Inula viscosa (L.) Aiton Ethanolic Extract Inhibits the Growth of Human AGS and A549 Cancer Cell Lines.

The present study shows the chemical profile and cytotoxic properties of the ethanolic extracts of Inula viscosa from Northeast Algeria. The extract was obtained by maceration using ethanol. Its phenolic profile was determined using ultra-high-performance liquid chromatography coupled with a diode array detector and an electrospray mass spectrometer (UHPLC-DAD-ESI/MS), which allowed the identification and quantification of 17 compounds, 1,5-O-caffeoylquinic acid being the most abundant. The cytotoxic activity was assessed against human gastric cancer (AGS) and human non-small-cell lung cancer (A549) cell lines, whereas ethanolic extract elicited nearly 60 % and 40 % viability loss toward AGS and A549 cancer cells, respectively. Results also showed that cell death is caspase-independent and confirmed the involvement of RIPK1 and the necroptosis pathway in the toxicity induced by the I. viscosa extract. In addition, the ethanolic extract would not provoke morphological traits in the cancer cells. These findings suggest that I. viscosa can be a source of new antiproliferative drugs or used in preparation plant-derived pharmaceuticals.

Overview of Phlorotannins' Constituents in Fucales.

Fucales are an order within the Phaeophyceae that include most of the common littoral seaweeds in temperate and subtropical coastal regions. Many species of this order have long been a part of human culture with applications as food, feedand remedies in folk medicine. Apart from their high nutritional value, these seaweeds are also a well-known reservoir of multiple bioactive compounds with great industrial interest. Among them, phlorotannins, a unique and diverse class of brown algae-exclusive phenolics, have gathered much attention during the last few years due to their numerous potential health benefits. However, due to their complex structural features, combined with the scarcity of standards, it poses a great challenge to the identification and characterization of these compounds, at least with the technology currently available. Nevertheless, much effort has been taken towards the elucidation of the structural features of phlorotannins, which have resulted in relevant insights into the chemistry of these compounds. In this context, this review addresses the major contributions and technological advances in the field of phlorotannins extraction and characterization, with a particular focus on Fucales.

Metabolite Profiling, Antioxidant and Key Enzymes Linked to Hyperglycemia Inhibitory Activities of Satureja hispidula: An Underexplored Species from Algeria.

In the present study, two extracts from the aerial parts of the endemic species Satureja hispidula were analyzed for the first time by ultra-high-performance liquid chromatography coupled with a diode array detector and an electrospray mass spectrometer (UHPLC-DAD-ESI/MS) method in order to identify and quantify their phenolic compounds. These extracts' antioxidant, α-glucosidase and α-amylase inhibitory activities were also evaluated. UHPLC-DAD-ESI/MS allowed the identification of 28 and 20 compounds in the ethanolic and aqueous extracts, respectively; among them, 5-O-caffeoylquinic acid was the most abundant in both extracts. The biological assay results indicate that the species S. hispidula, besides its high antioxidant power, is also potentially useful for inhibiting the α-glucosidase enzyme. In both antioxidant and α-glucosidase inhibitory assays, the aqueous extract exhibited the most promising results, significantly better than the standards used as positive controls.

Camel (Camelus spp.) Urine Bioactivity and Metabolome: A Systematic Review of Knowledge Gaps, Advances, and Directions for Future Research.

Up to the present day, studies on the therapeutic properties of camel (Camelus spp.) urine and the detailed characterization of its metabolomic profile are scarce and often unrelated. Information on inter individual variability is noticeably limited, and there is a wide divergence across studies regarding the methods for sample storage, pre-processing, and extract derivatization for metabolomic analysis. Additionally, medium osmolarity is not experimentally adjusted prior to bioactivity assays. In this scenario, the methodological standardization and interdisciplinary approach of such processes will strengthen the interpretation, repeatability, and replicability of the empirical results on the compounds with bioactive properties present in camel urine. Furthermore, sample enlargement would also permit the evaluation of camel urine's intra- and interindividual variability in terms of chemical composition, bioactive effects, and efficacy, while it may also permit researchers to discriminate potential animal-intrinsic and extrinsic conditioning factors. Altogether, the results would help to evaluate the role of camel urine as a natural source for the identification and extraction of specific novel bioactive substances that may deserve isolated chemical and pharmacognostic investigations through preclinical tests to determine their biological activity and the suitability of their safety profile for their potential inclusion in therapeutic formulas for improving human and animal health.

Phytochemical and Antioxidant Profile of the Medicinal Plant Melia azedarach Subjected to Water Deficit Conditions.

Environmental stress triggered by climate change can alter the plant's metabolite profile, which affects its physiology and performance. This is particularly important in medicinal species because their economic value depends on the richness of their phytocompounds. We aimed to characterize how water deficit modulated the medicinal species Melia azedarach's lipophilic profile and antioxidant status. Young plants were exposed to water deficit for 20 days, and lipophilic metabolite profile and the antioxidant capacity were evaluated. Leaves of M. azedarach are rich in important fatty acids and oleamide. Water deficit increased the radical scavenging capacity, total phenol, flavonoids, and catechol pools, and the accumulation of ß-sitosterol, myo-inositol, succinic acid, sucrose, d-glucose and derivatives, d-psicofuranose, d-(+)-fructofuranose, and the fatty acids stearic, α-linolenic, linoleic and palmitic acids. These responses are relevant to protecting the plant against climate change-related stress and also increase the nutritional and antioxidant quality of M. azedarach leaves.

Chemical Variability of Hexane Extracts from Five Subspecies of Calendula suffruticosa from Spain.

The chemical profile of the hexane extracts of the subspecies carbonellii, greuteri, marginata, trialata, and vejerensis of Calendula suffruticosa growing in Spain, herein described for the first time, were studied to access their value as a chemo taxonomical tool and search for potentially useful compounds. The subsp. greuteri and carbonellii showed higher extract yields. Terpenoids were the most abundant chemical class in subsp. carbonellii, greuteri, trialata, and vejerensis, while alkanes were the most abundant in subsp. marginata. Differences in chemical constituents were identified among the subspecies of C. suffruticosa analysed, which the PCA can prove. The subsp. trialata and greuteri showed more significant phytochemical similarity, which might indicate genetic proximity between these two subspecies. C. suffruticosa subsp. marginata presented the fewest number of compounds and in the smallest quantities, and C. suffruticosa subsp. vejerensis presented the largest number, however, both showed no alcohols. Furthermore, some of the compounds found in significant amounts are known for their pharmacological and nutraceutical properties, denoting potential use.

Chemical Composition and Antioxidant, Anti-Inflammatory, and Enzyme Inhibitory Activities of an Endemic Species from Southern Algeria: Warionia saharae.

Warionia saharae Benth. & Coss. (Asteraceae) is an endemic species of North Africa naturally grown in the southwest of the Algerian Sahara. In the present study, this species' hydromethanolic leaf extract was investigated for its phenolic profile characterized by ultra-high-performance liquid chromatography coupled with a diode array detector and an electrospray mass spectrometer (UHPLC-DAD-ESI/MS). Additionally, the chemical composition of W. saharae was analyzed by gas chromatography-mass spectrometry, and its antioxidant potential was assessed through five in vitro tests: DPPH● scavenging activity, ABTS●+ scavenging assay, galvinoxyl scavenging activity, ferric reducing power (FRP), and cupric reducing antioxidant capacity. The UHPLC-DAD-ESI/MS analysis allowed the detection and quantification of 22 compounds, with taxifolin as the dominant compound. The GC-MS analysis allowed the identification of 37 compounds, and the antioxidant activity data indicate that W. saharae extract has a very high capacity to capture radicals due to its richness in compounds with antioxidant capacity. The extract also showed potent α-glucosidase inhibition as well as a good anti-inflammatory activity. However, weak anti-α-amylase and anticholinesterase activities were recorded. Moreover, an in silico docking study was performed to highlight possible interactions between three significant compounds identified in W. saharae extract and α-glucosidase enzyme.

Inter-Individual versus Inter-Population Variability of Calendula suffruticosa subsp. algarbiensis Hexane Extracts.

Calendula suffruticosa subsp. algarbiensis (Boiss.) Nyman is very common on the Portuguese coast, but it has only recently begun to be studied chemically and belongs to a genus of difficult taxonomic classification. To improve the knowledge on the chemical variability of this taxon and evaluate the possible use of this tool for taxonomical purposes, the aim of this work was to determine the extent of chemical variation between individuals collected in the same geographic region, and to compare with samples mixing fragments of several individuals each (populations) from different local environments. Overall, hexane extract analysis by GC/MS allowed to identify 42 compounds, eight fatty acids, 24 terpenoids, three alcohols, five alkanes, and two pollutants. Greater chemical differences were found between individuals, grown in the same region, than were found between population samples from different regions. Additionally, 25 phytochemicals were identified for this taxon for the first time and may be used for taxonomic classification, even to distinguish between subspecies of C. suffruticosa. Furthermore, plants collected near urban areas accumulated pollutants, indicating the importance of controlling local environmental conditions when C. suffruticosa cultivation is for human consumption.

Genista tridentata L.: A Rich Source of Flavonoids with Anti-inflammatory Activity.

: Background: Genista tridentata L. is an endemic species from the Iberian Peninsula used in Portuguese traditional medicine to treat inflammation-related diseases; this and other health-promoting effects are usually associated with the flavonoids produced by this species. In fact, anti-inflammatory properties were established for several of these flavonoid derivatives. Methods: A careful survey of the reported data, using mainly the Scopus database and Genista tridentata and Pterospartum tridentatum as keywords, was done. We have examined the papers involving the plant and those about the most relevant flavonoids anti-inflammatory activity. Results: The literature survey demonstrates that species are used to treat several health problems such as antihyperglycemia, hypertension, and inflammatory episodes. It was also possible to establish its richness in flavonoid derivatives, from which several are potential anti-inflammatory agents. Conclusions: From our described and discussed analysis, it can be concluded that Genista tridentata is an excellent source of bioactive flavonoids. Moreover, its traditional use to treat inflammation episodes may be due to its flavonoid content, from which genistein, biochanin A, rutin, and daidzein can be emphasized.

Flavonoid Profile of the Genista tridentata L., a Species Used Traditionally to Treat Inflammatory Processes.

Ethnopharmacological surveys on Portuguese flora reveal that Genista tridentata L. is a shrub used in traditional medicine for the treatment of various inflammation-related health problems, although scientific support of its benefits is still necessary. In order to establish the anti-inflammatory potential of G. tridentata and support its traditional use, ethanolic extracts of three sections of the plant (root, stem, and leaves) were subjected to in vitro evaluation of anti-inflammatory activity using lipopolysaccharide (LPS)-stimulates macrophages as an inflammation model. Simultaneously, we also aimed to establish the extracts' flavonoids profile. The ethanolic extracts, obtained by Soxhlet extraction, profile of the three sections confirmed their richness in flavonoids, being three prenylated flavonoids isolated and characterized in the root, including a new natural compound, the 3-methoxymundulin. The extracts from the three plant sections showed strong antioxidant activity at the cellular level and significantly inhibit the LPS-triggered NO production by downregulating Nos2 gene transcription and consequently iNOS expression. Additionally, root and stem extracts also decreased the LPS-induced transcription of the pro-inflammatory genes Il1b, Il6, and Ptgs2. Thus, the results support the anti-inflammatory properties attributed to G. tridentate preparations. Relevantly, the roots of the shrub, plant part not used, is an unexplored source of compounds with pharmacological and nutraceutical value.

Puccinellia maritima, Spartina maritime, and Spartina patens Halophytic Grasses: Characterization of Polyphenolic and Chlorophyll Profiles and Evaluation of Their Biological Activities.

Halophytic grasses have been recently targeted as possible sources of nutraceutical and medicinal compounds. Nonetheless, few studies have been conducted on the phytochemistry and biological activities of metabolites produced by these plants. Among these, Spartina maritima (Curtis) Fernald, Spartina patens (Aiton.) Muhl., and Puccinellia maritima (Hudson) Parl. are three halophytic grasses whose chemical composition and bioactivities are unknown. The present work broadens the knowledge on the polyphenolic and chlorophyll composition of these species identifying for the first time hydroxycinnamic acids and their derivatives, flavones, flavonols, lignans, as well as chlorophylls and xantophylls. The extracts were particularly rich in caffeic and ferulic acids as well as in trihydroxymethoxyflavone, apigenin and tricin derivatives. Interestingly, several of the identified compounds are relevant from a medicinal and nutraceutical point of view putting in evidence the potential of these species. Thus, the antioxidant, anti-acetylcholinesterase, antibacterial, and antifungal activities of the polyphenolic extracts were assessed as well as the photophysical properties of the chlorophyll-rich extracts. The results, herein presented for the first time, reinforce the nutritional and the medicinal potential of these halophytic grasses.

Halophytic Grasses, a New Source of Nutraceuticals? A Review on Their Secondary Metabolites and Biological Activities.

The Poaceae family, known as grasses, is distributed worldwide and is considered the most important group of monocotyledonous crops. Salt stress is multifactorial, therefore to survive, halophytes evolved a variety of adaptations, which include the biosynthesis of different primary and secondary metabolites. This trait enhances the accumulation of important families of compounds crucial to the prevention of a variety of chronic diseases. Besides, if proven edible, these species could cope with the increased soil salinity responsible for the decline of arable land due to their high nutritional/nutraceutical value. Herein, the phytochemical investigations performed in halophytes from the Poaceae family as well as their biological properties were explored. Among the 65 genera and 148 species of known halophytic grasses, only 14% of the taxa were studied phytochemically and 10% were subjected to biological evaluation. Notably, in the studied species, a variety of compound families, as well as bioactivities, were demonstrated, highlighting the potential of halophytic grasses.

Scabiosa Genus: A Rich Source of Bioactive Metabolites.

The genus Scabiosa (family Caprifoliaceae) is considered large (618 scientific plant names of species) although only 62 have accepted Latin binominal names. The majority of the Scabiosa species are widely distributed in the Mediterranean region and some Scabiosa species are used in traditional medicine systems. For instance, Scabiosa columbaria L. is used traditionally against diphtheria while S. comosa Fisch. Ex Roem. and Schult. is used in Mongolian and Tibetan traditional medical settings to treat liver diseases. The richness of Scabiosa species in secondary metabolites such as iridoids, flavonoids and pentacyclic triterpenoids may contribute to its use in folk medicine. Details on the most recent and relevant pharmacological in vivo studies on the bioactive secondary metabolites isolated from Scabiosa species will be summarized and thoroughly discussed.

Salicornia ramosissima J. Woods seeds affected the normal regenerative function on carbon tetrachloride-induced liver and kidney injury.

The growing importance of Salicornia plants as bioactive agents and health promoters associated with the continuous demand for alternative treatments for liver disorders, has stimulated us to evaluate the renal and hepatic effects of S. ramosissima seeds in mice under normal conditions and exposure to toxic products as carbon tetrachloride (CCl4). Thus, histopathological and lipid peroxidation evaluations of the liver and kidneys were performed. Powdered dried seeds of S. ramosissima (SRS) were administered orally for 22 days at a dose of 2000 mg/kg/day to male mice in three different settings: 1) seed effects, 2) protection against CCl4 acute toxicity (0.2 mL/kg) and 3) regeneration after acute exposure to CCl4 (0.2 mL/kg), each study being performed with appropriate control animals. Mice treated with SRS per se had slightly enlarged hepatic sinusoids and noticeable renal inflammation. SRS did not show effective protection against mice exposed to CCl4 and had no positive influence on liver and kidney recovery after CCl4 administration. These results demonstrated that SRS failed to improve hepato- and nephrotoxicity, in addition to the apparent synergism between CCl4 and SRS under these experimental conditions. Although the biological mechanisms of S. ramosissima are not fully understood, the evidence suggests further research to elucidate its adverse biological effects.

Scabiosa stellata L. Phenolic Content Clarifies Its Antioxidant Activity.

The phenolic profile of Scabiosa stellata L., a species used in Moroccan traditional medicine, is disclosed. To obtain that profile the species extract was analyzed by ultra-high-performance chromatography coupled to photodiode-array detection and electrospray ionization/ion trap mass spectrometry (UHPLC-DAD-ESI/MSn). Twenty-five phenolic compounds were identified from which isoorientin and 4-O-caffeoylquinic acid can be highlighted because they are the major ones. The antioxidant activity was significantly controlled by the fraction type, with the n-butanol fraction showing the highest antioxidant activity (FRS50 = 64.46 µg/mL in the DPPH assay, FRS50 = 27.87 µg/mL in the ABTS assay and EC50 = 161.11 µg/mL in the reducing power assay). A phytochemical study of the n-butanol fraction was performed, and some important flavone glycosides were isolated. Among them the tamarixetin derivatives-the less common ones-can be emphasized. This phytochemical study and polyphenolic profile can be correlated with S. stellata extracts in vitro antioxidant activity. Moreover, it can be regarded as an evidence of its medicinal use and can incentivize its consumption.

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application.

Cancer is a multistage process resulting in an uncontrolled and abrupt division of cells and is one of the leading causes of mortality. The cases reported and the predictions for the near future are unthinkable. Food and Drug Administration data showed that 40% of the approved molecules are natural compounds or inspired by them, from which, 74% are used in anticancer therapy. In fact, natural products are viewed as more biologically friendly, that is less toxic to normal cells. In this review, the most recent and successful cases of secondary metabolites, including alkaloid, diterpene, triterpene and polyphenolic type compounds, with great anticancer potential are discussed. Focusing on the ones that are in clinical trial development or already used in anticancer therapy, therefore successful cases such as paclitaxel and homoharringtonine (in clinical use), curcumin and ingenol mebutate (in clinical trials) will be addressed. Each compound's natural source, the most important steps in their discovery, their therapeutic targets, as well as the main structural modifications that can improve anticancer properties will be discussed in order to show the role of plants as a source of effective and safe anticancer drugs.

Seaweeds as Preventive Agents for Cardiovascular Diseases: From Nutrients to Functional Foods.

Being naturally enriched in key nutrients and in various health-promoting compounds, seaweeds represent promising candidates for the design of functional foods. Soluble dietary fibers, peptides, phlorotannins, lipids and minerals are macroalgae's major compounds that can hold potential in high-value food products derived from macroalgae, including those directed to the cardiovascular-health promotion. This manuscript revises available reported data focusing the role of diet supplementation of macroalgae, or extracts enriched in bioactive compounds from macroalgae origin, in targeting modifiable markers of cardiovascular diseases (CVDs), like dyslipidemia, oxidative stress, vascular inflammation, hypertension, hypercoagulability and activation of the sympathetic and renin-angiotensin systems, among others. At last, the review also describes several products that have been formulated with the use of whole macroalgae or extracts, along with their claimed cardiovascular-associated benefits.

Recent Breakthroughs in the Antioxidant and Anti-Inflammatory Effects of Morella and Myrica Species.

Oxidative stress is one of the risk factors for the development of several chronic diseases, such as diabetes, cancer, cardiovascular and neurodegenerative diseases. Antioxidants are therefore highly sought and can be seen as a type of preventive medicine against several diseases. Myrica and Morella genus (Myricaceae) are taxonomically very close and their species are trees or shrubs with edible fruits that exhibit relevant uses in traditional medicine, for instance in Chinese or Japanese folk medicine they are used to treat diarrhea, digestive problems, headache, burns and skin diseases. Nearly 36 compounds were isolated from different morphological parts of Myrica and/or Morella species and their antioxidant and anti-inflammatory activities evaluated. Thirteen of these compounds exhibit greater effects than the positive controls used. Adenodimerin A was the most active compound reported (in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay EC50= 7.9 ± 0.3 µM). These results are just one aspect of the antioxidant and anti-inflammatory evaluations reported regarding Myrica and Morella species, so a comprehensive overview on the current status, highlighting the antioxidant health promoting effect of these species, their key antioxidant compounds as well as the compounds with protective effects against oxidative stress related diseases such as inflammation, is relevant.

Metabolomic Profile of the Genus Inula.

Plants have a long history as therapeutics in the treatment of human diseases and have been used as source of medicines for ages. Searching for new biologically active natural products, many plants and herbs are screened for natural products with pharmacological activities. In this field, the genus Inula, which comprises more than 100 species, several of them being used in traditional medicine, is very important, especially due to the finding that several of the isolated pure secondary metabolites proved to possess important biological activities. Inula species have been reported as rich sources of sesquiterpene lactones, including eudesmanes, germacranes, guaianes, and dimeric structures, and since 2006 ca. 400 secondary metabolites, including more than 100 new natural products, some of them with relevant pharmacological activities, have been identified. Herein, we critically compile and update the information regarding the types of secondary metabolites found in the genus Inula and the progress in their isolation.

The genus Inula and their metabolites: from ethnopharmacological to medicinal uses.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Inula comprises more than one hundred species widespread in temperate regions of Europe and Asia. Uses of this genus as herbal medicines have been first recorded by the Greek and Roman ancient physicians. In the Chinese Pharmacopoeia, from the 20 Inula spp. distributed in China, three are used as Traditional Chinese medicines, named Tumuxiang, Xuanfuhua and Jinfeicao. These medicines are used as expectorants, antitussives, diaphoretics, antiemetics, and bactericides. Moreover, Inula helenium L. which is mentioned in Minoan, Mycenaean, Egyptian/Assyrian pharmacotherapy and Chilandar Medical Codex, is good to treat neoplasm, wound, freckles and dandruff. Many other Inula spp. are used in Ayurvedic and Tibetan traditional medicinal systems for the treatment of diseases such as bronchitis, diabetes, fever, hypertension and several types of inflammation. This review is a critical evaluation of the published data on the more relevant ethnopharmacological and medicinal uses of Inula spp. and on their metabolites biological activities. This study allows the identification of the ethnopharmacological knowledge of this genus and will provide insight into the emerging pharmacological applications of Inula spp. facilitating the prioritirization of future investigations. The corroboration of the ethnopharmacological applications described in the literature with proved biological activities of Inula spp. secondary metabolites will also be explored. MATERIALS AND METHODS: The major scientific databases including ScienceDirect, Medline, Scopus and Web of Science were queried for information on the genus Inula using various keyword combinations, more than 180 papers and patents related to the genus Inula were consulted. The International Plant Name Index was also used to confirm the species names. RESULTS: Although the benefits of Inula spp. are known for centuries, there are insufficient scientific studies to certify it. Most of the patents are registered by Chinese researchers, proving the traditional use of these plants in their country. Although a total of sixteen Inula species were reported in the literature to have ethnopharmacological applications, the species Inula cappa (Buch.-Ham. ex D.Don) DC., Inula racemosa Hook.f., Inula viscosa (L.) Aiton [actually the accepted name is Dittrichia viscosa (L.) Greuter], Inula helenium, Inula britannica L. and Inula japonica Thunb. are the most frequently cited ones since their ethnopharmacological applications are vast. They are used to treat a large spectrum of disorders, mainly respiratory, digestive, inflammatory, dermatological, cancer and microbial diseases. Fifteen Inula spp. crude extracts were investigated and showed interesting biological activities. From these, only 7 involved extracts of the reported spp. used in traditional medicine and 6 of these were studied to isolate the bioactive compounds. Furthermore, 90 bioactive compounds were isolated from 16 Inula spp. The characteristic compounds of the genus, sesquiterpene lactones, are involved in a network of biological effects, and in consequence, the majority of the experimental studies are focused on these products, especially on their cytotoxic and anti-inflammatory activities. The review shows the chemical composition of the genus Inula and presents the pharmacological effects proved by in vitro and in vivo experiments, namely the cytotoxic, anti-inflammatory (with focus on nitric oxide, arachidonic acid and NF-κB pathways), antimicrobial, antidiabetic and insecticidal activities. CONCLUSIONS: Although there are ca. 100 species in the genus Inula, only a few species have been investigated so far. Eight of the sixteen Inula spp. with ethnopharmacological application had been subjected to biological evaluations and/or phytochemical studies. Despite Inula royleana DC. and Inula obtusifolia A. Kerner are being used in traditional medicine, as far as we are aware, these species were not subjected to phytochemical or pharmacological studies. The biological activities exhibited by the compounds isolated from Inula spp., mainly anti-inflammatory and cytotoxic, support some of the described ethnopharmacological applications. Sesquiterpene lactone derivatives were identified as the most studied class, being britannilactone derivatives the most active ones and present high potential as anti-inflammatory drugs, although, their pharmacological effects, dose-response relationship and toxicological investigations to assess potential for acute or chronic adverse effects should be further investigated. The experimental results are promising, but the precise mechanism of action, the compound or extract toxicity, and the dose to be administrated for an optimal effect need to be investigated. Also human trials (some preclinical studies proved to be remarkable) should be further investigated. The genus Inula comprises species useful not only in medicine but also in other domains which makes it a high value-added plant.