Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 1498768 10.3389/fphar.2024.1498768 Pharmacology Review Traditional utilization, botany, phytochemistry, pharmacology, pharmaceutical analysis, processing and application of the seeds of Herpetospermum pedunculosum (Ser.) C.B. Clarke: a comprehensive review Jiang et al. 10.3389/fphar.2024.1498768 Jiang Zhixia † Zhang Chuang † Yu Xinran † Wang Kaiyi Sang Zhenqi Gong Wan Zhang Qiaoyan Meng Xiongyu * Qin Lupin * Zhao Qiming * College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China

Edited by: Hongbo Li, Shaanxi University of Science and Technology, China

Reviewed by: Claudio Frezza, Università Link Campus, Italy

Changfu Wang, Guangdong Pharmaceutical University, China

 *Correspondence: Xiongyu Meng, mengxiongyu@zcmu.edu.cn; Lupin Qin, lpqin@zcmu.edu.cn; Qiming Zhao, qmzhao@zcmu.edu.cn

These authors have contributed equally to this work

 19 12 2024 2024 15 1498768 19 09 2024 26 11 2024 Copyright © 2024 Jiang, Zhang, Yu, Wang, Sang, Gong, Zhang, Meng, Qin and Zhao. 2024 Jiang, Zhang, Yu, Wang, Sang, Gong, Zhang, Meng, Qin and Zhao

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The seed of Herpetospermum pedunculosum (Ser.) C.B. Clarke, known in Chinese as Bo-Leng-Gua-Zi and in Tibetan as Sejimedo, are here abbreviated as H. pedunculosum seeds. Herpetospermum pedunculosum seeds is a traditional Chinese medicine for protecting the liver, clearing heat, and detoxifying. A total of 125 chemical metabolites of H. pedunculosum seeds are found, including lignans, fatty acids, terpenes, coumarins, and others. The pharmacological activities of H. pedunculosum seeds are mainly in hepatoprotective, antioxidant, anti-cancer cells, and anticholestatic effects. In clinical application, it is mainly used in combination with other traditional Chinese medicines to play a key role in treating the liver disease. This paper gives a systematic review of above research aspects, proposes the potential limitations and put forward plausible solutions. Relevant literatures were searched in PubMed, Web of Science and Chinese National Knowledge Infrastructure with Herpetospermum as the key word. A number of studies have shown that H. pedunculosum seeds exert excellent hepatoprotective effects by acting on NF-κB, TGF-β, and Keap1-Nrf2 signaling pathways, which provide a solid base for its clinic application. However, more research is needed to explore the standard cultivation and quality evaluation of H. pedunculosum seeds and systematical structure-activity relationship of its active metabolites.

 Herpetospermum pedunculosum (Ser.) C.B. Clarke phytochemistry pharmacological activity liver protection lignan section-at-acceptance Ethnopharmacology 1 Introduction

With the continuous development of various drugs, phytomedicines with fewer side effects and significant effects are gradually attracting people. Especially for some effective ethnodrugs, further development of their hidden medicinal value through in-depth research is increasingly popular and desirable. Herpetospermum pedunculosum (Ser.) C.B. Clarke (H. pedunculosum) is mainly distributed in several high-altitude areas such as Tibet, Yunnan, India and Nepal. As the main medicinal part of H. pedunculosum (Ser.) C.B. Clarke, H. pedunculosum seeds are traditional Tibetan drug, which have traditional effects of clearing heat and softening liver. At the same time, H. pedunculosum seeds are also the core ingredient of clinical traditional Chinese prescriptions, such as Jiuwei Zhangya Pill (for treating cholecystitis), Wuwei Jinse Pill (for treating jaundice hepatitis), and Songshi pill (for treating hepatitis and liver fibrosis). Modern studies have shown that H. pedunculosum seeds contain a variety of chemical metabolites, including lignans, coumarins, terpenes, etc. (Xu, 2012), and have shown a variety of pharmacological activities, including liver protection, antioxidant, anti-tumor, and anti-cholestasis effects (Gong, 2012; Shen et al., 2015).

The excellent pharmacological effects and particular characteristics of H. pedunculosum seeds undoubtedly deserve systematical induction and summary, which is hardly reported to the best of our knowledge. Therefore, we investigated relevant literatures in Web of Science, PubMed and CNKI with Herpetospermum as the key word, and focused on the literatures of the H. pedunculosum seeds with excluding that on other parts, such as stem, leaf and flesh. Based on these literatures, this paper comprehensively reviews the traditional use, botany, chemical metabolites, pharmacological effects, pharmaceutical analysis, processing and application in Chinese herbal prescriptions of H. pedunculosum seeds, which can provide scientific basis for further research and promote the potential for development.

 2 Traditional uses

As a classic Tibetan medicine, H. pedunculosum seeds often used in the treatment of Tri-pa (a disease be traditionally characterized by diffusion of bile, disorders of the blood-heat, and yellow color in the muscles and eyes), which was first recorded in Yue Wang Yao Zhen (《月王药诊》) in the early 8th century. At the same time, in the middle of the 8th century, Tara Materia Medica (《度母本草》, Shivatso) recorded that H. pedunculosum seeds can treat heat disease, and bacon disease (diseases caused by the combination of food accumulation and cold). Beside these, Si Bu Yi Dian (《四部医典》, Yutog Yontan Gonpo), written and revised during the late 8th to 12th century, further proposed that H. pedunculosum seeds can remove the heat of the lower organs. In addition, it supplemented the bitter taste of H. pedunculosum seeds. Jingzhu Materia Medica (《晶珠本草》, Dema Tenpe Nyima), written in 1840, proposed that H. pedunculosum seeds could treat Tri-pa in the viscera. Diqing Tibetan medicine (《迪庆藏药》, Yang and Chu cheng) and Chinese Tibetan medicine (《中华藏本草》Luo, 1997) supplement recorded its effects of treating liver and gallbladder heat and indigestion, which was also supported by the record of Chinese Materia Medica (《中华本草》, National Administration of Traditional Chinese Medicine). In 2015, the “Interpretation of Tibetan Medicine Jinsui Materia Medica” (《藏药金穗本草诠释》, Gama Qupei) concluded that H. pedunculosum seeds could treat the liver and gallbladder diseases of the Tri-pa type. In summary, H. pedunculosum seeds have been used as its prototype medicine for over 13 centuries, and its effects on protecting the liver and treating indigestion have gained tremendous application as recorded in traditional medical books.

 3 Botany

Herpetospermum pedunculosum (Ser.) C. B. Clarke, is usually harvested at around October, and adapts to grow on warm, humid subtropical roadsides, hillsides, shrubland, and forest edges at the altitude of 2,300–3,500 m (Flora Reipublicae Popularis Sinicae Commission, 1983) and its botanical organs including the flower, leaf, fruit and seed were shown in Figures 1A–D. As displayed in Figure 1D, H. pedunculosum seeds is slightly oblong with uneven carving and the surface from brown to black brown. One end of H. pedunculosum seeds has triangular protrusions, and the other end is tapered, slightly wedge-shaped and slightly concave in the center (Chinese Materia Medica Commission, 1998). The further investigation of H. pedunculosum seeds characters and sources can enhance the standardization of commercial H. pedunculosum seeds and is of great significance in cultivating it.

Flower (A), leaf (B), fruit (C) and seed (D) of Herpetospermum pedunculosum (Ser.) C.B. Clarke.

 4 Phytochemistry

The chemical metabolites of H. pedunculosum seeds are reported to include lignans, fatty acids, terpenoids, and coumarins. The other metabolites such as amino acids, alkaloids, and flavones were also discussed. Details can be found in Figures 2–6 and Table 1.

Lignan types in Herpetospermum pedunculosum seeds.

Structures of lignan metabolites in Herpetospermum pedunculosum seeds.

Structures of fatty acids from Herpetospermum pedunculosum seeds.

Structures of terpenoids (92–101) and coumarins (102–108).

Structures of other metabolites from Herpetospermum pedunculosum seeds.

Metabolites extracted from Herpetospermum pedunculosum seeds.

No. Name Molecular formula Extract Separation method Identification method References
Lignan
1 Herpetriol C30H34O9 Ethyl alcohol — UV, IR,MS, 1H-NMR, 13C-NMR Kaouadji et al. (1979)
2 Herpetetrol C40H44O12 Ethyl alcohol — UV, MS, 1H-NMR, 13C-NMR Kaouadji et al. (1979)
3 Herpepentol C50H54O15 MeOH — MS, 1H-NMR, 13C-NMR Kaouadji and Pieraccini (1984a)
4 Herpetetradione C40H42O12 MeOH — MS, 1H-NMR, 13C-NMR Kaouadji and Favre-Bonvin (1984a)
5 Herpetetrone C40H42O13 MeOH Polyamide CC6 and sephadex LH-20, chromatography UV, IR, MS, 1H-NMR Kaouadji et al. (1987)
6 Herpetrione C30H32O10 Ethyl alcohol — MS, 1H-NMR, 13C-NMR Kaouadji and Jean (1983)
7 Herpetone C29H30O9 Ethyl alcohol Silica gel column chromatography, preparative HPLC MS, IR, 1H-NMR, 13C-NMR Zhang et al. (2006)
8 Herpetol C20H20O6 Ethyl alcohol — UV, MS, 1H-NMR, 13C-NMR Kaouadji and Pieraccini (1984a)
9 Dehydrodiconiferyl alcohol C20H22O6 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC UV, 1H-NMR, 13C-NMR Ma (2020)
10 Herpetosin B C20H22O7 Ethyl acetate Silica gel column chromatography UV, IR, MS, 13C-NMR, 1H-NMR Xu (2012)
11 Herpetal C20H18O6 Ethyl acetate — UV, 1H-NMR, 13C-NMR Kaouadji et al. (1978)
12 Herpetotriol C30H32O9 Ethyl acetate — UV, 1H-NMR, 13C-NMR Kaouadji et al. (1978)
13 Herpepropenal C30H30O10 Ethyl acetate Silica gel column chromatography, RPC18, HPLC MS, 13C-NMR, 1H-NMR, DEPT, HMBC, COSY, HSQC, NOESY Yang et al. (2010)
14 7,8′-didehydlroherpetotriol C30H32O9 Ethyl acetate Reversed phase silica gel column chromatography, Preparation for HPLC Chromatography UV, IR, MS, 1H-NMR,13C-NMR Xu (2012)
15 (7S,8R,7′R,8′S)-7'-[7′-ethoxyl-7'-(4′-hydroxyl-3′-methoxylphenyl)]methyl-7-(4-hydroxyl-3-methoxylphenyl)-8-hydroxymethyl-tetrahydrofuran C22H28O7 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi- preparative HPLC UV, IR, 1H-NMR, 13C-NMR Ma (2020)
16 (7S,8R)-threo-1'-[3′-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-8-hydroxymethyl-7,8-dihydrobenzofuran] acrylaldehyde C19H18O6 Ethyl aceta Normal phase silica gel column chromatography, MPLC, semi- preparative HPLC UV, IR, 1H-NMR, 13C-NMR Ma (2020)
17 (−)-Tanegool-7′-methyl etherl C21H26O7 Ethyl acetate Silica gel column chromatography, sephadex LH-20 MS, 1H-NMR, 13C-NMR Zhou (2014)
18 Herpetin C30H34O9 Ethyl acetate Silica gel column chromatography, Rp-Si -gel, semi- preparative HPLC MS, IR, 1H-NMR, 13C-NMR Yuan et al. (2005)
19 Lariciresino C20H24O6 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC UV, 1H-NMR,13C-NMR Ma (2020)
20 (+)-(7′S,7′′S,8′R,8′′R)-4,4′,4′′-Trihydroxy-3,5′,3′′-trimethoxy-7-oxo-8-ene[8-3′,7′-O-9′′,8′-8′′,9′-O-7′′] lignoid C30H30O9 Petroleum ether Silica gel column chromatography, preparative HPLC MS, IR, 1H-NMR, 13C-NMR, 1H-1H COSY, HMQC, HMBC Yu et al. (2014)
21 Ent-isolariciresinol C20H24O6 Ethyl acetate Silica gel column chromatography, MPLC, semi-preparative HPLC UV, MS, 1H-NMR, 13C-NMR Ma (2020)
22 Herpetenol C20H22O6 Ethyl acetate Silica gel column chromatography UV, IR, MS, 1H-NMR, 13C-NMR Wang (2005)
23 Herpetfluorenone C16H14O6 Ethyl acetate Silica gel column chromatography, sephadex LH-20 MS, 1H-NMR, 13C-NMR Gong et al. (2016)
24 (1S)-4hydroxy-3-[2-(4-hydroxy-3-methoxy-phenyl)-1-hydroxymethyl2-oxo-ethyl]-5-methoxy-benzaldehyde C18H18O7 Petroleum ether Silica gel column chromatography, RPC18, sephadex LH-20 MS, IR, 1H-NMR, 13C-NMR, 1H-1H COSY, HMQC, HMBC Yu et al. (2014)
25 Hedyotol A C30H32O9 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
26 Picrasmalignan C30H30O9 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
27 Balanophonin C20H20O6 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
28 1-Propanone, 3-hydroxy-1-(4-hydrpxy-3-methoxyphenyl)-2-[4-(3-hydroxy-1-propen-1-yl)-2-methoxyphenoxy] C21H24O6 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
29 Erythro-guaiacylglycerol-b-coniferyl ether C20H24O7 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
30 Threo-guaiacylglycerol- b-coiferyl ether C20H24O7 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
31 (7R,8S)-Dehydrodiconiferyl alcohol γ′- methyl ether C21H24O6 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
32 3-Benzofuranmethanol, 2, 3-dihydro-2-(4-dydroxy-3-methoxypenyl)-7-methoxy-5-(3-methoxyl-1-propenyl)-,[2S-[2a,3b, 5(E)]]-(9CI) C21H24O6 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
33 Evofolin-B C17H18O6 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
34 1-Propanon, 3-hydroxy-1-(2-hydrpxy-5-methoxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)- C20H24O7 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
35 Herpetatol A C19H18O5 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
36 Herpetatol B C19H16O5 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
37 Herpetatol C C20H22O7 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
38 Herpetatol D C31H32O9 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
39 Herpetatol E C30H30O9 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
40 Herpetatol F C29H28O8 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
41 Herpetatol G C29H28O8 Ethyl acetate Silica gel/gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Hu (2016)
42 (−)-pinoresinol monomethyl ether C21H24O6 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC MS, IR,1H-NMR, 13C-NMR Ma (2020)
43 epipinoresinol C20H22O6 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC UV, MS, 1H-NMR, 13C-NMR Ma (2020)
44 (+)-pinoresinol C20H22O6 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC MS, IR, 1H-NMR, 13C-NMR Ma (2020)
45 (+)-menbrine C21H24O5 Ethyl acetate Normal phase silica gel column chromatography, semi-preparative HPLC MS, IR, 1H-NMR, 13C-NMR Ma (2020)
46 cinncassins D C28H28O9 Ethyl acetate Normal phase silica gel column chromatography, semi-preparative HPLC MS, UV, IR, 1H-NMR, 13C-NMR Ma (2020)
47 (7R,7′R,7″R,8S,8′S,8″S)-4′,4″-dihydroxy-3,3′,3″,5-tetramethoxy-7,9':7′,9-diepoxy-4,8″-oxy-8,8′-sesqoineolignan-7″,9″-diol C31H36O11 Ethyl acetate Normal phase silica gel column chromatography, MPLC, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Ma (2020)
48 3-Benzofuranmethanol-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-4-:methoxy-6-[tetra-hydro-2-(3-hydroxy-4-methoxyphenyl)-3-methanol]-2-furanmethyl C31H36O8 Ethyl acetate Normal phase silica gel column chromatograpy MS, 1H-NMR, 13C-NMR Yuan et al. (2006b)
49 Ehletianol C C30H36O10 Ethyl acetate Normal phase silica gel column chromatography, semi-preparative HPLC MS, UV, 1H-NMR, 13C-NMR Ma (2020)
50 Herpetosiol G C20H22O5 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HMBC Ma (2020)
51 Herpetosiol H C23H30O8 Ethyl acetate Normal phase silica gel column chromatography, sephadex LH-20, semi-preparative HPLC UV, IR, MS, 1H-NMR, 13C-NMR, HSQC, HMBC, COSY, NOESY Ma (2020)
52 Herpetosiol I C30H34O10 Ethyl acetate Normal phase silica gel column chromatography, sephadex LH-20, semi-preparative HPLC UV, IR, MS, 1H-NMR, 13C-NMR, HSQC, HMBC, COSY, NOESY Ma (2020)
53 Herpetosiol J C23H24O9 Ethyl acetate Normal phase silica gel column chromatography, semi-preparative HPLC UV, MS, 1H-NMR, 13C-NMR, HSQC, HMBC, COSY, NOESY Ma (2020)
54 Herpetosiol K C30H30O9 Ethyl acetate Normal phase silica gel column chromatography, semi-preparative HPLC UV, IR, MS, 1H-NMR, 13C-NMR, HSQC, HMBC, COSY, NOESY Ma (2020)
55 Herpetosiol L C19H18O6 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC UV, MS, 1H-NMR, 13C-NMR, HSQC, HMBC, COSY, NOESY Ma (2020)
56 Herpetosiol M C20H20O7 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HMBC Ma (2020)
57 Herpetosiol N C32H38O11 Ethyl acetate Normal phase silica gel column chromatography, MPLC, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HSQC, HMBC, COSY, NOESY Ma (2020)
58 Phyllanglaucin B C30H34O9 Ethyl acetate Normal phase silica gel column chromatography, recrystallization MS, 1H-NMR, 13C-NMR Huang et al. (2021)
59 Buddlenol E C32H38O10 Ethyl acetate Normal phase silica gel column chromatography, sephedax LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Huang et al. (2021)
60 Spathulated C30H34O9 Ethyl acetate — HPLC Wei et al. (2020)
61 Threo-buddlenol E C31H36O11 Ethyl acetate — HPLC Wei et al. (2020)
62 Picrasmalignan A C29H28O9 Ethyl acetate — HPLC Wei et al. (2020)
63 9,3′-Dimethoxyhierochin A C21H24O6 Ethyl acetate — HPLC Wei et al. (2020)
64 Sesquilignan C30H34O9 Ethyl acetate — HPLC Yuan et al. (2019)
65 Herpedulin A C50H52O16 Ethyl acetate Silica gel column chromatography, preparative TLC MS, 1H-NMR, 13C-NMR, HMBC Meng et al. (2022)
66 Herpedulin B C30H34O10 Ethyl acetate Silica gel column chromatography, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HMBC Meng et al. (2022)
67 Herpedulin C C31H36O11 Ethyl acetate Silica gel column chromatography, MPLC, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, 1H-1H COSY, HSQC, HMBC, CD spectrum Meng et al. (2022)
68 Herpedulin D C31H36O11 Ethyl acetate Silica gel column chromatography, MPLC, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, 1H-1H COSY, HSQC, HMBC, CD spectrum Meng et al. (2022)
69 Herpedulin E C30H30O9 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HMBC, CD spectrum Meng et al. (2022)
70 Herpedulin F C32H38O11 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HSQC, COSY Meng et al. (2022)
71 Herpedulin G C30H32O11 Ethyl acetate Silica gel column chromatography, MPLC, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HSQC, CD spectrum Meng et al. (2022)
72 Herpedulin H C30H32O11 Ethyl acetate Silica gel column chromatography, MPLC, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, CD spectrum Meng et al. (2022)
73 Herpedulin I C30H32O11 Ethyl acetate Silica gel column chromatography, MPLC, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, CD spectrum Meng et al. (2022)
74 Herpedulin J C23H24O9 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HSQC, NOSY, HMBC Meng et al. (2022)
75 Herpedulin K C30H26O9 Ethyl acetate Silica gel column chromatography, recrystalization MS, 1H-NMR, 13C-NMR, HSQC, HMBC Meng et al. (2022)
76 Herpedulin L C23H30O8 Ethyl acetate Silica gel column chromatography, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HMBC, NOESY, CD spectrum Meng et al. (2022)
77 Herpedulin M C19H18O6 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HSQC, 1H-1HCOSY, HMBC Meng et al. (2022)
78 Herpedulin N C20H20O7 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Meng et al. (2022)
79 Herpedulin O C20H22O5 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, HMBC, CD spectrum Meng et al. (2022)
80 Herpedulin P C19H20O5 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR CD spectrum Meng et al. (2022)
Fatty acids
81 Palmitic acid C16H32O2 Petroleum ether — GC-MS Liu et al. (2005a)
82 Oleic acid C18H34O2 Petroleum ether — GC-MS Liu et al. (2005a)
83 Stearic acid C18H34O2 Petroleum ether — GC-MS Liu et al. (2005a)
84 Linoleic acid C18H32O2 Petroleum ether — GC-MS Zhang et al. (2004)
85 Linolenic acid C18H30O2 Petroleum ether Normal phase silica gel column chromatography, semi- preparative HPLC MS, 1H-NMR, 13C-NMR Dong et al. (2019)
86 Trilinolein C57H98O6 Petroleum ether Normal phase silica gel column chromatography, preparative HPLC MS, 1H-NMR, 13C-NMR Dong et al. (2019)
87 9-Octadecenoic acid C18H34O2 Petroleum ether — GC-MS Liu et al. (2005b)
88 Octadecanoic acid C18H36O2 Petroleum ether — GC-MS Liu et al. (2005a)
89 cis-5-Dodecaenoic acid C12H22O2 Petroleum ethe Silica gel column chromatography MS, 1H-NMR, 13C-NMR Chen (2020)
90 Dodecanoic acid C12H24O2 Ethyl acetate Silica gel column chromatography MS, 1H-NMR, 13C-NMR Xu, (2012)
91 10-Eicossenoic acid C20H38O2 Ethyl acetate Silica gel column chromatography, sephadex LH-20 MS, 1H-NMR, 13C-NMR Xu, (2012)
Terpenoids
92 Neocucurbitacin D C31H44O8 90% EtOH Silica gel column chromatography, sephadex LH-20, RP-HLPC MS, IR, 1H-NMR, 13C-NMR, HMBC, NOESY Jiang et al. (2020)
93 Cucurbitacin E C32H44O8 90% EtOH Silica gel column chromatography, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Jiang et al. (2020)
94 Cucurbitacin D C30H44O7 90% EtOH Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Jiang et al. (2020)
95 Cucurbitacin B C31H44O8 90% EtOH Silica gel column chromatography, sephadex LH-20, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Jiang et al. (2020)
96 Cucurbitacin I C30H46O7 90% EtOH Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR, 13C-NMR Jiang et al. (2020)
97 23, 24-Dihydroisocucurbitacin B C32H48O8 90% EtOH Silica gel column chromatography, sephadex LH-20, RP-HLPC MS, 1H-NMR, 13C-NMR Jiang et al. (2020)
98 Cucurbitacin M C30H44O6 Ethyl acetate Normal phase silica gel column chromatography, MPLC, semi-preparative HPLC MS, 1H-NMR, 13C-NMR, DEPT, HMBC, 1H-H COSY Ma (2020)
99 Herpetosin A C22H30O6 Ethyl acetate Silica gel column chromatography UV, IR, MS, 13C-NMR, 1H-NMR Xu (2012)
100 Cucurbitacin L C30H44O7 Ethyl acetate Silica gel column chromatography, Sephadex LH-20 MS, 1H-NMR Dai et al. (2017)
101 Oleanic acid C30H48O3 Ethyl acetate Silica gel column chromatography, Sephadex LH-20 MS, 1H-NMR Dai et al. (2017)
Coumarins
102 Herpetolide A C16H14O6 Ethyl acetate Silica gel column chromatography, recrystallization MS, IR, 1H-NMR, 13C-NMR, HMBC, NOESY, DEPT, HMQC Zhang et al. (2008)
103 Herpetolide B C16H12O6 Ethyl acetate Silica gel column chromatography, recrystallization MS, IR, 1H-NMR, 13C-NMR, HMBC Zhang et al. (2008)
104 Herpetosperin A C22H24O11 Ethyl acetate Silica gel column chromatography, ODS silica gel CC, semi-preparative HPLC MS, IR, 1H-NMR, 13C-NMR, HMBC Xu et al. (2015)
105 Herpetosperin B C22H24O11 Ethyl acetate Silica gel column chromatography, ODS silica gel CC, semi-preparative HPLC MS, IR, 1H-NMR, 13C-NMR, HMBC Xu et al. (2015)
106 Herpetospin C C23H26O10 Ethyl acetate Reverse phase silica gel column chromatography UV, IR, MS, 13C-NMR, 1H-NMR Xu (2012)
107 Herpetolide H C19H16O6 Ethyl acetate Normal phase silica gel column chromatography, recrystallization MS, 1H-NMR, 13C-NMR Huang et al. (2021)
108 Herpetospin D C22H22O11 Ethyl acetate Normal phase silica gel column chromatography, recrystallization MS, 1H-NMR, 13C-NMR Xu (2012)
Others
109 Arginine C6H14N4O2 HCl — HITACHI 835-50 High-speed amino acid analyzer, XDY-I atomic fluorescence spectrometer Li et al. (2005)
110 Histidine C6H9N3O2 HCl — HITACHI 835-50 High-speed amino acid analyzer, XDY-I atomic fluorescence spectrometer Li et al. (2005)
111 Lysine C6H14N2O2 HCl — HITACHI 835-50 High-speed amino acid analyzer, XDY-I atomic fluorescence spectrometer Li et al. (2005)
112 Leucine C6H13NO2 HCl — HITACHI 835-50 High-speed amino acid analyzer, XDY-I atomic fluorescence spectrometer Li et al. (2005)
113 Isoleucine C6H13NO2 HCl — HITACHI 835-50 High-speed amino acid analyzer, XDY-I atomic fluorescence spectrometer Li et al. (2005)
114 Tryptophan C11H12N2O2 HCl — HITACHI 835-50 High-speed amino acid analyzer, XDY-I atomic fluorescence spectrometer Li et al. (2005)
115 Kaempferitrin C27H30O14 Ethyl acetate Reversed phase silica gel column chromatography, semi-preparative HPLC UV, IR, 1H-NMR, 13C-NMR Fan et al. (2016)
116 3′-Hydroxydaidzein C15H10O5 Ethyl acetate Silica gel column chromatography, semi-preparative HPLC MS, 1H-NMR Dai et al. (2017)
117 Stigmasterol C29H48O Ethyl acetate Silica gel column chromatography, recrystalization MS, 1H-NMR, 13C-NMR Liu et al. (2010)
118 β-Stigmasterol C29H48O Ethyl acetate Silica gel column chromatography, Sephadex LH-20 MS, 1H-NMR, 13C-NMR Gong (2013)
119 Spinasterol glucoside C35H56O6 Ethyl acetate Silica gel column chromatography, recrystalization UV, IR, MS, 1H-NMR, 13C-NMR Liu et al. (2010)
120 Arbutin, 1-acetate C14H18O8 Ethyl acetate Reversed phase silica gel column chromatography Uv, IR, MS, 1H-NMR, 13C-NMR Hu (2016)
121 Herpetolide C C16H14O6 Petroleum ether Silica gel column chromatography, sephadex LH-20, smi-preparative HPLC UV, IR, MMS, 1H-NMR, 13C-NMR, HMQC, HMBC Fan et al. (2016)
122 Eicosanoic acid, 2-propenyl ester C23H44O2 Ethyl acetate Silica gel column chromatography, sephadex LH-20 MS, 1H-NMR Dai et al. (2017)
123 3-Dodecen-1-yne C12H20 petroleum ether — GC-MS Liu et al. (2005)
124 2,6,10,14,18,22-Tetracosahexaen C24H38 petroleum ether — GC-MS Zhang et al. (2004)
125 Herpecaudin C17H22O4 Ethyl acetate RPHPLC, silica gel column chromatography, RP-18, sephadex LH-20 MS,1H-NMR,13C-NMR, HMBC, NOESY, CD spectrum, X-ray Jiang et al. (2016)
4.1 Lignans

As collected in Figure 2 and summarized in Figure 3, lignans in H. pedunculosum seeds can be mainly divided into benzofurans, tetrahydrofurans and furofuran. In benzofuran lignan such as dehydrodiconiferyl alcohol (9) and herpetotriol (12), the benzene ring is linked to the side chain to form the furan oxygen ring (Figure 2; Table 1). In furfuran lignan, bimolecular phenylpropanin side chains are connected to form a bis-tetrahydrofuran ring, such as herpetetradione (4), herpetetrone (5) and herpetrione (6). Tetrahydrofurans lignans can be further divided into three types with 7-O-7' (a), 7-O-9' (b), and 9-O-9' (c) structures (Figure 2). The tetrahydrofuran of 7-O-9′ is predominant in H. pedunculosum seeds, represented by herpetriol (1) and herpetetrol (2). Beside above three main lignan types, H. pedunculosum seeds also contains dibenzylbutane (chemicals of 29 and 30) as shown in Figure 2.

 4.2 Fatty acids

It has been found that H. pedunculosum seeds contain various fatty acids (81-91, Figure 4; Table 1), with comparatively greater concentrations of linoleic (84) and linolenic acid (85) (Zhao et al., 2009). Oleic (82), palmitic (81), and linoleic acids (84) are reported to be physiologically active in decreasing blood cholesterol levels and alleviating the formation of cholesterol in the vascular wall (Dobrzyńska and Przysławski, 2020). Therefore, it is essential to study the fatty acids in H. pedunculosum seeds.

 4.3 Terpenoids

Ten terpenoids (92-101, Figure 5) were identified in H. pedunculosum seeds, and triterpenoid was the dominant type among them. Triterpenoids have the activities of anti-inflammatory, antibacterial, and antiviral properties (Xiao et al., 2018). For example, cucurbitacin B (95) was reported to show anti-inflammatory, antioxidant, and neuroprotective effects (Dai et al., 2023). These bioactive triterpenoids in H. pedunculosum seeds doubtlessly contribute to its favorable pharmacologic actions.

 4.4 Coumarins

Coumarin is widely acknowledged to have extensive biological activities including anti-tumor, anti-oxidation, anti-inflammation, and anti-coagulation (Kirsch et al., 2016; Wu et al., 2020). And there are 7 coumarins (102-108 in Figure 5) found in H. pedunculosum seeds up to now. For example, Huang et al. (2021) found that herpetolide H (107) from H. pedunculosum seeds had the effects of anti-inflammatory in vitro.

 4.5 Others

In addition to the aforementioned metabolites, H. pedunculosum seeds also contain amino acids (109–114), flavonoids (115, 116), sterols (117–119), glucosides (120), esters (121, 122), olefin (123–124), and ketones (125) as illustrated in Figure 6. It is reported that leucine (112) and isoleucine (113) can prevent the fat accumulation from in hepatocyte (Zhang et al., 2022). Kaempferitrin (115) has anti-inflammatory and anti-oxidation effects (Patel D. K., 2021). The biological activity of stigmasterol (117) is found to include anti-inflammatory, antioxidant, and anti-cancer properties (Bakrim et al., 2022). Therefore, the role of these metabolites in the application of H. pedunculosum seeds deserves further research.

 5 Pharmacology

Diverse studies have demonstrated the hepatoprotective, antioxidant, and anti-cholestasis effects of H. pedunculosum seeds and aforementioned metabolites. Especially, the action mechanism on liver protection effect of H. pedunculosum seeds was systematically generalized. The specific hepatoprotective action and other pharmacological effects were summarized in Table 2 and Table 3, respectively.

The hepatoprotective pharmacology of H. pedunculosum seeds.

Liver disease Extract/Compound Animal/cell and intervention Indicators and results (control, model, treatment, positive control groups) Refs.
Hepatic fibrosis Ethyl acetate (EAEHPS) Animal: Sprague-Dawley rats (male)Model: Induction of CCl4 (50%, 3 mL/kg)Treatment: EAEHPS (1 and 3 g/kg) for 6 weeksPositive control: Silymarin (0.1 g/kg) for 6 weeks ALT↓, AST↓, TNF-a↓, IL-1β↓, IL-6↓, TGF-β1↓, NF-κB 65↓, IκBα↑, Smad3↑.(Compared with the model group) HA/μg . L-1: 49.35 ± 5.26, 75.37 ± 22.65, 61.27 ± 8.46 (L) 54.97 ± 8.63 (H), 39.94 ± 12.61; LN/μg . L-1: 73.55 ± 13.06, 131.74 ± 20.94, 110.38 ± 27.89 (L), 108.78 ± 6.61 (H), 112.87 ± 16.94; PCⅢ/μg . L-1: 75.57 ± 5.11, 117.65 ± 29.45, 98.38 ± 10.28 (L), 93.11 ± 10.19 (H), 88.60 ± 6.92; ColⅣ/μg L-1: 58.75 ± 23.14, 78.15 ± 14.70, 54.86 ± 16.03 (L), 46.31 ± 10.88 (H), 56.75 ± 15.14 Feng et al. (2018a)
Chloroform Animal: Sprague-Dawley rats (male)Model: Induction of CCl4 (50%, 3 mL/kg)Treatment: 1 and 3 g/kg) for 10 weeks GPT↓, GOT↓, TBIL↓, CP↓, HA↓, LN↓, PCIII↓, ColIV↓, TBA↓, MDA↓, CAT↑, SOD↑, ALB↑.(Compared with the model group) Li et al. (2019)
Hepatic fibrosis Chloroform Animal: KM miceModel: Induction of CCl4 (1%, 5 mL/kg)Treatment: 10 (L), 30 (M), 60 (H) g/kg for 1 week ALT/U . L-1: 26.07 ± 3.23, 121.04 ± 9.8, 53.99 ± 3.21 (L), 37.25 ± 9.80 (M), 30.40 ± 2.44 (H),/); AST/U . L-1: 66.09 ± 8.99, 231.84 ± 18.32, 139.67 ± 13.98 (L), 126.63 ± 8.53 (M), 99.63 ± 36.89 (H),/; MDA/nmol . mg-1: 6.35 ± 1.49, 11.74 ± 1.07, 8.80 ± 1.87 (L) 7.77 ± 0.32 (M) 7.01 ± 0.48 (H),/; SOD/U . mg-1: 45.20 ± 6.00, 22.80 ± 4.3, 30.99 ± 2.80 (L), 41.06 ± 1.73 (M), 36.91 ± 7.89 (H),/; Caspase-3:/, 0.1674 ± 0.0061, 0.1555 ± 0.0010 (L), 0.1356 ± 0.0099 (M), 0.1096 ± 0.0083 (H),/ Jiang (2011)
Liver protection Water Animal: KM miceModel: Induction of CCl4 (1%, 5 mL/kg)Treatment: 10 (L), 30 (M), 60 (H) g/kg for 1 week ALT/U . L-1: 26.07 ± 3.23, 121.04 ± 9.8, 72.16 ± 4.9 (L), 59.59 ± 9.81 (M), 54.92 ± 7.03 (H),/; AST/U.L-1: 66.09 ± 8.99, 231.84 ± 18.32, 185.29 ± 19.63 (L) 172.25 ± 12.61 (M), 160.15 ± 12.91 (H),/; MDA/nmol . mg-1: 6.35 ± 1.49, 11.74 ± 1.07, 8.80 ± 1.87 (L), 7.77 ± 0.32 (M), 7.01 ± 0.48 (H),/; SOD/U . mg-1: 45.20 ± 6.00, 22.80 ± 4.3, 30.99 ± 2.80 (L), 41.06 ± 1.73 (M), 36.91 ± 7.89 (H),/; Caspase-3:/, 0.1674 ± 0.0061, 0.1505 ± 0.0062 (L), 0.1366 ± 0.0012 (M), 0.1026 ± 0.0096 (H),/
Chemical liver injury Water Animal: C57BL/6 male mice at 8–10 weeks of ageCell: BRL-3A and AML12Model: Induction of APAP (300 mg/kg, 40 mM)Treatment: Water extract (0.3 mg/kg, 3 g/kg) in mice for 2 weeks; Water extract (100–400 μg/mL) in BRL-3A for 24 h. Water extract (100–400 μg/mL) in AML12 for 8 h ALT↓, AST↓, ROS↓, TNF-α↓, 1L-1β↓, HO-1↓, NQO1↓, Cell viability↑, GSH↑ Li J. et al. (2023)
Drug-induced liver injury Ethanol Animal: C57BL/6 (male); Cell: BRL-3AModel: Induction of APAP (Cell: 40 mM, 8 h; Mice: 200 mg/kg); Treatment: ethanol extract (6.25, 12.5, 25 μg/mL) in BRL-3A; ethanol extract (0.3, 1, 3 g/kg) in mice for 15 days ALT↓, AST↓, ROS↓, MDA↓, Bax↓, Caspase3↓, Cleaved Caspase3↓, HO-1↑, NQO1↑, Cell viability↑, GSH↑ Liao (2023)
Liver protection Petroleum ether Animal: Sprague-Dawley rats (male)Model: Induction of ANIT (60 mg/kg)Treatment: Petroleum ether extract of 350 (L), 700 (M), 1400 mg/kg (H) for 5 daysPositive control: Ursodeoxycholic acid (UDCA) (100 mg/kg) for 5 days ALT↓, AST↓, ALP↓, γ-GTP↓, TBIL↓, DBIL↓, TBA↓, degree of tissue damage↓.(Compared with the model group)MDA/nmol . mg-1: 1.24 ± 0.04, 4.02 ± 0.06, 3.91 ± 0.49 (L), 2.61 ± 0.32 (M), 1.84 ± 0.09 (H), 2.65 ± 0.28); MPO/U . mg-1: 3.70 ± 0.42, 24.10 ± 4.26, 23.44 ± 3.01 (L), 19.79 ± 1.74 (M), 12.13 ± 0.64 (H), 15.62 ± 0.75; NO/μmol . L-1: 5.007 ± 2.678, 4.006 ± 0.732 (L), 3.523 ± 0.223 (M), 3.351 ± 0.194 (H), 2.678 ± 0.375; SOD/U . mg-1: 166.81 ± 10.80, (56.07 ± 4.62, 57.11 ± 4.19 (L), 62.56 ± 4.44 (M), 84.52 ± 7.02 (H), 109.02 ± 12.21; GST/nmol . min-1. mg-1: 56.15 ± 6.39, 37.40 ± 2.85, 38.66 ± 3.92 (L), 43.75 ± 2.59 (M), 47.60 ± 1.66 (H), 47.93 ± 3.27; NO/: 1.884 ± 0.122, 5.007 ± 2.678, 4.006 ± 0.732 (L) 3.523 ± 0.223 (M), 3.351 ± 0.194(H), 2.678 ± 0.375 Cao et al. (2017)
Chemical liver injury Total lignans Animal: ICR mice (male)Model: Induction of CCl4 (0.1%, 20 mL/kg)Treatment: Total lignans (0.375, 0.75, 1.5, 3 g/kg) for 7 daysPositive control: Compound glycyrrhizin tablets of 113 mg/kg (P1) and biphenyl diester of 200 mg/kg (P2) for 7 days ALT/U . L-1: 50.68 ± 3.66, 259.70 ± 3.58, 231.81 ± 16.73 (0.375 g/kg) 210.71 ± 9.08 (0.75 g/kg) 218.25 ± 6.17 (1.5 g/kg) 202.86 ± 11.80 (3 g/kg), 194.85 ± 17.46 (P1) 220.29 ± 7.77 (P2); AST/U.L-1: 97.83 ± 8.04, 274.50 ± 7.35, 240.38 ± 12.23 (0.375 g/kg) 233.17 ± 17.42 (0.75 g/kg) 226.55 ± 16.93 (1.5 g/kg) 213.31 ± 27.07 (3 g/kg), 209.38 ± 11.61 (P1) 232.90 ± 11.61 (P2); ALP/U.L-1: 117.88 ± 12.99, 195.67 ± 16.08, 143.28 ± 12.46 (0.375 g/kg) 138.61 ± 10.53 (0.75 g/kg) 134.61 ± 12.73 (1.5 g/kg) 124.14 ± 14.72 (3 g/kg), 158.29 ± 9.55 (P1) 131.74 ± 21.67 (P2); MDA/nmol . mgprot-1: 12.54 ± 1.59, 35.32 ± 2.54, 23.64 ± 2.82 (0.375 g/kg) 20.72 ± 1.49 (0.75 g/kg) 19.73 ± 1.28 (1.5 g/kg) 16.03 ± 2.76 (3 g/kg), 17.43 ± 2.44 (P1) 20.67 ± 1.98 (P2); SOD/U . mgprot-1: 76.84 ± 3.59, 43.39 ± 1.72, 52.75 ± 2.58 (0.375 g/kg) 54.58 ± 3.24 (0.75 g/kg) 55.02 ± 1.20 (1.5 g/kg) 59.99 ± 2.35 (3 g/kg), 50.79 ± 1.93 (P1) 49.75 ± 1.93 (P2); GSH-Px/U . mgprot-1: 996.76 ± 81.60, 534.00 ± 50.58, 873.88 ± 96.38 (0.375 g/kg) 896.26 ± 151.70 (0.75 g/kg) 924.47 ± 125.97 (1.5 g/kg) 975.95 ± 152.21 (3 g/kg), 751.57 ± 46.27 (P1) 796.84 ± 83.47 (P2) Zhao et al. (2015)
Hepatic fibrosis Total lignans Animal: Sprague-Dawley rats (male)Model: Induction of CCl4 (40%, 25 mg/kg)Treatment: Total lignans of 100 (L), 200 (M), 400 mg/kg (H) for 8 weeks ALT/U . L-1: 82.25 ± 5.47, 200.00 ± 22.60, 139.86 ± 21.05 (L) 106.63 ± 16.60 (M) 92.75 ± 18.42 (H), 87.75 ± 114.47; AST/U . L-1: 169.25 ± 13.96, 217.57 ± 33.76, 225.86 ± 9.86 (L) 202.38 ± 38.03 (M) 178.00 ± 31.96 (H), 185.50 ± 30.87; ALP/U . L-1: 158.00 ± 4.04, 201.29 ± 25.45, 151.14 ± 226.17 (L) 171.25 ± 31.32 (M) 145.50 ± 18.53 (H), 136.50 ± 28.4; TGF-β1/ng . L-1: 173.37 ± 2.94, 225.15 ± 17.99, 210.64 ± 11.67 (L) 196.79 ± 15.77 (M) 188.32 ± 16.64 (H), 193.11 ± 13.22; HA/ng . L-1: 248.21 ± 9.99, 313.55 ± 16.29, 291.63 ± 11.37 (L) 273.21 ± 19.14 (M) 272.20 ± 21.30 (H), 271.04 ± 10.42; HYP/μg . L-1: 672.15 ± 10.85, 810.04 ± 25.60, 791.46 ± 21.34 (L) 742.96 ± 27.21 (M) 728.60 ± 40.68 (H), 725.27 ± 19.86; SOD/μg . L-1: 10.88 ± 0.28, 9.04 ± 0.46, 9.40 ± 0.46 (L) 10.02 ± 0.44 (M) 10.23 ± 0.67 (H), 10.23 ± 0.39 Liu et al. (2017a)
Acute alcoholic liver injury Total lignans Animal: KM mice (male)Model: 56° Beijing Red Star Erguotou wineTreatment: Total lignans of 15 (L), 25 (M), 35 mg/kg (H) for 30 daysPositive control: Polyene phosphatidylcholine (135 mg/kg) for 30 days AST/U . L-1: 143.7 ± 12.0, 258.7 ± 28.3, 230.0 ± 23.3 (L) 200.2 ± 25.5 (M) 222.2 ± 28.2 (H), 185.8 ± 39.6; ALT/U . L-1: 56.5 ± 6.5, 155.0 ± 27.8, 1123.3 ± 26.1 (L) 92.8 ± 14.7 (M) 98.5 ± 15.3 (H), 99.8 ± 9.6; MDA/[nmol.(mg . pro)−1]: 1.07 ± 0.14, 1.99 ± 0.87, 1.69 ± 1.26 (L) 1.14 ± 0.27 (M) 1.21 ± 0.28 (H), 1.22 ± 0.15; XOD/[U.(mg pro)−1]: 13.7 ± 1.3, 5.3 ± 3.1, 6.5 ± 1.2 (L) 8.6 ± 1.7 (M) 7.4 ± 1.0 (H), 9.9 ± 22.9; Na+-K+-ATP/[μmolPi . (mg . pro . h)−1]: 0.98 ± 0.14, 0.38 ± 0.06, 0.63 ± 0.18 (L) 0.76 ± 0.08 (M) 0.82 ± 0.10 (H), 0.75 ± 0.07; SOD/[U.(mg . pro)−1]: 65.8 ± 5.1, 61.2 ± 2.8 (L) 62.7 ± 5.7 (M) 60.0 ± 4.3 (H), 59.6 ± 2.8; GSH-Px/[U.(mg . pro)−1]: 21.1 ± 7.9, 9.5 ± 2.5, 14.3 ± 1.2 (L) 12.2 ± 1.7 (M) 13.4 ± 0.7 (H), 13.7 ± 1.0 Huang et al. (2017)
Chronic alcoholic liver injury Animal: Wistar rats (male)Model: 56° liquor (8 mL/kg-15 mL/kg) for 8 weeksTreatment: Total lignans of 100 (L), 200 (M), 400 mg/kg (H) for 8 weeksPositive control: Yishanfu (95 mg/kg) for 8 weeks AST/U . L-1: 24.42 ± 2.79, 58.21 ± 14.83, 41.21 ± 7.69 (L) 29.92 ± 2.99 (M) 25.69 ± 10.74 (H), 36.05 ± 15.47; ALT/U . L-1: 11.34 ± 0.69, 51.53 ± 2.18, 34.83 ± 4.77 (L) 27.45 ± 1.82 (M) 331.99 ± 2.30 (H), 331.68 ± 5.09; MDA/[nmol.(mg . prot)−1]: 1.15 ± 0.33, 3.35 ± 1.15, 1.57 ± 0.19 (L) 1.09 ± 0.29 (M) 1.17 ± 0.29 (H), 1.32 ± 0.31; ADH/[nmol/(min . mg pro)]: 3.83 ± 0.82, 12.38 ± 3.60, 7.75 ± 2.89 (L) 5.99 ± 1.77 (M) 6.91 ± 1.42 (H), 8.39 ± 44.43; TG/mmol . L-1: 7.63 ± 0.73, 10.62 ± 0.74, 9.55 ± 0.99 (L) 8.51 ± 0.67 (M) 8.75 ± 0.63 (H), 8.01 ± 1.67; SOD/[U.(mg . prot)−1]: 423.81 ± 75.64, 193.52 ± 40.85, 317.09 ± 52.41 (L) 233.66 ± 64.95 (M) 296.12 ± 34.64 (H), 196.23 ± 80.47; GSH/[mg . (g . prot)−1]: 4.47 ± 1.81, 1.47 ± 0.47, 2.77 ± 0.39 (L) 3.60 ± 0.33 (M) 2.93 ± 0.53 (H), 2.11 ± 1.04; GSH-Px/[U . (mg . prot)−1]: 40.2 ± 4.45, 34.1 ± 3.85, 39.1 ± 4.85 (L) 39.5 ± 3.25 (M) 35 ± 2.71 (H), 41.5 ± 4.23; CAT/U . mL-1: 10.03 ± 1.13, 7.09 ± 1.26, 9.08 ± 0.51 (L) 9.17 ± 1.18 (M) 8.31 ± 0.95 (H), 9.36 ± 0.93; ALDH2/[nmol/(min . mg pro)]: 9.62 ± 1.96, 3.40 ± 1.33, 4.96 ± 1.59 (L) 5.78 ± 3.53 (M) 3.07 ± 1.37 (H), 5.83 ± 3.78 Huang et al. (2018)
Cholestatic liver injury Animal: KM mice (male)Model: Induction of ANIT (0.4%, 80 mg/kg)Treatment: Total lignans (0.05, 0.1, 0.2, 0.4 g/kg) for 7 daysPositive control: Bifendate Pills group (0.15 g/kg) for 7 days AST/U . L-1: 36.81 ± 11.13, 197.99 ± 11.67, 173 ± 21.48 (0.05 g/kg) 127.02 ± 11.07 (0.1 g/kg) 120.56 ± 16.87 (0.2 g/kg) 107.67 ± 44.34 (0.4 g/kg), 156.83 ± 16.49; ALT/U . L-1: 26.87 ± 14.69, 470.15 ± 18.68, 275.82 ± 17.69 (0.05 g/kg) 223.29 ± 42.17 (0.1 g/kg) 206.47 ± 25.35 (0.2 g/kg) 384.08 ± 26.11 (0.4 g/kg), 220.50 ± 46.87; ALP/U . L-1: 3.4 ± 0.6, 18.27 ± 2.53, 13.40 ± 1.87 (0.05 g/kg) 11.89 ± 3.12 (0.1 g/kg) 9.98 ± 2.04 (0.2 g/kg) 11.91 ± 1.36 (0.4 g/kg), 8.26 ± 2.23; TBA/μmol . L-1: 3.63 ± 0.35, 78.10 ± 8.38, 48.13 ± 8.98 (0.05 g/kg) 44.13 ± 13.28 (0.1 g/kg) 31.83 ± 5.84 (0.2 g/kg) 50.57 ± 17.10 (0.4 g/kg), 26.94 ± 110.15; TBIL/μmol . L-1: 1.62 ± 0.66, 191.57 ± 34.47, 106.56 ± 22.48 (0.05 g/kg) 41.65 ± 17.54 (0.1 g/kg) 229.89 ± 17.11 (0.2 g/kg) 96.07 ± 18.03 (0.4 g/kg), 41.96 ± 24.65; DBIL/μmol . L-1: 0.87 ± 0.19, 124.94 ± 18.72, 27.23 ± 9.13 (0.05 g/kg) 16.76 ± 10.48 (0.1 g/kg) 10.91 ± 6.21 (0.2 g/kg) 48.08 ± 21.09 (0.4 g/kg), 8.98 ± 3.92; SOD/U . mg-1: 527.97 ± 18.82, 243.02 ± 31.43, 297.27 ± 24.09 (0.05 g/kg) 2,295.93 ± 20.08 (0.1 g/kg) 322.70 ± 20.08 (0.2 g/kg) 312.37 ± 15.70 (0.4 g/kg), 368.28 ± 15.36); MDA/nmol . mg-1: 2.41 ± 0.92, 12.66 ± 1.61, 6.91 ± 0.95 (0.05 g/kg) 8.02 ± 2.18 (0.1 g/kg) 5.69 ± 1.27 (0.2 g/kg) 8.21 ± 2.56 (0.4 g/kg), 5.93 ± 2.28; CAT/U . mg-1: 22.96 ± 1.17, 8.87 ± 1.26, 12.56 ± 1.39 (0.05 g/kg) 17.97 ± 5.30 (0.1 g/kg) 13.53 ± 4.83 (0.2 g/kg) 18.77 ± 3.78 (0.4 g/kg), 19.41 ± 3.14; GSH-Px/mg.g-1: 132.54 ± 24.50, 21.51 ± 8.74, 54.45 ± 14.00 (0.05 g/kg) 70.80 ± 9.17 (0.1 g/kg) 83.14 ± 24.01 (0.2 g/kg) 77.28 ± 10.77 (0.4 g/kg), 89.81 ± 30.43; TNF-α/ng . L-1: 43.63 ± 2.07, 65.14 ± 7.40, 52.38 ± 3.34 (0.05 g/kg) 48.20 ± 1.91 (0.1 g/kg) 45.81 ± 2.09 (0.2 g/kg) 46.75 ± 3.10 (0.4 g/kg), 44.22 ± 2.5; MCP-1/ng . L-1: 31.11 ± 2.34, 226.06 ± 43.42, 155.01 ± 30.14 (0.05 g/kg) 117.14 ± 24.86 (0.1 g/kg) 110.79 ± 19.70 (0.2 g/kg) 154.40 ± 36.39 (0.4 g/kg), 129.28 ± 32.20 Li et al. N. J. (2023)
acute alcoholic liver injury Total sterols Animal: ICR mice (male)Model: Induction of CCl4 (0.3%, 10 mL/kg)Treatment: Total sterols extract(10, 20, 50 mg/kg) for 7 daysPositive control: Silymarin (50 mg/kg) for 7 days AST↓, ALT↓, IL-1β↓, IL-6↓, COX-2↓, IL-10↑ Liu et al. (2022)
Immunological liver injury Fatty acid Animal: Swiss miceModel: 2.5 mg BCG was given by tail injectionTreatment: Fatty acid extract of 7 (L), 10 (M), 14.5 mL/kg (H) for 12 daysPositive control: Bifendate (200 mg/kg) for 12 days MDA/nmol . mg-1: 16.26 ± 4.29, 20.56 ± 3.61, 16.51 ± 2.89 (L) 19.36 ± 3.01 (M) 19.29 ± 1.99 (H), 17.73 ± 1.01; ALT/U . L-1: 7.67 ± 1.27, 90.71 ± 16.62, 23.32 ± 8.30 (L) 45.83 ± 16.92 (M) 29.16 ± 16.90 (H), 18.84 ± 8.73; AST/U . L-1: 23.48 ± 4.39, 92.39 ± 10.81, 47.61 ± 5.37 (L) 51.54 ± 13.11 (M) 44.72 ± 15.61 (H), 54.44 ± 17.37; NO/μmol . L-1: 3.33 ± 1.69, 21.26 ± 8.20, 8.45 ± 2.13 (L) 14.21 ± 9.43 (M) 10.77 ± 3.70 (H), 7.38 ± 4.66; SOD/U.mg-1: 184.40 ± 17.25, 105.00 ± 22.71, 219.95 ± 16.13 (L) 196.19 ± 23.09 (M) 228.28 ± 27.69 (H), 127.89 ± 12.69 Chen et al. (2014)
Liver protection Animal: Sprague-Dawley rats (male)Model: Induction of CCl4 (3 mL/kg)Treatment: Fatty acid extract of 1(L), 2 (M), 4 g/kg (H) for 5 daysPositive control: Bifendate (200 mg/kg) for 5 days TG/nmol . L-1: 0.67 ± 0.21, 2.18 ± 0.53, 1.10 ± 0.38 (L) 1.03 ± 0.40 (M) 0.82 ± 0.1 (H), 1.44 ± 0.34; HDL/nmol . L-1: 0.99 ± 0.19, 1.30 ± 0.11, 0.43 ± 0.32 (L) 0.50 ± 0.13 M) 0.59 ± 0.12 (H), 0.57 ± 0.11; LDL/nmol . L-1:1.03 ± 0.24, 1.65 ± 0.10, 1.11 ± 0.37 (L) 1.08 ± 0.33 (M) 1.14 ± 0.20 (H), 1.06 ± 0.19; MDA/[nmol.(mg prot-1)]: 1.30 ± 0.11, 0.43 ± 0.32 (L) 0.50 ± 0.13 (M) 0.59 ± 0.12 (H), 0.57 ± 0.11; SOD/U . L-1: 57.69 ± 15.08, 42.86 ± 10.76, 74.28 ± 17.91 (L) 97.30 ± 12.51 (M) 102.69 ± 29.39 (H), 100.57 ± 21.66; TBIL/Umol . L-1: 1.15 ± 0.98, 11.89 ± 3.87, 6.54 ± 1.58 (L) 5.67 ± 2.07 (M) 4.75 ± 1.09 (H), 9.7 ± 2.6; AST/U . L-1: 229.00 ± 35.03, 1084.86 ± 289.13, 1181.38 ± 178.33 (L) 1039.43 ± 244.18 (M) 310.10 ± 33.99 (H), 1394.20 ± 278.11; ALT/U . L-1: 39.60 ± 5.41, 1263.43 ± 361.30, 1285.38 ± 322.05 (L) 1109.14 ± 365.50 (M) 297.40 ± 76.87 (H), 1394.20 ± 278.11; ALP/U . L-1: 136.7 ± 23.3, 281.6 ± 36.30, 220.8 ± 34.3 (L) 185.0 ± 21.3 (M) 141.3 ± 27.8 (H), 191.4 ± 29.4 Li et al. (2014)
Immunological liver injury Polysaccharide Animal: KM mice (male)Model: ConA (30 mg/kg) injection into the tail veinTreatment: Polysaccharide of 0.71 (L), 0.99 (M), 1.44 g/kg (H) for 8 daysPositive control: Bifendate (0.2 g/kg) for 8 days ALT/U . L-1: 9.0 ± 0.8, 143.6 ± 7.0, 130.2 ± 6.2(L) 115.9 ± 9.4 (M) 45.8 ± 4.7 (H), 42.6 ± 6.0; AST/U . L-1: 24.6 ± 2.4, 172.3 ± 9.4, 146.2 ± 15.4 (L) 124.2 ± 8.0 (M) 55.9 ± 4.4 (H), 172.3 ± 9.4; LDH/U . L-1: 1952.7 ± 133.7, 4606.6 ± 191.6, 3,948.3 ± 232.1 (L) 3,814.3 ± 227.8 (M) 3,187.9 ± 192.9 (H), 2,742.9 ± 179.3; NO/μmol . L-1: 2.3 ± 0.2, 6.7 ± 0.5, 4.5 ± 0.3 (L) 4.1 ± 0.5 (M) 3.6 ± 0.4 (H) 3.4 ± 0.2; IL-6/pg . mL-1: 30.4 ± 1.1, 74.5 ± 2.1, 56.5 ± 3.7 (L) 50.1 ± 2.8 (M) 45.7 ± 2.9 (H), 51.4 ± 3.2; MDA/[(nmol/mg . prot)]: 6.5 ± 0.3, 9.3 ± 0.5, 11.2 ± 0.7 (L) 9.0 ± 0.4 (M) 6.4 ± 0.7 (H), 7.5 ± 0.3; SOD/[(U/mg . prot)]: 187.6 ± 4.4 59.7 ± 4.3, 74.6 ± 3.1 (L) 99.9 ± 7.0 (M) 126 ± 10.7 (H), 90.9 ± 10.0; Degree of tissue damage↓ Li et al. (2015a)
Acute alcoholic liver injury Herpetfluorenone Animal: C57BL/6 mice; Cell: BMSCsModel: Induction of CCl4 Treatment: 100 μM of Herpetfluorenone AST↓, ALT↓, ALP↓, TBA↓, MDA↓, ALB↑, SOD↑, GSH↑ Yang et al. (2023)
Acute alcoholic liver injury Herpetin Animal: C57BL/6 mice (male)Cell: BMSCs; Model: Induction of CCl4 Treatment: 10 μM of Herpetin AST↓, ALT↓, AKP↓, ALB↑ Ding et al. (2023)
Immunological liver injury Herpetin Animal: ICR mice (male); Model: ConA (20 mg/kg) injection into the tail vein; Treatment: 10 (L), 20 mg/kg (H) of herpetin for 7 daysPositive control: Qingkailing injection (20 mg/kg) for 5 days iNOS: 0.215 ± 0.004, 0.290 ± 0.013, 0.275 ± 0.012 (L) 0.239 ± 0.009 (H), 0.237 ± 0.008; TNF-α: 0.130 ± 0.006, 0.166 ± 0.008, 0.145 ± 0.004 (L) 0.139 ± 0.005 (H), 0.141 ± 0.005; NF-κB: 0.129 ± 0.006, 0.150 ± 0.004, 0.153 ± 0.006 (L) 0.130 ± 0.002 (H), 0.141 ± 0.003; IFN-γ: 0.131 ± 0.006, 0.149 ± 0.006, 0.134 ± 0.003 (L) 0.132 ± 0.003 (H), 0.132 ± 0.005; IL-4: 0.104 ± 0.002, 0.129 ± 0.004, 0.121 ± 0.004 (L) 0.118 ± 0.002 (H) 0.117 ± 0.003; SOCS1: 0.120 ± 0.007, 0.081 ± 0.005, 0.087 ± 0.007 (L) 0.091 ± 0.008 (H), 0.105 ± 0.011 Wang et al. (2016)
Immunological liver injury Herpetin Animal: ICR mice (male)Model: Induction of BCG (2.5 mg) +LPS (7.5 μg)Treatment: 10 (L), 20 mg/kg (H) of herpetin for 12 daysPositive control: Qingkailing injection (20 mg/kg) for 12 days AST/U . L-1: 96.01 ± 9.40, 197.55 ± 8.1, 184.33 ± 15.86 (L) 161.59 ± 18.20 (H), 123.55 ± 11.07; ALT/U . L-1: 42.24 ± 1.52, 101.61 ± 5.05, 92.69 ± 2.75 (L), 68.35 ± 0.94 (M), 58.32 ± 2.44; LDH/U . L-1: 239.11 ± 20.05, 546.87 ± 18.16, 481.84 ± 9.04 (L) 393.70 ± 32.96 (H), 340.78 ± 16.13; MDA/nmol . mgprot-1: 15.98 ± 1.39, 38.41 ± 1.59, 35.61 ± 1.87 (L) 29.6 ± 1.52 (H), 24.38 ± 2.03; SOD/U . (mg . prot-1:97.47 ± 9.15, 68.08 ± 12.80, 75.75 ± 9.09 (L) 85.04 ± 8.75 (H), 88.64 ± 11.92; GSH-Px/U . mg . prot-1:545.37 ± 54.86, 292.78 ± 57.38, 380.12 ± 33.94 (L) 414.53 ± 48.03 (H), 463.56 ± 32.30 Liu (2017b)

The other pharmacology effects of Herpetospermum pedunculosum seeds.

Effects Extract/Compound Animal/Cell and intervention Indicators and results (control, model, treatment, positive control groups) Refs.
Antioxidation Chloroform Animal: SD ratsModel: Induction of CCl4 (50%, 0.6 mg/kg)Treatment: chloroform extract of 200 (L), 400 mg/kg (H) for 7 days. Water extract of 200 (L), 400 mg/kg (H) for 7 daysPositive control: VitE (400 mg/kg) for 7 days MDA/nmol . mg-1 protein: 8.65 ± 2.89, 16.92 ± 4.75, 7.22 ± 1.94 (L) 7.34 ± 0.97 (H), 5.16 ± 0.64; SOD/unit . mg-1 protein: 316.68 ± 19.05, 237.62 ± 17.81, 292.83 ± 41.64 (L) 289.52 ± 40.07 (H), 289.00 ± 25.29; GSH-px/unit . mg-1 protein: 146.36 ± 24.67, 101.82 ± 24.17, 118.51 ± 18.36 (L) 121.68 ± 223.16 (H), 142.56 ± 16.61 Fang et al. (2008)
Water MDA/nmol . mg-1 protein: 8.65 ± 2.89, 6.89 ± 1.26 (L) 6.11 ± 0.48 (H), 5.16 ± 0.64 SOD/unit . mg-1 protein: 316.68 ± 19.05, 272.29 ± 25.97 (L) 308.15 ± 13.34 (H), 289.00 ± 25.29; GSH-px/unit . mg-1 protein: 146.36 ± 24.67, 142.48 ± 10.83 (L) 148.25 ± 12.35 (H), 142.56 ± 16.61
Anti-fatigue Chloroform Animal: KM mice (the mice that could learn to swim, male)Treatment: chloroform extract of 80 (L), 160 (M), 320 mg/kg (H); Ethyl acetate extract of 80 (L), 160 (M), 320 mg/kg (H); n-Butanol extract of 80 (L), 160 (M) 320 mg/kg (H) for 30 days; herpetrione of 15 (L), 30 (M), 60 mg/kg(H) for 30 days Swimming time↑, survival time↑; HG/mg . g-1:9.99 ± 1.58,/, 10.40 ± 1.47 (L) 10.53 ± 1.56 (M) 10.58 ± 1.97 (H),/; LDH/U . L-1: 874.50 ± 64.22,/, 900.56 ± 143.87 (L) 942.11 ± 127.10 (M) 961.84 ± 70.95 (H),/; SOD/U . mL-1: 69.52 ± 9.79,/, 119.84 ± 16.13 (L) 118.50 ± 9.52 (M) 121.28 ± 8.44 (H),/; GSH-Px/U . L-1: 109.56/, 119.84 ± 16.13 (L) 118.50 ± 9.52 (M) 121.28 ± 8.44 (H),/; BLA/ng.100mL-1: 24.49 ± 1.99,/, 23.91 ± 2.85 (L) 23.19 ± 1.84 (M) 23.37 ± 1.67 (H),/; MDA/nmol . L-1:14.04 ± 2.07,/, 13.92 ± 1.58 (L) 13.56 ± 1.91 (M) 13.43 ± 1.42 (H),/ Jin et al. (2016)
Ethyl acetate Swimming time↑, survival time↑; HG/mg . g-1: 9.99 ± 1.58,/, 10.55 ± 1.60 (L) 10.90 ± 1.58 (M) 11.56 ± 1.28 (H),/; LDH/U . L-1: 874.50 ± 64.22,/, 916.63 ± 137.80 (L) 996.50 ± 112.53 (M) 1073.66 ± 140.79 (H),/; SOD/U . mL-1 : 69.52 ± 9.79,/, 118.69 ± 9.38 (L) 120.54 ± 11.04 (M) 123.78 ± 8.18 (H),/; GSH-Px/U . L-1: 109.56 ± 9.58,/, 118.69 ± 9.38 (L) 120.54 ± 11.04 (M) 123.78 ± 8.18 (H) 1,/; BLA/ng.100mL-1: 24.49 ± 1.99,/, 23.09 ± 1.70 (L) 22.16 ± 2.16 (M) 21.94 ± 2.24 (H),/; MDA/nmol . L-1: 14.04 ± 2.07,/, 13.26 ± 1.47 (L) 12.261 ± 1.13 (M) 11.77 ± 1.44 (H),/
n-Butanol HG/mg . g-1: 9.99 ± 1.58,/, 10.04 ± 1.44 (L) 10.40 ± 1.79 (M) 11.45 ± 1.14 (H),/; LDH/U . L-1: 874.50 ± 64.22,/, 914.42 ± 153.03 (L) 926.89 ± 111.32 (M) 1028.14 ± 104.08 (H),/; SOD/U . mL-1: 69.52 ± 9.79,/, 117.02 ± 17.47 (L) 120.28 ± 17.46 (M) 119.15 ± 8.56 (H),/; GSH-Px/U . L-1:/, 117.02 ± 17.47 (L) 120.28 ± 17.46 (M) 119.15 ± 8.56 (H),/; BLA/ng.100mL-1: 24.49 ± 1.99,/, 25.41 ± 2.18 (L) 24.54 ± 2.64 (M)23.44 ± 2.56 (H),/; MDA/nmol . L-1 : 14.04 ± 2.07,/, 13.63 ± 2.11 (L) 13.27 ± 1.70 (M) 13.09 ± 1.21 (H),/
herpetrione Swimming time↑, survival time↑; HG/mg . g-1; 9.99 ± 1.58,/, 10.87 ± 1.38(L) 11.67 ± 1.37 (M) 11.75 ± 1.25 (H),/; LDH/U . L-1:874.50 ± 64.22,/,1003.27 ± 92.20 (L) 1046.10 ± 109.91 (M) 1092.73 ± 109.60 (H),/; SOD/U . mL-1: 69.52 ± 9.79,/, 115.18 ± 11.96 (L) 10,220.44 ± 8.07 (M) 123.04 ± 11.36 (H),/; GSH-Px/U . L-1: 109.56 ± 9.58, 109.56 ± 9.58/, 115.18 ± 11.96 (L) 120.44 ± 8.07 (M) 123.04 ± 11.36 (H),/; BLA/ng.100mL-1: 24.49 ± 1.99,/, 22.40 ± 1.85 (L) 21.75 ± 1.78 (M) 20.91 ± 1.91 (H),/; MDA/nmol . L-1: 14.04 ± 2.07/, 12.15 ± 1.14 (L) 11.65 ± 1.24 (M) 11.50 ± 1.21 (H),/
Anti-tumor Lignans Cell: BEL-7402, BEL-7404, HCT IC50: 1.45 μg/mL, 1.68 μg/mL, 2.36 μg/mL Yuan (2006a)
Anti-hyperuricemia Ethanol Animal: KM mice (male); Model: Intraperitoneal injection of potassium oxonate emulsion (300 mg/kg). Treatment: ethanol extract (100, 200, 400 mg/kg) for 10 days. Positive control: colchicine (0.3 mg/kg) for 10 days UA↓, XO(/) Wang et al. (2022b)
Anti-gouty arthritis Weight↑, Articular swelling↓, IL-1β↓, TNF-α↓, UA↓ Wang et al. (2022b)
Anti-cholestasis Ethyl acetate Animal: SD rats (male); Model: Induction of ANIT (60 mg/kg); Treatment: Ethyl acetate extract (100, 200, 400 mg/kg) for 7 daysPositive control: UDCA (100 mg/kg) for 7 days ALT↓, AST↓, ALP↓, γ-GTP↓, TBIL↓, DBIL↓ TBA↓, GSH↓, SOD↓, GPx↓, CAT↓ Wei et al. (2020)
Anti-skin inflammation Ethanol Animal: BALB/c mice (female); Cell: HaCatModel: Mice induced by IMQ for 7 days; Hacat cell induced by IFN-γ (2 ng/mL) for 24 hTreatment: ethanol extract (0.125, 1.25 and 12.5 μg/g) in mice for 7 days. Ethanol extract (12.5 mg/mL) in HaCat cell IFN-γ↓, TNF-α↓, IL-17A↓, ICAM-1↓, CXCL9↓ Zhong et al. (2023)
Anti-candida albicans Herpetin, herpetrione — Minimal inhibitory concentration of 10.5 μM and 9.2 μM, respectively Dai et al. (2019)
5.1 Hepatoprotective effect

Liver is a vital metabolic organ implementing multiple functions such as toxicant detoxification, protein synthesis, and special compound production, thus the increasing prevalence of liver illnesses including fatty liver, liver damage, fibrosis, cirrhosis, and cancer aroused great attention nowadays (Asrani et al., 2019). As collected in Table 2, plentiful researches showed the remarkable hepatoprotective effect of H. pedunculosum seeds through the adjustment of some enzymes in animal models with the induction of CCl4, paracetamol (APAP), concanavalin A (ConA), α-naphthyl isothiocyanate (ANIT), liquor, bacillus calmette-guérin (BCG) and lipopolysaccharides (LPS). For instance, the ethyl acetate extract of H. pedunculosum seeds (EAEHPS) showed hepatoprotective activity against CCl4-induced hepatic fibrosis in rats via the inflammatory pathway with obviously inhibiting the expression of NF-κB (IκBα), Samd3, and TGF-β1 proteins (Feng et al., 2018a). The water extract of H. pedunculosum seeds could alleviate APAP-induced liver injury by inhibiting oxidative stress and ferroptosis through activating the Nrf2 signal pathway (Li N. Z. et al., 2023). In addition, some proteins, such as NLRP3, TLR-2, TLR-4, and JNK, will have their expression reduced by the total lignan of H. pedunculosum seeds (TLHPS), so as to protect mice against ANIT-induced liver damage (Li J. et al., 2023). Some metabolites such as herpetfluorenone (HPF, 23) and herpetin (18) from H. pedunculosum seeds were further found to have a positive pharmaceutical effect on acute liver injury by promoting the differentiation of bone marrow mesenchymal stem cells into hepatocellular-like cells and controlling autoimmune oxidation (Yang et al., 2023; Ding et al., 2023).

Based on above discussions and previous literatures, the hepatoprotective mechanism of H. pedunculosum seeds can be summarized into three pathways as illustrated in Figure 7. The first one is the inhibition of NF-κB signaling pathway to alleviate the inflammation during liver diseases (Figure 7A). Herpetospermum pedunculosum seeds can inhibit the phosphorylation of IκB through the inhibition of IKK, which in turn has anti-inflammatory and hepatoprotective effects (Li N. Z. et al., 2023). The second mechanism is inhibiting the TGF-β signaling pathway (Figure 7B). EAEHPS an inhibit the phosphorylation of Smad3, which in turn inhibits the expression of relevant genes after the complex enters the nucleus, thus playing a role in inhibiting liver fibrosis (Feng et al., 2018a). The third one is the promotion of Keap1-Nrf2 signaling pathway (Figure 7C). Nrf2 plays a crucial role in cellular defense against oxidative stress. When activated by H. pedunculosum seeds, the stability of Nrf2 increases, leading to reduced degradation and subsequent activation of genes driven by the antioxidant response element (ARE), thereby exerting a protective effect against liver damage (Li N. Z. et al., 2023; Liao, 2023).

The mechanism of protective effect of Herpetospermum pedunculosum seeds on liver. (A) NF-κB signaling pathway; (B) TGF-β signaling pathway; (C) Keap1-Nrf2 signaling pathway.

 5.2 Antioxidation

Fang et al. (2007), Fang et al. (2008) demonstrated the antioxidant activities of CHCl3, water and ethanol extracts of H. pedunculosum seeds to prevent lipid peroxidation brought on by CCl4 in vivo experiments. Jiang et al. (2020) tested the significant inhibitory activity of neocucurbitacin D (92) (IC50 = 15.27 ± 0.29 μM) and 23, 24-dihydrocucurbitacin B (97) (IC50 = 24.18 ± 0.26 μM) on XOD. Gong, (2013) showed that herpetone (7) has good DPPH free radical scavenging ability and antioxidant activity. Although many studies have shown that H. pedunculosum seeds has antioxidant effects, there are still some problems, such as the simplistic evaluation index and the unclear relationship between dose and activity.

 5.3 Anti-cancer cells

The lignan of H. pedunculosum seeds demonstrated considerable in vitro inhibitory action against several cancer cells. The IC50 of lignans in H. pedunculosum seeds were 1.45 μg/mL, 1.68 μg/mL, and 2.36 μg/mL for human hepatocellular carcinoma cells (BEL-7402, BEL-7404), and HCT, respectively (Yuan, 2006a). Zhang et al. (2007) demonstrated the inhibitory effects of herpetolide A (102) and herpetolide B (116) on the growth of human promyelocytic leukemia cells (HL-60). The metabolites of H. pedunculosum seeds including including herpetosiol A (42), herpetosiol C (44), 7′, 8′-didehydlroherpepetotriol (14), herpetetrol (2), herpepropenal (13), herpetrione (6) showed significant cytotoxicity on human gastric adenocarcinoma cells (SGC7901), human lung cancer cells (A549), human breast cancer cells (MDA-MB-231), and human hepatocellular carcinoma cells (HepG2) (Ma, 2020; Kong et al., 2023). However, these studies only perform a simple detection of IC 50 and cytotoxicity, and lack other powerful indicators to reflect the efficacy of the drug. In addition, it is worth noting that the anti-tumor effects are mainly tested at the cellular level, lacking in animal and mechanism investigations, which are noteworthy in further research.

 5.4 Anticholestasis effects

EAEHPS exerted an anti-cholestatic effect with increasing bile flow in a dose-dependent manner, which promoted bile acid transport by activating the farnesoid X receptor (FXR) signaling pathway (Wei, 2020). Meanwhile, the EAEHPS activated the Keap1-Nrf2 pathway to alleviate oxidative stress and inhibit of NF-κB/Are signaling pathway to inhibit inflammatory response, which could prevent and treat ANIT-induced cholestasis in rats (Wei et al., 2020).

 5.5 Other effects

Wang S. W. et al. (2022) found that EAEHPS also had anti-hyperuricemia and anti-gouty arthritis activities, through reducing serum uric acid (UA) levels, suppressing the production and releasing pertinent inflammatory components, and lessening inflammatory damage and pathological tissue necrosis. Jin et al. (2016) demonstrated the anti-fatigue effects of ethanol extract of H. pedunculosum seeds with longer swimming time and hypoxia tolerance of experimental mice than that of the control group. The ethanol extract further showed a therapeutic effect on skin inflammation caused by imiquimod (Zhong et al., 2023). Moreover, Dai et al. (2019) showed that herpetin (18) and herpetrione (6) had favorable anti-candida albicans effects with minimal inhibitory connection of 10.5 μM and 9.2 μM, respectively.

 6 Structure-activity relationship of lignan

Considering the key role of lignans in H. pedunculosum seeds, their structure-activity relationship was summarized according to previous literatures. For benzofuran lignans (Figure 2), H-5 can improve its anti-inflammatory capacity when it remains unchanged (Wang L. X. et al., 2022). The electron-withdrawing or electron-donor groups on the benzene ring of benzofuran lignans can decrease their anti-tuberculosis activity (Xu Z. et al., 2019). The anti-tumor activity of tetrahydrofuran lignans with the 7-O-9′ structure (Figure 2B.) can be increased by fixing the following sites: C-7′ is carbonyl group, H-5/5′is not substituted, and C-4/4′is methoxy (Wang L. X. et al., 2022). The antioxidant capacity of furofuran lignans is reported to decrease with the number of substituted methoxy groups on their benzene ring (Wang L. X. et al., 2022). Meanwhile, the presence of methoxy benzene in furofuran lignans enhances its toxicity to tumor cells (Xu W. H. et al., 2019), which could provide a structure-activity basis for the anti-tumor effect of herpetrione (6, Figure 3) (Yuan, 2006a; Yuan et al., 2006b; Yuan et al., 2011). For dibenzylbutane lignans (Figure 2), stronger antiviral activity can be achieved when the hydrogens at C-4 and C-5 are substituted by hydroxyl and methoxy groups respectively, and that at C-3'/4'/5′are substituted by methoxy or hydroxyl groups (Xu et al., 2022). Therefore, the separation and structural modification of lignan compounds from H. pedunculosum seeds show great potential for the development of drug leads.

 7 Pharmaceutical analysis

Herpetospermum pedunculosum seeds are only stipulated qualitatively in the Chinese Pharmacopoeia, and their quantitative provisions are still lacking. The existing regulations are not enough to accurately evaluate the quality of H. pedunculosum seeds. Therefore, this section briefly introduces the latest research on modern analytical methods to provide guidance for quality evaluation for H. pedunculosum seeds.

Lignans such as herpetrione (6), herpetotriol (12), herpetin (18), and herpetfluorenone (23) are considered to be typical metabolites of the genus Herpetospermum and also the main active metabolites of H. pedunculosum seeds, which undoubtedly have a direct effect on the quality research of H. pedunculosum seeds and are indispensable to be detected. Wang, (2014) used herpetotriol (12) as the chemical reference materials in TLC to compare H. pedunculosum seeds from different areas. Cong et al. (2008) detected seven lignans from different areas by reversed-phase HPLC method. The results showed that herpetrione (6) was the most abundant among the seven metabolites, followed by herpetotriol (12). Qian et al. (2011) further accurately analyzed the average content of herpetrione (6) in 10 batches of H. pedunculosum seeds from different areas by UPLC, which was found to be 3.7223 mg g-1. Except lignan, other metabolites such as fatty acids and polysaccharides also contribute to the bioactivity of H. pedunculosum seeds, and their analysis are meaningful for the quality evaluation of H. pedunculosum seeds. Ling et al. (2018) detected four fatty acids in H. pedunculosum seeds by GC, the result showed that the content of oleic acid (82) was highest, followed by palmitic acid (81). Liu M. L., (2017a) combined UV-Vis and phenol-sulfuric acid methods to detect the polysaccharides in 10 batches of H. pedunculosum seeds, indicating higher polysaccharide content (2.16%) of H. pedunculosum seeds produced in Yunnan province. However, it is difficult to accurately evaluate the quality of H. pedunculosum seeds based on single or several metabolite analyses owing to its plentiful active metabolites, and establishing their fingerprint for similarity evaluation and principal component analysis could be a feasible choice in this aspect. Wang, (2014) found that there were 18 common peaks in the HPLC fingerprint, and the content of herpetolide A (102) was relatively high in all the samples to be analyzed. Subsequently, the HPLC fingerprint of H. pedunculosum seeds from Nyingchi region of Tibet was also studied, and 17 common peaks were identified, among which herpetrione (6) was the highest (Chen et al., 2020b).

In brief, among the active metabolites suitable for quantitative analysis, herpetrione (6) and herpetolide (102) exhibit various pharmacological activities with relatively high content, which have the potential to serve as markers for evaluating the quality of H. pedunculosum seeds. The current analysis methods for H. pedunculosum seeds are still far from perfect to establishing their quality evaluation system. It is urgent to elucidate the key indicative metabolites of H. pedunculosum seeds and develop standard determination methods capable of evaluating its quality comprehensively.

 8 Processing

Processing methods are able to change the effect of H. pedunculosum seeds. For example, the stir-frying with grit can effectively alleviate the side effects of diarrhea caused by the shell of H. pedunculosum seeds. Meanwhile, the content of herpetrione (6) significantly decreased by 40.9% during this process, which can affect the clinical efficacy (Ling et al., 2018). Research further revealed that H. pedunculosum seeds processed by stir-frying with vinegar has better effects on protecting the liver and reducing enzymes, compared with sand owing to the lower herpetrione loss (12%) than that stir-frying with sand (41.4%). (Chen et al., 2016). Additionally, preparing the lignans of H. pedunculosum seeds into nanosuspension can improve their bioavailability and stability (Li et al., 2018; Shen et al., 2016). Therefore, the processing optimization could be a feasible approach to enhance the efficacy of H. pedunculosum seeds, which deserves more detailed research.

 9 Application

The commercial herbal formulae including H. pedunculosum seeds and related details were collected in Table 4. For example, H. pedunculosum seeds is often combined with Swertia bimaculata, Terminalia schedule, and Carthami flos (1, 2, 3 in Table 4) to soothe the liver, promote bile flow, clear heat, and detoxify. When it is paired with Rosa multiflora, T. schedule, Phylanthus emblica (1, 2, 3, 4 in Table 4), formed compound medicines have the effects of strengthening the spleen, as well as promoting digestion. These summarizations and analyses supported the clinical practice of H. pedunculosum seeds and provided reference value for the development of other H. pedunculosum seed-derived prescriptions.

Formulations and preparations of H. pedunculosum seeds.

No Name Composition Efficacy Refs.
1 Sanwei Qiangwei powder Rosa multiflora, Herpetospermum caudigerum, Terminalia chebula Clear heat and remove toxins, promote bile flow, For the treatment of Tri-pa and gallbladder diseases Chinese Pharmacopoeia Commission (1995)
2 Jiuwei Zhangyacai pill Swertia bimaculata, Herpetospermum caudigerum, Aconitum tanguticum, Ixeris polycephala, Berberis kansuensis, Lagotis Gaertn, Hypecoum erectum, Radix Aucklandiae, Chrysosplenium sinicum Clear heat, anti-inflammatory, alleviates pain. For cholecystitis and incipient icteric hepatitis
3 Wuwei Jinse pill Terminalia chebula, Herpetospermum caudigerum, semen punicae granati, faeces soris scrofae, Radix aucklandiae Clear heat and promote bile flow, promote digestion. For the treatment of jaundice hepatitis, and gallbladder pain
4 Shiwei gaining pill Carthami flos, Crocus sativus, Herpetospermum caudigerum, Meconopsis integrifolia, Dracocephalum tanguticum, Saxifraga stolonifera, Corydalis impatiens, Bear gallbladder, Calculus bovis, Brag-zhun, Calciosinti, and Turquoisis It is used to treat fatty liver, viral hepatitis, liver fibrosis, cirrhosis, and other liver injuries Feng et al. (2018b)
5 Qiwei hezi powder Terminalia chebula, Herpetospermum caudigerum, Bombax ceiba, Amomum tsaoko Crevost, Syzygium aromaticum, Nardostachys chinensis, Piper longum Clear heat and relieve pain. It is used for spleen enlargement, pain and spleen heat caused by strain injury Yuandan and Song (1987)
6 Songshi pill Songshi, Borneol, Syzygium aromaticum, Santalum album, Pulvis fellis ursi, Forest musk abelmosk, Herpetospermum caudigerum Clear heat and remove toxins, soothe liver. It is used to treat liver pain, cirrhosis, hepatitis and cholecystitis Xu et al. (2023)
7 Shiwei heibingpian powder Borneol, Pomegranate seed, Cinnamomum cassia, Myristica fragrans, Piper longum、Terminalia chebula、Light halititum, Herpetospermum caudigerum、Holarrhena antidysenteriaca, Pulvis fellis ursi It is used to treat nausea, cholecystitis, gallstones, and jaundice Cang and De (2020)
10 Conclusions and prospects

Herpetospermum pedunculosum seeds is a traditional Tibetan medicine with long history, rich chemical metabolites and high medicinal value. The research of H. pedunculosum seeds has achieved fruitful results and provided a scientific basis for the clinical medication. However, there are some shortcomings that need to be addressed in follow-up studies.

Although H. pedunculosum seeds is present in many Chinese patent medicines for the treatment of liver diseases, the interaction between the chemical metabolites in the prescriptions remains unclear and needs further investigation. Secondly, the supply of H. pedunculosum seeds is restricted due to the particular growth environment and limited wild resources. The large-scale cultivation of H. pedunculosum seeds could be of high research and economy value. Herpetospermum pedunculosum seeds are reported to contain 125 chemical metabolites, and lignan, terpenoids and coumarin are the main metabolites. Among them, lignan has been widely studied, which is usually recognized as the main pharmacological metabolite of H. pedunculosum seeds to exert hepatoprotective effect. However, the research on many other potentially active components such as polysaccharide is still in shortage. More advanced technologies can be used to extract, enrich, separate and purify the metabolites with low content and attention for better understanding of the medicinal material base of H. pedunculosum seeds. Moreover, there is a lack of structure-activity relationship studies of other active mmetabolites except lignans in H. pedunculosum seeds. The systematic structure-activity relationship studies can accelerate the synthesis of active metabolites and the development of related drugs derived from H. pedunculosum seeds.

The pharmacological effects of H. pedunculosum seeds, especially its effects on liver diseases, have been extensively researched. However, there are few in-depth studies on other pharmacological effects, and the current pharmacological research only remains at the cell and animal levels without comprehensive clinical research. Future research should take this as the direction to accelerate the clinical translation of drugs. Moreover, the quality standard of H. pedunculosum seeds still lacks the indicative components and standard detection method, which can be disadvantageous for standard pharmacology research and clinic practice. At present, some analytical methods have been used to detect the main bioactive ingredients with relatively high content such as herpetrione (6) and herpetolide (102), which may be a promising direction for better quality evaluation.

Although the current medical use of H. pedunculosum seeds is without processing, some studies have shown that H. pedunculosum seeds stir-fried with sand and vinegar can reduce their side effect of diarrhea and also the content of active ingredients. Therefore, the effect of processing method needs to be systematically determinated and optimized in combination with pharmacology and clinical research. In summary, this paper has comprehensively reviewed and analyzed the botany, phytochemistry, pharmacology, analytical methods and quality evaluation, processing and application of H. pedunculosum seeds, which can provide more insights for further research and development of traditional Tibetan medicine.

 Author contributions

ZJ: Writing–original draft. CZ: Writing–original draft. XY: Writing–original draft. KW: Writing–original draft. ZS: Writing–original draft. WG: Writing–original draft. QaZ: Writing–original draft. XM: Formal analysis, Funding acquisition, Writing–review and editing. LQ: Writing–review and editing. QmZ: Writing–review and editing.

 Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Financial support from Zhejiang Provincial Natural Science Foundation of China (LY24H290005), National Natural Science Foundation of China (82004208), and Research Project of Zhejiang Chinese Medical University (2023GJYY16; GQD23SH23, BZXCG-2022-37).

It is also appreciated for the assistance from the Public Platform of Pharmaceutical Research Center, Academy of Chinese Medical Science, Zhejiang Chinese Medical University and Shiyanjia Lab (www.shiyanjia.com).

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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