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Hypericum perforatum (Hypericaceae), known as Saint John’s wort (SJW), has been used in different systems of traditional medicine such as Chinese traditional medicine, Greek traditional medicine, and Islamic traditional medicine. The plant and its active constituents such as hyperforin and hypericin have a wide range of medicinal uses, particularly as anti-depressant, wound-healing, and antibacterial agents. In recent decades, many clinical trials have been performed to investigate the safety and efficacy of this medicinal plant. However, to the best on our knowledge, there is no comprehensive review article in this regard. In the current study, we aim to have a comprehensive review of the clinical trials of SJW to evaluate its efficacy and safety as well as its application in traditional medicine. Clinical studies investigating the safety, interactions, and efficacy of SJW were identified and summarized, including contributions from 2000 until December 2021. According to the results, these clinical studies were divided into three main categories based on the type of disease: psychiatric, endocrine, and skin problems. Important details of the studies, including the type and duration of the study, the type and percentage of the effective compounds or the extract used, the number of patients, and the obtained results were also discussed. In addition, co-administration and drug interaction of SJW with other drugs were summarized. SJW is a valuable medicinal plant, especially for psychiatric disorders. However, precautions should be taken while administrating the plant.

Diabetes mellitus is a very common chronic disease with progressively increasing prevalence. Besides the well-known autoimmune and inflammatory pathogenesis of type 1 diabetes, in many people, metabolic changes and inappropriate lifestyle favor a subtle chronic inflammatory state that contributes to development of insulin resistance and progressive loss of β-cell function and mass, eventually resulting in metabolic syndrome or overt type 2 diabetes. In this paper, we review the anti-inflammatory effects of the extract of Hypericum perforatum L. (St. John’s wort, SJW) and its main active ingredients firstly in representative pathological situations on inflammatory basis and then in pancreatic β cells and in obese or diabetic animal models. The simultaneous and long-lasting inhibition of signal transducer and activator of transcription (STAT)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs)/c-jun N-terminal kinase (JNK) signaling pathways involved in pro-inflammatory cytokine-induced β-cell dysfunction/death and insulin resistance make SJW particularly suitable for both preventive and therapeutic use in metabolic diseases. Hindrance of inflammatory cytokine signaling is likely dependent on the hyperforin content of SJW extract, but recent data reveal that hypericin can also exert relevant protective effects, mediated by activation of the cyclic adenosine monophosphate (cAMP)/protein kinase cAMP-dependent (PKA)/adenosine monophosphate activated protein kinase (AMPK) pathway, against high-fat-diet-induced metabolic abnormalities. Actually, the mechanisms of action of the two main components of SJW appear complementary, strengthening the efficacy of the plant extract. Careful quantitative analysis of SJW components and suitable dosage, with monitoring of possible drug–drug interaction in a context of remarkable tolerability, are easily achievable pre-requisites for forthcoming clinical applications.

Oxidative stress and the hypoxic microenvironment play a key role in the progression of human melanoma, one of the most aggressive skin cancers. The aim of our study was to evaluate the effect of Hypericum perforatum extracts of different origins (both commercially available (HpEx2) and laboratory-prepared from wild grown (HpEx12) and in vitro cultured (HpEx13) plants) and hyperforin salt on WM115 primary and WM266-4 lymph node metastatic human melanoma cells cultured under normoxic and hypoxic conditions. The polyphenol content, radical scavenging activity, and hyperforin concentration were determined in the extracts, while cell viability, apoptosis, ROS production, and expression of NRF2 and HO-1, important oxidative stress-related factors, were analyzed after 24 h of cell stimulation with HpExs and hyperforin salt. We found that cytotoxic, pro-apoptotic and antioxidant effects depend on the extract composition, the stage of melanoma progression, and the oxygen level. Hyperforin salt showed lower activity than H. perforatum extracts. Our study for the first time showed that the anticancer activity of H. perforatum extracts differs in normoxia and hypoxia. Importantly, the composition of extracts of various origins, including in vitro cultured, resulting in their unique properties, may be important in the selection of plants for therapeutic application.

(1) Background: Medicinal plants are widely used in folk medicine. Hypericum perforatum L. (St. John’s wort) is a medicinal plant that is used domestically and exported to other countries. This study addresses the need to develop methods for determining the composition and content of St. John’s wort to determine its biological activity. (2) Methods: High-performance liquid chromatography (HPLC) equipped with an Electrochemical Detector (ECD) and a Photodiode Array Detector (PDA) was employed to identify and quantify major phenolic compounds—gallic acid, catechin, epicatechin, hyperoside, quercetin, and hyperforin—in extracted and lyophilized St. John’s wort flower; stem; and leaf samples. Key analytes exhibited linear responses across both detection systems, within a quantification range of 0.5–10 µg/mL. (3) Results: The PDA method, validated according to ICH Q2(R1) guidelines, demonstrated specificity, linearity, precision, and accuracy, with limits of detection (LOD) ranging from 0.24 to 0.61 µg/mL and limits of quantification (LOQ) between 0.26 and 0.62 µg/mL. PDA effectively identified gallic acid, epicatechin, hyperoside, quercetin, and hyperforin, although catechin was not detected. ECD yielded comparable compound levels across the samples. (4) Conclusions: The novelty of this study lies in identifying the influence of climatic factors associated with the altitude at which St. John’s wort is grown on the content and ratio of biologically active components. Overall, the chemometric approach demonstrates the utility of raw chromatographic data in distinguishing samples by plant part and geographic origin; even when traditional compound-based comparisons may be limited.

Hyperforin is a major active constituent of Hypericum perforatum  L. extract, which is widely used for the treatment of depressive disorders. Recent studies have reported that hyperforin reduced inflammation in stroke and suppressed proliferation and differentiation in keratinocytes. Psoriasis is a chronic immune-mediated inflammatory skin disease in which the IL-23/IL-17 axis plays an important role. To investigate the underlying inflammatory mechanisms and response of hyperforin in psoriasis, we use imiquimod (IMQ)-induced mice model, in vitro cultured murine splenic γδ T cells, and HaCaT cells in this study. Data showed that hyperforin reduced epidermal thickness and decreased IMQ-induced pathological scores of cutaneous skin lesions in mice. Meanwhile we proved that hyperforin suppressed infiltration of CD3 + T cells and downregulated expression of Il1 , Il6 , Il23 , Il17a , Il22 , antimicrobial peptides (AMPs) in the skin lesion. Hyperforin significantly inhibited imiquimod-induced splenomegaly, reduced serum levels of TNF-α and IL-6, and IL-17A in splenocytes and draining lymph nodes. Our study also suggested that hyperforin lessened the infiltration of γδ T cell and CCR6 + γδ T cells in spleen and lymph nodes. Hyperforin also suppressed the typical psoriasis-like inflammatory responses and the infiltration of IL-17A + cells in dermal γδ T cells of IMQ treated Tcrd −/− mice transferred with γδ T cells. In vitro studies, hyperforin reduced the expression and secretion of IL-17A in γδ T cells, and suppressed the activation of MAPK/STAT3 pathways in human keratinocyte HaCaT cells and γδ T cells. In conclusion, hyperforin alleviates IMQ-induced inflammation in psoriasis through suppressing the immune responses exerted by IL-17 A-producing γδ T cells and related cytokines by modulating MAPK/STAT3 pathways. Our study provided a novel therapeutic tragedy for psoriasis by which hyperforin attenuates psoriasis-related inflammatory responses.

Hypericum perforatum L., commonly known as St. John’s wort is an important medicinal plant, belonging to family Hypericaceae. Among all species of Hypericum, H. perforatum is most investigated and exploited. It is sold as one of the world’s topmost retailing antidepressants. This plant possesses antibacterial, antiviral, anti-inflammatory, and anticancerous properties. These medicinal properties are attributed to the presence of bioactive compounds, such as hypericins and pseudohypericins (naphthodianthrones), hyperforin and adhyperforin (prenylated acylphloroglucinols), quercetin, rutin, isoquercetin, and catechin (flavonoids), chlorogenic acid, caffeic acid, and tannic acid (phenols) and xanthones. The conventional methods of propagation of H. perforatum are time consuming and field grown plants are exposed to biotic and abiotic challenges which affect its phytochemical constituents. Moreover, these methods are also unable to meet the commercial demand of secondary metabolites. Therefore, in order to meet the growing raw material demand of pharmaceutical industries there is a need to develop effecient in vitro plant regeneration protocols for large scale production of H. perforatum plants and other biotechnological methods (cell, tissue and organ culture, cell suspension culture, hairy root culture, elicitation, etc.) for improvement of target bioactive compounds. The present review provides a comprehensive account of the available information on in vitro plant regeneration and biotechnological approaches used to enhance the secondary metabolite(s) content in H. perforatum during the past years. It also deals with the unexplored areas which might be exploited for drug discovery.

Background/Objectives: This study aims to gain insights into the antimicrobial and antiherpetic activity of hyperforin-rich Hypericum perforatum L. (HP) extract using nanostructured lipid carriers (NLCs) as delivery platforms. Methods: Two established NLC specimens, comprising glyceryl behenate and almond oil or borage oil, and their extract-loaded counterparts (HP-NLCs) were utilized. Their minimal bactericidal/fungicidal concentrations (MBC; MFC) were investigated against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 10145, Klebsiella pneumoniae ATCC 10031, and Candida albicans ATCC 10231. The anti-herpesvirus (HSV-1) potential was evaluated concerning antiviral and virucidal activity and impact on viral adsorption. Results: The borage oil-based extract-loaded nanodispersion (HP-NLC2) exhibited pronounced microbicidal activity against S. aureus (MBC 6.3 mg/mL), K. pneumoniae (MBC 97.7 µg/mL), and C. albicans (MFC < 48.8 µg/mL), unlike the almond oil-containing sample (HP-NLC1), which showed only weak inhibition of the fungal growth. HP-NLC2 was found to be less cytotoxic and to suppress HSV-1 replication slightly more than HP-NLC1, but generally, the effects were weak. Neither the empty lipid nanoparticles nor the HP extract-loaded carriers expressed activity against E. coli, P. aeruginosa, the HSV-1 extracellular virions, or viral adhesion. Conclusions: It could be concluded that both HP-NLC samples revealed only minor antiherpetic potential of the hyperforin-rich extract, but HP-NLC2 demonstrated significant antibacterial and antimycotic activity. Therefore, the latter was featured as a more convenient HP-carrier system for nano-designed dermal pharmaceutical formulations. Such a thorough investigation of hyperforin-determined anti-HSV-1 effects and antibacterial and antimycotic properties, being the first of its kind, contributes to the fundamental knowledge of HP and reveals new perspectives for the utilization, limitations, and therapeutic designation of its non-polar components.

Hypericin, a polycyclic naphthodianthrone and active plant pigment with the molecular formula C30H16O8, is a crucial phytochemical extracted from the dark-colored glands present on the aerial parts of the genus Hypericum. It is biosynthesized through the polyketide pathway by plant-specific type III polyketide synthases (PKSs). In addition to hypericin, the genus Hypericum is rich in various classes of phytochemicals. Alongside other bioactive compounds like hyperforin and flavonoids, hypericin exhibits antidepressant activity. Recently, hypericin has gained increased importance in the research due to its unique properties. Its photodynamic nature makes it an effective natural photosensitizer, extending its use in investigating skin disorders. Moreover, hypericin demonstrates antiviral and antitumoral properties. Despite its effectiveness in treating cancers and neurological disorders, hypericin production faces challenges due to its site-specific nature. Conventional methods struggle to meet the growing demand for hypericin. Biotechnological approaches, including plant tissue culture and bioreactor-based large-scale production, offer promising solutions to address this demand. This review focuses on various plant tissue culture techniques, such as cell and organ culture, and elucidates their biosynthetic pathways. It also discusses hypericin production using elicitation strategies involving biotic and abiotic components, as well as genetic engineering approaches to enhance hypericin yields. Bioreactor-scale production presents significant potential for sustainable hypericin production. Further advancements in understanding and engineering biosynthetic pathways hold promise for unlocking new avenues in hypericin production.

Hypericum perforatum , commonly known as St. John’s wort, is a popular herbal supplement used for the treatment of mild to moderate depression. The major secondary metabolites of St. John’s wort extracts include phenylpropanoids, flavonoids, xanthones, phloroglucinols, and naphthodianthrones. There are over 400 species in the genus Hypericum world-wide, most of which are little or not characterized in terms of phytochemical or pharmacological properties. Metabolomics techniques were used to investigate the natural product diversity within the genus Hypericum (Hypericaceae) and its correlation to bioactivity, exemplified by cytotoxic properties. Utilizing nuclear magnetic resonance (NMR) fingerprinting and mass spectrometry (MS) metabolic profiling techniques, MS and NMR spectra of extracts from H. perforatum , H. polyphyllum , H. tetrapterum , H. androsaemum , H. inodorum , H. undulatum and H. kouytchense were evaluated and submitted to statistical multivariate analyses. Although comparable score plots in principal component analysis were derived from both MS and NMR datasets, loading plots reveal, that different set of metabolites contribute for species segregation in each dataset. Major peaks in 1 H NMR and MS spectra contributing to species discrimination were assigned as those of hyperforins, lipids, chlorogenic and shikimic acid. Shikimic acid and its downstream phenylpropanoids were more enriched in H. perforatum , H. androsaemum , H. kouytchense and H. inodorum extracts; whereas a novel hyperforin was found exclusively in H. polyphyllum . Next to H. perforatum , H. polyphyllum and H. tetrapterum show the highest levels of hypericins, and H. perforatum and H. polyphyllum are highest in phloroglucinols, suggesting that the latter species might be used as an alternative to St. John’s wort. However, the major hyperforin-type compound in H. polyphyllum possesses a novel constitution of yet unknown bioactivity. Anti-cancer in vitro assays to evaluate the ability of extracts from Hypericum species in inhibiting prostate and colon cancer growth suggest that such bioactivity might be predicted by gross metabolic profiling.