1 s2.0 S0753332223013094 Main

Biomedicine & Pharmacotherapy 167 (2023) 115511
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
The composition, pharmacological effects, related mechanisms and drug

delivery of alkaloids from Corydalis yanhusuo
Jia-hua Feng a, b, Kang Chen c, Si-yu Shen d, Yun-feng Luo d, Xi-hong Liu e, Xin Chen a, Wei Gao d,
Yu-ru Tong b, *
a
School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
b
School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
c
National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
d
School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
e
School of Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China
A R T I C L E I N F O A B S T R A C T
Corydalis yanhusuo W. T. Wang, also known as yanhusuo, yuanhu, yanhu and xuanhu, is one of the herb components
Keywords:
Corydalis yanhusuo of many Chinese Traditional Medicine prescriptions such as Jin Ling Zi San and Yuanhu-Zhitong priscription.
Papaveraceae C. yanhusuo was traditionally used to relieve pain and motivate blood and Qi circulation. Now there has been
Alkaloids growing interest in pharmacological effects of alkaloids, the main bioactive components of C. yanhusuo. Eighty-four
Pharmacological effects alkaloids isolated from C. yanhusuo are its important bioactive components and can be characterized into proto
Traditional Chinese medicine berberine alkaloids, aporphine alkaloids, opiate alkaloids and others and proper extraction or co-administration
Chemical compounds studied in this article: methods modulate their contents and efficacy. Alkaloids from C. yanhusuo have various pharmacological effects
Tetrahydropalmatine (PubChem CID: 72301) on the nervous system, cardiovascular system, cancer and others through multiple molecular mechanisms such as
berberine (PubChem CID: 2353) modulating neurotransmitters, ion channels, gut microbiota, HPA axis and signaling pathways and are potential
dehydrocorydaline (PubChem CID: 34781) treatments for many diseases. Plenty of novel drug delivery methods such as autologous red blood cells, self-
protopine (PubChem CID: 4970)
microemulsifying drug delivery systems, nanoparticles and others have also been investigated to better exert the
corydaline (PubChem CID: 101301)
coptisine (PubChem CID: 72322)
effects of alkaloids from C. yanhusuo. This review summarized the alkaloid components of C. yanhusuo, their
glaucine (PubChem CID: 16754) pharmacological effects and mechanisms, and methods of drug delivery to lay a foundation for future investigations.
Abbreviations: Aβ, amyloid-β; AChE, acetylcholinesterase; AD, Alzheimer’s disease; ALT, Alanine transaminase; AMPK, AMP-activated protein kinase; APP,
amyloid precursor protein; AST, aspartate aminotransferase; AUC, area under the curve; BACE1, beta-site APP cleaving enzyme-1; BBB, blood brain barrier; BDNF,
Brain Derived Neurotrophic Factor; CaM, calmodulin; CaMK, calmodulin kinase; CAT, catalase; CCP, conditioned place preference; CDK1, cyclin dependent kinase-1;
CDK4, cyclin dependent kinase-4; CDL, corydalmine; CGRP, Calcitonin gene-related peptide; COX-2, cyclooxygenase-2; CREB, cAMP responsive element binding
protein; D1R, Dopamine D1 receptor; Δψm, mitochondrial membrane potential; DHC, dehydrocorydaline; DHCB, dehydrocorybulbine; eIF2α, eukaryotic initiation
factor-2α; EMT, epithelial-to-mesenchymal transition; eNOS, endothelial NO synthase; ERK, extracellular signal-regulated kinase; FFA, free fatty acid; GABA,
Gamma-aminobutyric acid; GSH, glutathione; GSK-3β, Glycogen synthase kinase-3β; HDAC, Histone deacetylase; HIF-1α, hypoxia inducible factor-1α; HMGB1, high
mobility group protein; HPA axis, hypothalamic-pituitary adrenal axis; HUVEC, human umbilical vein endothelial cell; IFN-γ, interferon-γ; IGF-1, insulin-like growth
factor-1; IL-1β, Interleukin-1 β; IL-6, Interleukin-6; iNOS, inducible nitric oxide synthase; IP3, inositol triphosphate; JAK2, Janus kinase 2; JLZS, Jin Ling Zi San;
JNK1, c-Jun N-terminal kinase 1; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCP1, monocyte chemoattractant
protein 1; MDA, malondialdehyde; miRNA, microRNA; MPO, myeloperoxidase; MRT, mean residence time; mTORC2, mammalian target of rapamycin complex-2;
nAChRs, nicotinic acetylcholine receptors; NF-κB, nuclear factor kappa-B; NLRP3: nucleotide-binding oligomerization domain, leucine- rich repeat and pyrin domain-
containing 3; NMDA, N-methyl-D-aspartate Receptor; NO, nitric oxide; Nrf2, nuclear factor-2 erythroid related factor-2; PD-L1, Programmed cell death 1 ligand 1;
PERK, PRKR-like endoplasmic reticulum kinase; PGC-1α, PPARγ coactivator-1α; PI3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PLC, phospholipase C;
PPAR-γ, peroxisome proliferator-activated receptor gamma; Rb, Retinoblastoma; ROS, reactive oxygen species; SIRT1, Silent Information Regulator-1; SOD, su
peroxide dismutase; STAT3, signal transducer and activator of transcription; T2D, type-2 diabetes; TGF-β, transforming growth factor-β; THB, canadine; THP, tet
rahydropalmatine; TLRs, toll like receptor; TNF-α, tumor necrosis factor-α; TrkB, tropomyosin receptor kinase B; TRPV1, transient receptor potential vanilloid 1;
VEGF, vascular endothelial growth factor; VGSCs, Voltage gated sodium channels; YHZTF, Yuanhu-Zhitong Formula.
* Corresponding author.
E-mail address: [email protected] (Y.-r. Tong).
https://doi.org/10.1016/j.biopha.2023.115511
Received 22 July 2023; Received in revised form 6 September 2023; Accepted 12 September 2023
Available online 18 September 2023
0753-3322/© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
J.-h. Feng et al. Biomedicine & Pharmacotherapy 167 (2023) 115511
palmatine (PubChem CID: 19009)

jatrorrhizine (PubChem CID: 72323)
columbamine (PubChem CID: 72310)
1. Introduction process using 8 Q-markers namely protopine, coptisine, palmatine hy

drochloride, dehydrocorydaline, (R)-(+)-corypalmine, tetrahy
Corydalis yanhusuo W. T. Wang, also known as yuanhu, yanhu and dropalmatine (+)-corydaline and glaucine. Twenty times of 70%
xuanhu, belonging to the Papaveraceae family, is widely used in many ethanol (pH=10 of diluted ammonia) was employed in total. The pro
prescriptions in traditional Chinese medicine including Jin Ling Zi San cess included 2 cycles of heating and refluxing, followed by a sixty-
(JLZS) and Yuanhu-Zhitong (YHZT) prescription. According to the minute extraction in each cycle. In the purification process, NKA-9
Chinese Pharmacopoeia [1], the effective part of C. yanhusuo is its dried was chosen for macroporous resin, the optimal diameter-to-height
tuber, Corydalis Rhizoma. The extract of C. yanhusuo contains several ratio was 1:8, the elution solvent was 70% ethanol in a rate of 1.5 Bed
components, such as alkaloids, organic acids, volatile oils, amino acids, Volume (BV)/h and the total dosage was 12BV. Five BV distilled water
alcohols, and sugars. Among them alkaloids are the main bioactive was used for washing off impurities at a rate of 2BV/h [22]. Wine pro
components [2]. Traditionally, C. yanhusuo was processed through cessing and vinegar processing are important measures for herbal
stir-frying with vinegar or wine either alone or in combination with medicine preparation in traditional Chinese medicine for advanced ef
other herbs, resulting in oral decoctions that alleviate pain and invigo ficacy. Vinegar forms salt with alkaloids to increase their solubility and
rate blood and Qi. Recent research indicates that alkaloids derived from it was validated that vinegar processing increased bioavailability,
C. yanhusuo exhibit a broad spectrum of pharmacological effects, slowed down the elimination and had low toxicity. Yellow rice wine
including anti-addiction [3], anti-ischemia/reperfusion injury [4], contains phenolic acids, thus increasing alkaloids solubility in the same
anti-cancer [5], and anti-diabetes [6]. As a result, these alkaloids show way [5,23]. Wu et al. examined the effect of wine and vinegar processing
potential in addressing various diseases. Nowadays new methods of drug on alkaloid contents of two common formulations namely water
delivery have also been developed for higher efficacy, selectivity and decoction of Corydalis Rhizoma and Jin Ling Zi San (JLZS). Wine pro
less toxicity. cessing increased protopine in water decoction of Corydalis Rhizoma and
The growing interest in the wide pharmacological effects of vinegar processing increased d,L-THP and corydaline. As for water
C. yanhusuo led to a great deal of researches on its pharmacological decoction of JLZS, wine processing increased the content of protopine,
mechanisms. Alkaloids, as the major bioactive components of α-allocryptopine, tetrahydrocolumbamine, d,L-THP, tetrahy
C. yanhusuo, play a crucial role in these therapeutic effects and an droberberine, corydaline, tetrahydrocoptisine and vinegar processing
increasing number of researches investigated their molecular mecha only increased tetrahydrocolumbamine, corresponding to the tradi
nisms and drug delivery methods. However, certain challenges persist. tional use of wine processed C. yanhusuo for JLZS decoction [23]. Be
C. yanhusuo contains a substantial variety of alkaloids, with ongoing sides affecting contents of the extract, Dou et al. demonstrated that wine
discovery of novel ones. Previous research occasionally conflated syn and vinegar processing also modulated the distribution of THP, proto
onyms for the same alkaloid or omitted specific constituents. Addi pine and DHC in tissues such as heart, liver, spleen, lung, kidney, ce
tionally, due to the abundance of C. yanhusuo alkaloids and their diverse rebrum, cerebellum, diencephalons, brainstem, hippocampus, and
pharmacological effects and mechanisms, a comprehensive overview of striatum as indicated by altered Tmax and mean residence time (MRT)
their shared molecular mechanisms is still lacking. Furthermore, a and unchanged Cmax and AUC0–24 h in different tissues [24].
comprehensive summary detailing drug delivery strategies for Besides wine or vinegar processing, co-treatment of different herbs
C. yanhusuo alkaloids is also absent. This review searched information with similar effects is another approach to enhance efficacy in tradi
from PubMed, google scholar and CNKI to summarize the alkaloid tional Chinese medicine. Toosendan Fructus which is another component
components, processing procedure and co-administration formulas of of JLZS increased the solubility of alkaloids from C. yanhusuo as indi
C. yanhusuo, pharmacological effects as well as molecular mechanisms cated by higher alkaloid content in water decoction of JLZS than
of alkaloids from C. yanhusuo and their drug delivery methods to facil Corydalis Rhizoma [23]. Similarly, it was also found that co-treatment of
itate investigations on natural-based lead compounds, pathogenesis of C. yanhusuo and Angelica dahurica which are both components of YHZT
diseases, new drug targets and drug delivery methods. prescription increased the AUC of THP, α-allocryptopine, corydaline and
tetrahydroberberine [25]. In addition, DHC was found to be absorbed
2. Alkaloid components of C. yanhusuo slower and eliminated faster compared to DHC in C. yanhusuo extract
and the underlying mechanism might be that DHC might compete with
Zhao Chenggu first isolated 13 alkaloids from C. yanhusuo. They other components in C. yanhusuo extract for P-gp, cytochrome P450 and
were identified as corydaline, tetrahydropalmatine (THP), protopine, L- plasma proteins [26].
tetrahydrocoptisine, ( ± )-tetrahydrocoptisine, L-tetrahydrocolumb
amine (isocorypalmine), D-corybulbine, D-glaucine and α-allocrypto 3. Pharmacological effects and related mechanisms of alkaloids
pine [7]. Today there are about 80 alkaloids isolated and identified as is from C. yanhusuo
shown in Table 1 [8–17]. He [18] demonstrated that alkaloids from
C. yanhusuo are mainly composed of tertiary amines, which comprise 3.1. Effects on the nervous system
0.65% of the original herb weight, and quaternary alkaloids, which
constitute 0.3%. As is shown in Table 1, alkaloids from C. yanhusuo are 3.1.1. Analgesic effects
mainly protoberberines (represented by tetrahydropalmatine, palma Pain is a tremendous worldwide concern that not only place a heavy
tine, tetrahydrocoptisine, corydaline and berberine), aporphines (rep burden on patients’ health and life quality but also on the economy [27].
resented by D-glaucine), opiates (represented by protopine) and others The analgesic effect of alkaloids from C. yanhusuo can be ascribed to
(including Saulatine, Bicuculline and Dihydrosanguinarine) [19]. The various mechanisms including modulating neurotransmitter systems,
parent nuclei and substitute groups of representative alkaloids are signaling pathways, inhibiting inflammation and voltage gated sodium
shown in Fig. 1. channels, etc.
A proper method of extraction is needed to fully exert the potential of Modulating neurotransmitter systems is crucial to the analgesic ef
herbs of Chinses medicine. Zhang reported an optimized extraction fect of alkaloids from C. yanhusuo. D1R has been reported to participate
2
Table 1 Table 1 (continued )

Alkaloid components of C. yanhusuo. Type No. Compounds Ref.
Type No. Compounds Ref.
71 N,N-dimethyl-N′-methyl-diphenyl-one [8]
Protoberberine 1 Tetrahydrocolumbamine [8,10, 72 N,N-dimethyl-N′,N′,-dimethyl- [8]
alkaloids 18] diphenyl-one
2 Corydaline [8,18] 73 N-methyl-tetrahydropalmatine [8]
3 Tetrahydroberberine [8,18] 74 N-methyl-canadine [8]
4 D, L-Tetrahydropalmatine [8,18] 75 Coryphenanthrine [8]
5 D, L-Tetrahydrocoptisine [8,18] 76 noroxyhydrastinine [10]
6 Yuanhunine [8,18] 77 Yanhusanine A [15]
7 Corybulbine [8,18] 78 Yanhusanine B [15]
8 Isocorybulbine [8,18] 79 Yanhusanine C [15]
9 Scoulerine [8] 80 Yanhusanine D [15]
10 Demethylcorydalmine [8] 81 Yanhusanine E [15]
11 Corydalmine [8] 82 Adenosine [16]
12 (+/-)-Corypalmine [8] 83 N5-acetylornithine [16]
13 Dehydrocorydaline [8,18] 84 Secoyanhusamine A [21]
14 Palmatine [8,18]
15 Columbamine [8,18]
16 Berberine [8,18]
17 Coptisine [8]
18 Jatrorrhizine [8] in THP’s analgesic effect against oxaliplatin-induced neuropathic pain
19 Berberrubine [8] [28]. D2R is also involved in analgesic activities of alkaloids from
20 Epiberberine [8] C. yanhusuo. Wang et al. validated the analgesic effects of C. yanhusuo
21 Dehydrocorybulbine [8]
extract on acute pain, neuropathic pain and inflammatory pain and
22 13-Methylpalmatrubine [8]
23 13-Methoxyberberine [8] demonstrated that the effect to relieve acute pain and neuropathic pain
24 8-Oxocoptisine [8] was mediated by D2R. In addition, it was also noticed that to exert the
25 Stepharanine [8] antinociception effect of C. yanhusuo extract, some other component
26 Demethyleneberberine [8] besides L-THP and Dehydrocorybulbine (DHCB) was required [29]. THP
27 Worenine [8]
and protopine has been verified for their binding affinity to D2R and
28 Tetrahydrocorysamine [8]
29 Corydayanine [8,9, inhibition of D2R transcription to ameliorate migraine [30]. In addition,
17] THP is a racemic mixture of 50% of the (+) and 50% of (-) enantiomer
30 Yanhusuine [8,9] and (-)-THP accounts for most of THP’s analgesic effect. Nevertheless,
31 Dehydroyanhunine [13]
THP is usually used as racemic mixture clinically [31,32]. The opioid
32 8-Trichloromethyl-7,8- [13]
dihydrocoptisine system, one of the most important neurotransmitter systems in noci
33 Yanhusanine F [15] ception, also contribute to the analgesic mechanisms of alkaloids from
34 13-methyl-columbamine [16] C. yanhusuo. It was reported that berberine increased mu-opioid recep
35 13-Methyl-dehydrocorydalmine [17] tor expression in mice with diabetic neuropathic pain [33]. Another
36 Yanhusanine G [20]
research indicated that berberine relieved visceral pain in mice with
37 Yanhusanine H [20]
38 Yanhusanine I [20] Predominant Irritable Bowel Syndrome through opioid receptors [34].
39 Yanhusanine L [20] Opioid receptor was also involved in DHC’s analgesic effect to inflam
Aporphine alkaloids 40 D-glaucine [8,18] matory pain as indicated by opioid antagonism blocked the anti
41 Oxoglaucine [8]
nociception activity of DHC in phase I in formalin-induced paw licking
42 7-Formyldidehydroglaucine [8,11]
43 Nantenine [8,18]
test but failed to fully block the effect in phase II which may due to
44 Dehydroglaucine [8,18] DHC’s anti-inflammation activity [35]. The glutaminergic system is also
45 N-methyllaurotetanine [8,18] modulated. L-THP alleviated acute and chronic pain by blocking sigma-1
46 Pulbocapnine [8,12] receptor, resulting in reduced expression of phospho-NR1 subunit of
47 Norglaucine [8,18]
NMDA [36]. Corydalmine (CDL) attenuated bone cancer pain by
48 Isoboldine [8,18]
49 Dehydronantenine [8,18] inhibiting NMDA receptor and metabotropic glutamate mGlu1/5 re
50 Corunine [8,10] ceptor, resulting in suppressed spontaneous Ca2+ oscillation which is
51 O-Methylbulbocapnine [8] involved in neuroplasticity [37]. Other neurotransmitters are also
52 Oxoglaucidaline [8,18]
regulated. Research indicated that THP suppressed the expression of
53 Pontevedrine [8]
54 Thaliporphine [8,18]
transient receptor potential vanilloid 1 (TRPV1) and purinergic P2×3
55 D-Lirioferine [8,13, receptor in the spinal cord which are both responsible for hyperalgesia
18] [38]. In addition, berberine also modulated TRPV1 in rats with pe
Opiate alkaloids 56 Protopine [8,18] ripheral nerve injury [39] and diabetic neuropathy [40]. Palmatine also
57 Cryptopine [8]
possess analgesic activity and was found to reduce the expression of
58 α-Allocryptopine [8,18]
59 Nordelporphine(pseudoprotopine) [8] CGRP (Calcitonin gene-related peptide) and its receptor and block the
Other alkaloids 60 Tetrahydroprotopapaverine [8] increase of purinergic P2×7 Receptor mRNA in mice with trigeminal
61 Fumaricine [8] neuralgia [41,42].
62 Chelerythrine [8]
Signaling pathways are also modulated by alkaloids from
63 Dihydrosanguinarine [8,18]
64 Dihydrochelerythrine [8]
C. yanhusuo and many are related to neurotransmitter receptors and
65 Leonticine [8,18] inflammation. Several signaling pathways such as MAPK signaling, PKC
66 Taxilamine [14] signaling, NF-κB signaling and AMPK signaling are of particular signif
67 6-Acetonyl-5,6-dihydrosanguinarine [8] icance. CDL was demonstrated to reduce expression of p-PKCγ and p-
68 Homochelidonine [8]
ERK1/2 which promotes neuron excitability by inhibiting NMDA re
69 Saulatine [8,18]
70 Bicuculline [8,18] ceptor, mGlu1/5 receptor and their downstream spontaneous Ca2+
oscillation to alleviate bone cancer pain [37]. It was also found that
L-CDL inhibited the formation of D1R-D2R complex. D1-D2R complex
3
has been reported to increase cytoplasmic calcium concentration Proto-oncogene tyrosine-protein kinase Src (SRC) and phosphorylation
through Gαq-phospholipase C (PLC)-inositol triphosphate (IP3) of JNK1 and ERK1/2 in spared nerve injury (SNI) rats [45]. Palmatine
pathway, which increased neuron excitability and increased the was also able to suppress p-PKC expression in trigeminal neuralgia rats
expression of p-PKCγ, p-calmodulin kinase II (p-CaMKII), p-MAPKs [41]. It was also reported that palmatine prevented the increase of P2×7
(p-ERK, p-JNK, p-p38) and p-CREB in the spinal cord and L-CDL reversed Receptor mRNA, resulting in reduced release of IL-1β and TNF-α and
these changes to relive neuropathic pain [43]. THP was also found to suppressed phosphorylation of p38 to reduce trigeminal neuralgia [42].
reduce the increased p-p38, p-NF-κB, iNOS and IL-1β level in SNI model BDNF/tropomyosin receptor kinase B (TrkB) pathway and ERK phos
mice [44]. In addition, Liu et al. identified 50 putative bioactive com phorylation was up-regulated in the trigeminal ganglia of trigeminal
ponents in YHZT prescription and validated the targets of is neuralgia rats, and palmatine blocked these changes [46]. It was also
anti-neuropathic pain effect through pharmacology network study. They validated that berberine decreased the expression of BDNF, insulin-like
found that YHZT prescription reversed the nociceptive behaviors and growth factor-1 (IGF-1) and peroxisome proliferator-activated recep
the increased expression of Amyloid-beta precursor protein (APP), tors-in (PPAR-γ) which is anti-inflammatory and activated adenosine
No. Substitute Groups

1 R1=R3=R4=OMe, R2=OH, R5=H 7 R1=OH, R2=R3=R4=OMe, R5=Me
2 R1=R2=R3=R4=OMe, R5=Me 8 R1=R3=R4=OMe, R2=OH, R5=Me
3 R1=R2=OCH2O, R3=R4=OMe, R5=H 9 R1=R3=OH, R2=R4=OMe, R5=H
4 R1=R2=R3=R4=OMe, R5=H 10 R1=R2=OMe, R3=R4=OH, R5=H
5 R1=R2=OCH2O, R3=R4=OCH2O, R5=H 11 R1=R2=R3=OMe, R4=OH, R5=H
6 R1=R2=R3=OMe, R4=OH, R5=H 12 R1=R2=R3=R4=OMe, R5=H

18 R1=OH, R2=R3=R4=OMe, R5=H
13 R1=R2=R3=R4=OMe, R5=Me 19 R1=R2=OCH2O, R3=OH, R4=Me, R5=H
14 R1=R2=R3=R4=OMe, R5=H 20 R1=R2=OMe, R3=R4=OCH2O, R5=H
15 R1=R3=R4=OMe, R2=OH, R5=H 21 R1=OH, R2=R3=R4=OMe, R5=Me
16 R1=R2=OCH2O, R3=R4=OMe, R5=H 22 R1=R2=R4=OMe, R3=OH, R5=Me
17 R1=R2=OCH2O, R3=R4=OCH2O, R5=H 23 R1=R2=OCH2O, R3=R4=OMe, R5=Me

40 R1=R2=R3=R4=OMe, R5=H, R6=Me, R7=R8=R9=H2
41 R1=R2=R3=R4=OMe, R5=R6=R7=R8=H, R9=O
42 R1=R2=R3=R4=OMe, R5=R7=R8=H, R6=Me, R9=CHO
43 R1=R2=OMe, R3=R4=OCH2O, R5=H, R6=Me, R7=R8=R9=H2
44 R1=R2=R3=R4=OMe, R5=R7=R8=R9=H, R6=Me
45 R1=R2=R4=OMe, R3=OH, R5=H, R6=Me, R7=R8=R9=H2
46 R1=R2=OCH2O, R3=R5=OH, R4=R6=Me, R7=R8=R9=H2
47 R1=R2=R3=R4=OMe, R5=H, R6=R7=R8=R9=H2
48 R1=R3=OH, R2=R4=OMe, R5=H, R6=Me, R7=R8=R9=H2
65. Leonticine
49 R1=R2=OMe, R3=R4=OCH2O, R5=R9=H, R6=Me, R7=R8=H2

56 R1=R2=OCH2O, R3=R4=OCH2O, R5=H
57 R1=R2=OMe, R3=R4=OCH2O, R5=H
58 R1=R2=OCH2O, R3=R4=OMe, R5=H
59 R1=R2=OCH2O, R3=H, R4=R5=OCH2O
69. Saulatine 70. Bicuculline 82. Adenosine
Fig. 1. Parent nuclei and structure of alkaloid representative from C. yanhusuo.
4
monophosphate activated protein kinase (AMPK) to relieve diabetic

neuropathy [47]. AMPK was also involved in the mechanisms of - -
+
berberine to relieve osteoarthritis and associated pain [48]. Another - + -
study indicated that berberine also reversed the decreased nuclear

factor-2 erythroid related factor-2 (Nrf2) expression in sciatic nerve of
mice with peripheral neuropathy pain [49]. Modulation of
Inflammation suppression is also of great importance of analgesic Neurotransmitter systems Inhibition of inflammation Inhibition of VGSCs
mechanisms of alkaloids from C. yanhusuo. THP reduced reactive oxygen

species (ROS) production thus inhibiting the activation of NACHT, LRR, sigma-1
receptor p-NR1
and PYD domains-containing protein 3 (NLRP3) inflammasome which is NF-κB iNOS
responsible for IL-1β release to relieve monosodium urate (MSU) crystal- NMDA
induced gouty arthritis pain [50]. THP also inhibited inflammation to mGlu1/5 Spontaneous Ca2+ oscillation
relieve inflammatory pain. THP on one hand promoted astrocyte and
microglia apoptosis, on the other hand suppressed microglia activation, D1-D2R
Gαq
complex PLC PIP2
NF-κB signaling and production of pro-inflammatory cytokines in p-PKCγ p-PKC
CFA-induced inflammatory pain [45]. Besides relieving inflammatory p-CaMKII p-ERK

pain, inhibition of NF-κB signaling and pro-inflammatory cytokines was TrkB
IP3
p-MAPK
also involved in THP’s analgesic activity against SNI-induced neuro BDNF
p-JNK
pathic pain [44]. As we have mentioned earlier, DHC suppressed in IGF-1 AMPK p-CREB p-p38
flammatory pain not only through opioid receptor, but also through
suppression of inflammation as indicated by reduced expression of BDNF Nrf-2
p-CASP6, a-CASP6, TNF-α, IL-1β and IL-6 in the spinal cord [35]. Pal P2X7
matine also suppressed IL-1β and TNF-α release [42]. Besides, berberine
also down-regulated pro-inflammatory cytokines including TNF-α, IL-6,
L-THP Corydalmine Corydaline Berberine Protopine Palmatine
and IL-1β to relieve inflammatory pain [51]. Apart from suppression of
DHC
pro-inflammatory cytokine release, berberine also suppressed Fig. 2. Analgesic mechanisms of alkaloids from C. yanhusuo. Alkaloids from
inflammatory-related enzymes including iNOS and Cyclooxygenase-2 C. yanhusuo relieve pain via modulation of neurotransmitters, inhibition of
(COX-2) to reduce the neuropathic pain in diabetic mice and reduced inflammation and voltage gated sodium channels, and modulation of signaling
NF-κB signaling to ameliorate chemotherapy-induced peripheral pathways. Mechanisms of different alkaloids are shown in different colors and
neuropathic pain [52,53]. It was also noticed that spinal cord microglia their overlaps.
polarization to M2 phenotype was promoted by DHC to attenuate bone
cancer pain [54]. neurotransmitters and intracellular signaling pathways.
Voltage gated sodium channels (VGSCs) are responsible for genera Neurotransmitters systems that are reported to be modulated by al
tion and conduction of action potentials and are targets of alkaloids from kaloids from C. yanhusuo include dopaminergic system, glutaminergic
C. yanhusuo. Xu confirmed the inhibition activity of tetrahy system and cholinergic system. According to Lewis, Dopamine D2 re
dropalmatine, corydaline, protopine and dehydrocorydaline on sodium ceptor (D2R) antagonist could be used against cocaine addiction [62].
channel Nav1.7 and Nav1.5 and among them protopine had the highest Many alkaloids from C. yanhusuo were reported to act as dopamine re
analgesic effect in phase II in formalin-induced paw licking test and the ceptor antagonists, hence they may possess anti-addiction effects. Wu
strongest inhibition activity on sodium channel, yet protopine also identified 8 alkaloids in C. yanhusuo with D1R antagonist activity. They
exhibited strong cardiac cytotoxicity. By contrast, THP had the highest were tetrahydropalmatine, corydaline, 13-methyl-dehydrocorydalmine,
analgesic effect among the four alkaloids in phase I in formalin-induced dehydrocorybulbine, dehydrocorydaline, palmatine, columbamine, and
paw licking test, it exerted less inhibition on sodium channels but also N-methyltetrahydrocolumbamine. Tetrahydropalmatine and N-methyl
had weaker cytotoxicity [55]. In Sun et al.’s research, they tested 33 tetrahydrocolumbamine only had partial antagonist activity for they are
alkaloids from C. yanhusuo and found that dihydrosanguinarine and unable to fully antagonize D1R at high concentrations. IC50 values
dihydrochelerythrine possessed the strongest binding affinity to Nav1.7 indicated that the two most effective D1R inhibitors are THP and
and Nav1.5 and demonstrated that they inhibited the peak currents and dehydrocorybulbine [63]. Demethylated metabolites of L-THP such as
promoted the activation phase of Nav1.7 and Nav1.5, the inactivation L-isocorypalmine, L-corypalmine and L-corydalmine also possessed
phase of Nav1.5 was also promoted [56]. binding affinity to dopamine receptors. L-isocorypalmine had high af
Corresponding to the traditional use of C. yanhusuo, alkaloids from finity to D1R and D5R and had moderate affinity to D2R, D3R, D4R.
C. yanhusuo exerted analgesic effect through multiple mechanisms L-corypalmine and L-corydalmine exhibited high affinity to D1R, D2R
including modulating neurotransmitter systems, signaling pathways, and D5R and had only moderate affinity to D3R and D4R [64,65]. Be
inhibiting inflammation and voltage gated sodium channels which is sides directly binding to dopamine receptors, modulation of expression
shown in Fig. 2. of dopamine receptors is another potential anti-addiction mechanism of
alkaloids from C. yanhusuo as it was reported that L-THP and corydaline
3.1.2. Anti-addiction reversed the morphine-induced reduction of D2R expression in Hippo
Drug addiction is one of the leading causes of mortality around the campus, Striatum and mPFC [66]. Besides dopamine signaling, alkaloids
world and is responsible for 11.8 million deaths annually [57]. from C. yanhusuo also modulate glutaminergic signaling which is
C. yanhusuo and its products have been validated for their effects against involved in consolidation of drug-associated memory [67,68]. Luo
substance abuse such as yuanhu-zhitong tablet for acquisition and verified that L-THP reduced glutamic acid and N-methyl-D-aspartate
expression of alcohol-induced CCP (conditioned place preference) and Receptor (NMDA) Subunit NR2B level in mice Ventral Tegmental Area
C. yanhusuo capsule for protracted opioid abstinence syndrome [3, (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC) [69]. It
58–60]. In Alhassen’s research, co-administration of C. yanhusuo extract was also demonstrated that L-THP and corydaline blocked the
strengthened morphine’s antinociceptive activity, prevented tolerance morphine-induced increase of striatal α-amino-3-
and abstinence and C. yanhusuo extract alone reversed established hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) GluA1
morphine dependence [61]. Alkaloids from C. yanhusuo possess expression [66]. Similarly, Shen demonstrated that berberine treatment
anti-addiction activities and the mechanisms include modulating after extinction training facilitated the extinction process of
5
drug-associated memory and delayed the spontaneous recovery of modulatory effects on TLR4, Sirtuin 1 (Sirt1), α-actin, and NF-κB.
drug-associated memory. They noticed that berberine strengthened Rezaeian’s research indicated that berberine restored METH-induced
extinction training’s effects of increasing GluA1, GluA2 and Brain decrease of expression of TLR4, Sirt1, α-actin and suppressed the in
Derived Neurotrophic Factor (BDNF) expression in the NAc. Moreover, crease of NF-κB in hippocampus which is partly contradictory to Liu’s
it was reported that nicotinic acetylcholine receptors (nAChRs) observation [82].
signaling was also regulated by alkaloids from C. yanhusuo. Huang re Other pharmacological effects of alkaloids from C. yanhusuo such as
ported that L-THP antagonized nicotinic acetylcholine receptors modulating the HPA axis and gut microbiota was also investigated. L-
(nAChRs) as indicated by prolonged rising time and delayed decay time THP mitigated anxiety-like and depression-like behaviors induced by
of nicotine induced current. Tetrahydroberberine, an analogue of THP, singled-prolonged-stress in rats. This effect was attributed to the down-
also showed anti-nAChRs effect [70]. regulation of corticosterone levels, indicating modulation of the
Besides regulating neurotransmitters, modulation of intracellular hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, the restora
signaling pathways is also a potential anti-addiction mechanism of al tion of decreased hypothalamic neuropeptide Y levels, a regulator of
kaloids from C. yanhusuo. Literature has pointed to THP’s effects on emotion, and the attenuation of increased corticotropin-releasing factor
extracellular-regulated kinase (ERK) and cAMP responsive element expression which is associated with stress were observed. Notably, the
binding protein (CREB). It was reported that THP inhibited acquisition efficacy of L-THP at 50 mg/kg was comparable to that of fluoxetine at
of ketamine-induced conditioned place preference and suppressed the 10 mg/kg [83]. Regulation of the composition of gut microbiota has
ketamine-induced increase of ERK and CREB phosphorylation in the been demonstrated to be pivotal to berberine’s effect on alleviating
hippocampus (Hip) and caudate putamen (CPu) [71]. L-THP could also ovariectomy-induced anxiety as indicated by the loss of berberine’s
suppress Methamphetamine (METH)-induced increase of ERK phos anxiolytic activity in germ-free rats. Fecal microbiota transplantation
phorylation in NAc and PFC [72]. Du’s research indicated that L-THP also validated the anxiolytic effect of changes in the gut microbiota.
also suppressed ERK and CREB phosphorylation in the Hip, NAc, and Spearman correlation analysis indicated that the upregulation of bene
PFC of fentanyl treated mice [73]. ficial microbiota was correlated to increased equol production which
In conclusion, alkaloids from C. yanhusuo relieve addiction through may in some ways ameliorate ovariectomy-induced estrogen deficiency
modulating neurotransmitters and signaling pathways such as ERK and to reduce anxiety [84]. Besides the alkaloids mentioned above, L-Scou
CREB signaling. These findings suggest that alkaloids from C. yanhusuo lerine also reduced METH-induced anxiety-like and addiction behaviors
have potential therapeutic effect on addiction. of zebra fish [85].
Concluding from above, alkaloids from C. yanhusuo are prospective
3.1.3. Anxiolytic effect treatments against anxiety and the mechanisms include regulating
The number of people suffering from anxiety and depression had a neurotransmitters, signaling pathways, modulating HPA axis and gut
significant increase in 2020 due to the COVID-19 pandemic [74]. Al microbiota, etc. These findings indicated that alkaloids from C. yanhusuo
kaloids from C. yanhusuo possess anxiolytic and anti-depressant effects are promising candidates for anxiety treatment.
and the mechanisms for the latter will be discussed later in Section 3.1.4
anti-depressant effect. The anxiolytic mechanisms of alkaloids from 3.1.4. Anti-depressant effect
C. yanhusuo include modulating neurotransmitters, intracellular Many alkaloids from C. yanhusuo were reported to relieve depression
signaling pathways and others such as regulating the HPA axis and gut and several mechanisms are related such as modulation of neurotrans
microbiota. mitters, HPA axis, NO generation, inflammation and signaling
Several neurotransmitters have been shown to be modulated by al pathways.
kaloids from C. yanhusuo. Disruption of serotonergic system is crucial to Modulation of neurotransmitters also play an important role in the
the pathogenesis of anxiety and berberine was demonstrated to be able anti-depressant mechanism of alkaloids from C. yanhusuo. Many alka
to activate somatodendritic 5-HT1A autoreceptors and inhibit post loids in C. yanhusuo, namely tetrahydrocolumbamine, protopine,
synaptic 5-HT1A and 5-HT2 receptors have anxiolytic effects [75,76]. jatrorrhizine, glaucine, THP, palmatine and DHC were identified to have
L-tetrahydroberberubine was also demonstrated to be anxiolytic via its the effect of inhibiting Monoamine oxidase-A which is essential in the
5-HT1A receptor agonist activity [77]. Apart from the serotonergic sys oxidative deamination of many neurotransmitters including serotonin,
tem, other neurotransmitters are also regulated by alkaloids from dopamine and norepinephrine hence contributing to ameliorating
C. yanhusuo. d, L-THP acted on Gamma-aminobutyric acid GABAA re depression [86,87]. Fang’s research also indicated that DHC restored
ceptor benzodiazepine site to alleviate anxiety [78]. As for berberine, 5-HT and DA in the serum and hippocampus of mice with chronic un
Peng demonstrated that berberine promoted the metabolism of exces predictable mild stress (CUMS)-induced depression [88]. Besides,
sive noradrenaline, dopamine (DA) and 5-hydroxytryptamine (5-HT) in berberine was also validated to restore noradrenaline (NA) and seroto
the brain stem [76] but Lee found that berberine reduced anxiety-like nin (5-HT) levels in the hippocampus and frontal cortex [89].
behavior and reversed the decreased DA level in the hippocampus and In addition, many researches converged in the anti-depressant ac
up-regulated the expression of tyrosine hydroxylase (TH), DA trans tivity of berberine and palmatine as they both modulated neurotrans
porter (DAT) and vesicular monoamine transporter-2 in rats with mitters, regulated HPA axis and reduced NO generation. HPA axis
post-traumatic stress disorder (PTSD) [79]. Berberine hydrochloride dysregulation is an important mechanism of depression [87]. Both
also modulated the pro-social oxytocin signaling via reversing berberine and palmatine reduced the elevated corticosterone level
METH-induced decrease of oxytocin receptor in accumbens and hippo which indicates regulation of the HPA axis and had antidepressant ef
campus and had anxiolytic effects [75,80]. fects [90,91]. In addition, C. yanhusuo extract also reduced corticoste
Alkaloids from C. yanhusuo also modulate signaling pathways to rone level, and it inhibited hippocampus cell apoptosis as well [92]. NO
ameliorate anxiety. Liu et al. reported that THP reduced anxiety-like disruption can have detrimental effects on neurons and NO production
behavior of rats and METH neurotoxicity through TrkB/CaM interac was found to be increased in patients with depression [93]. Palmatine
tion. Upon METH treatment, the pro-survival BDNF/TrkB signaling was reported to reduce plasma NO level and berberine was reported to
which could promote BDNF expression through its downstream mole reduce inducible NO synthase (iNOS) level [91,94].
cules was impaired and the expression of TrkB, Akt, pAkt, NF-κB and Inflammation is also involved in pathophysiology of depression [95].
BDNF was decreased but the expression of calmodulin (CaM) which is Berberine reversed the increase in interleukin-1β (IL-1β), interleukin-6
related to stress and apoptosis was increased. THP reversed all these (IL-6) and tumor necrosis factor-α (TNF-α) level on RNA and protein
changes via up-regulating BDNF expression through the interaction level induced by chronic unpredictable mild stress (CUMS). Further
between TrkB and CaM [81]. Additionally, berberine also exerts more, a reduction in the expression of CD11b, a leukocyte marker,
6
alongside the attenuation of nuclear factor kappa-light-chain-enhancer 3.1.5. Anti-Alzheimer’s disease effect
of activated B cells (NF-κB) phosphorylation and its downstream About 6.2 million Americans age 65 and older have Alzheimer’s
iNOS, was observed, suggesting the amelioration of neuroinflammation disease (AD) and this number was estimated to grow up to 13.8 million
as one aspect of berberine’s antidepressant mechanism. It was also found by 2060 [100]. Many research indicated the potential of alkaloids from
that berberine reduced the increased activation level of NLRP3 inflam C. yanhusuo in treatment of Alzheimer’s disease and there are several
masome and reduced impairment of neural functions as well as major mechanisms such as modulating neurotransmitters, preventing
depressant-like behaviors [96]. Besides berberine, Fang et al.’s research Tau and amyloid-β aggregation and others. In addition, network phar
demonstrated that DHC also ameliorated depression through reducing macology and molecular docking studies revealed that Akt pathway
NLRP3 inflammasome activation, proinflammatory cytokines produc plays a crucial role in therapeutic effects of alkaloids from C. yanhusuo
tion and decreasing microglia and A1 astrocyte activation in the hip against AD [101,102].
pocampus of CUMS mice. Their research also indicated that the Deterioration of cholinergic transmission is one of the causes of
activation of A1 astrocyte is possibly through NLRP3 overactivation of Alzheimer’s disease (AD) [103]. Inhibiters of acetylcholinesterase
microglia [88]. In addition, oxidative stress has also been shown as one (AChE) can be used to restore acetylcholine (ACh) and are potential
of pathophysiology of depression and palmatine reduced oxidative stress treatments for Alzheimer’s disease [104]. Eight alkaloids from
as indicated by decreased MDA and catalase level and increased gluta C. yanhusuo have been validated for their acetylcholinesterase inhibitory
thione level in mice brain [91]. effect. They are: columbamine, jatrorrhizine, coptisine, palmatine,
Alkaloids from C. yanhusuo also modulate signaling pathways to berberine, dehydrocorydaline, tetrahydropalmatine and corydaline
relieve depression. Palmatine reduced the expression of P2×7 receptor [105–108]. Wang et al. identified a new alkaloid, Secoyanhusamine A,
on glia cells which is involved in diabetes-induced pain and depression from C. yanhusuo and confirmed its binding affinity and inhibition ac
on both transcriptional and protein level via dephosphorylation of tivity on AChE hence it might also be used against Alzheimer’s disease
ERK1/2 [97]. Berberine restored BDNF level in ovariectomy induced [21]. In addition, excessive activity of glutaminergic neurons can lead to
depressant mice and relieved depression through neurodegenerative disorders such as AD and DHC was able to suppress
BDNF-CREB-eukaryotic Elongation Factor 2 (eEF2) pathway. The glutamate exocytosis via inhibiting Ca2+ channels and ERK1/2-synapsin
expression of c-Fos as indication of depression amelioration was also I hence it might possess anti-AD activity [109].
restored. In addition, the effect of berberine was abolished by 5-HT2 Tau and amyloid-β are two crucial proteins in Alzheimer’s disease
antagonist ketanserin except in the mPFC. [98]. MiRNA also partici [110]. Both Yuanhu-Zhitong prescription and protopine have been
pated in regulation of depression. It was reported that berberine blocked demonstrated to promote proteasomal degradation of tau [111,112].
the enhancement in miR-34b-5p and miR-470–5p hence restoring BDNF Palmatine suppressed aggregation of tau into fibrils and disassemble
level, resulting in a decrease in depressant-like behaviors and enhanced pre-formed aggregates [113]. Berberine also affected tau to ameliorate
hippocampal neuron activity and lowered apoptosis [99]. Alzheimer’s disease. The tau hyperphosphorylation suppression activity
In conclusion, alkaloids from C. yanhusuo are promising anti- of berberine was at least partially mediated by
depressants and they mainly act through modulation of neurotrans phosphatidylinositol-3-kinase (PI3K)/Akt/GSK-3β pathway [114,115].
mitters, HPA axis, NO generation, inflammation and signaling path Berberine was also found to promote tau autophagic degradation via
ways. We can see from above that there are many overlaps in the classIII PI3K activation [115].
mechanisms of alkaloids from C. yanhusuo on addiction, anxiety, and Many alkaloids were also found to reduce amyloid-β (Aβ) accumu
depression, which is shown in Fig. 3. lation. Berberine suppressed Aβ biosynthesis and promoted its
Fig. 3. Overlaps in the mechanisms of alkaloids from C. yanhusuo on addiction, anxiety and depression. The anti-addiction, anxiolytic and anti-depressant mech
anisms of alkaloids from C. yanhusuo overlapped in modulation of neurotransmitters and signaling pathways. Regulation of the HPA axis was involved in anxiolytic
and anti-depressant effects. Gut microbiota was regulated to alleviate anxiety. Inflammation, NO generation and oxidative stress was inhibited to relieve depression.
7
decomposition as indicated by reduced expression of Aβ producing en neuronal restrictive silencing factor (NRSF) in mice with epilepsy [135].
zymes such as beta-site APP cleaving enzyme-1 (BACE1) and γ-secretase It was also noticed that berberine reduced photosensitive seizures
and enhanced expression of Aβ decomposition enzyme Neprilysin [116]. through Syntaxin 1b (Stx1b) as indicated by weakened effect of
Autophagy was also activated by berberine via PI3K, resulting in Aβ berberine in Stx1b knockdown pentylenetetrazole-treated zebrafish
degradation [117]. Wang et al. also found that berberine reduced tau larvae [136]. In conclusion, alkaloids from C. yanhusuo exert curative
and Aβ accumulation and restored cognitive impairment induced by effects on epilepsy through multiple mechanisms and are promising
D-ribose through preserving mitophagy through inhibiting PINK1 candidates for epilepsy treatment.
(PTEN induced kinase 1) promoter methylation [118]. Endoplasmic
reticulum (ER) stress plays an important role in AD and berberine could 3.2. Effects on the cardiovascular system
down-regulate it. ER stress up-regulates phosphorylation of GSK3β
which leads to tau hyperphosphorylation, activates PRKR-like endo 3.2.1. Anti-myocardial ischemia/reperfusion (MIR) injury
plasmic reticulum kinase (PERK)/eukaryotic initiation factor-2α (eIF2α) Myocardial infarction is myocardial cell death caused by ischemia
pathway which promotes BACE-1 expression and consequently pro including apoptosis and necrosis and acute myocardial infarction is one
motes Aβ42 aggregation [119]. Berberine was found to reduce GSK3β of the leading causes of morbidity and mortality [137,138]. Many re
activity and inhibit PERK/eIF2α/BACE1 signaling to reduce tau phos searches pointed that alkaloids from C. yanhusuo could alleviate MIR
phorylation and Aβ42 production to alleviate AD [119,120]. injury. C. yanhusuo extract has been proven to significantly reduce
Several other mechanisms were also involved in these alkaloids’ anti- infarct size and inhibit myocardial apoptosis [4]. L-THP, palmatine,
AD effect. Berberine also reduced oxidative stress and neuro DHC and berberine have been proven to relieve MIR. All the four al
inflammation in the hippocampus of AD mice via down regulation of NF- kaloids are all able to reduce inflammation. Among them palmatine,
κB pathway [121]. Inhibition of apoptosis and promotion of angiogen DHC and berberine have also been demonstrated to relieve oxidative
esis also contribute to berberine’s effect on AD [122]. Hussien applied stress and L-THP, DHC and berberine have also been verified for inhi
docking analysis and confirmed that berberine was able to inhibit the bition of myocardium apoptosis. Also, berberine modulated autophagy
activity of AChE, COX-2 and tumour necrosis factor-alpha converting in a peculiar way as we will discuss later. Moreover, berberine also
enzyme (TACE) through binding to them. Also, berberine improved cardiac function and protected normal structure of myocardial
down-regulated the transcription of various AD-inducing factors cells through modulation of microRNA (miRNA).
including AChE, TNF-α, APP and Tau, reduced the levels of oxidative L-THP relived MIR through modulation of signaling pathways and
stress, detrimental Aβ42 and proinflammatory markers and induced inhibition of apoptosis and oxidative stress. Han demonstrated that L-
protective Aβ40 in the brain tissue of heavy metals-induced AD-like rats THP on one hand activated the PI3K/Akt/endothelial NO synthase
[123]. Besides berberine, Duan reported that jatrorrhizine up-regulated (eNOS) pathway by increasing phosphorylation of Akt, on the other
miR-223–3p level which inhibited histone deacetylase (HDAC4) to hand decreased iNOS expression on transcription level to modulate NO
promote nerve cells survival [124]. Jatrorrhizine was found to restore biosynthesis. Also, L-THP reduced myocardial and plasma myelperox
the balance of AD-disrupted microbiota in amyloid precursor protein iadase (MPO) activity and TNF-α production by myocardium which in
(APP)/presenilin-1 (PS1) transgenic mice [125]. Coptisine could also dicates inhibition of inflammation. The expression of HIF-α and vascular
ameliorate AD. Yu reported that coptisine, as a potent Indoleamine 2, endothelial growth factor (VEGF) which plays an important part in
3-dioxygenase (IDO) inhibitor, suppressed the activation of microglia angiogenesis was increased as well [139]. Another research also indi
and astrocytes, protected neurons, reduced Aβ1–42 accumulation, and cated the important role of PI3K/Akt pathway in relieving myocardial
ameliorated cognitive impairment [126]. In addition, iron and copper infarction via utilizing network pharmacology and verified THP’s
dysregulation can cause neurodegenerative diseases, cardiovascular binding affinity to Akt. The research also demonstrated that THP pro
diseases and cancer. Parvin’s study tested 28 isoquinoline alkaloids and tected myocardium from ischemia/reperfusion injury, reduced
found that all the tested alkaloids except protopine reduced ferric and apoptosis and inflammation through activating PI3K/Akt pathway
especially cupric ions, although they had different potency, indicating [140]. Palmatine was reported to suppress myocardial I/R damage via
the potential use of these alkaloids against the diseases mentioned above inhibition of oxidative stress and inflammatory response [141]. Pal
[127]. matine decreased oxidative stress as indicated by the decreased serum
In conclusion, alkaloids from C. yanhusuo are promising candidates levels of lactate dehydrogenase (LDH), creatine kinase (CK) and malo
for AD treatment thanks to their pharmacological effects including naldehyde (MDA) as well as decreased superoxide dismutase (SOD) and
regulating neurotransmitters, preventing Tau and amyloid-β aggrega catalase (CAT) activity. Palmatine also decreased level of myocardium
tion and others. COX-2 and iNOS as well as increased heme oxygenase (HO-1) in human
aortic endothelial cells (HAEC), it was also noticed that the release of
3.1.6. Anti-epilepsy effect high-mobility group box1 (HMGB1) which regulates induction of other
Approximately 65 million people worldwide are suffering from epi inflammatory factors in lipopolysaccharide (LPS)-stimulated RAW
lepsy [128]. Several alkaloids from C. yanhusuo exert anti-epilepsy effect 264.7 cells was decreased. DHC was found to ameliorate MIR injury
through multiple mechanisms. THP was found to inhibit both the through inhibition of apoptosis, inflammation and oxidative stress
development of epilepsy and the epilepsy symptoms in amygdala through inhibition of TNF receptor-associated factor 6 (TRAF6)/NF-κB
kindled mice models [129]. Chang’s research indicated that THP signaling pathway in LPS-treated H9C2 cardiomyocytes [142]. Many
reduced the release of DA in amygdaloid hence reducing researches also highlighted the anti-apoptotic, anti-oxidant and
picrotoxin-induced epilepsy attacks [130]. It was also found that both anti-inflammatory effects of berberine. Yu demonstrated that berberine
berberine and palmatine possessed anti-epilepsy effects and combina ameliorated MI/R injury by reducing apoptosis, ROS production, IL-6,
tion of these two alkaloids exhibited significantly higher therapeutic TNF-α and MPO level in mice heart and in cultured cardiomyocytes in
value [131]. Berberine was also studied for its anti-epilepsy mecha a way that involved activation of Silent Information Regulator-1 (SIRT1)
nisms. It was validated that berberine reversed many changes including signaling pathway after MI/R [143]. Zhao reported that berberine
factors related to oxidative stress, inflammation markers, proteins activated of Janus kinase 2/signal transducer and activator of tran
related to brain injury and apoptosis in mice with epilepsy [132–135]. scription (JAK2/STAT3) signaling pathway, resulting in attenuated
Berberine also restored the expression of BDNF, the neurotrophic factor, apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress in
reduced the expression of hypoxia inducible factor-1α (HIF-1α), and vivo and in vitro to reduce MIR injury [144]. Yu validated that berberine
participated in epigenetic and transcription regulation as indicated by inhibited apoptosis and ameliorated MI/R damage via Notch1/Hairy
down-regulation of the expression of Histone deacetylase (HDAC) and and enhancer of split 1-phosphatase and tensin homolog deleted on
8
chromosome ten/Akt (Notch1/Hes1-PTEN/Akt) signaling pathway 3.2.2. Anti-cerebral ischemia/reperfusion (CIR) injury
using Notch1 siRNA, Hes1 siRNA and LY294002 (an Akt inhibitor) Cerebral ischemia/reperfusion injury easily develops into stroke and
[145]. is a leading cause of morbidity and mortality worldwide [151]. Alka
Berberine modulated autophagy in a peculiar way. Berberine pro loids from C. yanhusuo was demonstrated to be effective against cerebral
motes autophagy during hypoxia but suppresses autophagy during I/R. Researches indicated that four alkaloids, namely L-THP, palmatine,
reperfusion. Zhu noticed that berberine pretreatment promoted auto protopine and berberine possess anti-CIR activity. Their major effects
phagy and cell survival by enhancing the binding of HIF-1α to Bcl-2/ converged in suppression of apoptosis, oxidative stress and inflamma
adenovirus E1B 19-kDa interacting protein-3(BNIP3) promoter hence tion. L-THP was also found to protect blood-brain barrier and berberine
increasing BNIP3 expression [146]. Yet Huang reported that berberine was reported to induce cell cycle arrest and modulate autophagy in a
(given before reperfusion) inhibited autophagy in a way that involved way similar to what we have discussed in the MIR section. The specific
phosphorylation of AMPK and mammalian target of rapamycin mechanisms or signaling pathways influenced by alkaloids are discussed
complex-2 (mTORC2), hence reducing the injury induced by excessive below.
autophagy [147]. The possible explanation to this contradiction might L-THP was found to reduce c-Abl expression and p38 hyper
be that according to Rouschop, autophagy initiated by HIF during phosphorylation hence reducing apoptosis [152]. Also, dL-THP was
hypoxia maintains homeostasis hence promoting survival yet autophagy found to reduce oxidative stress as indicated by restored SOD activity,
independent of HIF can lead to cell death [148]. Sciarretta also pointed reduced MDA level and peripheral LDH activity in rat brain [153].
that autophagy during ischemia is beneficial yet is detrimental during L-THP also reduced BBB injury via multiple mechanisms [154]. L-THP
reperfusion [149]. inhibited Src/myosin light chain kinase/myosin light chain signaling
Berberine also increased miR-26b-5p level to suppress the COX-2/ (MLCK/MLC signaling) via binding to Src and restored the
MAPK pathway to restore the viability of cardiomyocytes. Berberine down-regulated expression of claudin-5, occludin and ZO-1(zonula
reversed the increased level of COX-2, p-ERK, p-JNK and p-p38 upon occludens-1) to protect the tight junctions. It was also found that
MIR injury and the effect was impaired upon miR-26b-5p inhibition. L-THP treatment significantly reduced the expression of metal
Also, berberine restored cardiac function as indicated by reduction of loproteinases (MMP)− 2/9 which degrade the ECM and mediate
the elevated of S-T segment on electrocardiogram (ECG) induced by IR degradation of tight junction proteins.
injury, restored hemodynamic parameters including left ventricular Palmatine exerted anti-apoptosis, anti-oxidative and anti-
end-systolic pressure (LVESP), left ventricular end-diastolic pressure inflammatory effects to protect mice against CIR injury. Palmatine
(LVEDP), left ventricular end-systolic diameter (LVESD), the left ven modulated Bax and Bcl-2 level, regulated SOD, CAT and MDA level, and
tricular end-diastolic dimension (LVEDD) and fractional shortening suppressed the expression of inflammatory cytokines such as IL-1β, IL-6,
(FS), reduced heart damage as indicated by reduced LDH and CK, and and TNF-α in PC12 cells through activation of AMPK/Nrf-2 pathway
retained cardiomyocyte structure but all these effects were impaired by [155]. Protopine pretreatment also reduced apoptosis and oxidative
miR-26b-5p inhibition [150]. stress in ischemic mice brain [156]. They also noticed that the calcium
In conclusion, alkaloids from C. yanhusuo suppressed apoptosis, disruption was also ameliorated, which could be the reason for inhibited
inflammation and oxidative stress, modulated autophagy, improved apoptosis.
cardiac function and protected the structure of myocardial tissue and are As for berberine, several mechanisms of berberine’s anti-apoptotic
promising candidates for treatment of MIR. The related mechanisms activity have been investigated. Solid dispersion of berberine with so
were shown in Fig. 4. dium caprate (HGSD) which had higher bioavailability reduced
Fig. 4. Mechanisms related to anti-MIR effects of alkaloids

from C. yanhusuo. Mechanisms of different alkaloids were
shown as different colors and overlaps. In addition, the
gray inhibition arrow pointing from Akt to apoptosis indi
cated that it was a shared pathway of the two alkaloids.
Alkaloids from C. yanhusuo reduced apoptosis, oxidative
stress and inflammation. Berberine also modulated auto
phagy in different phases of the IR injury. Besides,
berberine also restored cardiac function and protected
cardiomyocyte structure.
9
apoptosis via down-regulation of AMPK [157]. Yang confirmed that HIF-1α accumulation and increased binding of HIF-1α to Sphk2 (sphin
berberine inhibited apoptosis by activating BDNF–TrkB–PI3K/Akt gosine kinase) promoter hence increasing S1P (sphingosine-1-phos
signaling pathway as indicated by increased expression of BDNF, TrkB phate) production. In addition, they noticed that there was a positive
and p-Akt [158]. Hu confirmed that berberine suppressed apoptosis feedback regulation between HIF-1α and Sphk2 or S1P [167].
through acting specifically through PI3K rather than RTK, PI3K’s up In general, alkaloids from C. yanhusuo ameliorate CIR through
stream. Their research also found that berberine stimulated the activity multiple mechanisms including reducing apoptosis, oxidative stress and
of the promoter of PI3K regulatory subunit p55γ to induce its consistent inflammation, protection of BBB, modulation of cell cycle arrest and
upregulation despite the treatment of various inhibiters including gen autophagy and are promising drugs for cerebral I/R injury. Related
istein (tyrosine kinase inhibitor), PD153035 (epidermal growth factor mechanisms were shown in Fig. 5.
receptor inhibitor), Ly294002 (PI3K inhibitor) or Akti-1/2 (Akt inhibi
tor) [159]. It was also found that berberine reduced ER stress through 3.2.3. Anti-thrombosis
suppressing canopy FGF signaling regulator 2 (CNPY2)/protein Corresponding to the traditional use of C. yanhusuo to motivate blood
kinase-like ER kinase (PERK) pathway to reduce neuronal apoptosis and and Qi, Chen verified that water, 90% ethanol and ethyl acetate extract
ameliorate CIR injury [160]. The anti-inflammatory activity of of C. yanhusuo inhibited adenosine diphosphate (ADP), thrombin (THR)
berberine has also been investigated. Berberine reduced HMGB1, and arachidonic acid (AA) induced rabbit platelet aggregation on
toll-like receptor 4 (TLR4) and NF-κB mRNA and protein level, different levels [168]. HPLC analysis confirmed 5 alkaloids from
decreased TNF-α, IL-1β, and IL-6 mRNA levels and suppressed HMGB1 C. yanhusuo that can bind to platelets, namely canadine (THB), dehy
and NF-κB translocation to reduce CIR injury in mice [161]. It was also drocorydaline (DHC), Glaucine, corydaline and tetrahydrocoptisine,
found that berberine inhibited NF-κB signaling via up-regulation of among them THB and DHC had the strongest anti-platelet aggregation
peroxisome proliferators-activated receptor-γ (PPAR-γ) [162]. effect. Tetrahydropalmatine and palmatine couldn’t bind to platelets
Berberine also modulated cell cycle arrest. Chai et al.’s research sug and had a weaker anti-platelet aggregation effect [169]. Tan examined
gested that berberine reduced cerebral I/R injury through a “hibernation the anti-platelet aggregation effect of DHC and THB. Their research
and resuscitation” mechanism. In the oxygen and glucose deprivation indicated that DHC had a stronger effect on ADP-induced platelet ag
model, berberine on one hand reduced p53 and cyclinD1 expression gregation and THB’s effect on THR induced platelet aggregation was
during ischemia stage to induce cell cycle in G0/G1 phase and on the stronger [170]. Based on previous and their own findings, Tan et al.
other hand, berberine activated PI3K/Akt signaling pathway to promote speculated that DHC may exert its effect in a way that involved ADP
cell survival [163]. Chai et al. also found that berberine increased receptors P2Y1 and P2Y12 and THB may bind to THR receptor protease
Retinoblastoma (Rb) mRNA level by interacting with the polyA tail activated receptor-1 (PAR1) to regulate its downstream Gi/PI3K
hence inhibiting its degradation, leading to cell cycle arrest at G1 phase pathway. Xuan investigated THB’s anti-thrombosis effect and found that
and amelioration of cerebral I/R injury [164]. The contradiction on THB inhibited rabbit platelet aggregation and reduced thromboxane B2
autophagy in CIR is similar to that in MIR as we’ve discussed earlier. Xie generation [171]. Berberine was also investigated for its anti-thrombosis
et al.’s research suggested that berberine given during reoxygenation activity. Wang [172] examined the effect of berberine and its metabolite
decreased autophagy and ER stress hence promoting cell survival [165]. berberrubine on platelet activation. Upon platelet activation, the
Yet Zhang et al.’s research indicated that berberine pretreatment pro PI3K/Akt pathway was activated, resulting in the translocation of Rasa3
moted autophagy and reduced apoptosis [166]. In another research of to the cell membrane and disrupted balance between GTP-Rap1 and
Zhang et al., they elucidated that berberine promoted GDP-Rap1. Increased GTP-Rap1 changes integrin αIIbβ3 into an active
sphingosine-1-phosphate (S1P) production and up regulated HIF-1α form thus allowing it to bind to fibrinogen and promoting thrombosis.
which as we’ve mentioned before, is an important factor contributing to Berberine and berberrubine was found to bind to PI3Kβ selectively to
autophagy and survival. Their findings suggested that berberine induced suppress the PI3K/Akt pathway, resulting in inhibited platelet
Fig. 5. Mechanisms related to anti-cerebral I/R injury ef

fects of alkaloids from C. yanhusuo. Mechanisms of
different alkaloids were shown as different colors and their
overlaps. Alkaloids from C. yanhusuo inhibited apoptosis,
oxidative stress and inflammation. Besides, THP protected
BBB and berberine induced cell cycle arrest and modulated
autophagy indifferent phases of the IR injury. Palmatine
and berberine induced opposing effect on p-AMPK as was
shown in green and red arrows next to the icon of p-AMPK.
10
aggregation and thrombosis. From what we have discussed above we directions by different alkaloids as is discussed below and was marked
can conclude that alkaloids from C. yanhusuo have good therapeutic with arrows on Fig. 6.
potential on thrombosis. Many alkaloids have the activity to inhibit cancer cell invasion and
migration. Berberine suppressed tumor invasion through suppression of
3.2.4. Effect on angiogenesis MMP-2 transcription via down-regulation of NF-κB pathway [182]. DHC
Alkaloids from C. yanhusuo was found to regulate angiogenesis from inhibited cancer cell proliferation and migration via down-regulation of
various aspects including NO production, signaling pathways such as MMP7/9 [183]. Columbamine up-regulated the expression of E-cad
VEGF, VEGF2 and MAPK signaling, inflammation, etc. Interestingly, herin, down-regulated the expression of N-cadherin and MMP-2/9 hence
alkaloids from C. yanhusuo can exert contradictory effects on angio suppressing migration and invasion of hepatocellular carcinoma cells
genesis. Cui’s research [173] indicated that tetrahydropalmatine exer [184]. Protopine also had a significant inhibitory effect on MDA-MB-231
ted pro-angiogenic effect as indicated by promotion of HUVEC (human cell migration and invasion. The morphology of cancer cells changed to
umbilical vein endothelial cell) proliferation, tube formation, and round shape rather than irregular shape in the control group. Protopine
migration. Their research indicated that THP regulated arginine significantly inhibited heterotypic adhesive ability between
biosynthesis, NO production and vascular endothelial growth factor MDA-MB-231 and HUVEC, western blotting showed that protopine
receptor-2 (VEGFR2) expression. THP reduced the level of citrulline, down-regulated the expression of epidermal growth factor receptor
furmarate and argininosuccinate synthase which are part of the urea (EGFR), intercellular adhesion molecule-1 (ICAM-1), αV-integrin,
cycle and can resynthesize arginine. The level of NO, which can be β1-integrin and β5-integrin [185]. Copstisine suppressed cancer cell
produced from arginine, was elevated. NO plays an essential role in invasion and migration through down regulation of VE-Cadherin and
promoting VEGFR2 expression and as expected, the expression of β3-integrin [186]. In addition, it was also found that C. yanhusuo extract
VEGFR2 was enhanced. Yet on the contrary, Wan reported that significantly reduced the transcription and activity of MMP-9 and
C. yanhusuo extract inhibited angiogenesis by suppressing phosphory inhibited phosphorylation of ERK1/2 and JNK to suppress cancer cell
lation of VEGFR2 and its downstream Akt, ERK and STAT3 [174]. Gao proliferation and migration [187].
also found that C. yanhusuo extract and berberine inhibited Alkaloids such as protopine, DHC, columbamine and berberine
VEGF-induced angiogenesis via reducing phosphorylation of ERK [175]. promotes cancer cell apoptosis. It was found that protopine had selective
Besides these opposite outcomes of THP, C. yanhusuo extract and cytotoxicity toward liver carcinoma cells and the inhibition of cell
berberine in no specific circumstances, other researches indicated that growth was verified in vivo. Protopine induced ROS and oxidative stress
the opposite effects of berberine on angiogenesis depended mainly on which inhibited PI3K/Akt pathway and activated apoptosis via the
the situation. Berberine promoted angiogenesis during I/R injury or intrinsic pathway in liver carcinoma cells. Oxidative stress was
stroke and suppressed angiogenesis to inhibit tumor growth. In mice increased as indicated by increased ROS, MDA and LDH level and
with MIR, berberine pretreatment elevated transcription level of VEGF reduced level of SOD and glutathione peroxidase (GPX). Generation of
and FGF2 (fibroblast growth factor-2) which are both pro-angiogenesis ROS inhibited the phosphorylation of Akt, which hence reduced
factors and down-regulated the transcription level of thrombospondin-1 expression of Bcl-2 and Bcl-xl, leading to apoptosis as indicated by
(TSP-1) and endostatin (ENDO) which are angiogenesis inhibitors, enhanced activities of caspase 3/9 and release of mitochondrial protein
although the difference in ENDO transcription level wasn’t significant. cytochrome c to the cytosol [188]. Another research indicated that
[176]. Berberine was also found to promote HUVEC migration, tube protopine promoted p53 phosphorylation which prevented its degra
formation and microglia M2 polarization via AMPK pathway to reduce dation through proteasome. Increased p53 level induced apoptosis and
cerebral I/R injury [177]. In circumstances related to tumor, berberine autophagy in colon cancer cells [189]. Coptisine promoted apoptosis via
inhibited angiogenesis. Jie et al.’s research suggested that berberine down-regulation of PI3K/Akt pathway in HCT-116 cells and it was also
suppressed HCC-induced angiogenesis and VEGF transcription and observed that coptisine reduced mitochondrial membrane potential
secretion of HCC [178]. Jin’s research indicated that berberine inhibited (Δψm) and increased ROS production [190]. DHC inhibited MCF-7 cells
angiogenesis in glioblastoma xenografts by suppressing the VEG proliferation and promoted apoptosis as indicated by up-regulated level
FR2/ERK pathway as indicated by reduced phosphorylation of VEGFR2, of Bcl-2, caspase-7/8 and cleaved PARP, and the apoptosis regulation
ERK and p38 [179]. Hamsa pointed that berberine inhibited angiogen didn’t affect mitochondrial membrane potential and caspase-9 [191].
esis induced by B16F-10 melanoma cells. Berberine down-regulated Columbamine also promoted apoptosis as indicated by increased level of
multiple pro-angiogenesis factors such as VEGF, iNOS, COX-2, pro-in cleaved caspase-3 and cleaved PARP and it was also demonstrated that
flammatory cytokines such as IL-1β, IL-6, TNF-α, and GM-CSF and columbamine suppressed ERK1/2, p38 and Akt pathway to inhibit
transcription factors such as NF-κB, c-FOS, Activating Transcription tumor growth [184]. It was also found that columbamine also decreased
Factor-2 (ATF-2), and CREB. HIF was also downregulated only under β-catenin expression to suppress colon cancer cell proliferation [192].
hypoxia conditions [180]. Besides, berberine was also validated to induce apoptosis in gastroin
In conclusion, alkaloids from C. yanhusuo modulate angiogenesis testinal cancer cell lines [193]. Another research indicated that
through multiple mechanisms such as regulating NO production, VEGF, C. yanhusuo extract induced ROS formation and decreased mitochon
VEGF2, MAPKs, inflammation and others and have the potential to be drial membrane potential which is related to apoptosis in MCF-7 cells
used in different occasions to treat different diseases. [194].
Autophagy is also involved in anticancer effects of alkaloids from
3.3. Anti-cancer effects C. yanhusuo. L-THP activated AMPK/mTOR/p-unc 51-like autophagy
activating kinase 1 (ULK1) pathway and mtROS/JNK/autophagy-
Cancer is the first or second cause of death in 112 of 183 countries. In related gene 7 (ATG7) pathways to promote autophagy in HepG2
2020, 19.3 million new cases of cancer were diagnosed and the number Cells. mtROS also up regulated ERK and Akt pathway which also
was estimated to grow to 28.4 million in 2040 [181]. Many researches resulted in autophagy. It was also noticed that AMPK converted oxida
indicated the anticancer effect of alkaloids from C. yanhusuo. The main tive phosphorylation (OXPHOS) to glycolysis which contributed to in
anticancer effects include inhibiting cancer cell invasion, migration, hibition of tumor cell growth [195]. Mori et al.’s research found that the
angiogenesis, drug resistance and telomerase activity, promoting im gastrointestinal cancer cell death induced by berberine is due to both
munity, cancer cell apoptosis, autophagy and ROS production, regu apoptosis and autophagy and the BBR-induced mitophagy can be
lating cell cycle arrest and reverse of EMT. There are several highlighted abrogated by agt5 knockdown [193]. Zhang et al. demonstrated that
molecules that can be regulated by multiple alkaloids such as p-Akt, berberine induced autophagy by acting on mTOR, MAPK and Akt
p-ERK, p-AMPK. Just for notice, p-Akt, p-ERK were regulated in different pathways in vivo and in vitro. After berberine treatment, the expression
11
Fig. 6. Anti-cancer mechanisms of alkaloids from C. yanhusuo. The mechanisms of different alkaloids were shown as different colors and their overlaps. Alkaloids
from C. yanhusuo inhibited cancer cell invasion, migration, angiogenesis, drug resistance and telomerase activity, promoted immunity, cancer cell apoptosis,
autophagy and ROS production, modulated cell cycle arrest and reversed EMT. The grey arrow pointing from p-gp to drug resistance indicated that it was the share
mechanism of THP and glaucine. Different alkaloids induced opposing changes in the levels of p-Akt and p-ERK which was shown as arrows of different colors that
are next to the icons of p-Akt and p-ERK. We can also see from the overlaps that Akt and MAPKs signaling pathways are of great significance.
12
of p-mTOR, p-p70S6K, p-Akt, p-ERK, p-JNK and p-p38 were significantly weren’t affected. [186].
reduced and their effect was verified by using their specific inhibiters. It There are also several other mechanisms of the anti-cancer activity of
was also noticed that mTOR pathway was regulated by MAPK but not alkaloids from C. yanhusuo. Some alkaloids may affect drug resistance of
Akt pathway [196]. Also, we have mentioned earlier that protopine cancer cells. Glaucine reduced the resistance of multidrug resistant MCF-
induced autophagy and apoptosis in colon cancer cells [189]. 7/ADR cells to adriamycin and mitoxantrone significantly. It was
Many alkaloids also modulate cell cycle arrest. L-THP, coptisine and revealed that glaucine acted as a substrate and inhibited P-glycoprotein
berberine induced cell cycle arrest in G0/G1 phase and protopine (P-gp) and multidrug resistance-associate protein 1 (MRP1) competi
induced cell cycle arrest in G2/M phase. L-THP inhibited breast cancer tively. The transcription of these ATP-Binding Cassette (ABC) trans
cell proliferation by inducing cell cycle arrest at G0/G1 phase rather porter genes was also inhibited. As a result, glaucin inhibited the cancer
than apoptosis as indicated by increased p27 expression, decreased cells to transport anti-cancer drugs out of the cell and reversed drug
CDK4, Cyclin D1, Rb and p-Rb expression and unaffected Bcl-2 and resistance [203]. It was also demonstrated that both enantiomers of THP
PARP. In addition, L-THP also promoted degradation of estrogen re inhibited P-gp but not MRP1 or breast cancer resistance protein (BCRP)
ceptor-α (ERα) via proteasomal pathway and restored the sensitivity of [204]. Telomerase is crucial to cell immortality. Telomerase reverse
breast cancer cell to tamoxifen and fulvestrant [197]. Coptisine also transcriptase (hTERT) is its rate-limiting, catalytic subunit and human
down-regulated expression of CDK4 and Cyclin D1 hence inducing cell telomerase RNA component (TERC) is the subunit that provides tem
cycle arrest in G0/G1 phase [186]. Liu’s research indicated that plate for 3′TTAGGG5′ addition at the end of the telomere. Berberine was
berberine also inhibited cancer cell proliferation and induced cell cycle found to inhibit telomerase activity and reduce hTERT and TERC
arrest by suppressing de novo lipogenesis. Berberine suppressed the expression in Colorectal Cancer Cell Line HCT 116 [200]. Chu et al.
expression of SREBP cleavage-activating protein (SCAP) protein and its demonstrated that epithelial-to-mesenchymal transition (EMT) could be
translocation from ER to Golgi. The interaction between SCAP and reversed by berberine. Berberine up-regulated E-cadherin expression
SREBP-1 decreased which has a negative effect on SREBP-1 activation partly through reducing snail-1 expression which suppresses E-cadherin
and nuclear localization where SREBP-1 regulates transcription of transcription thus reversing EMT [182]. Liu [205] pointed that berber
lipogenesis related genes, resulting in reduced expression of lipogenesis ine’s antitumor effect could also be ascribed to its immune modulating
enzymes fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC) and effect. Their research indicated that berberine promoted Programmed
(ATP citrate lyase) ACL thus inhibiting de novo lipogenesis. Reduced cell death 1 ligand 1 (PD-L1) degradation in cancer cells by binding to
lipid level inhibited β-catenin signaling pathway which regulated cell CSN5 (constitutive photomorphogenic-9 signalosome 5) which deubi
proliferation and resulted in cell cycle arrest in G0/G1 phase [198]. Gu’s quitinates PD-L1 to activate T-cells. In addition, in a clinical trial
research came to a similar conclusion that berberine inhibited cell berberine manifested suppressant effect on recurrence of colorectal
growth by regulating de novo lipogenesis by 13C-based metabolic anal adenoma, no serious adverse events were observed [206].
ysis. It was verified that berberine inhibited ACC activity by activating In conclusion, alkaloids from C. yanhusuo inhibited cancer cell in
AMPK hence inhibiting de novo lipogenesis. Suppression of de novo vasion, migration, angiogenesis, drug resistance and telomerase activity,
lipogenesis resulted in inhibition of extracellular vesicle generation promoted immunity, cancer cell apoptosis, autophagy and ROS pro
which also affected tumor growth as it was verified that adding exoge duction, modulated cell cycle arrest and reversed EMT. Some signaling
nous extracellular vesicles attenuated berberine-induced cell death and pathways played especially important roles such as MAPKs, AMPK and
cell cycle arrest in G1 phase [199]. Samad’s research came to a different Akt signaling. These findings suggest that alkaloids from C. yanhusuo
conclusion that the effect of berberine on cell cycle is time dependent. have promising potentials to become treatments for cancer. Various
Berberine increased the proportion of G2/M in the first 6 h and the alkaloids and mechanisms were involved in alkaloids from C. yanhusuo’
proportion of G1/M started increasing at 12 h in in colorectal cancer cell anticancer effect, which is displayed in Fig. 6.
line HCT 116 [200] in comparison to Liu’s observation at 48 h after
berberine co-incubation and Gu’s observation at 60 h after berberine 3.4. Other effects
treatment. Samad observed that berberine up-regulated Cyclin D1 level
but down-regulated CDK4 level, resulting in insufficient binding of 3.4.1. Anti-diabetic and diabetic complications
Cyclin D1 to CDK4 and led to cell cycle arrest in G0/G1 phase [200]. Diabetes is a serious, fast-growing disease that is estimated to affect
Another research investigated protopine’s anti-cancer effect on human 693 adults in 2045 and its complications are the main cause of its
hormone refractory prostate cancer. Protopine promoted tubulin poly increasing morbidity, disability, and mortality rate [207,208]. Many
merization which disturbed tubulin formation during mitosis, activated researches pointed to the use of berberine against diabetes for its pro
cyclin dependent kinase-1(CDK1)/cyclin B complex which regulates the motion of insulin release, reduction of insulin resistance, modulation the
transition from G2 to M phase, and inhibited mitosis as indicated by gut microbiota and its low liver toxicity. Besides, berberine also
increased mitotic protein monoclonal-2 (MPM-2) expression, explaining ameliorated diabetes complications. Among others, AMPK and Akt
the cell cycle arrest in G2/M protopine induced. CDK1 also phosphor signaling pathways played an essential role.
ylated Bcl-2 and degraded Mcl-1 via proteasome related pathway, A meta-analysis demonstrated that berberine significantly reduced
leading to cell apoptosis. Moreover, protopine is not a P-gp substrate, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c) and 2-h
meaning it cannot be translocated out of the cell to decrease its plasma blood glucose (2hPBG) and the glucose-lowering effect was
anti-cancer efficacy in multidrug-resistance cancer cells [201]. In correlated with baseline mean FPG and HbA1c levels. Also, berberine
addition, C. yanhusuo extract also induced cell cycle arrest in G2/M alone or in combination with oral hypoglycemic agents (OHAs) reduced
phase through suppression of cdc-2, Rb and p21 expression [194]. the incidence of adverse events indicating better safety [209]. A recent
Angiogenesis was also regulated. Berberine suppressed the growth of studied found that berberine stimulated insulin release
non-alcoholic steatohepatitis-derived hepatocellular carcinoma by dose-dependently and the effect depends on high glucose level. More
inhibiting angiogenesis and inflammation through suppression of the importantly, they elucidated that berberine stimulated insulin release by
expression of p-p38, p-ERK and their downstream COX-2 [202]. pancreatic islet β-cells through binding to KCNH6 potassium channel.
Berberine also inhibited angiogenesis induced by human cervical cancer Berberine was found to bind to KCNH6 and accelerate its closure,
cells through down-regulation of the expression of VEGF and HIF-1α, resulting in delayed repolarization, prolonged action potential duration
which has an important role in VEGF transcription [182]. Coptisine (APD), increased Ca2+ influx and insulin exocytosis, which is consistent
reduced the mRNA level of VE-cadherin and β3-integrin to reduce with their observation that the promotion of insulin release is
angiogenesis induced by osteosarcoma cells. It was noticed that STAT3 high-glucose dependent [210]. Besides stimulating insulin release,
phosphorylation was slightly increased whereas Akt, ERK and NF-κB berberine also reversed insulin resistance. Berberine was found to
13
increase insulin receptor expression in T2D patients [211]. Various was also validated in db/db mice [222]. In Qin’s another research,
studies indicated the role of PI3K/Akt signaling and AMPK signaling in berberine promoted fatty acid oxidation and mitochondrial function in
berberine’s effect on insulin resistance. Geng’s study indicated that podocytes through up-regulation of the AMPK/PPARγ coactivator-1α
berberine on one hand promoted insulin receptor phosphorylation and (PGC-1α) signaling pathway, hence reducing oxidative damage induced
enhanced insulin receptor downstream Akt and eNOS phosphorylation by lipid overload [223]. Berberine also attenuated diabetes-associated
in HUVECs to improve insulin resistance and insulin-induced dilation of cognitive decline as indicated by improved fear-memory deficit.
mesenteric arteries. On the other hand, berberine promoted phosphor Further investigation showed that berberine reduced insulin resistance
ylation of AMPK to enhance autophagy to improve insulin resistance as indicated by suppressed p-insulin receptor substrate-1
[212]. Another research verified that berberine increased glucose up (p-IRS-1Ser307), p-PI3K, p-Akt and p-GSK3βser9 expression yet insulin
take and consumption in insulin-resistant H9c2 cells in part through receptor expression was not significantly changed. Their research also
phosphorylation of AMPK. In contrast, p-Akt was only slightly altered by demonstrated that berberine suppressed inflammation in prefrontal
berberine [213]. Berberine was also found to restore AMPK and Akt cortex by down regulation of phosphorylation levels of the inhibitor of
signaling in the liver of mice with fructose-induced insulin resistance nuclear factor kappa-B kinase (IKK) and NF-κB. Berberine also restored
[214]. Another study revealed that berberine on one hand activated glucose metabolism in neurons and suppressed the production of Aβ42
AMPK in 3T3-L1 adipocytes and L6 myotubes through suppressing in PFC yet metformin had little effects on them [224].
aerobic respiration and increasing anaerobic respiration and on the In conclusion, berberine promoted insulin release, reduced insulin
other hand promoted insulin-induced glucose uptake without altering resistance, modulated the gut microbiota, had low liver toxicity and
insulin receptor signaling pathways. Additionally, berberine only ameliorated diabetes complications. AMPK and Akt signaling pathways
enhanced insulin-induced glucose consumption in 3T3-L1 adipocytes are of great significance in berberine’s pharmacological effects. The
and C2C12 myotubes but not in L6 myotubes and H4IIE hepatocytes above findings indicate that berberine a promising candidate for treat
[215]. However, there are also opposing findings suggesting that the ment of diabetes.
role of AMPK is dispensable. Xu’s research also validated that berberine
reduced aerobic respiration, stimulated anaerobic respiration and 3.4.2. Liver protection
increased AMPK phosphorylation. Nevertheless, inhibition of AMPK Many researches pointed to the liver protection effect of alkaloids
through compound C, AMPKα1/α2 siRNA and adenovirus did not alter from C. yanhusuo and the mechanisms include suppressing apoptosis,
berberine-induced glucose consumption and lactate release [216]. autophagy, inflammation and fibrosis, reducing lipid accumulation and
Dong’s research indicated that although berberine relieved modulating liver biotransformation. Yu et al. demonstrated that L-THP
intralipid-induced insulin resistance, the AMPK signaling activated by reduced autoimmune hepatitis damage by ameliorating apoptosis and
berberine was suppressed by intralipid infusion. Instead, Dong identified autophagy through TNF receptor associated factor 6 (TRAF6)/JNK
that berberine’s effect against insulin resistance was mediated by CypD pathway. TNF-α interacts with TRAF6 and TNFR thus activating JNK
which regulated mitochondrial permeability as indicated by deficiency which phosphorylates Bcl2 to promote apoptosis. Inactivated Bcl2
of CypD abolished berberine’s effect on insulin resistance [217]. disintegrate with beclin-1 thus releasing beclin-1 to promote autophagy.
Berberine also modulated gut microbiota. Clinical trial showed that L-THP reduced TNF-α and IL-6 production, consequently reducing
berberine had better effect in lowering glycated hemoglobin than pro apoptosis and autophagy to relieve autoimmune hepatitis [225]. Yu
biotics. Further investigation showed that berberine induced significant et al.’s later research demonstrated that L-THP also ameliorated liver
change in the composition of gut microbiomes, inhibited microbial BA fibrosis injury. L-THP up-regulated PPARγ/NF-κB signaling pathway
transformation, altered the blood BA pool and might have reduced and down-regulated transforming growth factor-β1 (TGF-β1)/Smad
diabetes through reducing gut Farnesoid X Receptor (FXR) activity [218, pathway, resulting in decreased activation, autophagy and ECM pro
219]. Also, the key strain that mediated the above effects of berberine duction in hepatic stellate cells to reduce liver fibrosis [226]. Several
has been identified as Ruminococcus bromii. Another research indicated studies also indicated that berberine reduced lipid accumulation in liver.
that co-treatment of probiotics and berberine, rather than berberine or Sun et al. reported that berberine promoted autophagy via SIRT-1 to
probiotics alone, significantly reduced postprandial lipidemia of pa reduce lipid accumulation, thus ameliorating hepatic steatosis. They
tients with type-2 diabetes (T2D). The key strain was identified as Bifi suspected that SIRT-1 may up-regulated the transcription of fibroblast
dobacterium breve (B. breve) which was down-regulated upon berberine growth factor-21 (FGF21) hence promoting whole-body energy expen
treatment but was up-regulated upon probiotics and berberine diture and white adipose tissue turning brown as indicated by an in
co-treatment. On the other hand, it was also validated that berberine crease in ketogenesis [227]. Zhu et al. reported that berberine promoted
promoted free fatty acid (FFA) import and mobilization in B. breve phosphorylation of AMPK which phosphorylated sterol regulatory
through inducing fadD (long-chain acyl-CoA synthetase) genes expres element-binding protein-1c (SREBP-1c). SREBP-1 bound to the SRE
sion [220]. Moreover, berberine also had low liver toxicity. Research motif in stearyl-coenzyme A desaturase 1 (SCD1) promotor to reduce
indicated that the therapeutic effect of berberine (1 g/d) is comparable SCD1 transcription, leading to reduced triglyceride accumulation and
to Metformin (1.5 g/d) and Rosiglitazone (4 mg/d). Alanine trans restored insulin sensitivity and glucose tolerance [228]. A clinical trial
aminase (ALT) and aspartate aminotransferase (AST) level was reduced also indicated that berberine had a strong hepatic lipid reducing effect
after berberine treatment in patients with type 2 diabetes mellitus or which is no less than pioglitazone (15 mg per day) in treatment of
impaired fasting glucose (IFG), indicating that berberine improved liver non-alcoholic fatty liver disease through regulation of transcription of
function in contrast to Metformin and Thiazolidinediones which are metabolism-related genes. Berberine plus lifestyle interference had no
known to have adverse effects on liver [211]. significant difference in serum glucose and serum insulin but had
Diabetic complications can also be ameliorated by berberine and additional benefits on BMI and serum lipids. Animal experiments
AMPK and Akt are also of great importance. Researches indicated that revealed that berberine is mainly distributed in the liver and the tran
berberine reduced diabetic nephropathy. Jin et al. found that berberine scription of microsomal triglyceride transfer protein (MTTP), carnitine
promoted AMPK phosphorylation to enhance autophagy and inhibit palmitoyltransferase-1α (CPT-1α) and glucokinase (GCK) was signifi
apoptosis of podocytes to alleviate high glucose-induced nephropathy cantly elevated corresponding to the second peak of berberine concen
[221]. Qin observed several protective effects of berberine on cultured tration in the liver [229]. Protopine was also reported to reduce liver
podocytes such as reduction of palmitic acid (PA)-induced podocyte damage. Janbaz et al. reported that protopine suppressed liver damage
injury, apoptosis, mtROS and mitochondrial fission thanks to the inhi induced by paracetamol and CCl4 thanks to its effect to suppress
bition of Drp1. Besides, the protective role of berberine on diabetic microsomal drug metabolizing enzymes and liver biotransformation
kidney disease symptoms, podocyte damage and mitochondrial damage [230]. We can conclude from these researches that alkaloids from
14
C. yanhusuo reduced apoptosis, autophagy, inflammation, fibrosis, liver [239]. Berberine reversed the increase of ERK, JNK and p38 induced by
lipid accumulation and modulated microsomal drug metabolizing en Chikungunya Virus hence suppressing virus replication and maturation
zymes and are promising candidates for liver protection. [240]. Alkaloids from C. yanhusuo also exhibited inhibitory effects on
enzymes directly related to virus replication. Wang et al. verified that
3.4.3. Anti-gastric ulcer alkaloids from C. yanhusuo have high inhibitory effect on human im
Alkaloids from C. yanhusuo was also found to alleviate gastric ulcer, munodeficiency virus type 1 (HIV-1) reverse transcriptase [241]. Pan
corresponding to its traditional use of relieving abdominal pain. Li et al. deya et al. performed a molecular docking study and demonstrated that
[231] identified 10 metabolites and 7 pathways related to gastric ulcer protopine and allocryptopine could be potential RNA dependent RNA
and administration of alkaloids from C. yanhusuo reversed these meta polymerase inhibitors and may have therapeutic effect on
bolic changes in different degrees. They are: D-glucose of glucur SARS-COVID-19 [242]. We can conclude from above that alkaloids from
onidation, L-Lysine of Biotin metabolism, Uric acid and D-tryptophan of C. yanhusuo possess anti-viral effect via modulating signaling pathways
folic acid network, pyruvic acid of glycolysis and gluconeogenesis, and suppressing virus replication, etc. Therefore, alkaloids from
corticosterone of biosynthesis of aldosterone and cortisol, C. yanhusuo are promising candidates for viral infection.
sphingosine-1-phosphate of sphingolipid metabolism, and glycocholate,
hexadecanedioic acid and stearic acid of fatty acid biosynthesis. Besides 4. Administration
signaling pathways, several factors related to gastric ulcer formation,
mucosa barrier, wound healing and NO production can also be modu We have mentioned earlier that processing or co-administration
lated to relieve gastric ulcer. Zhao investigated Jin Ling Zi San’s methods modulated the components and efficacy of decoction of
anti-gastric ulcer activity. The alkaloid components of JLZS C. yanhusuo. Besides oral administration of C. yanhusuo decoction, novel
down-regulated serum IL-8, TNF-α, platelet activating factor (PAF) and methods of drug delivery have also been investigated. Several studies
Thromboxane B2 (TBX2) which are related to mucosal damage. investigated nanoparticles. Natural nanoparticles (Nnps) from
Furthermore, these alkaloid components also increased AChE level and C. yanhusuo, mainly composed of proteins, were found to adsorb
restored serum neurotensin (NT) level which inhibits gastrointestinal berberine and enhance its intestinal absorption. It was also demon
motility and secretion of gastric acid and pepsin. On the other hand, the strated that Nnps reduced P-gp-mediated BBR efflux and protected
levels of Prostaglandin E2 (PGE2), VEGF and basic fibroblast growth berberine from degradation [243]. Another study found that d,L-THP
factor (bFGF) which are beneficial to wound healing were up-regulated. could be transported through the skin via amphiphilic poly{[α-maleic
In addition, alkaloid components of JLZS play a relatively smaller role anhydride-ω-methoxy-poly(ethylene glycol)]-co-(ethyl cyanoacrylate)
compared to other components. [232]. Palmatine also significantly graft copolymer nanoparticles (PEGECAT NPs) [244].
reduced serum PAF level and increased the PGE2 in gastric tissue but had Self-microemulsifying drug delivery systems (SMEDDS) and
no effect on 5-HT in the brain and norepinephrine (NE) in the adrenal self-emulsifying drug-delivery systems (SEDDs) also attracted atten
glands which are both related to the HPA axis and affects ulcer recovery tions. SMEDDs/SEDDs spontaneously form oil-in-water dispersion under
and recidivation [233]. Coptisine was also found to relieve gastric ulcer. mild agitation of the gastrointestinal tract. It was found that
Coptisine reduced oxidative stress and inflammation and increased the self-microemulsifying drug delivery systems significantly elevated the
levels of COX-1, COX-2 and their product PGE2. Additionally, it was bioavailability of L-THP and L-isocorypalmine (L-ICP) which is the main
found that coptisine increased nucleus translocation of Nrf2 and the metabolite of L-THP by delaying and sustaining the release of L-THP
expression of its target gene HO-1 and it also suppressed the expression [245]. Another research verified that optimized SEDDs formed droplets
of MKK6 and nucleus translocation of p38 [234]. NO also plays an that were less than 100 nm and enhanced the bioavailability of L-THP
important role in gastric ulcer and its production can also be modulated and protopine [246]. It was also reported that palmatine-loaded cationic
by alkaloids from C. yanhusuo. NO produced by eNOS is cytoprotective lipid emulsions was eliminated slower, had stronger anti-infection ac
yet that produced by iNOS is detrimental. Tetrahydrocoptisine reduced tivity hence possessing better anti-keratitis activity, and increased pal
both NO level and inflammation as indicated by reduced TNF-α, IL-6, matine uptake of human corneal epithelial cells [247]. Red emissive
myeloperoxidase (MPO) level and NF-κB expression to attenuate carbon dots as carriers of coptisine have been proven to sustain the
gastric ulcer [235]. Berberine pretreatment resulted in higher NO level release of coptisine and have a stronger antitumor activity [248].
in gastric juice and gastric tissue at 1 or 2 h but lower NO level at 6 h Several novel methods for delivery of berberine have also been inves
after oral administration of ethanol which induced gastric ulcer. It was tigated. Autologous red blood cell encapsulated with berberine pro
also noticed that eNOS transcription level was increased and iNOS longed the release and significantly ameliorated hyperlipidemia in mice
transcription level was decreased [236]. These findings suggest that [249]. As we mentioned before, co-treatment with sodium caprate
alkaloids from C. yanhusuo modulated signaling pathways, various fac (HGSD) increased concentration of berberine in brain [157]. Moreover,
tors related to gastric ulcer formation, mucosa barrier, wound healing it was found that intranasal delivery of thermoresponsive hydrogel
and NO production and are potential treatments for gastric ulcers. significantly improved berberine bioavailability and its anti-depressant
effect [250]. Sucrosomial berberine, a new formulation of berberine
3.4.4. Anti-viral effect covered by phospholipid bilayer membrane and sucrester matrix, was
Some researches indicated the antiviral effect of alkaloids from also investigated. The effect of 6.25 mg/kg/d of Sucrosomial berberine
C. yanhusuo. The common mechanisms of the anti-viral activity of these oral administration on AMPK activation, glucokinase (GK) expression
alkaloids include modulating signaling pathways, inhibiting virus and insulin resistance was comparable to 50 mg/kg/d of berberine oral
replication, etc. Li [237] identified 10 alkaloids with anti-hepatic B virus administration. Also, Sucrosomial berberine significantly increased the
activity, berberine and coptisine were included. MAPKs are regulated by level of berberine metabolites including reduced, demethylated and
many alkaloids. L-THP has been verified for its anti-Japanese encepha glucuronide berberine in mice brain [251]. Drug delivery methods for
litis virus (JEV) activity. L-THP reduced the level of virus in brain and berberine on the nanometer level have also been developed including
had neuroprotective effects by reducing apoptosis, oxidative stress, natural polymers, magnetic mesoporous silica based, lipid-based, den
activation of microglial cells and proinflammatory cytokines including drimer based and graphene based nanocarriers, gold and silver nano
TNF-a, IL-6, interferon-γ (IFN-γ) and monocyte chemoattractant protein particles and others [252].
(MCP-1). L-THP also reduced expression of phospho-p38, phos
pho-c-Jun, Hsp-70 and increased phospho-ERK1/2 and phospho-Akt 5. Conclusion and prospective
[238]. Corydaline suppressed enterovirus 71 protein synthesis by
reducing COX-2 via down-regulation of phosphorylation of p38 and JNK To date, 84 alkaloids have been identified from C. yanhusuo and can
15
be classified into protoberberine alkaloids, aporphine alkaloids, opiate Declaration of Competing Interest
alkaloids and others. Traditionally, C. yanhusuo was processed with
vinegar or wine alone or in combination with other herbs which mod The authors declare that they have no known competing financial
ulates its components to increase efficacy and selectivity and reduce interests or personal relationships that could have appeared to influence
toxicity. Alkaloids from C. yanhusuo have been found to have pharma the work reported in this paper.
cological effects on the nervous system, cardiovascular system, cancer
and others such as diabetes, viral infection, etc. Alkaloids from Data Availability
C. yanhusuo act through interacting with the neurotransmitter systems,
directly binding to proteins, regulating the HPA axis, composition of gut No data was used for the research described in the article.
microbiota, various signaling pathways and others to relieve diseases
related to the nervous system, cardiovascular system, cancer, and others. Acknowledgements
There is also an interesting fact that alkaloids from C. yanhusuo may
have effects that are opposite but curative in different diseases or This work was supported by the National Key R&D Program of China
different phases of the same disease as is discussed in the 3.2.1/2/4 anti- (2020YFA0908000), the National Natural Science Foundation of China
myocardial/cerebral IR injury and angiogenesis sections. Novel methods (82003894), the Key Project at central government level: The ability
of drug delivery have also been investigated such as alkaloid-encapsuled establishment of sustainable use for valuable Chinese Medicine Re
autologous red blood cell, co-treatment of sodium caprate, natural sources (2060302), and National Program for Special Support of
nanoparticles, SMEDDs/SEDDs, etc. Eminent Professionals. Team and Talents Cultivation Program of Na
Alkaloids from C. yanhusuo are potential remedies for multiple dis tional Administration of Traditional Chinese Medicine (ZYYCXTD-D-
eases such as psychoactive drug use disorders, anxiety, depression, 202005).
myocardial/cerebral IR injury, cancer, diabetes and others. These dis
eases placed tremendous burden on patients’ health thus alkaloids from
C. yanhusuo have extensive application prospects. Also, compared to Declaration of Generative AI and AI-assisted technologies in the writing
current drugs, alkaloids from C. yanhusuo alone or as co-mediaction had process
comparable therapeutic effects but less side effects [61,83,197,211].
The alkaloid components of C. yanhusuo are a rich source of potential During the preparation of this work the authors used GPT-3.5 in
lead compounds to inspire drug discovery. The pharmacological mech order to improve grammar and readability. After using this tool/service,
anisms of alkaloids from C. yanhusuo will provide new insights into the authors reviewed and edited the content as needed and take full
pathogenesis of diseases and drug targets. The drug delivery methods responsibility for the content of the publication.
may shed new lights on pharmacokinetics of alkaloids from C. yanhusuo
and co-administration formulas or delivery methods to increase potency
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Biomedicine & Pharmacotherapy 167 (2023) 115511

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

The composition, pharmacological effects, related mechanisms and drug

palmatine (PubChem CID: 19009)

1. Introduction process using 8 Q-markers namely protopine, coptisine, palmatine hy­

Table 1 Table 1 (continued )

No. Substitute Groups

No. Substitute Groups

No. Substitute Groups

No. Substitute Groups

69. Saulatine 70. Bicuculline 82. Adenosine

Fig. 1. Parent nuclei and structure of alkaloid representative from C. yanhusuo.

monophosphate activated protein kinase (AMPK) to relieve diabetic

study indicated that berberine also reversed the decreased nuclear

mechanisms of alkaloids from C. yanhusuo. THP reduced reactive oxygen

CFA-induced inflammatory pain [45]. Besides relieving inflammatory p-CaMKII p-ERK

Fig. 4. Mechanisms related to anti-MIR effects of alkaloids

Fig. 5. Mechanisms related to anti-cerebral I/R injury ef­

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Fig. 5. Mechanisms related to anti-cerebral I/R injury ef