category has been proposed to identify patients who may obtain greater benefit from more intensive lipid-lowering therapy.The definition and terminology of extreme risk varies among different guidelines and consensuses;however,they all recommended an aggressive lipid-lowering therapeutic approach and/or a more stringent low-density lipoprotein cholesterol target for patients at extreme risk.Regardless of the definitions,this general approach may have a remarkable effect on the treatment of this condition in clinical practice.To help clinicians and patients to better understand the new strategy for the secondary prevention of ASCVD,this review provides a summary highlighting the necessity of further risk stratification among ASCVD patients,how patients at extreme risk can be identified,and the potential impact of applying the new“extreme risk”category in clinical practice.