Zanthoxylum bungeanum Maxim: A Review of Its Phytochemistry,Pharmacology,and Pharmacokinetics

Abstract

Zanthoxylum bungeanum Maxim (ZBM) belongs to Rutaceae family and has been used as traditional spice and herb for hundreds of years in China. Accumulating evidence suggests a series of pharmacological effects associated with ZBM. This review aims to provide a systematic analysis of the composition, structural properties, pharmacology, and pharmacokinetics of ZBM. Chemical composition analysis of ZBM showed that the main compositions were volatile oil, amide compounds, flavonoids, alkaloids, coumarins, lignans, and phenylpropanoids. Interestingly, ZBM exhibits a wide range of significant biological activities including anti-inflammatory and analgesic effect, anesthetic effect, neuroprotective effect, antiobesity activity, antineoplastic activity, antibacterial, and other activities. However, there is currently no comprehensive review available on ZBM. Therefore, an up-to-date research was accomplished through systematic searching of multiple electronic databases. In a word, this review summarizes the recent researches investigating the chemical composition and biological properties which will provide a better understanding about the health benefits and preclinical assessment of novel application of ZBM.

Keywords

phytochemistry pharmacology pharmacokinetics flavonoids

Introduction

Zanthoxylum bungeanum Maxim (ZBM) is generally referred to as Huajiao in China, widely distributed around the world.^1,2 As a type of deciduous shrubs or small arbor that belongs to the Rutaceae family, its roots, leaves, fruit, and peel including both fresh and dried parts can be used as medicine,³ treating toothache, cancer, dyspepsia, eczema, and so on.^4-6 In the food industry, it is used as a seasoning and characteristic spice with unique tingling taste.⁷ The chemical composition of ZBM includes alkaloids, amides, volatile oil, coumarins, lignans, and flavonoids.^8-10 Up to now, many scholars have investigated on the extraction, separation, and the physiological activity of ZBM, providing application foundation into the comprehensive utilization of ZBM. However, the material foundation of its therapeutic effect and mechanisms still unclear.

With the Chinese and English words of “Zanthoxylum bungeanum Maxim,” “pharmacological effects effects,” “sanshool,” “ingredients,” “essential oil,” “extraction,” “separation,” “purification.” and “pharmacokinetic” as keywords, we combined and searched the relevant literatures published in PubMed, Web of Science, Google Scholar, Science Direct, Elsevier, and China National Knowledge Internet from 1999 to 2023. Based on a large number of literatures, the objective of this review is to provide a systematic review of the bioactive compounds, biological activities, and pharmacokinetics of ZBM, looking for possible perspectives of its natural bioactive molecules as a function food.

Chemical Constituents

In recent years, the chemical composition of ZBM has been extensively studied by many scholars. So far, about 198 compounds have been isolated and identified from ZBM, including volatile oil, amide compounds, flavonoids, alkaloids, coumarins, lignans, and phenylpropanoids. In this section, all the collated compounds were comprehensively listed in the following figures (Figures 1–13) for detailed type statistics.

Figure 1.

Structures of volatile organic compounds 1–31.

Figure 2.

Structures of volatile organic compounds 32–56.

Figure 3.

Structures of volatile organic compounds 57–90.

Figure 4.

Structures of volatile organic compounds 91–114.

Figure 5.

Structures of amide compounds 115–130.

Figure 6.

Structures of amide compounds 131–144.

Figure 7.

Structures of amide compounds 145–148.

Figure 8.

Structures of flavonoids 149–160.

Figure 9.

Structures of flavonoids 161–167.

Figure 10.

Structures of alkaloids 168-188.

Figure 11.

Structures of coumarins 189-192.

Figure 12.

Structures of lignans 193-196.

Figure 13.

Structures of phenylpropanoids 197-198.

Volatile Oil

Volatiles are considered to be important factors in determining fruit quality and sensory cues for the nutritional composition of plant products. Due to its unique properties, ZBM peel can facilitate the percutaneous absorption of active components in a prescription, and its function is mainly derived from its essential oil (EO). According to the literature reports, EO extracted from ZBM by hydrodistillation or supercritical fluid CO₂ extraction has antimicrobial, antioxidant, and insect repellent and feeding deterrent properties.^11,12

Up to now, more than 114 constituents of volatile oil have been identified by gas chromatography-mass spectrometry method, which mainly consisted of high contents of alcohols and olefins (1-114).¹ The corresponding structures of volatile organic compounds are comprehensively presented (Figures 1-4).

Amide Compounds

Alkylamides, as the characteristic compounds in ZBM, are a series of long-chain unsaturated fatty acid amides with a strong numbing sensation and unique taste in the mouth. The content of alkylamides is an important index to evaluate the quality of ZBM. Previous studies showed that 34 kinds of alkylamides were found, as shown in Figures 5 to 7, mainly including hydroxy-α-sanshool (HAS) (115), hydroxy-β-sanshool (HBS) (116), and hydroxy-γ-sanshool (HRS) (117).^1,13,14

Among the alkylamides, HAS, extensively existed in the peel of ZBM fruit, is the ingredient related to the unique tingling, buzzing sensations, and anesthetic properties.^15,16 When the human tongue touches HAS (115) (25-50 μg) directly, the tingling sensation caused by HAS (115) lasts for several minutes.¹⁷

Flavonoids

As we all know that flavonoids, generally found in many foods and herbs, have many specific effects used as nutraceuticals.¹⁸ Flavonoids are secondary metabolites with strong biological activities produced by plants in the process of long-term ecological adaptation.^19,20 The modification of flavonoids, such as glycosylation and methylation, greatly enriched the derivatives varieties and also improved the stability of these substances in plants.^21,22 Based on their structural differences, flavonoids are generally divided into 9 main types, including chalcones, flavonoids, flavonols, dihydro-flavonoids, flavanols, flavonoid glycosides, isoflavones, proanthocyanin and anthocyanins.^23-25

Zanthoxylum bungeanum Maxim is a flavonoid-rich wild plant. It has been reported that more than 40 different flavonoids have been isolated and identified from ZBM. Figures 8 and 9 present the structures of some common flavonoids in ZBM. Moreover, rutin (151) and quercetin (153) are found to be the most abundant and bioactive flavonoids in ZBM peels.^5,6,8,26

Alkaloids

Alkaloids exist widely in plants, exhibiting various physiological activities such as antirheumatism, anti-inflammatory, analgesic, adiabatic, and antidepressant.^27,28 Zanthoxylum species generally contain alkaloids, divided into 4 classes according to their parent nucleus: Quinoline derivatives(I), Isoquinoline derivatives(II), Benzophyridine derivatives(III), and Quinolone derivatives(IV). These alkaloids may exist either in the free-floating state or in the form of quaternary salts.²⁹ Schinifoline (168) is the first 4-quinolinone alkaloid identified from ZBM.³⁰ These alkaloids (168-188) are summarized in Figure 10.

Coumarins

Coumarins are the lactones of o-hydroxycinnamic acid and have an aromatic smell. The parent nucleus of coumarins include simple coumarins, furan coumarins, and pyran coumarins.³¹ Coumarins in ZBM contain bergapten (192) and herniarin(7-methoxylcoumarin) (191) identified by Ultra-high performance liquid chromatography tandem quadrupole time-of-flight secondary mass spectrometry (UPLC-Q-TOF-MS).^32-34 Figure 11 shows the structure of the main coumarins component of ZBM.

Lignans

Lignans are mainly clustered by bimolecular phenylpropanoid derivatives.³⁵ The molecules of lignans contain multiple asymmetric carbon atoms, which are prone to isomerization in the case of acid and alkali. The bioactivity of lignans varies with different structures.³⁶ Zanthoxylum lignans usually exist in the free state, and very few exist in the form of glycosides. The lignans in ZBM are mostly asarinin (195), eudesmin (193), sesamin (194), fargesin (196), and so on.³⁷ The lignans in ZBM have anticancer, insecticidal, cathartic, and muscle relaxation effects.³⁵ The identified compounds are listed, and the corresponding structures are also comprehensively presented (Figure 12).

Phenylpropanoids

Natural ingredients have a class of benzene ring and 3 linear carbon linked together as a unit of compounds, collectively known as phenylpropanoids. So far, neochlorogenic acid (197) and chlorogenic acid (198) have been isolated from ZBM. Their structures are shown in Figure 13.

Biological Activities of ZBM

Zanthoxylum bungeanum Maxim, as an important Chinese herb, has a wide range of clinical applications. It has been recognized to possess anti-inflammatory and analgesic effect, anesthetic effect, neuroprotective effect, antiobesity and antidiabetic effect, antineoplastic activity, and antibacterial and antioxidant activities. For the past few years, its pharmacological effects mainly focus on anti-inflammatory, analgesic, and anesthetic effect.

Anti-Inflammatory and Analgesic Effect

It is commonly acknowledged that the anti-inflammatory properties of ZBM, particularly EO, have been extensively reported. Further mechanism analysis showed that the EO of ZBM inhibited inflammation through regulating nuclear factor kappa-B (NF-κB) and peroxisome proliferator-activated receptor (PPAR) γ pathways.³⁸ In studies,³⁹ EO extract and dichloromethane extract of ZBM could decrease ear swelling caused by xylene, paw swelling caused by carrageenan, the number of writhing responses induced by acetic acid, and the licking foot time of phase Ⅱ induced by formalin in mice. Western blot results indicated that high doses of EO extract and dichloromethane extract from ZBM could inhibit the expressions of phosphatidylinositol 3-kinase catalytic subunit gamma isoform (PIK3CG), phosphonated NF-κB (p-NF-κB), and phosphonated p38 (p-p38 MAPK) protein.³⁹ Meanwhile, Ha et al also identified that all 3 doses of volatile oil groups (16, 48, 144 mg/kg) significantly inhibited the writhing and ear swelling in mice (P < .05).⁴⁰ Bian et al found that the EO parts of ZBM can resist the increase of writhing body times induced by glacial acetic acid, indicating a significant anti-inflammatory and analgesic activity.⁴¹ Moreover, Zanthoxyli Pericarpium extract may regulate the immune system through PPAR and Th17 cell differentiation signaling pathways to exert its middle-warming and pain-alleviating effect, with hydroxy-sanshool components used as Q-Marker for the effect of ZBM.⁴² Signaling pathways involved in anti-inflammatory mechanisms of ZBM are shown in Figure 14.

Figure 14.

Signaling pathways involved in anti-inflammatory mechanisms of Zanthoxylum bungeanum Maxim (ZBM).

Through the study on the mechanism of ZBM for treating pain, its pain relief function in the practice of traditional medicine was verified with network pharmacology and molecular docking. Amide alkaloids are important substance bases, and ZBM is more suitable for treating inflammatory pain, such as bone fracture, muscle injury, and urgent intestinal contracture.⁴³ Li et al suggested that ZBM is a “multi-component, multi-target and multi-pathway” synergistic treatment of allergic conjunctivitis, which plays the role of inhibiting inflammatory response and regulating immunity.⁴⁴ Zanthoxylum bungeanum Maxim may act on interleukin 6 (IL-6), tumor necrosis factor-alpha, vascular endothelial growth factor, protein kinase B (AKT) 1, and other key targets and regulate inflammatory immune processes through the AGE-RAGE, IL-17, and NF-κB signaling pathway. In addition, Ma et al also showed that ZBM regulates the expression of factors related to IκB-α/IKK-β/NF-κB signaling pathway in stable mast cell degranulation, so as to play a part in the treatment of allergic conjunctivitis.⁴⁵

Anesthetic Effect

Zanthoxylum bungeanum Maxim pericarp is rich in numbness flavor produced by long-chain unsaturated alkylamides (115-148), with sanshool（including α-, β-, γ-, and δ-sanshool, and their derivatives) as main active constituents, which cause numbness and analgesia during treatment of toothache.^46-48 Li et al⁴⁹ found that the extraction site of water reflux has a strong anesthetic effect on the isolated sciatic nerve of mice by altering the amplitude of action potentials. Meanwhile, Bian et al⁵⁰ also demonstrated that the ethyl ether extract of different prepared products of ZBM had infiltration anesthetic effect, and the vinegar product has a significantly anesthetic effect, comparable to the positive control lidocaine hydrochloride. Behavioral assays and nerve fiber recordings were used to assess the numbing analgesia effect of HAS (115) by Makoto et al.⁵¹ They investigated that sanshool inhibits Aδ mechanosensory nociceptors and the activity of multiple voltage-gated sodium channel subtypes playing an important role in anesthetic effect.

Shen et al⁵² investigated the analgesic activity of Zanthoxylum-made oil for acute injury on the early model of tibiofibular middle segment closed fracture in Sprague-Dawley (SD) rats, with mechanical pain threshold, thermal pain threshold, 5-hydroxytryptamine (5-HT), transient receptor potential vanilloid 1 (TRPV1), and protein kinase D1 (PKD1) as target system. The analgesic mechanism for external application of Zanthoxylum-made oil for acute injury in the treatment of early closed fracture in rats may be through the 5-HT-phospholipase Cβ–protein kinase Cε pathway, which reduces the secretion of 5-HT by platelets and inhibits the gene expression of TRPV1 and PKD1 mRNA in dorsal root nerve nodules.

In addition, psychophysical experiments with regard to tactile frequency perception were used to assess how chemoreceptor events could connect with the tingling somatosensory experience. Hagura et al investigated the tingling sensation in humans to recognize the characteristic temporal frequency and made a contrast with the established selectivity of tactile afferents.⁵³ It is concluded that the specific reason for its anesthesia is that it plays the role of activating nerve fibers, which are mainly used for tactile afferents.

Effect on the Nervous System

Liu et al⁵⁴ conducted experiments of Morris water maze test (MWM) to comprehensively evaluate the effect of HAS (115) on the nervous system. The experiment results of MWM indicated that HAS markedly enhanced the spatial learning and memory ability of aged mice. The neuroprotective mechanisms of HAS (115) were relevant to the inhibition of oxidative stress and apoptosis by regulating Nrf2/heme oxygenase-1 (HO-1) signaling pathways. Meanwhile, Zhang et al⁵⁵ provided the basis that HAS (115) alleviated attenuated scopolamine-induced cognitive impairments mainly by enhancing the activity of the cholinergic system and protein expression of brain-derived neurotrophic factor. After intragastric administration of HAS (115), some changes of mice in hippocampal neuronal morphology and apptosis were prevented, inhibiting acetylcholinesterase activity and increasing the acetylcholine content, compared with those in the model group (P < .05). Moreover, Li et al⁵⁶ studied the neuroprotective effect of HAS (115) and its relevant mechanisms. It is found that HAS (115) could decrease the H₂O₂-induced cell apoptosis via an increase of mitochondrial membrane potential and reduction of intracellular reactive oxygen species.

It is reported that Zanthoxylum eliminates depression-like behaviors induced by lipopolysaccharide (LPS) in mice by regulating neuroinflammation in the hippocampus.⁵⁷ Tail suspension test, forced swimming test, and sucrose preference test were indicated that Zanthoxylum extract relieved the depressive symptoms induced by LPS in mice. Moreover, treatments of these extract reversed the LPS-induced changes of 5-HT in mice, inhibiting the expression of pro-inflammatory cytokines. A series of researches demonstrated that ZBM hold obvious antidepressant effects.^58,59 Modern network pharmacology provided a new design idea and approach for further study about the mechanism of ZBM for treating depression, by analyzing the characteristics of multicomponent, multitarget, and multipathway.⁶⁰ These results suggested that the extract of ZBM has the potential to be developed as antidepression drug for the prevention and the therapy of Alzheimer's disease (AD).

Antiobesity and Antidiabetic Effect

A series of pharmacological researches demonstrated that ZBM has antiobesity properties.⁶¹ Some constituents occurring in ZBM, for example, quercetin (153),⁶² rutin (151),⁶³ and HAS (115)⁶⁴ have been mentioned to exhibit antiobesity effects. A great quantity of experiments reported that the abdominal adipose tissues and liver adipocytes of high-fat diet (HFD) treated rats were decreased after 4 weeks of HAS (115) treatment. Moreover, HAS (115) treatment remarkably reduce the total cholesterol, low-density lipoprotein cholesterol, and triglycerides. However, high-density lipoprotein cholesterol in serum of HFD rats can be increased. HAS (115) treatment increased the glutathione extent and superoxide dismutase activity in the liver, nevertheless, it decreased the extent of malondialdehyde in HFD rats by improving the expression of proliferator-activated receptor γ and peroxisome apolipoprotein E.⁶⁴ An experiment proved that dietary supplement of sanshoamides intervened lipid metabolism in mice and increased histological characteristics of fatty liver, by downregulating mRNA expression levels of cholesterol 7-alpha-hydroxylase and 3-hydroxyl-3-methylglutary CoA.⁶⁵ Wang et al⁶⁶ investigated that ZBM possesses antiobesity effects through the network pharmacology. The apoptotic effects of ZBM are further validated in HFD-induced obesity mice, suggesting ZBM can be developed into potential antiobesity therapeutic drug. The summary of the activities is shown in Table 1.

Table 1.

Antiobesity Activity of ZBM and its Main Compounds.

In vitro	In vivo	Compound	Observed effects	Refs.
	Obese mice	Ethanol extract	↓ Lipid accumulation	61
			↓Weight gain
			↓White adipose tissue mass
			↓Serum triglyceride and cholesterol levels
3T3-L1 adipocyte		Ethanol extract	↓Transcription factors (PPARγ, C/EBPα and SREBP-1)	61
	Male C57BL/6 mice	Quercetin	↑Mitochondrial biogenesis	62
			↑Oxidative metabolism
			↑HO-1
			↑Nuclear erythroid related factor 2 (Nrf-2)
	Obesity mice	Rutin	↑Whole-body energy metabolism	63
			↑Brown adipose tissue (BAT) activity
			↑Deacetylase activity
			Activates the SIRT1/PGC1α/Τ signaling pathway
	Hyperlipidemic rats	HAS	↓T-CHO	64
			↓TG
			↓ LDL-C
			↑HDL-C
	Female SD rats	Sanshoamides	↓ Lipid levels	65
	Female SD rats	Sanshoamides	↓mRNA expression levels (CYP7A1, HMG-CoA and FXR)	65
	Obesity mouse	Ethanol extract	Induced apoptosis in adipocytes	66
	Obesity mouse	Ethanol extract	↓Body weight	66
3T3-L1 cells		ZBM	Induces apoptosis in 3T3-L1 cells	66

In 2018, Fiaz et al found that the extracts of fruit, bark, and leaf from ZBM indicated significant antidiabetic activity in vitro and in vivo. α-glucosidase (α-Glu) enzyme plays an important role in the degradation of carbohydrates. In an in-vitro research, the extracts from ZBM showed significant suppression of α-Glu enzyme, with percentage inhibition of 83.76 ± 3.01%.⁶⁷deriment, Zanthoxylum extract significantly reduced blood glucose levels in both normal mice and diabetic mice (P < .05) with a dose of 500 mg/kg. In 2021, Zhang also reported that 4 phenols and HAS (115), recognized as main ingredients, presented an antagonistic effect in the inhibition of α-Glu, verified by principal component analysis and component recombination models.⁶⁸ In 2019, it was reported that tambulin, a compound isolated from Zanthoxylum, produced powerful insulin-activating effect. Tambulin promotes the secretion of insulin dependent on Ca²⁺ channels, by activating the cAMP-PKA pathway.⁶⁹ Essential oils of ZBM were analyzed for their phytochemical profiles and biological activities, including antidiabetes. Remarkably, EOs from ZBM (IC50 = 0.73 mg/mL) showed a stronger anti-α-Glu ability than acarbose (IC50 = 2.69 mg/mL), a known antidiabetic agent.⁷⁰ The summary of the activities is shown in Table 2.

Table 2.

Antiobesity Activity of ZBM and its Main Compounds.

In vitro	In vivo	Compound	Observed effects	Refs.
α-glucosidase enzyme		Leaves and bark extracts	Inhibit α-glucosidase enzyme	67
	Diabetic mice	Leaves extract	↓LDL level	67
	Diabetic mice	Leaves extract	↓Fasting blood glucose levels	67
α-glucosidase enzyme		Phenols and HAS	Inhibit α-glucosidase enzyme	68
Islets and MIN6 cells		Tambulin	Induce insulin secretion	69
α-glucosidase enzyme		Essential oils	Inhibit α-glucosidase enzyme	70

Zhang et al used network pharmacology in conjunction with experimental validation to investigate the potential mechanisms of freeze-dried ZBM powder's beneficial effects in the management of type 2 diabetes mellitus (T2DM).⁷¹ The drug component-target network indicated that 39 differentially expressed overlapping genes were screened as the possible targets of ZBM in T2DM. In vitro experiments further confirmed that ZBM significantly inhibited palmitic acid-induced lipid formation in HepG2 cells, through promoting the phosphatidylinositol-3-kinase (PI3 K)/Akt and the adenosine monophosphate-activated protein kinase expressions in HepG2 cells.

Antineoplastic Activity

In vivo and in vitro experiments indicated that ZBM has an anticancer activity. In a study, the results showed that Zanthoxylum bungeanum seed oil (ZBSO) can significantly inhibit the activities of Hep-2 cells with dose- and time dependency, which facilitated cell apoptosis and suppressed cell proliferation.⁷² Further studies showed that the significant reduction of phosphorylation with PI3 K/AKT/mTOR pathway was related to ZBSO-induced autophagy and apoptosis. Moreover, ZBSO demonstrated the selective toxicity on the invasion and proliferation of cancer A375 cells, in comparison with normal human epiderma keratinocyte cells by G1 phase arrest and induction of apoptosis.⁷ In a study by Fu et al,⁷³ the results indicated that all obtained alkaloids from the roots of Zanthoxylum expressed significant antiproliferative activities against diverse human cancer cell lines with IC50 values from 0.85 ± 0.06 to 29.56 ± 0.17 µM, which is equivalent to the positive control (cisplatin) showing IC50 values ranging from 1.58 ± 0.09 to 28.69 ± 0.21 µM. Another experiment investigated that treatment with Zanthoxylum armatum bark (MeZb) restored the altered mRNA and protein expression of Nrf2 and Keap1 in mammary carcinoma-bearing SD rats, certifying the anticancer activity of MeZb and postulating it as a functional food to treat mammary carcinoma.⁷⁴ Besides, a report provides evidence that sanshools induced human colorectal cancer cell apoptosis by upregulating P53 and Caspase 8. Cells were exposed to different concentrations (0, 50, 90, or 130 µM) of sanshools to evaluate apoptosis and cell cycle arrest.⁷⁵ Sanshools profoundly suppressed growth of HCT-116 cells in dose- and time-dependent manners. The anticancer activity and possible mechanisms of ZBM are shown in Figure 15.

Figure 15.

The anticancer activity and possible mechanisms of Zanthoxylum bungeanum Maxim (ZBM).

Antibacterial and Antioxidant

Drug-resistant bacteria have emerged because of the abuse of antibiotics. Natural medicinal plants have a wide range of bacteriostatic effects, with rarely suffering from resistance issues. In 2020, Li et al reported that Z bungeanum peels had significant effective activity against Gram-positive bacteria, including Escherichia coli, Pseudomonas aeruginosa, and Salmonella enteritidis, with minimum inhibitory concentration (MIC) values of 2.5 mg/mL and 5 mg/mL, respectively.⁶ Later, a study revealed that ZBSO showed strong antibacterial activity against Aspergillus flavus, with an MIC value of 0.8 µL/mL.⁷⁶ Zanthoxylum bungeanum seed oil has attracted significant interest as a potential antibacterial agent and is generally considered safety. Therefore, they have been applied as biopreservatives and widely used as food flavors.⁷⁷

The antioxidant activity of ZBM is one of the major reasons for its use. Ma et al reported that most flavanones contents show the highest antioxidant power based on DPPH and β-carotene bleaching assays.⁷⁸ Free radicals are one of the most important contributors for many diseases, such as tissue-specific inflammations, thrombosis, and carcinogenesis. Deng et al reported that about 20 compounds such as rutin (151), quercitrin (149), and chlorogenic acid (198) from Zanthoxylum plants have been chemically or biochemically proved effective in eradicating free radicals.⁷⁹ Also, red pigment is present in ZBM, showing a strong scavenging activity on DPPH radical.⁸⁰ According to Cao et al, July and August ZBM have highest antioxidant capacity, attributing this activity to flavonoid and phenolic acids.⁸¹

Others

In addition to the abovementioned activities, ZBM also has antiosteoporosis activity, antidiarrheal activity, immunomodulatory activity, therapeutic effects on diseases induced by oxidative stress (DOS), and other activities. Zanthoxylum bungeanum seed oil, as a promising agent for antibone loss, exhibited an inhibitory effect on osteoclastogenesis via suppressing the ERK/c-JUN/NFATc1 pathway and regulating cell cycle arrest through receptor-activator of NF-κB ligand.⁸²

In a study, experimental result demonstrated that the extracts (fruit, bark, and leaf) of Zanthoxylum have antidiarrheal activity in vivo and spasmolytic effect with feasible mechanism through the blockage of Ca²⁺ channels.⁸³ Another experiment investigated that Zanthoxylum therapy improved the viability and inflammatory cytokine production of spleen cells.⁸⁴ A series of researchers have found that ZBM possess therapeutic effects on diseases induced by DOS, such as atherosclerosis and diabetes complication. Zhao et al studied the action principle of ZBM in the therapy of DOS by network pharmacology and molecular docking methods.⁸⁵

Pharmacokinetics Studies

Pharmacokinetic studies of the active components will clarify their mechanisms of action and improve development of the quality in Chinese medicine. The major ingredients of ZBM are HAS (115), HBS (116), HRS (117), and xanthotoxin (XAT) (190). Therefore, the pharmacokinetic studies concentrated on these compounds with high content and specific pharmacological activity.

The plasma concentration of HAS (115) reached the maximum concentration (C_max) within 30 min after single oral administration to healthy volunteers. Its median half-life (T_1/2) was 1.6 to 1.7 h, indicating its rapid absorption and elimination. The plasma concentration of HBS exhibited a pattern parallel to the plasma concentration of the HAS (115).⁸⁶ Rong et al performed a comparative pharmacokinetic study of HAS (115), HBS (116), and HRS (117) in rat plasma after the subcutaneous and intravenous administration of the extract of ZBM by HPLC-MS. The study showed that HAS (115), HBS (116), and HRS (117) were remarkably absorbed following subcutaneous administration of ZBM extract and the time to peak (T_max) was approximately within 1 h. These compounds were eliminated, displaying an elimination T_1/2 with not exceeding 2.5 h. The bioavailability of HAS (115), HBS (116), and HRS (117) by subcutaneous injection were 100.2%, 76.2%, and 90.3%, respectively.⁸⁷ It has been reported that oral absorption rate of XAT (190) is very low, and the absolute bioavailability of XAT (190) in rat plasma after oral administration is less than 1%. They measured the concentration of XAT (190) in plasma by UPLC-MS and found that XAT(190) was rapidly absorbed after oral administration of XAT (190), with T_max of about 55 min and T_1/2 of about 90 min.⁸⁸

Conclusions and Future Perspectives

Medicinal plants are widely used in traditional and modern medicine and their associated pharmaceutical systems. Zanthoxylum bungeanum Maxim, especially as a flavoring agent, has been widely used as an ingredient in the food industry. Also, due to its wide range of therapeutic characteristics, ZBM has been utilized as a traditional herbal medicine. This review has provided an overall view about the chemical constituents, pharmacological properties, and pharmacokinetics of ZBM. In recent years, ZBM has been proven to have a variety of pharmacological activities, for instance, anti-inflammatory activity, antiobesity activity, antidiabetic activity, antibacterial activity, analgesic effect, immunomodulatory effects, anesthetic effect, neuroprotective effects, and so on. At present, more than 198 compounds have been isolated. Among them, amide compounds and volatile oil are primary bioactive constituents. However, only compounds absorbed by the body can exert an effect. Consequently, it is important to comprehensively investigate bioactive compounds, serum pharmacology, and serum pharmaco-chemistry characteristics of ZBM in the near future.

Footnotes

Authors’ Contribution

Design of the work: Han Yan, Ting Wang; drawing chemical structure: Fen Zhou; literature review for pharmacological aspects: Han Yan, Ying Liu; literature review for pharmacological aspects: Han Yan; data collection: Han Yan, Jing Wang; analysis and interpretation of the data: Han Yan, Huan Xu; drafting the manuscript: Han Yan, Jingmin Zhang; critical revision of the manuscript: Han Yan, Shujuan Jiang, Daogang Qin.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Traditional Chinese Medicine Science and Technology Project of Shandong Province (202006010083, 2021Q009). Traditional Chinese Medicine Science and Technology Project of Shandong Province, (grant number 2021Q009).

ORCID iDs

Ying Liu

Ting Wang

References

Zhang

Tan

, et al. Comparison of volatile components in fresh and dried Zanthoxylum bungeanum Maxim. Food Sci Biotechnol. 2019;28(4):1083-1092.

Zhuo

Wang

. Predicting distribution of Zanthoxylum bungeanum Maxim. in China. BMC Ecol. 2020;20(1):46.

Lin

Han

Yuan

. Chemical composition of the volatile oil from Zanthoxylum avicennae and antimicrobial activities and cytotoxicity. Pharmacogn Mag. 2014;10(1):S164-S170. doi:10.4103/0973-1296.127369

Okagu

Ndefo

Aham

Udenigwe

. Zanthoxylum species: a review of traditional uses, phytochemistry and pharmacology in relation to cancer, infectious diseases and sickle cell anemia. Front Pharmacol. 2021;12:713090.

Zhang

Wang

Zhu

, et al. Zanthoxylum bungeanum Maxim. (Rutaceae): a systematic review of its traditional uses, botany, phytochemistry, pharmacology, pharmacokinetics, and toxicology. Int J Mol Sci. 2017;18(10):2172.

Pan

, et al. Quality evaluation of different varieties of Zanthoxylum bungeanum Maxim. peels based on phenolic profiles, bioactivity, and HPLC fingerprint. J Food Sci. 2020;85(4):1090-1097.

Pang

Liu

, et al. Anticancer activities of Zanthoxylum bungeanum seed oil on malignant melanoma. J Ethnopharmacol. 2019;229:180-189.

Yang

Tan

Jiang

. Polyphenolics composition of the leaves of Zanthoxylum bungeanum Maxim. grown in Hebei, China, and their radical scavenging activities. J Agric Food Chem. 2013;61(8):1772-1778.

You

Sun

Suo

. Compositional and antioxidant activity analysis of Zanthoxylum bungeanum seed oil obtained by supercritical CO2 fluid extraction. J Am Chem Soc. 2011;88:23-32.

10.

Lan

Chen

, et al. Essential oil from Zanthoxylum bungeanum Maxim. and its main components used as transdermal penetration enhancers: a comparative study. J Zhejiang Univ Sci B. 2014;15(11):940-952.

11.

Zhang

Guo

Wang

, et al. Correction: protective mechanisms of Zanthoxylum bungeanum essential oil on DSS-induced ulcerative colitis in mice based on a colonic mucosal transcriptomic approach. Food Funct. 2023;14(3):1795.

12.

Wang

Zhang

Chen

. Effect of pepper (Zanthoxylum bungeanum Maxim.) essential oil on quality changes in rabbit meat patty during chilled storage. J Food Sci Technol. 2022;59(1):179-191.

13.

Kasimu

Sun

Zheng

Wang

. Development of (1) H-NMR methods for quantitative determination of alkylamides in Zanthoxylum bungeanum and quality evaluation based on its fingerprint. J Food Sci. 2021;86(9):3951-3963.

14.

Yang

Zhang

Sun

. Studies on the preparation of biodiesel from Zanthoxylum bungeanum Maxim seed oil. J Agric Food Chem. 2008;56:7891-7896.

15.

Yang

. Aroma constituents and alkylamides of red and green huajiao (Zanthoxylum bungeanum and Zanthoxylum schinifolium). J Agric Food Chem. 2008;56(17):1689-1696.

16.

Bautista

Sigal

Milstein

, et al. Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat Neurosci. 2008;11(7):772-779.

17.

Bryant

Mezine

. Alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons. Brain Res. 1999;842(2):452-460.

18.

Mattila

Hellstrom

Karhu

Pihlava

Vetelainen

. High variability in flavonoid contents and composition between different north-European currant (Ribes spp.) varieties. Food Chem. 2016;204:14-20.

19.

Chen

Xie

, et al. Integrated metabolomics and transcriptomics analyses reveal the molecular mechanisms underlying the accumulation of anthocyanins and other flavonoids in cowpea pod (Vigna unguiculata L.). J Agric Food Chem. 2020;68(34):9260-9275.

20.

Liu

Leng

Liu

, et al. Identification and quantification of target metabolites combined with transcriptome of two rheum species focused on anthraquinone and flavonoids biosynthesis. Sci Rep. 2020;10(1):20241.

21.

Zeka

Ruparelia

Arroo

RRJ

Budriesi

Micucci

. Flavonoids and their metabolites: prevention in cardiovascular diseases and diabetes. Diseases. 2017;5(3):1-18. doi:10.3390/diseases5030019

22.

Ebegboni

Dickenson

Sivasubramaniam

. Antioxidative effects of flavonoids and their metabolites against hypoxia/reoxygenation-induced oxidative stress in a human first trimester trophoblast cell line. Food Chem. 2019;272:117-125.

23.

Chu

, et al. Dynamics of antioxidant activities, metabolites, phenolic acids, flavonoids, and phenolic biosynthetic genes in germinating Chinese wild rice (Zizania latifolia). Food Chem. 2020;318:126483.

24.

Qian

Shang

, et al. UPLC-Q-TOF/MS-based screening and identification of the main flavonoids and their metabolites in rat bile, urine and feces after oral administration of Scutellaria baicalensis extract. J Ethnopharmacol. 2015;169:156-162.

25.

Bennett

Mellon

Rosa

Perkins

Kroon

. Profiling glucosinolates, flavonoids, alkaloids, and other secondary metabolites in tissues of Azima tetracantha L. (Salvadoraceae). J Agric Food Chem. 2004;52(19):5856-5862.

26.

Zhang

Wang

Yang

Zhou

Zhang

. Purification and characterization of flavonoids from the leaves of Zanthoxylum bungeanum and correlation between their structure and antioxidant activity. PLoS One. 2014;9(8):e105725.

27.

Bai

Peng

, et al. Simple quantitative analytical methods for the determination of alkaloids from medicinal and edible plant foods using a homemade chromatographic monolithic column. J Chromatogr B. 2019;1128:121784.

28.

Tan

Sharma

SSA

. Phyto-Carbazole alkaloids from the Rutaceae family as potential protective agents against neurodegenerative diseases. Antioxidants. 2022:11.

29.

Sun

Duan

. Research progress on medicinal plants of Zanthoxylum SPP. Acta Pharm. 1996:231-240.

30.

Liu

Wei

Wang

Gao

. Study on chemical constituents of green prickly ash. Acta Pharm Sin B. 1991;26(11):836-840.

31.

Tine

Renucci

Costa

Wele

Paolini

. A method for LC-MS/MS profiling of coumarins in Zanthoxylum zanthoxyloides (Lam.) B. Zepernich and timler extracts and essential oils. Molecules. 2017;22(1):174.

32.

Cheng

Luo

Shen

Zhang

. Identification of two bitter components in Zanthoxylum bungeanum Maxim. and exploration of their bitter taste mechanism through receptor hTAS2R14. Food Chem. 2021;338:127816.

33.

Yang

Mei

Wang

, et al. Comprehensive identification of non-volatile bitter-tasting compounds in Zanthoxylum bungeanum Maxim. by untargeted metabolomics combined with sensory-guided fractionation technique. Food Chem. 2021;347:129085.

34.

Zhang

Yang

Chen

Zhu

. Research progress on chemical constituents of Zanthoxyli pericarpium and its prevention and treatment of nervous and mental diseases. Nat Prod Res Dev. 2021;33:1969-1981.

35.

Zhou

Shi

Chen

Kang

Liang

. Research progress of the medicinal value of Zanthoxylum bungeanum Maxim. Farm Products Process. 2020(1):65-72.

36.

Dou

. Analysis of Components and Insecticidal Activity of Prickly Ash. Wuhan Polytechnic University; 2015.

37.

Hou

Hong

Zhu

. Extracts of Zanthoxylum bungeanum regulate cholesterol accumulation induced by sterols and LPS in vitro and in vivo. J Chin Pharm Sci. 2012;21(6):582-590. doi:10.5246/jcps.2012.06.074

38.

Zhang

Shen

Liu

, et al. In Vivo study of the efficacy of the essential oil of Zanthoxylum bungeanum Pericarp in dextran sulfate sodium-induced murine experimental colitis. J Agric Food Chem. 2017;65(16):3311-3319.

39.

Wei

Zong

Zeng

, et al. Network pharmacological analysis and experimental verification of anti-inflammatory and analgesic effect of Zanthoxyli pericarpium. China J Chin Mater Med. 2021;46(12):3034-3042.

40.

Yang

Yin

Gong

. Extraction process optimization of volatile oil from Zanthoxylum Armatum DC. and study of analgesic and anti-inflammatory activity. Pharmacol Clin Chin Med. 2021;37(03):127-132.

41.

Bian

Niu

, et al. Anti - inflammatory and analgesic effects of volatile oil from Zanthoxylum bungeanum Maxim before and after processing by stir frying in mice. Chin J Clin Pharmacol. 2019;35(04):369-376.

42.

Zhang

Wang

Wei

, et al. Study on quality markers of Zanthoxyli pericarpium on warming middle energizer to alleviate pain based on serum medicinal chemistry. Chin Tradit Herb Drugs. 2022;53(09):2731-2739.

43.

Zhou

, et al. Network pharmacology-based analysis of the underlying mechanism of huajiao for pain relief. J Evid Based Complement Altern Med. 2021:5526132.

44.

Qin

Wang

Song

. On the mechanism of chuanjiao prescription in treating allergic conjunctivitis based on network pharmacology. J Tradit Chin Ophthalmol. 2021;31(03):224-232.

45.

. Study on the Mechanism of Chuanjiao Recipe in the Treatment of Allergic Conjunctivitis Based on IKK/IκB/NF-κB Signaling Pathway. China Academy of Chinese Medical Science; 2019.

46.

Chen

Jin

Chen

Kan

. Preparation and characterization of molecularly-imprinted polymers for extraction of sanshool acid amide compounds followed by their separation from pepper oil resin derived from Chinese prickly ash (Zanthoxylum bungeanum). J Sep Sci. 2018;41(2):590-601.

47.

Tan

Liu

, et al. Design of hydroxy-alpha-sanshool loaded nanostructured lipid carriers as a potential local anesthetic. Drug Delivery. 2022;29(1):743-753.

48.

Zhang

Zhou

Yan

Liu

. Surfactant-assisted enzymatic extraction of the flavor compounds from Zanthoxylum bungeanum. Sep Sci Technol. 2019;55(9):1667-1676.

49.

Zhang

Bian

, et al. Study on conduction anesthesia of water extract from different processed products of Zanthoxylum bungeanum. Chin J Clin Pharmacol. 2021(06):727-744. -

50.

Bian

Niu

, et al. Local anesthetic effect and composition analysis of ether extracts of differently processed products of Zanthoxylum bungeanum. Chin J New Drugs. 2021;30(3):274-279.

51.

Tsunozaki

Lennertz

Vilceanu

Katta

Stucky

Bautista

. A ‘toothache tree’ alkylamide inhibits adelta mechanonociceptors to alleviate mechanical pain. J Physiol. 2013;591(13):3325-3340.

52.

Shen

. Study on Analgesic Mechanism of External Application of Xinjang Oil in Treatment of Rat Closed Fracture Based on TRPV1 Pathway. Chengdu Physical Education University; 2020.

53.

Hagura

Barber

Haggard

. Food vibrations: Asian spice sets lips trembling. Proc Biol Sci. 2013;280(1770):20131680.

54.

Liu

Meng

Sun

, et al. Protective effects of hydroxy-alpha-sanshool from the pericarp of Zanthoxylum bungeanum Maxim. on D-galactose/AlCl(3)-induced Alzheimer's disease-like mice via Nrf2/HO-1 signaling pathways. Eur J Pharmacol. 2022;914:174691.

55.

Zhang

Xie

Wei

, et al. Hydroxy-alpha-sanshool isolated from Zanthoxylum bungeanum attenuates learning and memory impairments in scopolamine-treated mice. Food Funct. 2019;10(11):7315-7324.

56.

Zhang

Liu

, et al. Hydroxy-alpha-sanshool possesses protective potentials on H(2)O(2)-stimulated PC12 cells by suppression of oxidative stress-induced apoptosis through regulation of PI3 K/Akt signal pathway. Oxid Med Cell Longev. 2020;2020:3481758.

57.

Barua

Haloi

Saikia

, et al. Zanthoxylum alatum abrogates lipopolysaccharide-induced depression-like behaviours in mice by modulating neuroinflammation and monoamine neurotransmitters in the hippocampus. Pharm Biol. 2018;56(1):245-252.

58.

Tan

Xie

, et al. Antidepressant effects of extracts from Zanthoxylum bungeanum and Zanthoxylum schinifolium in mice exposed to chronic restraint stress. Acta Univ Med Anhui. 2022;57(04):593-598.

59.

Chen

Yang

Huang

, et al. Determination of total flavone content in Zanthoxylum residue and study on its antidepressant effect. Pharm Clin Chin Mater Med. 2022;13(03):73-77.

60.

Wei

Chen

Zeng

, et al. Mechanism of Zanthoxylum bungeanum Maxim. intreatment of depression based on network pharmacology. J Med Forum. 2022;43(03):9-15.

61.

Gwon

Ahn

Kim

. Zanthoxylum piperitum DC ethanol extract suppresses fat accumulation in adipocytes and high fat diet-induced obese mice by regulating adipogenesis. J Nutr Sci Vitaminol. 2012;58(6):393-401.

62.

Kim

Kwon

Choe

, et al. Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1. Nutr Metab (Lond). 2015;12:33.

63.

Yuan

Wei

You

, et al. Rutin ameliorates obesity through brown fat activation. FASEB J. 2017;31(1):333-345.

64.

Wang

Fan

Zhang

, et al. Antiobesity, regulation of lipid metabolism, and attenuation of liver oxidative stress effects of hydroxy-alpha-sanshool isolated from Zanthoxylum bungeanum on high-fat diet-induced hyperlipidemic rats. Oxid Med Cell Longev. 2019;2019:5852494. doi:10.1155/2019/5852494

65.

Chen

Liu

Wang

Chen

Liu

. Effects of sanshoamides and capsaicinoids on plasma and liver lipid metabolism in hyperlipidemic rats. Food Sci Biotechnol. 2019;28(2):519-528.

66.

Wang

Yang

Zhong

, et al. Network pharmacology-based strategy for the investigation of the anti-obesity effects of an ethanolic extract of Zanthoxylum bungeanum Maxim. Front Pharmacol. 2020;11:572387.

67.

Alam

Saqib

Ashraf

. Zanthoxylum armatum DC extracts from fruit, bark and leaf induce hypolipidemic and hypoglycemic effects in mice- in vivo and in vitro study. BMC Complement Altern Med. 2018;18(1):68.

68.

Zhang

Liu

Yang

, et al. Interactions between phenols and alkylamides of sichuan pepper (Zanthoxylum Genus) in alpha-glucosidase inhibition: a structural mechanism analysis. J Agric Food Chem. 2021;69(20):5583-5598.

69.

Hameed

Raza

Israr Khan

, et al. Tambulin from Zanthoxylum armatum acutely potentiates the glucose-induced insulin secretion via K(ATP)-independent ca(2+)-dependent amplifying pathway. Biomed Pharmacother. 2019;120:109348.

70.

Quan

Anh

Lam

, et al. Anti-diabetes, anti-gout, and anti-leukemia properties of essential oils from natural spices Clausena indica, Zanthoxylum rhetsa, and Michelia tonkinensis. Molecules. 2022;27(3):774.

71.

Zhang

Zheng

, et al. Fructus Zanthoxyli extract improves glycolipid metabolism disorder of type 2 diabetes mellitus via activation of AMPK/PI3 K/Akt pathway: network pharmacology and experimental validation. J Integr Med. 2022;20(6):543-560.

72.

Bai

Hou

Zhang

Gao

Zhou

. Zanthoxylum bungeanum seed oil elicits autophagy and apoptosis in human laryngeal tumor cells via PI3 K/AKT/mTOR signaling pathway. Anticancer Agents Med Chem. 2021;21(18):2610-2619.

73.

Guo

Xie

, et al. Structural characterization, antiproliferative and anti-inflammatory activities of alkaloids from the roots of Zanthoxylum austrosinense. Bioorg Chem. 2020;102:104101.

74.

Sahu

Kar

Sunita

, et al. LC-MS characterized methanolic extract of zanthoxylum armatum possess anti-breast cancer activity through Nrf2-Keap1 pathway: an in-silico, in-vitro and in-vivo evaluation. J Ethnopharmacol. 2021;269:113758.

75.

Chen

Tan

Feng

Singab

Lei

Liu

. Hydroxy-gamma-sanshool from Zanthoxylum bungeanum (prickly ash) induces apoptosis of human colorectal cancer cell by activating P53 and caspase 8. Front Nutr. 2022;9:914638. doi:10.3389/fnut.2022.914638

76.

Chen

Ren

, et al. Antifungal activity of essential oil from Zanthoxylum armatum DC. On Aspergillus flavus and aflatoxins in stored platycladi semen. Front Microbiol. 2021;12:633714.

77.

Wang

Sui

, et al. Physicochemical properties and antibacterial activity of corn starch-based films incorporated with Zanthoxylum bungeanum essential oil. Carbohydr Polym. 2021;254:117314.

78.

Wang

Hou

Wei

. Sensory characteristics and antioxidant activity of Zanthoxylum bungeanum Maxim. pericarps. Chem Biodivers. 2019;16(2):e1800238.

79.

Deng

Rong

, et al. Molecular basis of neurophysiological and antioxidant roles of szechuan pepper. Biomed Pharmacother. 2019;112:108696.

80.

Chen

Wei

Zhu

, et al. Efficient approach for the extraction and identification of red pigment from Zanthoxylum bungeanum Maxim and its antioxidant activity. Molecules. 2018;23(5):1109.

81.

Cao

Ren

Yang

, et al. Comparative metabolomics analysis of pericarp from four varieties of Zanthoxylum bungeanum Maxim. Bioengineered. 2022;13(6):14815-14826.

82.

Luo

Liu

, et al. Zanthoxylum bungeanum seed oil inhibits RANKL-induced osteoclastogenesis by suppressing ERK/c-JUN/NFATc1 pathway and regulating cell cycle arrest in RAW264.7 cells. J Ethnopharmacol. 2022;289:115094.

83.

Alam

Shah

. Butyrlycholine esterase inhibitory activity and effects of extracts (fruit, bark and leaf) from Zanthoxylum armatum DC in gut, airways and vascular smooth muscles. BMC Complement Altern Med. 2019;19(1):180.

84.

Lee

Park

Lee

, et al. Immunostimulatory effect of Zanthoxylum schinifolium-based complex oil prepared by supercritical fluid extraction in splenocytes and cyclophosphamide-induced immunosuppressed rats. Evid Based Complement Alternat Med. 2018;2018:8107326. doi:10.1155/2018/8107326

85.

Zhao

Zhang

Wang

, et al. Network pharmacology and molecular docking approaches to investigating the mechanism of action of Zanthoxylum bungeanum in the treatment of oxidative stress-induced diseases. Comb Chem High Throughput Screen. 2021;24(10):1754-1768.

86.

Munekage

Kitagawa

Ichikawa

, et al. Pharmacokinetics of daikenchuto, a traditional Japanese medicine (kampo) after single oral administration to healthy Japanese volunteers. Drug Metab Dispos. 2011;39(10):1784-1788.

87.

Rong

Cui

Zhang

, et al. Anesthetic constituents of Zanthoxylum bungeanum Maxim.: a pharmacokinetic study. J Sep Sci. 2016;39(14):2728-2735.

88.

Zhong

Zhang

. Xanthotoxin (8-methoxypsoralen): a review of its chemistry, pharmacology, pharmacokinetics, and toxicity. Phytother Res. 2022;36(10):3805-3832.