Chlorogenic acid ameliorates heart failure by attenuating cardiomyocyte ferroptosis

Objective:To elucidate the effects of chlorogenic acid(CGA),a bioactive polyphenol compound prevalent in traditional Chinese medicine and various foods,including Lonicera japonica Thunb.(Jin Yin Hua),Eucommia ulmoides Oliv.(Du Zhong Ye),tea,and coffee,on cardiomyocyte ferroptosis and heart failure.Methods: We assessed the effect of CGA on cardiac function using a mouse model of heart failure induced by transverse aortic constriction(TAC).These indicators included the left ventricular ejection fraction(LVEF),fractional shortening(LVFS),end-systolic volume(LVESV),end-diastolic volume(LVEDV),end-systolic diameter(LVESD),and end-diastolic diameter(LVEDD).An isoprenaline hydrochloride(ISO)-induced H9c2 cardiomyocyte cell model was also established,and the cells were treated with various concentrations of CGA.To assess the effect of CGA on ferroptosis in cardiomyocytes,we measured cell viability and evaluated the levels of intracellular reactive oxygen species(ROS),ferrous ions(Fe^(2+)),and lipid peroxidation using fluorescent staining.To clarify the ferroptosis signaling pathway regulated by CGA,western blotting was used to examine the expression of ferroptosis biomarkers,specifically solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),in H9c2 cardiomyocytes and mouse myocardial tissues.Results: CGA significantly enhanced cardiac performance indices such as LVEF,LVFS,LVESV,LVEDV,LVESD,and LVEDD.H9c2 cardiomyocytes exposed to ISO showed decreased cell viability and increased ROS levels,Fe^(2+)content,and lipid peroxidation levels.However,CGA treatment significantly ameliorated these changes.Additionally,in both H9c2 cardiomyocytes and myocardial tissue obtained from mice with TAC,CGA increased the expression of ferroptosis-related proteins,including SLC7A11 and GPX4.Conclusion: CGA has the potential to enhance cardiac function and diminish lipid peroxidation and ROS levels in cardiomyocytes via the SLC7A11/GPX4 signaling pathway.This process alleviates ferroptosis in cardiomyocytes.These results provide new insights into the clinical use of CGA and the management of heart failure.

TCM-HIN2Vec:A strategy for uncovering biological basis of heart qi deficiency pattern based on network embedding and transcriptomic experiment

Objective:To elucidate the biological basis of the heart qi deficiency(HQD)pattern,an in-depth understanding of which is essential for improving clinical herbal therapy.Methods: We predicted and characterized HQD pattern genes using the new strategy,TCM-HIN2Vec,which involves heterogeneous network embedding and transcriptomic experiments.First,a heterogeneous network of traditional Chinese medicine(TCM)patterns was constructed using public databases.Next,we predicted HQD pattern genes using a heterogeneous network-embedding algorithm.We then analyzed the functional characteristics of HQD pattern genes using gene enrichment analysis and examined gene expression levels using RNA-seq.Finally,we identified TCM herbs that demonstrated enriched interactions with HQD pattern genes via herbal enrichment analysis.Results: Our TCM-HIN2Vec strategy revealed that candidate genes associated with HQD pattern were significantly enriched in energy metabolism,signal transduction pathways,and immune processes.Moreover,we found that these candidate genes were significantly differentially expressed in the transcriptional profile of mice model with heart failure with a qi deficiency pattern.Furthermore,herbal enrichment analysis identified TCM herbs that demonstrated enriched interactions with the top 10 candidate genes and could potentially serve as drug candidates for treating HQD.Conclusion: Our results suggested that TCM-HIN2Vec is capable of not only accurately identifying HQD pattern genes,but also deciphering the basis of HQD pattern.Furthermore our finding indicated that TCM-HIN2Vec may be further expanded to develop other patterns,leading to a new approach aimed at elucidating general TCM patterns and developing precision medicine.

Effect of gender on the association between cumulative cardiovascular risk factors and depression:results from the US National Health and Nutrition Examination Survey

Background The comorbidity of cardiovascular disease(CVD)and depression has been well established,as depression usually presents simultaneously with CVD risk factors.However,the potential association between cumulative exposure to CVD risk and depression remains unclear,so we conducted the current investigation.To our knowledge,this is the first study that employs the cumulative risk model to examine the effect of CVD risk factors on depression using nationally representative population and gender,age and CVD status-stratified subpopulations.Aims To systematically study the possible individual and cumulative effect of 18 CVD risk factors on depression.Methods A cross-sectional,secondary analysis investigated associations between 18 CVD risk factors and depression.The interaction effect between CVD risk factors and age,gender and CVD status was also examined.Enrolment included 20816 participants from the US National Health and Nutrition Examination Survey 2005–2016.Participants with Patient Health Questionnaire-9 scores over 15 or who were using an antidepressant were considered depressive;18 known cardiovascular risk factors were incorporated in the present study.Results At the individual risk factor level,smoking,drinking,living alone,sleep quality,body mass index,waist circumference and diabetes status had differential associations with depression risk according to the gender,age or CVD status of the participants.Most importantly,gender-stratified cumulative risk analysis indicated that similar depression risk was found in both genders with a small number of CVD risk factors(odds ratio(OR)adjusted=1.32;95%confidence interval(CI):0.87 to 1.99),but females had a significantly higher depression risk compared with males under high cumulative risk exposure(ORadjusted=2.86;95%CI:1.79 to 4.59).Conclusions Clarifying the association of numerous CVD risk factors with depression according to gender,age and overall CVD status may be beneficial for risk stratification and the prevention of depression in clinical practice.Moreover,the observed novel evidence of high cumulative risk exposure-mediated gender disparities in depression risk may shed light on the underlying mechanism of females’greater vulnerability to depression.

6-Gingerol, asarinin, and deoxyschizandrin improve bronchial epithelium functions in an interleukin-13einduced BEAS-2B cell model

Objective:To explore the effects of 6-gingerol,asarinin,and deoxyschizandrindthe main components of Zingiber officinale(Willd.)Rosc.(Gan Jiang),Asarum heterotropoides f.var.mandshuricum(Maxim.)(Xi Xin),and Schisandra chinensis(Turcz.)Baill.(Wu Wei Zi),respectivelydon an interleukin(IL)-13einduced BEAS-2B cell model in vitro.Methods:The BEAS-2B cell model was established using 25 ng/mL IL-13 combined with 1%fetal bovine serum(FBS)in vitro.Mitoquinone mesylate(Mito-Q)treatment was used as a positive control group,and different concentrations of 6-gingerol,asarinin,and deoxyschizandrin were used to treat the models.The level of reactive oxygen species(ROS)production was detected by flow cytometry.The expression levels of LC3B,Beclin1,adenosine 50-monophosphate(AMP)eactivated protein kinase(AMPK),phosphory-lated-AMPeactivated protein kinase(P-AMPK),dynamin-related protein 1(DRP1),and mitochondrial fusion protein 2(MFN2)were detected by Western blot.Mitochondrial membrane potential(MMP)assay kit with JC-1 was utilized to detect the level of MMP.Results:The BEAS-2B cells exposed to 25 ng/mL IL-13 with 1%FBS showed an increased ROS level and a decreased MMP.6-Gingerol,asarinin,and deoxyschizandrin were able to downregulate ROS level and upregulate the MMP in the BEAS-2B model.Asarinin and deoxyschizandrin reduced the expression of autophagy protein LC3B,while deoxyschizandrin significantly increased the expression of DRP1 in the BEAS-2B model.Conclusion:6-Gingerol,asarinin,and deoxyschizandrin can reduce ROS generation and increase MMP,but have different regulatory effects on the expression of autophagy protein and mitochondrial mitotic protein.The three components have both synergistic and complementary effects in classic medicine compatibility.This study may provide an innovative strategy to reduce the lung inflammation related to IL-13.

Neuroprotective effect of Longshengzhi capsule following permanent middle cerebral artery occlusion in rats

Objective:Longshengzhi capsule(LSZC)is an optimized preparation based on the traditional Chinese Medicine formula Buyanghuanwu Decoction(BYHWD),and is approved by the China Food and Drug Administration for treating stroke-induced disability and vascular diseases.Herein,we examined the pharmacodynamics,anti-apoptotic and anti-oxidant actions,and potential mechanisms of action of LSZC following stroke in rats.Methods:Permanent middle cerebral artery occlusion(MCAO)was used as an ischemic stroke model.LSZC was administered intragastrically.We examined the survival rate,bodyweight,and neurological deficits in stroke rats.Brain infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining.Brain pathology was examined using hematoxylin and eosin staining,Nissl staining,and TdT-mediated dUTP Nick-End Labeling staining.Malondialdehyde,catalase,superoxide dismutase,and glutathione levels were examined by commercial kits.Expression of Nrf2,heme oxygenase-1,Bax,Bcl-2,cleaved caspase-3,and caspase-3 proteins in brain tissue was measured by Western blot.Results:LSZC markedly improved the survival rate and bodyweight,and reduced infarct volume and neurological deficit scores,in MCAO stroke rats.LSZC also significantly attenuated oxidative stress,as indicated by decreased expression of malondialdehyde,and upregulation of Nrf2,heme oxygenase-1,catalase,superoxide dismutase,and glutathione.Moreover,LSZC significantly decreased apoptosis,including a decrease in Bax and cleaved caspase-3 expression,and an increase in Bcl-2,as well as a reduction in numbers of apoptotic neurons.Conclusion:LSZC treatment is neuroprotective against ischemic stroke,potentially via reducing oxidative stress and apoptosis.The Nrf2 and apoptotic signaling pathways may play important roles in the antioxidant and anti-apoptotic actions of LSZC.

Chinese herbal medicine for chronic heart failure:a multicenter,randomized,double-blind,placebo-controlled trial

Objective:The purpose of this study was to assess the efficacy and safety of Chinese herbal medicine(CHM)in the treatment of chronic heart failure(CHF)patients according to syndrome differentiation.Methods:In this multicenter,randomized,double-blind,placebo-controlled clinical trial,a total of 220 CHF patients were assigned to receive CHM or placebo granules without decoction according to syndrome differentiation in addition to their standard western treatment for 4 weeks.The change in the left ventricular ejection fraction(LVEF)was the primary outcome,and the changes in the TCM syndrome scores(TCM-SS)and New York Heart Association functional classification(NYHA-FC)were the secondary outcomes.

Plasma metabolomics combined with personalized diagnosis guided by Chinese medicine reveals subtypes of chronic heart failure

Background:Chronic heart failure(CHF)is characterized by insufficient blood supply from heart to meet the body’s metabolic demands.Integrating Western and traditional Chinese medicine to treat CHF has proved a validated therapeutic approach.In recent years,metabolomics has been regarded as a potential platform to provide biomarkers for diseasesubtypes.Objective:To examine 38 patients,combined NMR plasma metabolomics and traditional Chinese medicine diagnosis in order to identify diagnostic biomarkers for two CHF syndrome subtypes.Methods:After processing the spectra,orthogonal partial least square discriminant analysis was performed,and the contributing NMR signals were analyzed using Y-scrambling statistical validation with good reliability.Results:Plasma metabolic patterns of yin deficiency and yang deficiency patients were clearly discriminated.The yin-deficiency group had increased level of lactate,glycoprotein,lipoprotein and lower levels of glucose,valine and proline.The yang-deficiency group had higher levels of lactate,glycoprotein and pyruvic acid,and lower levels of glucose and lipoprotein.Potential biomarkers of CHF based on the two traditional Chinese medicine syndromes indicated alternative modes of metabolites and metabolic pathways in the disease,e.g.dysfunction of energy utilization and disturbance in fatty acids,amino acids.Conclusion:This study suggests that combining metabolomics with traditional Chinese medicine diagnosis can reveal metabolic signatures for CHF syndrome subtypes.The plasma metabolites identified might be of special clinical relevance for subtypes of CHF,which could lead to further understanding of mechanisms involved and an improvement in personalized treatment for CHF.

Exploring the biological mechanism of qi deficiency syndrome with chronic obstructive pulmonary disease(COPD)based on integrated pharmacology

Objective:To explore the potential biological mechanism of chronic obstructive pulmonary disease(COPD)qi deficiency syndrome,we used the integrated pharmacology network computing platform and carried out experimental verification.Methods:Using an integrated pharmacology strategy to analyze the potential biological targets of COPD qi deficiency syndrome.Based on the established qi deficiency syndrome rat model of COPD,the biological targets of lung and skeletal muscle were detected by electron microscopy,adenosine triphosphate(ATP)content assays,and western blotting.Results:According to the integrated pharmacological results,it was found that the locations of cell components related to COPD qi deficiency syndrome were mainly mitochondria.Electron microscopy results using lung tissue showed that mitochondria in the lipopolysaccharide(LPS group)and pulmonary instillation of LPS combined with cigarette smoke(LPStCS group)were swollen,deformed,and fragmented,with disappearing or broken crista.Results also showed that the total content of ATP in the lung and skeletal muscle of both groups was significantly lower than that in the control group at the 12th week(P<.05).At the 12th week,the expression of dynamin-related protein 1(DRP1)and mitofusin 1(MFN1)protein was significantly difference than that of the control group(P<.05).At the 10th and 14th weeks,changes in fission and fusion proteins in mitochondria of the lung and skeletal muscle were further detected.There was also a significant difference in the expression between the two groups compared to that in the control group at the 10th week and 14th week(P<.05).Conclusion:These findings suggest that the changes in mitochondrial morphology and ATP content and the unbalanced expression of DRP1 and MFN1 might be the key mechanisms underlying qi deficiency syndrome in rats with COPD.

Astragalus Salvia Granules to Benefit the Qi (Qishen Yiqi Keli) protects H9C2 cardiomyocytes by suppressing oxidative stress

Objective:To investigate the effects of Qishen Yiqi Keli(QSYQ;Astragalus Salvia Granules to Benefit the Qi)on ROS scavenging and inhibition of NADPH oxidase in an effort to identify new natural antioxidants.Methods:A total of 23 representative components in QSYQ were investigated,their effects on hydrogen peroxide induced ROS were assayed by dichlorofluorescein assay.Lucigenin chemiluminescence was adopted to test the effect on NADPH oxidase activity in H9C2 cardiomyocyte cells,and pyrogallol autoxidation was adopted to test the superoxide scavenging capacity.Results:Nine compounds in QSYQ could significantly inhibited H2O2-induced ROS increase compared with the model group(P<.05),including tanshinone I,salvianolic acid A,danshinone IIA,and cryptotanshinone from salvia root,luteolin from salvia root,harpagoside,harpagide,and angoroside C from scrophularia root.Nine compounds in QSYQ could significantly inhibited the production of
O2in H9C2 cell.Tanshinone I showed a lowest IC50 value 0.07 mM,the other including salvianolic acid A,cryptotanshinone,and salvianolic acid B,luteolin,isochlorogenic acid C,astragaloside IV,and glycyrrhetinic acid.Licochalcone A inhibited the autoxidation of pyrogallol at a low concentration,and tanshinone I showed no significant inhibitory effect from 2 mM to 20 mM.Conclusion:QSYQ had significant effects on ROS scavenging and inhibition of NADPH oxidase.Tanshinone I and salvianolic acid A are potential NADPH oxidase inhibitors.

Biological basis of “depression with liver-qi stagnation and spleen deficiency syndrome”: A digital gene expression profiling study

Objective:To investigate the biological basis of“depression with liver-qi stagnation and spleen deficiency syndrome”.Methods:A digital gene expression profiling method was conducted to explore global changes in the mRNA transcriptome in a rat model of depression with liver-qi stagnation and spleen deficiency syndrome.Real-time quantitative polymerase chain reaction(q-PCR)was performed to verify the five genes most interest based on the Kyoto Encyclopedia of Genes and Genome(KEGG)analysis.Sini San,which disperses stagnated liver qi and strengthens the spleen,was administered to the model rats to observe whether it could reverse these genetic changes in the liver.Results:Forty-six differentially expressed genes were identified.Three of the five genes of most interestdHnf4a,Hnf4g and Cyp1a1dbased on KEGG analysis,were confirmed by realtime q-PCR.Sini San reduced the gene expression changes of Hnf4a,Hnf4g and Cyp1a1 in the rat model.Conclusions:Hnf4a,Hnf4g and Cyp1a1 are involved in“depression with liver-qi stagnation and spleen deficiency syndrome”.These findings indicate that depressed rats with liver-qi stagnation and spleen deficiency syndrome are at risk of liver diseases.Furthermore,our results will inform exploration of the etiology of depression and help in the development of effective therapeutic strategies.

Protective effects of Pulsatilla chinensis Regel against isoproterenol-induced heart failure in mice

Objective:To study the cardioprotective effect of Baitouwen(Pulsatilla chinensis Regel,PR)in isoproterenol(ISO)induced heart failure in mice,and investigated the molecular targets using network pharmacological prediction and experimental validation.Methods:PR were orally administered to ISO induced HF mice for two weeks.The cardiac function was analyzed by echocardiography.Hematoxylin-eosinstaining(HE)was used to evaluate the pathological changes.The PR targets for HF were predicted by bioinformatics analysis tool(BATMAN-TCM).The expression of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),and HF related genes Phosphodiesterase(PDEs),were detected by real-time fluorescence quantitative PCR or Immunohistochemical staining in heart tissues.Results:Cardiac hypertrophy was observed after ISO treatment,and hypertrophic cardiomyocytes were arranged in disorder.Moreover,the expression of ANP and BNP gene in myocardium were upregulated(P<0.05).Treatment of HF mice with PR aqueous extract improved cardiac function characterized by enhanced ejection fraction(EF)and fraction shortening(FS).Furthermore,PR extract also downregulated the expression of ANP and BNP in the heart tissues.Arrangement of cardiomyocytes was also improved.Furthermore,administration of PR group decreased target genes PDE5 and PDE1C expression in the hearts.In addition,PR treatment also improved myocardial fiber distribution and decreased myocardial thickness in the hearts of HF mice.Conclusion:PR treatment may suppress cardiac hypertrophy and improve myocardial function in HF mice via inhibiting the predicted targets PDE5 expression.These results suggest the potential of using PR in preventing the development of HF.

Effects of Sini San used alone and in combination with fluoxetine on central and peripheral 5-HT levels in a rat model of depression

OBJECTIVE: To investigate the effects of Sini San and fluoxetine on the levels of central and peripheral 5-HT in a rat model of depression, and provide new insight into the treatment of depression with integrated Chinese-Western Medicine.METHODS: A rat model of depression was established by chronic mild stress(CMS). Model rats received either Sini San, fluoxetine, a combination of the two drugs, or no drug treatment. Healthy naive rats were used as controls. Open field and sucrose preference tests were used to assess depression-like behavior. ELISA and immunohistochemistry were used to determine central and peripheral levels of 5-HT.RESULTS: In the group with no drug treatment,central 5-HT expression decreased while peripheral5-HT concentrations increased as CMS continued.Four weeks after CMS, Sini San alone was less effective in reducing depression-like behavior than fluoxetine alone or in combination with Sini San,but combined use was more effective than fluoxetine alone. Eight weeks after CMS, Sini San alone or in combination with fluoxetine was more effective in reducing depression-like behavior than fluoxetine alone. Furthermore Sini San and fluoxetine used alone or in combination notably increased central 5-HT expression and decreased peripheral 5-HT levels in the rat model.CONCLUSION:The results of the present study indicate that there is a synergistic action between the two medicines in the treatment of depression. Sini San exhibited a relatively long lag before its effects were observed; however, by eight weeks the Traditional Chinese Medicine appeared at least as effective as fluoxetine. We suggest that Sini San can replace fluoxetine in the later stages of depression treatment to minimize side effects observed with long-term fluoxetine administration.

A COVID-19 Outbreak Emerging in a Food Processing Company——Harbin City,Heilongjiang Province,China,January-February 2021

Summary What is already known about this topic?The coronavirus disease 2019(COVID-19)epidemic in China had been effectively controlled for several months,but as the ambient temperature dropped,large gathering-initiated epidemics occurred in northern China,including Hebei,Liaoning,and Jilin provinces.