Medicinal Plant Hypericum Research Articles

Technology of Cultivation of Medicinal Preparation “Hуperiсum Perfоratum I”

In the article, the medicinal properties, botanical description of the promising medicinal plant Hypericum perforatum species are studied, and the morpho-biological characteristics of the Hypericum perforatum species in the gray soils of Samarkand region are based on the comparative aspect. Depending on the planting conditions and periods of Hypericum perforatum, the seed yield, phytomass yield was determined, and recommendations for the cultivation of quality seeds and raw materials were developed.

Cellular neurobiology of hyperforin.

Hyperforin is a phloroglucinol derivative isolated from the medicinal plant Hypericum perforatum (St John's wort, SJW). This lipophilic biomolecule displays antibacterial, pro-apoptotic, antiproliferative, and anti-inflammatory activities. In addition, in vitro and in vivo data showed that hyperforin is a promising molecule with potential applications in neurology and psychiatry. For instance, hyperforin possesses antidepressant properties, impairs the uptake of neurotransmitters, and stimulates the brain derived neurotrophic factor (BDNF)/TrkB neurotrophic signaling pathway, the adult hippocampal neurogenesis, and the brain homeostasis of zinc. In fact, hyperforin is a multi-target biomolecule with a complex neuropharmacological profile. However, one prominent pharmacological feature of hyperforin is its ability to influence the homeostasis of cations such as Ca2+ , Na+ , Zn2+ , and H+ . So far, the pathophysiological relevance of these actions is currently unknown. The main objective of the present work is to provide an overview of the cellular neurobiology of hyperforin, with a special focus on its effects on neuronal membranes and the movement of cations.

Impact of habitat variability on phenotypic attributes of Hypericum Perforatum L. along an elevational gradient in Kashmir Himalaya

A number of environmental factors such as mean temperature, precipitation, soil characteristics etc. changes with elevational gradient and thereby, affect the morphological pattern of a plant species. Phenotypic attributes of a particular species varies along different altitudes in order to adapt and also to overcome these changeable and stressful conditions. The present study was undertaken to assess the distribution pattern and impact of habitat variability along an elevational gradient on morphology of an important medicinal plant Hypericum perforatum L. growing in the Kashmir Himalaya. Hypericum perforatum L., member of family Hypericaceae, is a perennial herb and distributed in North Western Himalaya. The species exhibited distinct variability and a peculiar trend in morphological traits in response to different environmental conditions along an elevational gradient.

Genomic and Metabolomic Insights into Secondary Metabolites of the Novel Bacillus halotolerans Hil4, an Endophyte with Promising Antagonistic Activity against Gray Mold and Plant Growth Promoting Potential.

The endophytic bacterial strain Hil4 was isolated from leaves of the medicinal plant Hypericum hircinum. It exhibited antifungal activity against Botrytis cinerea and a plethora of plant growth promoting traits in vitro. Whole genome sequencing revealed that it belongs to Bacillus halotolerans and possesses numerous secondary metabolite biosynthetic gene clusters and genes involved in plant growth promotion, colonization, and plant defense elicitation. The Mojavensin cluster was present in the genome, making this strain novel among plant-associated B. halotolerans strains. Extracts of secreted agar-diffusible compounds from single culture secretome extracts and dual cultures with B. cinerea were bioactive and had the same antifungal pattern on TLC plates after bioautography. UHPLC-HRMS analysis of the single culture secretome extract putatively annotated the consecutively produced antimicrobial substances and ISR elicitors. The isolate also proved efficient in minimizing the severity of gray mold post-harvest disease on table grape berries, as well as cherry tomatoes. Finally, it positively influenced the growth of Arabidopsis thaliana Col-0 and Solanum lycopersicum var. Chondrokatsari Messinias after seed biopriming in vitro. Overall, these results indicate that the B. halotolerans strain Hil4 is a promising novel plant growth promoting and biocontrol agent, and can be used in future research for the development of biostimulants and/or biological control agents.

Nitrogen modulates strontium uptake and toxicity in Hypericum perforatum plants

Strontium is an unavoidable element occurring in plants due to its abundance in the soil and similarity with calcium. To mimic natural conditions, impacts of additional inorganic (nitrate) or organic (urea and allantoin) nitrogen sources (1 mM of each N form in addition to 3.53 mM N in the basic cultivation solution) or N deficit on strontium-induced changes (100 µM Sr) in the widely used medicinal plant Hypericum perforatum L. were studied. Though various effects of Sr on primary (stimulation of amino acids but depression of most Krebs acids, ascorbic acid and thiols) and secondary metabolites (stimulation of phenols but no change of pseudo/hypericin) or mineral elements were observed (reduction of Ca amount in both shoots and roots), organic N forms often mitigated negative action of Sr or even combined stimulatory impact was observed. Organic N forms also elevated shoot accumulation of Sr while N deficit reduced it. Additional N forms, rather than Sr itself, modulated reactive oxygen species and nitric oxide formation in the root tissue. Germination experiment showed no toxicity of Sr to H. perforatum up to 1 mM Sr and even stimulated accumulation of amino acids and phenols, indicating similar ontogenetic-related responses.

An assessment of ITS rDNA PCR-based molecular identification, and characterization of fungal endophytes isolated from Hypericum japonicum

Traditionally used herbs have been recognized as an important niche for fungal endophytes and the interaction between them has prompted the invention of novel metabolite. In this regard, the present investigation has been conducted to isolate the fungal endophytes from a traditionally used medicinal plant Hypericum japonicum and discuss their antioxidant potential together with the plant growth-promoting activity. The use of ITS-rDNA based strategies to outline the link of fungal endophytes of different genera could extend the difficulties that have grown from conventional taxonomical classification strategies. The present study has successfully differentiated two fungal endophytes such as Aspergillus flavus and Fusarium equiseti at the species level from Hypericum japonicum. The antioxidant potential of the fungal isolates from this study offers insights into the developments of bio-active metabolites which are essential to enhance the plant growth. Such inoculants can be used to develop a sustainable system.

Determination of Potential Drug Candidate Molecules of the Hypericum perforatum for COVID-19 Treatment.

The novel human coronavirus was firstly emerged in December 2019 in Wuhan, China, and has spread rapidly around the world. There is no known specific effective treatment of COVID-19. The most commonly used agents against this disease both in Turkey and around the world include chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir, and remdesivir. In the study, we investigated the drug potential of molecules that the components of an important medicinal plant Hypericum perforatum by using molecular docking and drug possibility properties of these molecules. The molecular docking results showed that the most stable complex was obtained with COVID-19 main protease and hypericin/isohypericin ligands with − 11 kcal/mol binding energy. Furthermore, ADMET, drug-likeness features of compounds of H. perforatum were investigated using the rules of Lipinski, Veber, and Ghose. According to the results obtained, it has been shown that H. perforatum has the potential to be an effective drug in the COVID-19 pandemic. In the next stage, it is necessary to carry out the clinically necessary reliability studies of these components. It is thought that it can be used for the treatment of COVID-19 if our molecular docking results are found to be in high correlation with clinical studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40495-021-00254-9.

Kuraklık Stresi Altında Sarı Kantaronun (Hypericum perforatum L.) Fizikokimyasal ve Antioksidan Tepkileri

This study investigated the effects of drought stress on the physiological and biochemical responses of the medicinal and aromatic plant Hypericum perforatum (St. John’s Wort). Changes were determined in leaf length, relative water content (RWC), osmotic potential, chlorophyll fluorescence (Fv/Fm), lipid peroxidation (TBARS), hydrogen peroxide (H2O2), and proline content as well as in the antioxidant system enzyme activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), ascorbate peroxidase (APX), and glutathione reductase (GR). These responses were examined in relation to the tolerance of drought stress in H. perforatum. Ninety-day-old seedlings were subjected to drought for three weeks. The physiological parameters of leaf length, RWC, Fv/Fm, and osmotic potential were reduced under drought. The H2O2, TBARS, and proline levels were increased significantly under drought stress. Moreover, the proline content increase was greatly pronounced (25.9-fold) compared to the control groups. The high accumulation of proline may have resulted from the 83.8% leaf RWC still remaining under drought stress. On the other hand, the SOD, CAT, and GR enzyme activities were enhanced, whereas the POX and APX activities were reduced. The results indicate that improved tolerance to drought stress in H. perforatum plants may be accomplished through increased capacity of the antioxidative defense system

Influence of Moderate Cd and Pb Soil Pollution on Seed Development, Photosynthetic Performance and Foliar Accumulation in the Medicinal Plant Hypericum perforatum

This study investigated whether moderate soil contamination by Cd and Pb may negatively affect seed germination, photosynthesis and foliar accumulation in the medicinal plant Hypericum perforatum. Seeds were incubated with Cd and Pb solutions of 10 and 100 µM, and two-month-old plants were watered weekly for three weeks with the same solutions. Control samples were treated with deionized water. The percentage of seed germination and seedling length, as well as chlorophyll content, chlorophyll fluorescence and foliar reflectance, were measured, along with the foliar Cd and Pb concentrations. The results indicated that seed germination is not affected, while seedling length is decreased by approximately 81% by high Cd levels. Cadmium was subjected to foliar translocation from the soil depending on the supplied concentration, thus causing reductions in the chlorophyll content (−24%). It is of interest that foliar Cd levels in Cd-treated plants were close to or above the limit for the European Pharmacopoeia. Negative effects of Pb were not detected, but accumulation and blockage of this metal at the root level, although not approached experimentally, cannot be ruled out.

Hypericibacter terrae gen. nov., sp. nov. and Hypericibacter adhaerens sp. nov., two new members of the family Rhodospirillaceae isolated from the rhizosphere of Hypericum perforatum.

Two strains of the family Rhodospirillaceae were isolated from the rhizosphere of the medicinal plant Hypericum perforatum. Cells of both strains were Gram-stain-negative, motile by means of a single polar flagellum, non-spore-forming, non-capsulated, short rods that divided by binary fission. Colonies were small and white. Strains R5913T and R5959T were oxidase-positive, mesophilic, neutrophilic and grew optimally without NaCl. Both grew under aerobic and microaerophilic conditions and on a limited range of substrates with best results on yeast extract. Major fatty acids were C19 : 0 cyclo ω8c and C16 : 0; in addition, C18 : 1ω7c was also found as a predominant fatty acid in strain R5913T. The major respiratory quinone was ubiquinone 10 (Q-10). The DNA G+C contents of strains R5913T and R5959T were 66.0 and 67.4 mol%, respectively. 16S rRNA gene sequence comparison revealed that the closest relatives (<92 % similarity) of the strains are Oceanibaculum pacificum MCCC 1A02656T, Dongia mobilis CGMCC 1.7660T, Dongia soli D78T and Dongia rigui 04SU4-PT. The two novel strains shared 98.6 % sequence similarity and represent different species on the basis of low average nucleotide identity of their genomes (83.8 %). Based on the combined phenotypic, genomic and phylogenetic investigations, the two strains represent two novel species of a new genus in the family Rhodospirillaceae, for which the name Hypericibacter gen. nov. is proposed, comprising the type species Hypericibacter terrae sp. nov. (type strain R5913T=DSM 109816T=CECT 9472T) and Hypericibacter adhaerens sp. nov. (type strain R5959T=DSM 109817T=CECT 9620T).

Morfoanatomía e histoquímica de Hypericum juniperinum (Hypericaceae)

Hypericum is a genus belonging to the Hypericaceae family, which has 469 species of herbs, trees and shrubs. Two sections in particular: Brathys and Trygynobrathys are an integral part of the Paramo vegetation type. Taking into account its composition and the antidepressant activity properties reported for this plant, the histochemistry and anatomy of Hypericum juniperinum collected in the Colombian Paramo is described. To achieve this goal, the aerial organs (stems, leaves and flowers) of Hypericum juniperinum were collected in the village Arbolocos of the municipality of Cuitiva, Boyacá (voucher code No.589611, COL). For the anatomical analysis, the organs of H. juniperinum were processed with fixation techniques, incorporation in paraffin, cutting in microtome and staining with Astra-blue and basic fuchsin; for the histochemical analysis freehand cuts were made with specific stains for lipids, phenol compounds, alkaloids and pectins. The anatomy of the organs of H. juniperinum should be understood in the context of the living conditions of the Paramo. The leaves are highly xeromorphic as they are chartaceous, rosette-shaped, convolute and upright, with parenchyma in bistratified palisade, thickened walls, thick cuticle and epicuticular wax in the two foliar epidermis, stomata on the abaxial side and with epidermal chamber. However, it has some mesomorphic characteristics such as parenchymatic bundle sheath and loose spongy parenchyma. Hypericum juniperinum presents translucent glands in leaves, calyx and gynoecium, and lacks black glands typical of the Hypericum section where the medicinal plant Hypericum perforatum belongs. Histochemical analysis showed lipids in leaf canals, radial parenchyma of the stem and in some floral structures. Phenolic compounds were detected along the leaf, in the phloem of the stem and in the anthers. Hypericum juniperinum lacks alkaloids and presents pectins in the parenchyma of the sheath surrounding the vascular bundle of the leaf. In this way, the present work contributes by relating the metabolites with their distribution in the tissues of this native species. In addition, the anatomy showed that H. juniperinum has characteristics of a plant from Paramo. The description given here could be used as a preliminary monograph of plants from the Hypericum genus with promising therapeutical properties.

Prenylated β-diketones, two new additions to the family of biologically active Hypericum perforatum L. (Hypericaceae) secondary metabolites

Two novel β-diketones, 2,6,9-trimethyl-8-decene-3,5-dione (A) and 3,7,10-trimethyl-9-undecene-4,6-dione (B), were identified from the renowned medicinal plant Hypericum perforatum L. The structures of β-diketones A and B were corroborated by syntheses (4 steps starting from methyl acetoacetate, overall yields 30% and 23%, respectively). In solution, these β-diketones predominantly exist as two rapidly interconverting β-keto-enol tautomers. The structures of A and B show some common fragments with the molecules of hyperforin and adhyperforin, respectively, the acknowledged multi-target secondary metabolites from St. John's wort. It is therefore not surprising that A displayed a noteworthy biological activity profile as well (including brine shrimp toxicity, antinociceptive, antidepressant and acetylcholinesterase inhibitory activity). β-Diketone A manifested the most outstanding potency as an acetylcholinesterase inhibitor with IC50 value of 1.51 μM pointing again to the β-keto-enol moiety as a promising lead structure for the development of drugs that could lessen symptoms of Alzheimer's disease (such as dementia, depression and pain).

Hyperforin protects against acute cerebral ischemic injury through inhibition of interleukin-17A-mediated microglial activation

Hyperforin, a pharmacologically active component of the medicinal plant Hypericum perforatum (St. John's wort), has been shown to be neuroprotective against acute ischemic stroke. However, the underlying mechanisms are still unclear and need to be fully elucidated. C57BL/6 wildtype (WT) mice or interleukin (IL)-17A knock-out mice were subjected to middle cerebral artery occlusion (60min) followed by reperfusion for 72h. Hyperforin (0.5μg) was injected slowly into the right ventricle of WT mice 1, 24 and 48h after middle cerebral artery occlusion (MCAO) onset. Here, we found that hyperforin treatment decreased the mRNA and protein expression of IL-17A at 72h after MCAO onset. Hyperforin reduced infarct volumes and increased neurologic scores accompanied by a decrease in microglial activation and a shift from M1 to M2 phenotypes in the peri-infarct striatum. Furthermore, we revealed that IL-17A was essential to the microglial activation in the acute phase of ischemic stroke. IL-17A knock-out (il-17a−/−) or anti-IL-17 A monoclonal antibody treatment markedly decreased the microglial activation and induced a shift from M1 to M2 phenotypes of activated microglia. In addition, treatment with recombinant mouse IL-17A abolished the protective effects of hyperforin on acute ischemic brain injury, attenuated the inhibitory effects of hyperforin on the microglial activation, and inhibited the enhanced shift from M1 to M2 phenotypes mediated by hyperforin. In conclusion, our results clearly showed that hyperforin could protect against acute cerebral ischemic injury through inhibition of interleukin-17A-mediated microglial activation and polarization of microglia to M2 phenotype.

Downstream processing of hyperforin from Hypericum perforatum root cultures

Hyperforin is a major metabolite of the medicinal plant Hypericum perforatum (St. John’s Wort) and has recently been found in hormone induced root cultures. The objective of this study is to identify a downstream process for the production of a hyperforin-rich extract with maximum extraction efficiency and minimal decomposition. The maximum extraction time was found to be 60min. The comparison of two equipment concepts for the extraction and solvent evaporation was performed employing two different solvents. While the rotary mixer showed better results for the extraction efficiency than a stirred vessel, the latter set-up was able to handle larger volumes but did not meet all process requirements. For the evaporation the prompt evaporation of the extraction agent using nitrogen stripping led to minor decomposition. In a 5L stirred vessel, the highest specific extraction of hyperforin was 4.3mg hyperforin/g dry weight bio material. Parameters for the equipment design for extraction and solvent evaporation were determined based on the experimental data.

Hyperforin promotes post-stroke functional recovery through interleukin (IL)−17A-mediated angiogenesis

Hyperforin, the main active ingredient of the medicinal plant Hypericum perforatum, has been shown to be neuroprotective against acute ischemic stroke. However, the long-term actions of hyperforin on the post-stroke functional recovery and underlying mechanisms have not been investigated. C57BL/6 wild-type mice or interleukin (IL)-17A knock-out mice underwent middle cerebral artery occlusion (60min) followed by reperfusion for 28 days. Here, we found that delayed treatment with hyperforin significantly promoted functional recovery and increased IL-17A expression in the ischemic hemisphere at 28 days post-ischemia (dpi). IL-17A knock-out or anti-IL-17A monoclonal antibody (mAb) treatment significantly attenuated the promoting effects of hyperforin on functional recovery. After screening for neurotrophic factors, we revealed that blocking IL-17A significantly decreased, whereas recombinant mouse IL-17A (rIL-17A) treatment significantly increased vascular endothelial growth factor (VEGF) expression. Our data also showed that rIL-17A treatment significantly increased CD34 expression and promoted functional recovery at 28dpi, and the promoting effects were attenuated by VEGF neutralizing antibody treatment. Furthermore, hyperforin treatment significantly increased the expression of VEGF and CD34 in the ischemic hemisphere at 28dpi, and the effects were attenuated by blocking IL-17A. Furthermore, VEGF neutralizing antibody significantly attenuated the promoting role of hyperforin on the cerebral CD34 expression. Thus, our results suggest that, in addition to the acute neuroprotection when delivered immediately after ischemic stroke, hyperforin could also promote functional recovery when delivered in the later phases of stroke recovery. Our results also reveal a previously uncharacterized property of IL-17A/VEGF signaling-induced angiogenesis in hyperforin-mediated functional recovery.

Hyperforin production in Hypericum perforatum root cultures

Extracts of the medicinal plant Hypericum perforatum are used to treat depression and skin irritation. A major API is hyperforin, characterized by sensitivity to light, oxygen and temperature. Total synthesis of hyperforin is challenging and its content in field-grown plants is variable. We have established in vitro cultures of auxin-induced roots, which are capable of producing hyperforin, as indicated by HPLC-DAD and ESI–MS analyses. The extraction yield and the productivity upon use of petroleum ether after solvent screening were ∼5mg/g DW and ∼50mg/L culture after six weeks of cultivation. The root cultures also contained secohyperforin and lupulones, which were not yet detected in intact plants. In contrast, they lacked another class of typical H. perforatum constituents, hypericins, as indicated by the analysis of methanolic extracts. Hyperforins and lupulones were stabilized and enriched as dicyclohexylammonium salts. Upon up-scaling of biomass production and downstream processing, H. perforatum root cultures may provide an alternative platform for the preparation of medicinal extracts and the isolation of APIs.

Effects of hypericin on the oxidative stress and modulation of cytochrome P450 (CYP1A) activity in microsomes

Hypericin is a pigment present in the widely distributed medicinal plant Hypericum perforatum L. (Hypericaceae). In our research, hypericin was found to be an inhibitor of NADPH/Fe2+ induced microsomal lipid peroxidation and NADPH-dependent lucigenin chemiluminescence emission in vitro. Hypericin also inhibited the microsomal CYP1Adependent 7-ethoxyresorufin O-deethylase (EROD) which participates in the metabolic activation of xenobiotics including chemical carcinogens.

Antimicrobial and cytotoxic constituents from native Cameroonian medicinal plant Hypericum riparium

Bioassay guided fractionation of Hypericum riparium leaves extract has resulted in the isolation and characterization of three new compounds namely chipericumin E (1), hyperenone C (3), and hyperixanthone (5), together with twenty known compounds. Their structures were elucidated based on comprehensive interpretation of spectroscopic and spectrometric data. Compounds 1–4, and 6–8 displayed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and cytotoxic effects on the human gastric cell line BGC-823 with IC50 values ranging from 6.54 to 18.50μM.

Protonophore properties of hyperforin are essential for its pharmacological activity.

Hyperforin is a pharmacologically active component of the medicinal plant Hypericum perforatum (St. John's wort), recommended as a treatment for a range of ailments including mild to moderate depression. Part of its action has been attributed to TRPC6 channel activation. We found that hyperforin induces TRPC6-independent H+ currents in HEK-293 cells, cortical microglia, chromaffin cells and lipid bilayers. The latter demonstrates that hyperforin itself acts as a protonophore. The protonophore activity of hyperforin causes cytosolic acidification, which strongly depends on the holding potential, and which fuels the plasma membrane sodium-proton exchanger. Thereby the free intracellular sodium concentration increases and the neurotransmitter uptake by Na+ cotransport is inhibited. Additionally, hyperforin depletes and reduces loading of large dense core vesicles in chromaffin cells, which requires a pH gradient in order to accumulate monoamines. In summary the pharmacological actions of the “herbal Prozac” hyperforin are essentially determined by its protonophore properties shown here.

Isolation of (–)–Avenaciolide as the Antifungal and Antimycobacterial Constituent of a Seimatosporium sp. Endophyte from the Medicinal Plant Hypericum perforatum

An extract of Seimatosporium sp., an endophyte from the Canadian medicinal plant Hypericum perforatum, exhibited significant antifungal and antimycobacterial activity against Candida albicans and Mycobacterium tuberculosis H37Ra. Bioassay guided fractionation led to the isolation of (-)-avenaciolide as the only bioactive constituent of the extract. This is the first report of both the antimycobacterial activity of avenaciolide and its isolation from a Seimatosporium sp. fungus.