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

BACKGROUND: Phellodendri Cortex (PC) or Huang Bai. According to the scientific database of China Plant Species and Chinese pharmacopeia 2015 edition, PC has two main species which are Phellodendron amurense Rupr (PAR) or "Guan Huang bai" in Chinese and Phellodendron chinense Schneid (PCS) or "Chuan Huang bai" in Chinese. The crude drugs of PAR and PCS are also called Phellodendri amurensis cortex (PAC) and Phellodendri chinense cortex (PCC), respectively. The medicinal part of the plant is the dried trunk bark. PC has comprehensive therapeutic effects which include anti-inflammatory, antimicrobial, anticancer, hypotensive, antiarrhythmic, antioxidant, and antipyretic agents. The exact ingredients in PC and its species are not fully summarised. AIM OF THE STUDY: This 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 effect 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. The 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: specifically, 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 effect. PC and its species possess a broad spectrum of pharmacological actions including anti-inflammatory effect, antibacterial effect, antiviral effect, antitumor effect, antigout effect, antiulcer effect, neuroprotective effect, and antiatopic dermatitis effect. PC could widely distribute in plasma, liver, spleen, kidney, and brain. Berberine may be responsible for the toxic effect on the susceptible users with hemolytic disease or in the peripartum and neonatal period.
CONCLUSIONS: The compounds of the crude bark of PC and its subspecies have showcased a wide range of pharmacological effects. Pharmacological efficacies of PC are supported by its diverse class of alkaloid, limonoid, phenolic acid, quinic acid, lignan, and flavonoid. 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

Phellodendri Cortex (PC) is also known as “Huang bai” in Chinese and “Obaku” in Japanese. PC is a plant grown in China, Korea, Japan, Vietnam, and Far East of Russia. The earliest record of this plant was on “Shennong's Classic of Materia Medica” [1]. According to the scientific database of China Plant Species and Chinese pharmacopeia 2015 edition, PC has two main species which are Phellodendron amurense Rupr (PAR) or “Guan Huang bai” in Chinese and Phellodendron chinense Schneid (PCS) or “Chuan Huang bai” in Chinese. The crude drugs of PAR and PCS are called Phellodendri amurensis cortex (PAC) and Phellodendri chinense cortex (PCC), respectively. PAR and PCS are naturally grown in the Northeast and Southwest part of China, respectively [2]. According to the latest information from “information system of Chinese rare and endangered plants,” PAR is categorized as one of the second degrees of endangered plants. PAR and PCS could be interchangeably used in clinical application because both species contain similar chemical constituents [3]. According to the scientific database of China Plant Species and Chinese pharmacopeia 2015 edition, PC is categorized in the family of Phellodendron Rupr. The medicinal part of the plant is the dried trunk bark. PC had been viewed as one of the 50 fundamental herbs in Chinese herbalism. Traditionally, its medicinal part could exert therapeutic effects in various diseases such as meningitis, cirrhosis, dysentery, pneumonia, tuberculosis, etc. [4, 5]. Nowadays, PC has comprehensive therapeutic effects which include immune modulation, anti-inflammatory, antimicrobial, antibacterial, anticancer, hypotensive, antiarrhythmic, antioxidant, antigastric ulcer, and antipyretic agents, etc. [5]. According to the Clinical Chinese Materia Medica, 2006 edition, PC has a bitter flavor and cold nature and can enter the meridian of kidney, bladder, and large intestine. PC could clear heat, dry dampness, drain fire, eliminate steam, resolve toxin, and treat sores [6]. PC and its species contain various chemical derivatives. One of the important ones is alkaloids which contain berberine and jatrorrhizine. Both compounds were proven to be effective against some type of tumours, infections, neurological diseases [7]. To further acquire the knowledge on PC, a systematic review of its phytochemical, pharmacological, and pharmacokinetic properties is required. The aim of this study is to review and evaluate the pharmacological actions of compounds as well as to explore the pharmacokinetic knowledge of the PC and its species. The chemical compounds that exert therapeutic effect for atopic dermatitis are also desired.

2. Methods

Data were searched from the following databases until May 2018: Encyclopaedia of Traditional Chinese Medicines; PubMed; EMBASE; MEDLINE; ScienceDirect; SCOPUS; Web of Science; China Network Knowledge Infrastructure. The keywords used for the literature search included: Huang Bai and its English, botanical, and pharmaceutical names. The selection criteria included process controls of the herbal substances, reporting reference standards such as authentication of reference materials and profile chromatograms, and analytical procedures and validation data. Papers in English or Chinese language are included for this review. Scientific rigidity was determined by the chemical markers of herbs through the use of strict parameters in testing, quantitative, and qualitative measures of the bioactive components, such as high-performance liquid chromatography, fingerprint spectrum, correlations differentiation, and stability evaluation, reference standards, and toxicological assessments. Plant voucher specimens are a guarantee for traceability of the plant material and data verification for other researchers or commercial purposes [60]. The chemical formulas of the compounds of PC and its species were acquired from selected studies. Chemical structures and molecular weights were extracted from ChemDraw professional 170.

3. Results

A total of 125 papers were identified through the literature search. Fifty-two papers were excluded based on the reasons for nonpharmacodynamic, nonphytochemistry, and nonpharmacological studies. 73 studies fitted the selection criteria. Among these articles, 32 studies are about pharmacodynamics, 38 studies are about phytochemistry, and 3 studies are about pharmacokinetics (Figure 1).

Figure 1

PC study selection flowchart.

4. Bioactive Compounds

The crude barks of PC and its species contain alkaloids, isoquinoline alkaloid, limonoids, phenolic acid, quinic acid, lignans, and flavonoid, and so on. A summary of the bioactive compounds of the PC and its species reported in the included studies is presented in Table 1. Molecular formula, molecular weight, and chemical structure of the major constituted alkaloids of PC, including berberine, palmatine, and jatrorrhizine, are listed in Tables 2, 3, 4, and 5. They could exert a broad spectrum of pharmacological influence which contains antimicrobial, anti-inflammation, antitumor, antidepressant, and antiulcer effects [47]. Limonoids including limonin and obakunone play an important role in the anti-inflammatory effects of PC [11]. Phenolic acid or phenol carboxylic acids belong to aromatic acid compound substances which are characterized by a phenolic ring and an organic carboxylic acid function [61]. According to the description on Buchler quinine plant in Braunschweig, Germany, quinic acid is a natural sugary compound which can be found in multiple plants such as well-known coffee beans and tobacco leaves. Based on the description on PubChem, lignans affiliate a class of dibenzylbutane derivatives which exists in plants and in body fluids such as bile, serum, urine, etc. These compounds have anticancer potential. Quercetin belongs to flavonoids which can reduce coronary heart disease according to PubChem data. Two species of PC, PCS and PAR, can be differentiated based on the contents of the chemical compounds. Specifically, the 2005 edition of Chinese Medicinal encyclopedia described the PCS's minimal content of berberine hydrochloride and phellodendron hydrochloride to be 3.0% and 0.34%, respectively; the PAR's minimal content of berberine hydrochloride and palmatine hydrochloride is 0.60% and 0.30%, respectively [62].

Table 1

Summary of chemical constituents isolated from PC and its different species (140 compounds).

Compound derivatives	Chemical compounds	Methods	References	Original species
Alkaloid	Berberine	(i) UPLC-ESI-Q-TOF-MS	(i) [8]	(i) PAC
		(ii) HPLC-DAD-ESI-MS2	(ii) [9]	(ii) PCS and PAR
		(iii) UPLC-Q/TOF-HDMS	(iii) [10]	(iii) PAC
		(iv) HPLC-TLC- NMR-EI-MS	(iv) [11]	(iv) PAR
		(v) HPLC-DAD-MS	(v) [12]	(v) PAR
		(vi) N/A	(vi) [13]	(vi) PAC and PCS
	8,13-dioxo-14-butoxycanadine	CC	[14]	PCS
	Berberrubine	UPLC-ESI-Q-TOF-MS	[8]	PAC
	Berberastine	UPLC-Q/TOF-HDMS	[10]	PAC
	Bis-[4-(dimethylamino)phenyl]methanone	HPLC-ESI-MS/MS	[15]	PAR
	Brucine	CE	[16]	PCS
	Δ7-dehydrosophoramine	N/A	[17]	PAC
	Dihydrocyclobuxine-D	HPLC-ESI-MS/MS	[15]	PAR
	3,4-dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy-2-methyl-8-isoquinolinol	HPLC-ESI-MS/MS	[15]	PAR
	3,4-dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy-2-methyl-6-isoquinolinol	HPLC-ESI-MS/MS	[15]	PAR
	7,8-dihydroxyrutaecarpine	HPLC-ESI-MS/MS	[15]	PAR
	4-dimethylamino-4 -isopropylbenzene	HPLC-ESI-MS/MS	[15]	PAR
	Evodiamine	HPLC-ESI-MS/MS	[15]	PAR
	Palmatine	(i) UPLC-ESI-Q-TOF-MS	(i) [8]	(i) PAC
		(ii) HPLC-DAD-ESI-MS2	(ii) [9]	(ii) PCS and PAR
		(iii) UPLC-Q/TOF-HDMS	(iii) [10]	(iii) PCC
		(iv) HPLC-DAD-MS	(iv) [12]	(iv) PAR
		(v) N/A	(v) [18]	(v) PCS
	Tetrahydropalmatine	UPLC-ESI-Q-TOF-MS	[8]	PAC
	Tetrahydroberberine	HPLC-ESI-MS/MS	[15]	PAR
	Phellodendrine	(i) UPLC-ESI-Q-TOF-MS	(i) [8]	(i) PAC
		(ii) HPLC-DAD-ESI-MS2	(ii) [9]	(ii) PCS and PAR
		(iii) UPLC-Q/TOF-HDMS	(iii) [10]	(iii) PAC
		(iv) HPLC-DAD-MS	(iv) [12]	(iv) PAR
		(v) N/A	(v) [18]	(v) PAC and PCS
	Magnocurarine	(i) HPLC-ESI-MS/MS	(i) [15]	(i) PAR
	Magnoflorine	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PCC
		(iii) HPLC-DAD-MS	(iii) [12]	(iii) PAR
		(iv) N/A	(iv) [19]	(iv) PCS
	Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol	(i) UPLC-ESI-Q-TOF-MS	(i) [8]	(i) PAC
		(ii) HPLC-DAD-ESI-MS2	(ii) [9]	(ii) PCS and PAR
		(iii) HPLC-DAD-MS	(iii) [12]	(iii) PAR
		(iv) N/A	(iv) [19]	(iv) PAC
	13-methoxyjatrorrhizine	HPLC-ESI-MS/MS	[15]	PAR
	Ƴ-Fagarine	CC	[20]	PAR
	Canthin-6-one	CC	[20]	PAR
	4-methoxy-N-methyl-2-quinolone	CC	[20]	PAR
	Oxypalmatine	CC	[20]	PAR
	Candicine	HPLC-DAD-ESI-MS2	[9]	PAR
	Lotusine	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PAC
	N-methylhigenamine-7-O-glucopyranoside	HPLC-ESI-MS/MS	[15]	PAR
	N-methylhigenamine-7-O-β-D-glucopyranoside	HPLC-DAD-ESI-MS2	[9]	PAR
	(−)-Oblongine	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PCC
	Isomer-of-berberine	HPLC-DAD-ESI-MS2	[9]	PAR
	Isomer-of-magnoflorine	HPLC-DAD-ESI-MS2	[9]	PCS and PAR
	Isomer-of-palmatine	HPLC-DAD-ESI-MS2	[9]	PAR
	Tetrahydroreticuline	HPLC-DAD-ESI-MS2	[9]	PAR
	Tetrahydrojatrorrhizine	HPLC-DAD-ESI-MS2	[9]	PCS and PAR
	Menisperine	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PCC
		(iii) N/A	(iii) [19]	(iii) PAC
	(+) N-methylcorydine	HPLC-DAD-ESI-MS2	[9]	PAR
	N-methyl Tetrahydropalmatine	HPLC-ESI-MS/MS	[15]	PAR
	N-methylflindersine	HPLC-ESI-MS/MS	[15]	PAR
	Litcubine	HPLC-DAD-ESI-MS2	[9]	PAR
	Hydroxyl-palmatine	HPLC-DAD-ESI-MS2	[9]	PAR
	11-hydroxylpalmatine	HPLC-ESI-MS/MS	[15]	PAR
13-hydroxypalmatine	HPLC-ESI-MS/MS	[15]	PAR
7-hydroxy-8-methoxydedihydrorutaecarpine	HPLC-ESI-MS/MS	[15]	PAR
Tetrahydropalmatine	HPLC-DAD-ESI-MS2	[9]	PAR
Xanthoplanine	HPLC-DAD-ESI-MS2	[9]	PAR
N-methylphoebine	HPLC-DAD-ESI-MS2	[9]	PAR
Columbamine	HPLC-DAD-ESI-MS2	[9]	PCS and PAR
Dihydroxyl-jatrorrhizine	HPLC-DAD-ESI-MS2	[9]	PAR
Epiberberine	HPLC-DAD-ESI-MS2	[9]	PAR
(6aS)-1,2,10,11-tetramethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,  g] quinolinium	UPLC-Q/TOF-HDMS	[10]	PCC
Dasycarpamin	UPLC-Q/TOF-HDMS	[10]	PCC
Pteleine	HPLC-UV	[21]	PAR
(-)-(R)-platydesmin	HPLC-UV	[21]	PAR
Noroxyhydrastinine	HPLC-UV	[21]	PAR
Chilenine	HPLC-UV	[21]	PAR
Rutecarpine	HPLC-ESI-MS/MS	[15]	PAR
Skimmianine	HPLC-ESI-MS/MS	[15]	PAR
Tembetarine	HPLC-ESI-MS/MS	[15]	PAR
Tetramethyl-O-scutellarin	UPLC-Q/TOF-HDMS	[10]	PCC
5,8,13,13a-Tetrahydro-2,9,10,11-tetrahydroxy-3-methoxy-7-methyl-6H-dibenzo[a,g]quinolizinium	HPLC-ESI-MS/MS	[15]	PAR
Ƴ-hydroxybutenolide derivatives II	UPLC-Q/TOF-HDMS	[10]	PCC
Isoquinoline alkaloid	Armepavine	UPLC-ESI-Q-TOF-MS	[8]	PAC
	Demethyleneberberine	UPLC-ESI-Q-TOF-MS	[8]	PAC
	8-oxoberberine	HPLC-ESI-MS/MS	[15]	PAR
	8-oxoepiberberine	HPLC-ESI-MS/MS	[15]	PAR
	8-oxopalmatine	HPLC-ESI-MS/MS	[15]	PAR
	Oxyberberine	HPLC	[20]	PAR
	Oxypalmatine	HPLC	[20]	PAR
Limonoid	Kihadanin B	N/A	[19]	PAC
	Niloticin	N/A	[18]	PAC
	Niloticin acetate	N/A	[18]	PCS
	Obaculactone or limonin	(i) UPLC-ESI-Q-TOF-MS	(i) [8]	(i) PAC
		(ii) CC	(ii) [20]	(ii) PAR
		(iii) UPLC-Q/TOF-HDMS	(iii) [10]	(iii) PCC
		(iv) HPLC-TLC- NMR- EI-MS	(iv) [11]	(iv) PAC
		(v) N/A	(v) [18]	(v) PAC
	Derivative of obaculactone	UPLC-Q/TOF-HDMS	[10]	PCC
	Obacunone or Obacunoic acid	(i) CC	(i) [20]	(i) PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PCC
		(iii) HPLC-TLC- NMR- EI-MS	(iii) [11]	(iii) PAC
		(iv) HPLC-DAD-ESI-MS2	(iv) [9]	(iv) PAR
		(v) N/A	(v) [18]	(v) PAC
	12α-hydroxylimonin	CC	[20]	PAR
	Piscidinol A	N/A	[18]	(i) PCS
	Rutaevin	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PCC
	Coniferin	HPLC-DAD-ESI-MS2	[9]	PAR
	Vanilloloside	HPLC-DAD-ESI-MS2	[9]	PAR
	N-methyltetrahydrocolumbamine	UPLC-Q/TOF-HDMS	[10]	PCC
N-acyl amines	Herculin	N/A	[19]	PAC
Phenolic acid	Ferulic acid	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) HPLC-TLC- NMR- EI-MS	(ii) [11]	(ii) PAC
	Methyl ferulate	CC	[4]	PCS
	Protocatechuic acid	CC	[4]	PCS
Quinic acid	Quinic acid	UPLC-Q/TOF-HDMS	[10]	PAC
	Neo-chlorogenic acid	HPLC-DAD-ESI-MS2	[9]	PCS and PAR
	3-O-feruloylquinic acid	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PAC
	3-O-feruloylquinic acid glucoside	UPLC-Q/TOF-HDMS	[10]	PCC
	4-O-feruloylquinic acid	HPLC	[22]	PCS
	5-O-feruloylquinic acid	HPLC	[22]	PCS
	Chlorogenic acid	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PAC
		(iii) HPLC	(iii) [23]	(iii) PAR
		(iv) HPLC-DAD-MS	(iv) [12]	(iv) PAR
	Methyl 3-O-feruloylquinate	HPLC-DAD-ESI-MS2	[9]	PAR
	Methyl 5-O-feruloylquinate	NMR	[24]	PAR
	3-Feruoyl-4-caffeoylquinic acid	HPLC-DAD-ESI-MS2	[9]	PAR
	Sanleng acid	NMR	[25]	PAC
Hydroxycinnamic acid	Caffeic Acid Methyl Ester	HPLC	[22]	PCS
Phytosterol	β-Sitosterol	N/A	[18]	PAC
Lignan	(+/-)-lyoniresinol	HPLC-DAD-ESI-MS2	[9]	PAR
	(+/-)-5,5′-dimethoxylariciresinol-4-O-glucoside	(i) HPLC-DAD-ESI-MS2	(i) [9]	(i) PCS and PAR
		(ii) UPLC-Q/TOF-HDMS	(ii) [10]	(ii) PCC
	Syringaresinol di-O-β-D-glucopyranoside	HPLC-DAD-ESI-MS2	[9]	PCS and PAR
	(-)-Syringaresinol	CC	[4]	PCS
Flavonoid	Amurensin	N/A	[13]	PAC
	Quercetin	HPLC-TLC- NMR- EI-MS	[11]	PAC
	Phellamurin	N/A	[18]	PAC
	Phellatin	N/A	[18]	PAC
	Phellavin	N/A	[18]	PAC
	Phellodendroside	N/A	[18]	PAC
	β-anhydronoricaritin	UV	[26]	PAR
	Icariside-1	UV	[26]	PAR
	Phellamuretin	UV	[26]	PAR
	Phelloside	UV	[26]	PAR
	Dihydrophelloside	UV	[26]	PAR
	Isovaleric acid	UV	[26]	PAR
	Kaempferol	UV	[26]	PAR
	D-glucose	UV	[26]	PAR
Rutaceae	Noricariside	N/A	[18]	PAC
Stigmastane	7-Dehydrostigmasterol	N/A	[17]	PAC
Coumarin	3-acetyl-3,4-dihydro-5,6-dimethoxy-1H-2-benzopyran-1-one	CC	[27]	PCS
Monosaccharide	Syringin	NMR	[25]	PAC
	Daucosterol	NMR	[25]	PAC
Paraben	N-propyl paraben	HPLC	[5]	PC
Phenolic lactone	Phellolactone	CC	[4]	PCS
Ferulate	N-butyl Ferulate	CC	[4]	PCS
	Amurenlactone A	CC	[4]	PCS
	Amurenamide A	NMR	[25]	PAC
Hydroxybenzaldehyde	4-hydroxybenzaldehyde	CC	[4]	PCS
Phenolic aldehyde	Vanillin	CC	[4]	PCS
Glycoside	Sinapyl aldehyde-4-O-beta-D-glucopyranoside	NMR	[24]	PAR
	3,4,5-Trimetoxyphenol O-β-D-glucopyranoside	HPLC	[22]	PCS
	2-methoxy-4-(2-propenyl)phenyl-beta-D-glucopyranoside	HPLC	[22]	PCS
	2-(p-hydroxyphenyl)-ethanol-1-O-β-D-apiofuranosyl (1–6)-O-β-D-glucopyranoside	HPLC-DAD-ESI-MS2	[9]	PCS and PAR
	2-(p-hydroxyphenyl) -ethanol-1-O-β-D-glucoside	UPLC-Q/TOF-HDMS	[10]	PCC
	3, 5-dihydroxybenzoicacid-O-xylopyranosyl-glucopyranoside	HPLC-DAD-ESI-MS2	[9]	PCS and PAR
Phenolic glycoside	Tachioside	HPLC	[22]	PCS
Glucoside	Salidroside	HPLC	[22]	PCS
	4-hydroxybenzyl alcohol	HPLC	[22]	PCS
Phenol	Methyl syringate	HPLC	[22]	PCS
Dehydrovomifoliol	(6S)-dehydrovomifoliol	HPLC	[22]	PCS
	(6R,7aR)-epiloliolide	HPLC	[22]	PCS

PAC: phellodendri amurensis cortex

PCS: phellodendron chinense schneid

PAR: phellodendron amurense rupr.

PCC: phellodendri Chinensis cortex

UPLC-ESI-Q-TOF-MS: ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry

CC: column chromatography

CE: capillary electrophoresis

HPLC/MSD: high-performance liquid chromatography coupled with mass spectrometric detection

UPLC–Qthe -TOF-MS: ultra-performance liquid chromatography with quadrupole TOF-MS

HPLC– ESI-MS2: high-performance liquid chromatography with electrospray ionization mass spectrometry coupled with photodiode array detection

UPLC-Q/TOF-HDMS: ultra-performance liquid chromatography-quadrupole/time-of-flight high-definition mass spectrometry

UV: UV detection

EI-MS: Electron ionization mass spectrometry

NMR: Nuclear magnetic resonance

TLC: Thin-layer chromatography

HPLC-DAD-MS: high-performance liquid chromatography coupled with diode array detection and mass spectrometry

Table 2

Molecular formula, molecular weight and chemical structures of compounds derived from PCC species (18 compounds).

Compound derivatives	Compound	Molecular formula	Molecular weight	Chemical structures
Alkaloid	Palmatine	C21H22NO4+	352.41 g/mol
	Magnoflorine	C20H24NO4+	342.41 g/mol
	(−)-Oblongine	C19H24NO3+	314.40 g/mol
	Menisperine	C21H26NO4+	356.44 g/mol
	(6aS)-1,2,10,11-tetramethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4H-dibenzo[de, g] quinolinium	C22H28NO4	370.47 g/mol
	Dasycarpamin	C17H21NO4	303.36 g/mol
	Tetramethyl-O-scutellarin	C19H18O6	342.35 g/mol
	Ƴ-hydroxybutenolide derivatives II	N/A
Limonoid	Niloticin acetate	C32H50O4	498.75 g/mol
	Obaculactone or limonin	C26H30O8	470.52 g/mol
	Derivative of obaculactone	N/A
	Obacunone or Obacunoic acid	C26H30O7	454.519 g/mol
	Piscidinol A	C30H50O4	474.73 g/mol
	Rutaevin	C26H30O9	486.52 g/mol
	N–methyltetrahydrocolumbamine	C21H26NO4+	356.44 g/mol
Phenolic acid	2-(p-hydroxyphenyl) -ethanol-1-O-β-D-glucoside	C9H12O	136.19 g/mol
Quinic acid	3-O-feruloylquinic acid glucoside	C22H28O15	532.45 g/mol
Lignan	(+/-)-5,5′-dimethoxylariciresinol-4-O-glucoside	C28H38O13	582.6 g/mol

Table 3

Molecular formula, molecular weight and chemical structures of compounds derived from PCS species (44 compounds).

Compound derivatives	Compound	Molecular formula	Molecular weight	Chemical structures
Alkaloid	Berberine	C20H18NO4+	336.37 g/mol
	8,13-dioxo-14-butoxycanadine	C24H25NO7	439.46 g/mol
	Brucine	C23H26N2O4	394.47 g/mol
	Palmatine	C21H22NO4+	352.41 g/mol
	Phellodendrine	C20H24NO4+	342.41 g/mol
	Magnoflorine	C20H24NO4+	342.41 g/mol
	Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol	C20H19NO4	337.38 g/mol
	Lotusine	C19H24NO3+	314.40 g/mol
	(−)-Oblongine	C19H24NO3+	314.40 g/mol
	Isomer-of-magnoflorine	N/A
	Tetrahydrojatrorrhizine	C20H23NO4	341.41 g/mol
	Menisperine	C21H26NO4+	356.44 g/mol
	Columbamine	C20H20NO4+	338.38 g/mol
	Niloticin acetate	C32H50O4	498.75 g/mol
	Piscidinol A	C30H50O4	474.73 g/mol
Quinic acid	Chlorogenic acid	C16H18O9	354.31 g/mol
	Neo-chlorogenic acid	C16H18O9	354.31 g/mol
	3-O-feruloylquinic acid	C17H20O9	368.34 g/mol
	4-O-feruloylquinic acid	C17H20O9	368.34 g/mol
	5-O-feruloylquinic acid	C17H20O9	368.34 g/mol
Hydroxycinnamic acid	Caffeic Acid Methyl Ester	C10H10O4	194.19 g/mol
Phenolic acid	Ferulic acid	C10H10O4	194.19 g/mol
	Methyl ferulate	C11H12O4	208.21 g/mol
	Protocatechuic acid	C7H6O4	154.12 g/mol
Lignan	(+/-)-5,5′-dimethoxylariciresinol-4-O-glucoside	C28H38O13	582.6 g/mol
	Syringaresinol di-O-β-D-glucopyranoside	C33H44O18	728.70 g/mol
	(-)-syringaresinol	C22H26O8	418.44 g/mol
Coumarin	3-acetyl-3,4-dihydro-5,6-dimethoxy-1H-2-benzopyran-1-one	C13H14O5	250.25 g/mol
Paraben	N-propyl paraben	C10H12O3	180.20 g/mol
Phenolic lactone	Phellolactone	C13H14O8	298.25 g/mol
Ferulate	N-butyl Ferulate	C14H18O4	250.29 g/mol
	Amurenlactone A	C17H20O9	368.34 g/mol
Hydroxybenzaldehyde	4-hydroxybenzaldehyde	C7H8O2	124.14 g/mol
Phenolic aldehyde	Vanillin	C8H8O3	152.15 g/mol
Glycoside	3,4,5-trimetoxyphenol O-β-D-glucopyranoside	C9H11O3	167.18 g/mol
	2-methoxy-4-(2-propenyl)phenyl-beta-D-glucopyranoside	C16H22O7	326.35 g/mol
	2-(p-hydroxyphenyl)-ethanol-1-O-β-D-apiofuranosyl (1–6)-O-β-D-glucopyranoside	C9H12O	136.19 g/mol
	3, 5-dihydroxybenzoicacid-O-xylopyranosyl-glucopyranoside	C8H8O3	152.15 g/mol
Phenolic glycoside	Tachioside	C12H16O8	288.25 g/mol
Glucoside	Salidroside	C14H20O7	300.31 g/mol
	4-Hydroxybenzyl alcohol	C7H8O2	124.14 g/mol
Phenol	Methyl Syringate	C10H12O5	212.20 g/mol
Dehydrovomifoliol	(6S)-dehydrovomifoliol	C13H18O3	222.28 g/mol
	(6R,7aR)-epiloliolide	C11H16O3	196.25 g/mol

Table 4

Molecular formula, molecular weight and chemical structures of compounds derived from PAC species (34 compounds).

Compound derivatives	Compound	Molecular formula	Molecular weight	Chemical structures
Alkaloid	Berberine	C20H18NO4+	336.37 g/mol
	Berberrubine	C19H16NO4+	322.34 g/mol
	Berberastine	C20H18NO5+	352.37 g/mol
	Δ7-Dehydrosophoramine	C15H18N2O	242.32 g/mol
	Palmatine	C21H22NO4+	352.41 g/mol
	Tetrahydropalmatine	C21H25NO4	355.43 g/mol
	Phellodendrine	C20H24NO4+	342.41 g/mol
	Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol	C20H19NO4	337.38 g/mol
	Lotusine	C19H24NO3+	314.40 g/mol
	Menisperine	C21H26NO4+	356.44 g/mol
Isoquinoline alkaloid	Armepavine	C19H23NO3	313.40 g/mol
	Demethyleneberberine	C19H18NO4+	324.36 g/mol
Limonoid	Kihadanin B	C26H30O9	486.52 g/mol
	Niloticin	C30H48O3	456.71 g/mol
	Obaculactone or limonin	C26H30O8	470.52 g/mol
	Obacunone or Obacunoic acid	C26H30O7	454.52 g/mol
N-acyl amines	Herculin	C16H29NO	251.41 g/mol
Phenolic acid	Ferulic acid	C10H10O4	194.19 g/mol
Quinic acid	Quinic acid	C7H12O6	192.17 g/mol
	3-O-feruloyl quinic acid or 5-O-feruloyl quinic acid	C17H20O9	368.34 g/mol
	Chlorogenic acid	C16H18O9	354.31 g/mol
	Sanleng acid	C18H34O5	330.47 g/mol
Phytosterol	β-sitosterol	C29H50O	414.72 g/mol
Flavonoid	Amurensin	C26H30O12	534.51 g/mol
	Quercetin	C15H10O7	302.24 g/mol
	Phellamurin	C26H30O11	518.52 g/mol
	Phellatin	C26H30O12	534.51 g/mol
	Phellavin	C26H32O12	536.53 g/mol
	7-dehydrostigmasterol	C29H50O	414.72 g/mol
Rutaceae	Noricariside	C26H30O12	534.51 g/mol
Stigmastane	Phellodendroside	C26H30O11	518.52 g/mol
Monosaccharide	Syringin	C17H24O9	372.37 g/mol
	Daucosterol	C34H58O6	562.83 g/mol
Ferulate	Amurenamide A	C17H25NO9	387.39 g/mol

Table 5

Molecular formula, molecular weight and chemical structures of compounds derived from PAR species (84 compounds).

Compound derivatives	Compound	Molecular formula	Molecular weight	Chemical structures
Alkaloid	Berberine	C20H18NO4+	336.37 g/mol
	Bis-[4-(dimethylamino)phenyl]methanone	C17H20N2O	268.36 g/mol
	Dihydrocyclobuxine-D	C25H44N2O	388.64 g/mol
	3,4-Dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy-2-methyl-8-isoquinolinol	C20H24NO4+	342.41 g/mol
	3,4-Dihydro-1-[(4-hydroxyphenyl)methyl]-7-methoxy-2-methyl-6-isoquinolinol	C20H17NO5	351.36 g/mol
	7,8-Dihydroxyrutaecarpine	C18H13N3O3	319.32 g/mol
	4-Dimethylamino-4 -isopropylbenzene	C18H22NO+	268.38 g/mol
	Evodiamine	C19H17N3O	303.37 g/mol
	Palmatine	C21H22NO4+	352.41 g/mol
	Pteleine	C13H13NO3	231.25 g/mol
	(-)-(R)-platydesmin	C15H19NO3	261.32 g/mol
	Noroxyhydrastinine	C10H9NO3	191.19 g/mol
	Chilenine	C19H15NO7	369.33 g/mol
	Phellodendrine	C20H24NO4+	342.41 g/mol
	Magnocurarine	C19H24NO3+	314.40 g/mol
	Magnoflorine	C20H24NO4+	342.41 g/mol
	Jatrorrhizine or Neprotin, 2,9,10-Trimethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol	C20H19NO4+	337.38 g/mol
	13-Methoxyjatrorrhizine	C21H22NO5+	368.41 g/mol
	Ƴ-Fagarine	C13H11NO3	229.24 g/mol
	Canthin-6-one	C14H8N2O	220.23 g/mol
	4-Methoxy-N-methyl-2-quinolone	C11H11NO2	189.21 g/mol
	Candicine	C10H16NO+	166.24 g/mol
	Lotusine	C19H24NO3+	314.40 g/mol
	N-Methylhigenamine-7-O-glucopyranoside	C17H20N2O	268.36 g/mol
	N-methylhigenamine-7-O-β-D-glucopyranoside	N/A	N/A
	(−)-Oblongine	C19H24NO3+	314.40 g/mol
	Isomer-of-berberine	N/A
	Isomer-of-magnoflorine
	Isomer-of-palmatine
	Tetrahydroreticuline	C19H22NO4+	328.39 g/mol
	Tetrahydrojatrorrhizine	C20H23NO4	341.41 g/mol
	Menisperine	C21H26NO4+	356.44 g/mol
	(+) N-methylcorydine	C21H26NO4+	356.44 g/mol
	N-Methyl Tetrahydropalmatine	C22H28NO4+	370.47 g/mol
	N-Methylflindersine	C15H15NO2	241.29 g/mol
	Litcubine	C19H22NO4+	328.39 g/mol
	Hydroxyl-palmatine	C22H22O5	366.41 g/mol
	11-Hydroxylpalmatine	C21H22NO5+	368.41 g/mol
	13-Hydroxypalmatine	C21H22NO5+	368.41 g/mol
	7-Hydroxy-8-methoxydedihydrorutaecarpine	N/A
	Tetrahydropalmatine	C21H25NO4	355.43 g/mol
	5,8,13,13a-Tetrahydro-2,9,10,11-tetrahydroxy-3-methoxy-7-methyl-6H-dibenzo[a,g]quinolizinium	C21H20NO6+	382.39 g/mol
	Tetrahydroberberine	C20H21NO4	339.39 g/mol
	Xanthoplanine	C21H26NO4+	356.44 g/mol
	N-methylphoebine	C22H26NO5+	384.45 g/mol
	Columbamine	C20H20NO4+	338.38 g/mol
	Dihydroxyl-jatrorrhizine	N/A
	Epiberberine	C20H18NO4+	336.37 g/mol
	Rutecarpine	C18H13N3O	287.32 g/mol
	Skimmianine	C14H14NO4+	260.27 g/mol
	Tembetarine	C21H22NO4+	352.41 g/mol
	8-Oxoberberine	C20H17NO5	351.36 g/mol
	8-Oxoepiberberine	C20H17NO5	351.36 g/mol
	8-Oxopalmatine	C21H21NO5	367.40 g/mol
	Oxyberberine	C20H17NO5	351.36 g/mol
	Oxypalmatine	C21H21NO5	367.40 g/mol
Limonoid	Obaculactone or limonin	C26H30O8	470.52 g/mol
	Obacunone or Obacunoic acid	C26H30O7	454.52 g/mol
	12α-hydroxylimonin	C26H30O9	470.52 g/mol
	Rutaevin	C26H30O9	486.52 g/mol
	Coniferin	C16H22O8	342.34 g/mol
	Vanilloloside	C14H20O8	316.31 g/mol
Phenolic acid	2-(p-hydroxyphenyl)-ethanol-1-O-β-D-apiofuranosyl (1–6)-O-β-D-glucopyranoside	C9H12O	136.19 g/mol
	3, 5-dihydroxybenzoicacid-O-xylopyranosyl-glucopyranoside	C8H8O3	152.15 g/mol
	Ferulic acid	C10H10O4	194.19 g/mol
Quinic acid	Neochlorogenic acid	C16H18O9	354.31 g/mol
	3-O-feruloyl quinic acid or 5-O-feruloyl quinic acid	C17H20O9	368.34 g/mol
	Chlorogenic acid	C16H18O9	354.31 g/mol
	Methyl 3-O-feruloylquinate	C18H22O9	382.37 g/mol
	Methyl 5-O-feruloylquinate	C8H13O6	205.19 g/mol
	3-Feruoyl-4-caffeoylquinic acid	C26H26O12	530.48 g/mol
Lignan	(+/-)-lyoniresinol	C22H28O8	420.46 g/mol
	(+/-)-5,5′-dimethoxylariciresinol-4-O-glucoside	C28H38O13	582.6 g/mol
	Syringaresinol di-O-β-D-glucopyranoside	C33H44O18	728.70 g/mol
Flavonoid	β-anhydronoricaritin	N/A
	Icariside-1	C26H28O11	516.50 g/mol
	Phellamuretin	C20H20O6	356.37 g/mol
	Phelloside	C31H40CrO17	736.64 g/mol
	Dihydrophelloside	C31H44CrO17	740.67 g/mol
	Isovaleric acid	C5H10O2	102.13 g/mol
	Kaempferol	C15H10O6	286.24 g/mol
	D-glucose	C6H12O6	180.16 g/mol
Paraben	N-propyl paraben	C10H12O3	180.20 g/mol
Glycoside	Sinapyl aldehyde-4-O-beta-D-glucopyranoside	C13H14O6	266.25 g/mol

5. Pharmacology

5.1. Anti-Inflammatory Effects

The PAR extract could efficiently adjust lipopolysaccharide (LPS)-induced release of nitric oxide (NO) and inducible nitric oxide sythase (iNOS) production in microglia of both BV2 cells and mice. Besides, PAR extract could also attenuate the LPS-stimulated release of tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) from microglia. More importantly, the latter mechanism is more significant than the previous one in terms of IL-1β release. The inhibition of NO suggested that the extract of PAR probably could affect NO-induced neuronal cell death [28]. Another study had also vindicated the anti-inflammatory effect of PC extract on ear swelling model of mice. Magnoflorine and phellodenrine belong to alkaloids isolated from PC that are the effective compounds against oxazolone-induced contact-delayed type hypersensitivity (DTH) reaction induced by picryl chloride. Another mechanism in this study is that PC could reduce myeloperoxidase (MPO) activity to its utmost by restraining leukocyte mobility and/or a secretory activity by phellodendron. In contrast, PC extract exerts no effect on phospholipase A2 (PLA2) activity and less effect in arachidonic acid (AA) induced swelling [29]. PC showcased the inhibitory effect on the build-up of NO in LPS-stimulated macrophage Raw 264.7 cells and inhibited iNOS expression. In contrast, PC has no effect on cyclooxygenase-2 (COX-2) expression in LPS-induced RAW 264.7 cells [30]. PCC and PAC could not only shrink the size of edema, but also reduce the activity of MPO and the content of reactive oxygen species (ROS) caused by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). They can also restrain the levels of TNF-α, Il-1β, IL-6, and COX-2 in mice treated by TPA. Remarkably, there are a number of chemical compounds in these two species of PC including berberine, palmatine, and phellodendrine. And they are viewed as the anti-inflammatory active candidates. In addition, they may jointly take effect in this regard [3]. The nonalkaloid PAR extract suppressed NO production; besides, limonin and obakunone significantly downregulated NO production and iNOS gene expression via an nuclear factor-κB (NF-κB)-mediated pathway [11]. PC could reverse the airway inflammation by reducing the infiltration of inflammatory cells and releasing of inflammatory mediators into the affected lung and airways. This could vindicate its applications on the infectious pulmonary diseases [31].

5.2. Antimicrobic Effects

For the antibacterial effect, the study showed both aqueous and ethanol extracts of PAR exerted an intermediate antimicrobial effect. Besides, PAR extracts had a slightly better effect on gram-positive bacteria than gram-negative one because of different sensitivity. The most sensitive bacteria is Streptococcus pyogenes [33]. For the bacteria in the oral cavity, PC could have a strong inhibitory effect on Porphyromonas gingivalis; moderate inhibitory effect on Streptococcus mutans; partial effect on Streptococcus sanguis; no effect on Streptococcus mitis [34]. Propionibacterium acnes which are the culprit for acne is active to PC which is one of the crude herbs in the clinical trial and the second best herb in terms of antiacne activity in this study [39]; Mycoplasma hominis which causes infections on humans genital tracts and respiratory tracts is susceptive to PC, and the susceptibility rate is 93% [35]. Salmonellosis which is responsible for food poisoning is vulnerable to PC extract because it can lower the IgG levels and induce TNF-α expression in RAW264.7 cells [36]. In case of PAR, berberine could restrain the bacterial adhesion of Staphylococcus aureus and intracellular invasion into human gingival fibroblasts [37]. Moreover, berberine could attenuate the aminoglycoside resistance of P. aeruginosa, A. xylosoxidans, and B. cepacia in the MexXY-dependent manner. It also inhibits MexXY- or MexVW-mediated resistance of P. aeruginosa mutants, synergistically restrains MexXY-mediated gentamicin resistance in P. aeruginosa mutants, and enhances the synergistic effect of piperacillin and amikacin in multimedication resistant P. aeruginosa strains. The extract of PCS significantly downregulated minimal inhibitory concentrations (MICs) of amikacin and gentamicin in the two multimedication resistant P. aeruginosa strains [38]. PC showed its potential on the inhibition of Propionibacterium acnes strains. Its MIC50 and MIC90 were 24 μg/ml and 190 μg/ml, respectively [39]. For fungal infections, the monomers of PC showed antifungal activity through compromising the integrity of fungal cell wall and cell membrane and increasing the expressions of energy metabolic genes. Therefore the life expectancy of Microsporum Canis is shortened. Furthermore, the mingling use of palmatine hydrochloride and berberine hydrochloride could effectively treat Microsporum Canis induced dermatomycosis in rabbit [40]. For virus infections, the ethanol extract of PAR exerted moderate effect against Herpes Simplex Virus by either interrupting virion envelope structures or disguising as indispensable viral compounds for absorption or infiltration of host cells [33]. Another study had proved that PAR has a broad spectrum of functions against virus-like VSV-GFP, PR8-GFP, NDV-GFP, HSV-GSP, H3-GFP, and EV-71 in vitro and also has effects on different strains of influenza A such as H1N1, H5N2, H7N3, and H9N2 in vivo mice model [41].

5.3. Antitumor Effects

There are 3 compounds in PCS that have been found to resist three types of tumours which included leukemic cell lines K562 and HEL, breast cancer cell line MDA, and prostate cancer cell line PC3. The compound [(21S, 23R) epoxy-24-hydroxy-21β, 25-diethoxy] tirucalla-7-en-3-one has a relatively strong effect as Adriamycin against four tumors with the measurement of IC50; toonaciliatin K and piscidinol A have a comparably moderate effect in this regard [42]. There are 9 most effective compounds of PC for prostate cancer, namely, magnoflorine-O-glucuronide, (p-hydroxybenzyl)-6, 7-dihydroxy-N-methyl tetrahydro iso-quinoline-7-O-p-D-glucopyranosid, magnoflorine, menisperine-O-glucuronide, menisperine, berberine, Jatrorrhizine, obaculactone, and obacunone [43]. Polysaccharides from an aqueous extract of PCS act on cell-mediated stimulation and humoral immunity instead of tumor cell inhibition to exert tumoricidal activity. Specifically, some polysaccharides stimulate macrophages and NK cells via β-glucan-binding lectin site of complement receptor type 3 [44].

5.4. Antigout Effects

Si-Miao-Wan (SMW) formula had been proved to be effective for gout and gouty arthritis. In this formula, PC is the monarch herb which is the core ingredient to guide the other three herbs indicating that the alkaloids and organic acids in PC are the potential compounds for SMW. Alkaloids include candicine, oblongine, phellodendrine, tembetarine, magnoflorine, lotusine, n-methylterahydrocolumbamine, menisperine, noroxyhydrastinine, demethyleneberberine, tetrahydropalmatine, oxyberberine, armepavine, oxypalmatine, columbamine, jatrorrhizine, thalifendine, berberrubine, n-methyl canadine, palmatine, berberine, obaculactone, obacunone, and amurenlaetone B, and organic acids include neochlorogenic acid, chlorogenic acid, cryptogenic acid, cryptochlorogenin acid, caffeoyl-CH2-O-quinic acid, 3-O-feruloylqinic acid, ferulic acid, and sanleng acid [45]. Er-Miao-Wan formula is a modified version of SMW, which had been elucidated for its chief ingredient PCS which exerts potent hypouricemic effect [46].

5.5. Antiulcer Effects

Peptic ulcers are associated with psychological stress and mental illness. The middle dosage of PC extract could significantly reduce the levels of serotonin in the brain and noradrenaline in the adrenal gland. Both serotonin and noradrenaline take effect in the mental depression. Besides, for the molecule in PC, berberine has the ability to inhibit monoamine oxidase-A and modulate the brain noradrenaline, serotonin, and dopamine levels [47]. Another study revealed that PC could protect the gastric mucosa by reinforcing the gastric mucosal barrier through endogenous sulfhydryl compounds and diethyldithiocarbamate-sensitive compounds [48].

5.6. Antioxidant Effects

The antioxidant activity of PAR is proportional to its extract's concentration. In another aspect, the ethanol extract exhibited a better antioxidant effect because of its high concentration of phenolics and flavonoids than aqueous extract [33]. Phellodendrine from PC could play an antioxidant role by modulating the AKT/NF-κB pathway in the zebrafish embryo. Besides, phellodendrine could undo the expression of AKT and NF-κB, IKK, and COX-2 [49].

5.7. Sun Screening Effects

The sun screening effects of PC have been demonstrated through an experiment which was designed for sun screening effect of 50% alcohol extracts of 100 Chinese herbal medicines. The study showed PC could absorb 91.8% of ultraviolet-C, 79.1% of ultraviolet-B, and 50.7% of ultraviolet-A. It is regarded as highly effective for sun screening if the absorption rate of ultraviolet is higher than 90%. Therefore, PC could be a strong candidate for sunproof of ultraviolet-C [50]. Also, PC could also improve skin oxidative lesion induced by ultraviolet radiation via decreasing lipid peroxidation and increasing antioxidant enzymes activities [51].

5.8. Other Effects

PC stimulates longitudinal bone growth and chondrocyte proliferation via upregulating bone morphogenetic protein-2 (BMP-2) and insulin-like growth factor (IGF-1) expression in the growth cartilage [52]. Besides, PC could activate the fibrinogen system to take the hemostatic effect. This validated charcoaled PC could stop bleeding [53]. The extract of PC also shows neuroprotective effect through adjusting the PC-12 cell apoptosis which was induced by 1-methyl-4-phenylpyridinium (MPP+) and hindered the release of cytochrome C into the cytosol [54]. PAR could ease the symptoms of atopic dermatitis by decreasing the numbers of mast cells, serum levels of TNF-α, and INF- γ and the expression levels of cytokines [56]. PAR could delay or even prevent the progression of diabetic nephropathy by correcting the high blood sugar state, antioxidant enzyme system, and kidney malfunction and reversing histopathological changes inflicted by diabetes on kidney [57]. To further elaborate its mechanism on the compound level, berberine could attenuate the renal malfunction by inhibiting renal aldose reductase and decreasing oxidative stress [58]. Magnoflorine and phellodendrine could inhibit the immune response by suppressing local graft versus host reaction and induction phase of picryl chloride-induced delayed-type hypersensitivity [59]. To counter asthma attack, the extract of PCS inhibits tracheal smooth muscle contraction induced by high K+. Meanwhile, it could also block tracheal smooth muscle concentration induced by Nifedipine [6]. The pharmacological activities of PC and its related derivatives have been listed in Table 6.

Table 6

Pharmacological activities of PC and processed PC.

Pharmacological Activity	Tested Substance	In vivo/ In vitro	Model or sample	Active concentration	Administration (In vivo)	References
Anti-inflammatory effect	PAR extract with voucher specimens	In vitro	BV2 cells (Mouse microglial cell line)	100 μg/ml		[28]
	PCC extract	In vivo, in vitro	12-O-Tetradecanoylphorbol-13-acetate-induced mouse ear edema	(i) TPA and AA tests: 0.5 mg/ear(ii) TPA multiple application: 1 mg/ear(iii) DTH test: 1 mg/ear	Topical application	[29]
	PCC extract with voucher specimens	In vivo, in vitro	lipopolysaccharides-induced systemic inflammation mice model and macrophage RAW 264.7 cells	1,10,100 μg/mL	Oral administration	[30]
	Ethanol extract of PCC with voucher specimens	In vivo	12-O-tetradecanoyl-phorbol-13-acetate- induced ear edema in mice	200-400 mg/kg	Administered intragastrically	[3]
	PAR methanol extract with voucher specimens	In vitro, in vivo	ICR mice and male Wistar rats	IC50:Methanol extract 20.9 ± 3.8 μg/mL;Non-alkaloids22.0 μg/mL;Limonin 15.8 ± 5.2 μm;Obakunone2.6 ± 1.1 μm	Oral administration	[11]
	PCC methanol extract with voucher specimens	In vivo	Lipopolysaccharides- induced acute airway inflammation on a mouse model	100, 200 and 400 mg/kg	Administrated by gavage	[31]
	Demethyleneberberine	In vivo	Acute colitis mice model	150,300 mg/kg	Oral administration	[32]
Anti-bacterial effect	Ethanol Extract of PAR;Aqueous extract of PAR	In vitro	Enterococcus faecium, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa	MIC and MBC: 3.676 mg/ml and 7.353 mg/ml for ethanol extract;6.25 mg/ml and 50 mg/ml for aqueous extract		[33]
	PCC extract with voucher specimens	In vitro	Streptococcus. mitis,Streptococcus. sanguis,Streptococcus. mutans,Streptococcus. gingivalis	2.5 g/ml		[34]
	PCC extract	In vitro	Mycoplasma hominis	0.24-250 mg/ml		[35]
	Aqueous extract of PCC	In vivo, In vitro	S. Typhimurium 21 infected mouse model	2.5 or 5 mg/day	Administrated by gavage	[36]
	Berberine in PAR	In vitro	Staphylococcus aureus	32 to 128 μg/mL		[37]
	Berberine in PCS	In vitro	P. aeruginosa	100 ml		[38]
	PCC	In vitro	Propionibacterium acnes	MIC50%: 24 μg/mLMIC90%:190 μg/mL		[39]
Anti-fungal effect	Berberine hydrochloride, palmatine hydrochloride	In vitro, In vivo	Microsporum Canis –induced dermatitis in rabbits	MICs 1 mg/ml	Administered through the sterile pipette tip	[40]
Anti-viral effect	Ethanol extract of PAR;Aqueous extract of PAR	In vitro	African green monkey kidney cells	6.73 ± 0.87 mg/ml for aqueous extract;4.26 ± 0.59 mg/ml for ethanol extract		[33]
	Aqueous extract of PAR with voucher specimens	In vitro, in vivo	H1N1, H5N2, H7N3 or H9N2 infected BALB/c mice	0.8 μg/g in a total volume of 200 μl at 1, 3 and 5 days before infection	Oral administration	[41]
Anti-tumor effect	PCS extract with voucher specimens	In vitro	(i) Leukemic cell lines K562(ii) Leukemic cell lines HEL(iii) Breast cancer cell line MDA(iv) Prostate cancer cell line PC3	(i) IC50 of Compound 1: 7.66 ±2.08;(ii) IC50 of compound 3: 14.30 ± 1.93;(iii) IC50 of compound 4: 11.81 ± 2.79		[42]
	PCC extract	In vivo, in vitro	Prostate cancer cell infested Male BALB/c-nude mice model	1.6 g/kg per day for 28 days	Administered intragastrically	[43]
	Aqueous extract of PCS with voucher specimens	In vitro In vivo	Sarcoma 180 ascites cells implanted Mice model	2 mg/100g;5 mg/100g;10 mg/100g	Injected intraperitoneally daily for 10 days	[44]
Anti-gout effect	Compounds of Si-Miao-Wan (containing PCC)	In vivo	Male Sprague-Dawley rats	1.0 ml/100 g	Oral administration	[45]
	PCS extract with voucher specimens	In vivo	Uricase inhibitor potassium oxonate induced male ICR mice model	480 mg/kg	Oral or intraperitoneal administration	[46]
Anti-ulcer effect	Ethanol extract of PCC with voucher specimens	In vivo In vitro	Acetic acid-induced chronic gastric ulcers on Sprague Dawley rats model	30 mg/kg/day	Administered intragastrically once a day for seven days.	[47]
	Aqueous extract of PCC	In vivo	Ethanol-induced gastric lesions on Male Wistar rats model	100 mg/kg	Oral administration	[48]
Anti-oxidant effect	Ethanol extract of PAR;Aqueous extract of PAR	In vitro	For anti-microbial Enterococcus faecium, Staphylococcus aureus, Streptococcus pyogenes,Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa;Anti-herpes simplex virus tested on African green monkey kidney cells	25 mg/ml		[33]
	Phellodendrine isolated from PCC extract	In vivo	AAPH-induced oxidative stress on zebrafish embryo model	200 μg/mL	Waterborne exposure	[49]
Sun screening effect	PCC extract + 50% ethanol	In vitro	PC extract+50% ethanol	0.5 mg/ml		[50]
	PCC extract	In vivo	UVB lamp inflicted skin lesions on the dorsal of the rats model	200, 400 or 800 mg/kg, once daily for 11 days	Oral administration	[51]
Bone-growth effect	PCC extract	In vivo	72 intact 21-day-old female Sprague–Dawley rats	100 and 300 mg/kg	Oral administration	[52]
Hemostatic effect	PCC Carbonisatus-carbon dots	In vivo In vitro	Mouse tail amputation and liver scratch on male Kunming mice models	5, 2 and 1 mg/kg	Subcutaneous administration	[53]
Neuroprotective effect	PCC extract with voucher specimens	In vitro	PC-12 cells	10 and 30 μg/mL		[54]
	PCC and PAC extract with voucher specimens	In vitro	PC-12 cells	0.1 and 1 g/ml for 2 hours		[55]
Counter-atopic dermatitis effect	Salt processed PAC extract with voucher specimens	In vivo	2,4-dinitrochlorobenzene induced skin lesions on the NC/Nga mice model	200 μl	Topical administration	[56]
Counter-diabetic nephropathy effect	PAR aqueous extract	In vivo	Streptozotocin-induced diabetes on male Sprague-Dawley rats model	379 mg/kg	Oral administration	[57]
	Berberine	In vivo	Streptozotocin-induced diabetes on male Wistar rats model	200 mg/kg once a day for 12 weeks	Oral intubation	[58]
Immunity suppressing effect	Phellodendrine and cyclophosphamide isolated from PCC in saline water	In vivo	ddY mice, BALB/c mice, and Hartlay guinea pigs	(i) 0.1 ml/10 g for mice(ii) 1 ml for guinea pigs	Administered intraperitoneally	[59]
Anti-asthmatic effect	n-butyl alcohol extract of PCS with voucher specimens	In vivo	BALB/c mice asthmatic model induced by saline solution	The IC50 of n-butyl alcohol extract of PCS was 12.2 ± 1.3 μg/mL	intranasally	[6]

6. Pharmacokinetics

According to Chinese Pharmacopeia (Edition 2015), phellodendrine has been used as one of the evaluating indexes of PC. Phellodendrine could be rapidly absorbed in tissues such as plasma, liver, spleen, kidney, and brain. Besides, kidney is the major distribution tissue and the target organ of phellodendrine. Furthermore, the experimental study on animal suggested that this constituent has no long-term build-up effect on the tissues. Intriguingly, the extract of phellodendrine could be found in the animal brain tissue indicating that this constituent may penetrate the common medication's biggest hurdle: blood-brain barrier. The maximum concentration time is at 5 minutes after intravenous administration. The elimination half-life is no longer than 2 hours [63]. Another constituent from PC is magnoflorine which shows low bioavailability and high absorption and elimination rates after oral and intravenous administration of this constituent in pure compound form. While its bioactivity can be dramatically increased, absorption and elimination rates can be significantly decreased after oral administration of the PC decoction. Similarly, with oral administration of mixture, magnoflorine (40 mg/kg) and berberine (696.4 mg/kg, the equivalent dosage in PC decoction), the bioavailability and absorption and elimination rates have a similar trend. It suggested berberine plays an important role in the drug-drug interaction with magnoflorine in the PC decoction. On the other hand, these findings also warn us that the mingling use of berberine and magnoflorine possibly increases the risk of toxicity which possibly gives some support to the theory that herbal medicine may achieve better therapeutic effects and fewer side effects [64]. When it comes to the different type of processed PC, they have different kinds of effects. For the raw PC, it could downregulate CYP1A2 and activate CYP3A4. As for rice-wine and salt-water processed PC, they can alter the activities of cytochrome P450. Also, rice-wine processed PC alone can counter the inhibitory effect of CYP1A2 and promote the induction of CYP3A4 [65].

6.1. Toxicity and Contraindication

Several studies have been conducted regarding the toxicology of PC applications. So far, no conclusive result has been reached due to the controversial results from different studies. The common allegation for PC application is neonatal jaundice and kernicterus. Due to this concern, it even causes the complete ban on the use of related herbs including PC in Singapore since 1978. Besides, according to the latest Singaporean official regulations for health supplements guideline, PC is still on the list of prohibited or restricted ingredients. However, according to a cohort study, under the guidance of Chinese medicine practitioners, the application of PC's berberine is clinically safe even in patients who have hematological diseases with profound cytopenia and multiple comorbidities. Despite these, some precautionary measures such as bilirubin and hemoglobin monitoring are still required for the patients who have underlining hemolytic disease. On the other hand, the restriction for PC is necessary for the users in their peripartum and neonatal period due to the concern of its aggravation risk for neonatal jaundice and kernicterus [66].

6.2. Processing, Differentiation, and Authentication

Traditional Chinese medicine (TCM) processing or preparation or “Pao Zhi” in Chinese is a unique technique and process in TCM. Pao Zhi is a technique to turn the raw herbs into decoction pieces. This technique must be performed under the guidance of TCM's theory to satisfy the different requirements of medicinal materials and special production processes. The quality of Pao Zhi directly affects the therapeutic effects of herbal medicine [67]. It has a time-honored history because as early as 5 B.C. during the Jin dynasty, “Leigong Treatise on the Preparation” was composed as a book for Pao Zhi. It systematically summarized the herbal processing techniques until the Jin dynasty. Intriguingly, it stated that the right way of using the bark of PC is to remove the coarse bark [68]. In the Song dynasty, Pao Zhi had regulated a mandatory process for Chinese medicinal product [67].

In terms of PC's processing, TCM doctors in history emphasized the importance of PC's processing and recorded 16 kinds of methods for PC's processing in the books. Nowadays, the most common types of processing are raw PC, PC fried with salt, PC fried with wine, PC fried with honey, and fried-to-charcoal PC [69]. However, it still lacks official standard when it comes to quantity and quality of the processed PC and its subspecies; some of the existing pioneer studies could explain this ambiguous and abstract concept in a scientific way. Besides, for PC's quality control, the most practical approach is to use thin layer chromatography (TLC) for qualitative and high-performance liquid chromatography (HPLC) for quantitative measurement [70]. According to the results of thin layer chromatography, water percentage in the raw PC is less than 10.0%, PC fried with salt is less than 8.0%, PC fried with wine is less than 7.0%, and PC fried with honey is less than 8.0%. Total ash content in the raw PC is less than 8.0%; acid insoluble ash content is less than 0.8%; PC fried 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 ash content is less than 0.8%; PC fried with honey is less than 8.0%; acid insoluble ash content is less than 0.4%. For alcohol-soluble extract, the raw PC is more than 16.0%, PC fried with salt is more than 20.0%, PC fried with wine is more than 16.0%, and PC fried with honey is more than 22.0%. For percentage of phellodendrine, the raw PC is more than 0.41%, and berberine is more than 3.92%; PC fried with salt is more than 0.36%, and berberine is more than 3.89%; PC fried with honey is more than 0.37%, and berberine is more than 3.90% [69].

Previously, the differentiation of PCS and PAR is based on the experiences of the herbal professionals to distinguish the minor differences from their appearances in naked eyes and microscope. Due to the increasing mixing applications and counterfeits, more efficient and accurate approaches are required. It is noticeable that the mass fractions of obaculactone and obacunone have a plunging order among raw PC, PC fried with wine, and PC fried with salt. Therefore, it is reasonable to deduce limonin and obacunone have been undergoing a series of chemical reactions during herbal processing. For differentiation of PCS and PAR, the mass fractions of limonin and obacunone have a significant difference between PCS and PAR. The mass fraction of obaculactone and obacunone in PAR is 10 times higher than in PCS. As a result, limonin and obacunone could be utilized as the differential targeted chemical constituents for PC's differentiation [71]. HPLC method demonstrates that PC and charcoaled PC have a significant disparity in terms of characteristic chromatograms and chemical constituents. The peak numbers and proportions of characteristic chromatograms are reducing with the increasing temperature of charcoaled PC. On the other hand, due to the heating effect, berberine hydrochloride will transfer into berberrubine by losing one methyl. As a result, berberrubine is vindicated to be another targeted chemical constituent for charred PC identification [72]. For authentication of PC and its subspecies, berberine hydrochloride could be used as another targeted chemical constituent except for limonin and obacunone as mentioned above [73].

7. Discussion

This review work has illustrated the diverse bioactive properties of PC and its species associated with active pharmacological actions in vitro and in vivo. Its clinical applications which are demonstrated in these experimental studies indicated the potency of the bioactive compounds and its pharmacological effects.

The diverse derivatives are the backbone for the pharmaceutical efficacies of PC and its species. The alkaloids play a very significant role in this regard not only because they account for a great proportion of constituents in the whole herb, but also because these constituents are relatively well-studied compared to other constituents in other derivatives. Berberine, magnoflorine, palmatine, and phellodendrine are viewed as the anti-inflammatory active candidates in experimental studies. Besides, palmatine and berberine could exert antimicrobial effects. Berberine also has the ability to inhibit monoamine oxidase-A and modulate the brain noradrenaline, serotonin, and dopamine for antiulcer efficacy. The nonalkaloid in PAR extract suppressed NO production; besides, limonin and obakunone significantly downregulated NO production and iNOS gene expression via an NF-κB-mediated pathway. [(21S, 23R) Epoxy-24-hydroxy-21β, 25-diethoxy] tirucalla-7-en-3-one, toonaciliatin K, and piscidinol have tumor-shrinking effects on four types of tumors. Polysaccharides from an aqueous extract of PCS act on cell-mediated stimulation and humoral immunity to exert tumoricidal activity.

Phellodendrine and magnoflorine have well absorption rate in the animal organs which could indicate their safety for human trials. However, berberine could interact with magnoflorine or other constituents which could further increase the tissue absorption rates. This should be noticed by other clinical trials or advanced studies to avoid adverse effects. It is also noticeable that different processing techniques or “Pao Zhi” could render the herb with different kind of therapeutic effects. For the raw PC, it could downregulate CYP1A2 and activate CYP3 A4. As for rice-wine and salt-water processed PC, they can alter the activities of cytochrome P450. Also, for rice-wine processed PC alone, it can counter the inhibitory effect of CYP1A2 and promote the induction of CYP3A4. For toxicology, there is no affirmative conclusion in terms of PC and its species' absolute clinical safety. Therefore, safety precautionary measures are still required for vulnerable groups of people. For the processed PC and its species, berberrubine, limonin, and obacunone became targeted chemical constituents for authentication of charred PC, PC, and its subspecies. Furthermore, obacunone and obaculactone are probably responsible for antiatopic dermatitis effect [56].

8. Conclusions

In summary, the compounds of the crude bark of PC and its species have showcased a wide range of pharmacological effects. Pharmacological efficacies of PC are supported by its diverse class of alkaloids, limonoids, phenolic acid, quinic acid, lignans, and flavonoid. Through this review, in total, 140 chemical compounds had been summarized. Among these compounds are 18 compounds from PCC, 44 compounds from PCS, 34 compounds from PAC, and 84 compounds from PAR. However, more studies are still needed to demonstrate more knowledge to allow a better understanding of this herb and its species.