3.1 Botanical origin

Viticis Fructus is considered to have two origins, namely V. rotundifolia and V. trifolia. It was found that the fruits of Vitex negundo var. cannabifolia were misused as Viticis Fructus by consulting relevant data (Zhou and Jin, 2001). The origin of Viticis Fructus has also been changing (Table S1). V. trifolia and V. negundo var. cannabifolia were not distinguished before the Northern and Southern Dynasties. It was written in Guangzhi and Guangya as “V. negundo var. cannabifolia was V. trifolia”. V. trifolia and V. negundo var. cannabifolia were distinguished by Tao Hongjing for the first time in the Bencao Jingji zhu after the Northern and Southern Dynasties (Tao, 1994). He recorded that the fruits of V. negundo var. cannabifolia were larger than Viticis Fructus. However, the statement was contrary to the present findings. In the Tang and Song Dynasties, there were two main changes. (1) In Xinxiu Bencao, the plant morphology was described in detail. It was consistent with the current statement that Viticis Fructus were larger than the fruits of V. negundo var. cannabifolia (Su, 1981). (2) In the Song Dynasty, the main difference between V. trifolia and V. negundo var. cannabifolia was whether it was a trailing plant, which was recorded in Bencao Yanyi (Kou, 1985). In the Ming Dynasty, it was listed and recorded in Bencao Gangmu: “Its branches were small and weak as V. trifolia, so it was called manjing (trailing plant)”. It could be found from the picture attached to the book that it was ternate compound leaves, which was in line with the characteristics of V. trifolia (Li, 2011). The mainstream view has been that V. rotundifolia and V. trifolia were the origin plants of Viticis Fructus since 1961 (Zhang et al., 2019).

Nowadays, the family and variety of Viticis Fructus are widely discussed. Viticis Fructus is stipulated as Verbenaceae family by the ChP (Chinese Pharmacopoeia, 2020) and Flora of China (https://www.iplant.cn/foc) according to relevant information. However, it is classified as Lamiaceae family by some botanical-related websites, such as Plants of the World Online database (https://powo.science.kew.org). The family of Viticis Fructus is uneven in the literature. In addition, the investigation on whether V. rotundifolia belongs to one of the varieties of V. trifolia also needs to be further conducted. Now V. rotundifolia is considered to be one of the varieties of V. trifolia in some standardized works of taxonomy and pharmacy in China, such as ChP and Flora of China. The Flora of China (English edition), Flora of Australia and Royal Botanic Gardens of the United Kingdom have listed V. rotundifolia as an independent species of Vitex (Sun, 2018).

3.2 Botanical taxonomy

Viticis Fructus belongs to the Lamiaceae family, mainly grown in Borneo, China, Thailand and Western Australia (https://powo.science.kew.org/). According to the Flora of China (English edition), there are three varieties of V. trifolia, namely Vitex trifolia var. taihangensis, Vitex trifolia var. trifolia and Vitex trifolia var. subtrisecta (Table S2). However, V. rotundifolia was also considered to be one of the varieties of V. trifolia in the ChP, called Vitex trifolia var. simplicifolia Cham.

3.3 Botanical description

The two origin plants of Viticis Fructus are clearly distinguished in the plant morphology. The leaves of V. trifolia are simple leaves and the leaves of V. rotundifolia are ternate compound leaves, but their fruits are very similar in morphology (Yang et al., 2023). It is spherical with a diameter of 4–6 mm and has four chambers each with one seed. The surface is gray-black or black-brown with gray powder cream-like fuzziness and has 4 longitudinal shallow ditches. Its base has gray-white calyx and short fruit stalk.

3.4 Botanical distribution

V. Rotundifolia grows in open sandy areas, usually near the sea. V. Rotundifolia is distributed in the north-central and southeast of China, such as Jiangxi and Shandong province. Besides, V. Rotundifolia is widely cultivated in Borneo, India, Japan, Korea, Vanuatu, Vietnam, Western Australia and other places. V. Rotundifolia is different from V. trifolia, which grows in plains, river beaches, sparse forests and villages. Furthermore, V. Trifolia spreads over the north-central, south-central and southeast of China. V. Trifolia is widely cultivated in Afghanistan, Algeria, Assam, Bangladesh, Bismarck Archipelago and so on (https://powo.science.kew.org/). They are all shrubs or trees that grow mainly in moist tropical communities

The origin plants of Viticis Fructus are currently unified as V. rotundifolia and V. trifolia. But the family of Viticis Fructus and varieties of V. trifolia should be unified. In addition, although the plant morphology of the two origin plants is easy to distinguish, their fruits are very similar in morphology.

4.1 Traditional medicinal applications

Viticis Fructus is pungent, bitter taste with a cold character, which enters the bladder, liver and stomach meridian (Chinese Pharmacopoeia, 2020). It was used for treating colds, headaches, gingivitis, dizziness, ophthalmalgia, etc. Recent studies have discovered that Viticis Fructus exerted preventive and therapeutic effects on various diseases, including trigeminal neuralgia (Wen et al., 2020), senile cataracts (Sun and Yang, 2010), arthritis (Chu et al., 2020) and inflammation (Fang et al., 2019). These pharmacological activities were matched with headaches, dizziness, blurred vision, rheumatism and anti-inflammation. In addition, Viticis Fructus had an effect on relieving or treating diseases, such as supraorbital neuralgia (Li, 1998) and neurovascular headache (Hu and Yang, 2016) in clinical.

Viticis Fructus has been employed in clinical practice for more than 2000 years as TCM. The main traditional effects recorded in different books were to dispel wind-heat (treating fever, chills, cough, thirst and other wind-heat syndromes), treat rheumatism, headache and promote hair growth and so forth (Table S3). In the Qin-Han Dynasties, Viticis Fructus was first recorded in Shennong Bencao Jing and listed as one of the top grades. It was employed to treat rheumatism, tapeworm parasites and had healthy effects of improving eyesight, firming teeth and anti-aging (Zhang et al., 2018). In the Southern and Northern Dynasties, it was applied to treat headaches, intracranial tinnitus and benefit qi (benefiting vital energy) as recorded in Mingyi Bielu (Tao, 1986). During the Five Dynasties and Ten States period, it had therapeutic effects on eye swelling, itching and ulcerous eyelid margin and promoted hair growth. In the Tang Dynasty, its efficacy had been clarified to relieve the symptoms of headaches and promote hair growth (Sun, 1982; Zhen, 1983). In the Song Dynasty, the usage of Viticis Fructus in the treatments of head and face wind (symptoms of head and face sweating, headaches, dizziness, etc) was more frequent (Wang, 1958b). The treatment of intermittent headaches by Viticis Fructus was introduced in Danxi Xinfa in the Yuan Dynasty. The description of its efficacy in Shennong Bencao Jing was reaffirmed in Bencao Gangmu (Li, 2011). In the Qing Dynasty, the functions of Viticis Fructus were emphasized by many Chinese ancient books, such as dispelling cold-dampness syndrome (treating rheumatism), removing headaches and improving visual acuity. Viticis Fructus was recorded in Depei Bencao, which could dispel cold-dampness, cure headaches, relieve eye pain and treat damp arthralgia, intracranial tinnitus and toothaches. Additionally, it was devoted to dispelling wind, treating solar wind headaches (migraine), vertigo and eye pain according to Bencao Shugou Yuan (Yang, 1958).

Furthermore, Viticis Fructus was also used in conjunction with other herbs to exert curative effects (Table S4). There are two classic prescriptions for Viticis Fructus, which are Qiang-Huo-Sheng-Shi Decoction and Qing-Shang-Juan-Tong Decoction. Qiang-Huo-Sheng-Shi Decoction derived from Neiwai Shangbian Huolun of Li DongYuan. It was combined with Notopterygii Rhizoma et Radix, Chuanxiong Rhizoma and so on (Li, 1959; Yan et al., 2022). Its effect was to dispel wind, eliminate dampness and relieve pain (Hu et al., 2022). It was commonly used to treat rheumatoid arthritis, bone hyperplasia, ankylosing spondylitis, etc. Notopterygii Rhizoma et Radix and Angelicae Pubescentis Radix in the prescription could dispel wind-dampness and dredge joints. Their combination had favorable effects in treating rheumatism around the body and relieving arthralgia, which were sovereign drugs (playing a major role in the treatment of main syndromes or main symptoms in prescriptions). Saposhnikoviae Radix cured pain and Chuanxiong Rhizoma could not only evacuate the wind evil around the body, but also could promote blood and qi circulation to alleviate body pain. They were used to minister drugs (assisting the sovereign drugs to cure the main symptoms) and helped the sovereign drugs to disperse evil and relieve pain. Ligustici Rhizoma et Radix evacuated wind-dampness and relieved headaches, which was the assistant drug (assisting the sovereign and minister drugs to treat concurrent syndromes and secondary symptoms). Glycyrrhizae Radix et Rhizoma mitigated the nature of various herbs and reconciled medicines as assistant drugs. The compatibility of multiple herbs could dispel wind-dampness and relieve pain (Zhang et al., 2023). Viticis Fructus was an assistant drug in the prescription and mainly played the role of dispelling wind and relieving pain. Pharmacological research has supported its therapeutic roles (Chu et al., 2020; Li et al., 2020b). The other is the Qing-Shang-Juan-Tong Decoction recorded in Shoushi Baoyuan of Gong TingXian. The prescription included Radix Angelicae Sinensis, Radix Angelicae Dahuricae, Viticis Fructus, etc (Gong, 1999). It was mainly used to treat intractable pain and trigeminal neuralgia. This effect had also been supported by pharmacological studies (Wen et al., 2020; Yu et al., 2021).

Viticis Fructus could cure colds, headaches, migraines and neuralgia in Korea (Kim, et al., 2012). In India, it could be employed to improve symptoms of amenorrhoea, liver disease, rheumatic pain and other disorders (Meng et al., 2023). In Japan, it had therapeutic effects on colds, headaches, migraine and eye pain (Yan et al., 2023). Furthermore, many countries not only used the fruits of V. trifolia and V. rotundifolia to treat diseases, but also their other parts could be utilized for various illnesses. For example, Samoans had applied V. trifolia to relieve sprains and rheumatic pain. In Tonga, its efficacy had been clarified to cure oral infections and inflammation. In Papua New Guinea and New Caledonia, its stems and leaves could remedy dysentery (Kamal et al., 2022). In India, the flowers and leaves of V. trifolia were employed for fever and alopecia, respectively (Yan et al., 2023). In European herbal medicine, V. rotundifolia was used to relieve various diseases associated with women (Azizul et al. 2022). It is listed as a protected plant in China and Japan, so the development and utilization of multiple parts can avoid waste of resources and is conducive to sustainable development.

4.2 Processing

There are mainly two specifications for clinical use according to the 2020 edition of ChP, namely crude and stir-fry processed Viticis Fructus. The processing not only could remove non-medicinal parts, but also could moderate the nature of Viticis Fructus (Wang et al., 2010). Various processing methods were recorded in ancient books, such as crude, stir-frying (micro-fried, stir-frying coke, stir-frying char, stir-frying liquor) and steaming with liquor (Fig. S1, Table S5). The crude Viticis Fructus was first recorded with “the persistent sepal removal” both in ShengJi ZongLu and Taiping Huimin Heji Jufang in Song Dynasty (Hejiju, 1985; Zhao, 1982). Viticis Fructus had been emphasized to the removal of non-medicinal parts and crushed before use in many works. Its stir-fry processed products had micro-fried, stir-frying char and so forth. The two methods of Viticis Fructus recorded in Boji Fang were “washed Viticis Fructus, baked with mild fire then crushed” (Wang, 1958a). The other was “washed and then fried”. According to the records of Danxi Xingfa, it was requested that should be “fried to black” (Zhu, 1956). “It was crushed, washed with liquor, fried and decocted” in Yizong Cuiyan (Luo, 1982). Bencao Tongxuan recorded that “the persistent calyx removal, fried with liquor and crushed” (Li, 2015). Micro-fried Viticis Fructus was the most widely used among them. Furthermore, Viticis Fructus also had a liquor steaming processing method. Traditional Chinese medicine believed that the quality of Viticis Fructus was light and the smell was mild. It moved upward to treat head and face wind. The liquor stir-frying method had contributed to treating headaches by Viticis Fructus (Yin et al., 2019). Liquor steaming was first recorded in Leigong Paozhi Lun (Lei, 1986). Viticis Fructus should be removed the persistent calyx and pedicle. After soaking in liquor for ten days, it was steamed for several hours and dried in the sun. Besides, it could also be prepared by boiling method, the steaming and frying method. It was recorded in Taiping Shenghui Fang that the ratio of medicine to liquor is 1:5. It was boiled in the liquor and dried in the sun (Wang, 1958b). However, the boiling method and the steaming and frying method were less used.

Viticis Fructus and its stir-fried products are commonly used in clinics. Their chemical constituents also changed during processing. First, whether the crude and fried products are crushed is particularly critical. The content of extract significantly increased after crushing compared with uncrushed Viticis Fructus (Wang et al., 2017a). It was explained that the scientific nature of the use after crushing was emphasized in ancient books. Secondly, the volatile oil and flavonoids in Viticis Fructus changed differently during processing. For example, the total volatile oil content in Viticis Fructus decreased after thermal processing (Wang et al., 2017b). However, the flavonoids with high melting points were not easily destroyed (Wang et al., 2010). Other studies had also displayed that the content of total flavonoids was stir-frying coke > stir-frying charcoal > slightly stir-frying = crude product (Guo et al., 2005; Zhang et al., 2003). Furthermore, the casticin content of each processed product was determined, crude Viticis Fructus < stir-frying Viticis Fructus < stir-frying Viticis Fructus with liquor < baking Viticis Fructus with liquor (Xu et al., 2020).

The pharmacological effects of processed products showed specific differences. Crude Viticis Fructus was often used for treating wind-heat headaches, red eyes, swelling and pains, while stir-fried Viticis Fructus was chiefly used for the treatment of deafness, rheumatic arthralgia and migraine (Wang et al., 2017b). The crushed crude product was suitable for the evacuation of wind-heat. The mixed frying of 10 % yellow rice liquor and Viticis Fructus was applied for analgesia (Jin et al., 2000). It was advisable to use stir-fried carbon or stir-frying Viticis Fructus with liquor to reduce blood pressure (Diao (2018)). However, there were some bifurcations in analgesic research. Some scholars regarded the analgesic effect of fried products were more potent than that of crude products. The intensity of the analgesic effect was as follows: stir-frying coke > micro-fried products > stir-frying char > crude products (Sun et al., 1997). Other scholars believed that the liquor products were more effective than the crude products, because liquor and Viticis Fructus had compatible medicinal properties (Jin et al., 2000). It had been advocated that the crude products analgesic effect was more vital than fried products (Liu, 2005). Another point of view was that the analgesic effect of crude Viticis Fructus is strong. Its analgesic effect was reduced after stir-frying and processing with liquor does not improve its analgesic effect. Crude Viticis Fructus should be used for analgesic (Gong and Wang, 2012).

Viticis Fructus has a long history as TCM application. It can cure headaches, eye diseases, head and face wind, rheumatism, intracranial tinnitus and promote hair growth according to ancient books. Furthermore, the processing products of Viticis Fructus are mainly divided into crude, stir-frying and liquor products according to the records of ancient books. However, the primary clinical applications at present are crude Viticis Fructus and micro-fried Viticis Fructus, and more attention should be paid to other processed products. Because the types and contents of flavonoids, volatile oils and other components have been altered during the processing process, diverse processed products are appropriate for different ailments. Therefore, it is paramount to select the best processed products for disease treatment.

5.1 Terpenoids

Terpenoids account for the largest proportion, mainly diterpenoids and iridoids (1–143) (Fig. 2, Fig. 3 and Fig. 4). Labdane-type diterpenoids vitexilactone (3), rotundifuran (4) and halimane-type diterpene vitetrifolin D (7) were isolated and purified from the ethyl acetate fraction of Viticis Fructus (Fang et al., 2019). Iridoids are also a class of special monoterpenoids composed of five-membered carbon rings and six-membered oxygen heterocycles. They mainly exist in the form of glycosides in Viticis Fructus. Two iridoids were isolated and identified from 80 % ethanol extract: 10-O-vanilloylaucubin (104) and agnuside (150) (Bao et al., 2018).

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Fig. 2

Structures of terpenoids (1–85).

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Fig. 3

Structures of terpenoids (86–132).

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Fig. 4

Structures of terpenoids (133–143).

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5.2 Flavonoids

Flavonoids are typical compounds in Viticis Fructus (144–177) (Fig. 5). Casticin is the only index component of Viticis Fructus in ChP, which is used to measure and evaluate the quality of Viticis Fructus. The flavonoids in Viticis Fructus are mainly divided into flavonoids, isoflavones, dihydroflavones and anthocyanins, among which flavonoids are the main compounds. Luteolin (152) was identified from cold soak of 95 % ethanol. Three flavonoids were isolated from chloroform fraction of Viticis Fructus: luteolin-4′-O-glucoside (156), casticin (162) and apigenin (173) (Chen et al., 2018). In addition, flavonoids in Viticis Fructus were recognized by ultra-high-performance-liquid chromatography-quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), including taxifolin (149), genistein (151), quercetin (153) (Zhang et al., 2021).

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Fig. 5

Structures of flavonoids (144–177) and phenolic acids (178–211).

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5.3 Phenolic acids

Viticis Fructus also includes phenolic acids (178–211) (Fig. 5), such as protocatechuic acid (183), neochlorogenic acid (184), chlorogenic acid (185), hydroxybenzoic acid (186), vanillic acid (189), ferulic acid (201) and so on (Yoshioka et al., 2004; Zhang et al., 2021). V. trifolia fruits were extracted with ethanol to obtain a crude extract and then further extracted with ethyl acetate. The ethyl acetate fraction was eluted with a mixture of petroleum ether and acetone, and the compounds (179–181) were successfully isolated and identified in the fraction (Djimabi et al., 2021).

5.4 Lignans

Thirteen lignan compounds were isolated from Viticis Fructus, which were divided into diepoxy lignans, neolignans and other types (212–224) (Fig. 6). Viticis Fructus extract was carried out repeatedly by column chromatography using silica gel, RP-18 and MCI gel to obtain viterolignan A (213), viterolignan B (214), ficusal (215) and so on (Lee et al., 2013).

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Fig. 6

Structures of lignan (212–224) and others (305–324).

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5.5 Volatile oil

Fresh Viticis Fructus contains massive volatile oil. The crude and processed products of Viticis Fructus were extracted by continuous reflux in soxhlet extractors and then identified by GC–MS. A total of 56 compounds (225–280) were identified, such as hentriacontane (276), hexatriacontane (277), tetracontane (278) (Wang et al., 2017b). In another study, the volatile oil was extracted by steam distillation for 6 h and 9 compounds (281–288, 299) were identified by GC–MS (Chen et al., 2007).

5.6 Other compounds

In addition to the above compounds, steroids, anthraquinones, sugars, fatty acids and alkaloids were also isolated from Viticis Fructus (Fig. 6). Three compounds (305–307) were identified by nuclear magnetic resonance (NMR) from Viticis Fructus extracted with 95 % ethanol (Djimabi et al., 2021). Five compounds such as karakoline (310) were identified from the extract of Viticis Fructus by UHPLC-Q-Orbitrap HRMS (Zhang et al., 2021). It may still contain other compounds in Viticis Fructus, which gives a direction for further research.

Various compounds had been isolated and identified from Viticis Fructus, most of which were from the fruits of V. rotundifolia. The main chemical constituents were terpenoids and flavonoids. Terpenoids had anti-tumor activity and most of terpenoids were diterpenes and iridoids in structure. Their structure–activity relationship should be further elucidated. Casticin had good activity in tumors, inflammation, oxidative damage and other ailments. Some studies revealed a difference in the casticin content of V. rotundifolia and V. trifolia fruits, which was possible to use as quality markers. Therefore, the extraction process optimization and batch preparation of casticin should be focused on. Moreover, the information on many compounds is not complete, such as CAS number. It is necessary to further improve the compound information to avoid the misuse of synonyms.

6.1 Antitumor

The extract and its main compounds of Viticis Fructus had different degrees of inhibitory and preventive effects on cervical cancer, nasopharyngeal carcinoma, lung cancer, breast cancer and other cancers (Fig. 7, Fig. 8 and Fig. 9). Helianane diterpenoids from Viticis Fructus slowed down cell division in human chronic myeloid leukemia K562 cells and mouse breast cancer tsFT210 cells, resulting in apoptosis of cancer cells (Li et al. 2005b). The flavonoids of Viticis Fructus, such as persicogenin, artemetin and luteolin, restrained G2/M of cell cycle progression and induced mammalian cancer cell death (Li et al., 2005a). However, the anti-tumor effect of Viticis Fructus was mostly in vitro tests and was rarely reported in vivo tests. The effect should be further evaluated in combination with clinical research.

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Fig. 7

Antitumor activity of casticin.

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Fig. 8

The molecular mechanism of the active components of Viticis Fructus on anti-nasopharyngeal cancer, anti-cervical cancer, anti-breast cancer and anti-inflammatory.

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Fig. 9

Changes of biological indexes of anti-hepatocarcinoma and anti-gastric cancer of Viticis Fructus.

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6.2 Anti-inflammation

The anti-inflammatory activity of Viticis Fructus mainly involves NF-κB, MAPK and AKT signaling pathways (Fig. 8). There was a certain gap in the anti-inflammatory activity of different extraction parts of Viticis Fructus, among which the n-butanol fraction had better activity. It was speculated that terpenoids and flavonoids, such as Viteagnusin I, Vitetrifolin D and others, inhibited the production of nitric oxide (NO) (Yan et al., 2023). Viterotulin C, Vitexilactone and Rotundifuran had anti-inflammatory activity and suppressed tumor necrosis factor-α (TNF-α)-induced NF-κB activation. The inhibition rate was 42.52 % − 68.86 % at a concentration of 50 μM (Fang et al., 2019). Casticin could repress the chemotaxis of cultured human neutrophils and produce anti-inflammatory effects (Ahmad et al., 2010). It attenuated the generation of pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and TNF-α by blocking NF-κB, AKT and MAPK signaling pathways, thereby inhibiting NO and Prostaglandin E2 levels and exerting anti-inflammatory activity (Liou et al., 2014).

Viticis Fructus played a therapeutic role in many diseases through anti-inflammation, such as systemic anaphylaxis reaction, allergic asthma, ulcerative colitis (UC), knee osteoarthritis (KOA), vascular inflammation, etc. Its extract and monomer components had been proven to have certain anti-inflammatory activities. The water extract (the fruits of V. rotundifolia) and pyranopyran-1,8-dione (PPY) had protective effects on systemic anaphylaxis reaction, pulmonary inflammation and asthma. They restrained secretion of inflammatory factors by declining the activation of ERK1/2 and NF-κB signaling pathways, such as TNF-α and IL-6 (Yan et al., 2023). Another study found that casticin was a prominent immunomodulator that improved the pathology by inhibiting the expression of T-helper two-cell cytokines in asthmatic mice (Liou et al., 2018). Casticin was also a potential remedy for KOA, particularly for fibrosis of synovial membrane. It reduced the release of inflammatory mediators and the elevation of fibrosis markers induced by monoiodoacetic acid/lipopolysaccharide through suppressing the stimulation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome (Chu et al., 2020). In addition, casticin was able to repress ROS-mediated NF-κB pathway to achieve marked relief of cartilage degeneration associated with experimental osteoarthritis (Chu et al., 2020). The protective effect of casticin on dextran sulfate sodium-induced UC was achieved by increasing the expression of antioxidant enzymes peroxiredoxin three and Mn-containing superoxide dismutase, and reducing the generation of proinflammatory cytokines via inhibiting AKT pathway (Ma et al., 2018). Casticin could markedly decrease vascular inflammation by inhibiting the NF-κB pathway of vascular endothelium cells (Lee et al., 2012).

6.3 Antioxidation

Viticis Fructus was discovered good antioxidant activity and individual compounds were even better than vitamin C in antioxidant activity. The compounds (such as vanillic acid and taxifolin) in the methanol extract of V. rotundifolia fruits showed more potent antioxidant action over 3-tert-butyl-4-hydroxyanisole (Ono et al., 1998b). The scavenging ability of alkaloids, total flavonoids and volatile oil on hydroxyl radicals and superoxide radicals displayed a significant dose–effect relationship with their concentrations (Yan et al., 2023). Ferruginol and vitrifolin A had certain antioxidant activity (Ono et al., 1999; Zhang et al., 2013). The superoxide quenching activity of orientin and 3, 4-di-O-caffeoylquinic acid was more powerful than that of vitamin C (Kim, 2009). In addition, it was found that 3,4-dihydroxybenzaldehyde, chlorogenic acid and orientin showed strong DPPH free radical scavenging ability (Le et al., 2022).

6.4 Premenstrual syndrome

The pathogenesis of PMS was generally believed to be the result of a combination of psychosocial factors and endocrine regulation, such as prolactin, ovarian hormones and brain neurotransmitter imbalance (Ye, 2010). Pharmacological studies had found that ethanol extract of V. rotundifolia fruits was used to alleviate PMS regulating prolactin levels, estrogen and progesterone levels (Hu, 2007). First, directly reduced the excessive estrogen content in the body so that the estradiol/progesterone ratio decreased. Casticin could reduce the content of estradiol in serum. At the same time, rotundifuran could increase serum progesterone content. Second, Decreased the content of β-endorphin in the hypothalamus. Third, Casticin could significantly reduce the content of prolactin (Ye, 2010).

6.5 Cardiovascular protection

Viticis Fructus had certain therapeutic effects on some cardiovascular diseases, such as hypertension, hyperlipidemia and coagulopathy. Viticis Fructus had an antihypertensive effect. The blood pressure of cats decreased significantly after administration of Viticis Fructus decoction and Viticis Fructus ethanol extract (Guan, 2011). Its extract could significantly prolong the time of bovine thrombin condensing human fibrinogen in vitro, indicating that it had a strong anticoagulant effect (Ou et al., 1987). Casticin could inhibit platelet aggregation, release, adhesion and plaque retraction, which was achieved by inhibiting PI3K/Akt signaling pathway (Xiong et al., 2022). Furthermore, V. rotundifolia fruits extract had strong activities toward the oxidation of low-density-lipoprotein (LDL) and high-density lipoprotein (HDL) (Kim et al., 2020). Viterofolin H, previtexilactone and other compounds indicated moderate activities in facilitating LDL uptake. These compounds showed certain anti-hyperlipidemic activity (Wang et al., 2019a).

6.6 Other activities

In addition to the above effects, Viticis Fructus can also be used for analgesic, antipyretic, expectorant, asthma, whitening, antibacterial, anti-fatigue, etc. It is a TCM with an analgesic effect. The methanol extract of V. trifolia fruits could effectively relieve migraines, among which the flavonoid fraction has a good analgesic response inhibition rate. Pedicularis-lactone, viteoid I and viteoid II significantly suppressed paclitaxel-induced mechanical allodynia. This is related to the levels of 5-hydroxytryptamine and γ-aminobutyric acid (GABA) increased, and the decrease of plasma calcitonin gene-related peptide and substance P levels (Yan et al., 2023). Crude and processed V. rotundifolia fruits products had an apparent antipyretic effect (Yan et al., 2023). It had expectorant and antiasthmatic effects. An obvious expectorant effect could be observed by phenol red excretion method in mice after oral administration of water decoction and alcohol extract of Viticis Fructus. The water decoction and petroleum ether extract of Viticis Fructus could relax the isolated guinea pig tracheal specimens. It could slow histamine-induced tracheal contraction (Liu, 2002). This was mutually supportive with its traditional efficacy in treating wind-heat colds (upper respiratory tract infections). Aldolase role of the rat lens was strongly inhibited by ether extract of V. rotundifolia fruits (Shin et al., 1994). Viticis Fructus water extract could also promote sleep in mice (Zhong et al., 1996). Viticis Fructus showed an effect against tyrosinase, indicating that it was able to inhibit the formation of melanin (Wang, 2003). Viticis Fructus water decoction had a moderate antibacterial effect on staphylococcus epidermidis in vitro and had moderate antibacterial effect on bacillus subtilis (Guan, 2011). Viticis Fructus could also interfere with pulmonary fibrosis by inhibiting apoptosis and improving excessive angiogenesis (Tian, 2017). Viticis Fructus could be used as a potential anti-menopausal osteoporosis drug. Within the safe range of casticin, it could inhibit the differentiation of RAW 264.7 cells into osteoclasts through the NF-κB/BCL-2 signaling pathway (Huang, 2022).

Viticis Fructus can trigger the apoptosis of various tumors and cancer cells to prevent and treat cancer with respect to antitumor activity. Many studies have manifested that Viticis Fructus induced apoptosis by regulating JNK, NF-κB, PI3K/AKT, ERK and other pathways. The hot water extract, ethanol extract, terpenoids and flavonoids of Viticis Fructus are the main components of its function. Among them, casticin can modulate key targets and pathways of breast cancer, cervical cancer, nasopharyngeal carcinoma and other cancers. It needs further research and may be used as a potential new drug to inhibit cancer cells. The anti-inflammatory properties of various Viticis Fructus fractions varied to some extent in terms of anti-inflammatory effects. The optimal extraction solvent should be selected to ensure better anti-inflammatory activity of Viticis Fructus. It could prevent the formation of anti-inflammatory proteins by modulating the NF-κB, AKT and MAPK signaling pathways, thereby reducing inflammation and curing various illnesses. However, the mechanism of many diseases was still unclear, such as systemic allergic reactions. In addition, the anti-rheumatic effect of Viticis Fructus was mentioned in many books such as Bencao Gangmu and Shennong Bencao Jing, which was mutually corroborated with pharmacological research, but the specific action mechanism should be further studied. Flavonoids and terpenoids in Viticis Fructus manifested favorable antioxidant activity in vitro. Oxidative-related diseases should be validated at the cellular and animal levels for better clinical application of Viticis Fructus. In the area of female diseases, Viticis Fructus had a good preventive and therapeutic effect on female illness by regulating hormone levels such as prolactin, estrogen and progesterone. In addition to improving the symptoms of PMS, it could also be used to relieve hyperprolactinemia and menopausal symptoms (Yan et al., 2023). The mechanism of Viticis Fructus in cardiovascular disease is still unclear. Further experiments in vivo are needed to prove its efficacy and clarify the corresponding mechanism of action. This can expand its use scope and provide a new direction for the treatment of cardiovascular.

10.1 Clinical application

Viticis Fructus is a commonly used TCM in clinics. It is used for treating various diseases combined with other herbs, such as nervous system disorders, eye diseases, otolaryngology diseases, digestive system diseases and so on (Fig. 10).

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Fig. 10

The application of prescriptions containing Viticis Fructus in clinical diseases.

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In the nervous system disorders, it was recorded in the ancient book that all headaches could be treated with Viticis Fructus., regardless of the left and right sides (Gong, 1999; Tian and Shi, 2022). It combined with other TCM in the treatment of headaches and curative effect was favorable. For example, Viticis Fructus combined with Bupleuri Radix, Chuanxiong Rhizome and Chrysanthemi Flos to treat migraine, played a role in clearing heat and relieving pain (Zhao, 2018; Niu et al., 2005). Neurovascular headache, tension headache, hypertension-related headache, trigeminal migraine, migraines and cluster headache could be treated with Chrysanthemi Flos, Notopterygii Rhizome et Radix, Scutellariae Radix, etc (Hu and Yang, 2016). One hundred and twenty patients with migraine were cured with Viticis Fructus Tou-Feng Decoction (Chrysanthemi Flos, Uncariae Ramulus Cum Uncis, Menthae Haplocalycis Herba, etc) for 10 days (twice a day). Headache symptoms disappeared in 92 patients. The degree of headache attack in 26 patients was significantly anesis and the frequency decreased. The total effective rate was 98.3 %. The difference was significant compared with the total effective rate of 88.3 % in the control group (intravenous ligustrozine hydrochloride injection, 60 volunteers). In addition, the recurrence rate was lower in the treatment group (10.87 %) than in the control group (32.43 %). Compared with the two groups, the treatment group was significantly better than the control group. Viticis Fructus mainly played an analgesic role in the prescription (Xu, 2007). Clinically, Viticis Fructus could be used alone to treat sciatica (Wang, 2001) and trigeminal neuralgia (Li, 1998). Fifty-six patients with sciatica were treated with Viticis Fructus juice twice a day for 21 days. The total effective rate was 98.2 %. Primary sciatica was mostly related to rheumatism, cold and other reasons. Viticis Fructus combined with liquor had a fine effect of expelling wind, removing dampness and cold-dispelling effect, so the effect is obvious (Wang, 2001).

In Otorhinolaryngological diseases, 110 patients with chronic suppurative otitis media were treated with Viticis Fructus Decoction (Cimicifugae Rhizoma, Peucedani Radix, Mori Cortex, etc) and Hong-Mian powder. Thirty-eight cases were treated with Western medicine (antibiotics and steroid hormones). The curative effect of TCM group was significantly better than that of the Western medicine group. The cure rate was better in the Chinese medicine group (89.1 %) compared with the Western medicine group (86.8 %). And the recurrence rate of the Chinese medicine group (1.8 %) was significantly lower than that of the Chinese medicine group (31.6 %) (Guo and Wang, 2003). Viticis Fructus, Eupatorii Herba, Angelicae Dahuricae Radix and Xanthii Fructus were applied clinically for the treatment of rhinitis, sinusitis, ethmoid sinusitis and maxillary sinusitis (Guo, 2006). It was worth mentioning that Viticis Fructus also had a good therapeutic effect on gastritis. Four groups were set up, namely superficial gastritis with Weishu No.1 (Angelicae sinensis radix, Paeoniae radix alba and so on) plus Viticis Fructus 20–30 g, atrophic gastritis with Weishu No.2 (Lilii bulbus, Codonopsis radix) plus Viticis Fructus 20–30 g and the control groups without the addition of Viticis Fructus. Patients were monitored and had a repeat gastroscopy after 2–3 sessions (2–3 months). The heartburn, distension and pain disappeared on average 14.3 days in the treatment group and the control group 26.1 days on average. Gastroscopy results in patients with gastritis displayed an efficacy rate of 91.7 % in the treatment group and the control group was 74 %. Viticis Fructus played an analgesic and anti-inflammatory role in the prescription (Huang and Wen, 2000). Combined external application of Viticis Fructus powder and yellow wine had a good therapeutic effect on 19 patients with acute mastitis. The clinical symptoms of 17 patients disappeared and the total number of white blood cells and neutrophils in blood tests were normal. The symptoms and signs of two patients were significantly reduced. The total number of white blood cells and neutrophils was close to normal (Xiang, 1999). In addition, it could also treat eye diseases and rheumatism. Viticis Fructus prescription could cure herpes simplex keratitis, bacterial keratitis and papillary closed keratitis. It plays the role of heat dissipation, dispelling wind and relieving pain (Jin, 2018). Qiang-Huo-Sheng-Shi Decoction containing Viticis Fructus could improve symptoms of knee osteoarthritis (Wang, 2021), ankylosing spondylitis (Yang et al., 2021) and lower back pain (Lin, 2019) in clinical practice. It helped to relieve pain of patients.

10.2 Other applications

Viticis Fructus is used in cosmetics, healthcare products and daily necessities (Table S6). For example, Viticis Fructus could be made into medicine pillows, health tea, health liquor, beverages and other health care products. It can be applied to lowering blood pressure, lowering blood lipid, lowering blood sugar, improving menopausal syndrome, hair growth, benefits qi and so on (Gao et al., 2022; Park, 1999; Shi, 2016). In cosmetics and daily necessities, casticin, as a sunscreen ingredient in cosmetics, could reduce the use of current chemical sunscreens and play a beneficial role in synergistic sunscreen effects (Wang et al., 2019b). Longanae Arillus and Viticis Fructus extract had excellent effects on promoting skin elasticity, relieving wrinkles, skin moisturizing and relieving skin problems (Kim et al., 2018). In addition, toothpaste containing Viticis Fructus had significant antibacterial, anti-inflammatory and analgesic effects, which could fundamentally reduce oral problems such as swelling, aching and bleeding of gum (Mu and Liu, 2017). There were two kinds of head care products containing Viticis Fructus. One kind of hair shampoo had an antipruritic effect and the other kind of plant hair dye enhanced the dyeing effect without any toxic or side effects (Yin, 2019; Jiang, 2016). The volatile oil of Viticis Fructus has a strong aroma and could be used as material for blending flavors. The combination of Viticis Fructus and camphor is an efficient aromatic repellent (Xin et al., 2004).

The clinical effect of Viticis Fructus is worthy of recognition, which can be applied to treat migraine, neurovascular headache, tension headache, gastritis, acute mastitis and so on, and achieve splendid therapeutic effects. However, the detection techniques currently in use are gastroscopy and blood sample detection, which is not enough. It should be combined with more advanced medical instruments and technologies to evaluate the indicators of Viticis Fructus in the treatment of various diseases and to reflect the therapeutic effect more comprehensively and accurately. Currently, Viticis Fructus is utilized finitely. We ought to focus on its application in different domains to broaden the use of Viticis Fructus and maybe discover novel approaches to treating intricate illnesses.

10.3 Patent information

Patents could reflect the development status of hot frontier technology and developmental trend of a field to a certain extent. It was closely related to all aspects of product production and was the carrier of scientific research achievements transformation (Chen et al., 2023). More than 2,000 results were obtained by searching on the Baiten Patent Search Platform, Yaozhi Network and CNKI. Baiten patent retrieval platform analyzed the patent-related situation of Viticis Fructus. The main technical field of Viticis Fructus patent was necessary for human life, chemistry, metallurgy, operations, transport, physical, textile and papermaking. The necessities for human life account for the largest proportion among them. Viticis Fructus was most widely studied from 2014 to 2018, among which the application and publication peak in 2015 were 445 and 415 respectively (Fig. S3). The main areas of patent applications for Viticis Fructus were in China and a few other countries were distributed. In China, the patent applications of Viticis Fructus were concentrated in Shandong Province, Anhui Province, Jiangsu Province and Guangxi Province. Patent applications include cosmetics, daily products, health products, medical use and technical methods (Table S6). Cosmetics, daily products and health products are discussed in application in other fields above. It can also be used for antibacterial, antidepressant, treatment of depression and so on in terms of medical use. Patent applications for technical methods focus on quality control and extraction separation, such as component quantification, fingerprint establishment, extraction and separation of total flavonoids.

The patent applications of Viticis Fructus are concentrated in the fields of necessary for human life, chemistry, metallurgy, operations, transport, physical, textile and papermaking in terms of patents. Viticis Fructus is listed as the top grade in the Shennong Bencao Jing and is considered to have favorable tonic, health care and therapeutic properties. In addition, it can be used as food in some countries. Its edible value can be studied more to promote the better use of Viticis Fructus.