key: cord-0813539-jyszwd8b authors: Burlou-Nagy, Cristina; Bănică, Florin; Jurca, Tünde; Vicaș, Laura Grațiela; Marian, Eleonora; Muresan, Mariana Eugenia; Bácskay, Ildikó; Kiss, Rita; Fehér, Pálma; Pallag, Annamaria title: Echinacea purpurea (L.) Moench: Biological and Pharmacological Properties. A Review date: 2022-05-05 journal: Plants (Basel) DOI: 10.3390/plants11091244 sha: 2dbd87c97f9be0b2a52f48e71f292866d36817b4 doc_id: 813539 cord_uid: jyszwd8b Echinacea purpurea (L.) Moench (EP)is a perennial herbaceous flowering plant, commonly known as purple coneflower and it belongs to the Asteraceae family. The Echinacea genus is originally from North America, in the United States, and its species are widely distributed throughout. There are nine different species of Echinacea, but only three of them are used as medicinal plants with wide therapeutic uses: Echinacea purpurea (L.) Moench, Echinacea pallida (Nutt.) Nutt. and Echinacea angustifolia DC. Several significant groups of bioactive compounds with pharmacological activities have been isolated from Echinacea species. Numerous beneficial effects have been demonstrated about these compounds. The immunomodulatory effect was initially demonstrated, but over time other effects have also been highlighted. The present review gives a comprehensive summary of the chemical constituents, bioactive compounds, biological effects and therapeutical uses of purple coneflower. Research shows that such a well-known and recognized species needs to be further studied to obtain efficient products with a guarantee of the safety. Nature has always been a great source of therapeutic substances, providing us with various medicinal plants that produce valuable phytochemicals. Medicinal plant use dates back to remote times and it is therefore believed to be the genesis of modern medicine. In addition, chemicals generated from plants are and will continue to be a valuable source of molecules for pharmaceuticals [1] . In the past, folk observations and experience were the guiding principles in the use of herbs, but today their active ingredients, their action mechanisms and their usage based on principles of evidence-based medicine have been discovered. Phytotherapy is widely utilized in the treatment and prevention of a variety of medical conditions and is well-known among the general populace [2] . Plant-based pharmaceuticals now represent about 30% of the drugs market made up of necessary medications, while the remaining 11% is made up of non-essential drugs [3, 4] . This evaluation's primary goal is the synthesis of the data from the specialized literature regarding the bioactive compounds, chemical composition, pharmacological and Plants 2022, 11 , 1244 2 of 20 biological properties of Echinacea purpurea (L.) Moench to highlight the possibilities and perspectives for future studies, and to obtain safe and pharmacologically effective products. The species of the genus Echinacea occupy an important place among medicinal plants, are native to North America and belong to the Asteraceae family. Echinacea comes in nine distinct species, but just three are utilized as medicinal herbs with wide therapeutic uses: Echinacea purpurea (L.) Moench, Echinacea pallida (Nutt.) Nutt. and Echinacea angustifolia DC [5, 6] . A large number of species in the Asteraceae family have been utilized for therapeutic purposes in comparison to other plant families because of the availability of chemicals with a broad spectrum of therapeutic properties, as well as the fact that the Asteraceae family of plants is one of the most prominent and well-known [7, 8] . Figure 1 shows the evolution over time of publications on the genus Echinacea and the species Echinacea purpurea (L.) Moench. There has been an increase in scientific research on these species over time until 2009, after which there was a slight decrease until 2015, followed by an increase again until today [9,10]. This evaluation's primary goal is the synthesis of the data from the specialized literature regarding the bioactive compounds, chemical composition, pharmacological and biological properties of Echinacea purpurea (L.) Moench to highlight the possibilities and perspectives for future studies, and to obtain safe and pharmacologically effective products. The species of the genus Echinacea occupy an important place among medicinal plants, are native to North America and belong to the Asteraceae family. Echinacea comes in nine distinct species, but just three are utilized as medicinal herbs with wide therapeutic uses: Echinacea purpurea (L.) Moench, Echinacea pallida (Nutt.) Nutt. and Echinacea angustifolia DC [5, 6] . A large number of species in the Asteraceae family have been utilized for therapeutic purposes in comparison to other plant families because of the availability of chemicals with a broad spectrum of therapeutic properties, as well as the fact that the Asteraceae family of plants is one of the most prominent and well-known [7, 8] . Figure 1 shows the evolution over time of publications on the genus Echinacea and the species Echinacea purpurea (L.) Moench. There has been an increase in scientific research on these species over time until 2009, after which there was a slight decrease until 2015, followed by an increase again until today [9, 10] . Echinacea purpurea (L.) Moench is a perennial plant, 100-150 cm tall, vigorous and herbaceous. The roots and rhizome are highly developed. Echinacea purpurea (L.) Moench is a perennial plant, vigorous, 100-150 cm tall and herbaceous. The roots are cylindrical, brownish-gray on the exterior and white on the interior. The aerial stem is branching and has rough hairs and reddish-brown patches, giving it the appearance of a bush. Linear-lanceolate leaves with three arching ribs and rough hairs are entire, 3-6 cm wide. It produces a rosette of leaves during the first year of cultivation and blooms only in the second year [11] [12] [13] . The flowers are grouped in inflorescences, the terminal anthodes are pink, pale red to deep red. At the base of the inflorescence there are sharp bracts that, when mature, lignify and become spiky. The sterile ray flowers are pink, located at the edge of the inflorescence, and the ligules are 5-7 cm long and 0.5 cm wide. The disk flowers are tubular, orange-brown, bisexual and are placed inside the inflorescence. The fruits are achene, white-gray, edged, with four edges and teeth at the top. It blooms in June-July [14] [15] [16] [17] [18] . Invasive weeds are a common problem for Echinacea crops. Chemicals such as herbicides are one of the most efficient weed control tactics. Herbicides are harmful to the Echinacea's physiological and morphological processes [19] . Echinacea purpurea (L.) Moench is a perennial plant, 100-150 cm tall, vigorous and herbaceous. The roots and rhizome are highly developed. Echinacea purpurea (L.) Moench is a perennial plant, vigorous, 100-150 cm tall and herbaceous. The roots are cylindrical, brownish-gray on the exterior and white on the interior. The aerial stem is branching and has rough hairs and reddish-brown patches, giving it the appearance of a bush. Linearlanceolate leaves with three arching ribs and rough hairs are entire, 3-6 cm wide. It produces a rosette of leaves during the first year of cultivation and blooms only in the second year [11] [12] [13] . The flowers are grouped in inflorescences, the terminal anthodes are pink, pale red to deep red. At the base of the inflorescence there are sharp bracts that, when mature, lignify and become spiky. The sterile ray flowers are pink, located at the edge of the inflorescence, and the ligules are 5-7 cm long and 0.5 cm wide. The disk flowers are tubular, orangebrown, bisexual and are placed inside the inflorescence. The fruits are achene, white-gray, edged, with four edges and teeth at the top. It blooms in June-July [14] [15] [16] [17] [18] . Invasive weeds are a common problem for Echinacea crops. Chemicals such as herbicides are one of the most efficient weed control tactics. Herbicides are harmful to the Echinacea's physiological and morphological processes [19] . This review was based on experimental research from a literature survey report on Echinacea species. The review involved a literature search and a selection was includedof published scientific evidence on the subject of Echinacea purpurea (L.) Moench. There were no constraints on the publication date of the selected articles, which included both recent and older works, to gather all essential details for the research. Furthermore, the most Plants 2022, 11, 1244 3 of 20 relevant databases for the aim mentioned above were the Web of Science Core Collection and Scopus. Figure 2 shows the distribution of the articles included in the Scopus database by scientific categories [9]. This review was based on experimental research from a literature survey report on Echinacea species. The review involved a literature search and a selection was includedof published scientific evidence on the subject of Echinacea purpurea (L.) Moench. There were no constraints on the publication date of the selected articles, which included both recent and older works, to gather all essential details for the research. Furthermore, the most relevant databases for the aim mentioned above were the Web of Science Core Collection and Scopus. Figure 2 shows the distribution of the articles included in the Scopus database by scientific categories [9]. To identify scientific articles published up to December 2021, the articles were searched using representative keywords to locate the primary data, outcomes and papers in the field. To search for articles, the following keywords were used: Echinacea and Echinacea purpurea (L.) Moench. A total of 3431 scientific articles were identified. A Prisma flow diagram was used for a description of how to select the studies, with the articles included in the review, as shown in Figure 3 [20, 21] . From the beginning, we established the eligibility criteria for the selection of studies. To identify scientific articles published up to December 2021, the articles were searched using representative keywords to locate the primary data, outcomes and papers in the field. To search for articles, the following keywords were used: Echinacea and Echinacea purpurea (L.) Moench. A total of 3431 scientific articles were identified. A Prisma flow diagram was used for a description of how to select the studies, with the articles included in the review, as shown in Figure 3 [20, 21] . This review was based on experimental research from a literature survey report on Echinacea species. The review involved a literature search and a selection was includedof published scientific evidence on the subject of Echinacea purpurea (L.) Moench. There were no constraints on the publication date of the selected articles, which included both recent and older works, to gather all essential details for the research. Furthermore, the most relevant databases for the aim mentioned above were the Web of Science Core Collection and Scopus. Figure 2 shows the distribution of the articles included in the Scopus database by scientific categories [9]. To identify scientific articles published up to December 2021, the articles were searched using representative keywords to locate the primary data, outcomes and papers in the field. To search for articles, the following keywords were used: Echinacea and Echinacea purpurea (L.) Moench. A total of 3431 scientific articles were identified. A Prisma flow diagram was used for a description of how to select the studies, with the articles included in the review, as shown in Figure 3 [20, 21] . From the beginning, we established the eligibility criteria for the selection of studies. From the beginning, we established the eligibility criteria for the selection of studies. The inclusion criteria included articles with extensive studies on the chemical composition and bioactive compounds of Echinacea species, especially EP, studies on the therapeutic use of EP, studies on the antioxidant, immunomodulatory, anti-inflammatory, antimicrobial, antiviral and pharmacological effects, and on side effects and toxicity. The exclusion criteria were as follows: if the subject area is from chemical engineering and veterinary, we found only the published abstract, not the whole study, and studies that were not published in English. Starting from this number of articles, we carried out the selection process for choosing the most relevant articles for this research. We discovered the most important data/results/papers in the field, resulting in 213 articles. Several significant groups of bioactive compounds, with pharmacological activities, have been isolated from Echinacea species. The most important components of Echinacea purpurea (L.) Moench are alkylamides, polysaccharides, glycoproteins, flavonoids and phenolic compounds, which include [22] derivates of caffeic acid, like caffeic acid, chicoric acid, caftaric acid, chlorogenic acid and echinacoside, Figure 4 , [23, 24] , whose amounts vary based on the plant's sections. In addition to these components, we also identified thatphylloxanthobilins, β-phellandrene, acetaldehyde, dimethyl sulfide, camphene, hexanal, α-pinene and limonene are present in all plant tissues, regardless of species. Fatty acids, aldehydes and terpenoidsare constituents whose presence depend on the parts of plants used [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] . tissues of Echinacea pallida Nutt, in one research study using gas chromatography/mass spectrometry. α-Myrcene was found in large concentrations in all three Echinacea species' flowers, leaves and stems, but was missing from the roots of Echinaceae angustifolia and Echinacea purpurea (L.) Moench and was only in small concentrations in the roots of Echinacea pallida Nutt. Acetaldehyde, dimethyl sulfide, camphene, hexanal, α-pinene and all plant tissues contain limonene, regardless of species. Dimethyl sulfide has been identified in trace amounts in all species' leaves, stems and flowers; nonetheless, it was the most abundant ingredient in Echinacea pallida roots and, second, was the most abundant component in Echinacea angustifolia and Echinacea purpurea (L.) Moench roots. Butanals and propanals, in particular, are aldehydes, comprising 41-57% of root tissue headspace and 19-29% of leaf tissue headspace, and just 6-14% of the headspace between the bloom and the stem tissue. Terpenoids such as α-myrcene, β-and α-pinene, ocimene, camphene, terpenene and limonene constitute between 82-91% of the headspace of stems and flowers, 46-58% of the leaf tissue's headspace and 6-21% of the roots. Furthermore, there are 14 hydrocarbons, 12 alcohols, 7 esters, 6 ketones and 7 other chemicals found [55] [56] [57] . In another study, we identified compounds in an n-hexane extract of Echinacea purpurea (L.) Moench such as fatty acids comprising 9,12-octadecadienoic acid (linoleic acid), hexadecanoic acid (palmitic acid) and octadecanoic acid (stearic acid), accounting for 25.8% of the extract, and after that come the next long-chain hydrocarbons (14.6%) and sterols (13.9%) [58] . EP has also been prepared for use as a topical treatment for skin and wound inflammation. In addition, Echinacea products are licensed in Europe to heal infections of the upper respiratory tract and wound healing [59] [60] [61] [62] . The chemical components responsible for the immunomodulatory activities of purple coneflower roots are glycoproteins, alkylamides and polysaccharides [39] . Glycoproteins are proteins and carbohydrate chains that have a role in a variety of physiological activities, including immunology. Alkylamides are a kind of chemical found in genus Echinacea (Asteraceae) that has been demonstrated to have high bioavailability and alsoimmunomodulatory properties. Structurally, they have a common feature of an amine bond and usually contained an aliphatic chain of polyunsaturated fatty acids connected to a short-chain amine. Polysaccharides are complex carbohydrate polymers made up of more than two monosaccharides. The Asteraceae family contains important polysaccharides, pectins, arabinogalactans and inulin. Bioactive polysaccharides may substantiate a part of the traditional uses of these species. EP supplements are, in general, sold as encapsulated tablets containing aerial parts or dried roots or as tablets containing extruded material from pressed plants or ethanol extracts. The above-ground parts of the plant contain smaller amounts of volatile oils and pyrolizid alkaloids such as tussilagin and isotussilagin than the root [40] . The most important derivative of caffeic acidof the Echinacea purpurea (L.) Moench species is considered to be chicoric acid, the most predominant phenolic component in the root and petiole [41] [42] [43] [44] [45] . Chicoric acid is the most abundant phenolic component in the root and petiole of Echinacea purpurea (L.) Moench. These antioxidant and antibacterial compounds can help the immunological system of the body to function better. However, caffeic acid derivative concentrations will vary according to EP species, organ type, growing conditions and environmental factors. Using the HPLC method, some studies demonstrated the retention of caffeic acid derivatives in dried EP. It was reported that chicoric acid accounted for 63% and 67%, respectively, of the relative peak area for aerial sections. By using the HPLC method, caffeic acid cannot be detected in all dried flowers. In contrast, the caffeic acid content was 8-18% of the measured relative peak area [46] [47] [48] . Chicoric acid (71.45%) is the most predominant caffeic acid derivative in flowers, followed by caffeic acid (23.25%) [49] . Echinacoside was discovered to have a variety of pharmacologically important benefits on human health, particularly neuroprotective and cardiovascular effects [35, 50] . Echinacosite is a caffeic acid derivative found in the flower at a concentration of 1.45% [48] . In addition to these substances, Echinacea species contain flavonoids, polyacetylenes and alkaloids [51, 52] . The constituents that are also important, isolated from the extracts of Echinacea purpurea (L.) Moench leaves, are phylloxanthobilins. The breakdown of chlorophyll produces these natural tetrapyrrole compounds. Phylloxanthobilins were identified in the leaves of deciduous trees about 10years ago and are currently considered a compound class with great bioactivity potential, which has yet to be studied. However, there have been no reports of phylloxanthobines being found in sections of a medicinal plant utilized in pharmaceutical formulations until now [53, 54] . β-phellandrene was discovered to be prominent in the roots of EP, but lacking in all tissues of Echinacea pallida Nutt, in one research study using gas chromatography/mass spectrometry. α-Myrcene was found in large concentrations in all three Echinacea species' flowers, leaves and stems, but was missing from the roots of Echinaceae angustifolia and Echinacea purpurea (L.) Moench and was only in small concentrations in the roots of Echinacea pallida Nutt. Acetaldehyde, dimethyl sulfide, camphene, hexanal, α-pinene and all plant tissues contain limonene, regardless of species. Dimethyl sulfide has been identified in trace amounts in all species' leaves, stems and flowers; nonetheless, it was the most abundant ingredient in Echinacea pallida roots and, second, was the most abundant component in Echinacea angustifolia and Echinacea purpurea (L.) Moench roots. Butanals and propanals, in particular, are aldehydes, comprising 41-57% of root tissue headspace and 19-29% of leaf tissue headspace, and just 6-14% of the headspace between the bloom and the stem tissue. Terpenoids such as α-myrcene, βand α-pinene, ocimene, camphene, terpenene and limonene constitute between 82-91% of the headspace of stems and flowers, 46-58% of the leaf tissue's headspace and 6-21% of the roots. Furthermore, there are 14 hydrocarbons, 12 alcohols, 7 esters, 6 ketones and 7 other chemicals found [55] [56] [57] . In another study, we identified compounds in an n-hexane extract of Echinacea purpurea (L.) Moench such as fatty acids comprising 9,12-octadecadienoic acid (linoleic acid), hexadecanoic acid (palmitic acid) and octadecanoic acid (stearic acid), accounting for 25.8% of the extract, and after that come the next long-chain hydrocarbons (14.6%) and sterols (13.9%) [58] . EP has also been prepared for use as a topical treatment for skin and wound inflammation. In addition, Echinacea products are licensed in Europe to heal infections of the upper respiratory tract and wound healing [59] [60] [61] [62] . Many bioactivities of EP have been discovered in modern pharmacological investigations, including immunomodulatory, anti-inflammatory, antioxidant, antiviral and antifungal activities [63, 64] . Chronic arthritis, cancer, antimicrobial action, persistent fatigue syndrome, HIV infection, a range of skin ailments, wounds and chronic pelvic infections were all mentioned as potential therapeutic uses for EP [65] . Preparations containing EP are among the best-selling herbal medications in Europe and the United States [60, 66] . EP supplementation may decrease the severity and duration of acute respiratory tract infections, according to current research; however, no studies have been identified using Echinacea to prevent or treat the SARS-CoV virus infection [67] . The immunomodulatory effects of Echinacea species are of primary concern for research, especially those related to upper respiratory tract infections. Discoveries made recently have also shown that certain standardized preparations of Echinacea have strong antiviral, antifungal, antimicrobial, anti-inflammatory, antioxidant and psychoactive activities. Given the available data, preparations obtained from Echinacea are well-tolerated by the human organism [68] . Therefore, further investigations are needed to ensure the quality and safety of the various preparations of Echinacea sp. [69] . Echinacea sp. can cause minor side effects; it should be considered if the patient who is receiving Echinacea sp. preparations is allergic to Ambrosia artemisifolia L. or other species of the Asteraceae family. Echinacea sp., like many other Asteraceae plants, includes phototoxic polyacetylene compounds that can be inactivated with minimal processing [70, 71] . It is important to note that during preservation, enzymatic processes have the potential to degrade bioactive substances as a result of long-term storage from collection to marketing, leading in compositional changes. Stuart and Wills (2000) studied the alkylamide and chicoric acid content of ground and dried Echinacea purpurea (L.) Moench roots for 60 days, Currently, the number of herbs that are subject to scientific studies is increasing. The well-known medicinal plants are intensively studied to obtain the most accurate data about the chemical composition, the pharmacological effects and the safety of use in therapy [73] . Table 2 summarizes the most important components identified in Echinacea purpurea (L.) Moench and the scientifically proven biological and pharmacological effects, according to the literature. It can be seen that most of the demonstrated effects are common to several compounds, such as the immunomodulatory, antioxidant or antimicrobial effects. Table 2 . Biological and pharmacological effects of the bioactive compounds of Echinacea purpurea (L.) Moench. Alkylamides Anti-inflammatory [74] [75] [76] [77] [78] [79] [80] [81] Immunomodulatory Reduction of NO and tumor necrosis factor -α Cannabinoid receptor type 2 Following the study of the literature, we identified a large number of scientifically proven therapeutic properties for Echinacea purpurea (L.) Moench ( Figure 5 ). Three pathways are responsible for the immunostimulant action of Echinacea species or preparations: phagocytosis activation, fibroblast stimulation and increased respiratory activity all contribute to increased leukocyte motility [127, 128] .Several in vivo investigations have been conducted on the immunomodulatory and anti-inflammatory properties of Echinacea purpurea (L.) Moench and suggest that administration of the plant boosts innate immunity and bolsters the immune system's ability to fight pathogenic in- Three pathways are responsible for the immunostimulant action of Echinacea species or preparations: phagocytosis activation, fibroblast stimulation and increased respiratory activity all contribute to increased leukocyte motility [127, 128] . Several in vivo investiga- tions have been conducted on the immunomodulatory and anti-inflammatory properties of Echinacea purpurea (L.) Moench and suggest that administration of the plant boosts innate immunity and bolsters the immune system's ability to fight pathogenic infections by activating neutrophils, macrophages, polymorphonuclear leukocytes (PMN) and natural killer (NK) cells [129] .The roots and the aerial part of EP include caffeic acid derivatives, alkamides, ketoalkenes, polysaccharides and glycoproteins; they are thought to be responsible for the immunostimulatory and anti-inflammatory properties [29, [130] [131] [132] [133] . In macrophages, phagocytosis and cytokine production (increased tumor necrosis factor -α (TNF-α), interleukin 1 (IL-1) and interferon beta (IFN-β) were established following treatment with Echinacea extract; increased leukocyte mobility and NK cell activation were also demonstrated reasonably in animals and humans [134] [135] [136] . These advancements will allow for the development of a more extensive range of Echinacea products to keep up with the ever-growing market potential. Many studies have been done on Echinacea for conditions such as the common cold and other upper respiratory tract infections or its immunostimulatory action, but there is much less research on the use of Echinacea for other purposes, such as preventing and curing dermatological conditions such as atopic eczema and pruritus. About 2-10% of adults and 15-30% of children suffer from atopic eczema, also known as atopic dermatitis, and this is perhaps the most widespread skin condition that causes inflammation [137] . This chronic inflammatory skin condition frequently manifests itself as a rash with extreme itching [138] . In the case of atopic eczema, there is still a demand that has not been satisfied for topical anti-inflammatory and anti-pruritic drugs with an outstanding safety profile [139] . Oláh A. et al. performed in vivo and in vitro studies on human subjects and cell culture, demonstrating that a root extract of Echinacea purpurea (L.) Moench formulated in a water/oil (W/O) emulsion exerts relevant anti-inflammatory effects clinically, enhances the epidermal lipid barrier and soothes skin complaints of patients with atopic dermatitis. Thus, this W/O emulsion containing EP extract has been shown to be a very promising product for the daily medical care of the skin in subjects with atopic dermatitis [140] . Many inflammatory skin conditions cause pruritus, including atopic eczema and psoriasis, which is a frequent and predominant symptom [141] . In one study, the antipruritic effects on human subjects were evaluated using two types of emulsions and a shampoo containing a lipophilic extract of root of Echinacea purpurea (L.) Moench. Finally, the use of an emulsion decreased dryness, erythema and pruritus considerably [142] . Inflammation is caused by the production of fibrin clots and the degranulation of aggregate platelets, which produce the chemotactic molecules required for the recruitment of leukocytes, especially neutrophils, as well as bone-marrow-derived stem cells or wound fibrocytes. Elastase and collagenase are produced by neutrophils, as well as TNF-α and IL-1, which attract fibroblasts and epithelial cells [143] . Echinacoside is a caffeine conjugate of Echinacea that has been shown to have antihyaluronidase effects. Rousseau et al. are the ones who investigated the effects of Echinacea to heal wounds and the effect of hyaluronuronidase was tested on the vocal folds in the larynx of pigs. The test was performed by random topical applications of different concentrations (1, 200, 600 or 300 mg) of standardized Echinacea on the injured side. A favorable result of antihyaluronidase therapy on the healing of acute vocal wounds has been obtained [144] .From the beginning of humanity [145] , it was also acknowledged that the antioxidant, anti-inflammatory and antimicrobial activity of herbal compounds aids the healing process [2] because of the active biological compounds, each of them with specific structure and action [146] . Therefore, in Chinese medicine, Echinacea purpurea (L.) Moench herba, is used as a treatment for trauma and eczema and improves the skin's barrier function and skin immunity. An in vitro study using a keratinocyte cell culture was performed and phototoxicity tests were performed. The results showed that it has a good moisturizing and water-blocking effect on the skin and does not cause skin irritation, phototoxicity or side effects [147] . According to the 2008 evaluation report, 10-20 g of liquid per 100 g of preparation was utilized in products on the European market. However, this could not be proven in 2013 and there is a tradition of utilizing that range; for example, there is information about ointments containing 10% of the squeezed juice of EP plants in the Rote list of 1961.It is considered that the dry juice equivalent to the juice mentioned above may be equally effective for traditional cutaneous medical products. According to information exchanged between competent authorities in 2013, 16 g of juice expressed per 100 g of preparation is utilized in medications licensed on the European market [148] . Viruses and bacteria cause many skin diseases, and some of them can be cured topically using Echinacea purpurea (L.) Moench. At the same time, it has been shown that a cream containing EP extract improves the symptoms of eczema and helps to repair the thin and protective outer layer of the skin. However, Echinacea extract has a shorter shelf life, making it difficult to incorporate into commercial skin care products [147, 148] . Alkamides have been shown to be effective on CB2 (cannabinoid receptor type 2), which is thought to be one of the mechanisms behind their immunomodulatory characteristics [149] [150] [151] . Echinacea alkamides exhibit cannabinomimetic activities on two specific types of G protein-coupled receptors, namely, CB1 and CB2 cannabinoid receptors; this might be owing to structural similarities between them and anandamide, which is a natural cannabinoid receptor ligand.CB1 and CB2 receptors mediate anandamide's actions in the brain and peripherally. With several research projects, it has been discovered that the endocannabinoid signaling system's actions are not limited to the brain but are used all over the body [152, 153] . The endocannabinoid system is a complicated signaling system that governs a wide range of physiological activities in central and peripheral nervous systems, including regulating and controlling allergic or inflammatory processes [154] . In contrast to the psychoactive effects of CB1 receptor agonists, drugs that act on CB2 receptors appear as promising drugs to fight inflammatory diseases. The CB2 receptor is located mainly in the periphery, especially in the blood cells and in the organs that produce blood cells [155] . One study showed that Echinacea sp. that is due to alkylamide derivatives binds even more strongly to the CB2 receptor than endogenous cannabinoids [152] . Recently, the results reconfirmed the agonist activity of alkylamide derivatives, which demonstrates selectivity for CB2 [156] . Other research found that TNF expression was revealed to be modulated by alkylamides found in Echinacea extracts. In human monocytes and macrophages, Echinacea extracts modulate mRNA through the CB2 receptor, as well as inhibition of stimulated LPS and TNF-α [157, 158] . Based on these data, extracts derived from Echinacea purpurea (L.) Moench support the promise of anti-inflammatory and anti-pruritic benefits [156, 159] . It is known that the endocannabinoid system regulates several parts of the immune functions and the skin barrier; therefore, targeting it may be a viable method of reducing the symptoms of atopic eczema [139] . Cannabinomimetic properties are also important for anxiolitic effect. Echinacea medicines were tested for anxiolytic efficacy among animals used in studies at reduced concentrations as compared to those that utilized unconventional applications. There is little information available about Echinacea and anxiety, but in the future, it will be possible to do research to prevent or even treat anxiety [159] . The former, when endogenous ligands activate it, takes an important role in the treatment of anxiety, while the latter is mostly involved immune system functions [160] .Herbs high in alkamides cause paresthesia and have been used as toothache relief, antitussive and sialagogue by Native Americans in the past, as well as by physicians in the early 20th century [161] .The alkamides have small structural variations, suggesting significant changes in CB receptor function; for example, the G-stimulating function was modified from reverse agonist to partial agonist when the isobutylamide fragment was replaced with a 2-methylbutylamide fragment [162] . The extracts of Echinacea purpurea (L.) Moench, on the other hand, were inactive in the antiacetylcholinesterase test [163] . White rats were used in a clofelin-induced depression test, where later the plant tincture improved the stimulating effect of L-DOPA and demonstrated antidepressant action [164] . In vitro, the aqueous extract of Echinacea purpurea (L.) Moench was effective against HSV-1 and HSV-2 (herpes simplex virus 1 and 2) strains that are acyclovir-resistant and acyclovir-susceptible [165] although the HSV-1 was suppressed by chicoric acid and hexane extract of the plant root [166] . Furthermore, chicoric acid inhibited the integrase of the human immunodeficiency virus type 1 (HIV-1) [167, 168] . For 24 hours, mouse embryonic fibroblasts, after being incubated with alcoholic root extract and plant juice, were resistant to herpes, influenza A2 and vesicular stomatitis virus infection [169] . The avian strains (H7N7) and (H5N1), influenza viruses A (H1N1) and (H3N2) and the pandemic new swine-origin influenza (H1N1) in direct contact with the standard preparation of the plant demonstrated substantial inhibition. Moreover, hemagglutination (HA) experiments revealed that the preparation suppressed HA activity, implying that it might prevent a virus from entering treated cells [170] . Weight loss was detected in contaminated mice with influenza A H1N1 after administration of a plant polysaccharide extract, although lung virus titers were identical in treated and untreated animals. In treated animals, lower levels of keratinocyte chemoattract (KC), interleukin 10 (IL-10), and systemic interferon-gamma (IFN) were found, suggesting that EP might influence the clinical symptoms of influenza via modulating cytokines [171] . According to the findings of the recent research studies, distinct plant components appear to have positive effects on influenza patients via various mechanisms [172] . Therefore, to be identified as a biological agent, more study is needed, particularly in vivo studies and research on the toxic effects of these compounds. There are already clinical trials of SARS-CoV supporting the use of EP against the coronavirus. Preparations of Echinacea purpurea (L.) Moench may be efficient as preventative therapy for all CoVs because of their structural similarities, but further studies are needed [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] . According to recent research, several standardized formulations exhibit potent and selective antiviral and antibacterial properties. Numerous investigations on the effects of Echinacea purpurea (L.) Moench formulations have lately been done in an endeavor to substantiate a few of the more common uses of EP. The Hudson JB study's findings revealed that EP and other Echinacea extracts have selective antibacterial activity, that different creatures had their sensitivity patterns varied significantly and that there were no correlations between the chemical components of the extracts, as measured by known marker compounds, and their antimicrobial activities. In addition, various preparations of EP have noticeably shown various bacterial impacts, demonstrating that EP has various antibacterial actions against each pathogen. Purple coneflower can generally overturn proinflammatory cytokine stimulation, regardless of the bacteria or virus that is causing the infection [184, 185] . Several groups investigated the effects of Echinacea purpurea (L.) Moench on the activation of LPS (inflammatory mediators by bacterial lipopolysaccharide) (typically produced from Escherichia coli) in various cultures of human cells and animals, in addition to research using live bacteria. Although such models may not always mimic living bacteria, they can be helpful in testing for anti-inflammatory drugs. These findings suggest that EP is a general anti-inflammatory drug capable of alleviating several of the symptoms of respiratory infections [186, 187] . The extract derived from the aerial elements of Echinacea purpurea (L.) Moench has higher antibacterial and antioxidant properties than the extract acquired by ultrasonic extraction [4] . Antibiotics and vaccinations are currently used to treat bacterial infections as prophylactic measures. In many circumstances, the management of respiratory infections is a critical issue because of several microorganisms in the disease. Using phytopreparations throughout this case might be a viable option [188, 189] . To gain a greater knowledge of the synergistic interactions of Echinacea extracts with antibiotics, further studies are needed to uncover the mechanism behind their antimicrobial action and then to identify numerous routes that may be targeted. Several reports have demonstrated the antioxidant properties of Echinacea purpurea (L.) Moench. Therefore, during infections, EP may give extra protection by maintaining the normal redox status [190, 191] . Echinacea purpurea (L.) Moench 70% aqueous ethanolic extracts are a possible source of bioactive natural and non-toxic chemicals that serve as antioxidants. The extract prepared by standard extraction from EP aerial sections had a higher concentration of bioactive components [4] . The antioxidant property of Echinacea purpurea (L.) Moench, using the aerial part, is made up of bioactive polyphenolic components. Polyphenols are antioxidants obtained from plants, which have photoprotective, anticarcinogenic and anti-inflammatory properties [192] [193] [194] . All of these therapeutic properties of the extract of EP, using the aerial parts, are beneficial in the cosmeceutical efficiency to prevent the aging of the skin. Antioxidants are compounds that can stop the oxidation reaction triggered by the use of free radicals. They can minimize skin injury by neutralizing the damaging effects of free radicals and reactive oxygen species [195, 196] . Significant antioxidant capacity measurements are broadly classified into two types: hydrogen atom transfer (single-electron transfer reaction-based assays and H reactionbased assays) [197] . The phenolic content and phenolic profiles of the extracts, as well as their antioxidant activity, may all be analyzed. The following methods can be used: scavenging of DPPH radicals, ABTS, FRAP, the Folin-Ciocalteu colorimetric method, voltametry-a sensitive electrochemical method, CUPRAC [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] . Antioxidant activity can be measured using any of the methods. Current studies highlight scientific information about the natural chemical compounds obtained from herbal remedies that have anti-osteoporosis or anti-osteonecrosis qualities. The emphasis is on international literature published during the previous 10 years [210] . Echinacea sp. contains echinacoside, which is a phenylpropanoid glycoside that was isolatedto produce substantial increases in alkaline phosphatase activity, MC3T3-E1 cell proliferation, osteocalcin levels, collagen 1 secretion and mineralization when isolated from Cistanche tubulosa. The scientists found that osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) may have a role in echinacoside's anti-osteoporotic activity. An in vivo follow-up study demonstrated the effects of echinacoside in counteracting the damage caused by ovariectomy, leading to improved bone mineral density and bone biomechanical properties [172] . Most osteoporotic patients are postmenopausal women and estrogen deficiency is the predominant cause of rapid hormone-related rapid bone loss after menopause. Natural alternatives are being investigated in this area to avoid bone loss and the danger of fracture caused by osteoporosis, as well as less desirable side effects [211] . Anti-inflammatory and antioxidant characteristics are linked to several osteoclast suppressants. According to Aarland et al. [156] , Echinacea purpurea (L.) Moench has been already explored for its antioxidant and anti-inflammatory properties. Therefore, it has also been thought to help with inflammation-related osteoclastogenesis. The accidental roots of EP were fractionated utilizing various chromatographic methods, yielding three novel chemicals and eight recognized compounds. Antioxidant and anti-inflammatory action were initially assessed to identify a novel chemical capable of suppressing osteoclasts. Among the new compounds, echinalkamide (compound 1, isobutylamide of undeca-2Z-4E-diene-8,10-diinoic acid) shows the best antioxidant and anti-inflammatory benefits. The possibility of echinalkamide as an osteoporosis therapy, as well as the mechanism behind it, has been evaluated [212] . According to the findings, echinacoside improves bone regeneration by boosting OPG ratios and promoting cell signaling pathways. The research indicates that echinacoside and echinalkamide enhance cell proliferation, differentiation and mineralization by modulating the stimulus of OPG and signaling pathways. As a result, Echinacea purpurea (L.) Moench is a potential herbal medication for osteoporosis prevention and treatment. A pharmaceutical preparation in the form of capsules containing Echinacea sp. in conjunction with Gentiana sp. has become available on the pharmaceutical market and can be prescribed for the prevention of osteoporosis. Given the potential in pharmaceutical applications, EP has attracted the interest of many pharmaceutical scientists, but further studies are needed to interpret the molecular mechanisms and clinical trials in the treatment of osteoporosis. Studies on the species Echinacea purpurea (L) Moench have discovered a large range of bioactive compounds, indicating that it is a rich source of phytochemicals that might be used to cure a number of diseases. Antioxidants, immunomodulators, anti-inflammatory, antibacterial, antiviral and antiosteoporotic are just a few of the positive biological effects that indicate how important this species is in the ecosystem. There are differences in the extracts' phytochemical, biological and pharmacological properties that come from different sources. The findings of the investigations show that standardization measures are needed to ensure not only the safety and identification of botanical products but also their pharmacological effectiveness. EP is a source of bioactive chemicals, but only a tiny portion of its characteristics have been studied, and some of them might be valuable therapeutic tools. For future perspectives, it is important to expand the studies on the dermatological effects. There are real chances for the development of EP-based products, effective in various common dermatological conditions, that are due to bioactive compounds. At the same time, further research into the in-depth understanding of the cannabinomimetic properties has major importance for the development of new pharmaceuticals. SIRT1 Activation by Equisetum arvense L. (Horsetail) Modulates Insulin Sensitivity in Streptozotocin Induced Diabetic Rats. Molecules Antioxidant and Antimicrobial Activities of Echinacea (Echinacea purpurea L.) Extracts Obtained by Classical and Ultrasound Extraction Analysis of Echinacea flower volatile constituents by HS-SPME-GC/MS using laboratory-prepared and commercial SPME fibers Extraction of caftaric and cichoric acids from Echinacea purpurea L. in subcritical water Ethnomedicinal uses of plants for the treatment of nervous disorders at the herbal markets of Bojnord The Medicinal Chemistry of Echinacea Species Morphology and anatomy of Echinacea purpurea, E. angustifolia, E. pallida and Parthenium integrifolium Herbal medicine: Echinacea The taxonomy of the genus Echinacea (Compositae) An anatomical study of the genus Echinacea American Herbal Pharmacopoeia: Botanical Pharmacognosy-Microscopic Characterization of Botanical Medicines Echinacea: Herbal Medicine with a Wild History Comparative analysis of the leaf anatomy of Echinacea purpurea and E. pallida Committee on Herbal Medicinal Products. Assessment Report on Echinacea purpurea (L.) Moench, Herba; European Medicines Agency Effects of Metribuzin Herbicide on Some Morpho-Physiological Characteristics of Two Echinacea Species The PRISMA 2020 statement: An updated guideline for reporting systematic reviews Updating guidance for reporting systematic reviews: Development of the PRISMA 2020 statement Improving growth and phenolic compounds of Echinacea purpurea root by integrating biological and chemical resources of phosphorus under water deficit stress Analytical methods for the study of bioactive compounds from medicinally used Echinacea species Comparative Study of Polyphenols, Flavonoids and Chlorophylls in Equisetum arvense L. Populations Determination of the Total Polyphenols Content and Antioxidant Activity of Echinacea Purpurea Extracts Using Newly Manufactured Glassy Carbon Electrodes Modified with Carbon Nanotubes Echinacea species as potential immunostimulatory drugs Microwave assisted extraction of bio-active compounds (phenolics and alkamides) from Echinacea purpurea Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): A review of their chemistry, pharmacology and clinical properties A Rapid UPLC Method for the Simultaneous Quantitation of Caffeic Acid Derivatives in Dried Extracts of Echinacea Purpurea Caftaric Acid Isolation from Unripe Grape: A "Green" Alternative for Hydroxycinnamic Acids Recovery Enhanced production of cichoric acid in cell suspension culture of Echinacea purpurea by silver nanoparticle elicitation Growth and nutrient content of Echinacea purpurea as affected by the combination of phosphorus with arbuscular mycorrhizal fungus and Pseudomonas florescent bacterium under different irrigation regimes The influence of Echinacea purpurea leaf microbiota on chicoric acid level Improving biomass and chicoric acid content in hairy roots of Echinacea purpurea L Synergistic Antioxidative Effects of Alkamides, Caffeic Acid Derivatives, and Polysaccharide Fractions from Echinacea purpurea on in Vitro Oxidation of Human Low-Density Lipoproteins Heavy metals analysis, GCMS-QP quantification of flavonoids, amino acids and saponins, analysis of tannins and organoleptic properties of powder and tincture of Echinacea purpurea (L.) and Rhapónticum carthamoídes Volatile constituents and biological activities of the leaf and root of Echinacea species from South Africa Identification of Echinacea Purpurea (L.) Moench Root LysM Lectin with Nephrotoxic Properties Pharmacological importance of Echinacea purpurea Caffeic Acid Derivatives Production by Hairy Root Cultures of Echinacea purpurea Optimization of callus cultures at Echinacea purpurea L. for the amount of caffeic acid derivatives Analysis of phenolic compounds and radical scavenging activity of Echinacea spp Antioxidant activity of cichoric acid and alkamides from Echinacea purpurea, alone and in combination Antioxidant and prooxidant activities of phenolic compounds of the extracts of Echinacea purpurea (L.) Retention of Caffeic Acid Derivatives in Dried Echinacea purpurea A quantitative HPLC method for the quality assurance of Echinacea Products on the North American market Optimization and single-laboratory validation study of a high-performance liquid chromatography (HPLC) method for the determination of phenolic Echinacea constituents Antidiabetic, and Antihypertensive Properties of Echinacea purpurea Flower Extract and Caffeic Acid Derivatives Using In Vitro Models Neuroprotective effects of echinacoside in the mouse MPTP model of Parkinson's disease Polysaccharide from Echinacea purpurea reduce the oxidant stress in vitro and in vivo Re-opening the stage for Echinacea research-Characterization of phylloxanthobilins as a novel anti-oxidative compound class in Echinacea purpurea Phylloxanthobilins are Abundant Linear Tetrapyrroles from Chlorophyll Breakdown with Activities Against Cancer Cells Volatile Components of Roots, Stems, Leaves, and Flowers of Echinacea Species Simultaneous analysis of caffeic acid derivatives and alkamides in roots and extracts of Echinacea purpurea by high-performance liquid chromatography-photodiode array detection-electrospray mass spectrometry Seasonal Variations in the Concentrations of Lipophilic Compounds and Phenolic Acids in the Roots of Echinacea purpurea and Echinacea pallida Echinacea purpurea (L.) Moench: Chemical Characterization and Bioactivity of Its Extracts and Fractions Nonvitamin and Nonmineral Nutritional Supplements The effects of the dietary supplementation of Echinacea purpurea extract and/or vitamin C on the intestinal histomorphology, phagocytic activity, and gene expression of the Nile tilapia Medicinal properties of Echinacea: A critical review Effects of Echinacea extracts on macrophage antiviral activities Recurrent erythema nodosum associated with echinacea herbal therapy Toxicology and Clinical Pharmacology of Herbal Products The effect of Echinacea spp. on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review Safety and Dose-Dependent Effects of Echinacea for the Treatment of Acute Cold Episodes in Children: A Multicenter, Randomized, Open-Label Clinical Trial Mapping of Echinacea-based food supplements on the Romania market and qualitative evaluation of the most commonly used products An Uncommon Plant Growth Regulator, Diethyl Aminoethyl Hexanoate, Is Highly Effective in Tissue Cultures of the Important Medicinal Plant Purple Coneflower Alkylamide and Cichoric Acid Levels inEchinacea purpureaTissues During Plant Growth Regulatory Aspects of Herbal Medicine A strategy for test article selection and phytochemical characterization of Echinacea purpurea extract for safety testing Bioavailability and Pharmacokinetics of Alkamides From the Roots of Echinacea angustifolia in Humans Pharmacokinetics of the Main Alkamides after Administration of three Different Echinacea purpurea Preparations in Humans Echinacea purpurea: Pharmacology, phytochemistry and analysis methods Alkylamides from Echinacea Modulate Induced Immune Responses in Macrophages Analysis of Alkylamides in Echinacea Plant Materials and Dietary Supplements by Ultrafast Liquid Chromatography with Diode Array and Mass Spectrometric Detection Echinacea and its alkylamides: Effects on the influenza A-induced secretion of cytokines, chemokines, and PGE2 from RAW 264.7 macrophage-like cells Untersuchungen zur Wirkung von Echinacea angustifolia auf die unspezifische zelluläre Immunantwort der Maus [The effect of Echinacea angustifolia on non-specific cellular immunity in the mouse Natural Polysaccharides in Drug Delivery and Biomedical Applications Fractionation and evaluation of proteins in roots of Echinacea purpurea (L.) Moench Anti-Inflammatory Activity of N-Butanol Extract from Ipomoea stolonifera In Vivo and In Vitro Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant Echinacea purpurea Bactericidal and anti-inflammatory properties of a standardized Echinacea extract (Echinaforce®): Dual actions against respiratory bacteria Anti-inflammatory effect, total polysaccharide, total phenolics content and antioxidant activity of the aqueous extract of three basidiomycetes In vitro screening for the tumoricidal properties of international medicinal herbs Botanical Medicines for the Treatment of Cancer: Rationale, Overview of Current Data, and Methodological Considerations for Phase I and II Trials Tumor inhibitors. 3. Identification and synthesis of a oncolytic hydrocarbon from American coneflower roots A Comparison of the Immunostimulatory Effects of Polysaccharides from Tetraploid and Diploid Echinacea purpurea The immunoregulatory effect of sulfated Echinacea purpurea polysaccharide on chicken bone marrow-derived dendritic cells Cytotoxic effects of Echinacea purpurea flower extracts and cichoric acid on human colon cancer cells through induction of apoptosis Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies Macrophage Activation by the Polysaccharide Arabinogalactan Isolated From Plant Cell Cultures of Echinacea purpurea Anticancer and biological properties of leaf and flower extracts of Echinacea purpurea (L.) Moench Echinacea purpurea polysaccharide prepared by fractional precipitation prevents alcoholic liver injury in mice by protecting the intestinal barrier and regulating liver-related pathways Echinacea purpurea suppresses the cell survival and metastasis of hepatocellular carcinoma through regulating the PI3K/Akt pathway Pharmacokinetics and immunomodulatory effects of phytotherapeutic lozenges (bonbons) with Echinacea purpurea extract Immunostimulants for preventing respiratory tract infection in children Immune Enhancing Effects of Echinacea purpurea Root Extract by Reducing Regulatory T Cell Number and Function Antiviral and Immunological Activity of Glycoproteins from Echinacea purpurea Radix Quantitative Analysis of the Polysaccharide and Glycoprotein Fractions in Echinacea purpurea. And Echinacea angustifolia. by HPLC-ELSD for Quality Control of Raw Material Flavonoids from Echinacea purpurea Pharmacological Activities of Flavonoids: A Review Anti-inflammatory effects of flavonoids The protective effect of Echinacea spp. (Echinacea angustifolia and Echinacea purpurea) in a rat colitis model induced by acetic acid Phenol and Polysaccharide Contents of Echinacea Purpurea, L. and Its Immunostimulant Capacity In Vitro Anti-inflammatory and cicatrizing activity of Echinacea pallida Nutt. root extract Effects of Caffeic Acid and Its Derivatives on Bone: A Systematic Review Bioactivity and Chemical Synthesis of Caffeic Acid Phenethyl Ester and Its Derivatives Altering effects of caffeic acid phenethyl ester (CAPE) and ischemia/reperfusion injury: An experimental study in a rat TRAM flap model Caffeic acid phenethyl ester (CAPE) revisited: Covalent modulation of XPO1/CRM1 activities and implication for its mechanism of action A comparative study of caffeic acid and a novel caffeic acid conjugate SMND-309 on antioxidant properties in vitro Caffeic acid derivatives, analogs and applications: A patent review Cytotoxic effects of Echinacea root hexanic extracts on human cancer cell lines Which Plant Part of Purple Coneflower (Echinacea purpurea (L.) Moench) Should be Used for Tea and Which for Tincture? Enhanced production of caftaric acid, chlorogenic acid and cichoric acid in suspension cultures of Echinacea purpurea by the manipulation of incubation temperature and photoperiod Preliminary data on antibacterial activity of Echinacea purpurea-associated bacterial communities against Burkholderia cepacia complex strains, opportunistic pathogens of Cystic Fibrosis patients Caffeic acid derivatives, total phenols, antioxidant and antimutagenic activities of Echinacea purpurea flower extracts Echinacoside and Cistanche tubulosa (Schenk) R. wight ameliorate bisphenol A-induced testicular and sperm damage in rats through gonad axis regulated steroidogenic enzymes Effects of Acteoside and Echinacoside on the Expression of the BMP2 in Rat Osteoblast Echinacoside, an Inestimable Natural Product in Treatment of Neurological and other Disorders Metabolism of Echinacoside, a Good Antioxidant, in Rats: Isolation and Identification of Its Biliary Metabolites Phytopharmacologic preparations as predictors of plant bioactivity: A particular approach to Echinacea purpurea (L.) Moench antioxidant properties Echinacoside induces apoptotic cancer cell death by inhibiting the nucleotide pool sanitizing enzyme MTH1 Nature's Immune Enhancer Protective effect of Echinacea purpurea (Immulant) against cisplatin-induced immunotoxicity in rats Chemical structure and anti-inflammatory effect of polysaccharide extracted from Morinda citrifolia Linn (Noni) Harvest Strategies for Optimization of the Content of Bioactive Alkamides and Caffeic Acid Derivatives in Aerial Parts and in Roots of Echinacea purpurea Immunity: Plants as Effective Mediators Use of Quantitative Flow Cytometry to Measure Ex Vivo Immunostimulant Activity of Echinacea: The Case for Polysaccharides Natural immunomodulators and their stimulation of immune reaction: True or false? Studies on phytochemical, antioxidant, anti-inflammatory, hypoglycaemic and antiproliferative activities of Echinacea purpurea and Echinacea angustifolia extracts Cytokine-and interferon-modulating properties of Echinacea spp. root tinctures stored at -20 degrees C for 2 years on behalf of British Association of Dermatologists and Royal College of General Practitioners. Guidance on the diagnosis and clinical management of atopic eczema Atopic dermatitis The endocannabinoid system of the skin in health and disease: Novel perspectives and therapeutic opportunities Echinacea purpurea -derived alkylamides exhibit potent anti-inflammatory effects and alleviate clinical symptoms of atopic eczema Efficacy of hydrophilic or lipophilic emulsions containing Echinacea purpurea extract in treatment of different types of pruritus Wound healing in development Investigation of Anti-Hyaluronidase Treatment on Vocal Fold Wound Healing Hydrocarbon Charging and Accumulation in the Permian Reservoirs of theWumaying Buried Hill, Huanghua Depression Statistical Analysis of the Relationship Between Antioxidant Activity and the Structure of Flavonoid Compounds Poly traditional Chinese medicine formulation prepared with skin moisturizing properties Assessment Report on Echinacea purpurea (L.) Moench, Herbarecens, European Medicines Agency Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects The Role of Alkamides as an Active Principle of Echinacea Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts The Endocannabinoid System as a Target for Alkamides fromEchinacea angustifoliaRoots Cannabimimetic plants: Are they new cannabinoidergic modulators? Planta Endocannabinoid signaling at the periphery: 50 years after THC Targeting Cannabinoid CB2 Receptors in the Central Nervous System Interactions of Echinacea spp. Root Extracts and Alkylamides With the Endocannabinoid System and Peripheral Inflammatory Pain Echinacea alkylamides modulate TNF-α gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways Permeability studies of alkylamides and caffeic acid conjugates from echinacea using a Caco-2 cell monolayer model The effect of Echinacea preparations in three laboratory tests of anxiety: Comparison with chlordiazepoxide The Endocannabinoid System as an Emerging Target of Pharmacotherapy Alkamides: Structural Relationships, Distribution and Biological Activity1 Alkamides and a neolignan from Echinacea purpurea roots and the interaction of alkamides with G-protein-coupled cannabinoid receptors Acetylcholinesterase inhibitory and antioxidant properties of Cyclotrichium niveum, Thymus praecox subsp. caucasicus var. caucasicus, Echinacea purpurea and E. pallida Antidepressant activity of some phytopharmaceuticals and phenylpropanoids Antiviral activity of Viracea®against acyclovir susceptible and acyclovir resistant strains of herpes simplex virus Antiviral Activity of Characterized Extracts from Echinacea spp. (Heliantheae: Asteraceae) against Herpes simplex Virus (HSV-I) Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase Chicoric acid, an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase, improves on the in vitro anti-HIV-1 effect of Zidovudine plus a protease inhibitor (AG1350) Virushemmung mit Echinacea purpurea Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian Influenza virus (H5N1, H7N7) and swine-origin H1N1 (S-OIV) Echinacea purpurea aerial extract alters course of influenza infection in mice There is nothing exempt from the peril of mutation-The Omicron spike CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target A systematic review on the effects of Echinacea supplementation on cytokine levels: Is there a role in COVID-19? Use of echinacea in medicine COVID-19 diagnosis and management: A comprehensive review The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system Swiss Echinacea extract shown safe and effective in preventing colds in largest Echinacea clinical trial Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection Induction of multiple pro-inflammatory cytokines by respiratory viruses and reversal by standardized Echinacea, a potent antiviral herbal extract In vitro virucidal activity of Echinaforce®, an Echinacea purpurea preparation, against coronaviruses, including common cold coronavirus 229E and SARS-CoV-2 Echinacea as a Potential Force against Coronavirus Infections? A Mini-Review of Randomized Controlled Trials in Adults and Children Applications of the Phytomedicine Echinacea purpurea (Purple Coneflower) in Infectious Diseases Extracts Contain Significant and Selective Activities Against Human Pathogenic Bacteria* The influence of traditional herbal formulas on cytokine activity Antagonism and antibiotic resistance drive a species-specific plant microbiota differentiation in Echinacea spp Traditional Medicinal Plants-A Possible Source of Antibacterial Activity on Respiratory Diseases Induced by Chlamydia pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae and Moraxella catarrhalis Antimicrobial activity of wild mushroom extracts against clinical isolates resistant to different antibiotics Effect of High Pressure Pasteurization on Bacterial Load and Bioactivity of Echinacea Purpurea Antifungal and Antiinflammatory Activity of the Genus Echinacea Echinacea plants as antioxidant and antibacterial agents: From traditional medicine to biotechnological applications Comparison of chemical components and antioxidant capacity of different Echinacea species Fenugreek seed and its active agent diosgenin treatment effects on different metabolic parameters in rats Skin improvement and stability of Echinacea purpurea dermatological formulations The Chemistry behind Antioxidant Capacity Assays Active polyphenolic compounds, nutrient contents and antioxidant capacity of extruded fish feed containing purple coneflower (Echinacea purpurea (L.) Moench.) An Investigation on the Antioxidant Activities of Hyssopus officinalis L. and Echinacea purpurea L. Plant Extracts in Oil Model System Biotechnological production of caffeic acid derivatives from cell and organ cultures of Echinacea species HPLC Method Validated for the Simultaneous Analysis of Cichoric Acid and Alkamides in Echinacea purpurea Plants and Products Antioxidative activity of Ginkgo, Echinacea, and Ginseng tinctures Solid-liquid and high-pressure (liquid and supercritical carbon dioxide) extraction of Echinacea purpurea L An on-line HPLC system for detection of antioxidant compounds in some plant extracts by comparing three different methods Ultrasound-assisted extraction of medicinal plants and evaluation of their biological activity Metabolic and antioxidant profiles of herbal infusions and decoctions Theoretical and Antioxidant Study of 3d-Transition Metals (Co(II) Electrochemical Determination of the Antioxidant Activity inEchinacea Purpurea-Roots Using Square Wave Voltammetry Echinacea Standardization: Analytical Methods for Phenolic Compounds and Typical Levels in Medicinal Species Natural Products from Chinese Medicines with Potential Benefits to Bone Health The Antimicrobial Activity of Origanum vulgare L. Correlated with the Gastrointestinal Perturbation in Patients with Metabolic Syndrome Antiosteoporotic activity of echinacoside in ovariectomized rats The authors wish to thank the University of Oradea for its technical support in conducting this study. The authors declare no conflict of interest.