Article(id=1193558473469293021, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193558470239678932, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0662, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1720886400000, receivedDateStr=2024-07-14, revisedDate=1730736000000, revisedDateStr=2024-11-05, acceptedDate=null, acceptedDateStr=null, onlineDate=1762496115319, onlineDateStr=2025-11-07, pubDate=1736611200000, pubDateStr=2025-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762496115319, onlineIssueDateStr=2025-11-07, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762496115319, creator=13701087609, updateTime=1762496115319, updator=13701087609, issue=Issue{id=1193558470239678932, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='1', pageStart='1', pageEnd='244', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1762496114549, creator=13701087609, updateTime=1764224942173, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200809698921402865, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193558470239678932, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200809698921402866, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193558470239678932, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=105, endPage=116, ext={EN=ArticleExt(id=1193558473993581025, articleId=1193558473469293021, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Network pharmacology-based mechanism of combined leech and bear bile on hepatobiliary diseases, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

In order to explore the possible role and molecular mechanism of the combined action of leech and bear bile in liver and gallbladder diseases, this study first used network pharmacology methods to screen the components and targets of leech and bear bile, as well as the related target genes of liver and gallbladder diseases. The selected key genes were subjected to interaction network and GO/KEGG enrichment analysis. Then, using sodium oleate induced HepG2 cell lipid deposition model and DL-ethionine induced mouse fatty liver model, the activity of leech and bear bile alone and in combination in reducing liver fat was evaluated in vitro and in vivo, and the expression of key pathway related proteins suggested by network pharmacology was detected by Western blot. The results of network pharmacology analysis showed that the active ingredients of leech and bear bile have 295 intersecting targets with liver and gallbladder related diseases, involving more than 200 signaling pathways, including the PI3K/Akt signaling pathway and phospholipase D signaling pathway closely related to glucose and lipid metabolism. The results of in vitro validation experiments showed that both leech and bear bile, alone and in combination, can significantly inhibit the lipid deposition induced by sodium oleate in human liver cells, reduce the triacylglycerol level in cell culture supernatant, and inhibit the lipid content in liver cells. The observation results of Nile red staining confocal microscopy showed that the combination of leech and bear bile had better activity in reducing lipid deposition in liver cells compared to using them alone. In a mouse fatty liver model, the combination of leech and bear bile can better reduce elevated organ indices, blood lipids, and liver lipid levels, as well as lower the levels of serum liver injury biomarkers. The animals used in this experiment and related disposal meet the requirements of animal welfare. Before the experiment, it was reviewed and approved by IACUC, Institute of Materia Medica, Chinese Academy of Medical Sciences. The Western blot experiment results showed that the combination of leech and bear bile can significantly upregulate the expression levels of p-PI3K and p-Akt proteins, and increase the p-PI3K/PI3K and p-Akt/Akt ratios, which is consistent with the predicted results of network pharmacology. The combination of leech and bear bile has great potential for treating fatty liver disease, and activating the PI3K/Akt pathway may be one of the important mechanisms for reducing lipid deposition in liver cells.

, correspAuthors=Tao MA, Hua SUN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Chen GAO, Yu-shi GUO, Xin-yi GUO, Ling-zhi ZHANG, Guo-hua YANG, Yu-sheng YANG, Tao MA, Hua SUN), CN=ArticleExt(id=1193558738280870102, articleId=1193558473469293021, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于网络药理学对水蛭与熊胆联用与肝胆相关疾病作用关系的研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

为了探究水蛭与熊胆联合作用于肝胆疾病的可能作用和分子机制, 本研究首先利用网络药理学方法筛选水蛭和熊胆成分及其靶点和肝胆疾病的相关靶基因, 将筛选出的关键基因进行交互作用网络和GO、KEGG富集分析, 然后利用油酸钠诱导的HepG2细胞脂质沉积模型和DL-乙硫氨酸诱导的小鼠脂肪肝模型, 在体内外对水蛭熊胆单独处理及联合作用降低肝脂的活性进行评价, 并采用Western blot法检测网络药理学提示的关键通路相关蛋白的表达。网络药理学分析结果显示, 水蛭、熊胆有效成分与肝胆相关疾病有295个交集靶点, 涉及200多条信号通路, 其中包括与糖脂代谢密切相关的PI3K/Akt信号通路、磷脂酶D信号通路等。体外验证实验结果显示, 水蛭与熊胆单独及联合应用均可显著抑制油酸钠诱导的人肝细胞内脂质沉积, 能够降低细胞培养上清TG水平, 抑制肝细胞内脂质含量, Nile red染色共聚焦显微镜观察结果表明, 水蛭与熊胆联合应用降低肝细胞内脂质沉积的活性相对单独用药更佳。在体内小鼠脂肪肝模型中, 水蛭与熊胆联合应用能够更好地降低升高的脏器指数、血脂和肝脂水平, 降低血清肝损伤生物标志物含量。本实验所用动物及相关处置符合动物福利的要求, 实验开展前经过中国医学科学院药物研究所实验动物管理和使用委员会(IACUC) 的审查批准。Western blot实验结果显示, 水蛭与熊胆联合应用能够显著上调p-PI3K、p-Akt蛋白的表达水平, 增加p-PI3K/PI3K、p-Akt/Akt比值, 与网络药理学预测结果一致。水蛭熊胆联合应用有治疗脂肪性肝病的良好潜能, 激活PI3K/Akt通路可能是其降低肝细胞脂质沉积的重要机制之一。

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Research on The Regulation of HRPE Cell Differentiation Based on WNT/PI3K/Akt Pathway and Growth Factor PEDF Hirudin (基于WNT/PI3K/Akt通路和生长因子PEDF水蛭素调控HRPE细胞分化的研究) [D]. Chengdu: Chengdu University of Traditional Chinese Medicine, 2016., articleTitle=null, refAbstract=null), Reference(id=1194708292925624647, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193558473469293021, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[36], rfOrder=35, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu M, Luo G, Dong L, et al. Network pharmacology and in vitro experimental verification reveal the mechanism of the hirudin in suppressing myocardial hypertrophy [J]. 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Item	Name of disease
1	Abnormality of the liver
2	Acute liver failure
3	Chemical and drug induced liver injury
4	Cholestatic liver disease
5	Copper accumulation in liver
6	Cystric liver disease
7	Decreased carnitine level in liver
8	Decreased liver function
9	Decreased mitochondrial complex Ⅲ activity in liver tissue
10	Depletion of mitochondrial DNA in liver
11	Fatal liver failure in infancy
12	Fatty liver
13	Non-alcoholic fatty liver disease
14	Inflammatory response in alcoholic liver disease
15	Ischemic injury of the liver
16	Liver abscess
17	Liver cirrhosis
18	Liver diseases
19	Liver failure
20	Liver fibrogenesis
21	Liver injury
22	Liver related disease
23	Abnormality of the gallbladder
24	Cystic fibrosis gallbladder
25	Gallbladder dysfunction
26	Chronic cholecystitis
27	Cholelithiasis
28	Cholestatic hepatitis

), ArticleFig(id=1194708288660017378, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193558473469293021, language=CN, label=Table 1, caption=

Hepatobiliary related diseases

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Item	Name of disease
1	Abnormality of the liver
2	Acute liver failure
3	Chemical and drug induced liver injury
4	Cholestatic liver disease
5	Copper accumulation in liver
6	Cystric liver disease
7	Decreased carnitine level in liver
8	Decreased liver function
9	Decreased mitochondrial complex Ⅲ activity in liver tissue
10	Depletion of mitochondrial DNA in liver
11	Fatal liver failure in infancy
12	Fatty liver
13	Non-alcoholic fatty liver disease
14	Inflammatory response in alcoholic liver disease
15	Ischemic injury of the liver
16	Liver abscess
17	Liver cirrhosis
18	Liver diseases
19	Liver failure
20	Liver fibrogenesis
21	Liver injury
22	Liver related disease
23	Abnormality of the gallbladder
24	Cystic fibrosis gallbladder
25	Gallbladder dysfunction
26	Chronic cholecystitis
27	Cholelithiasis
28	Cholestatic hepatitis

), ArticleFig(id=1194708288735514854, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193558473469293021, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=

Item	Component name	PubChem ID	Mol. wt.
SZ1	Putrescine	1045	88.15
SZ2	Glycerol	753	92.09
SZ3	2-Piperidone	12665	99.13
SZ4	Hexanal	6184	100.16
SZ5	Histamine	774	111.15
SZ6	Uracil	1174	112.09
SZ7	Proline	145742	115.13
SZ8	Valine	6287	117.15
SZ9	Succinic acid	1110	118.09
SZ10	Nicotinic acid	938	123.11
SZ11	L-Isoleucine	6306	131.17
SZ12	Adenine	190	135.13
SZ13	Hypoxanthine	135398638	136.11
SZ14	Spermidine	1102	145.25
SZ15	Acetylcholine	187	146.21
SZ16	Glutamic acid	33032	147.13
SZ17	Xanthine	1188	152.11
SZ18	Camphor	2537	152.23
SZ19	Dopamine	681	153.18
SZ20	Menthol	1254	156.26
SZ21	Tryptamine	1150	160.22
SZ22	Phenylalanine	6140	165.19
SZ23	Methyl(2E, 8Z-decadien-4, 6-diynoate	6443002	174.2
SZ24	Citrulline	9750	175.19
SZ25	Serotonin	5202	176.21
SZ26	Tyrosine	6057	181.19
SZ27	Spermine	1103	202.34
SZ28	Genipinic acid	12310086	242.22
SZ29	Lipase	1369	299.3
SZ30	Capsaicin	1548943	305.4
SZ31	Hirudinoidine A	101844805	310.4
SZ32	Crocetin	5281232	328.4
SZ33	Ecdysone	19212	464.6
SZ34	Leucine	6106	131.17
SZ35	Indole-3-carboxaldehyde	10256	145.16
SZ36	Lysine	5962	146.19
SZ37	Methionine	6137	149.21
SZ38	Histidine	6274	155.15
SZ39	Tryptophan	6305	204.22
SZ40	Diacetazotol	6751	309.4
SZ41	1, 3-Dimethyl-6-methylsulfinylthieno[3, 2-g]pteridine-2, 4-dione	101844805	310.4
SZ42	CPA inhibitor	44374998	313.3
SZ43	ELI	9549220	320.4

), ArticleFig(id=1194708288811012328, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193558473469293021, language=CN, label=Table 2, caption=

The active ingredients of leech (SZ)

, figureFileSmall=null, figureFileBig=null, tableContent=

Item	Component name	PubChem ID	Mol. wt.
SZ1	Putrescine	1045	88.15
SZ2	Glycerol	753	92.09
SZ3	2-Piperidone	12665	99.13
SZ4	Hexanal	6184	100.16
SZ5	Histamine	774	111.15
SZ6	Uracil	1174	112.09
SZ7	Proline	145742	115.13
SZ8	Valine	6287	117.15
SZ9	Succinic acid	1110	118.09
SZ10	Nicotinic acid	938	123.11
SZ11	L-Isoleucine	6306	131.17
SZ12	Adenine	190	135.13
SZ13	Hypoxanthine	135398638	136.11
SZ14	Spermidine	1102	145.25
SZ15	Acetylcholine	187	146.21
SZ16	Glutamic acid	33032	147.13
SZ17	Xanthine	1188	152.11
SZ18	Camphor	2537	152.23
SZ19	Dopamine	681	153.18
SZ20	Menthol	1254	156.26
SZ21	Tryptamine	1150	160.22
SZ22	Phenylalanine	6140	165.19
SZ23	Methyl(2E, 8Z-decadien-4, 6-diynoate	6443002	174.2
SZ24	Citrulline	9750	175.19
SZ25	Serotonin	5202	176.21
SZ26	Tyrosine	6057	181.19
SZ27	Spermine	1103	202.34
SZ28	Genipinic acid	12310086	242.22
SZ29	Lipase	1369	299.3
SZ30	Capsaicin	1548943	305.4
SZ31	Hirudinoidine A	101844805	310.4
SZ32	Crocetin	5281232	328.4
SZ33	Ecdysone	19212	464.6
SZ34	Leucine	6106	131.17
SZ35	Indole-3-carboxaldehyde	10256	145.16
SZ36	Lysine	5962	146.19
SZ37	Methionine	6137	149.21
SZ38	Histidine	6274	155.15
SZ39	Tryptophan	6305	204.22
SZ40	Diacetazotol	6751	309.4
SZ41	1, 3-Dimethyl-6-methylsulfinylthieno[3, 2-g]pteridine-2, 4-dione	101844805	310.4
SZ42	CPA inhibitor	44374998	313.3
SZ43	ELI	9549220	320.4

), ArticleFig(id=1194708288924258538, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193558473469293021, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=

Item	Component name	PubChem ID	Mol. wt.
XD1	Acetylcholine	187	146.21
XD2	Chenodeoxycholic acid	10133	392.6
XD3	Cherianoine	5315819	235.24
XD4	Cholicacid	221493	408.6
XD5	Choline	305	104.17
XD6	Deoxycholic acid	222528	392.6
XD7	Deoxycorticosterone	6166	330.5
XD8	Taurochenodeoxycholic acid	387316	499.7
XD9	Taurocholic acid	6675	515.7
XD10	Taurodeoxycholic acid	2733768	499.7
XD11	Tauroursodeoxycholic acid	9848818	499.7
XD12	Taxachitriene A	124511123	636.7
XD13	Ursodeoxycholic acid	31401	392.6
XD14	Ursolic acid	64945	456.7
XD15	Quercetin	5280343	302.23
XD16	Succinic acid	1110	118.09
XD17	Caffeic acid	689043	180.16
XD18	Aspartic acid	5960	133.1
XD19	Threonine	6288	119.12
XD20	Glutamic acid	33032	147.13
XD21	Taurolithocholic acid	439763	483.7
XD22	Bilirubin	5280352	584.7
XD23	Biliverdin	5280353	582.6

), ArticleFig(id=1194708288991367406, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193558473469293021, language=CN, label=Table 3, caption=

The active ingredients of bear bile (XD)

, figureFileSmall=null, figureFileBig=null, tableContent=

Item	Component name	PubChem ID	Mol. wt.
XD1	Acetylcholine	187	146.21
XD2	Chenodeoxycholic acid	10133	392.6
XD3	Cherianoine	5315819	235.24
XD4	Cholicacid	221493	408.6
XD5	Choline	305	104.17
XD6	Deoxycholic acid	222528	392.6
XD7	Deoxycorticosterone	6166	330.5
XD8	Taurochenodeoxycholic acid	387316	499.7
XD9	Taurocholic acid	6675	515.7
XD10	Taurodeoxycholic acid	2733768	499.7
XD11	Tauroursodeoxycholic acid	9848818	499.7
XD12	Taxachitriene A	124511123	636.7
XD13	Ursodeoxycholic acid	31401	392.6
XD14	Ursolic acid	64945	456.7
XD15	Quercetin	5280343	302.23
XD16	Succinic acid	1110	118.09
XD17	Caffeic acid	689043	180.16
XD18	Aspartic acid	5960	133.1
XD19	Threonine	6288	119.12
XD20	Glutamic acid	33032	147.13
XD21	Taurolithocholic acid	439763	483.7
XD22	Bilirubin	5280352	584.7
XD23	Biliverdin	5280353	582.6

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