molecules Review Pharmacological Insights into Halophyte Bioactive Extract Action on Anti-Inflammatory, Pain Relief and Antibiotics-Type Mechanisms Rocco Giordano 1,† , Zeinab Saii 1,†, Malthe Fredsgaard 2,†, Laura Sini Sofia Hulkko 2,†, Thomas Bouet Guldbæk Poulsen 1 , Mikkel Eggert Thomsen 1, Nanna Henneberg 1 , Silvana Maria Zucolotto 3 , Lars Arendt-Nielsen 1 , Jutta Papenbrock 4 , Mette Hedegaard Thomsen 2 and Allan Stensballe 1,* 1 Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark; [email protected] (R.G.); [email protected] (Z.S.); [email protected] (T.B.G.P.); [email protected] (M.E.T.); [email protected] (N.H.); [email protected] (L.A.-N.) 2 Department of Energy Technology, Aalborg University, 9220 Aalborg, Denmark; [email protected] (M.F.); [email protected] (L.S.S.H.); [email protected] (M.H.T.) 3 Center of Health Sciences, Department of Pharmaceutical Science, Federal University of Santa Catarina, Campus Universitário, Trindade, 88040–970 Florianópolis, Brazil; [email protected] 4 Institute of Botany, Leibniz University Hannover, D-30419 Hannover, Germany; [email protected] * Correspondence: [email protected]; Tel.: +45-61608786 † These authors contributed equally to this work. Citation: Giordano, R.; Saii, Z.; Abstract: The pharmacological activities in bioactive plant extracts play an increasing role in sustain- Fredsgaard, M.; Hulkko, L.S.S.; able resources for valorization and biomedical applications. Bioactive phytochemicals, including Poulsen, T.B.G.; Thomsen, M.E.; natural compounds, secondary metabolites and their derivatives, have attracted significant attention Henneberg, N.; Zucolotto, S.M.; for use in both medicinal products and cosmetic products. Our review highlights the pharmaco- Arendt-Nielsen, L.; Papenbrock, J.; logical mode-of-action and current biomedical applications of key bioactive compounds applied as et al. Pharmacological Insights into anti-inflammatory, bactericidal with antibiotics effects, and pain relief purposes in controlled clinical Halophyte Bioactive Extract Action studies or preclinical studies. In this systematic review, the availability of bioactive compounds from on Anti-Inflammatory, Pain Relief several salt-tolerant plant species, mainly focusing on the three promising species Aster tripolium, and Antibiotics-Type Mechanisms. Molecules 2021, 26, 3140. https:// Crithmum maritimum and Salicornia europaea, are summarized and discussed. All three of them have doi.org/10.3390/molecules26113140 been widely used in natural folk medicines and are now in the focus for future nutraceutical and pharmacological applications. Academic Editor: Lakshmi Kotra Keywords: secondary metabolites; halophytes; hydroxycinnamic acid; inflammation; nutraceuticals Received: 22 April 2021 Accepted: 21 May 2021 Published: 24 May 2021 1. Halophyte Species for Current and Future Biomedical Applications Publisher’s Note: MDPI stays neutral Salt-tolerant plant species, also called halophytes, belong to many botanical families. with regard to jurisdictional claims in Halophytes are defined as plants that can grow and complete their life-cycle in a salt published maps and institutional affil- concentration of at least 200 mM NaCl [1]. They do not form a systematical group and, iations. phylogenetically, they are not related to each other. Through evolution, they have adapted to saline conditions in several ways: morphologically, physiologically, and biochemically. Hence, halophyte species are found to produce high levels of bioactive compounds and free radical-scavenging secondary metabolites, potentially due to their adaptation to harsh Copyright: © 2021 by the authors. environmental conditions. High salinity during growth and development also increases Licensee MDPI, Basel, Switzerland. the level of free radicals in plants [2,3]. Such potential beneficial dietary factors in small This article is an open access article doses and complex combinations (e.g., polyphenols, fibers, polyunsaturated fatty acids, distributed under the terms and etc.) for lifestyle changes can lead to reduced inflammation and improved health; how- conditions of the Creative Commons ever, metabolic disturbances are key contributors to disease progression [4]. Screening Attribution (CC BY) license (https:// and testing of extracts from medicinal plants species, including halophytes, against a creativecommons.org/licenses/by/ variety of pharmacological targets and disease conditions in order to benefit from the 4.0/). Molecules 2021, 26, 3140. https://doi.org/10.3390/molecules26113140 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x 2 of 16 Molecules 2021, 26, 3140 2 of 15 however, metabolic disturbances are key contributors to disease progression [4]. Screen- ing and testing of extracts from medicinal plants species, including halophytes, against a immense naturalvariety chemical of pharmacological diversity is a targets research and focus disease in conditions many laboratories in order to benefit and companies from the im- worldwide [5,6].mense For natural halophytes, chemical the diversity relevant is a research compound focus in classes many laboratories are a combination and companies of worldwide [5,6]. For halophytes, the relevant compound classes are a combination of com- components typicalponents of typical lignocellulosic of lignocellulosic biomass biomass and and components components unique unique for fora family a family or species or species (Figure1(Figure). The 1). majority The majority of the of freethe free radical-scavenging radical-scavenging phenolic phenolic compounds compounds are biosyn- are biosynthesizedthesized through through the shikimic the shikimic acid, acid, acetic acetic acid,acid, and and phenylpropanoid phenylpropanoid pathways, pathways, resulting resulting in phenylpropanoids,in phenylpropanoids, simple simple phenols, phenols, and phenolics, phenolics, respectively respectively [7,8]. [7,8]. Figure 1. Phytochemical composition of some common coastal halophytes. Created with BioRen- Figureder.com. 1. Phytochemical (Pictures composition reproduced of some with common permission coastal halo [9]).phytes. Created with BioRender.com. (Pictures repro- duced with permission [9]) Over time, nature has been a rich source for various natural bioactive substances that have many applicationsOver in time, folk nature medicine has been and a rich ethnopharmaceuticals source for various natural [10 bioactive–12]. For substances thousands that of years, plants werehave many the only applications source in of folk medicine medicine due and to ethnopharmaceuticals the absence of other [10–12]. compounds For thou- sands of years, plants were the only source of medicine due to the absence of other com- available, and they were used for a broad spectrum of medical purposes as therapies based pounds available, and they were used for a broad spectrum of medical purposes as ther- on their contentsapies of secondary based on their metabolites contents of secondary and their me bioactivetabolites and properties their bioactive [13]. properties [13]. The present reviewThe present will focus review on will reviewing focus on reviewing the current the current state of state the of art the forart for biomedical biomedical applications of bioactiveapplications molecules of bioactive present molecules in three present halophytic in three halophytic plant species, plant species,Aster tripoliumAster tripo- (Jacq.) Dobrocz.,liumCrithmum (Jacq.) Dobrocz., maritimum CrithmumL., and maritimumSalicornia L., europaea and Salicorniaagg. (illustratedeuropaea agg. in (illustrated Figure1), in due to their potentialFigure use 1), in due nutraceutical to their potential foods, use cosmetics,in nutraceutical and foods, also as cosmetics, bioactive and components also as bioactive for components for medicinal applications because they contain health-promoting com- medicinal applicationspounds becausesuch as minerals, they contain fibers, health-promotingoils, phenolics and vitamins compounds [14]. The such biological as minerals, qualities fibers, oils, phenolicsof these and three vitamins halophytic [14 plants]. The species biological can overall qualities be divided of these into three anti-inflammatory, halophytic plants species canantioxidant-rich overall be divided and antibacterial into anti-inflammatory, activities, and future antioxidant-rich use in medicinal and practice. antibacterial The bi- activities, and futureoactive use compounds in medicinal are listed practice. in Table The 1 and bioactive summarized compounds in Section are 2. The listed chemical in Table struc-1 and summarizedture in Sectionand biological2. The activities chemical of secondary structure metabolites and biological isolated activities from Salicornia of secondary europaea L. have recently been reviewed [15]. metabolites isolated from Salicornia europaea L. have recently been reviewed [15]. Molecules 2021, 26, 3140 3 of 15 Table 1. Anti-inflammatory and antibacterial activities of several halophytes based on their bioactive compounds. Anti-Inflammatory Antibacterial Antioxidative References - Caffeoyl esters (isomer of - Caffeic acid (from chlorogenic chlorogenic acid) - Quercetin (flavonoid) Aster tripolium acid) [11,12,14,16–21] - Quercetin (flavonoid) - Chlorogenic acid (hydroxycin- namic acids) - p-Cymene - Essential oils - Chlorogenic acid (hydroxycin- - β-Phellandrene, gamma- Crithmum maritimum - Falcarindiol namic acids) [11,12,14,21–24] terpinene, thymol methyl ether and dillapiole (essential