Aconiti lateralis Radix Praeparata inhibits Alzheimer’s disease by regulating the complex regulation network with the core of GRIN1 and MAPK1

Figures & data

Figure 1. The gene interaction and the change pattern of cells. (A) The modification pattern for the cell viability and the length of cell’s projections, when APP cells were treated by Fuzi solution of different concentration. Statistically (p ≤ 0.05) and extremely (p ≤ 0.01) significant difference were symbolled as “*” and “**”, and p ≤ 0.1 was symbolled as “#”. (B) The gene interaction pattern for the AD relevant Fuzi target genes.

Figure 2. The microscope images for cell morphology. NC symbol the APP cells were not treated by Fuzi. The other images symbol the APP cells were treated by Fuzi solution of different concentration, from 0.4 to 300 mg/ml.

Figure 3. The KEGG pathway of AD.

Table 1. The information for the 17 AD relevant target genes of Fuzi.

Gene Symbol	Gene Name	Related Scores for AD^1	RMS_P values of DEG^2	The Highest Related Scores for the Fuzi’s Ingredients^3
ADRB3	Adrenoceptor Beta 3	5.39	0.020355572	122.778
AR	Androgen Receptor	9.49	0.034383704	48
CHRM1	Cholinergic Receptor Muscarinic 1	7.82	0.021075246	48
CHRM3	Cholinergic Receptor Muscarinic 3	13.88	0.028798586	48
GABRA1	Gamma-Aminobutyric Acid Type A Receptor Alpha1 Subunit	17.46	0.020776697	80.882
GABRA4	Gamma-Aminobutyric Acid Type A Receptor Alpha4 Subunit	8.26	0.009644649	80.882
GABRA5	Gamma-Aminobutyric Acid Type A Receptor Alpha5 Subunit	7.93	0.02979358	80.882
GABRB3	Gamma-Aminobutyric Acid Type A Receptor Beta3 Subunit	16.56	0.021044654	80.882
GABRD	Gamma-Aminobutyric Acid Type A Receptor Delta Subunit	13.35	0.018002658	80.882
GABRG2	Gamma-Aminobutyric Acid Type A Receptor Gamma2 Subunit	9.96	0.016433434	80.882
GRIN1	Glutamate Ionotropic Receptor NMDA Type Subunit 1	17.06	0.022782919	22.373
HTR2A	5-Hydroxytryptamine Receptor 2A	24.18	0.027636956	80.882
MAPK1	Mitogen-Activated Protein Kinase 1	11.21	0.022727156	48
NOS1	Nitric Oxide Synthase 1	9.64	0.025594657	22.373
NRG1	Neuregulin 1	5.38	0.018124479	22.373
PDE5A	Phosphodiesterase 5A	5.56	0.020541902	22.373
SLC6A2	Solute Carrier Family 6 Member 2	11.15	0.017844332	48

¹The related scores for AD showed in GeneCards database. ²The RMS_P values were calculated basing on the gene expression data for AD showed in GEO database. ³The related scores for the Fuzi’s ingredients were provided by BATMAN-TCM database. The genes enriched in the classical AD pathway of KEEG were highlighted by boldface.

Table 2. The pathway enrichment results of 17 Fuzi’s target genes.

Pathway identifier	Pathway name	Candidate	Total	Ratio	P Value	FDR
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission	8	232	1.60E-02	2.75E-10	7.71E-08
R-HSA-112315	Transmission across Chemical Synapses	8	352	2.43E-02	7.12E-09	9.97E-07
R-HSA-977443	GABA receptor activation	5	67	4.62E-03	2.31E-08	2.15E-06
R-HSA-1236394	Signalling by ERBB4	5	82	5.65E-03	6.27E-08	4.39E-06
R-HSA-112316	Neuronal System	8	498	3.43E-02	1.03E-07	5.79E-06
R-HSA-375280	Amine ligand-binding receptors	4	88	6.06E-03	4.87E-06	2.24E-04
R-HSA-1306955	GRB7 events in ERBB2 signalling	2	6	4.13E-04	2.91E-05	1.02E-03
R-HSA-390648	Muscarinic acetylcholine receptors	2	6	4.13E-04	2.91E-05	1.02E-03
R-HSA-9006934	Signalling by Receptor Tyrosine Kinases	6	622	4.29E-02	1.04E-04	3.21E-03
R-HSA-1358803	Downregulation of ERBB2:ERBB3 signalling	2	16	1.10E-03	2.05E-04	5.19E-03
R-HSA-162582	Signal Transduction	12	3364	2.32E-01	2.27E-04	5.19E-03
R-HSA-438064	Post NMDA receptor activation events	3	96	6.61E-03	2.59E-04	5.19E-03
R-HSA-8847993	ERBB2 Activates PTK6 Signalling	2	18	1.24E-03	2.59E-04	5.19E-03
R-HSA-6785631	ERBB2 Regulates Cell Motility	2	19	1.31E-03	2.89E-04	5.20E-03
R-HSA-1963642	PI3K events in ERBB2 signalling	2	22	1.52E-03	3.86E-04	6.57E-03
R-HSA-442755	Activation of NMDA receptors and postsynaptic events	3	114	7.85E-03	4.27E-04	6.65E-03
R-HSA-416476	G alpha (q) signalling events	4	283	1.95E-02	4.43E-04	6.65E-03
R-HSA-5673001	RAF/MAP kinase cascade	4	290	2.00E-02	4.86E-04	6.80E-03
R-HSA-5684996	MAPK1/MAPK3 signalling	4	297	2.05E-02	5.31E-04	6.86E-03
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signalling	3	126	8.68E-03	5.71E-04	6.86E-03
R-HSA-9607240	FLT3 Signalling	4	311	2.14E-02	6.31E-04	7.51E-03
R-HSA-199418	Negative regulation of the PI3K/AKT network	3	134	9.23E-03	6.83E-04	7.51E-03
R-HSA-9620244	Long-term potentiation	2	31	2.14E-03	7.61E-04	8.38E-03
R-HSA-8940973	RUNX2 regulates osteoblast differentiation	2	34	2.34E-03	9.14E-04	9.14E-03
R-HSA-5683057	MAPK family signalling cascades	4	348	2.40E-02	9.60E-04	9.21E-03
R-HSA-9665686	Signalling by ERBB2 TMD/JMD mutants	2	35	2.41E-03	9.68E-04	9.21E-03
R-HSA-1250196	SHC1 events in ERBB2 signalling	2	36	2.48E-03	1.02E-03	9.21E-03
R-HSA-8863795	Downregulation of ERBB2 signalling	2	36	2.48E-03	1.02E-03	9.21E-03
R-HSA-442742	CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signalling	2	39	2.69E-03	1.20E-03	1.06E-02
R-HSA-392154	Nitric oxide stimulates guanylate cyclase	2	41	2.82E-03	1.32E-03	1.06E-02
R-HSA-8941326	RUNX2 regulates bone development	2	43	2.96E-03	1.45E-03	1.16E-02
R-HSA-9664565	Signalling by ERBB2 KD Mutants	2	46	3.17E-03	1.66E-03	1.33E-02
R-HSA-1227990	Signalling by ERBB2 in Cancer	2	48	3.31E-03	1.80E-03	1.44E-02
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	4	462	3.18E-02	2.71E-03	1.90E-02
R-HSA-8848021	Signalling by PTK6	2	71	4.89E-03	3.87E-03	2.71E-02
R-HSA-9006927	Signalling by Non-Receptor Tyrosine Kinases	2	71	4.89E-03	3.87E-03	2.71E-02
R-HSA-5619109	Defective SLC6A2 causes orthostatic intolerance (OI)	1	3	2.07E-04	3.92E-03	2.74E-02
R-HSA-1227986	Signalling by ERBB2	2	78	5.37E-03	4.65E-03	3.25E-02
R-HSA-1257604	PIP3 activates AKT signalling	3	316	2.18E-02	7.70E-03	4.62E-02
R-HSA-2219530	Constitutive Signalling by Aberrant PI3K in Cancer	2	103	7.10E-03	7.95E-03	4.77E-02

The lines in boldface were the pathways MAPK1 or GRIN1 genes taking part in.

Table 3. The structure and targets for AD relevant Fuzi’s compounds.

Database	Chemical	Structure	Targets and AD relevant pathway
TCMSP	Arachic acid		PTGS2: memory, learning, positive regulation of synaptic plasticity, positive regulation of synaptic transmission, glutamatergic, inflammatory response, lipoxygenase pathway, maintenance of blood-brain barrier
	14-Deoxy-11,12- didehroandrographolide
	Delphin_qt
	Deoxyandrographolide
	Myristic acid		PTGS2/ BCHE: acetylcholine catabolic process, learning, negative regulation of synaptic transmission, neuroblast differentiation, synaptic transmission
	Mescaline		PTGS2/ CHRM1: adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signalling pathway, G-protein coupled acetylcholine receptor signalling pathway, synaptic transmission, cholinergic
	Salsolinol
	EIC		PTGS2/ CHRM1/ CHRM2
	Fuzitine		PTGS2/ CHRM1/ ACHE: acetylcholine catabolic process, acetylcholine catabolic process in synaptic cleft, negative regulation of synaptic transmission, cholinergic, synapse assembly, synaptic transmission
BATMAN-TCM	Coryneine		MAPK1: Alzheimer disease, activation of MAPK activity, apoptotic process, axon guidance, long-term synaptic potentiation, Activation of NMDA receptor upon glutamate binding and postsynaptic events
	M-Aminophenol		GRIN1: Alzheimer disease, Glutamatergic synapse, activation of MAPKK activity, adult locomotory behavior, axon guidance, regulation of long-term neuronal synaptic plasticity, regulation of synapse assembly, synaptic transmission, glutamatergic
	Ortho-Aminophenol
	P-Aminophenol

Figure 4. The relationship of 17 candidate genes and 4 compounds (m-aminophenol, o-aminophenol, p-aminophenol, and coryneine) related genes. (A) The crossover relationship of the genes. (B) The crossover relationship of enrichment pathways that the genes enriched in.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its Supplementary materials.