Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2019, Article ID 7621929, 45 pages https://doi.org/10.1155/2019/7621929

Review Article Phellodendri Cortex: A Phytochemical, Pharmacological, and Pharmacokinetic Review

YueSun,GeorgeBinhLenon ,andAngelaWeiHongYang

School of Health and Biomedical Sciences, RMIT University, Victoria, Australia

Correspondence should be addressed to George Binh Lenon; [email protected]

Received 18 November 2018; Accepted 5 February 2019; Published 26 March 2019

Guest Editor: Jesus R. R. Amado

Copyright © 2019 Yue Sun et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Phellodendri Cortex (PC) or Huang Bai. According to the scientifc database of Species and Chinese pharmacopeia 2015 edition, PC has two main species which are amurense Rupr (PAR) or “Guan Huang bai” in Chinese and Phellodendron chinense Schneid (PCS) or “Chuan Huang bai” in Chinese. Te crude drugs of PAR and PCS are also called Phellodendri amurensis cortex (PAC) and Phellodendri chinense cortex (PCC), respectively. Te medicinal part of the plant is the dried trunk bark. PC has comprehensive therapeutic efects which include anti-infammatory, antimicrobial, anticancer, hypotensive, antiarrhythmic, antioxidant, and antipyretic agents. Te exact ingredients in PC and its species are not fully summarised. Aim of the Study. Tis study was designed to review and evaluate the pharmacological actions of compounds and to explore the pharmacokinetic knowledge of PC and its species and to also identify the chemical compound(s) with a potential therapeutic efect on atopic dermatitis. Methods. “Huang Bai” and its English, botanical, and pharmaceutical names were used as keywords to perform database search in Encyclopaedia of traditional Chinese Medicines, PubMed, EMBASE, MEDLINE, Science Direct, Scopus, Web of Science, and China Network Knowledge Infrastructure. Te data selection criteria included all the studies that were related to the phytochemical, pharmacological, and pharmacokinetic perspectives of PC and its species or their active constituents. More importantly, the voucher number has been provided to ensure the genuine bark of PC used as the medicinal part in the studies. Results. 140 compounds were summarized from PC and its species: specifcally, 18 compounds from PCC, 44 compounds from PCS, 34 compounds from PAC, and 84 compounds from PAR. Obacunone and obaculactone are probably responsible for antiatopic dermatitis efect. PC and its species possess a broad spectrum of pharmacological actions including anti- infammatory efect, antibacterial efect, antiviral efect, antitumor efect, antigout efect, antiulcer efect, neuroprotective efect, and antiatopic dermatitis efect. PC could widely distribute in plasma, liver, spleen, kidney, and brain. may be responsible for the toxic efect on the susceptible users with hemolytic disease or in the peripartum and neonatal period. Conclusions.Te compounds of the crude bark of PC and its subspecies have showcased a wide range of pharmacological efects. Pharmacological efcacies of PC are supported by its diverse class of , limonoid, phenolic acid, quinic acid, lignan, and favonoid. Obacunone and obaculactone could be the bioactive compounds for atopic dermatitis management. PC and its subspecies are generally safe to use but extra care is required for certain conditions and group of people.

1. Introduction Phellodendron chinense Schneid (PCS) or “Chuan Huang bai” in Chinese. Te crude drugs of PAR and PCS are Phellodendri Cortex (PC) is also known as “Huang bai” in called Phellodendri amurensis cortex (PAC) and Phelloden- Chinese and “Obaku” in Japanese. PC is a plant grown in dri chinense cortex (PCC), respectively. PAR and PCS are China, Korea, Japan, Vietnam, and Far East of Russia. Te naturally grown in the Northeast and Southwest part of earliest record of this plant was on “Shennong’s Classic of China, respectively [2]. According to the latest information Materia Medica” [1]. According to the scientifc database of from “information system of Chinese rare and endangered China Plant Species and Chinese pharmacopeia 2015 edi- ,” PAR is categorized as one of the second degrees of tion, PC has two main species which are Phellodendron endangered plants. PAR and PCS could be interchangeably amurense Rupr (PAR) or “Guan Huang bai” in Chinese and used in clinical application because both species contain 2 Evidence-Based Complementary and Alternative Medicine similar chemical constituents [3]. According to the scientifc reasons for nonpharmacodynamic, nonphytochemistry, and database of China Plant Species and Chinese pharmacopeia nonpharmacological studies. 73 studies ftted the selection 2015 edition, PC is categorized in the family of Phellodendron criteria. Among these articles, 32 studies are about pharmaco- Rupr. Te medicinal part of the plant is the dried trunk bark. dynamics, 38 studies are about phytochemistry, and 3 studies PC had been viewed as one of the 50 fundamental herbs are about pharmacokinetics (Figure 1). in Chinese herbalism. Traditionally, its medicinal part could exert therapeutic efects in various diseases such as meningi- 4. Bioactive Compounds tis, cirrhosis, dysentery, pneumonia, tuberculosis, etc. [4, 5]. Nowadays, PC has comprehensive therapeutic efects which Te crude barks of PC and its species contain , include immune modulation, anti-infammatory, antimicro- isoquinoline alkaloid, limonoids, phenolic acid, quinic acid, bial, antibacterial, anticancer, hypotensive, antiarrhythmic, lignans, and favonoid, and so on. A summary of the bioactive antioxidant, antigastric ulcer, and antipyretic agents, etc. [5]. compounds of the PC and its species reported in the included According to the Clinical Chinese Materia Medica, 2006 studies is presented in Table 1. Molecular formula, molecular edition, PC has a bitter favor and cold nature and can weight, and chemical structure of the major constituted enter the meridian of kidney, bladder, and large intestine. alkaloids of PC, including berberine, palmatine, and jatror- PC could clear heat, dry dampness, drain fre, eliminate rhizine, are listed in Tables 2, 3, 4, and 5. Tey could exert a steam, resolve toxin, and treat sores [6]. PC and its species broad spectrum of pharmacological infuence which contains contain various chemical derivatives. One of the important antimicrobial, anti-infammation, antitumor, antidepressant, ones is alkaloids which contain berberine and jatrorrhizine. and antiulcer efects [47]. Limonoids including limonin and Both compounds were proven to be efective against some obakunone play an important role in the anti-infammatory type of tumours, infections, neurological diseases [7]. To efects of PC [11]. Phenolic acid or phenol carboxylic acids further acquire the knowledge on PC, a systematic review belong to aromatic acid compound substances which are of its phytochemical, pharmacological, and pharmacokinetic characterized by a phenolic ring and an organic carboxylic properties is required. Te aim of this study is to review and acid function [61]. According to the description on Buchler evaluate the pharmacological actions of compounds as well quinine plant in Braunschweig, Germany, quinic acid is a as to explore the pharmacokinetic knowledge of the PC and natural sugary compound which can be found in multiple its species. Te chemical compounds that exert therapeutic plants such as well-known cofee beans and tobacco leaves. efect for atopic dermatitis are also desired. Based on the description on PubChem, lignans afliate a class of dibenzylbutane derivatives which exists in plants 2. Methods andinbodyfuidssuchasbile,serum,urine,etc.Tese compounds have anticancer potential. belongs to Data were searched from the following databases until favonoids which can reduce coronary heart disease accord- May 2018: Encyclopaedia of Traditional Chinese Medicines; ing to PubChem data. Two species of PC, PCS and PAR, PubMed; EMBASE; MEDLINE; ScienceDirect; SCOPUS; can be diferentiated based on the contents of the chemical Web of Science; China Network Knowledge Infrastructure. compounds. Specifcally, the 2005 edition of Chinese Medic- Te keywords used for the literature search included: Huang inal encyclopedia described the PCS’s minimal content of Bai and its English, botanical, and pharmaceutical names. berberine hydrochloride and phellodendron hydrochloride Te selection criteria included process controls of the herbal to be 3.0% and 0.34%, respectively; the PAR’sminimal content substances, reporting reference standards such as authenti- of berberine hydrochloride and palmatine hydrochloride is cation of reference materials and profle chromatograms, and 0.60% and 0.30%, respectively [62]. analytical procedures and validation data. Papers in English or Chinese language are included for this review. Scientifc 5. Pharmacology rigidity was determined by the chemical markers of herbs through the use of strict parameters in testing, quantitative, .. Anti-Inflammatory Effects. Te PAR extract could ef- and qualitative measures of the bioactive components, such as ciently adjust lipopolysaccharide (LPS)-induced release of high-performance liquid chromatography, fngerprint spec- nitric oxide (NO) and inducible nitric oxide sythase (iNOS) trum, correlations diferentiation, and stability evaluation, production in microglia of both BV2 cells and mice. Besides, reference standards, and toxicological assessments. Plant PAR extract could also attenuate the LPS-stimulated release voucher specimens are a guarantee for traceability of the of tumor necrosis factor-� (TNF-�)andinterleukin1� (IL- plant material and data verifcation for other researchers or 1�) from microglia. More importantly, the latter mechanism commercial purposes [60]. Te chemical formulas of the is more signifcant than the previous one in terms of IL- compounds of PC and its species were acquired from selected 1� release. Te inhibition of NO suggested that the extract studies. Chemical structures and molecular weights were of PAR probably could afect NO-induced neuronal cell extracted from ChemDraw professional . death [28]. Another study had also vindicated the anti- infammatory efect of PC extract on ear swelling model 3. Results of mice. Magnoforine and phellodenrine belong to alka- loids isolated from PC that are the efective compounds A total of 125 papers were identifed through the litera- against oxazolone-induced contact-delayed type hypersensi- ture search. Fify-two papers were excluded based on the tivity (DTH) reaction induced by picryl chloride. Another Evidence-Based Complementary and Alternative Medicine 3

125 articles Identification

52 excluded due to irrelevance to 73 included pharmacodynamics, photochemistry, and Screening pharmacokinetic

73 included Eligibility

Pharmacodynamics:

Included Photochemistry: 38 Pharmacokinetic: 3 32

Figure 1: PC study selection fowchart.

mechanism in this study is that PC could reduce myeloper- .. Antimicrobic Effects. For the antibacterial efect, the oxidase (MPO) activity to its utmost by restraining leukocyte study showed both aqueous and ethanol extracts of PAR mobility and/or a secretory activity by phellodendron. In exerted an intermediate antimicrobial efect. Besides, PAR contrast, PC extract exerts no efect on phospholipase A2 extracts had a slightly better efect on gram-positive bacteria (PLA2) activity and less efect in arachidonic acid (AA) than gram-negative one because of diferent sensitivity. Te induced swelling [29]. PC showcased the inhibitory efect most sensitive bacteria is Streptococcus pyogenes [33]. For on the build-up of NO in LPS-stimulated macrophage Raw the bacteria in the oral cavity, PC could have a strong 264.7 cells and inhibited iNOS expression. In contrast, PC has inhibitory efect on Porphyromonas gingivalis; moderate no efect on cyclooxygenase-2 (COX-2) expression in LPS- inhibitory efect on Streptococcus mutans; partial efect on inducedRAW264.7cells[30].PCCandPACcouldnotonly Streptococcus sanguis; no efect on Streptococcus mitis [34]. shrink the size of edema, but also reduce the activity of MPO Propionibacterium acnes which are the culprit for acne and the content of reactive oxygen species (ROS) caused is active to PC which is one of the crude herbs in the by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Tey can clinical trial and the second best herb in terms of antiacne also restrain the levels of TNF-�,Il-1�,IL-6,andCOX- activity in this study [39]; Mycoplasma hominis which causes 2 in mice treated by TPA. Remarkably, there are a num- infections on humans genital tracts and respiratory tracts ber of chemical compounds in these two species of PC is susceptive to PC, and the susceptibility rate is 93% [35]. including berberine, palmatine, and . And Salmonellosis which is responsible for food poisoning is they are viewed as the anti-infammatory active candidates. vulnerable to PC extract because it can lower the IgG levels In addition, they may jointly take efect in this regard [3]. and induce TNF-� expression in RAW264.7 cells [36]. In Te nonalkaloid PAR extract suppressed NO production; case of PAR, berberine could restrain the bacterial adhesion besides, limonin and obakunone signifcantly downregulated of Staphylococcus aureus and intracellular invasion into NO production and iNOS gene expression via an nuclear human gingival fbroblasts [37]. Moreover, berberine could factor-�B(NF-�B)-mediated pathway [11]. PC could reverse attenuate the aminoglycoside resistance of P. aeruginosa, A. the airway infammation by reducing the infltration of xylosoxidans, and B. cepacia in the MexXY-dependent man- infammatory cells and releasing of infammatory media- ner. It also inhibits MexXY- or MexVW-mediated resistance tors into the afected lung and airways. Tis could vindi- of P. aeruginosa mutants, synergistically restrains MexXY- cate its applications on the infectious pulmonary diseases mediated gentamicin resistance in P.aeruginosa mutants, and [31]. enhances the synergistic efect of piperacillin and amikacin in 4 Evidence-Based Complementary and Alternative Medicine PCS PCS PAR PAR PAR PAR PAR PAR PAR PAR PAC PAC PAC PAC (i) PAC (i) PAC (i) PAC (v) PCS (v) PAR (iv) PAR (iv) PAR (iv) PAR (iii) PAC (iii) PAC (iii) PCC Original species (v) PAC and PCS (ii) PCS and PAR (ii) PCS and PAR (ii) PCS and PAR (vi) PAC and PCS [8] [8] [15] [17] [15] [15] [15] [15] [15] [15] [15] [16] [14] [10] (i) [8] (i) [8] (i) [8] (ii) [9] (ii) [9] (ii) [9] (v) [12] (v) [18] (v) [18] (vi) [13] (iv) [12] (iv) [12] (iii) [10] (iii) [10] (iii) [10] References 2 2 2 CE CC N/A (v) N/A (v) N/A (vi) N/A Methods HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS (v) HPLC-DAD-MS (iv) HPLC-DAD-MS (iv) HPLC-DAD-MS UPLC-Q/TOF-HDMS UPLC-ESI-Q-TOF-MS UPLC-ESI-Q-TOF-MS (ii) HPLC-DAD-ESI-MS (ii) HPLC-DAD-ESI-MS (ii) HPLC-DAD-ESI-MS (i) UPLC-ESI-Q-TOF-MS (i) UPLC-ESI-Q-TOF-MS (i) UPLC-ESI-Q-TOF-MS (iii) UPLC-Q/TOF-HDMS (iii) UPLC-Q/TOF-HDMS (iii) UPLC-Q/TOF-HDMS (iv) HPLC-TLC- NMR-EI-MS (iv) [11] Brucine Berberine Palmatine Evodiamine Berberastine Berberrubine Phellodendrine -dehydrosophoramine Tetrahydroberberine Tetrahydropalmatine 7 Chemical compounds Dihydrocyclobuxine-D methyl-8-isoquinolinol methyl-6-isoquinolinol Δ 7,8-dihydroxyrutaecarpine 8,13-dioxo-14-butoxycanadine 4-dimethylamino-4 -isopropylbenzene Bis-[4-(dimethylamino)phenyl]methanone Table 1: Summary of chemical constituents isolated from PC and its diferent species (140 compounds). 3,4-dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy-2- 3,4-dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy-2- Compound derivatives Alkaloid Evidence-Based Complementary and Alternative Medicine 5 PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR (i) PAC (i) PAR (ii) PAC (ii) PCC (iv) PCS (ii) PCC (ii) PCC (iv) PAC (iii) PAR (iii) PAR (iii) PAC PCS and PAR PCS and PAR PCS and PAR Original species (i) PCS and PAR (i) PCS and PAR (i) PCS and PAR (i) PCS and PAR (ii) PCS and PAR [9] [9] [9] [9] [9] [9] [9] [9] [9] [9] [9] [9] [9] [9] [9] [9] [15] [15] [15] [15] [15] [15] [15] [20] [20] [20] [20] (i) [8] (i) [9] (i) [9] (i) [9] (i) [9] (ii) [9] (i) [15] (ii) [10] (ii) [10] (ii) [10] (ii) [10] (iv) [19] (iv) [19] (iii) [12] (iii) [12] (iii) [19] References 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 CC CC CC CC (iv) N/A (iv) N/A (iii) N/A Methods HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS (iii) HPLC-DAD-MS (iii) HPLC-DAD-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS (i) HPLC-ESI-MS/MS (i) HPLC-DAD-ESI-MS (i) HPLC-DAD-ESI-MS (i) HPLC-DAD-ESI-MS (i) HPLC-DAD-ESI-MS (ii) HPLC-DAD-ESI-MS (i) UPLC-ESI-Q-TOF-MS (ii) UPLC-Q/TOF-HDMS (ii) UPLC-Q/TOF-HDMS (ii) UPLC-Q/TOF-HDMS (ii) UPLC-Q/TOF-HDMS Table 1: Continued. -D-glucopyranoside � ,1-b]isoquinolin-7-ium-3-ol -Fagarine Lotusine [2 Litcubine )-Oblongine Candicine » Menisperine − Epiberberine Magnoforine Oxypalmatine Columbamine ( Xanthoplanine Canthin-6-one Magnocurarine N-methylphoebine Isomer-of-berberine Hydroxyl-palmatine N-methylfindersine Tetrahydroreticuline Isomer-of-palmatine Tetrahydropalmatine 13-hydroxypalmatine 11-hydroxylpalmatine Chemical compounds (+) N-methylcorydine Tetrahydrojatrorrhizine Isomer-of-magnoforine 13-methoxyjatrorrhizine Dihydroxyl-jatrorrhizine N-methyl Tetrahydropalmatine 4-methoxy-N-methyl-2-quinolone N-methylhigenamine-7-O-glucopyranoside 7-hydroxy-8-methoxydedihydrorutaecarpine N-methylhigenamine-7-O- Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6- dihydroisoquinolino Compound derivatives 6 Evidence-Based Complementary and Alternative Medicine PAR PAR PAR PAR PAR PAR PAR PAR PCC PCC PCC PCC Original species [21] [21] [15] [15] [15] [21] [21] [15] [10] [10] [10] [10] References Methods HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS UPLC-Q/TOF-HDMS UPLC-Q/TOF-HDMS UPLC-Q/TOF-HDMS UPLC-Q/TOF-HDMS Table 1: Continued. g ] , quinolizinium ] de [ a,g [ Pteleine Chilenine Rutecarpine quinolinium Tembetarine Skimmianine Dasycarpamin 4H-dibenzo (-)-(R)-platydesmin Noroxyhydrastinine Chemical compounds Tetramethyl-O-scutellarin -hydroxybutenolide derivatives II » methyl-6H-dibenzo 5,8,13,13a-Tetrahydro-2,9,10,11-tetrahydroxy-3-methoxy-7- (6aS)-1,2,10,11-tetramethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro- Compound derivatives Evidence-Based Complementary and Alternative Medicine 7 PCS PAR PAR PAR PAR PAR PAR PAR PAR PAC PAC PAC PAC PAC PCC PCC (i) PCS (i) PAR (i) PAR (i) PAC (v) PAC (v) PAC (ii) PAR (ii) PCC (ii) PCC (iv) PAC (iv) PAR (iii) PAC (iii) PCC Original species [8] [9] [9] [8] [18] [18] [15] [18] [15] [10] [15] [19] [19] [10] [20] [20] [20] (i) [8] (i) [9] (iv) [9] (i) [20] (v) [18] (v) [18] (ii) [10] (ii) [10] (iii) [11] (ii) [20] (iii) [10] References 2 2 2 2 CC N/A N/A N/A N/A N/A (i) CC HPLC HPLC EI-MS (ii) CC (v) N/A (v) N/A Methods HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-ESI-MS/MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS UPLC-Q/TOF-HDMS UPLC-Q/TOF-HDMS UPLC-ESI-Q-TOF-MS UPLC-ESI-Q-TOF-MS (iii) HPLC-TLC- NMR- (i) HPLC-DAD-ESI-MS (i) UPLC-ESI-Q-TOF-MS (ii) UPLC-Q/TOF-HDMS (ii) UPLC-Q/TOF-HDMS (iv) HPLC-DAD-ESI-MS (iii) UPLC-Q/TOF-HDMS (iv) HPLC-TLC- NMR- EI-MS (iv) [11] Table 1: Continued. Niloticin Herculin Rutaevin Coniferin Piscidinol A Armepavine Kihadanin B Vanilloloside -hydroxylimonin Oxyberberine Oxypalmatine 8-oxoberberine 8-oxopalmatine Niloticin acetate � 8-oxoepiberberine 12 Chemical compounds Demethyleneberberine Obaculactone or limonin Derivative of obaculactone Obacunone or Obacunoic acid N-methyltetrahydrocolumbamine Compound derivatives Isoquinoline alkaloid Limonoid N-acyl amines 8 Evidence-Based Complementary and Alternative Medicine PCS PCS PCS PCS PCS PCS PCS PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAR PAC PAC PAC PAC PAC PAC PAC PAC PAC PAC PCC (ii) PAC (ii) PAC (ii) PAC (ii) PCC (iv) PAR (iii) PAR PCS and PAR PCS and PAR Original species (i) PCS and PAR (i) PCS and PAR (i) PCS and PAR (i) PCS and PAR [9] [9] [9] [9] [9] [4] [4] [4] [11] [18] [18] [18] [13] [18] [18] [17] [10] [10] [22] [22] [22] [25] [27] [26] [26] [26] [26] [26] [26] [26] [26] [24] (i) [9] (i) [9] (i) [9] (i) [9] (ii) [10] (ii) [10] (ii) [10] (iv) [12] (iii) [23] References 2 2 2 2 2 2 2 2 2 CC CC CC CC UV UV UV UV UV UV UV UV N/A N/A N/A N/A N/A N/A N/A NMR NMR HPLC HPLC HPLC Methods (iii) HPLC (iv) HPLC-DAD-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS UPLC-Q/TOF-HDMS UPLC-Q/TOF-HDMS (i) HPLC-DAD-ESI-MS (i) HPLC-DAD-ESI-MS (i) HPLC-DAD-ESI-MS (i) HPLC-DAD-ESI-MS (ii) UPLC-Q/TOF-HDMS (ii) UPLC-Q/TOF-HDMS (ii) UPLC-Q/TOF-HDMS HPLC-TLC- NMR- EI-MS (ii) HPLC-TLC- NMR- EI-MS (ii) [11] Table 1: Continued. -glucoside O -D-glucopyranoside � -feruloylquinate O -Sitosterol N/A [18] PAC Phellatin Phellavin Quercetin D-glucose Icariside-1 Phelloside Amurensin Ferulic acid � Quinic acid Noricariside Phellamurin Sanleng acid Phellamuretin Isovaleric acid Methyl ferulate Chlorogenic acid (+/-)-lyoniresinol Phellodendroside (-)-Syringaresinol -anhydronoricaritin Dihydrophelloside Protocatechuic acid � Neo-chlorogenic acid Chemical compounds 7-Dehydrostigmasterol 3-O-feruloylquinic acid 5-O-feruloylquinic acid 4-O-feruloylquinic acid Cafeic Acid Methyl Ester Methyl 3- Methyl 5-O-feruloylquinate -dimethoxylariciresinol-4-  3-Feruoyl-4-cafeoylquinic acid 3-O-feruloylquinic acid glucoside Syringaresinol di-O- (+/-)-5,5 3-acetyl-3,4-dihydro-5,6-dimethoxy-1H-2-benzopyran-1-one Compound derivatives Phenolic acid Quinic acid Hydroxycinnamic acid Phytosterol Lignan Stigmastane Coumarin Evidence-Based Complementary and Alternative Medicine 9 PC PCS PCS PCS PCS PCS PCS PCS PCS PCS PCS PCS PCS PCS PAR PAC PAC PAC PCC PCS and PAR PCS and PAR Original species [5] [9] [9] [4] [4] [4] [4] [4] [10] [22] [22] [25] [22] [22] [25] [22] [22] [22] [25] [22] [24] References ry 2 2 CC CC CC CC CC NMR NMR NMR NMR HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC HPLC Methods HPLC-DAD-ESI-MS HPLC-DAD-ESI-MS UPLC-Q/TOF-HDMS Table 1: Continued. -D-glucoside � -D-apiofuranosyl � -D-glucopyranoside � Vanillin Syringin -D-glucopyranoside Tachioside Salidroside Daucosterol � Phellolactone N-butyl Ferulate Methyl syringate Amurenamide A Amurenlactone A N-propyl paraben (6R,7aR)-epiloliolide Chemical compounds (6S)-dehydrovomifoliol 4-hydroxybenzaldehyde 4-hydroxybenzyl alcohol (1–6)-O- Sinapyl aldehyde-4-O-beta-D-glucopyranoside 3,4,5-Trimetoxyphenol O- 2-(p-hydroxyphenyl) -ethanol-1-O- 2-(p-hydroxyphenyl)-ethanol-1-O- 2-methoxy-4-(2-propenyl)phenyl-beta-D-glucopyranoside 3, 5-dihydroxybenzoicacid-O-xylopyranosyl-glucopyranoside Compound derivatives Monosaccharide Paraben Phenolic lactone Ferulate Hydroxybenzaldehyde Phenolic aldehyde Glycoside Phenolic glycoside Glucoside Phenol Dehydrovomifoliol PAC: phellodendri amurensis cortex PCS: phellodendron chinense schneid PAR: rupr. PCC: phellodendri Chinensis cortex UPLC-ESI-Q-TOF-MS: ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-fight mass spectromet CC: column chromatography CE: capillary electrophoresis HPLC/MSD: high-performance liquid chromatography coupled with massUPLC–Qthe spectrometric -TOF-MS: ultra-performance detection liquid chromatography with quadrupole TOF-MS HPLC– ESI-MS2: high-performance liquid chromatography with electrosprayUPLC-Q/TOF-HDMS: ionization ultra-performance mass liquid high-defnition spectrometry chromatography-quadrupole/time-of-fight mass coupled spectrometry with photodiodeUV: array UV detection detection EI-MS: Electron ionization mass spectrometry NMR: Nuclear magnetic resonance TLC: Tin-layer chromatography HPLC-DAD-MS: high-performance liquid chromatography coupled with diode array detection and mass spectrometry 10 Evidence-Based Complementary and Alternative Medicine 3 OH 3 O H- CH CH O + + N N O O + N + N N H O + O O Palmatine H H N Oblongine Magnoflorine O dibenzo[ de,g ]quinolin-6-ium OH O O O O O HO HO O CO HO 3 MeO MeO H O Chemical structures O O O O O 11-hydroxy-1,2,10-trimethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4 5,6,7-trimethoxy-2-(4-methoxyphenyl)chromen-4-one O 4,7,8-trimethoxy-3-[(E)-3-methylbut-1-enyl]-1H-quinolin-2-one (6aS)-1,2,10,11-tetramethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4H-dibenzo[de, g] (6aS)-1,2,10,11-tetramethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4H-dibenzo[de, quinolinium weight Molecular 352.41 g/mol 342.41 g/mol 314.40 g/mol 370.47 g/mol 342.35 g/mol 303.36 g/mol 356.44 g/mol + + + + 4 4 4 4 3 4 6 O NO NO NO NO NO NO 18 28 21 22 24 24 26 H H H H H H H 19 formula 22 17 21 20 19 21 C Molecular C C C C C )-Oblongine C Palmatine Compound Menisperine quinolinium − Magnoforine Dasycarpamin ( Tetramethyl-O-scutellarin tetrahydro-4H-dibenzo[de, g] Table 2: Molecular formula, molecular weight and chemical structures of compounds derived from PCC species (18 compounds). (6aS)-1,2,10,11-tetramethoxy-6,6-dimethyl-5,6,6a,7- Compound derivatives Alkaloid Evidence-Based Complementary and Alternative Medicine 11 O O O OH O OH O O O O O O O O O O 3 HO H O O CH OH O O O + N H limonin Obacunone Rutaevin H Piscidinol A Piscidinol Niloticin acetate acetate Niloticin H O H O O H H H O O O O O O Chemical structures H O O O HO N/A a ]isoquinolin-7-ium 2-hydroxy-3,9,10-trimethoxy-7-methyl-5,6,7,8,13,13a-hexahydroisoquinolino[3,2- weight Molecular 474.73 g/mol 470.52 g/mol 498.75 g/mol 486.52 g/mol 356.44 g/mol 454.519 g/mol + 4 4 8 7 4 9 O O O O O Table 2: Continued. NO 50 30 30 50 30 26 H H H H H H 32 26 26 30 26 formula 21 C C C C C Molecular C Rutaevin Compound Piscidinol A Niloticin acetate Obaculactone or limonin Derivative of obaculactone Obacunone or Obacunoic acid -hydroxybutenolide derivatives II N/A N–methyltetrahydrocolumbamine » Compound derivatives Limonoid 12 Evidence-Based Complementary and Alternative Medicine OH O OH OH abs OH abs abs abs 6)glu 3 3 OCH OCH O HO O OAPI(1 OAPI(1 O C 2 3-O-feruloylquinic acid glucoside 3-O-feruloylquinic 3 HOH OCH O OH (+/-)-5,5'-dimethoxylariciresinol-4-O-glucoside CO 3 OCIG H O O Chemical structures HO HO OH HO HO 2-(p-hydroxyphenyl)-ethanol-1-O-beta-D-apiofuranosyl (1-6)-O-beta-D-glucopyranoside (1-6)-O-beta-D-glucopyranoside 2-(p-hydroxyphenyl)-ethanol-1-O-beta-D-apiofuranosyl weight Molecular 582.6 g/mol 532.45 g/mol 15 13 O136.19g/mol O O Table 2: Continued. 12 28 38 H H H 9 22 28 formula Molecular C C -glucoside O -D-glucoside C � Compound -dimethoxylariciresinol-4-  3-O-feruloylquinic acid glucoside (+/-)-5,5 Compound derivatives Phenolic acid 2-(p-hydroxyphenyl) -ethanol-1-O- Quinic acid Lignan Evidence-Based Complementary and Alternative Medicine 13 3 3 OH O O O OCH OCH O H O O OH 3 3 O H O + N CH CH OH 3 3 O CH CH + H N + + + N N N N + + N H O N N dione N ium H Brucine Berberine Palmatine Jatrorrhizine O g ]isoquinolino[3,2- a ]isoquinoline-8,13- H -[1,3]dioxolo[4,5- Magnoflorine Phellodendrine CO H 2 OH O tetrahydroisoquinolin-2-ium CH O 2 O O HO HO CH 2 H O CO CH O O 3 - 3 O H HO CO H 3 O O O H O Chemical structures HO ( S )-8-hydroxy-1-(4-hydroxybenzyl)-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-2- ( S )-6-hydroxy-1-(4-hydroxybenzyl)-7-methoxy-2,2-dimethyl-1,2,3,4- 13a-butoxy-9,10-dimethoxy-5,13a-dihydro-6 337.38 g/mol 352.41 g/mol 342.41 g/mol 342.41 g/mol 314.40 g/mol 314.40 g/mol 336.37 g/mol 439.46 g/mol 394.47 g/mol 4 + + + + + + 7 4 4 4 4 4 3 3 O 2 NO NO N NO NO NO NO NO NO 25 19 26 18 22 24 24 24 24 H H H H H H H H H 24 20 23 20 21 20 20 19 19 C C C C C C C C Molecular formula Molecular weight Brucine Lotusine Berberine )-Oblongine C Palmatine Compound − Magnoforine ( Phellodendrine 8,13-dioxo-14-butoxycanadine Table 3: Molecular formula, molecular weight and chemical structures of compounds derived from PCS species (44 compounds). Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6- dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol Compound derivatives Alkaloid 14 Evidence-Based Complementary and Alternative Medicine OH 3 O OH O OH OH OH O OH O OH abs OCH OH 3 OH 3 CH CH OH O OH abs O + N OH HO abs abs OH OH HO H O O O N HO H O OH + N H -isoquinolino[3,2- a ]isoquinolin-9-ol O O , g ]quinolin-6-ium OH OH de OH O H H HO Piscidinol A Piscidinol O 1-carboxylic acid 1-carboxylic Niloticin acetate acetate Niloticin H dibenzo[ Chlorogenic Acid Acid Chlorogenic O Neochlorogenic Acid Acid Neochlorogenic a ]isoquinolin-7-ium O 3-O-Feruloylquinic acid 3-O-Feruloylquinic O H CO HO 3 MeO MeO H HO O H - 11-hydroxy-1,2,10-trimethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4 CO CO O 3 3 ( E )-1,3,5-trihydroxy-4-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)cyclohexane- 2-hydroxy-3,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2- H H Chemical structures O HO HO HO O O HO 2,3,10-trimethoxy-5,8,13,13a-tetrahydro-6 N/A 341.41 g/mol 354.31 g/mol 354.31 g/mol 474.73 g/mol 338.38 g/mol 498.75 g/mol 356.44 g/mol 368.34 g/mol 368.34 g/mol + + 4 4 4 4 4 9 9 9 9 O O O O O O NO NO NO 50 50 18 18 20 20 23 26 20 H H H H H H H H H 32 30 16 16 17 17 20 21 20 C C C C C C C C C Molecular formula Molecular weight Table 3: Continued. Compound Piscidinol A Menisperine Columbamine Niloticin acetate Chlorogenic acid Neo-chlorogenic acid 3-O-feruloylquinic acid Tetrahydrojatrorrhizine 4-O-feruloylquinic acid Isomer-of-magnoforine Compound derivatives Quinic acid Evidence-Based Complementary and Alternative Medicine 15 OH OH OH O OH 3 3 OH OH OH HO O OMe 3 OCH OCH c ]furan-l-yl)-2,6- H ,3 -furo[3,4- O O S ,3 R ,4 ,5 ,6 )-3,4,5-trihydroxy-6- OCH O OH O O OMe HO OH O H O H -pyran-2,3,4,5-tetraol O COOH OH O 3 O Ferulic acid Ferulic carboxylic acid carboxylic C OCH 2 3 3,4-dihydroxybenzoic acid 3,4-dihydroxybenzoic Caffeic Acid Methyl Ester HOH OCH H (+/-)-5,5'-dimethoxylariciresinol-4-O-glucoside OMe OH O HO HO H -pyran-2-yl)oxy)phenyl)tetrahydro-1 HO Chemical structures O CO OH HO 3 OCIG )-3-(4-hydroxy-3-methoxyphenyl)acrylate ( E )-3-(4-hydroxy-3-methoxyphenyl)acrylate methyl H O MeO dimethoxyphenoxy)tetrahydro-2 O OH (1 R ,3 ,4 S ,5 )-1,3,4-trihydroxy-5-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)cyclohexane-1- HO HO (2 R ,3 ,4 ,5 S ,6 )-6-(4-((1 ,3a ,6a )-4-(3,5-dimethoxy-4-(((2 (hydroxymethyl)tetrahydro-2 582.6 g/mol 154.12 g/mol 194.19 g/mol 194.19 g/mol 208.21 g/mol 728.70 g/mol 368.34 g/mol 9 4 4 4 13 18 4 O O O O O O O 20 10 10 12 6 38 44 H H H H H H H 7 17 10 10 11 28 33 C C C C C C Molecular formula Molecular weight Table 3: Continued. -glucoside O -D-glucopyranoside C � Compound Ferulic acid Methyl ferulate Protocatechuic acid 5-O-feruloylquinic acid Cafeic Acid Methyl Ester -dimethoxylariciresinol-4-  Syringaresinol di-O- (+/-)-5,5 Compound derivatives Hydroxycinnamic acid Phenolic acid Lignan 16 Evidence-Based Complementary and Alternative Medicine E )-3-(4-hydroxy-3- O 3 3 O CH 2 OH O O OH OCH CH 3 2 O CH O 2 OCH CH CO O 3 OH H O O 3 OH H O H OH O c ]furan-1,4-diyl)bis(2,6-dimethoxyphenol) O O O O 3 O O CHO OH methoxybenzoate OCH 3 H 3 H ,3 -furo[3,4- 3 OCH methoxyphenyl)acrylate OCH -hept-1-en-1-yl)-1-hydroxy-2-methoxybenzene OCH 6 propyl 4-hydroxybenzoate 4-hydroxybenzoate propyl 3  OCH CO 3 3-acetyl-5,6-dimethoxyisochroman-1-one HO H CO 3 Chemical structures H OH )-4-hydroxy-3-methoxy-5-oxotetrahydrofuran-2-yl)ethyl ( S ,3 ,4 R )-4-hydroxy-3-methoxy-5-oxotetrahydrofuran-2-yl)ethyl HO OH OH )-3,4-dihydroxy-5-oxotetrahydrofuran-3-yl)methyl 4-hydroxy-3- ((3 R ,4 )-3,4-dihydroxy-5-oxotetrahydrofuran-3-yl)methyl 4-hydroxybenzaldehyde compound with dihydrogen (1:1) dihydrogen with compound 4-hydroxybenzaldehyde ( E )-4-(3,7-dioxo-7 4,4'-((1 R ,3a S ,4 ,6a )-tetrahydro-1 ( R )-2-hydroxy-2-((2 124.14 g/mol 180.20 g/mol 418.44 g/mol 298.25 g/mol 250.25 g/mol 250.29 g/mol 368.34 g/mol 8 5 3 8 4 9 2 O O O O O O O 26 14 12 14 18 20 8 H H H H H H H 7 22 13 10 13 14 17 C C C C C C C Molecular formula Molecular weight Table 3: Continued. 1-one Compound Phellolactone N-butyl Ferulate (-)-syringaresinol Amurenlactone A N-propyl paraben 4-hydroxybenzaldehyde 3-acetyl-3,4-dihydro-5,6-dimethoxy-1H-2-benzopyran- Compound derivatives Coumarin Paraben Phenolic lactone Ferulate Hydroxybenzaldehyde Evidence-Based Complementary and Alternative Medicine 17 6)glu 3 OAPI(1 OAPI(1 3 OCH O OXyI-GIc OH OCH 3 OCH O-glc O OH OH CHO CO O OH 3 H HOOC 4-hydroxy-3-methoxybenzaldehyde OH Chemical structures 3, 5-dihydroxybenzoicacid-O-xylopyranosyl-glucopyranoside 3, 5-dihydroxybenzoicacid-O-xylopyranosyl-glucopyranoside 3,4,5-Trimethoxyphenol O-ß-D-glucopyranoside O-ß-D-glucopyranoside 3,4,5-Trimethoxyphenol HO 2-methoxy-4-(2-propenyl)phenyl-beta-D-glucopyranoside HO 2-(p-hydroxyphenyl)-ethanol-1-O-beta-D-apiofuranosyl (1-6)-O-beta-D-glucopyranoside (1-6)-O-beta-D-glucopyranoside 2-(p-hydroxyphenyl)-ethanol-1-O-beta-D-apiofuranosyl l o m / g 9 1 . 6 3 167.18 g/mol 152.15 g/mol 152.15 g/mol 326.35 g/mol 7 3 3 3 O1 O O O O 12 8 22 8 11 H H H H H 9 8 8 9 16 C C C C C Molecular formula Molecular weight Table 3: Continued. -D-apiofuranosyl � -D-glucopyranoside � Vanillin -D-glucopyranoside Compound � glucopyranoside glucopyranoside (1–6)-O- 2-methoxy-4-(2-propenyl)phenyl-beta-D- 3, 5-dihydroxybenzoicacid-O-xylopyranosyl- 3,4,5-trimetoxyphenol O- 2-(p-hydroxyphenyl)-ethanol-1-O- Compound derivatives Phenolic aldehyde Glycoside 18 Evidence-Based Complementary and Alternative Medicine H -pyran-3,4,5-triol H -pyran- O O O 3 OH O CH O O OH O OH 3 C OH O OH 3 3 CH H OH C CH OH 3 OH H O OH O 2,3,4,5-tetraol O OH C 3 H O O 4-(hydroxymethyl)phenol OH C HO 3 OH H HO HO methyl 4-hydroxy-3,5-dimethoxybenzoate methyl Chemical structures ( S , E )-4-hydroxy-3,5,5-trimethyl-4-(3-oxobut-1-en-1-yl)cyclohex-2-en-1-one (2 S ,3 ,4 ,5 R ,6 )-6-(4-hydroxy-3-methoxyphenoxy)tetrahydro-2 H )-one (6 S ,7a )-6-hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydrobenzofuran-2(4 (2 R ,3 S ,4 ,5 ,6 )-2-(hydroxymethyl)-6-(4-hydroxyphenethoxy)tetrahydro-2 124.14 g/mol 300.31 g/mol 212.20 g/mol 196.25 g/mol 288.25 g/mol 222.28 g/mol 8 7 5 3 3 2 O O O O O O 16 20 8 12 18 16 H H H H H H 7 12 14 10 13 11 C C C C C C Molecular formula Molecular weight Table 3: Continued. Tachioside Salidroside Compound Methyl Syringate (6R,7aR)-epiloliolide (6S)-dehydrovomifoliol 4-Hydroxybenzyl alcohol Compound derivatives Phenolic glycoside Glucoside Phenol Dehydrovomifoliol Evidence-Based Complementary and Alternative Medicine 19 O O O O H O O O O O O O O O OH N O + + + + N H H N N N N + + N N H Palmatine Berberine Berberastine Berberrubine Jatrorrhizine N Phellodendrine Tetrahydropalmatine O O O O Delta-7-dehydrosophoramine O H O O O O O - O O O HO Chemical structures O l o m / g 2 3 . 2 4 337.38 g/mol 352.41 g/mol 352.37 g/mol 342.41 g/mol 336.37 g/mol 355.43 g/mol 322.34 g/mol + + + + + 4 4 4 4 5 4 4 O2 2 N NO NO NO NO NO NO NO 18 25 19 18 16 18 22 24 H H H H H H H H 15 21 20 20 19 20 21 20 C C C C C C C C Molecular formula Molecular weight Berberine Palmatine Compound Berberastine Berberrubine Phellodendrine -Dehydrosophoramine Tetrahydropalmatine 7 Δ Table 4: Molecular formula, molecular weight and chemical structures of compounds derived from PAC species (34 compounds). Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6- dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol Compound derivatives Alkaloid 20 Evidence-Based Complementary and Alternative Medicine H - OH N H O O O O O O 3 OH O 3 3 3 OH OH CH O CH O O CH CH O O + abs N abs + O N O abs abs HO O O N HO O O abs H abs + H H N limonin de,g ]quinolin-6-ium Niloticin Armepavine H Kihadanin B Kihadanin Obacunone H abs abs H O Demethyleneberberine H dibenzo[ tetrahydroisoquinolin-2-ium CO HO 3 O MeO MeO O H O O O O O O CO HO 3 O H Chemical structures O 11-hydroxy-1,2,10-trimethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4 ( S )-6-hydroxy-1-(4-hydroxybenzyl)-7-methoxy-2,2-dimethyl-1,2,3,4- O (2E,8E)-N-(2-methylpropyl)dodeca-2,8-dienamide 251.41 g/mol 313.40 g/mol 314.40 g/mol 456.71 g/mol 324.36 g/mol 470.52 g/mol 454.52 g/mol 356.44 g/mol 486.52 g/mol + + + 3 3 4 4 9 3 8 7 O O O O NO NO NO NO NO 30 48 30 30 29 23 24 26 18 H H H H H H H H H 26 30 26 26 16 19 Table 4: Continued. 19 21 19 C C C C C C C C Molecular formula Molecular weight Lotusine Niloticin Herculin Compound Armepavine C Menisperine Kihadanin B Demethyleneberberine Obaculactone or limonin Obacunone or Obacunoic acid Compound derivatives Isoquinoline alkaloid Limonoid N-acyl amines Evidence-Based Complementary and Alternative Medicine 21 OH O OH OH OH OH OH O OH OH abs OH OH O OH abs OH H abs abs O O OH OH OH O HO O H OH OH OH OH Ferulic Acid Ferulic O O Quercetin Amurensin O H Quinic acid OH O HO Chlorogenic acid Chlorogenic Beta-Sitosterol OH O OH H O 3-O-feruloylquinic acid 3-O-feruloylquinic OH HO OH HO )-6,9,10-trihydroxyoctadec-7-enoic acid ( E )-6,9,10-trihydroxyoctadec-7-enoic O O OH O HO HO Chemical structures HO O HO HO HO HO l o m / g 2 7 . 4 1 192.17 g/mol 194.19 g/mol 354.31 g/mol 534.51 g/mol 330.47 g/mol 302.24g/mol 368.34 g/mol 4 9 9 5 7 6 12 O4 O O O O O O O 50 10 20 18 34 10 12 30 H H H H H H H H 29 7 10 17 16 18 15 26 C C Table 4: Continued. C C C C C C Molecular formula Molecular weight -sitosterol Quercetin Amurensin � Compound Ferulic acid Quinic acid Sanleng acid Chlorogenic acid 5-O-feruloyl quinic acid 3-O-feruloyl quinic acid or Compound derivatives Phenolic acid Quinic acid Phytosterol Flavonoid 22 Evidence-Based Complementary and Alternative Medicine OH OH OH OH H - OH OH OH H OH OH OH OH OH O H O O H -chromen-4-one O O O O O O O O S ,3 R ,4 ,5 ,6 )-3,4,5-trihydroxy-6- OH H OH Phellavin OH OH OH OH OH a ]phenanthren-3-ol Phellamurin OH H -pyran-2-yl)oxy)butyl)-4 O O H O OH O 3 cyclopenta[ CH H O O OH O O (hydroxymethyl)oxan-2-yl]oxychromen-4-one 3 O OH OH O OH CH OH (hydroxymethyl)oxan-2-yl]oxy-2,3,9,10-tetrahydropyrano[2,3-h]chromen-4-one S ,13 R ,14 ,17 )-17-((2 ,5 )-5-ethyl-6-methylheptan-2-yl)-10,13- (hydroxymethyl)tetrahydro-2 HO 5-hydroxy-2-(4-hydroxyphenyl)-8,8-dimethyl-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- OH Chemical structures C 2 dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1 OH HO HO 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-8-(3-methyl-3-(((2 HOH OH OH OH HO (3 S ,5 ,9 R ,10 HO OH 3,5-dihydroxy-6-(3-hydroxy-3-methylbutyl)-2-(4-hydroxyphenyl)-7-[(2S,4S,5S)-3,4,5-trihydroxy-6- l o m / g 2 7 . 4 1 518.52 g/mol 518.52 g/mol 534.51 g/mol 534.51 g/mol 536.53 g/mol 11 12 12 12 11 O4 O O O O O 50 30 30 32 30 30 H H H H H H 29 26 26 26 26 26 C Table 4: Continued. C C C C C Molecular formula Molecular weight Phellatin Phellavin Compound Noricariside Phellamurin Phellodendroside 7-dehydrostigmasterol Compound derivatives Rutaceae Stigmastane Evidence-Based Complementary and Alternative Medicine 23 3 OCH OH H H H - H H H O H OH H H H H -pyran-3,4,5-triol OH O H E )-3-hydroxyprop-1-en-1-yl)-2,6- O OH O H O H O OH O O OH H OH HO HO H -pyran-2,3,4,5-tetraol a ]phenanthren-3-yl)oxy)tetrahydro-2 HO H OH 3 HO OCH cyclopenta[ yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1 H dimethoxyphenoxy)tetrahydro-2 H OH Chemical structures (2 S ,3 ,4 ,5 R ,6 )-6-(((3 ,8 ,9 ,10 ,13 ,14S,17 )-17-((2 )-5-ethyl-6-methylheptan-2- O (2 R ,3 S ,4 ,5 ,6 )-2-(hydroxymethyl)-6-(4-(( 2 NH 6-amino-2,3,5-trihydroxy-4-methoxy-6-oxohexyl 3-(4-hydroxy-3-methoxyphenyl)propanoate 3-(4-hydroxy-3-methoxyphenyl)propanoate 6-amino-2,3,5-trihydroxy-4-methoxy-6-oxohexyl 8.9g/mol 387.39 372.37 g/mol 562.83 g/mol 9 9 6 O O NO 24 58 25 H H H 17 34 17 Table 4: Continued. C C C Molecular formula Molecular weight Syringin Compound Daucosterol Amurenamide A Compound derivatives Monosaccharide Ferulate 24 Evidence-Based Complementary and Alternative Medicine H ,12 - H - 3 3 CH CH 3 3 3 CH O CH O O CH N H )-one b ]quinazolin-5(7 H )-one b ]quinazolin-5(7 OH O N H O + O N O 3 3 C N 3 + N H N N CH h ]isoquinolino[2,1- b ]isoquinolin-14-one CH N N OH C 3 O H O Berberine , g ]quinolin-6-ium H N N H O H -[1,3]dioxolo[4,5- 3 O O OH HO CH dibenzo[ de 3 O O bis(4-(dimethylamino)phenyl)methanone 3 O CH + H N N CH Chemical structures e ]phenanthren-4-ol a ]cyclopropa[ cyclopenta[ HN N , -dimethylbenzenaminium 4-(4-isopropylbenzoyl)- C 3 C H 3 H C 3 H 1,11-dihydroxy-2,10-dimethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4 8,9-dimethoxy-11,12-dihydro-14 (7 R )-7,8-dihydroxy-8,13-dihydroindolo[2',3':3,4]pyrido[2,1- 14-methyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1- 2a,5a,8-trimethyl-9-(methylamino)-3-(1-(methylamino)ethyl)tetradecahydro-1 l l o o m m / / g g 6 7 3 3 . . 3 8 0 6 319.32 g/mol 351.36 g/mol 342.41 g/mol 336.37 g/mol 268.38 g/mol 388.64 g/mol 3 + + 5 + 4 4 O2 O O3 O 2 2 3 3 N N NO N NO N NO NO 20 44 17 17 22 13 18 24 H H H H H H H H 20 17 25 19 18 18 20 20 C C C C C C C C Molecular formula Molecular weight Berberine Compound Evodiamine Dihydrocyclobuxine-D 2-methyl-8-isoquinolinol 2-methyl-6-isoquinolinol 7,8-Dihydroxyrutaecarpine Table 5: Molecular formula, molecular weight and chemical structures of compounds derived from PAR species (84 compounds). 4-Dimethylamino-4 -isopropylbenzene Bis-[4-(dimethylamino)phenyl]methanone 3,4-Dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy- 3,4-Dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy- Compound derivatives Alkaloid Evidence-Based Complementary and Alternative Medicine 25 OH O O OH O O NH 3 O O OH O b ]isoquinoline-7,12(5 H ,11b )- CH b ]quinolin-2-yl)propan-2-ol O 3 OH + N OCH N O + + H N N g ]isoindolo[2,1- N dione 3 Palmatine O ethane Phellodendrine OCH N O H O O O O CO 3 H O Chemical structures O HO CO HO 3 b ]quinoline 4,6-dimethoxy-4a,8a-dihydrofuro[2,3- H g ]isoquinolin-5(6 H )-one 7,8-dihydro-[1,3]dioxolo[4,5- 11b-hydroxy-8,9-dimethoxy-[1,3]dioxolo[4,5- 2-((2 R )-4-methoxy-2,3,4a,8a-tetrahydrofuro[2,3- 7-hydroxy-1-(4-hydroxybenzyl)-6-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-ium 191.19 g/mol 231.25 g/mol 352.41 g/mol 261.32 g/mol 314.40 g/mol 369.33 g/mol 342.41 g/mol + + + 3 3 7 3 4 4 3 NO NO NO NO NO NO NO 9 13 19 15 22 24 24 H H H H Table 5: Continued. H H H 10 13 15 19 21 20 19 C C C C C C C Molecular formula Molecular weight Pteleine Chilenine Palmatine Compound Phellodendrine Magnocurarine (-)-(R)-platydesmin Noroxyhydrastinine Compound derivatives 26 Evidence-Based Complementary and Alternative Medicine 3 3 OCH OCH O O N O + O N H 3 3 CH 3 CH + 3 + + N N N CH OCH N 3 N O N CH OH O Jatrorrhizine Magnoflorine Gamma-Fagarine Canthin-6-one CO 3 H O O O HO HO 4-Methoxy-N-methyl-2-quinolone O O - N , -trimethylmethanaminium 1-(4-hydroxyphenyl)- Chemical structures HO CO 3 H a ]isoquinolin-7-ium 3-hydroxy-2,9,10,13-tetramethoxy-5,6-dihydroisoquinolino[3,2- 189.21 g/mol 337.38 g/mol 342.41 g/mol 368.41 g/mol 166.24 g/mol 229.24 g/mol 220.23 g/mol + + + 3 2 + 4 4 5 O 2 NO NO NO N NO NO NO 8 11 11 16 24 19 22 H H H H Table 5: Continued. H H H 14 13 11 10 20 20 21 C C C C C C Molecular formula Molecular weight -Fagarine C Candicine » Compound Magnoforine Canthin-6-one 13-Methoxyjatrorrhizine 4-Methoxy-N-methyl-2-quinolone Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6- dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol Compound derivatives Evidence-Based Complementary and Alternative Medicine 27 OH OH 3 N CH OH 3 OH 3 + CH N 3 3 CH 3 CH CH + O CH N 3 3 + CH CH N N + N N O OH ium , g ]quinolin-6-ium H H de dibenzo[ O H tetrahydroisoquinolin-2-ium OH CO HO CO CO 3 3 HO 3 MeO MeO H H H O H - 11-hydroxy-1,2,10-trimethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4 H HO CO bis(4-(dimethylamino)phenyl)methanone CO 3 N-methylhigenamine-7-O-beta-D-glucopyranoside 3 H H N OH Chemical structures 7-hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-2-methyl-3,4-dihydroisoquinolin-2-ium OCIG ( S )-6-hydroxy-1-(4-hydroxybenzyl)-7-methoxy-2,2-dimethyl-1,2,3,4- 2,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinolin-3-ol ( S )-8-hydroxy-1-(4-hydroxybenzyl)-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-2- N/A l o m / g 6 N/A 3 . 8 6 341.41 g/mol 314.40 g/mol 314.40 g/mol 328.39 g/mol 356.44 g/mol + + + + 4 3 3 4 4 O2 2 N NO NO NO NO NO 20 23 24 24 22 26 N/A H H Table 5: Continued. H H H H 20 17 19 19 19 21 C C C C C Molecular formula Molecular weight -D-glucopyranoside � Lotusine )-Oblongine C Compound Menisperine − ( Isomer-of-berberine Tetrahydroreticuline Isomer-of-palmatine Tetrahydrojatrorrhizine Isomer-of-magnoforine N-Methylhigenamine-7-O-glucopyranoside N-methylhigenamine-7-O- Compound derivatives 28 Evidence-Based Complementary and Alternative Medicine 3 3 a ]isoquinolin- 3 3 O OCH OCH 3 3 OCH OCH OMe OMe CH CH a ]isoquinolin-7-ium 3 OH + CH O N 3 OH OH CH H + N + N 3 , g ]quinolin-6-ium de 3 + CH O N N c ]quinolin-5-one H -pyrano[3,2- CH 7-ium H H H H -dibenzo[ Hydroxyl-palmatine CO HO 3 MeO MeO H Caution: A net charge appears to be present be to present appears A net charge Caution: tetrahydro-4 HO 1-hydroxy-2,10,11-trimethoxy-6,6-dimethyl-5,6,6a,7- O CO CO MeO MeO 3 3 CO CO 3 3 Chemical structures H H H H 2,2,6-trimethyl-2,6-dihydro-5 11-hydroxy-2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[3,2- 3,10-dimethoxy-7-methyl-5,6,12,12a-tetrahydroindolo[2,1-a]isoquinolin-7-ium-2,9-diol 2,3,9,10-tetramethoxy-7-methyl-5,6,7,8,13,13a-hexahydroisoquinolino[3,2- 241.29 g/mol 368.41 g/mol 328.39 g/mol 366.41 g/mol 370.47 g/mol 356.44 g/mol + + + + 2 4 4 4 5 5 O NO NO NO NO NO 22 15 26 28 22 22 H H Table 5: Continued. H H H H 22 15 21 22 19 21 C C C C C C Molecular formula Molecular weight Litcubine Compound Hydroxyl-palmatine N-Methylfindersine 11-Hydroxylpalmatine (+) N-methylcorydine N-Methyl Tetrahydropalmatine Compound derivatives Evidence-Based Complementary and Alternative Medicine 29 O a ]isoquinolin-7-ium H - 3 3 O 3 a ]isoquinolin-7-ium 3 3 CH CH + O O OCH O N H OCH OCH + N N H H ]quinolin-6-ium salt g ]quinolin-6-ium N + + N N g ]isoquinolino[3,2- H -[1,3]dioxolo[4,5- OMe OH a ]isoquinoline Tetrahydropalmatine HO O Xanthoplanine CO 2 ]oxireno[2',3':4,5]benzo[1,2- OH H CO 3 MeO H O O O O O benzo[ de Chemical structures O CO CO 3 3 CO CO 2 2 H H formaldehyde, 1,2,3-trimethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4 formaldehyde, OH OH -oxidaneyl)methoxy)-9,10-dimethoxy-5,6-dihydroisoquinolino[3,2- 9,10-dimethoxy-5,8,13,13a-tetrahydro-6 1  13-hydroxy-2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[3,2- 2,3-bis(( N/A 339.39 g/mol 368.41 g/mol 355.43 g/mol 382.39 g/mol 384.45 g/mol 356.44 g/mol + + + + 4 4 5 6 4 5 NO NO NO NO NO NO 25 21 22 20 26 26 H H Table 5: Continued. H H H H 21 20 21 21 21 22 C C C C C C Molecular formula Molecular weight Compound Xanthoplanine N-methylphoebine Tetrahydroberberine Tetrahydropalmatine 13-Hydroxypalmatine 7-Hydroxy-8-methoxydedihydrorutaecarpine 5,8,13,13a-Tetrahydro-2,9,10,11-tetrahydroxy-3- methoxy-7-methyl-6H-dibenzo[a,g]quinolizinium Compound derivatives 30 Evidence-Based Complementary and Alternative Medicine 3 O OMe OMe OCH O O O O O a ]isoquinolin-7-ium O OH 3 H H )-one b ]quinazolin-5(7 N + N b ]quinolin-9-ium N + N H OCH N + N + N 3 Epiberberine H N OCH O O Caution: A net charge appears to be present be to present appears A net charge Caution: O O Chemical structures O O CO 3 CO CO H 4,7,8-trimethoxyfuro[2,3- 3 3 3,9,10-trimethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium-2-ol H H 8,13-dihydroindolo[2',3':3,4]pyrido[2,1- 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[3,2- g ]isoquinolino[3,2- a ]isoquinolin-8-one H -[1,3]dioxolo[4,5- 9,10-dimethoxy-5,6-dihydro-8 N/A l o m / g 2 3 . 7 8 352.41 g/mol 351.36 g/mol 338.38 g/mol 336.37 g/mol 260.27 g/mol + + + + 5 4 4 4 4 O2 3 N NO NO NO NO NO 13 17 20 18 14 22 H H Table 5: Continued. H H H H 20 18 20 20 14 21 C C C C C C Molecular formula Molecular weight Compound Rutecarpine Tembetarine Epiberberine Skimmianine Columbamine 8-Oxoberberine Dihydroxyl-jatrorrhizine Compound derivatives Evidence-Based Complementary and Alternative Medicine 31 3 3 3 3 O hydrogen cation cation hydrogen O OCH OCH O O + propane O O OCH OCH H H+ O O O O O propane O hydrogen cation cation hydrogen O O O O O N N N N H H -isoquinolino[3,2- a ]isoquinolin-8-one O limonin H Oxypalmatine g ]isoquinolino[3,2- H -[1,3]dioxolo[4,5- Obacunone H O O a ]isoquinolin-8-one H O O O Chemical structures O CO CO O 3 3 O O H H CO CO 3 3 H H 2,3,9,10-tetramethoxy-5,6-dihydro-8 9,10-dimethoxy-5,6-dihydro-8 h ]isoquinolino[2,1- b ]isoquinolin-14-one H -[1,3]dioxolo[4,5- 8,9-dimethoxy-11,12-dihydro-14 351.36 g/mol 351.36 g/mol 6.0g/mol 367.40 g/mol 367.40 470.52 g/mol 454.52 g/mol 5 5 5 5 8 7 O O NO NO NO NO 30 30 17 21 17 21 H H H H H H Table 5: Continued. 26 26 20 21 20 21 C C C C C C Molecular formula Molecular weight Compound Oxyberberine Oxypalmatine 8-Oxopalmatine 8-Oxoepiberberine Obaculactone or limonin Obacunone or Obacunoic acid Compound derivatives Limonoid 32 Evidence-Based Complementary and Alternative Medicine O OH O OH 2 O CH O OAPI(1 6)glu OAPI(1 O O O OXyI-GIc OH OH O O O O O OH OH HO HO Coniferin Rutaevin O H O Vanilloloside H O CO 12-alpha-Hydroxylimonin 3 O H O HOOC H O O OCIG HO OH Chemical structures 3, 5-dihydroxybenzoicacid-O-xylopyranosyl-glucopyranoside 2-(p-hydroxyphenyl)-ethanol-1-O-beta-D-apiofuranosyl (1-6)-O-beta-D-glucopyranoside 2-(p-hydroxyphenyl)-ethanol-1-O-beta-D-apiofuranosyl l o m / g 9 1 . 6 3 316.31 g/mol 152.15 g/mol 470.52 g/mol 486.52 g/mol 342.34 g/mol 9 9 8 8 3 O1 O O O O O 12 30 30 22 20 8 H H H H H H 9 8 Table 5: Continued. 26 26 16 14 C C C C C Molecular formula Molecular weight -D-apiofuranosyl � Rutaevin Coniferin -D-glucopyranoside Compound � Vanilloloside -hydroxylimonin C glucopyranoside � 12 (1–6)-O- 3, 5-dihydroxybenzoicacid-O-xylopyranosyl- 2-(p-hydroxyphenyl)-ethanol-1-O- Compound derivatives Phenolic acid Evidence-Based Complementary and Alternative Medicine 33 OH OH OH OH OH OH O abs OH O OH O OH OH abs Feruloyl HO abs abs OH O O O OH HO O O OH OH 3 O Ferulic acid Ferulic OH Chlorogenic Acid Acid Chlorogenic COOCH OFeruloyl HO OH 3-O-Feruloylquinic acid 3-O-Feruloylquinic Neochlorogenic Acid Acid Neochlorogenic O Methyl 3-O-feruloylquinate 3-O-feruloylquinate Methyl Methyl 5-O-feruloylquinate 5-O-feruloylquinate Methyl OOCMe HO O O HO Chemical structures O HO HO HO HO 194.19 g/mol 354.31 g/mol 354.31 g/mol 205.19 g/mol 382.37 g/mol 368.34 g/mol 4 9 9 9 9 6 O O O O O O 10 18 20 18 22 13 H H H H H H Table 5: Continued. 8 10 16 17 16 18 C C C C Molecular formula Molecular weight -feruloylquinate C O Compound Ferulic acid Chlorogenic acid Neochlorogenic acid Methyl 3- Methyl 5-O-feruloylquinate 3-O-feruloyl quinic acid or 5-O-feruloyl quinic acid C Compound derivatives Quinic acid 34 Evidence-Based Complementary and Alternative Medicine OH OH OH O H ,8 -pyrano[2,3- OH 3 3 O HO OCH OCH O OMe O R ,3 ,4 S ,5 ,6 )-3,4,5,6- c ]furan-1-yl)-2,6- H ,3 -furo[3,4- OH 3 OH OH 2 2 CH CH OCH OH OMe O H OH H -pyran-2,3,4,5-tetraol OH OCaffeloyl O O O O OH 3 O H -chromen-4-one H -pyran-2-yl)oxy)-4 O OCH O CO 3 f ]chromen-4-one H COOH OFeruloyl OH C O OH 2 HO HO 3-Feruoyl-4-caffeoylquinic acid 3-Feruoyl-4-caffeoylquinic 3 HOH H OCH CO OH 3 H HO HO OMe H -pyran-2-yl)oxy)phenyl)tetrahydro-1 Chemical structures (+/-)-5,5'-dimethoxylariciresinol-4-O-glucoside dimethoxy-1,2,3,4-tetrahydronaphthalene-2,3-diyl)dimethanol tetrahydroxytetrahydro-2 ((1 S ,2 R ,3 )-7-hydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-6,8- OH HO dimethoxyphenoxy)tetrahydro-2 CO 3 OCIG H O 3,5-dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-7-(((2 MeO OH O (2 R ,3 )-3,5-dihydroxy-2-(4-hydroxyphenyl)-8,8-dimethyl-2,3,9,10-tetrahydro-4 S ,3 R ,4 ,5 ,6 )-3,4,5-trihydroxy-6- (2 R ,3 ,4 ,5 S ,6 )-6-(4-((1 ,3a ,6a )-4-(3,5-dimethoxy-4-(((2 (hydroxymethyl)tetrahydro-2 HO HO N/A 582.6 g/mol 516.50 g/mol 356.37 g/mol 728.70 g/mol 530.48 g/mol 420.46 g/mol 8 6 12 13 18 11 O O O O O O 28 20 26 38 44 28 H H H H H H Table 5: Continued. 22 20 26 28 33 26 C C C C C C Molecular formula Molecular weight -glucoside O -  -D-glucopyranoside � (+/-)-5,5 Icariside-1 Compound Phellamuretin (+/-)-lyoniresinol -anhydronoricaritin � 3-Feruoyl-4-cafeoylquinic acid dimethoxylariciresinol-4- Syringaresinol di-O- Compound derivatives Lignan Flavonoid Evidence-Based Complementary and Alternative Medicine 35 OH H - OH H -pyran-2- OH CHO OH OH OH OH OH OH O O O O O O O H -pyran-2-yl)oxy)chroman-8- 3 3 CH CH 2 2 OH O 2 2 OH CH CH H -chromen-8- H -pyran-2-yl)oxy)-4 Cr O HO O CH CH Cr C OMe 3 C 3 H H yl)oxy)chromium O O pyran-2-yl)oxy)chromium O O OH HO 3-methylbutanoic acid 3-methylbutanoic OH O OH OH O propyl 4-hydroxybenzoate 4-hydroxybenzoate propyl OH OH 2 2 OH O O OH OH OH CH CH MeO GlcO OH HO Chemical structures OH OH (hydroxymethyl)tetrahydro-2 OH OH C C 2 2 trihydroxy-6-(hydroxymethyl)tetrahydro-2 HO H -chromen-4-one 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4 HOH HOH OH R ,4 S ,5 ,6 )-3,4,5-trihydroxy-6- (2-(3,5-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-7-(((3 R ,4 S ,5 ,6 )-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 yl)ethyl)dimethyl(((3 R ,4 S ,5 ,6 )-3,4,5- (2-(3,5-dihydroxy-2-(4-hydroxycyclohexa-1,3-dien-1-yl)-4-oxo-7-(((3 )-2,6-dimethoxy-4-(3-oxoprop-1-en-1-yl)phenyl 2-hydroxyacetate ( E )-2,6-dimethoxy-4-(3-oxoprop-1-en-1-yl)phenyl H -pyran-2,3,4,5-tetraol (3 R ,4 S ,5 ,6 )-6-(hydroxymethyl)tetrahydro-2 R ,4 S ,5 ,6 )-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 yl)ethyl)dimethyl(((3 102.13 g/mol 180.16 g/mol 180.20 g/mol 740.67 g/mol 286.24 g/mol 266.25 g/mol 736.64 g/mol 17 17 6 3 6 2 6 O O O O O CrO CrO 10 12 14 10 12 40 44 H H H H H Table 5: Continued. 5 6 H H 15 10 13 C C C C C 31 31 C C Molecular formula Molecular weight D-glucose Phelloside Compound Kaempferol Isovaleric acid N-propyl paraben Dihydrophelloside Compound derivatives Paraben Glycoside Sinapyl aldehyde-4-O-beta-D-glucopyranoside 36 Evidence-Based Complementary and Alternative Medicine multimedication resistant P.aeruginosa strains. Te extract of acid, and sanleng acid [45]. Er-Miao-Wan formula is a PCS signifcantly downregulated minimal inhibitory concen- modifed version of SMW, which had been elucidated for its trations (MICs) of amikacin and gentamicin in the two mul- chief ingredient PCS which exerts potent hypouricemic efect timedication resistant P. aeruginosa strains [38]. PC showed [46]. its potential on the inhibition of Propionibacterium acnes strains. Its MIC50 and MIC90 were 24 �g/ml and 190 �g/ml, .. Antiulcer Effects. Peptic ulcers are associated with psy- respectively [39]. For fungal infections, the monomers of chological stress and mental illness. Te middle dosage of PC PC showed antifungal activity through compromising the extract could signifcantly reduce the levels of serotonin in the integrityoffungalcellwallandcellmembraneandincreasing brain and noradrenaline in the adrenal gland. Both serotonin the expressions of energy metabolic genes. Terefore the and noradrenaline take efect in the mental depression. life expectancy of Microsporum Canis is shortened. Fur- Besides, for the molecule in PC, berberine has the ability to thermore, the mingling use of palmatine hydrochloride and inhibit monoamine oxidase-A and modulate the brain nora- berberine hydrochloride could efectively treat Microsporum drenaline, serotonin, and dopamine levels [47]. Another Canis induced dermatomycosis in rabbit [40]. For virus study revealed that PC could protect the gastric mucosa by infections, the ethanol extract of PAR exerted moderate reinforcing the gastric mucosal barrier through endogenous efect against Herpes Simplex Virus by either interrupting sulfydryl compounds and diethyldithiocarbamate-sensitive virion envelope structures or disguising as indispensable viral compounds [48]. compounds for absorption or infltration of host cells [33]. Another study had proved that PAR has a broad spectrum of . . Antioxidant Effects. Te antioxidant activity of PAR is functions against virus-like VSV-GFP, PR8-GFP, NDV-GFP, proportional to its extract’s concentration. In another aspect, HSV-GSP,H3-GFP,and EV-71 in vitro and also has efects on the ethanol extract exhibited a better antioxidant efect diferent strains of infuenza A such as H1N1, H5N2, H7N3, because of its high concentration of phenolics and favonoids and H9N2 in vivo mice model [41]. than aqueous extract [33]. Phellodendrine from PC could play an antioxidant role by modulating the AKT/NF-�B . . Antitumor Effects. Tere are 3 compounds in PCS that pathway in the zebrafsh embryo. Besides, phellodendrine have been found to resist three types of tumours which in- could undo the expression of AKT and NF-�B, IKK, and cluded leukemic cell lines K562 and HEL, breast cancer cell COX-2 [49]. line MDA, and prostate cancer cell line PC3. Te compound [(S,  R) epoxy- -hydroxy-�,-diethoxy]tirucalla-- .. Sun Screening Effects. Te sun screening efects of PC en- -one has a relatively strong efect as Adriamycin against have been demonstrated through an experiment which was four tumors with the measurement of IC50; toonaciliatin K designed for sun screening efect of 50% alcohol extracts of and piscidinol A have a comparably moderate efect in this 100 Chinese herbal medicines. Te study showed PC could regard [42]. Tere are 9 most efective compounds of PC absorb 91.8% of ultraviolet-C, 79.1% of ultraviolet-B, and for prostate cancer, namely, magnoflorine-O-glucuronide, (p- 50.7% of ultraviolet-A. It is regarded as highly efective for hy-droxybenzyl)- , -dihydroxy-N-methyl tetrahydro iso- sun screening if the absorption rate of ultraviolet is higher quinoline--O-p-D-glucopyranosid, magnoflorine, menisper- than 90%. Terefore, PC could be a strong candidate for ine-O-glucuronide, menisperine, berberine, Jatrorrhizine, sunproof of ultraviolet-C [50]. Also, PC could also improve obaculactone,andobacunone [43]. Polysaccharides from an skin oxidative lesion induced by ultraviolet radiation via aqueous extract of PCS act on cell-mediated stimulation decreasing lipid peroxidation and increasing antioxidant and humoral immunity instead of tumor cell inhibition to enzymes activities [51]. exert tumoricidal activity. Specifcally, some polysaccharides stimulate macrophages and NK cells via �-glucan-binding . . Other Effects. PC stimulates longitudinal bone growth lectin site of complement receptor type 3 [44]. and chondrocyte proliferation via upregulating bone mor- phogenetic protein-2 (BMP-2) and insulin-like growth factor . . Antigout Effects. Si-Miao-Wan (SMW) formula had been (IGF-1) expression in the growth cartilage [52]. Besides, PC proved to be efective for gout and gouty arthritis. In could activate the fbrinogen system to take the hemostatic this formula, PC is the monarch herb which is the core efect. Tis validated charcoaled PC could stop bleeding ingredient to guide the other three herbs indicating that the [53]. Te extract of PC also shows neuroprotective efect alkaloids and organic acids in PC are the potential com- through adjusting the PC-12 cell apoptosis which was induced + pounds for SMW. Alkaloids include candicine, oblongine, by 1-methyl-4-phenylpyridinium (MPP ) and hindered the phellodendrine, tembetarine, magnoforine, lotusine, n- releaseofcytochromeCintothecytosol[54].PARcould methylterahydrocolumbamine, menisperine, noroxyhydras- ease the symptoms of atopic dermatitis by decreasing the tinine, demethyleneberberine, tetrahydropalmatine, oxyber- numbers of mast cells, serum levels of TNF-�,andINF-� berine, armepavine, oxypalmatine, columbamine, jatror- and the expression levels of cytokines [56]. PAR could delay rhizine, thalifendine, berberrubine, n-methyl canadine, pal- or even prevent the progression of diabetic nephropathy by matine, berberine, obaculactone, obacunone, and amuren- correcting the high blood sugar state, antioxidant enzyme laetone B, and organic acids include neochlorogenic acid, system, and kidney malfunction and reversing histopatho- chlorogenic acid, cryptogenic acid, cryptochlorogenin acid, logical changes inficted by diabetes on kidney [57]. To cafeoyl-CH2-O-quinic acid, 3-O-feruloylqinic acid, ferulic further elaborate its mechanism on the compound level, Evidence-Based Complementary and Alternative Medicine 37 berberine could attenuate the renal malfunction by inhibiting health supplements guideline, PC is still on the list of renal aldose reductase and decreasing oxidative stress [58]. prohibited or restricted ingredients. However, according to Magnoforine and phellodendrine could inhibit the immune a cohort study, under the guidance of Chinese medicine response by suppressing local graf versus host reaction practitioners, the application of PC’s berberine is clinically and induction phase of picryl chloride-induced delayed- safe even in patients who have hematological diseases with type hypersensitivity [59]. To counter asthma attack, the profound cytopenia and multiple comorbidities. Despite extract of PCS inhibits tracheal smooth muscle contraction these, some precautionary measures such as bilirubin and + induced by high K . Meanwhile, it could also block tracheal hemoglobin monitoring are still required for the patients smooth muscle concentration induced by Nifedipine [6]. Te who have underlining hemolytic disease. On the other hand, pharmacological activities of PC and its related derivatives the restriction for PC is necessary for the users in their have been listed in Table 6. peripartum and neonatal period due to the concern of its aggravation risk for neonatal jaundice and kernicterus 6. Pharmacokinetics [66].

According to Chinese Pharmacopeia (Edition 2015), phel- .. Processing, Differentiation, and Authentication. Tradi- lodendrine has been used as one of the evaluating indexes tional Chinese medicine (TCM) processing or preparation of PC. Phellodendrine could be rapidly absorbed in tissues or “Pao Zhi” in Chinese is a unique technique and process such as plasma, liver, spleen, kidney, and brain. Besides, in TCM. Pao Zhi is a technique to turn the raw herbs kidney is the major distribution tissue and the target organ into decoction pieces. Tis technique must be performed of phellodendrine. Furthermore, the experimental study on under the guidance of TCM’s theory to satisfy the diferent animal suggested that this constituent has no long-term requirements of medicinal materials and special production build-up efect on the tissues. Intriguingly, the extract of processes. Te quality of Pao Zhi directly afects the thera- phellodendrine could be found in the animal brain tissue peutic efects of herbal medicine [67]. It has a time-honored indicating that this constituent may penetrate the common history because as early as 5 B.C. during the Jin dynasty, medication’s biggest hurdle: blood-brain barrier. Te maxi- “Leigong Treatise on the Preparation” was composed as a mum concentration time is at 5 minutes afer intravenous book for Pao Zhi. It systematically summarized the herbal administration. Te elimination half-life is no longer than processing techniques until the Jin dynasty. Intriguingly, it 2 hours [63]. Another constituent from PC is magnoforine stated that the right way of using the bark of PC is to which shows low bioavailability and high absorption and removethecoarsebark[68].IntheSongdynasty,PaoZhi elimination rates afer oral and intravenous administration of had regulated a mandatory process for Chinese medicinal this constituent in pure compound form. While its bioactivity product [67]. can be dramatically increased, absorption and elimination IntermsofPC’sprocessing,TCMdoctorsinhistory rates can be signifcantly decreased afer oral administra- emphasized the importance of PC’s processing and recorded tion of the PC decoction. Similarly, with oral administra- 16 kinds of methods for PC’s processing in the books. Nowa- tion of mixture, magnoforine (40 mg/kg) and berberine days, the most common types of processing are raw PC, PC (696.4 mg/kg, the equivalent dosage in PC decoction), the fried with salt, PC fried with wine, PC fried with honey, bioavailability and absorption and elimination rates have a and fried-to-charcoal PC [69]. However, it still lacks ofcial similar trend. It suggested berberine plays an important role standard when it comes to quantity and quality of the in the drug-drug interaction with magnoforine in the PC processed PC and its subspecies; some of the existing pioneer decoction. On the other hand, these fndings also warn us studies could explain this ambiguous and abstract concept in that the mingling use of berberine and magnoforine possibly a scientifc way. Besides, for PC’s quality control, the most increases the risk of toxicity which possibly gives some practical approach is to use thin layer chromatography (TLC) support to the theory that herbal medicine may achieve better for qualitative and high-performance liquid chromatography therapeutic efects and fewer side efects [64]. When it comes (HPLC) for quantitative measurement [70]. According to the to the diferent type of processed PC, they have diferent kinds results of thin layer chromatography, water percentage in the of efects. For the raw PC, it could downregulate CYP1A2 and raw PC is less than 10.0%, PC fried with salt is less than 8.0%, activate CYP3A4. As for rice-wine and salt-water processed PC fried with wine is less than 7.0%, and PC fried with honey PC, they can alter the activities of cytochrome P450. Also, is less than 8.0%. Total ash content in the raw PC is less than rice-wine processed PC alone can counter the inhibitory 8.0%; acid insoluble ash content is less than 0.8%; PC fried efect of CYP1A2 and promote the induction of CYP3A4 [65]. with salt is less than 8.0%; acid insoluble ash content is less than 0.6%; PC fried with wine is less than 8.0%; acid insoluble .. Toxicity and Contraindication. Several studies have been ash content is less than 0.8%; PC fried with honey is less conducted regarding the toxicology of PC applications. So far, than 8.0%; acid insoluble ash content is less than 0.4%. For no conclusive result has been reached due to the controversial alcohol-soluble extract, the raw PC is more than 16.0%, PC results from diferent studies. Te common allegation for fried with salt is more than 20.0%, PC fried with wine is more PC application is neonatal jaundice and kernicterus. Due to than 16.0%, and PC fried with honey is more than 22.0%. For this concern, it even causes the complete ban on the use of percentage of phellodendrine, the raw PC is more than 0.41%, related herbs including PC in Singapore since 1978. Besides, and berberine is more than 3.92%; PC fried with salt is more according to the latest Singaporean ofcial regulations for than 0.36%, and berberine is more than 3.89%; PC fried with 38 Evidence-Based Complementary and Alternative Medicine [33] [35] [28] [34] Topical application [29] Oral administration [11] Oral administration [30] ± m; � 5.2 m � ± g/mL : � g/ml 50 g/mL; 1.1 g/mL; � � � ± IC extract; 2.5 g/ml 100 0.5 mg/ear 3.8 2.6 Obakunone 22.0 Non-alkaloids 1,10,100 200-400 mg/kg Administered intragastrically [3] MIC and MBC: 0.24-250 mg/ml 3.676 mg/ml and (ii) TPA multiple for aqueous extract application: 1 mg/ear Active concentration Administration (In vivo) References (i) TPA and AA tests: Limonin 15.8 (iii) DTH test: 1 mg/ear 7. 3 5 3 mg / m l for e t h a n ol 100, 200 and 400 mg/kg Administrated by gavage [31] Methanol extract 20.9 6.25 mg/ml and 50 mg/ml line) mice edema 264.7 cells aeruginosa mouse model Model or sample Streptococcus. mitis, Mycoplasma hominis -Tetradecanoylphorbol-13- Enterococcus faecium, Streptococcus. mutans, Staphylococcus aureus, Streptococcus. sanguis, Streptococcus pyogenes, Streptococcus. gingivalis Acute colitis mice model 150,300 mg/kg Oral administration [32] O pneumonia, Pseudomonas Escherichia coli, Klebsiella acetate-induced mouse ear systemic infammation mice lipopolysaccharides-induced model and macrophage RAW acetate- induced ear edema in iooyacaie-induced Lipopolysaccharides- ICR mice and male Wistar rats 12- acute airway infammation on a 12-O-tetradecanoyl-phorbol-13- BV2 cells (Mouse microglial cell vitro vitro in vivo In vivo In vivo In vivo In vitro In vitro In vitro In vitro In vitro In vivo/ In vitro, In vivo, in In vivo, in Table 6: Pharmacological activities of PC and processed PC. specimens specimens specimens PCC extract PCC extract voucher specimens voucher specimens voucher specimens Demethyleneberberine Ethanol Extract of PAR; Aqueous extract of PAR PAR extract with voucher PCC extract with voucher PCC extract with voucher PAR methanol extract with PCC methanol extract with Ethanol extract of PCC with Pharmacological ActivityAnti-infammatory efect Tested Substance Anti-bacterial efect Evidence-Based Complementary and Alternative Medicine 39 [37] [33] [39] [ 3 8] [42] [40] pipette tip Oral administration [41] Administered through the sterile g/mL � g/mL 1.93; 2.79 � 2.08; g/mL ± ± ± 1mg/ml � 59 mg/ml for 87 mg/ml for s . . 1 0 0 m l of compound 4: of compound 3: 0 0 of Compound 1: MIC90%: 190 7. 6 6 11.81 50 14.30 50 ± ± lat1,3and5days 50 MIC ethanol extract � 2.5 or 5 mg/day Administrated by gavage [36] before infection aqueous extract; 73 26 g/g in a total volume of . MIC50%: 24 Active concentration Administration (In vivo) References � 6 . 4 200 (i) IC (ii) IC (iii) IC 1.6 g/kg per day for 28 days Administered intragastrically [43] 0.8 cells P. a e r u g i n o sa mouse model Model or sample Table 6: Continued. dermatitis in rabbits infected BALB/c mice Staphylococcus aureus 32 to 128 Typhimurium 21 infected Propionibacterium acnes BALB/c-nude mice model S. (i) Leukemic cell lines K562 (ii) Leukemic cell lines HEL H1N1, H5N2, H7N3 or H9N2 African green monkey kidney Microsporum Canis –induced (iii) Breast cancer cell line MDA (iv) Prostate cancer cell line PC3 Prostate cancer cell infested Male vitro in vivo In vivo In vitro In vitro In vitro In vivo, In vitro In vitro In vitro In vitro In vivo/ In vitro, In vitro, In vivo, in PCC specimens PCC extract Berberine in PCS Berberine in PAR voucher specimens Ethanol extract of PAR; Aqueous extract of PAR Aqueous extract of PCC palmatine hydrochloride Berberine hydrochloride, PCS extract with voucher Aqueous extract of PAR with Pharmacological Activity Tested Substance Anti-fungal efect Anti-viral efect Anti-tumor efect 40 Evidence-Based Complementary and Alternative Medicine [33] [47] [44] [46] for 10 days administration Oral administration [48] Oral administration [45] Waterborne exposure [49] Oral or intraperitoneal once a day for seven days. Administered intragastrically Injected intraperitoneally daily g/mL � 25 mg/ml 100 mg/kg 480 mg/kg 5mg/100g; 2mg/100g; 200 10 mg/100g 1.0 ml/100 g 30 mg/kg/day Active concentration Administration (In vivo) References cells model rats model aeruginosa; Model or sample Table 6: Continued. implanted Mice model Streptococcus pyogenes, Sarcoma 180 ascites cells Male Sprague-Dawley rats Escherichia coli, Klebsiella on Male Wistar rats model on zebrafsh embryo model Uricase inhibitor potassium Acetic acid-induced chronic pneumonia, and Pseudomonas Ethanol-induced gastric lesions AAPH-induced oxidative stress oxonate induced male ICR mice faecium, Staphylococcus aureus, Anti-herpes simplex virus tested For anti-microbial Enterococcus gastric ulcers on Sprague Dawley on African green monkey kidney vitro In vivo In vivo In vivo In vivo In vivo In vitro In vitro In vitro In vivo/ In vivo In specimens PCC extract (containing PCC) voucher specimens voucher specimens Ethanol extract of PAR; Aqueous extract of PAR Aqueous extract of PCC PCS extract with voucher Ethanol extract of PCC with Aqueous extract of PCS with Compounds of Si-Miao-Wan Phellodendrine isolated from Pharmacological Activity Tested Substance Anti-gout efect Anti-ulcer efect Anti-oxidant efect Evidence-Based Complementary and Alternative Medicine 41 [6] [55] [58] [50] [54] intranasally Oral intubation Oral administration [57] Oral administration [52] Oral administration [51] Topical administration [56] Administered intraperitoneally [59] ± kg Subcutaneous administration [53] / g/mL l � � g/mL � weeks 200 1.3 0.5 mg/ml 379 mg/kg 5, 2 and 1 mg 10 and 30 100 and 300 mg/kg once daily for 11 days Active concentration Administration (In vivo) References (i) 0.1 ml/10 g for mice (ii) 1 ml for guinea pigs 200, 400 or 800 mg/kg, extract of PCS was 12.2 0.1and1g/mlfor2hours Te IC50 of n-butyl alcohol 200 mg/kg once a day for 12 model models PC-12 cells PC-12cells Model or sample Table 6: Continued. Hartlay guinea pigs NC/Nga mice model Sprague–Dawley rats PC extract+50% ethanol 2,4-dinitrochlorobenzene induced by saline solution on male Wistar rats model 72 intact 21-day-old female induced skin lesions on the ddY mice, BALB/c mice, and on male Sprague-Dawley rats BALB/c mice asthmatic model on the dorsal of the rats model scratch on male Kunming mice UVB lamp inficted skin lesions Mouse tail amputation and liver Streptozotocin-induced diabetes Streptozotocin-induced diabetes vitro In vivo In vivo In vivo In vivo In vivo In vivo In vivo In vitro In vitro In vitro In vitro In vivo/ In vivo In Berberine specimens PCC extract PCC extract voucher specimens voucher specimens Phellodendrine and PCC in saline water PAR aqueous extract with voucher specimens PCC extract with voucher PCCandPACextractwith n-butyl alcohol extract of PCS Salt processed PAC extract with cyclophosphamide isolated from Pharmacological ActivitySun screening efect Tested Substance Bone-growth efect PCC extract + 50% ethanol Hemostatic efect efect Neuroprotective PCC Carbonisatus-carbon dots Counter-atopic dermatitis efect Counter-diabetic nephropathy efect Immunity suppressing efect Anti-asthmatic efect 42 Evidence-Based Complementary and Alternative Medicine honey is more than 0.37%, and berberine is more than 3.90% on cell-mediated stimulation and humoral immunity to exert [69]. tumoricidal activity. Previously, the diferentiation of PCS and PAR is based Phellodendrine and magnoforine have well absorption on the experiences of the herbal professionals to distinguish rate in the animal organs which could indicate their safety for the minor diferences from their appearances in naked eyes human trials. However, berberine could interact with mag- and microscope. Due to the increasing mixing applications noforine or other constituents which could further increase and counterfeits, more efcient and accurate approaches are the tissue absorption rates. Tis should be noticed by other required. It is noticeable that the mass fractions of obacu- clinical trials or advanced studies to avoid adverse efects. It lactone and obacunone have a plunging order among raw is also noticeable that diferent processing techniques or “Pao PC, PC fried with wine, and PC fried with salt. Tere- Zhi” could render the herb with diferent kind of therapeutic fore, it is reasonable to deduce limonin and obacunone efects. For the raw PC, it could downregulate CYP1A2 and have been undergoing a series of chemical reactions during activate CYP3 A4. As for rice-wine and salt-water processed herbal processing. For diferentiation of PCS and PAR, the PC, they can alter the activities of cytochrome P450. Also, for mass fractions of limonin and obacunone have a signifcant rice-wine processed PC alone, it can counter the inhibitory diference between PCS and PAR. Te mass fraction of efect of CYP1A2 and promote the induction of CYP3A4. For obaculactone and obacunone in PAR is 10 times higher than toxicology, there is no afrmative conclusion in terms of PC in PCS. As a result, limonin and obacunone could be utilized and its species’ absolute clinical safety. Terefore, safety pre- as the diferential targeted chemical constituents for PC’s cautionary measures are still required for vulnerable groups diferentiation [71]. HPLC method demonstrates that PC and of people. For the processed PC and its species, berber- charcoaled PC have a signifcant disparity in terms of charac- rubine, limonin, and obacunone became targeted chemical teristic chromatograms and chemical constituents. Te peak constituents for authentication of charred PC, PC, and its numbers and proportions of characteristic chromatograms subspecies. Furthermore, obacunone and obaculactone are are reducing with the increasing temperature of charcoaled probably responsible for antiatopic dermatitis efect [56]. PC. On the other hand, due to the heating efect, berberine hydrochloride will transfer into berberrubine by losing one 8. Conclusions methyl. As a result, berberrubine is vindicated to be another targeted chemical constituent for charred PC identifcation In summary, the compounds of the crude bark of PC and [72]. For authentication of PC and its subspecies, berberine its species have showcased a wide range of pharmacological hydrochloride could be used as another targeted chemical efects. Pharmacological efcacies of PC are supported by its constituent except for limonin and obacunone as mentioned diverse class of alkaloids, limonoids, phenolic acid, quinic above [73]. acid, lignans, and favonoid. Trough this review, in total, 140 chemical compounds had been summarized. Among these 7. Discussion compounds are 18 compounds from PCC, 44 compounds from PCS, 34 compounds from PAC, and 84 compounds Tis review work has illustrated the diverse bioactive proper- from PAR. 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