Depression is a psychological disease with no particularly effective therapy currently available.In the present study,we aimed to examine the antidepressive activity of a pharmaceutical Chinese medicine called TaiZi(T...Depression is a psychological disease with no particularly effective therapy currently available.In the present study,we aimed to examine the antidepressive activity of a pharmaceutical Chinese medicine called TaiZi(TZ)capsule,consisting of total polysaccharides of Radix Pseudostellariae and total flavonoids of both Radix Pueraria and Herba Epimedii.A tail suspension test and forced swimming test were performed to assess the effect of TZ in vivo.A plasmid of TPH2(tryptophan hydroxylase-2)was constructed to determine the exact target of TZ in vitro.In addition,mRNA expression was detected using a real-time PCR assay,and the protein expression was investigated using a Western blotting analysis.The results showed that TZ had an anti-depression effect in mouse and rat models with increased serotonin in the brain,and in the upregulation of mRNA and protein expression of TPH2 in the brain simultaneously by inhibition of NRSF(neuron restrictive silencer factor)expression because NRSF could bind to NRSE(neuron restrictive silencer element)to repress TPH2 transcription during the depression conditions.Icariin could bind to NRSE directly and block NRSF protein toward to NRSE for TPH2 inhibition.Therefore,we concluded that TZ had potential antidepressive effects because it could ameliorat the depression-like behavior in the animals,and the underlying mechanism of the effect was involved in NRSF/NRSE-TPH2 signaling.Icariin was identified as the active component of TZ.This study provided a new perspective for the development of antidepression drugs(Chinese medicines)based on NRSF/NRSE-TPH2 signaling.展开更多
Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium(EF)and possess excellent therapeutic effects on various diseases.Encouragingly,in 2022,icaritin soft capsules were approve...Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium(EF)and possess excellent therapeutic effects on various diseases.Encouragingly,in 2022,icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma(HCC)by National Medical Products Administration(NMPA)of China.Moreover,recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects.Nonetheless,both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content,poor bioavailability,and unfavorable in vivo delivery efficiency.Recently,various strategies,including enzyme engineering and nanotechnology,have been developed to increase productivity and activity,improve delivery efficiency,and enhance therapeutic effects of epimedium flavonoids.In this review,the structure-activity relationship of epimedium flavonoids is described.Then,enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed.The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized.Finally,the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.展开更多
OBJECTIVE:To evaluate the effects of a combination of Yinyanghuo(Herba Epimedii Brevicornus)(HEB)and Cheqianzi(Semen Plantaginis)(SP)on erectile dysfunction caused by essential hypertension in spontaneously hypertensi...OBJECTIVE:To evaluate the effects of a combination of Yinyanghuo(Herba Epimedii Brevicornus)(HEB)and Cheqianzi(Semen Plantaginis)(SP)on erectile dysfunction caused by essential hypertension in spontaneously hypertensive rats(SHRs),and to elucidate the role of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor(ACE2/Ang[1-7]/Mas receptor)axis in this process.METHODS:A total of 24 SHRs were randomly assigned to three groups:SHR-control,low-dose(12.5 g/kg)and high-dose(25 g/kg)HEB+SP(HEBSP).Eight Wistar-Kyoto rats were used as normal controls.HEBSP was administered by oral gavage for 28 d.Erectile function was measured once a week using the Heaton test.After 4 weeks of treatment,the corpus cavernosum was harvested from each rat to measure nitric oxide(NO),nitric oxide synthase(e NOS)and Ang(1-7)levels,as well as ACE2,Mas receptor and neuronal nitric oxide synthase(n NOS)protein expression.RESULTS:After 4 weeks of treatment,HEBSP significantly increased erectile function in the treated group compared with SHR-control group(P<0.01).Additionally,HEBSP treatment significantly increased cavernosal levels of Ang(1-7),e NOS and NO.Moreover,HEBSP significantly elevated the expression levels of ACE2,Mas receptor and n NOS.These beneficial effects were elevated in the high-dose HEBSP group.CONCLUSION:HEBSP improved erectile function in SHRs by upregulating the ACE2/Ang(1-7)/Mas receptor axis,e NOS and n NOS pathways.展开更多
OBJECTIVE:To identify active compounds in an Yinyanghuo(Herba Epimedii Brevicornus)-Xianmao(Rhizoma Curculiginis)drug pair(ECD)and investigate its efficacy on polycystic ovary syndrome(PCOS),and its possible mechanism...OBJECTIVE:To identify active compounds in an Yinyanghuo(Herba Epimedii Brevicornus)-Xianmao(Rhizoma Curculiginis)drug pair(ECD)and investigate its efficacy on polycystic ovary syndrome(PCOS),and its possible mechanism in a rat model of PCOS.METHODS:A network pharmacology approach involving a characteristic drug assessment,active compound and target prediction,PCOS gene collection as well as network analysis was employed.The ovary morphology after treatment was observed using an animal model and western blotting and real-time PCR were used to verify AKT1 as the molecular target.RESULTS:Six networks were constructed,an active compound-target network for the ECD(C-T network),a drug-target network(D-T network),a related genes network,a targets interaction network,a key genes interaction network,and a gene-pathway network.A total of 41 compounds and 261 targets were identified for the ECD,232 PCOS-related genes,31 cogenes,and 14 pathways.These pathways may be involved in the efficacy of ECD on PCOS.The proteins most involved in the signal pathways for all targets were AKT1,IL6,INSR,ESR,and GSK3B.The AKT1 target was selected for experimental verification.Based on the Western blot and real-time PCR results,the expression of AKT1 in the PCOS model varied after treatment with ECD.CONCLUSIONS:Our findings suggest that the ECD can reverse the negative morphological changes in ovarian tissue that occur in model rats of PCOS.AKT1 may be a key mediator of the observed ability of the ECD to protect against PCOS in the model rats.展开更多
OBJECTIVE:To integrate Meta-analysis and bioinformatics strategies in the preliminary exploration of the potential mechanism of Yinyanghuo(Herba Epimedii Brevicornus) and its extract in treating chronic obstructive pu...OBJECTIVE:To integrate Meta-analysis and bioinformatics strategies in the preliminary exploration of the potential mechanism of Yinyanghuo(Herba Epimedii Brevicornus) and its extract in treating chronic obstructive pulmonary disease(COPD).METHODS:First,Meta-analysis was carried out.The Chinese and English literature of Yinyanghuo(Herba Epimedii Brevicornus) in treating COPD was searched using the systematic strategy of combining subject words with free words.The included studies were evaluated by the SYRCLE risk bias assessment tool,after which the review manager software was used to combine the effect quantities for statistical analysis.Then,based on bioinformatics technology,the active ingredients and their targets of Yinyanghuo(Herba Epimedii Brevicornus) were screened,and the intersection genes were obtained by mapping and comparing with the targets of COPD.The "medicinal materials-compounds-targets model" was constructed,and the key pathways were annotated.Finally,the core target was docked with important compounds.RESULTS:A total of 8 studies were included in the Metaanalysis.The results showed that the Yinyanghuo(Herba Epimedii Brevicornus) group could significantly downregulate pro-inflammatory factors such as tumor necrosis factor-α(TNF-α) and interleukin(IL)-8 and increase the expression of anti-inflammatory factors and antioxidant factors such as IL-10 and phospho-protein kinase B(pAKT) in the COPD model(all P < 0.05).A total of 23 active components and 102 corresponding target genes of Yinyanghuo(Herba Epimedii Brevicornus) were obtained by bioinformatics technology,among which 17 compounds and 63 targets were closely related to COPD.The results of enrichment analysis mainly included TNF signaling pathway,phosphoinositide 3-kinase(PI3K)/Akt signaling pathway,cancer signaling pathway,and other inflammatory reactions,oxidative stress,and tumorrelated pathways.The molecular docking results showed that the binding energy fractions of the top five components of 24-epicampesterol with 10 core targets such as IL-6 were all less than ﹣5.0 kcal/mol,suggesting good binding ability.CONCLUSIONS:Meta-analysis and bioinformatics results indicated that the therapeutic effect of Yinyanghuo(Herba Epimedii Brevicornus) and its components on COPD might be related to antagonizing inflammation and oxidative stress.The above findings provide a preliminary basis for the development of Yinyanghuo(Herba Epimedii Brevicornus) as a natural drug for preventing and treating COPD.展开更多
<strong>Objective:</strong> To investigate the potential mechanism of Drynariae Rhizoma-Epimedii Folium in the treatment of osteoarthritis (OA) based on network pharmacology. <strong>Methods:</str...<strong>Objective:</strong> To investigate the potential mechanism of Drynariae Rhizoma-Epimedii Folium in the treatment of osteoarthritis (OA) based on network pharmacology. <strong>Methods:</strong> The potential active constituents and targets of Drynariae Rhizoma-Epimedii Folium were screened through the traditional Chinese medicine (TCM) systems pharmacology database and analysis platform (TCMSP). Genecards database is used to find relevant targets of OA. The targets of “Drynariae Rhizoma-Epimedii Folium” were mapped to the targets of OA, and used Cytoscape software to build a “drug-ingredient-target-di- sease” regulatory network and protein protein interaction (PPI) network. R software was used to analyze the Gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment of traditional Chinese medicine-disease targets. <strong>Results:</strong> Thirty-four effective ingredients and 130 traditional Chinese medicine-disease targets were screened out for the treatment of OA. The GO functions of traditional Chinese medicine-disease targets mainly included cytokine activity, cytokine receptor binding, nuclear receptor activity, transcription factor activity, proximal promoter DNA-binding transcription activator activity, DNA-binding transcription activator activity, phosphatase binding and so on. KEGG pathways involved in traditional Chinese medicine-disease targets mainly included TLR4 signaling pathway, TNF signaling pathway, IL-17 signaling pathway, MAPK signaling pathway, PI3K/AKT signaling pathway, apoptotic signaling pathway and so on. <strong>Conclusion:</strong> Network pharmacology may predict the multiple targets and multiple signaling pathways in Drynariae Rhizoma-Epimedii Folium treatment for OA, providing new ideas for future research.展开更多
Objective:EpimediiFolium(EF),a traditional Chinese medicinal material,has the effect of tonifying kidney Yang,strengthening bones and treating rheumatism.However,its clinical applications are limited by its drug-induc...Objective:EpimediiFolium(EF),a traditional Chinese medicinal material,has the effect of tonifying kidney Yang,strengthening bones and treating rheumatism.However,its clinical applications are limited by its drug-induced liver injury(DILI)effects and the underlying mechanisms have not been elucidated.Methods:Active EF compounds were obtained from the TCMSP database and their targets predicted in Targetnet.Next,DILI-targets were obtained from CTD,Genecards and Digsee databases.Protein-protein interactions of EF DILI-targets were determined using STRING and hub targets identified via topological analyses.Then,hub targets were subjected to GO and KEGG pathway enrichment analyses.Finally,HepaRG cells were used for further validation of molecular mechanisms.Results:Fifty seven active compounds and 164 targets that interacted with these active compounds were identified with Sagittatoside A,icariside I,and Icariin being the best active compounds.Enrichment analysis revealed the PI3K/Akt and NF-kB signaling pathways to be markedly enriched.Molecular docking revealed that Sagittatoside A,icariside I and Icariin had good binding activities to RAC1,PTGS2,and NOS3.Validation analysis in HepaRG cells revealed that Epimedium flavonoids upregulated RAC1,PTGS2 and NOS3 levels.Conclusion:Our findings show that EF induces oxidative stress,inflammation,and apoptosis via PI3K/Akt and NF-kB signaling pathways,and provides a basis for more in-depth studies on EF-induced DILI.展开更多
Epimedii Folium(EF)combined with Psoraleae Fructus(PF)is a common modern preparation,but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years.Zh...Epimedii Folium(EF)combined with Psoraleae Fructus(PF)is a common modern preparation,but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years.Zhuangguguanjiewan pills(ZGW),which contain EF and PF,could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide(LPS)model.This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model.Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats;however,EF or PF alone could lead to liver injury in LPS-treated rats.Moreover,EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats.Furthermore,EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production,implying that IL-1β,which is processed and released by activating the NLRP3 inflammasome,is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity.Thus,EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome.In addition,the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model,suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways.Therefore,EF and PF combination indicates traditional Chinese medicine incompatibility,considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.展开更多
Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely u...Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely used herbal medicine,has shown to cause idiosyncratic liver injury,but the underlying mechanisms are poorly understood.Increasing evidence has indicated that most cases of IDILI are immune mediated.Here,we report that icarisideⅡ(ICSⅡ),the major active and metabolic constituent of EF,causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation.ICSⅡexacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate(ATP)and nigericin,but not silicon dioxide(SiO2),monosodium urate(MSU)crystal or cytosolic lipopolysaccharide(LPS).Additionally,the activation of NLRC4 and AIM2 inflammasomes is not affected by ICSⅡ.Mechanistically,synergistic induction of mitochondrial reactive oxygen species(mtROS)is a crucial contributor to the enhancing effect of ICSⅡon ATP-or nigericin-induced NLRP3 inflammasome activation.Importantly,in vivo data show that a combination of non-hepatotoxic doses of LPS and ICSⅡcauses the increase of aminotransferase activity,hepatic inflammation and pyroptosis,which is attenuated by Nlrp3 deficiency or pretreatment with MCC950(a specific NLRP3 inflammasome inhibitor).In conclusion,these findings demonstrate that ICSⅡcauses idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICSⅡmay be a risk factor and responsible for EF-induced liver injury.展开更多
Objective： To comparatively analyze the difference in the expression of 54 transcription factors in the hypothalamus using protein chips following the medication of Chinese drugs for Shen （肾）-tonification, Herba E...Objective： To comparatively analyze the difference in the expression of 54 transcription factors in the hypothalamus using protein chips following the medication of Chinese drugs for Shen （肾）-tonification, Herba Epimedii, and Fructus Ligustri lucidi （FL） to aged rats. Methods： Wistar rats, aged 15 months of SPF grade, were randomized into three groups, three males and three females in each group. They were medicated with Herba Epimedii decoction （HED, 0.14 g/kg）, Fructus Ligustri lucidi decoction （FLD, 0.12 g/kg）, and distilled water, respectively, twice a day for 15 days. The rats were sacrificed at the morning of the 16th day 1 h after medication, and their hypothalamus was taken and made into homogenate under an ice-bath for detecting the expression of transcription factors with chip technique. Results： The expressions of signal transduction and transcription activation factor-6 （Stat-6） and androgen receptor （AR） were up-regulated, and those of pre-B transcription factor1 （Pbx-1）, stat-1 and AP-2 were down-regulated in both HED and FLD treated groups, but these changes occurred mainly in female rats in the former while mainly in males in the latter. Conclusions： Chinese drugs for Shen-tonification could impact the expression of transcription factors in the hypothalamus of aged rats, dominantly on the neuro-endocrine factors responsible for the growth and development. The effects of drugs for tonifying Shen-yang and for tonifying Shen-yin are different, which is probably one of the pharmacological mechanisms of the Shen-tonifying drugs.展开更多
Background: Idiosyncratic drug-induced liver injury(IDILI) is a serious side effect of drugs, Epimedii Folium(EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to pert...Background: Idiosyncratic drug-induced liver injury(IDILI) is a serious side effect of drugs, Epimedii Folium(EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3(NLRP3) inflammasome. Fructus Ligustri Lucidi(FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusions: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.展开更多
中枢神经系统疾病(central nervous system diseases,CNSD)已成为日益严峻的全球性健康难题。中医药在CNSD方面展现独特的疗效与丰富的临床实践积累。淫羊藿Epimedii Folium作为一味传统中药,通过多靶点调控、多通路干预及多途径作用机...中枢神经系统疾病(central nervous system diseases,CNSD)已成为日益严峻的全球性健康难题。中医药在CNSD方面展现独特的疗效与丰富的临床实践积累。淫羊藿Epimedii Folium作为一味传统中药,通过多靶点调控、多通路干预及多途径作用机制在神经系统疾病的治疗中发挥重要作用。随着淫羊藿药理作用的不断深入研究,发现其活性成分淫羊藿苷、淫羊藿素、淫羊藿次苷Ⅱ等是治疗CNSD的主要物质基础。淫羊藿活性成分可通过抑制炎症反应与氧化应激、抑制β-淀粉样蛋白沉积与微管相关蛋白异常磷酸化、抑制细胞凋亡、调节细胞自噬、改善神经元功能、调节神经递质等途径在阿尔茨海默病、帕金森病、癫痫、多发性硬化、脑缺血再灌注损伤、焦虑障碍、抑郁症、精神分裂症等CNSD中发挥作用。通过总结淫羊藿活性成分及其复方干预CNSD的作用机制,为进一步开发药物与临床运用奠定理论基础,为淫羊藿在CNSD研究中提供新的治疗方案和思路。展开更多
目的研究淫羊藿女贞子配伍改善哮喘大鼠内源性糖皮质激素(Glucocorticoids,GC)抑制的作用机制。方法SD雄性大鼠,随机分为5组,分别是正常组、模型组、淫羊藿组、女贞子组、配伍组。卵蛋白致敏及激发建立大鼠哮喘模型,灌胃给予药物治疗2...目的研究淫羊藿女贞子配伍改善哮喘大鼠内源性糖皮质激素(Glucocorticoids,GC)抑制的作用机制。方法SD雄性大鼠,随机分为5组,分别是正常组、模型组、淫羊藿组、女贞子组、配伍组。卵蛋白致敏及激发建立大鼠哮喘模型,灌胃给予药物治疗2周。酶联免疫法检测大鼠血清促肾上腺皮质激素释放激素(Corticotropin-releasing hormone,CRH)、促肾上腺皮质激素(Adrenocorticotropic hormone,ACTH)、皮质酮(Corticosterone,CORT)水平,靶向代谢组学检测尿液内源性GC代谢物水平,免疫组化法检测肺羟基类固醇脱氢酶(Hydroxysteroid dehydrogenase,HSD)11B1、HSD11B2,及肾上腺细胞色素P450家族11亚家族B成员1(Cytochrome P450 family 11 subfamily B member 1,CYP11B1)、类固醇生成因子1(Steroid generating factor 1,SF1)的蛋白表达,蛋白免疫印迹法检测肝组织CYP11B1、SF1、HSD11B1、HSD11B2的蛋白表达。结果淫羊藿女贞子单用或合用能升高模型大鼠血清CRH、ACTH、CORT含量,改善尿液内源性GC代谢紊乱,上调肺组织HSD11B1、HSD11B2蛋白表达,肾上腺CYP11B1、SF1蛋白表达,肝组织HSD11B2、CYP11B1的蛋白表达。结论补肾药淫羊藿女贞子治疗哮喘的作用与调节下丘脑-垂体-肾上腺轴、调节GC合成或代谢途径关键因子表达、上调内源性GC水平,改善内源性GC紊乱有关。展开更多
基金The Student Research Training(SRT)Program of Tsinghua University(Grant No.1522T0221)the National Natural Science Foundation of China(Grant No.81374006 and 81073092)。
文摘Depression is a psychological disease with no particularly effective therapy currently available.In the present study,we aimed to examine the antidepressive activity of a pharmaceutical Chinese medicine called TaiZi(TZ)capsule,consisting of total polysaccharides of Radix Pseudostellariae and total flavonoids of both Radix Pueraria and Herba Epimedii.A tail suspension test and forced swimming test were performed to assess the effect of TZ in vivo.A plasmid of TPH2(tryptophan hydroxylase-2)was constructed to determine the exact target of TZ in vitro.In addition,mRNA expression was detected using a real-time PCR assay,and the protein expression was investigated using a Western blotting analysis.The results showed that TZ had an anti-depression effect in mouse and rat models with increased serotonin in the brain,and in the upregulation of mRNA and protein expression of TPH2 in the brain simultaneously by inhibition of NRSF(neuron restrictive silencer factor)expression because NRSF could bind to NRSE(neuron restrictive silencer element)to repress TPH2 transcription during the depression conditions.Icariin could bind to NRSE directly and block NRSF protein toward to NRSE for TPH2 inhibition.Therefore,we concluded that TZ had potential antidepressive effects because it could ameliorat the depression-like behavior in the animals,and the underlying mechanism of the effect was involved in NRSF/NRSE-TPH2 signaling.Icariin was identified as the active component of TZ.This study provided a new perspective for the development of antidepression drugs(Chinese medicines)based on NRSF/NRSE-TPH2 signaling.
基金supported by the National Natural Science Foundation of China(Grant No.:81873196)Sino-German Center for Research Promotion(Project No.:GZ1505)Chinese Scholarship Council,and Science and Technology Planning Projects of Jiaxing City(Project No.:2022AY10014).
文摘Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium(EF)and possess excellent therapeutic effects on various diseases.Encouragingly,in 2022,icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma(HCC)by National Medical Products Administration(NMPA)of China.Moreover,recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects.Nonetheless,both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content,poor bioavailability,and unfavorable in vivo delivery efficiency.Recently,various strategies,including enzyme engineering and nanotechnology,have been developed to increase productivity and activity,improve delivery efficiency,and enhance therapeutic effects of epimedium flavonoids.In this review,the structure-activity relationship of epimedium flavonoids is described.Then,enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed.The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized.Finally,the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.
文摘OBJECTIVE:To evaluate the effects of a combination of Yinyanghuo(Herba Epimedii Brevicornus)(HEB)and Cheqianzi(Semen Plantaginis)(SP)on erectile dysfunction caused by essential hypertension in spontaneously hypertensive rats(SHRs),and to elucidate the role of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor(ACE2/Ang[1-7]/Mas receptor)axis in this process.METHODS:A total of 24 SHRs were randomly assigned to three groups:SHR-control,low-dose(12.5 g/kg)and high-dose(25 g/kg)HEB+SP(HEBSP).Eight Wistar-Kyoto rats were used as normal controls.HEBSP was administered by oral gavage for 28 d.Erectile function was measured once a week using the Heaton test.After 4 weeks of treatment,the corpus cavernosum was harvested from each rat to measure nitric oxide(NO),nitric oxide synthase(e NOS)and Ang(1-7)levels,as well as ACE2,Mas receptor and neuronal nitric oxide synthase(n NOS)protein expression.RESULTS:After 4 weeks of treatment,HEBSP significantly increased erectile function in the treated group compared with SHR-control group(P<0.01).Additionally,HEBSP treatment significantly increased cavernosal levels of Ang(1-7),e NOS and NO.Moreover,HEBSP significantly elevated the expression levels of ACE2,Mas receptor and n NOS.These beneficial effects were elevated in the high-dose HEBSP group.CONCLUSION:HEBSP improved erectile function in SHRs by upregulating the ACE2/Ang(1-7)/Mas receptor axis,e NOS and n NOS pathways.
基金Supported by the Natural Science Foundation of Liaoning Province:Functional Identification and Molecular Regulation of mi R-26b-5p Associated with Premature Ovarian Failure(No.20170540373)Jinzhou Foundation for Science and Technology:Study on the Rule and Mechanism of Prescriptions for Premature Ovarian Failure Based on Network Pharmacology,China(No.16B1G35)。
文摘OBJECTIVE:To identify active compounds in an Yinyanghuo(Herba Epimedii Brevicornus)-Xianmao(Rhizoma Curculiginis)drug pair(ECD)and investigate its efficacy on polycystic ovary syndrome(PCOS),and its possible mechanism in a rat model of PCOS.METHODS:A network pharmacology approach involving a characteristic drug assessment,active compound and target prediction,PCOS gene collection as well as network analysis was employed.The ovary morphology after treatment was observed using an animal model and western blotting and real-time PCR were used to verify AKT1 as the molecular target.RESULTS:Six networks were constructed,an active compound-target network for the ECD(C-T network),a drug-target network(D-T network),a related genes network,a targets interaction network,a key genes interaction network,and a gene-pathway network.A total of 41 compounds and 261 targets were identified for the ECD,232 PCOS-related genes,31 cogenes,and 14 pathways.These pathways may be involved in the efficacy of ECD on PCOS.The proteins most involved in the signal pathways for all targets were AKT1,IL6,INSR,ESR,and GSK3B.The AKT1 target was selected for experimental verification.Based on the Western blot and real-time PCR results,the expression of AKT1 in the PCOS model varied after treatment with ECD.CONCLUSIONS:Our findings suggest that the ECD can reverse the negative morphological changes in ovarian tissue that occur in model rats of PCOS.AKT1 may be a key mediator of the observed ability of the ECD to protect against PCOS in the model rats.
基金Supported by National Natural Science Foundation of China:Construction of"Three Dimensional Model of Shenqi deficiency syndrome COPD-Bushenyigi Formulae-biomarker spectrum"of Traditional Chinese Medicine (No. 81760901)Tianshan Innovation Team Plan of Xinjiang:Traditional Chinese Medicine Research Team on Prevention and Treatment of Chronic Obstructive Pulmonary Disease (No. 2017D14013)。
文摘OBJECTIVE:To integrate Meta-analysis and bioinformatics strategies in the preliminary exploration of the potential mechanism of Yinyanghuo(Herba Epimedii Brevicornus) and its extract in treating chronic obstructive pulmonary disease(COPD).METHODS:First,Meta-analysis was carried out.The Chinese and English literature of Yinyanghuo(Herba Epimedii Brevicornus) in treating COPD was searched using the systematic strategy of combining subject words with free words.The included studies were evaluated by the SYRCLE risk bias assessment tool,after which the review manager software was used to combine the effect quantities for statistical analysis.Then,based on bioinformatics technology,the active ingredients and their targets of Yinyanghuo(Herba Epimedii Brevicornus) were screened,and the intersection genes were obtained by mapping and comparing with the targets of COPD.The "medicinal materials-compounds-targets model" was constructed,and the key pathways were annotated.Finally,the core target was docked with important compounds.RESULTS:A total of 8 studies were included in the Metaanalysis.The results showed that the Yinyanghuo(Herba Epimedii Brevicornus) group could significantly downregulate pro-inflammatory factors such as tumor necrosis factor-α(TNF-α) and interleukin(IL)-8 and increase the expression of anti-inflammatory factors and antioxidant factors such as IL-10 and phospho-protein kinase B(pAKT) in the COPD model(all P < 0.05).A total of 23 active components and 102 corresponding target genes of Yinyanghuo(Herba Epimedii Brevicornus) were obtained by bioinformatics technology,among which 17 compounds and 63 targets were closely related to COPD.The results of enrichment analysis mainly included TNF signaling pathway,phosphoinositide 3-kinase(PI3K)/Akt signaling pathway,cancer signaling pathway,and other inflammatory reactions,oxidative stress,and tumorrelated pathways.The molecular docking results showed that the binding energy fractions of the top five components of 24-epicampesterol with 10 core targets such as IL-6 were all less than ﹣5.0 kcal/mol,suggesting good binding ability.CONCLUSIONS:Meta-analysis and bioinformatics results indicated that the therapeutic effect of Yinyanghuo(Herba Epimedii Brevicornus) and its components on COPD might be related to antagonizing inflammation and oxidative stress.The above findings provide a preliminary basis for the development of Yinyanghuo(Herba Epimedii Brevicornus) as a natural drug for preventing and treating COPD.
文摘<strong>Objective:</strong> To investigate the potential mechanism of Drynariae Rhizoma-Epimedii Folium in the treatment of osteoarthritis (OA) based on network pharmacology. <strong>Methods:</strong> The potential active constituents and targets of Drynariae Rhizoma-Epimedii Folium were screened through the traditional Chinese medicine (TCM) systems pharmacology database and analysis platform (TCMSP). Genecards database is used to find relevant targets of OA. The targets of “Drynariae Rhizoma-Epimedii Folium” were mapped to the targets of OA, and used Cytoscape software to build a “drug-ingredient-target-di- sease” regulatory network and protein protein interaction (PPI) network. R software was used to analyze the Gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment of traditional Chinese medicine-disease targets. <strong>Results:</strong> Thirty-four effective ingredients and 130 traditional Chinese medicine-disease targets were screened out for the treatment of OA. The GO functions of traditional Chinese medicine-disease targets mainly included cytokine activity, cytokine receptor binding, nuclear receptor activity, transcription factor activity, proximal promoter DNA-binding transcription activator activity, DNA-binding transcription activator activity, phosphatase binding and so on. KEGG pathways involved in traditional Chinese medicine-disease targets mainly included TLR4 signaling pathway, TNF signaling pathway, IL-17 signaling pathway, MAPK signaling pathway, PI3K/AKT signaling pathway, apoptotic signaling pathway and so on. <strong>Conclusion:</strong> Network pharmacology may predict the multiple targets and multiple signaling pathways in Drynariae Rhizoma-Epimedii Folium treatment for OA, providing new ideas for future research.
文摘Objective:EpimediiFolium(EF),a traditional Chinese medicinal material,has the effect of tonifying kidney Yang,strengthening bones and treating rheumatism.However,its clinical applications are limited by its drug-induced liver injury(DILI)effects and the underlying mechanisms have not been elucidated.Methods:Active EF compounds were obtained from the TCMSP database and their targets predicted in Targetnet.Next,DILI-targets were obtained from CTD,Genecards and Digsee databases.Protein-protein interactions of EF DILI-targets were determined using STRING and hub targets identified via topological analyses.Then,hub targets were subjected to GO and KEGG pathway enrichment analyses.Finally,HepaRG cells were used for further validation of molecular mechanisms.Results:Fifty seven active compounds and 164 targets that interacted with these active compounds were identified with Sagittatoside A,icariside I,and Icariin being the best active compounds.Enrichment analysis revealed the PI3K/Akt and NF-kB signaling pathways to be markedly enriched.Molecular docking revealed that Sagittatoside A,icariside I and Icariin had good binding activities to RAC1,PTGS2,and NOS3.Validation analysis in HepaRG cells revealed that Epimedium flavonoids upregulated RAC1,PTGS2 and NOS3 levels.Conclusion:Our findings show that EF induces oxidative stress,inflammation,and apoptosis via PI3K/Akt and NF-kB signaling pathways,and provides a basis for more in-depth studies on EF-induced DILI.
基金supported by the National Natural Science Foundation of China(Nos.81874368 and 81630100)the Beijing Nova Program(No.Z181100006218001)+2 种基金the National Key Technology R&D Program(No.2015ZX 09501-004-001-008)the National Key R&D Program of China(No.2018YFC1707000)the National TCM Industry Science and Technology Program(No.201507004-4-2).
文摘Epimedii Folium(EF)combined with Psoraleae Fructus(PF)is a common modern preparation,but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years.Zhuangguguanjiewan pills(ZGW),which contain EF and PF,could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide(LPS)model.This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model.Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats;however,EF or PF alone could lead to liver injury in LPS-treated rats.Moreover,EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats.Furthermore,EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production,implying that IL-1β,which is processed and released by activating the NLRP3 inflammasome,is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity.Thus,EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome.In addition,the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model,suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways.Therefore,EF and PF combination indicates traditional Chinese medicine incompatibility,considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.
基金supported by National Natural Science Foundation of China(81874368,81630100,and 81903891)Beijing Nova Program(Z181100006218001,China)+1 种基金National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(2017ZX09301022 and 2018ZX09101002-001-002,China)the Innovation Groups of the National Natural Science Foundation of China(81721002)
文摘Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely used herbal medicine,has shown to cause idiosyncratic liver injury,but the underlying mechanisms are poorly understood.Increasing evidence has indicated that most cases of IDILI are immune mediated.Here,we report that icarisideⅡ(ICSⅡ),the major active and metabolic constituent of EF,causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation.ICSⅡexacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate(ATP)and nigericin,but not silicon dioxide(SiO2),monosodium urate(MSU)crystal or cytosolic lipopolysaccharide(LPS).Additionally,the activation of NLRC4 and AIM2 inflammasomes is not affected by ICSⅡ.Mechanistically,synergistic induction of mitochondrial reactive oxygen species(mtROS)is a crucial contributor to the enhancing effect of ICSⅡon ATP-or nigericin-induced NLRP3 inflammasome activation.Importantly,in vivo data show that a combination of non-hepatotoxic doses of LPS and ICSⅡcauses the increase of aminotransferase activity,hepatic inflammation and pyroptosis,which is attenuated by Nlrp3 deficiency or pretreatment with MCC950(a specific NLRP3 inflammasome inhibitor).In conclusion,these findings demonstrate that ICSⅡcauses idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICSⅡmay be a risk factor and responsible for EF-induced liver injury.
基金Supported by the National Natural Science Foundation of China (No.30672729)CHEN Ke-ji Development Fund of Integrative Medicine(No.CKJ2010025)
文摘Objective： To comparatively analyze the difference in the expression of 54 transcription factors in the hypothalamus using protein chips following the medication of Chinese drugs for Shen （肾）-tonification, Herba Epimedii, and Fructus Ligustri lucidi （FL） to aged rats. Methods： Wistar rats, aged 15 months of SPF grade, were randomized into three groups, three males and three females in each group. They were medicated with Herba Epimedii decoction （HED, 0.14 g/kg）, Fructus Ligustri lucidi decoction （FLD, 0.12 g/kg）, and distilled water, respectively, twice a day for 15 days. The rats were sacrificed at the morning of the 16th day 1 h after medication, and their hypothalamus was taken and made into homogenate under an ice-bath for detecting the expression of transcription factors with chip technique. Results： The expressions of signal transduction and transcription activation factor-6 （Stat-6） and androgen receptor （AR） were up-regulated, and those of pre-B transcription factor1 （Pbx-1）, stat-1 and AP-2 were down-regulated in both HED and FLD treated groups, but these changes occurred mainly in female rats in the former while mainly in males in the latter. Conclusions： Chinese drugs for Shen-tonification could impact the expression of transcription factors in the hypothalamus of aged rats, dominantly on the neuro-endocrine factors responsible for the growth and development. The effects of drugs for tonifying Shen-yang and for tonifying Shen-yin are different, which is probably one of the pharmacological mechanisms of the Shen-tonifying drugs.
基金supported by the State Key Program of National Natural Science of China (81930110)Military Logistics Research Project on Health Special Project (23BJZ33)the Key Project at Central Government Level: The ability establishment of sustainable use for valuable Chinese medicine resources (2060302)。
文摘Background: Idiosyncratic drug-induced liver injury(IDILI) is a serious side effect of drugs, Epimedii Folium(EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3(NLRP3) inflammasome. Fructus Ligustri Lucidi(FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusions: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.
文摘中枢神经系统疾病(central nervous system diseases,CNSD)已成为日益严峻的全球性健康难题。中医药在CNSD方面展现独特的疗效与丰富的临床实践积累。淫羊藿Epimedii Folium作为一味传统中药,通过多靶点调控、多通路干预及多途径作用机制在神经系统疾病的治疗中发挥重要作用。随着淫羊藿药理作用的不断深入研究,发现其活性成分淫羊藿苷、淫羊藿素、淫羊藿次苷Ⅱ等是治疗CNSD的主要物质基础。淫羊藿活性成分可通过抑制炎症反应与氧化应激、抑制β-淀粉样蛋白沉积与微管相关蛋白异常磷酸化、抑制细胞凋亡、调节细胞自噬、改善神经元功能、调节神经递质等途径在阿尔茨海默病、帕金森病、癫痫、多发性硬化、脑缺血再灌注损伤、焦虑障碍、抑郁症、精神分裂症等CNSD中发挥作用。通过总结淫羊藿活性成分及其复方干预CNSD的作用机制,为进一步开发药物与临床运用奠定理论基础,为淫羊藿在CNSD研究中提供新的治疗方案和思路。
文摘目的研究淫羊藿女贞子配伍改善哮喘大鼠内源性糖皮质激素(Glucocorticoids,GC)抑制的作用机制。方法SD雄性大鼠,随机分为5组,分别是正常组、模型组、淫羊藿组、女贞子组、配伍组。卵蛋白致敏及激发建立大鼠哮喘模型,灌胃给予药物治疗2周。酶联免疫法检测大鼠血清促肾上腺皮质激素释放激素(Corticotropin-releasing hormone,CRH)、促肾上腺皮质激素(Adrenocorticotropic hormone,ACTH)、皮质酮(Corticosterone,CORT)水平,靶向代谢组学检测尿液内源性GC代谢物水平,免疫组化法检测肺羟基类固醇脱氢酶(Hydroxysteroid dehydrogenase,HSD)11B1、HSD11B2,及肾上腺细胞色素P450家族11亚家族B成员1(Cytochrome P450 family 11 subfamily B member 1,CYP11B1)、类固醇生成因子1(Steroid generating factor 1,SF1)的蛋白表达,蛋白免疫印迹法检测肝组织CYP11B1、SF1、HSD11B1、HSD11B2的蛋白表达。结果淫羊藿女贞子单用或合用能升高模型大鼠血清CRH、ACTH、CORT含量,改善尿液内源性GC代谢紊乱,上调肺组织HSD11B1、HSD11B2蛋白表达,肾上腺CYP11B1、SF1蛋白表达,肝组织HSD11B2、CYP11B1的蛋白表达。结论补肾药淫羊藿女贞子治疗哮喘的作用与调节下丘脑-垂体-肾上腺轴、调节GC合成或代谢途径关键因子表达、上调内源性GC水平,改善内源性GC紊乱有关。
