The genus Porana (Convolvulaceae) - A phytochemical and pharmacological review

Hongxun Tao

There are about 20 species of Porana Burm. f. worldwide in tropical and subtropical Asia, Africa and neighboring islands, Oceania, and the Americas. In China, India, and other places, this genus enjoys a wealth of experience in folk applications. Nevertheless, the chemical composition of only five species has been reported, and 59 compounds have been isolated and identified, including steroids, coumarins, flavonoids, quinic acid derivatives, and amides. Pharmacological studies revealed that extracts from this genus and their bioactive components exhibit anti-inflammatory, analgesic, antioxidant, anti-gout, anti-cancer, and anti-diabetic effects. Although this genus is abundant, the development of its pharmacological applications remains limited. This review will systematically summarize the traditional and current uses, chemical compositions, and pharmacological activities of various Porana species. Network analysis was introduced to compare and confirm its output with current resea...

Review 18 October 2022 10.3389/fphar.2022.998965 TYPE PUBLISHED DOI OPEN ACCESS EDITED BY Wei Peng, Chengdu University of Traditional Chinese Medicine, China REVIEWED BY Mahdi Moridi Farimani, Shahid Beheshti University, Iran Jun Yu Liu, Chengdu University of Traditional Chinese Medicine, China *CORRESPONDENCE Hongxun Tao, thxshutcm@163.com Zhiyong Chen, chenzhiyong0612@sina.com The genus Porana (Convolvulaceae) - A phytochemical and pharmacological review Yu Peng 1,2†, Ye Li 1†, Yuanyuan Yang 3, Yuanqing Gao 2, Hui Ren 1, Jing Hu 1, Xiaomin Cui 1, Wenjing Lu 1, Hongxun Tao 4* and Zhiyong Chen 1* 1 Shaanxi Academy of Traditional Chinese Medicine, Xi’an, Shaanxi, China, 2Jiangsu Provincial Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China, 3Xi’an Institute for Food and Drug Control, Xi’an, Shaanxi, China, 4 School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, China † These authors have contributed equally to this work and share ﬁrst authorship SPECIALTY SECTION This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology 20 July 2022 10 October 2022 PUBLISHED 18 October 2022 RECEIVED ACCEPTED CITATION Peng Y, Li Y, Yang Y, Gao Y, Ren H, Hu J, Cui X, Lu W, Tao H and Chen Z (2022), The genus Porana (Convolvulaceae) - A phytochemical and pharmacological review. Front. Pharmacol. 13:998965. doi: 10.3389/fphar.2022.998965 COPYRIGHT © 2022 Peng, Li, Yang, Gao, Ren, Hu, Cui, Lu, Tao and Chen. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. There are about 20 species of Porana Burm. f. worldwide in tropical and subtropical Asia, Africa and neighboring islands, Oceania, and the Americas. In China, India, and other places, this genus enjoys a wealth of experience in folk applications. Nevertheless, the chemical composition of only ﬁve species has been reported, and 59 compounds have been isolated and identiﬁed, including steroids, coumarins, ﬂavonoids, quinic acid derivatives, and amides. Pharmacological studies revealed that extracts from this genus and their bioactive components exhibit anti-inﬂammatory, analgesic, antioxidant, antigout, anti-cancer, and anti-diabetic effects. Although this genus is abundant, the development of its pharmacological applications remains limited. This review will systematically summarize the traditional and current uses, chemical compositions, and pharmacological activities of various Porana species. Network analysis was introduced to compare and conﬁrm its output with current research progress to explore the potential targets and pathways of chemical components in this genus. We hope to increase understanding of this genus’s medicinal value and suggest directions for rational medicinal development. KEYWORDS Porana burm. f., traditional use, phytochemistry, network analysis, pharmacological activity Abbreviations: Akt, protein kinase B; COX-2, cyclooxygenase-2; C-T-P, compound-target-pathway; FGF-2, ﬁbroblast growth factor 2; HIF, hypoxia inducible factor; HPLC, high performance liquid chromatography; Ig, intragastric administration; IL-6, interleukin 6; iNOS, inducible nitric oxide synthase; Ip, intraperitoneal injection; KEGG, Kyoto Encyclopedia of Genes and Genomes; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinases; MDA, malonic dialdehyde; MSU, monosodium urate; MyD88, myeloid differentiation factor 88; NF-κB, nuclear transcription factorκB; NO, nitric oxide; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PPI, protein-protein interaction; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TLR2, toll-like receptor 2; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor. Frontiers in Pharmacology 01 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 1 Introduction Porana plants usually have only one spherical and glabrous seed (Chen et al., 2004). The medicinal records of Porana plants are extensive. Porana paniculata Roxb. has been used in folk medicine to treat pain and inﬂammation in Ayurveda and India (Kumar et al., 2015). Porana sinensis Hemsl. is a direct substitute for commercial Dingongteng medicinal materials and is known for its therapeutic effect on rheumatoid arthritis and bruises (Ren et al., 2019). According to the National Compendium of Chinese Herbal Medicine, the whole plant of Porana racemosa Roxb. is used to treat colds and indigestion (Guoqiang, 2014), while its stems and roots are used to treat rheumatism (Liu and Li, 1997). Research on the phytochemistry of Porana plants focuses on Porana discifera C.K.Schneid., P. racemosa, P. sinensis, Porana spectabilis Kurz, and Porana duclouxii Gagnep. & Courchet; 59 compounds have been isolated from Porana plants, including 14 steroids, six coumarins, seven ﬂavonoids, six quinic acid derivatives, and three amides (Zhu et al., 2007; Li et al., 2013; Ding et al., 2014; Chen et al., 2015; Xue et al., 2019). Pharmacological studies revealed that the extracts of Porana plants and their bioactive compounds treat arthritis (Dou et al., 2013), gout (Chen et al., 2014; Du et al., 2020), inﬂammation (Wu et al., 2016; Xue et al., 2019), and cancer (Huang et al., 2019). There are more than 20 species of Porana Burm. f. worldwide in tropical and subtropical Asia, Africa and neighboring islands, Oceania, and the Americas. Fifteen species are displayed in Table 1 (for more information, see http://www. plantsoftheworldonline.org or www.theplantlist.org). The global distribution of Porana plants based on the Global Biodiversity Information Facility (https://www.gbif.org/) and the herbarium diagrams of three mainstream species are shown in Figure 1. Porana plants are vines, woody, herbaceous, or climbing shrubs. Their ovate leaves are mostly cordate at the base, with petioles. The inﬂorescence morphology of Porana plants is divided into racemes or panicles, with some single-ﬂower forms. Their bracts are leaﬂike, small and subulate, or absent. Their corollas are neatly arranged, presenting white, reddish, and some lavender. The ovaries are primarily glabrous. Some are one-celled, containing two ovules, while some are one-to two-celled, containing two to four ovules. Their stigmas are spherical, each connecting to the ovary by one style. Capsules of Porana plants are relatively small, subglobose to oblong, dehiscent in two petals, or not dehiscent. TABLE 1 Synonyms and distribution of Porana species. No. Species Synonyms Distribution 1 Porana acuminata P.Beauv Neuropeltis acuminata (P.Beauv.) Benth West Tropical Africa 2 Porana densiﬂora Hallier f Metaporana densiﬂora (Hallier f.) N.E.Br Tanzania 3 Porana dinetoides C.K.Schneid Dinetus dinetoides (C.K.Schneid.) Staples Assam, China South-Central, Myanmar 4 Porana discifera C.K.Schneid Poranopsis discifera (C.K.Schneid.) Staples Assam, China South-Central, Laos, Myanmar, Thailand, Vietnam 5 Porana duclouxii Gagnep. & Courchet Dinetus duclouxii (Gagnep. & Courchet) Staples China South-Central 6 Porana grandiﬂora Wall Dinetus grandiﬂorus (Wall.) Staples East Himalaya, Nepal, Tibet 7 Porana henryi Verdc Poranopsis sinensis (Hand.-Mazz.) Staples China South-Central 8 Porana mairei Gagnep Dinetus decorus (W.W.Sm.) Staples Assam, China South-Central, Myanmar 9 Porana paniculata Roxb Poranopsis paniculata (Roxb.) Roberty Assam, Bangladesh, East Himalaya, India, Myanmar, Nepal, Pakistan, Tibet, West Himalaya 10 Porana parvifolia (K.Afzel.) Verdc Metaporana parvifolia (K.Afzel.) Verdc Madagascar 11 Porana racemosa Roxb Dinetus racemosus (Roxb.) Sweet Assam, Bangladesh, China North-Central, China South-Central, China Southeast, East Himalaya, India, Jawa, Laos, Lesser Sunda Is., Myanmar, Nepal, Pakistan, Sulawesi, Thailand, Vietnam, West Himalaya 12 Porana sinensis Hemsl Tridynamia sinensis (Hemsl.) Staples China North-Central, China South-Central, China Southeast, Vietnam 13 Porana spectabilis Kurz Tridynamia spectabilis (kurz) Parmar Andaman Is., Assam, Cambodia, China South-Central, China Southeast, Hainan, Laos, Malaya, Myanmar, Thailand, Vietnam 14 Porana subrotundifolia De Wild Paralepistemon shirensis (Oliv.) Lejoly & Lisowski Angola, KwaZulu-Natal, Malawi, Mozambique, Northern Provinces, Zambia, Zaïre, Zimbabwe 15 Porana velutina (M.Martens & Galeotti) Hallier f Porana nutans (Choisy) O’Donell Mexico Central, Mexico Southwest Frontiers in Pharmacology 02 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 FIGURE 1 The global distribution of Porana Burm. f., and the plant specimens of P. sinensis, P. racemosa, and P. dinetoides. “biological activity,” “substitute,” “toxicity,” and “quality control.” The bibliographies of all selected articles were scanned to seek additional relevant articles. Although Porana has a wide range of medicinal uses, and its extracts and bioactive compounds show excellent efﬁcacy, current research remains limited, complicating the investigation of its chemical components, pharmacological activities, quality control, and safety. Therefore, it is critical to perform a systematic literature review on Porana to promote rational medicinal development. 3 Traditional uses The medicinal parts of P. sinensis are canes, which have been used to substitute for the endangered traditional Chinese medicine Dinggongteng (Erycibes caulis) in China (Xue et al., 2017). Dinggongteng is a traditional Chinese folk medicine, ﬁrst recorded in the Supplement to Medica, which recorded the effect of dispelling wind and strengthening the waist (Shang, 2004). The National Collection of Chinese Herbal Medicine, the Dictionary of Chinese Herbal Medicine, and the Chinese Materia Medica have documented Dinggongteng, which dispels wind and dampness, relaxes tendons, activates collaterals, reduces swelling, and relieves pain. The traditional clinical 2 Methodology An extensive search of studies was conducted from scientiﬁc journals (original research, reviews, and short communications), books, and reports from internationally recognized databases (Web of Science, PubMed, ScienceDirect, China National Knowledge Infrastructure, and Google Scholar). The following keywords were selected: “Porana,” “pharmacology,” “ethnopharmacology,” “compound,” “phytotherapy,” Frontiers in Pharmacology 03 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 ﬂavonoids, six quinic acid derivatives, three amides, and 23 other compounds. These compounds are displayed in Table 2 according to their chemical name, chemical type, and their original plants. The structural formulas of these compounds are shown in Figure 2. application of Dinggongteng has been to treat rheumatoid arthritis, bruises, and other diseases, according to the 2020 edition of the Chinese Pharmacopoeia. With E. caulis as the main medicinal material, and more than ten Chinese patent medicines have been developed, including Feng Liaoxing Rheumatism Dieda Liquor and Tengluoning Capsule (Fan et al., 2021; Peng et al., 2021). Dinggongteng is often combined with Cinnamomi ramulus, Ephedrae herba, Angelicae sinensis radix, and other medicinal materials. Wu et al. (2005) investigated the commercial medicinal materials in Guangxi, the main production area for E. caulis, as well as Shanghai, Jiangsu, Zhejiang, and other places, and found that the wild resources of Erycibe obtusifolia Benth. and Erycibe schmidtii Craib could no longer meet the demand for clinical medication. P. sinensis has already become a mainstream substitute for E. caulis on the market. The widespread application of P. sinensis has promoted the sustainable utilization of the endangered traditional Chinese medicine E. caulis while accumulating evidence for the effectiveness and safety of P. sinensis. P. racemosa is also a traditional folk medicine of the Dai, Yi, and Tujia nationalities in China, and its whole herb is the medicinal part (Fang et al., 2007). According to the National Compendium of Chinese Herbal Medicine, the whole plant of P. racemosa relieves the surface, eliminates food accumulation, and is primarily used for colds and food accumulation (Editorial Board, 1975). Its stem and root treat rheumatism (Liu and Li, 1997). In the treatment of cold and fever, it is often used in combination with Peucedanum praeruptorum and Periliae fructus, while in the treatment of food accumulation, it is often used in combination with Crataegi fructus and Serissa serissoides (Fang et al., 2007). In Guangxi Province, P. spectabilis is used to treat uterine prolapse, with its whole herb as the medicinal part (Li et al., 1985). P. spectabilis contains scopoletin, ethyl caffeate, and other compounds (Zhu et al., 2001); however, no pharmacodynamic study has been reported. According to the Chinese Materia Medica, the root of Porana mairei Gagnep. relieves cough and asthma (Editorial Board, 2009). In summary, Porana plants are used as folk medicines. The genus has received increasing attention due to the widespread use of P. sinensis as a substitute for E. caulis. 4.1 Steroids Fourteen steroids have been isolated from Porana species, of which 12 were isolated from P. discifera, including compounds 1–10 (Zhu et al., 2000) and 12–13 (Yu et al., 2003); four were found in P. racemosa, including compounds 11–14 (Liu and Li, 1997; Wang, 2003; Li et al., 2004); two were found in P. sinensis, including compounds 12–13 (Zhang et al., 2006). Compounds 1–10 are phytoecdysteroids, natural polyhydroxylated compounds with a four-ringed skeleton, usually comprising 27 carbon atoms or 28–29 carbon atoms with the characteristic 7-en6 ketone on the steroid nucleus (Tarkowská and Strnad, 2016). Phytoecdysteroids are a class of natural steroids with insect ecdysis activity. They also exhibit extensive pharmacological effects on higher animals, including hypoglycemia, wound repair, and immune regulation (Taha-Salaime et al., 2019; Yusupova et al., 2019). Compounds 1–7 have no anti-inﬂammatory, sedative, anti-convulsant, or anti-cerebra-hypoxic activities in animal testing with Kunming mice (Zhu et al., 2000). Most steroids reported in Porana species have been found in P. discifera. In this case, several issues need to be addressed. Are these compounds also present in other plants of this genus, and can they be used as the chemical indicators of the Porana Burm. f.? Answering these questions must address the biological activity of steroids among the pharmacological activities of this genus. 4.2 Coumarins Three coumarin compounds have been isolated from P. racemosa, including compounds 15–17 (Li et al., 2004). Four coumarin compounds have been found in P. sinensis, including compounds 15–16 (Zhang et al., 2006) and 18–19 (Xue et al., 2019). Three coumarin compounds have been reported in P. discifera, including compounds 15–16 and 20 (Yu et al., 2003). Two coumarin compounds are found in P. spectabilis, including compounds 15–16 (Zhu et al., 2001). The coumarins obtained from Porana plants are simple coumarins, and compounds 15 and 16 have been found in four species; these are thought to be the primary pharmacodynamic substances and chemical indicators of E. caulis (Chen et al., 2014; Chen et al., 2020). Therefore, compounds 15 and 16 are essential for applying P. sinensis as a substitute for E. caulis. 4 Chemical compositions of Porana plants Based on literature reports and our previous research, we concluded that the research on the phytochemical constituents of this genus focused on P. discifera, P. racemosa, P. sinensis, P. spectabilis, and P. duclouxii. Fifty-nine compounds have been isolated from Porana species, including 14 steroids, six coumarins, seven Frontiers in Pharmacology 04 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 2 Chemical compositions of Porana plants. No Compounds Molecular formula Type Plant parts and species References 1 β-ecdysterone C27H44O7 Steroids Aerial parts of P. discifera Zhu et al. (2000) 2 β-ecdysterone-2-acetate C29H46O8 Steroids Aerial parts of P. discifera Zhu et al. (2000) 3 β-ecdysterone-3-acetate C29H46O8 Steroids Aerial parts of P. discifera Zhu et al. (2000) 4 β-ecdysterone-25-acetate C29H46O8 Steroids Aerial parts of P. discifera Zhu et al. (2000) 5 2,3-acetonide-β-ecdysterone C30H48O7 Steroids Aerial parts of P. discifera Zhu et al. (2000) 6 20,22-acetonide-β-ecdysterone C30H48O7 Steroids Aerial parts of P. discifera Zhu et al. (2000) 7 2-deoxy-20-hydroxyecdysone C27H44O6 Steroids Aerial parts of P. discifera Zhu et al. (2000) 8 2-deoxyecdysterone-20,22-acetonide C30H48O6 Steroids Aerial parts of P. discifera Zhu et al. (2000) 9 2-deoxyecdysterone-3-O-β-D-glucopyranoside C33H54O11 Steroids Aerial parts of P. discifera Zhu et al. (2000) 10 Posterone C21H30O5 Steroids Aerial parts of P. discifera Zhu et al. (2000) 11 Racemosol C30H50O Steroids Whole plants of P. racemosa Li et al. (2004) 12 β-sitosterol C29H50O Steroids Stems and roots of P. racemosa Liu and Li, (1997); Yu et al., (2003); Zhang et al., (2006) Stems of P. sinensis Leaves and stems of P. discifera 13 β-daucosterol C35H60O6 Steroids Whole plants of P. racemosa Wang, (2003); Yu et al., (2003); Zhang et al., (2006) Stems of P. sinensis Leaves and stems of P. discifera 14 Stigmasterol C29H48O Steroids 15 Scopoletin C10H8O4 Coumarins Whole plants of P. racemosa Wang, (2003) Stems of P. sinensis Zhu, (2001); Yu et al., (2003); Li et al., (2004); Xue et al., (2019) Whole plants of P. racemosa Leaves and stems of P. discifera Barks of P. spectabilis 16 Scopolin C16H18O9 Coumarins Stems of P. sinensis Whole plants of P. racemosa Zhu, (2001); Yu et al., (2003); Li et al., (2004); Xue et al., (2019) Leaves and stems of P. discifera Barks of P. spectabilis 17 Umbelliferone C9H6O3 Coumarins Whole plants P. racemosa Li et al. (2004) 18 Isoscopoletin C10H8O4 Coumarins Stems of P. sinensis Xue et al. (2019) 19 7-O-[4′-O-(3″,4″-dihydroxycinnamyl)-β-Dglucopyranosyl]-6-methoxycoumarin C26H26O11 Coumarins Stems of P. sinensis Xue et al. (2019) 20 Isofraxidin C11H10O5 Coumarins Leaves and stems of P. discifera Yu et al. (2003) (Continued on following page) Frontiers in Pharmacology 05 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 2 (Continued) Chemical compositions of Porana plants. No Compounds Molecular formula Type Plant parts and species References 21 Quercetin-3-O-β-D-glucopyranoside C21H20O12 Flavonoids Whole plants of P. racemosa Li et al. (2004) 22 Quercetin-3-O-α-L-rhamnopyranoside C21H20O11 Flavonoids Whole plants of P. racemosa Li et al. (2004) 23 Eupatilin C18H16O7 Flavonoids Whole plants of P. racemosa Li et al. (2004) 24 4ʹ-Hydroxywogonin C16H12O6 Flavonoids Leaves and stems of P. discifera Yu et al. (2003) 25 Quercetin C15H10O7 Flavonoids Leaves and stems of P. discifera Wang, (2003); Yu et al., (2003) Whole plants of P. racemosa 26 Kaempferol-3-O-β-D-glucopyranoside C21H20O11 Flavonoids Whole plants of P. racemosa Wang, (2003) 27 Rutin C27H30O16 Flavonoids Whole plants of P. racemosa Wang, (2003) 28 Chlorogenic acid C16H18O9 Quinic acid derivatives Stems of P. sinensis Chen et al., (2013); Chen et al., (2019); Chen et al., (2020) 29 4-O-caffeoylquinic acid C16H18O9 Quinic acid derivatives Stems of P. sinensis Chen et al., (2019); Chen et al., (2020) 30 5-O-caffeoylquinic acid C16H18O9 Quinic acid derivatives Stems of P. sinensis Chen et al., (2019); Chen et al., (2020) 31 3,4-dicaffeoylquinic acid C25H24O12 Quinic acid derivatives Stems of P. sinensis Chen et al., (2019); Chen et al., (2020) 32 4,5-dicaffeoylquinic acid C25H24O12 Quinic acid derivatives Stems of P. sinensis Chen et al., (2019); Chen et al., (2020) 33 3,5-dicaffeoylquinic acid C25H24O12 Quinic acid derivatives Stems of P. sinensis Chen et al., (2019); Chen et al., (2020) 34 (E)-N-2-(2,3-dihydroxyphenyl) ethyl cinnamamide C17H17NO3 Amides Whole plants of P. racemosa Li et al. (2004) 35 N-trans-feruloyltyramine C18H19NO4 Amides Stems of P. sinensis Zhang et al. (2006) 36 N-trans-coumaroyltyramine C17H17NO3 Amides Stems of P. sinensis Zhang et al. (2006) 37 Methyl β-D-frucopyranoside C7H14O6 Others Whole plants of P. racemosa Zhu et al., (2001); Li et al., (2004) 38 Syringaresinol-4-O-β-D-glucopyranoside C28H36O13 Others Whole plants of P. racemosa 39 Poranaside A C38H66O18 Others Roots of P. duclouxii Ding et al. (2014) 40 Poranic acid A C32H58O16 Others Roots of P. duclouxii Ding et al. (2014) 41 Poranic acid B C32H58O17 Others Roots of P. duclouxii Ding et al. (2014) 42 Disciferitriol C15H28O3 Others Aerial parts of P. discifera Zhu et al. (2007) 43 Cassiachromone C13H12O4 Others Leaves and stems of P. discifera Yu et al. (2003) 44 Vanillic acid C8H8O4 Others Whole plants of P. racemosa Wang, (2003) 45 Ethyl 4′-hydroxy-3′-methoxycinnamate C12H14O4 Others Whole plants of P. racemosa Wang, (2003) 46 Lupeol C30H50O Others Whole plants of P. racemosa Wang, (2003) 47 α-amyrin acetate C32H52O2 Others Whole plants of P. racemosa Wang, (2003) Barks of P. spectabilis Zhu et al., (2001); Li et al., (2004) Barks of P. spectabilis (Continued on following page) Frontiers in Pharmacology 06 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 2 (Continued) Chemical compositions of Porana plants. No Compounds Molecular formula Type Plant parts and species References 48 4-methoxycinnamic acid C10H10O3 Others Whole plants of P. racemosa Wang, (2003) 49 2,5-dimethoxy-1,4-benzoquinone C8H8O4 Others Stems of P. sinensis Zhang et al. (2006) 50 Ethyl caffeate C11H12O4 Others Stems of P. sinensis Zhu et al., (2001); Zhang et al., (2006) Barks of P. spectabilis 51 3-(3,5-dihydroxyphenyl)-2E-propenoic acid C9H8O4 Others Barks of P. spectabilis Zhu et al. (2001) 52 Methyl α-D-frucofuranoside C7H14O6 Others Barks of P. spectabilis Zhu et al. (2001) 53 2,5-dihydroxybenzoic acid C7H6O4 Others Barks of P. spectabilis Zhu et al. (2001) 54 Disciferoside A C21H38O8 Others Aerial parts of P. discifera Zhu, (2001) 55 (4R)-menthane-1S,2S,8-triol C10H20O3 Others Aerial parts of P. discifera Zhu, (2001) 56 1β,2β,3α,4β,5α-cyclohexanepentol C6H12O5 Others Aerial parts of P. discifera Zhu, (2001) 57 Dodecandral-3-O-β-D-xylopyranoside C38H54O4 Others Aerial parts of P. discifera Zhu, (2001) 58 E-piceid C20H22O8 Others Aerial parts of P. discifera Zhu, (2001) 59 2,5-dihydroxybenzaldehyde C7H6O3 Others Aerial parts of P. discifera Zhu, (2001) 4.3 Flavonoids 4.5 Amides Six ﬂavonoids have been isolated from P. racemosa, including compounds 21–23 (Li et al., 2004) and 25–27 (Wang, 2003). Two ﬂavonoids were found in P. discifera, including compounds 24–25 (Yu et al., 2003). Flavonoids are very common in plants. According to reports, no characteristic ﬂavonoid has been found in this genus; this might be due to the lack of reports on the chemical constituents of Porana plants. However, several characteristic isoﬂavones, pterocarpans, and rotenoids were identiﬁed in Erycibes plants (Peng et al., 2021). Based on this, we speculate that ﬂavonoids might be the components differentiating Porana from Erycibes. Considering ﬂavonoids’ excellent biological activity, exploring such compounds should not be ignored. Three amides have been isolated from Porana plants, among which compound 34 has been found in P. racemosa (Li et al., 2004) and compounds 35–36 have been found in P. sinensis (Zhang et al., 2006). The chemical structures of the three amides are similar. It was reported that compound 36 has better activity than compound 35 in inhibiting nitric oxide (NO) release from lipopolysaccharide (LPS)-induced RAW 264.7 cells, suggesting that introducing a methoxy group at the two-position reduces the anti-inﬂammatory activity of these compounds (Zheng et al., 2018). 4.6 Other compounds Twenty-three compounds were found in Porana species, including one lignin (compound 38), one monoterpenoid (compound 55), two sesquiterpenes (compound 42, 54), three triterpenoids (compound 46, 47, 57), one benzoquinone (compound 49), seven phenols (compounds 44, 45, 48, 50, 51, 53, 59), one stilbene (compound 58), ﬁve glycosides compounds (compound 37, 39–41, 52), one chromone (compound 43), and one cyclohexanol (compound 56). There are many phenolic acids and their derivatives in Porana plants. Resin glycosides are characteristic of constituents in Convolvulaceae, and three such components (compounds 39–41) have been isolated 4.4 Quinic acid derivatives Six quinic acid derivatives have been reported in the Porana species, including compounds 28–33 (Chen et al., 2013; Chen et al., 2019; Chen et al., 2020), all from P. sinensis. Our ﬁngerprint study has revealed that Porana dinetoides C.K.Schneid., P. racemosa, and P. duclouxii also contained quinic acid derivatives (Figure 3). Because many quinic acid derivatives have been detected in ﬁngerprints, this group of compounds can be used as chemical markers for quality control, and this potential deserves further evaluation. Frontiers in Pharmacology 07 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 FIGURE 2 Structural formulas of chemical components of genus Porana. a phytochemical study of other species needs to be performed urgently. from Porana plants (Ding et al., 2014). Compounds 39–41 all have a common trisaccharide moiety and (11S)hydroxytetradecanoic acid or (3S,11S)dihydroxytetradecanoic acid as the aglycone. These 23 compounds have not shown any regularity. There is no evidence to assess the importance of these compounds regarding quality control or biological activity. In summary, only ﬁve species of Porana plants have been reported, with a total of 59 compounds to date. Combined with the literature reports and ﬁngerprints, phenolic acids and coumarins are widely represented in this genus. Phytoecdysteroids and resin glycosides have speciﬁc characteristics; however, their distribution is narrow in this genus. This ﬁnding suggests that there might be substantial differences in the chemical compositions of these plants, and Frontiers in Pharmacology 5 Pharmacological activities of Porana plants 5.1 Network analysis of Porana plants Because the research on this genus is not systematic, to maximize its medicinal value, we ﬁrst predicted its targets based on its chemical components using network analysis. Using follow-up comparisons with reported pharmacological research results, the pharmacological effects of this genus were explored. 08 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 FIGURE 3 HPLC ﬁngerprints of four species of genus Porana 1) 5-O-caffeoylquinic acid; 2) Scopolin; 3) Chlorogenic acid; 4) 4-O-caffeoylquinic acid; 5) Scopoletin; 6) 3,5-dicaffeoylquinic acid; 7) 3,4-dicaffeoylquinic acid; 8) 4,5-dicaffeoylquinic acid. 5.1.1 Enrichment of critical targets diseases such as prostate cancer, viral carcinogenesis, glioma, or other irrelevant items, with p < 0.01 as the screening condition, the top 20 most signiﬁcant pathways were selected for the subsequent enrichment analysis using R language software (Supplementary Table S1). As shown in Figure 4, the abscissa (enrichment) of the bubble chart represents the ratio of the core targets involved in each pathway to the total number of targets in the pathway; the size of the bubble represents the number of core targets involved in the pathway; the color ranges from red to green, indicating that the p-value is from small to large, and deeper redness indicates the higher signiﬁcance of the pathway. The two-dimensional structures of all 59 compounds found in Porana plants were identiﬁed in the PubChem database (https://pubchem.ncbi.nlm.nih.gov/search/), their sdf ﬁles were downloaded, and they were imported into the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) to predict their targets (Gfeller et al., 2014). After removing the duplicate targets, the potential targets were obtained. We obtained 713 targets in this manner. 5.1.2 The construction and topological parameter analysis of a protein-protein interaction network 5.1.4 The construction and analysis of the compound-target-pathway network All 713 targets obtained in section 5.1.1 were imported into the STRING platform (https://string-db.org/) to construct a PPI network. The topological parameters of the PPI network were calculated and analyzed using Cytoscape 3.6.0. The critical targets were determined with greater values of the degree, closeness centrality, and betweenness centrality than the mean value. This analysis revealed that the mean degree of potential target nodes was 39.5, the mean value of closeness centrality was 0.4326, and the mean value of betweenness centrality was 0.0019. The output was 135 targets with a higher value than the corresponding mean. According to the top 20 pathways of gene enrichment in the KEGG pathway enrichment analysis, the potential targets and the corresponding components enriched in these pathways were outputted. The data table of the C-T-P was imported into Cytoscape 3.6.0 to construct the C-T-P network with a total of 148 nodes (20 pathways, 73 targets, 55 components) and 772 edges. Then the Network Analyzer was used to calculate the topology parameters of the C-T-P network, while a Degree Sorted Circle Layout was applied to lay out nodes. The C-T-P network topology parameters were also analyzed using Network Analyzer, and the results are displayed in Supplementary Table S2. The mean degree of the 55 differentially active components was 7.29, the mean value of closeness centrality was 0.3505, and the mean value of betweenness centrality was 0.0067. Three network topology parameters with 17 components were higher than the corresponding mean value (compounds 1–5, 7, 16–17, 23–25, 34–36, 45, 48, and 50). The mean degree of the 73 potential target nodes was 10.58, the mean value of closeness 5.1.3 Kyoto encyclopedia of genes and genomes pathway enrichment analysis To explore the related signaling pathways of the 135 targets obtained in Section 5.1.2, the targets were imported into DAVID (https://david.ncifcrf.gov/home.jsp), with the species limited to humans. KEGG pathway enrichment analysis was performed to identify the relevant signaling pathways. After removing speciﬁc Frontiers in Pharmacology 09 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 FIGURE 4 Analysis of KEGG pathway. rats by inhibiting inﬂammatory responses and angiogenesis (Pan et al., 2009); the mechanisms might involve the PI3KAkt, HIF-1, and MAPK signaling pathways (Park et al., 2015; Qu et al., 2016; Yang et al., 2018). Porana plants are widely used in traditional Chinese and Indian medicine to relieve inﬂammation and pain and to treat rheumatoid arthritis. Recent studies demonstrated that the PI3KAkt pathway inhibits apoptosis in chondrocytes, and modulation of the pathway might be a potential target for the therapy of rheumatic arthritis (Malemud, 2015). HIF-1α increases the production of inﬂammatory cytokines and promotes angiogenesis in rheumatic arthritis patients (Park et al., 2015). We reported that the 40% ethanol extract of P. sinensis alleviates rheumatoid arthritis by regulating the PI3K-Akt and HIF-1 signaling pathways (Hu et al., 2022). P. racemosa is another plant in the genus Porana with welldocumented medicinal applications, which could be used for the treatment of colds. The results of network analysis revealed its primary active components to be scopolin, umbelliferone, eupatilin, and quercetin, which act on AKT1, EGFR, MAPK1, NFκB1, PIK3R1, SRC, TNF, and other targets to regulate PI3KAkt, MAPK, and the chemokine signaling pathway, indicating the main involvement of inﬂammatory pathway. MAPK participates in cell proliferation, differentiation, transformation, and apoptosis regulation through phosphorylation of nuclear transcription factors, cytoskeletal proteins, and enzymes (Yeung et al., 2018). PI3K-Akt regulates survival, cell growth, differentiation, cellular centrality was 0.3732, and the mean value of betweenness centrality was 0.0122. Three network topology parameters of 20 targets were higher than the corresponding mean value (MAPK1, PIK3CA, AKT1, MAP2K1, MAPK3, EGFR, MMP2, PRKCA, ESR2, GSK3B, MAPK14, ESR1, PIK3R1, NRAS, SRC, PTGS2, MMP9, TNF, KDR, and ADORA3). The mean degree of the 20 pathways was 18.55, the mean value of closeness centrality was 0.4054, and the mean betweenness centrality was 0.0254. Three network topology parameters of six signaling pathways were higher than the corresponding mean value (PI3K-Akt, HIF1, estrogen, MAPK, chemokine, and the thyroid hormone signaling pathway). The results of the network analysis revealed 17 active compounds in Porana species, including six steroids, three ﬂavonoids, three amides, two coumarins, and three organic acid esters. In the follow-up quality control study, critical research should be carried out on the actual content of these compounds. Coumarins are widely distributed in Porana species, presenting in P. sinensis, P. racemosa, P. discifera, and P. spectabilis. Taking coumarin scopolin as an example, its targets include GSK3B, EGFR, MAPK1, IL2, HSPA8, MMP9, HK1, GAPDH, TNF, ADORA3, acting on PI3K-Akt, HIF-1, estrogen, MAPK, and other signaling pathways. Scopolin promotes the differentiation of osteoblasts and inhibits the decrease of bone mineral density, participating in osteoporosis treatment (Park et al., 2020), possibly associated with the regulation of the estrogen pathway. Intraperitoneal injection of scopolin alleviates the symptoms of adjuvant arthritis in Frontiers in Pharmacology 10 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 3 Bioactivities of the extracts of Porana plants. No. Extracts Species Part Condition Quality control Activity Model Results References 1 40% ethanol extract P. sinensis Stem 40% ethanol ultrasonic extraction HPLC, scopolin 20.07 mg/g, chlorogenic acid 33.86 mg/g, scopoletin 7.68 mg/g plant material Antiinﬂammatory and antinociceptive activities In vivo: Xyleneinduced ear edema, formalin induced inﬂammation, carrageenan-induced mice air pouch inﬂammation in mice, acetic acidinduced writhing, formalin-induced nociception; ig, 143, 285, and 570 mg/kg; positive control: dexamethasone 2 mg/kg, aspirin 200 mg/kg, paracetamol 100 mg/kg Inhibit the ear swelling, the synthesis of PGE2, reduce the number of writings, and relieve phase II pain in mice Chen et al. (2013) 2 80% methanol extract P. sinensis Stem 80% methanol ultrasonic extraction HPLC, scopolin 1.95 mg/g, chlorogenic acid 2.55 mg/g, scopoletin 0.25 mg/g plant material Antiinﬂammatory activity In vitro: LPS-induced RAW 264.7 cells; 25, 50, 100 μg/ml Inhibit LPSinduced RAW 264.7 release of NO, and iNOS, COX-2 and IL-6 mRNA expression Xue et al. (2017) 3 40% ethanol extract P. sinensis Stem 40% ethanol reﬂux extraction HPLC, 5-Ocaffeoylquinic acid 13.4268 mg/g, scopolin 12.6935 mg/ g, chlorogenic acid 48.5457 mg/g, 4-Ocaffeoylquinic acid 8.2953 mg/g, scopoletin 20.9330 mg/g, 3,4dicaffeoylquinic acid 28.6063 mg/g, 3,5dicaffeoylquinic acid 13.5660 mg/g, 4,5dicaffeoylquinic acid 18.3498 mg/g plant material Antiinﬂammatory activity In vitro: LPS-induced RAW 264.7 cells; 120 μg/ml; positive control: methotrexate 120 μg/ml Inhibit the release of NO, TNF-α, IL1β and IL-6 in LPSinduced RAW 264.7 cell; attenuate the severity, pathological changes, and release of cytokines (IL-6 and HIF-1α) during rheumatoid arthritis progression by regulating the PI3K/AKT and HIF-1 pathways Hu et al. (2022) In vivo: Collageninduced arthritis model; ig, 0.6, 0.3, and 0.15 g/kg; positive control: methotrexate 1 mg/kg 4 60% ethanol extract P. paniculata Whole plants Cold maceration method Total ﬂavonoids 59.86 mg/g of quercetin, total phenols 33.34 mg/g of gallic acid Anti-oxidant Activity In vitro: DPPH assay, superoxide anion scavenging activity assay, nitric oxide scavenging activity assay, hydrogen peroxide scavenging assay and metal chelating activity; 20, 40, 60, 80 and 100 μg/ ml; positive control: L-ascorbic acid, butylated hydroxyanisole, alpha tocopherol, 20, 40, 60, 80 and 100 μg/ml Present good antioxidant activity Kumar et al. (2015) 5 80% methanol extract of ten samples P. sinensis Stem 80% methanol ultrasonic extraction HPLC, chlorogenic acid, 4-Ocaffeoylquinic acid, 5O-caffeoylquinic acid, 3,4-dicaffeoylquinic Anti-oxidant Activity In vitro: DPPH assay; IC50 211–439 μg/ml; positive control: ascorbic acid, IC50 38.65 μmol/L Present good DPPH_ scavenging activity, with IC50 values ranging from 211 to 439 μg/ml Chen et al. (2020) (Continued on following page) Frontiers in Pharmacology 11 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 3 (Continued) Bioactivities of the extracts of Porana plants. No. Extracts Species Part Condition Quality control Activity Model Results References acid, 4,5dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, scopolin, scopoletin 6 40% ethanol extract P. sinensis Stem 40% ethanol reﬂux extraction HPLC, 5-Ocaffeoylquinic acid 6.76 mg/g, scopolin 16.97 mg/g, chlorogenic acid 21.53 mg/g, 4-Ocaffeoylquinic acid 7.84 mg/g, scopoletin 4.92 mg/g, 3,5dicaffeoylquinic acid 12.41 mg/g, 3,4dicaffeoylquinic acid 14.94 mg/g, 4,5dicaffeoylquinic acid 18.17 mg/g Anti-gout Activity In vivo: monosodium urate crystal induced gout arthritis; ig, 1.0, 0.5, and 0.25 g/kg; positive control: colchicine 1.5 mg/kg Regulate the release of inﬂammatory factors and oxygen free radicals to prevent and treat gouty arthritis by mediating the TLR2-MyD88 signaling pathway Du et al. (2020) 7 80% methanol extract of ten samples P. sinensis Stem 80% methanol ultrasonic extraction HPLC, chlorogenic acid, 4-Ocaffeoylquinic acid, 5O-caffeoylquinic acid, 3,4-dicaffeoylquinic acid, 4,5dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, scopolin, scopoletin Anti-gout Activity In vitro: xanthine oxidase inhibitory activity assay; IC50 26.7–45.5 mg/ml; positive control: allopurinol, IC50 0.01 mmol/L Present good xanthine oxidase inhibitory activity, with IC50 values ranging from 26.7 to 45.5 mg/ml Chen et al. (2020) Because in vitro studies of extracts have not considered systemic absorption or metabolism of active compounds, the results of these studies might be biased. metabolism, and cytoskeletal reorganization of cells. Modiﬁcation of this pathway is strongly implicated in the pathogenesis of most cancers (Malemud, 2015). The treatment of cancers is not a traditional application of Porana plants. Due to the regulatory effect of compounds on multiple anti-cancer pathways, the genus Porana has excellent application prospects in anti-cancer drugs. The targeting pathway of the chemical constituents of Porana species supports the application of this genus in the treatment of rheumatoid arthritis, colds, and cancer. However, the application of Porana plants in treating these diseases needs to be veriﬁed in animal and clinical trials. 5.2.1 Anti-inﬂammatory and analgesic effects In a previous study, our group adopted the xylene-induced mouse ear swelling model, the formalin-induced inﬂammation model, and the carrageenan-induced mice air pouch inﬂammation model to investigate the anti-inﬂammatory activity of 40% ethanol extracts of P. sinensis (extract 1). We also applied the mouse acetic acid writhing model and the formalin-induced pain model to investigate its analgesic effects (Chen et al., 2013). We found that the oral administration of extract 1 (570 and 285 mg/kg) inhibits ear swelling in mice by 39.0% and 29.5%, respectively, and the induced inﬂammation in formalin mice by 37.3% and 30.8%, respectively. In the carrageenan-induced mice air pouch inﬂammation model, extract 1 signiﬁcantly inhibits the synthesis of PGE2. Extract 1 signiﬁcantly reduces the number of writings in mice and relieves phase II pain in the formalininduced pain model. The 80% methanol ultrasonic extract of P. sinensis (extract 2) inhibits LPS-induced RAW 264.7 release of NO at 25, 50, and 100 μg/ml, with inhibition of iNOS, COX-2, and IL-6 mRNA expression (Xue et al., 2017). However, this 5.2 Pharmacological activities of the extracts of Porana plants For the extracts, various preparation methods lead to signiﬁcant differences in chemical composition and bioactivities. When reviewing the pharmacological effects of Porana extracts, we focused on the following to facilitate identifying the reasons for the differences in pharmacological effects: plant origin and part, extraction methods, quality control methods, biological activities, and screening models (Table 3). Frontiers in Pharmacology 12 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 xanthine oxidase inhibitory activity of ten batches of the 80% methanol extract of P. sinensis (extract 7), revealing its good activity, with IC50 values ranging from 26.7 to 45.5 mg/ml (Chen et al., 2020). The treatment of gout-related diseases is not traditionally applied to the genus Porana. Although the in vitro and in vivo experiments demonstrated the anti-gout potential of P. sinensis, it remains needs to be veriﬁed by clinical research. In addition, due to the different extraction methods of these extracts, the active components of anti-gout should be clariﬁed in the future. study lacked a positive control. COX-2 is a critical enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, and this study conﬁrmed the inhibitory effect of extract 1 on PGE2 synthesis. We reported that 40% ethanol extract of P. sinensis (extract 3) inhibits the release of inﬂammatory mediators (NO, TNF-α, IL-1β, and IL-6) in LPS-induced RAW 264.7 cells (Hu et al., 2022). Extract 3 attenuates the severity, pathological changes, and release of cytokines (IL-6 and HIF-1α) during rheumatoid arthritis progression by regulating the PI3K/Akt and HIF-1 pathways (Hu et al., 2022). There are many studies on the anti-inﬂammatory and analgesic efﬁcacy of the extract of P. sinensis in vitro and in vivo. Compared with methotrexate, aspirin, and other positive control drugs, these extracts’ anti-inﬂammatory and analgesic effects are insigniﬁcant. Except for P. sinensis, species such as P. spectabilis have been recorded for the treatment of chest pain in folk medicine (Li et al., 1985); however, no experimental veriﬁcation has been reported. 5.2.4 Toxicity Only acute toxicity of P. sinensis has been reported. No mice died with a single intragastric 40% ethanol extract of P. sinensis at 5 g/kg. The weights, behaviors, and anatomical examinations showed no apparent abnormalities within 14 days (Chen et al., 2013). However, because it is a medicinal plant, acute toxicity evaluation is insufﬁcient, and chronic toxicity tests and clinical safety evaluations of Porana plants need to be performed. In summary, the current research on the medicinal effects of Porana species concentrates on P. sinensis. Although Porana is widely distributed, its medicinal value is limited. Especially for P. racemosa, which enjoys abundant folk medicinal records and good development prospects, its systematic pharmacodynamic and clinical research is lacking. For the pharmacological study of the extract, to clarify its pharmacodynamic components, chemical analysis is required. Some studies have not provided quality control on the extracts, which would affect the reliability of these studies. 5.2.2 Anti-oxidant activity As a chronic inﬂammatory autoimmune disease, rheumatoid arthritis is closely related to oxidative stress (Peng et al., 2021). The 60% ethanol extract (extract 4) of P. paniculata presented good anti-oxidant activity in DPPH assay, superoxide anion scavenging activity assay, nitric oxide scavenging activity assay, hydrogen peroxide scavenging assay and metal chelating activity (Kumar et al., 2015). In the superoxide anion scavenging assay, extract 4 exhibited more robust activity than the positive control butylated hydroxyanisole. In the hydrogen peroxide scavenging assay, extract 4 (IC50: 25.65 μg/ml) performed almost as well as gallic acid (IC50: 24.29 μg/ml). Our group also tested ten batches of 80% methanol extract (extract 5) of P. sinensis, all of which showed good DPPH_ scavenging activity, with IC50 values ranging from 211 to 439 μg/ml (Chen et al., 2020). However, the above-mentioned test method for anti-oxidant activity is based on chemical reaction in vitro, which is far from practical. Therefore, it is necessary to explore the antioxidant activity in vivo to clarify the molecular mechanisms of its antioxidant activity. 5.3 Pharmacological activities of the active constituents of Porana plants To further analyze the pharmacological activities of this genus, we followed the pharmacological studies of compounds in this genus and discussed their correlation with the results of our network analysis. The results are summarized in Table 4. 5.3.1 Anti-inﬂammatory and analgesic effects The results of long-term folk medicinal and network analysis indicated that anti-inﬂammatory and analgesic effects are the primary medicinal effects of Porana plants. The intraperitoneal injection of scopoletin (compound 15, 1, 5, 10 mg/kg) reduced serum levels of NO, TNF-α, and PGE2 of carrageenan-induced paw edema mice, and the protein expression of iNOS and COX-2 (Chang et al., 2012). Scopoletin reduced the amount of writhing in the mouse acetate writhing model and formalin-induced pain in the late phase. The anti-inﬂammatory and analgesic effects of scopoletin (10 mg/kg) are equivalent to that of indomethacin (10 mg/kg) (Chang et al., 2012). However, scopoletin was given by intraperitoneal injection, which would limit its application. In the carrageenan-induced mouse model of pleurisy, 5.2.3 Anti-gout effect In a previous study, we applied the strategy of network analysis combined with experimental veriﬁcation to study the mechanism of the 40% ethanol extract of P. sinensis (extract 6) against gout. Extract 6 (0.25, 0.5, 1.0 g/g) dose-dependently reduced joint swelling in rats with monosodium urate (MSU) crystal-induced gout arthritis, with decreased serum MDA and IL-1β levels, and increased serum SOD, TGF-β, and IL-4 levels. By mediating the TLR2-MyD88 signaling pathway, it regulates the release of inﬂammatory factors and oxygen free radicals to prevent and treat gouty arthritis (Du et al., 2020). Because xanthine oxidase is a target for gout treatment, we tested the Frontiers in Pharmacology 13 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 4 Bioactivities of the active compounds of Porana plants. No. Compounds Activities Dosage Model Positive control Results References 1 Scopoletin Antiinﬂammatory and antinociceptive activities Ip: 1, 5, 10 mg/kg Acetic acid induced writhing response, formalin test and λ-carrageenan induced paw edema in ICR mice Indomethacin, ip, 10 mg/kg Reduce the levels of NO, TNF-α, PGE2, and the protein expression of iNOS and COX-2 in the serum of carrageenan-induced paw edema mice, reduce the number of writhing in the mouse acetate writhing model, and the formalininduced pain in the late phase Chang et al. (2012) 2 Scopoletin Antiinﬂammatory activity Ip: 0.1, 1, 5 mg/kg Carrageenan-induced inﬂammation in the mouse model of pleurisy Dexamethasone, ip, 0.5 mg/kg Reduce serum NO, TNF-α and IL-1β levels, and inhibit p65, p38 phosphorylation in mouse lungs Pereira dos Santos Nascimento et al. (2016) 3 Scopoletin Antiinﬂammatory activity 15, 30, 60 μmol/L IL-1β induced ﬁbroblast-like synoviocytes - Inhibit the production of IL6, and the phosphorylation of p38, ERK, PKC and CREB Dou et al. (2013) 4 Scopolin Antiinﬂammatory and antinociceptive activities Ip: 25, 50, 100 mg/kg Adjuvant-induced arthritis in rats Dexamethasone, ip, 2 mg/kg Alleviate the symptoms of adjuvant-induced arthritis by inhibiting the expression of IL-6, VEGF and FGF-2 in synovial tissue Pan et al. (2009) 5 Umbelliferone Antiinﬂammatory activity Oral administration: 20, 40 mg/kg 2,4-dinitrochlorobenzene and house dust mite extract treated mice Dexamethasone, oral administration, 1 mg/kg Reduce ear thickness, spleen size and weight, serum levels of IgE, IgG1, IgG2a, TNF-α, and IL-4, and mast cell inﬁltration Lim et al. (2019) 6 Isofraxidin Antiinﬂammatory activity 1, 10, 50 μmol/L IL-1β induced inﬂammatory response in human osteoarthritis chondrocytes - Block IL-1β-stimulated production of NO and PGE2, inhibit the expression of COX-2, iNOS, MMP-1, MMP-3, MMP-13, ADAMTS-4 and -5, suppress IκB-α degradation and NF-κB activation Lin et al. (2018) 7 3,4dicaffeoylquinic acid Antiinﬂammatory activity 35, 70, 140 μmol/L LPS-induced RAW 264.7 cells Inhibit NO/iNOS and PGE2/COX-2 pathways, block the nucleus translocation of NF-κB Xue et al. (2019) Antiinﬂammatory activity Ig: 10, 20 mg/kg Acute airway inﬂammation induced by ammonia liquor in mice Prednisone acetate, ig, 10 mg/kg Reduce the total leukocytes in the bronchoalveolar lavage ﬂuid Wu et al. (2016) 3,5dicaffeoylquinic acid 4,5dicaffeoylquinic acid 8 3,4dicaffeoylquinic acid 3,5dicaffeoylquinic acid 4,5dicaffeoylquinic acid 9 Eupatilin Antiinﬂammatory activity 1, 10, 100 μmol/L LPS-stimulated macrophages - Inhibit the inﬂammatory modulators and NF-κB activation Choi et al. (2011) 10 Eupatilin Antiinﬂammatory activity 1, 2, 5, 10 μmol/L Murine arthritis model; human rheumatoid synoviocytes - Inhibit TNF-α-induced IL-6 and IL-1β mRNA Kim et al. (2015) (Continued on following page) Frontiers in Pharmacology 14 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 4 (Continued) Bioactivities of the active compounds of Porana plants. No. Compounds Activities Dosage Model Positive control Results References expression, suppress osteoclast differentiation 11 Quercetin Antiinﬂammatory activity Oral gavage: 30 mg/kg Collagen-induced arthritis in C57BL/6 mice Methotrexate, ip, 0.5 mg/kg Decrease serum TNF-a, IL1β, IL-17, and MCP-1 levels Haleagrahara et al. (2017) 12 Quercetin Antiinﬂammatory activity Ip Adjuvant-induced arthritis in C57BL/6 mice; mice air pouch model Dexamethasone Reduce neutrophil inﬁltration and promote the apoptosis of activated neutrophils by inhibiting neutrophil activities Yuan et al. (2020) 13 β-ecdysterone Antiinﬂammatory activity Subcutaneous injection: 0.6, 0.8, 1.0 mg/kg Monoiodoacetate-induced osteoarthritis in rats 3-methyladenine, ip, 30 mg/kg; rapamycin, ip, 1 mg/kg Inhibit 3-methyladenineinduced apoptosis of chondrocytes, downregulate PI3K, p-AKT1, p-mTOR, p-p70S6K and caspase-3 expression, activate autophagy in chondrocytes Tang et al. (2020) 14 N-transferuloyltyramine Antiinﬂammatory activity 6.25, 12.5, 25, 50 μg/ml LPS-induced RAW 264.7 cells - Suppress mRNA expression of COX-2 and iNOS via suppression of AP-1 and JNK signaling pathway Jiang et al. (2015) 15 Scopoletin Anti-gout activity Ip: 50, 100, 200 mg/kg; 30, 100, 300 μmol/L Monosodium urate (MSU) crystal-induced inﬂammation in mouse air pouch model; MSU crystalstimulated RAW 264.7 cells Prednisolone, ip, 10 mg/kg Decrease the number of neutrophils and mononuclear phagocytes of monosodium urate (MSU) crystal-induced inﬂammation in mouse; suppress the secretions of IL-1β, TNF-α, IL-6, PGE2 and NO in MSU crystal-stimulated RAW 264.7 cells, involving the suppression of NF-κB activation and blockade of MAPK signal pathway Yao et al. (2012) 16 Scopoletin Anti-gout activity Ig: 4.9 mg/kg Monosodium urate crystal induced gout arthritis in rats Colchicine, ig, 1.5 mg/kg Inhibit the production of serum MDA, IL-1β, TGF1β, promote the release of SOD and IL-4, as well as inhibit the expression of TLR2 and MyD88 mRNA in rat joint synovium Du et al. (2020) 17 3,5dicaffeoylquinic acid Anti-gout activity 60, 120, 240, 480, 960 μmol/L Xanthine oxidase Allopurinol Exhibit weak xanthine oxidase inhibitory activity Chen et al. (2014) Anti-cancer activity 3.56, 6.12, 12.5, 25, 50, 100 μmol/L The normal cell line HCvEpC and the cervical cancer cell lines DoTc2, SiHa, HeLa, and C33A - Inhibit the growth of DoTc2, SiHa, HeLa, and C33A cells; the apoptotic cell death in HeLa cells has involved the up-regulation of Bax, caspase 3, 8, and 9, the downregulation of Bcl-2, and the blockade of the PI3K/AKT pathway Tian et al. (2019) 3,4dicaffeoylquinic acid 4,5dicaffeoylquinic acid 18 Scopoletin (Continued on following page) Frontiers in Pharmacology 15 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 4 (Continued) Bioactivities of the active compounds of Porana plants. No. Compounds Activities Dosage Model Positive control Results References 19 Umbelliferone Anti-cancer activity 5, 25, 50, 100, 150 μmol/L Human renal carcinoma cells - Reduce cell proliferation and induce apoptotic events by regulating Ki67, MCM2, Bcl-2, CDK2, CyclinE1, CDK4, and CyclinD1 Wang et al. (2019) 20 Isofraxidin Anti-cancer activity 5, 10, 20, 40, 80 μmol/L Human colorectal cancer cells HT-29 and SW-480 - Bate cell proliferation, induce cell apoptosis, and decrease the expression of anti-apoptotic protein Bcl-2; block Akt pathway via inhibition expression of p-Akt Shen et al. (2017) 21 5-Ocaffeoylquinic acid Anti-cancer activity 1, 10, 50 μmol/L p53 wild-type A549 and p53deﬁcient H1299 non-small cell lung cancer cells - Abrogate mitogenstimulated invasion but not proliferation by the inactivation of p70S6Kdependent signaling pathway In et al. (2016) 22 Chlorogenic acid Anti-cancer activity 50, 100, 200 μmol/L U2OS, Saos-2, and MG-63 osteosarcoma cells - Inhibit cell proliferation Sapio et al. (2020) 23 Chlorogenic acid Anti-cancer activity 40 mg/kg 4T1 breast cancer tumors in BALB/c mice - Participated in the induction of apoptosis, involving the increase of Bax/Bcl-2 ratio, the genes of p53 and caspase-3 Changizi et al. (2021) 24 Chlorogenic acid Anti-cancer activity 250, 1000 μmol/L HCT116 and HT29 human colon cancer cell lines - Inhibit the viability associated with the induction of cell cycle arrest at the S phase and the suppression of extracellular signal related kinase activation Hou et al. (2017) 25 Eupatilin Anti-cancer activity 40, 80, 120, 160, 200, 240, 280, 320 μmol/L Human malignant glioma cell lines U251MG, U118, T98G, and U87MG - Inhibit the viability and proliferation of glioma cells by arresting the cell cycle at the G1/S phase, and disrupt the structure of the cytoskeleton and affect F-actin depolymerization via the p-LIMK/coﬁlin pathway Fei et al. (2019b) 26 Eupatilin Anti-cancer activity 12.5, 25, 50 μmol/L Human prostate PC3, LNCaP cancer cells and prostatic epithelial RWPE-1 cells - Inhibit the proliferation, metastasis and spread of prostate cancer cells through modulation of PTEN and NF-κB pathway Serttas et al. (2021) 27 Eupatilin Anti-cancer activity 2.5, 5, 10, 20, 40 μmol/L; 10, 50 mg/kg Human esophageal cancer cell line TE1; TE1 xenograft mouse model - Inhibit the Akt and ERK pathways Wang et al. (2018b) 28 4ʹHydroxywogonin Anti-cancer activity 0.1, 1, 10 μg/ml SW620 colorectal cancer cell Wortmannin, 10 μmol/L Reduce the viability, suppress the proliferation by disrupting PI3K/AKT pathway Sun et al. (2018) 29 N-transferuloyltyramine Anti-cancer activity 64, 128, 192, 256, 320 μmol/L HepG2 and L02 human hepatoma cells Taxol Inhibit the proliferation Gao et al. (2019) 30 Scopoletin Anti-diabetic activity Ig: 0.01 g/100 g diet Streptozotocin induced diabetic mice Metformin, 0.5 g/ 100 g diet Reduce blood glucose and glycated hemoglobin, serum ALT, TNF-α, IL-6 levels, glucose intolerance, and hepatic lipid accumulation, down-regulate hepatic gene Choi et al. (2017) (Continued on following page) Frontiers in Pharmacology 16 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 TABLE 4 (Continued) Bioactivities of the active compounds of Porana plants. No. Compounds Activities Dosage Model Positive control Results References expression of triglyceride and cholesterol synthesis as well as inﬂammation (TLR4, MyD88, NF-κb1, TNF-α, and IL-6) 31 Scopoletin Anti-diabetic activity Ig: 1 mg/kg High fructose diet induce type 2 diabetes rats - Reduce blood glucose, insulin and lipid levels, involving the activation of IRS1, PI3K and AKT phosphorylation Kalpana et al. (2019) 32 Scopoletin Anti-diabetic activity Ig: 10 mg/kg Streptozotocin induced diabetes mice Acarbose, Ig, 10 mg/kg Inhibit the activity of αglucosidase and α-amylase and reduce postprandial blood glucose levels Jang et al. (2018) 33 Scopoletin Phagocytic activity 50 μg/ml Human U937 monocytic cell line - Enhance the phagocytic activity, which involving the down-regulation of seven genes (CDC42, FCGR1A/ FCGR1C, ITGA9, ITGB3, PLCE1, RHOD & RND3) and up-regulation of ﬁve genes (DIRAS3, ITGA1, PIK3CA, PIK3R3 & PLCD1) Alkorashy et al. (2020) 34 Scopoletin Anti-fungal activity 12.5–200 μg/ml Candida tropicalis Fluconazole, 62.5–1000 μg/ml Affect both planktonic and bioﬁlm forms Lemos et al. (2020) injection of scopolin (compound 16, 50, and 100 mg/kg) alleviated the symptoms of adjuvant-induced arthritis in rats by inhibiting the expression of IL-6, VEGF, and FGF-2 in rat synovial tissue. Li et al. (2019) established an LC-MS/MS method for the simultaneous determination of scopolin and scopoletin in rat biomatrices, while the bioavailability of scopolin was exceptionally low. There are also many reports on umbelliferone’s antiinﬂammatory and analgesic activities (compound 17) and isofraxidin (compound 20). Oral administration of umbelliferone (20 and 40 mg/kg) for 28 days led to signiﬁcant decreases in ear thickness, spleen size and weight, and serum levels of IgE, IgG1, IgG2a, TNF-α, and IL-4. There were also decreases in mast cell inﬁltration on 2,4-dinitrochlorobenzene and house dust mite extract-treated mice (Lim et al., 2019). Umbelliferone reduced the secretion of pro-inﬂammatory cytokines and chemokines in TNF-α/IFN-γ-treated HaCaT cells via the regulation of the MAPK, IkB-α/NF-κB, and STAT1 signaling pathways (Lim et al., 2019). There are many reports on isofraxidin in the treatment of osteoarthritis (Jin et al., 2018; Wang and Wang, 2021). For example, isofraxidin (1, 10, and 50 μmol/L) blocked IL-1β-stimulated production of NO and PGE2, inhibited the expression of COX-2, iNOS, MMP-1, MMP-3, MMP-13, ADAMTS-4 and -5, and suppressed IL-1βinduced IκB-α degradation and NF-κB activation in human osteoarthritis chondrocytes (Lin et al., 2018); it should be noted that there was no positive control group in this study. intraperitoneal injection of scopoletin (1 mg/kg) reduced serum NO, TNF-α, and IL-1β levels and inhibited p65, p38 phosphorylation in mouse lungs (Pereira dos Santos Nascimento et al., 2016). Dou et al. (2013) reported that scopoletin (15, 30, 60 μmol/L) signiﬁcantly inhibited the production of IL-6 in ﬁbroblast-like synoviocytes induced by IL-1β and the phosphorylation of p38, ERK, PKC, and CREB. These ﬁndings suggest that scopoletin might play a role by mediating the MAPK/PKC/CREB pathways. It should be noted that this study lacks a positive control. P38 MAPK is relevant to human inﬂammatory disease, and inhibition of p38 phosphorylation reduces gene expression of many inﬂammatory mediators (Dou et al., 2013). The regulatory effect of scopoletin on the MAPK signaling pathway is consistent with the results of network analysis. These ﬁndings suggest that scopoletin exerts anti-inﬂammatory and analgesic effects through multiple targets and pathways, indicating its good medicinal potential (Parama et al., 2022). However, due to the instability of scopoletin under physiological media and poor water solubility, its oral bioavailability is only 6.0%, severely restricting its medicinal application (Sakthivel et al., 2022). With the rapid development of pharmaceutical technology, new drug delivery systems have introduced possible applications of scopoletin in recent years. For example, there is a formulation of soluplus-based micelles for scopoletin, which increases its absorption, bioavailability, and tissue distribution 33-fold (Zeng et al., 2017). Pan et al. (2009) reported that intraperitoneal Frontiers in Pharmacology 17 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 There are several anti-inﬂammatory and analgesic active ingredients in Porana species, including coumarins, quinic acid derivatives, ﬂavonoids, steroids, and amides. The results of the components (scopolin, umbelliferone, eupatilin, quercetin, N-trans-feruloyltyramine) pathways (PI3K-Akt, HIF-1, MAPK, chemokine) in our network analysis are consistent with the results of the literature review, which suggests the potential of Porana species in the treatment of arthritis. However, it should be noted that, although components such as scopoletin and eupatilin show good anti-inﬂammatory and analgesic effects, their bioavailability is relatively low. Further structural modiﬁcation is needed, or new drug delivery systems should be developed to improve their bioavailability. Pharmacokinetic studies demonstrated in vivo its rapid absorption after oral applications (Majnooni et al., 2020). The HPLC ﬁngerprints of the Porana plants (Figure 3) showed that quinic acid derivatives frequently appear in different Porana species. The anti-inﬂammatory, analgesicrelated pharmacodynamics of chlorogenic acid has been reported in many studies and associated with the NF-κB, MAPK, and JNK/AP-1 signaling pathways; they have also been associated with the downregulation of TNF-α, COX-2, and PGE2 (Bagdas et al., 2020). Xue et al. (2019) applied the method of D101 macroporous resin to track the antiinﬂammatory components in P. sinensis; Compounds 31–33 inhibited NO/iNOS and PGE2/COX-2 pathways, and the nuclear translocation of NF-κB was also blocked. Wu et al. (2016) reported that compounds 31–33 reduce mouse ammonia liquor-induced acute airway inﬂammation by reducing the total leukocytes in bronchoalveolar lavage ﬂuid. Among these three compounds, 4,5-dicaffeoylquinic acid exhibited the most potent effect, suggesting that the structureactivity relationship requires further elaboration. Seven ﬂavonoids have been isolated from Porana species. Eupatilin (compound 23) and quercetin (compound 25) present diverse anti-inﬂammatory activities. Eupatilin exerts antiinﬂammatory effects by regulating NF-κB (Choi et al., 2011), TLR4/MyD88 (Fei et al., 2019a), AMPK (Zhou et al., 2018), and by suppressing osteoclast differentiation (Kim et al., 2015), inhibiting oxidative stress (Ali et al., 2017). Although eupatilin has broad bioactivity, its oral bioavailability is only 2.7% (Wang et al., 2018a). Quercetin is a broad-spectrum anti-inﬂammatory and analgesic substance without speciﬁcity. Considering the folk medicinal application of Porana plants, we only focused on its application in arthritis. Quercetin decreased serum TNF-a, IL-1β, IL-17, and MCP-1 levels in a collagen-induced mouse arthritis model (Haleagrahara et al., 2017). The authors claimed that quercetin produces better activity than methotrexate, which might not be accurate due to the different doses and routes of administration (quercetin, Po with 30 mg/kg; methotrexate, Ip with 0.5 mg/kg). MCP-1 (chemokine ligand 2) has a critical role in inﬂammation (Singh et al., 2021). These studies conﬁrmed the regulatory effect of Porana plants on the chemokine pathway in network analysis. Yuan et al. (2020) found that quercetin reduces neutrophil inﬁltration and promotes apoptosis in activated neutrophils; however, this study did not provide the dosage of quercetin and the positive control dexamethasone. β-Ecdysterone (compound 1) inhibited 3-methyladenineinduced apoptosis of chondrocytes, downregulated PI3K, p-AKT1, p-mTOR, p-p70S6K, and caspase-3 expression, and activated autophagy in chondrocytes in a rat model of monoiodoacetate-induced osteoarthritis (Tang et al., 2020). N-trans-feruloyltyramine (compound 35) strongly suppressed mRNA expression of COX-2 and iNOS via suppression of AP-1 and the JNK signaling pathway in LPS-induced RAW 264.7 cells (Jiang et al., 2015). Frontiers in Pharmacology 5.3.2 Anti-gout effect Intraperitoneal injection of scopoletin (compound 15, 100, and 200 mg/kg) signiﬁcantly lowered the number of neutrophils and mononuclear phagocytes of MSU-induced inﬂammation in a mouse air pouch model. The secretion of IL-1β, TNF-α, IL-6, PGE2, and NO were suppressed by scopoletin (30–300 μmol/L) at the transcriptional level in MSU-stimulated RAW 264.7 cells, mediated by the suppression of NF-κB activation and blockade of the MAPK signal pathway (Yao et al., 2012). In our previous study, we also found that scopoletin (4.9 mg/kg) inhibited the production of serum MDA, IL-1β, and TGF-1β, promoted the release of SOD and IL-4 and inhibited the expression of TLR2 and MyD88 mRNA in rat joint synovium (Du et al., 2020). In another study, we found that 3,4-dicaffeoylquinic acid (compound 31, IC50: 0.32 mmol/L), 4,5-dicaffeoylquinic acid (compound 32, IC50: 0.26 mmol/L), and 3,5dicaffeoylquinic acid (compound 33, IC50: 0.21 mmol/L) exhibited weak xanthine oxidase inhibitory activity (Positive control: allopurinol, IC50: 0.01 mmol/L) (Chen et al., 2014), partially explaining the phytochemistry of anti-gout activity. In summary, scopoletin plays an anti-gout role primarily by regulating inﬂammatory pathways, and quinic acid derivatives have xanthine oxidase inhibitory activity. Due to a large amount of anti-inﬂammatory, analgesic, antioxidant, and xanthine oxidase-inhibiting ingredients, the genus Porana has excellent application prospects as anti-gout therapies. However, only P. sinensis has been reported to treat acute gouty arthritis. Therefore, the anti-gout efﬁcacy of other species in this genus must be further explored. 5.3.3 Anti-cancer activity Scopoletin (compound 15) inhibited the growth of cervical cancer cell lines, including DoTc2, SiHa, HeLa, and C33A cells, with the IC50 values ranging from 7.5 to 25 μmol/L. The apoptotic cell death in HeLa cells induced by scopoletin involved the upregulation of Bax, caspase 3, 8, and 9, the downregulation of Bcl-2, and the blockade of the PI3K/Akt pathway. Scopoletin also caused cell cycle arrest at the G2/M phase and inhibited cell migration (Tian et al., 2019). 18 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 the expression of VEGF-A decreased dose-dependently (Sun et al., 2018). Based on this study, it could be presumed that the anti-angiogenic activity of PI3K inhibitors was at least partially mediated by their capacity to reduce VEGF levels. N-trans-feruloyltyramine (compound 35) inhibits the proliferation of HepG2 cells with an IC50 of 194 ± 0.894 μmol/L, which was signiﬁcantly lower than the positive control taxol (IC50: 26 ± 0.128 μmol/L) (Gao et al., 2019). Comparing the results on HepG2 and LO2 cells revealed that N-trans-feruloyltyramine might have selective cytotoxic effects. In summary, there are many anti-cancer active components in Porana plants, including coumarins, quinic acid derivatives, and ﬂavonoids. Of these, scopoletin, umbelliferone, chlorogenic acid, and eupatilin have many reports on their anti-cancer activity. These components are widely distributed in nature and are not speciﬁc. Since the related research mostly stays at the level of in vitro research, and more in vivo research and clinical studies are needed. Umbelliferone (compound 17) exerted anti-cancer effects on various cells and animal models through induction of apoptosis, cell cycle arrest, reduction of cell proliferation, and inhibition of the release of inﬂammatory factors. For example, treating human renal carcinoma cells with umbelliferoneinduced dose-dependent decreases in Ki67, MCM2, Bcl-2, CDK2, CyclinE1, CDK4, and CyclinD1 and an increase in Bax (Wang et al., 2019). Isofraxidin (compound 20, 5–80 μmol/L) signiﬁcantly bate cell proliferation, induced cell apoptosis, and decreased the expression of anti-apoptotic protein Bcl-2 in human colorectal cancer cell lines (HT-29 and SW-480). Isofraxidin blocks the Akt pathway via inhibition expression of p-Akt (Shen et al., 2017). There are many reports on the anti-cancer properties of quinic acid derivatives in Porana species. 5-O-caffeoylquinic acid (compound 30) abrogated mitogen-stimulated invasion but not proliferation in p53 wild-type A549 and p53-deﬁcient H1299 NSCLC cells. The anti-invasive activity of 5-Ocaffeoylquinic acid in A549 cells might be mediated by the inactivation of the p70S6K-dependent signaling pathway (In et al., 2016). Chlorogenic acid (compound 28) inhibited the proliferation of U2OS, Saos-2, and MG-63 osteosarcoma cells (50, 100, 200 μmol/L) (Sapio et al., 2020). This compound also participates in the apoptosis of 4T1 breast cancer tumors in BALB/c mice, involving the increase of the Bax/Bcl-2 ratio and the genes for p53 and caspase-3 (Changizi et al., 2021); it inhibits the viability of HCT116 and HT29 colon cancer cell lines associated with the induction of cell cycle arrest at the S phase and the suppression of extracellular signal-related kinase activation (Hou et al., 2017). These ﬁndings suggest that caffeoylquinic acids exhibit relatively broad anti-cancer activity, with targeted cancer types including lung cancer, osteosarcoma, breast cancer, and colon cancer. Chlorogenic acid inhibits cell proliferation and blocks the cell cycle; however, 5-O-caffeoylquinic acid does not inhibit cell proliferation. As isomers, the difference in antiproliferative effect between these two compounds deserves further explanation. The ﬂavonoid eupatilin (compound 23) inhibits the viability and proliferation of glioma cells by arresting the cell cycle at the G1/S phase. Eupatilin disrupts the structure of the cytoskeleton and affects F-actin depolymerization via the p-LIMK/coﬁlin pathway (Fei et al., 2019b). However, this study did not report a proapoptotic effect of eupatilin on glioma, which was inconsistent with other studies. Eupatilin (12.5, 25, 50 μmol/L) inhibits the proliferation, metastasis, and spread of prostate cancer cells through modulation of PTEN and NF-κB signaling (Serttas et al., 2021); it blocks the proliferation of esophageal cancer TE1 cells associated with the inhibition of the Akt and ERK pathways (Wang et al., 2018b). Another ﬂavonoid, 4ʹ-hydroxywogonin (compound 24), reduced the viability and suppressed the proliferation of SW620 colorectal cancer cells angiogenesis by disrupting PI3K/Akt signaling, while Frontiers in Pharmacology 5.3.4 Anti-diabetic activity In the streptozotocin-induced diabetic mice model, scopoletin (compound 15, 0.01 g/100 g diet) reduced blood glucose and glycated hemoglobin, glucose intolerance, hepatic lipid accumulation and downregulated hepatic gene expression of triglyceride and cholesterol synthesis and inﬂammation (TLR4, MyD88, NF-κb1, TNF-α, and IL-6). These results suggest that scopoletin protects against diabetes-induced steatosis and inﬂammation by inhibiting lipid biosynthesis and the TLR4-MyD88 pathway (Choi et al., 2017). However, this was a single-dose study with substantial differences in the dosage of the positive control metformin (0.5 g/100 g diet) and scopoletin, which cannot be used for comparison. In another study, scopoletin (1 mg/kg) reduced blood glucose, insulin, and lipid levels in high-fructose diet-induced type 2 diabetes, involving the activation of IRS1, PI3K, and Akt phosphorylation (Kalpana et al., 2019). Scopoletin inhibited the activity of α-glucosidase and α-amylase and reduced postprandial blood glucose levels in streptozotocin-induced diabetes mice. Unfortunately, the IC50 value of scopoletin was 85.12 and 37.36 μmol/L for α-glucosidase and α-amylase, which were lower than acarbose (Jang et al., 2018), indicating that its potential is limited. Another study reported that scopoletin stimulated insulin secretion via a K+ATP channel-dependent pathway in INS-1 pancreatic β cells (Park et al., 2022). Scopoletin could play a role in treating diabetes by stimulating insulin secretion, inhibiting α-glucosidase and α-amylase, and downregulating triglyceride and cholesterol synthesis and inﬂammation. However, the inhibitory effect of scopoletin on α-glucosidase and α-amylase would be weaker than that of the positive control drug acarbose. There are many reports on the efﬁcacy and mechanism of chlorogenic acid (compound 28), quercetin (compound 25), and rutin (compound 27) in the treatment of diabetes. For example, 19 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 only the chemical composition, efﬁcacy, and quality control of P. sinensis have been systematically reported, while the medicinal value of other species in this genus has not yet been explored. Therefore, we systematically reviewed this genus’s traditional and current use, chemical compositions, and pharmacological activities. We applied network analysis to predict the key targets and pathways of chemical components in this genus to clarify the research status of Porana species and highlight the directions for the rational medicinal development of this genus. Regarding chemical components, only ﬁve species of genus Porana have been reported, with 59 compounds isolated and identiﬁed, including steroids, coumarins, ﬂavonoids, quinic acid derivatives, and amides. Combined with the ﬁngerprints (Figure 3), coumarins and quinic acid derivatives are widely distributed in this genus, while steroids have only been reported in P. discifera. Because the research on chemical constituents is the forerunner of medicinal value development, the phytochemical study of other species in this genus needs to be performed. In terms of pharmacological effects, the extracts of Porana plants exhibit anti-inﬂammatory, analgesic, antioxidant, and anti-gout activities. However, studies on the pharmacological effects of Porana plants are focused on P. sinensis, and there are few pharmacological studies on other species. Especially for plants with extensive folk medicinal records (such as P. racemosa), detailed pharmacodynamic research needs to be performed. The chemical constituents of Porana present antiinﬂammatory, analgesic, anti-gout, anti-cancer, and diabetes treatment activities. Gout and diabetes treatment are not the traditional medicinal applications of Porana plants. However, this genus contains chemical substances with appropriate biological activities. Therefore, we speculate that this genus has the potential to develop in the direction of anti-gout and anti-diabetes. Future research needs to investigate different species’ anti-gout and antidiabetic efﬁcacy, explain their mechanism of action, and systematically elucidate their active components. Network analysis showed that steroids, ﬂavonoids, amides, coumarins, and other components maybe be relevant for anti-inﬂammatory, analgesic, anti-gout, anticancer, and diabetes treatment activities of Porana plants. Their targets include GSK3B, EGFR, MAPK1, IL2, HSPA8, MMP9, HK1, GAPDH, TNF, ADORA3, and their pathways include PI3K-Akt, HIF-1, estrogen, and MAPK. The enriched targets and pathways are consistent with the results of our literature review. In summary, Porana plants are abundant in natural resources and are widely recorded in folk medicine; nevertheless, the study of their medicinal value is limited. Research on the systematic chemical constituents of this genus is urgently needed. Anti-inﬂammatory, analgesic, anti-gout, anti-cancer, and diabetes treatments are critical directions for future study. quercetin stimulated insulin secretion (Kittl et al., 2016), alleviated ferroptosis in pancreatic cells (Li et al., 2020), and ameliorated diabetic encephalopathy through the SIRT1/ER stress pathway (Hu et al., 2020). Rutin decreased carbohydrate absorption from the small intestine, inhibited tissue gluconeogenesis, increased tissue glucose uptake, stimulated insulin secretion from beta cells, and protected pancreatic islets against degeneration (Ghorbani, 2017). Chlorogenic acid prevented diabetic nephropathy (Bao et al., 2018), rescued sensorineural auditory function, attenuated insulin resistance, and modulated glucose uptake (Hong et al., 2017). In summary, many anti-diabetic ingredients are found in Porana plants, including coumarins, quinic acid derivatives, and ﬂavonoids. The content of coumarins and quinic acid derivatives is relatively high in the genus Porana, suggesting that this genus could be used to treat diabetes. The network analysis shows that the pathways regulated by the chemical components of Porana plants play an essential role in diabetes treatment. For example, the PI3K/Akt pathway damaged in various body tissues leads to obesity and type 2 diabetes as the result of insulin resistance; in turn, insulin resistance exacerbates the PI3K/Akt pathway, forming a vicious circle (Huang et al., 2018). The progression of diabetes and its complications can be prevented or treated by modulating HIF-1 expression or activity (Catrina and Zheng, 2021). However, apart from the pharmacological or clinical studies of these compounds, there are no reports on the application of Porana plants in diabetes treatment; relevant research needs to be performed. 5.3.5 Other activities Alkorashy et al. (2020) used transcriptomic methods to study the effect of scopoletin (compound 15) on the phagocytosis of stimulated U937-derived macrophages. Scopoletin enhanced the phagocytic activity, involving the downregulation of seven genes (CDC42, FCGR1A/FCGR1C, ITGA9, ITGB3, PLCE1, RHOD, and RND3) and upregulation of ﬁve genes (DIRAS3, ITGA1, PIK3CA, PIK3R3, and PLCD1). These results provide a basis for applying scopoletin in treating cancer progression and metastasis, autoimmune disorders, pelvic organ prolapse, and cystic ﬁbrosis. ITGB3 is upregulated in pelvic organ prolapse disorders in women, and the downregulation of these genes supports the folk medicinal application of P. spectabilis in the treatment of uterine prolapse. Scopoletin also acts as an antifungal phytocompound against a multidrug-resistant strain of Candida tropicalis, with properties affecting planktonic and bioﬁlm forms of this pathogen (Lemos et al., 2020). 6 Conclusion The genus Porana is abundant in natural resources and is widely distributed in Asia, Africa, Oceania, America, and other regions. In China and India, this genus has several medicinal records. Currently, Frontiers in Pharmacology 20 frontiersin.org Peng et al. 10.3389/fphar.2022.998965 Author contributions Conﬂict of interest YP and YL: original and ﬁnal drafting, editing, revision, and ﬁgure editing; YY, YG, HR, JH, and WL: ﬁgures, tables and review of the literature; XC: network analysis; HT and ZC: revised the draft and ﬁnal editing. The authors declare that the research was conducted in the absence of any commercial or ﬁnancial relationships that could be construed as a potential conﬂict of interest. Publisher’s note Funding All claims expressed in this article are solely those of the authors and do not necessarily represent those of their afﬁliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. This work was ﬁnancially supported by the National Natural Science Foundation of China [grant numbers 81973419]; Key Research and Development Program of Shaanxi [grant number 2019ZDLSF04-07, 2022SF-315]; Shaanxi Administration of Traditional Chinese Medicine Projects [grant number 2022-SLRH-YQ-003, 2021-PY-003]. 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