Effect of borneol and electroacupuncture on the distribution of hyperforin in the rat brain

Hyperforin is an antidepressant drug that has unstable therapeutic effects, due to its poor ability to cross the blood-brain barrier. Borneol and electroacupuncture have both been found to increase the permeability of the blood-brain barrier. As such, the current study examined the distribution of hyperforin in the rat brain, and the effects on the brain distribution of hyperforin of borneol alone （orally administered）, and borneol combined with electroacupuncture treatment. High-performance liquid chromatography technology and pharmacokinetic analysis revealed that treatment with borneol alone （300, 600 mg/kg） increased peak concentration and the area under the curve for hyperforin in the brain. In addition, the bioavailability of hyperforin in rat brain increased by 42.7%. However, increasing the dose of borneol dose did not appear to increase the distribution of hyperforin in the brain. Importantly, applying electroacupuncture at Baihui （GV 20） or Yamen （GV 15） appeared to enhance the brain-delivery effects of borneol, although this effect was weak. Overall, our results indicated that borneol alone or combined with electroacupuncture can provide promising strategies for brain-targeted delivery in central nervous system therapy.

Super Antibiotics, Part II. Hyperforin, Mass Spectroscopy (MS) and Gas Chromatography-Mass Spectrometry (GC-MS), Evidence of Permeability of the Blood-Testis Barrier (BTB) and the Blood-Brain Barrier (BBB) to Hyperforin

In the first article of this series, we presented some evidence of hyperforin as an antibiotic, antiprotozoal, antiviral, anticancer, and immunomodulatory substance. In the present article, evidence of the permeability of the blood-testis barrier (BTB) and blood-brain barrier (BBB) to hyperforin and its distribution in other organs of the domestic pig (Sus scrofa domesticus) are revealed. Seven-month-old male boars with a body mass of 100 kg were fed a diet containing hyperforin. Organs were surgically removed under anesthesia. Organs were suitable prepared and extracted, and then analyzed using gas chromatography-mass spectrometry with supersonic molecular beams (GC-MS with SMB). The presence of hyperforin was recorded in all organs and body fluids. Special attention was paid to the evaluation of the presence of hyperforin in the brain and testes of experimental animals. The presence of hyperforin in the brain and testes of experimental animals was established by GC-MS with SMB. The results are of interest because penicillin and numerous other antibiotics cannot pass through the BTB or BBB if healthy or non-inflamed, which limits their use in patients with meningitis and gonorrhea. The findings are also of interest in cases of penicillin- and multi-antibiotic-resistant bacterial infections.

Super Antibiotics, Part IV. Hyperforin, Relative and Absolute Stereochemistry Elucidated by Gas-Chromatography Mass-Spectrometry with Supersonic Molecular Beams

Relative and absolute stereochemistry for hyperforin has been proposed by Brondz et al. was supported and new isomer of hyperforin-perforatrin has been discovered. Relative and absolute stereochemistry for perforatrin was proposed and elucidated by using gas-chromatography mass-spectrometry with supersonic molecular beams (SMB). The possibility of the existence of ambiguities in chirality as a hypothesis for the existence, and a new understanding, of chiral substances with shifting chirality is presented.

Super Antibiotics, Part VI: Hyperforin, Revision of Stereochemistry. Short Communications

This short communication is an overview and revision of previous published papers about the relative and absolute stereochemistry of hyperforin and discovery of a new isomer of hyperforin that has been named perforatrin.

Recent enhancement of the immunity in AIDS and other immunocompromised patients by hyperforin an antibiotic from <i>Hypericum perforatum</i>L. (<i>in vitro</i>model) part I

Today, Hypericum perforatum L. is probably one of the best-characterized medicinal plants, and hyperforin is its best-characterized constituent. Extracts from H. perforatum are widely used as antidepressants;however, less attention has been given to other properties of hyperforin, such as antitumor, fungicidal, antiviral and antibacterial action, or its possible use as a substance with immunomodulation properties. The present study summarizes results that describe the influence of hyperforin as an immunomodulation agent on phagocytosis and the breakdown of Escherichia coli by human polymorphonuclear neutrophils (PMNs). Hyperforin at 1 - 100 μg/mL concentrations was found to have a major influence on phagocytosis and the breakdown of E. coli by PMNs in vitro. A 100 μg/mL solution of hyperforin increased the uptake of non-opsonized E. coli almost 50-fold, and the uptake of IgG-opsonized E. coli more than threefold;on the other hand, the uptake of serum-opsonized bacteria was reduced to approximately 60% of that of the control. Hyperforin seems to bind to both PMNs and E. coli and acts like an opsonin. The elimination of remnants of IgG-opsonized E. coli from the PMNs was stimulated by hyperforin, while the elimination of remnants from non-op-so nized and serum-opsonized material was unaffected by the drug. Hyperforin exhibited clear immunomodulation ability as a phagocytosisstimulating agent. Hyperforin is probably inactive against human immunodeficiency virus (HIV) and most Gram-negative bacteria. However, it can protect acquired immunodeficiency syndrome (AIDS) patients and other immunocompromised patients by its antibacterial activity against Gram-positive bacteria and by enhancement of phagocytosis of Gram-positive and Gram-negative bacteria;some Gram-negative bacteria, such as Neisseria, are sensitive to hyperforin. Hyperforin has the ability to penetrate the blood-brain barrier (BBB) and blood-testis barrier (BTB) and is a valuable antibacterial agent against meningitis and gonorrhea. These properties of hyperforin are important for an antibiotic with immunomodulation activity in the struggle against the growing mortality in AIDS patients as a result of opportunistic bacteria, as recently shown by Bekondi et al. (2006, Int. J. Infect. Dis. 10, 387-395). It could also help to combat primary and opportunistic pathogens associated with meningitis in adults' relation to HIV serostatus.

Single-cell RNA sequencing facilitates the elucidation of the complete biosynthesis of the antidepressant hyperforin in St. John's wort

Hyperforin is the compound responsible for the effectiveness of St.John's wort(Hypericum perforatum)as an antidepressant,but its complete biosynthetic pathway remains unknown.Gene discovery based on co-expression analysis of bulk RNA-sequencing data or genome mining failed to discover the missing steps in hyperforin biosynthesis.In this study,we sequenced the 1.54-Gb tetraploid H.perforatum genome assem-bled into 32 chromosomes with the scaffold N50 value of 42.44 Mb.By single-cell RNA sequencing,we iden-tified a type of cell,“Hyper cells”,wherein hyperforin biosynthesis de novo takes place in both the leaves and flowers.Through pathway reconstitution in yeast and tobacco,we identified and characterized four transmembrane prenyltransferases(HpPT1-4)that are localized at the plastid envelope and complete the hyperforin biosynthetic pathway.The hyperforin polycyclic scaffold is created by a reaction cascade involving an irregular isoprenoid coupling and a tandem cyclization.Our findings reveal how and where hy-perforin is biosynthesized,enabling synthetic-biology reconstitution of the complete pathway.Thus,this study not only deepens our comprehension of specialized metabolism at the cellularlevel but also provides strategic guidance for elucidation of the biosynthetic pathways of other specializied metabolites in plants.

中医情志病抑郁障碍的发病机制及贯叶连翘在抗抑郁领域中的研究进展

随着社会高速发展,抑郁症的患病率、致残率、致死率日益增高。其发病机制具有复杂性,异质性,尚未完全了解。目前的治疗方法机制不同效,正在广泛探讨中。本文总结了中医情志病抑郁障碍的发病机理和中医药抗抑郁的研究进展,着重阐述了贯叶连翘及其提取物金丝桃素的抗抑郁效果和分子机制。

Pseudohypericin and Hyperforin in Hypericum perforatum from Northern Turkey:Variation among Populations,Plant Parts and Phenological Stages

Hypericum perforatum is a perennial medicinal plant known as ＂St. John＇s wort＂ in Western Europe and has been used in the treatment of several diseases for centuries. In the present study, morphologic, phenologic and population variability in pseudohypericin and hyperforin concentrations among H. perforatum populations from Northern Turkey was investigated for the first time. The aerial parts of H. perforatum plants representing a total of 30 individuals were collected at full flowering from 10 sites of Northern Turkey to search the regional variation in the secondary metabolite concentrations. For morphologic and phenologic sampling, plants from one site were gathered in five phenological stages： vegetative, floral budding, full flowering, fresh fruiting and mature fruiting. The plant materials were air-dried at room temperature and subsequently assayed for chemical concentrations by high performance liquid chromatography. Secondary metabolite concentrations ranged from traces to 2.94mg/g dry weight （DW） for pseudohypericin and traces -6.29mg/g DW for hyperforin. The differences in the secondary metabolite concentrations among populations of H. perforatum were found to be significant. The populations varied greatly in hyperforin concentrations, whereas they produced a similar amount of pseudohypericin. Concentrations of both secondary metabolites in all tissues increased with advancing of plant development and higher accumulation levels were reached at flowering. Among different tissues, full opened flowers were found to be superior to stems, leaves and the other reproductive parts with regard to pseudohypericin and hyperforin accumulations. The present findings might be useful to optimize the processing methodology of wild-harvested plant material and obtain increased concentrations of these secondary metabolites.

Targeting the biological activity and biosynthesis of hyperforin:amini-review

Hyperforin is a representative polycyclic polyprenylated acylphloroglucinols(PPAPs)that exerts a variety of pharmacological activities.The complete biosynthesis pathway of hyperforin has not been elucidated due to its complex structure and unclear genetic background of its source plants.This mini-review focuses on the bioactivity and biosynthesis of hyperforin.These analyses can provide useful insights into the biosynthesis investigations of hyperforin and other PPAPs with complex structures.

The antiangiogenic phloroglucinol hyperforin inhibits the secretion of proMMP-2, proMMP-9 and VEGF-A during apoptosis of primary acute myeloid leukemia cells

Aim:Angiogenesis is observed in acute myeloid leukemia(AML).AML cells abnormally proliferate and are resistant to death.Positive regulators of angiogenesis,VEGF-A and matrix metalloproteinases(MMPs)2 and 9 are markers of disease status in AML.The natural phloroglucinol hyperforin(HF)displays antitumoral properties of potential pharmacological interest.Herein,we investigated the effects of HF on MMP-2/9 and VEGF-A expression and survival of primary AML cells.Methods:Blood and bone marrow samples were collected in 45 patients with distinct subtypes defined by French American British classification,i.e.,M0,M1,M2,M3,M4,and M5.Levels of MMPs and VEGF-A in leukemic blood cells and culture supernatants were determined by RT-PCR,ELISA,and gelatin zymography(MMPs).The balance between cell death and survival was assessed by flow cytometry with analysis of phosphatidylserine externalization and caspase-3 activation.Results:The administration of HF promoted a caspase-associated apoptosis in primary AML blasts(from blood and bone marrow),but not normal blood cells and monocytes.In addition,HF inhibited the levels of secreted proMMP-2,proMMP-9,and VEGF-A without altering transcripts.The induction of apoptosis by HF significantly paralleled the inhibition of MMP-2/9 and VEGF-A release by HF.No differences were seen in response to the deleterious effects of HF between AML cells of distinct subtypes.Conclusion:Our results suggest that HF,through its proapoptotic and potential antiangiogenic properties(by inhibiting MMP-2/9 and VEGF-A)on primary AML cells,might be a useful experimental agent,in combination with existing drugs,for new therapeutic approaches in the treatment of this incurable disease.

贯叶金丝桃素在神经精神疾病中的作用机制研究

贯叶金丝桃素是中药贯叶金丝桃的重要活性成分,除了抗抑郁效果,贯叶金丝桃素在其他神经精神疾病中具有潜在的治疗作用。本文从其对神经递质、TRPC6、细胞因子影响等方面对现阶段贯叶金丝桃素在神经精神疾病中的作用机制进行归纳和阐述,为进一步深入研究奠定基础。

贯叶连翘抗抑郁研究新进展

贯叶连翘 ,又名圣约翰草 ,是传统中药材之一 ,圣约翰草在德国用于抗抑郁症已有几百年的历史。贯叶连翘提取物对轻度和中度抑郁症患者和动物模型都有很好疗效 ,最新药理学研究表明贯叶连翘提取物中抗抑郁的主要成分是贯叶金丝桃素。贯叶金丝桃素是神经递质 5 羟色胺 ( 5 HT)、多巴胺 (DA)、去甲肾上腺素 (NE)的非竞争性重吸收抑制剂 ,贯叶金丝桃素还可以抑制突触体对γ氨基丁酸 (GABA)和L 谷氨酸 (L glu)的重吸收 ,其作用机理至今还不甚明了 ,研究表明它的作用很可能是通过提高突触体细胞内钠离子浓度或通过降低突触体内突触小泡的跨膜pH梯度实现的。

贯叶金丝桃素及其衍生物的合成与神经药理学研究进展

贯叶金丝桃素是抗抑郁植物药贯叶连翘及其制剂的重要活性成分,具有独特的acylphlorogluciol结构,但其遇光、氧气、热极易发生化学氧化降解。贯叶金丝桃素除具有抗抑郁作用外,还具有抗肿瘤、抗菌、抗阿尔茨海默病、促进学习记忆等多方面的药理活性,是目前国际上研究的热点天然药物之一。综述近年来贯叶金丝桃素的结构修饰与改造的研究进展,总结了贯叶金丝桃素及其衍生物在抗抑郁、抗阿尔茨海默病等方面的神经药理活性,并在此基础上展望了以贯叶金丝桃素为先导化合物开发新药的研究前景。

贯叶金丝桃素的化学不稳定性及药理活性

贯叶金丝桃素是贯叶连翘植物的特征成分 ,由于其遇光后 ,极易发生化学氧化降解 ,一直未受重视。最近的研究发现 ,该化合物是贯叶连翘及其制剂抗抑郁的重要活性成分之一 ,其作用机制可能是多位点 ,并且与金丝桃素以及其他临床上常用的抗抑郁化学合成药物不同。通过加入化学保护剂 ,可以实现提取物或其制剂的质量控制与药品的安全稳定。贯叶金丝桃素除具有抗抑郁作用外 ,还具有抗肿瘤、抗菌与促进学习记忆等药理活性 ,是目前国际上研究的热点天然药物之一。

贯叶连翘醇提条件的多指标优化

本研究采用超声波提取法 ,对贯叶连翘中总黄酮、金丝桃素类和贯叶金丝桃素等主要有效成分在醇提过程中的提取条件 (溶媒种类、浓度、提取时间等 )进行了考察。结果表明 ,以总黄酮和金丝桃素类化合物为指标 ,用 6 5 %～ 80 %的乙醇水溶液超声提取 30min ,提取效率较高 ;以贯叶金丝桃素为指标 ,则以用 75 %～90 %的甲醇提取 30min效果较好。

槲皮素与贯叶连翘提取物合用抗抑郁作用初步研究

目的:比较不同剂量的槲皮素和贯叶连翘提取物(有效成分为贯叶金丝桃素hyperforin,HF)合用的抗抑郁效果,探索二者的协同作用。方法:雄性ICR小鼠,分为9组,即:空白对照组,阳性对照(帕罗西汀10 mg/kg)组,槲皮素组(A:5 mg/kg,B:10 mg/kg,C:20 mg/kg),贯叶连翘提取物(HF 10 mg/kg)组,合用组(A:2.5 mg/kg槲皮素+HF 5 mg/kg;B:5 mg/kg槲皮素+HF 5 mg/kg;C:10 mg/kg槲皮素+HF 5 mg/kg);灌胃给药。用利血平拮抗试验比较各组(n=11~12)拮抗利血平所致低体温、运动不能和低体温的作用,用小鼠悬尾实验比较各组(n=15)动物的悬尾不动时间。结果:合用B组的利血平拮抗作用和缩短悬尾不动时间的作用与合用C组无显著差异(P>0.05),其拮抗利血平所致低体温的作用极显著(P<0.01)强于槲皮素B组,其缩短小鼠悬尾不动时间的作用显著(P<0.05)或极显著(P<0.01)强于贯叶连翘提取物(HF 10 mg/kg)组或槲皮素B组。结论:槲皮素和贯叶连翘提取物在特定剂量比例合用时有协同抗抑郁作用。

贯叶连翘提取物的研究新进展

贯叶连翘提取物具有很高的药用价值,作为镇静剂、抗炎药、抗抑郁药、抗肿瘤药及爱滋病治疗药物具有广阔的应用前景,越来越受到人们的重视。介绍了贯叶连翘提取物的化学成分、提取分析方法、各成分的药理及功效,总结了提取物当前研究的最新水平,分析了未来研究的可行方向并提出关于药效机理研究的量子化学计算方法。

不同产地贯叶连翘中贯叶金丝桃素含量分析比较

目的 :比较不同产地贯叶连翘中贯叶金丝桃素的含量。方法 :采用反相高效液相法 (RP -HPLC)测定贯叶金丝桃素含量。结果与结论 :不同产地贯叶连翘中贯叶金丝桃素含量有差异 。

贯叶金丝桃(贯叶连翘)研究进展

介绍了贯叶金丝桃的植物形态及分布，化学成分及分布规律，采集、干燥、加工、贮存及质量标准，药理及临床应用，国外管理现状等五方面的情况。

茉莉酸甲酯(MeJA)对贯叶连翘悬浮细胞生长和贯叶金丝桃素产量的影响

培养基中添加100μmol·L-1MeJA后,贯叶连翘悬浮细胞生物量增加量和贯叶金丝桃素(HF)的产量分别是未经MeJA处理的1.3倍和1.73倍;培养3d时,培养基中添加100μmol·L-1MeJA能提高HF产量,是未经MeJA处理的2.4倍。