Nandina domestica Thunb.: a review of traditional uses, phytochemistry, pharmacology, and toxicology

Nandina domestica: Thunb. is a traditional Chinese herbal drug that has long been used in China and Japan for the treatment of colds, fevers, asthma, chronic bronchitis, conjunctivitis, whooping cough, pharyngeal tumors, etc. Published data have reported at least 366 constituents from N. domestica, including alkaloids, flavonoids, lignans, terpenoids, phenolic acids and their derivatives, fatty acids, and others. Of these, the isoquinoline alkaloids are considered characteristic markers for N. domestica. These alkaloids also showed the most promising bioactivities. The crude extracts or semi-purified constituents of N. domestica exhibit a variety of activities, including antitumor, dermatological, anti-inflammatory, antioxidant, antimicrobial, and detoxification activities, as well as effects on respiratory system, etc. The fruit is considered poisonous when eaten raw, with nausea, vomiting, diarrhea, and abdominal pain as side effects after ingestion. Most traditional uses are supported by biological activities demonstrated in modern experimental studies, suggesting a potential medicinal value of N. domestica. However, more information is needed on its mechanisms of activity, pharmacokinetic profile of the constituents, and its safety and efficacy profile in humans.


Introduction
Nandina domestica Thunb.belongs to the family Berberidaceae and is widely distributed in China, Japan, India, and Korea.N. domestica is frequently used in gardening as a landscape shrub.Its fruits ripen to a vivid red hue akin to coral and are grouped together like grapes.Its leaves have the appearance of bamboo leaves, and they can change from a beautiful green to a striking red in the fall and winter, giving the impression of a blazing fire (Tang, et al., 2007).The plant grows 2-3 m tall, with a typically cespitose stem that has few branches.Older branches are usually grey, whereas younger branches are often crimson.Leaves are habitually alternate, clustered in the upper part of the stem.Typically, leaves are commonly ternate-pinnate.The elliptic or elliptic-lanceolate leaflets have a form like feathers.The thin, leathery-textured leaflets have a rich green color that frequently becomes crimson in the winter.The tiny, white flowers have a strong, fragrant scent.Large panicles of flowers typically form at the apex of the stems and branches.The fruit is a berry and ripens in October-November.When the fruits reach maturity, they have a striking crimson color.Plant images of N. domestica are showed in Figure 1.Ecologically, N. domestica can adapt to limestone soil that is just slightly alkaline and significantly improve the ecological balance of the limestone regions that are otherwise not suitable to life.Besides, it also plays a vital role in greening the environment, purifying the air, conserving water, providing wind prevention and sand fixation, and maintaining soil and water (Liu, 2004).With regard to agricultural applications, N. domestica is an essential resource for the preparation of fungicides of botanical origin (Bajpai, et al., 2009b).Besides, N. domestica's seeds are rich in fatty oils and can be used as raw material for extracting fatty oils (Liu, 2004).
To date, there has been no comprehensive review on N. domestica.Therefore, this review thoroughly outlines the traditional applications, phytochemistry, pharmacological activity, and toxicity of N. domestica based on a large body of domestic and international literature, which provides guidance and reference for further research, utilization, and promotion of N. domestica.

Methodology
The existing scientific databases covering Google Scholar, Web of Science, PubMed, ScienceDirect, Elsevier, Wiley, Springer, Baidu Scholar, China Knowledge Resource Integrated Database (CNKI), Wanfang Data, and J-STAGE were used to gather the literature about the traditional uses, phytochemistry, and pharmacology of N. domestica."N.domestica" in combination with "traditional uses," "phytochemistry," "pharmacology" was used as the search items from March 1949 to January 2024.ChemDraw 19.0 was used to draw the chemical structures.
3 Traditional uses N. domestica, which is extensively distributed in China, Japan, India, and Korea, has been used as traditional herb for quite a long time.In China, the first record of N. domestica dates to the Song Dynasty's "Tujing Ben Cao" (图经本草).This book recorded the plant morphology of N. domestica in detail and pointed out that it was often planted in the courtyard for ornamental purposes.The "Supplements to Compendium of Materia Medica" (本草纲目拾 遗) from the Qing Dynasty recorded that N. domestica fruits could detoxify arsenic, as well as treating pubic lice and asthma.According to "Chinese Materia Medica" (中华本草), N. domestica's roots, stems, branches, and leaves were bitter and cold in nature.According to its records, the roots are slightly toxic and have the function of clearing away heat and detoxification, removing dampness, expelling wind, resolving phlegm, and relieving cough.Its primary application is to treat lung-heat cough, damp-heat jaundice, diarrhea, rheumatic paralysis, sores, and scrofula.The stems, and branches function as a remedy for clearing dampness and heat and lowering rebellious qi, which are used to treat damp-heat jaundice, diarrhea, feverish gonorrhea, eye redness and swelling, cough and dysphagia.The leaves are known to be effective in clearing away heat and inducing dampness, diarrhea, and detoxification, which primarily treat lung-heat cough, whooping cough, febrile gonorrhea, blood in urine, swelling and pain in the eyes, sores and carbuncles, and scrofula.N. domestica's fruits are sour and sweet in taste, and poisonous.Despite its toxicity, they are used to astringe lung for relieving cough, and reduce asthma.In Chinese medicine, they are used clinically to cure prolonged cough, wheezing and whooping cough.Moreover, in the "Jiangxi Province Chinese medicine concoction specification" (江西省中药炮制规 范), the fruit of N. domestica was reported to have the effect of clearing the liver and brightening the eyes and was used for the treatment of malaria and skin ulcers.Furthermore, the roots, stems, leaves, and seeds of N. domestica are traditionally employed in China as folk medicine for the treatment of colds, fevers, asthma, chronic bronchitis, conjunctivitis, whooping cough, pharyngeal tumors, and uterine bleeding (Zhao, 1963;Xie, et al., 1983;Guo, et al., 2018).In Chinese medicine, N. domestica is frequently combined with other herbs for clinical applications.For instance, the combination of the stem and branches of N. domestica and the fibers of the mature fruits of Luffa cylindrica (L.) M. Roem.(family Cucurbitaceae), in addition to the pericarps of Lagenaria siceraria (Molina) Standl.(family Cucurbitaceae), is very effective in the treatment of acute and chronic nephritis (Dong, 1991).In addition, the fruits of N. domestica, the tuberous roots of Stemona japonica (Blume) Miq.(family Stemonaceae), and the pericarps of Cynanchum rostellatum (Turcz.)Liede & Khanum (family Apocynaceae) are combined for the treatment of acute and chronic or persistent prolonged cough, paroxysmal cough, coughing with no phlegm in severe coughing, and difficult coughing with little phlegm (Dai, 2007).
In Japan, the leaves, stems, and fruits of N. domestica are applied as folk medicine.The fruits, also called "nantenjitsu," have been used to treat respiratory ailments such as asthma, whooping cough, and pharyngeal tumors (Takase and Ohashi, 1926).Additionally, the fruits are used to calm down inebriated people and treat impotence.Furthermore, the fruits are regarded as a therapeutic tonic that helped restore the neurological system's equilibrium.A decoction of the leaves is ingested to treat fish and shrimp poisoning.The branches and leaves are reported to prolong life and the seeds strengthen manhood.Tuberculosis patients are treated with the roots' aqueous extract (Lipp, et al., 1981).In addition, a throat lozenge called Nanten-nodo-ame, which contains extracts of the fruit of N. domestica, is being sold in the Japanese market (Okano, et al., 2017).In Korean folk medicine, the leaves are used to treat whooping cough, hematuria, and bruises.The fruits are effective in nourishing yin, clearing heat and tonifying qi, and are commonly used as a cough suppressant (Seo, et al., 2011).

Phytochemistry
Numerous in-depth phytochemical investigations have demonstrated that N. domestica generated a substantial number of secondary metabolites.Up to date, at least 366 compounds have been reported from the various parts of N. domestica, including alkaloids, flavonoids, lignans, terpenoids, phenolic acids and their derivatives, fatty acids, and others.N. domestica's primary active components are isoquinoline alkaloids.Supplementary Table S1 displays the names, classifications, formulation, and other relevant information.
According to earlier studies, fruits were discovered to contain anthocyanins (73-75), including cyanidin 3-xylosylglucoside (73), pelargonidin 3-glucoside (74), and pelargonidin 3-xylosylglucoside (75) (Ishikura, 1971).Under the guidance of the anti-inflammatory activity, robustaflavone (78), a biflavone, was extracted from the methanol extract of N. domestica fruits (Jo, et al., 2019).Further, amentoflavone (79) was isolated from the leaves and fruits, which demonstrated notable antioxidant property and was able to inhibit the growth of Staphylococcus aureus and Escherichia coli (Bajpai, 2019).Currently, there is no research on the types and contents of flavonoids in the various medicinal parts of N. domestica.Thus, additional studies are essential to thoroughly investigate the flavonoids of N. domestica.

Pharmacology
N. domestica has long been used therapeutically in China and Japan for treating lung-heat cough, whooping cough, wheezing, asthma, chronic bronchitis, conjunctivitis, sores, and scrofula, etc. Pharmacological experiments have disclosed that N. domestica extracts, volatile oils and its isolated compounds exhibited significant pharmacological activities, such as effect on respiratory system, anti-inflammatory, dermatological, and detoxification activities, as discovered in traditional uses.Apart from this, its other significant pharmacological activities have been reported, including antitumor, antioxidant, as well as, antimicrobial activities, etc. Supplementary Table S2 and Figure 8 present the specific pharmacological activity.

Antitumor activity
The incidence of malignant tumors is rising annually around the world owing to several factors, including chronic infections, dietary habits, environmental pollution, and increasing in the age of the global population.Malignant tumors currently remain a major global public health issue.Current medications for the treatment of malignant tumors have several drawbacks, including poor efficacy, adverse effects, drug resistance, and high costs.The treatment of malignant tumors requires the use of safe, efficient pharmaceuticals or molecules derived from natural remedies.The roots, stems, leaves, and seeds of N. domestica are traditionally employed to treat pharyngeal tumors.An in vivo study demonstrated that chloroform and methanol extracts of rootbarks exhibited comparatively strong in vitro cytotoxic activity against P388 leukaemia cells with IC 50 of 1.5 and 3.0 μg/ mL, respectively.Subsequently, berberine (1) was extracted from the aforementioned extracts and demonstrated a noteworthy cytotoxic activity against P388 leukaemia cells with IC 50 of 0.4 μg/mL (Funayama, et al., 1996).

Dermatological activity
Atopic dermatitis (AD), occasionally referred to as atopic eczema, is a recurring, itchy, and chronic inflammatory skin disease.In China, N. domestica has been used for the treatment of sores and scrofula.From the perspective of Western medicine, sores and scrofula are understood to be purulent skin diseases.From the perspective of Chinese medicine treatment, heat-clearing and detoxification drugs are frequently used to treat sores and scrofula.Notably, N. domestica's leaves have the effect of clearing heat and removing toxins, which might be used for sores and scrofula.Their application has also been proven in several modern research studies.In a 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis model in NC/Nga mice, 70% ethanol extract of leaves treatment at the dose of 300 mg/kg for 5 weeks normalized the total cell number (TCN) in the spleen, axillary lymph node (ALN), and dorsal skin tissue while lowering blood immunoglobulin E (IgE) levels.Furthermore, the experiments revealed a noteworthy reduction in the quantity of CD23+/ B220+ cells in the ALN and CD3 + cells in the dorsal skin, as well as a decline in the levels of interleukin (IL)-4, IL-5, and IL-13.Besides, the splenocytes' expression of interferon-γ (IFN-γ) was elevated, and the claudin1 and sirt1 protein expression was notably upregulated.Taken together, 70% ethanol extract of leaves remarkably improved DCNB-induced AD (Yun, et al., 2021b).A similar study found the ethyl acetate fraction of the 70% ethanol extract from the leaves exhibited anti-eczematic activity against DNCB induced eczema in mice, which was superior to the positive  The structures of phenolic acids and their derivatives (159-179).
The antidermatophytic activity of the essential oil and several chemical extracts (n-hexane, chloroform, ethyl acetate, and methanol) from flowers was assessed against fungal pathogens that caused skin infections, such as Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis.The essential oils demonstrated moderate to high antidermatophytic efficacy against all tested dermatophytes with inhibition of 51.90%-68.60%.Furthermore, essential oils displayed a strong suppression of spore germination in all tested dermatophytes and revealed a concentration-and time-dependent kinetic inhibition of Trichophyton rubrum.Additionally, the extracts showed mild to moderate antidermatophytic effect against fungal pathogens that cause skin infections with inhibition of 19.2%-55.1%.Taken together, essential oils and extracts could serve as a natural fungicide to treat skin fungus infections (Bajpai, et al., 2009a).To summarize, the different extracts of N. domestica produced promising anti-eczema and anti-skin fungal activities.Nevertheless, further research is needed to determine the main active ingredients in the extracts of N. domestica.

Anti-inflammatory activity
Inflammation is a defense response of the immune system to infection or injury.It can get rid of dangerous substances and damaged tissue but can also lead to tissue damage and malfunction.N. domestica has been used for many years in the treatment of inflammatory respiratory diseases such as asthma, whooping cough, and pharyngeal tumors.Existing modern investigations employing lipopolysaccharide (LPS)-induced models of inflammation have validated the anti-inflammatory properties of the extract of N. domestica and its active ingredients.A study demonstrated that aqueous extract from N. domestica fruits treatment at concentrations of 1~10 μg/mL suppressed dose-dependently the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in LPS-stimulated human pulmonary epithelial A549 cells without affecting COX-1 expression and COX activity (Ueki, et al., 2012).A recent study investigated that 70% ethanol extract of N. domestica leaves decreased nitric oxide (NO) production and inhibited interleukin (IL)-6 and IL-1β mRNA expression in LPS-stimulated RAW 264.7 macrophages in a dose-dependent manner.70% Ethanol extract suppressed phosphorylated activation of mitogen-activated protein kinase (MAPK) signaling pathways, encompassing extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK).Mechanistic studies indicated that 70% ethanol extract exerted anti-inflammatory effects by mediating MAPK phosphorylation and down-regulating inflammatory mediator levels (Yun, et al., 2020).An investigation using a fine dust mixture of coal, flay ash, and diesel exhausted particle (CFD)-induced lung injury mice model demonstrated that 70% ethanol extract of leaves reduced lung injury through suppressing inflammatory cytokines and reducing neutrophil accumulation.To be more precise, 70% ethanol extract of leaves suppressed the level of inflammatory cytokines such as IL-17, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein-2 (MIP-2), and C-X-C motif chemokine 1 (CXCL-1) and dramatically decreased neutrophil counts.Furthermore, the 70% ethanol extract led to improvements in lung tissue, such as goblet cell hyperplasia and inflammatory cell infiltration, based on a histological assessment.Also, the elevation of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) levels was suppressed by 70% ethanol extract (Yun, et al., 2021a).In LPS-stimulated RAW 264.7 macrophages, the pro-inflammatory cytokines IL-1β, IL-6, and NO were reduced by the administration with robustaflavone (78).Furthermore, robustaflavone (78) suppressed the expression of inducible nitric oxide synthase (iNOS) and COX-2, and down-regulated nuclear factor-κB (NF-κB) expression and phosphorylation of extracellularly regulated kinases (pERK 1/2).All the findings demonstrated that robustaflavone (78) had anti-inflammatory property (Jo, et al., 2019).Besides, in LPS-mediated endothelial inflammatory responses elicited in human umbilical vein endothelial (HUVEC) cells, two caffeoyl glucosides, nandinaside A (173), and nantenoside B (175), dose-dependently suppressed LPS-induced leukocyte hyperpermeability, adhesion and migration on human endothelial cell monolayers (Kulkarni, et al., 2015).From the studies mentioned above and their remarkable results, extracts from N. domestica and its active compounds has anti-inflammatory properties.It is still necessary to thoroughly investigate additional anti-inflammatory components and conduct extensive animal model studies to fully understand the anti-inflammatory effect of N. domestica extract.

Antioxidant activity
The extracts of N. domestica are confirmed to exhibit certain antioxidant activity by various antioxidant methods such as DPPH, ABTS, and superoxide radical scavenging, reducing power, and metal chelating ability assays.Some studies have shown that 70% ethanol extract and 80% methanol extract of N. domestica's leaves dose-dependently possessed favourable DPPH radical scavenging activity (He, et al., 2003;Yun, et al., 2020).Moreover, ethanol extract of leaves demonstrated exceptionally high tyrosinase inhibitory action at 0.5 and 0.15 mg/mL, with inhibitory rates of 81.5% ± 2.0% and 65.7% ± 1.7%, respectively (Masuda, et al., 2007).One study demonstrated that the volatile oil from the flowers possessed good scavenging effects on ABTS radicals as well as metal chelating ability in a concentration-dependent manner (Zhang, et al., 2014).Another similarity study confirmed that the volatile oil from fruits exhibited relatively high ferric ion reducing power with an IC 50 value of 145.35 ± 4.10 μg/mL, which was equivalent to that of ascorbic acid.Moreover, the volatile oil of the fruits displayed pronounced scavenging activity against DPPH and ATBS radicals with IC 50 values of 28.39 ± 1.12 and 20.61 ± 0.75 μg/ mL, respectively.The oil showed moderate scavenging activity against superoxide radicals with an IC 50 value of 53.22 ± 2.51 μg/ mL.However, its anti-metal chelating activity was low with an IC 50 value of 92.5 ± 3.16 μg/mL (Bi, et al., 2016).Besides, amentoflavone (79) displayed potent antioxidant activity on scavenging DPPH, ABTS, superoxide, and hydroxyl radicals in a concentration-dependent manner with inhibition ranging from 19.21% to 75.52% (Bajpai, et al., 2019).According to the aforementioned findings, N. domestica exhibits favourable antioxidant activity and may be employed as a functional material with antioxidant properties.

Antimicrobial activity
The extracts of N. domestica stems have been found to have antibacterial effects on S. aureus, Streptococcus faecalis, B. thuringiensis.Meanwhile, the extracts of N. domestica leaves displayed antibacterial activity against Bacillus thuringiensis (Li, 2007;Li, et al., 2008).Moreover, one study showed that aqueous extract of leaves reduced the growth of both Gram-positive (S. aureus, S. pyogenes) and Gram-negative bacteria (E.coli, P. aeruginosa, A. baumannii) by disrupting the bacterial membrane.The aqueous extracts of the leaves were further separated into ethanol, petroleum ether, and ethyl acetate fractions, in which the ethyl acetate fraction exhibited the highist antibacterial activity.Using antimicrobial activity-guided fractionation, alkaloids and flavonoids were isolated from leaf extracts.Antimicrobial tests revealed that the alkaloids inhibited Grampositive bacteria, whereas the flavonoids suppressed Gramnegative bacteria (Guo, et al., 2018).The aforementioned tests demonstrate the antibacterial activity of N. domestica's varous extract.Additional studies may be conducted to determine the active components of the various extracts and their safety as medications.

Detoxification activity
Arsenic trioxide is used internationally as one of the targeted drugs for the treatment of acute promyelocytic leukaemia.However, arsenic trioxide inhibits antioxidant enzyme activities such as glutathione or selectively enhanced cytochrome P450-dependent monooxygenase activity during therapy, which results in oxidative damage to the liver and kidneys, which severely limits its use in clinical practice.Therefore, there is a critical need to discover the specific components responsible for the detoxifying effect.In the Qing Dynasty's "Supplements to Compendim of Materia Medica" (本草纲目拾遗), it was documented that the aqueous extract of N. domestica's fruits could detoxify arsenic.Many modern studies have been conducted to evaluate the detoxification effects of N. domestica on the antitumor drug arsenic trioxide using a chronic arsenic trioxide-induced hepatotoxicity and nephrotoxicity in rats.The findings showed that aqueous extract of seeds decreased arsenic trioxide-induced hepatotoxicity and nephrotoxicity.Concretely, aqueous extract of seeds treatment at the dose of 20 g/kg reduced structural damage to liver and renal tissue without hepatocellular necrosis, lowered alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr), and blood urea nitrogen (BUN) levels, attenuated the decrease in endogenous creatinine clearance rate (Ccr), decreased catalase (CAT) levels and increased superoxide dismutase (SOD) and malondialdehyde (MDA) levels in the homogenates of the renal cortex, which compared to the untreated group (Peng, et al., 2014a;Liu, et al., 2015).Interestingly, 70% ethanol extracts of roots, stems, and fruits showed significant protective effects against arsenic trioxide oxidative stress-induced hepatotoxicity and nephrotoxicity, whereas N. domestica's leaves were less effective (Sun, et al., 2019).A similar study demonstrated that total alkaloids from a 70% ethanol extract significantly ameliorated arsenic trioxideinduced cardiac, renal, and hepatic damage.Accordingly, total alkaloids were considered to present an attenuating effect on arsenic trioxide toxicity.Notably, the aporphine alkaloids, such as nantenine (23) and domesticine (26), were characterized by comparatively high content and high specificity, which could serve as indicator components for the quality control methods of N. domestica with regards to the cardiac, renal, and hepatic protective affords (Cheng, et al., 2020).Besides, a recent study demonstrated that different fractions (chloroform, ethyl acetate, n-butanol and aqueous) from the 70% ethanol extract of roots exhibited a favourable protective effect against arsenic trioxide-induced hepatotoxicity and nephrotoxicity.Notably, the most pronounced antagonistic effect on toxicity was observed with the chloroform fraction.Meanwhile, berberine (1), the principal component of the chloroform fraction, showed a dose-dependent protective effect against arsenic trioxide-induced hepatotoxicity and nephrotoxicity (Fu, et al., 2023).Based on the above-mentioned results, the extracts from N. domestica exhibit detoxifying effects on arsenic trioxide induced nephrotoxicity and hepatotoxicity.

Effect on respiratory system
Asthma is characterized by severe airway constriction brought on by airway inflammation.For the treatment of asthma, glucocorticosteroids are currently the first option.However, a safer and more effective asthma medication, or adjunctive therapy, is needed in the clinic considering its long duration and various observed adverse effects.Traditionally, N. domestica's leaves, and fruits have long been used in the treatment of asthma, and chronic bronchitis in China.Remarkably, aqueous extract of leaves at the dose of 1 g/kg for 16 days showed beneficial effects on asthma symptoms, such as dyspnea, cough, and allergy in an ovalbumin (OVA)-specific asthma in guinea pig.Further investigation uncovered that alkaloids were the key constituents of the aqueous extract of leaves for asthma alleviation (Guo, et al., 2018).N. domestica additionally alleviated symptoms of asthma by relaxing smooth muscles.Tsukiyama et al. examined the impact of the aqueous extract from fruits and one of its constituents, nantenine (23), on histamine and serotonin-produced tracheal constriction in isolated guinea pigs.The findings demonstrated that histamine-induced competitive and non-competitive contractions were reduced by aqueous extract administration at doses ranging from 0.1 to 1 mg/mL.Moreover, aqueous extract treatment at the dose of 0.01-1 mg/mL suppressed serotonin-induced contractions in a competitive manner.Notably, nantenine (23) treatment at concentrations ranging from 2 to 20 μM did not impact histamine-induced contraction and only marginally decreased serotonin-induced contraction.The above-mentioned results showed that the aqueous extract had an inhibitory effect on tracheal smooth muscle contraction, whereas nantenine (23) alone could not explain the inhibitory effect of the aqueous extract on tracheal smooth muscle contraction (Tsukiyama, et al., 2007).Similarly, treatment with aqueous extract of fruits at a concentration of 1 mg/mL induced a biphasic relaxation of tracheal precontraction in response to high K + stimulation in histamine-and serotonin-induced contraction of isolated guinea pig trachea.In actuality, the primary active components of the aqueous extract were higenamine (50) and nantenine (23).Furthermore, the aqueous extract of fruits relaxed tracheal smooth muscles immediately through β-adrenergic receptor stimulation by higenamine (50) and slowly through Ca 2+ antagonism by nantenine (23) (Tsukiyama, et al., 2009;Ueki, et al., 2011).Taken together, the aqueous extract significantly inhibits the contraction of tracheal smooth muscle.However, further investigation is needed into the additional bioactive ingredients in aqueous extract besides nantenine (23).

Toxicity
N. domestica is a commonly grown decorative plant that is great for observing its leaves and fruits.Also, the aerial parts of N. domestica offers therapeutic benefits.However, the whole plant is also known for its toxic effects, especially the fruits which exhibit the highest level of toxicity.To date, two cyanohydrins, p-glucosyloxy-mandelonitrile (362) and nandinin (363) were found in young shoots and young leaves, respectively.The cyanohydrins are transformed into hydrogen cyanide when consumed, and this chemical paralyzes the nerve system.Even though N. domestica is believed to be toxic, little information about their possible toxicity is now accessible.Numerous cedar waxwing carcasses were found in Thomas County, Georgia, in April 2009, according to one case report.Out of them, a visual and microscopic examination of five cases revealed hemorrhage in the trachea, mediastinum, and lungs of the bird.Furthermore, the gastrointestinal tract contained the only food that had been consumed-wholly and partially digested N. domestica fruits.N. domestica fruits contained cyanide and were one of the few berries that could be the only food that was available at this time of year.The cedar waxwing was an omnivorous predator that often consumed more food than it could possibly need.The birds died from poisoning after consuming a hazardous amount of N. domestica fruits as a result of their voracious eating habits (Woldemeskel and Styer, 2010).According to another case, Texas, United States saw 875 incidents between 2000 and 2015 in which a patient, who was 5 years old or younger, consumed N. domestica fruits.There was a noticeable seasonal pattern in the amount of N. domestica fruits consumed, with March and April seeing the largest percentage of consumption.The most common clinical reactions were vomiting (3.7%), abdominal pain (1.0%), diarrhoea (0.9%), and nausea (0.7%) (Forrester, 2018).An in vivo toxicological experiment confirmed that the maximum daily dosage of the aqueous extract from N. domestica root was 122.4 g/kg, equivalent to 195.8 times the recommended clinical dosage.At this dosage, the mice showed no overt toxicological reactions and all of them lived for 14 days.Furthermore, during autopsy, no overt pathological alterations were found in the mice's visceral organs.The aforementioned test results demonstrate that N. domestica root infusion administered by gavage has no discernible toxicological effects on mice, indicating that N. domestica root is a safe and dependable product (Qiu, et al., 2019).In general, people's lives and health are closely related to the safety of pharmaceuticals.Therefore, to adequately expose the toxicity of the various medicinal parts of N. domestica and guarantee the safety of clinical use, more in vivo tests are required.

Conclusions and future perspectives
In the present review, we methodically compiled data on the traditional uses, phytochemistry, pharmacology, and toxicity of N. domestica.Traditionally, N. domestica have the effects of clearing away heat and dampness, energizing the meridians, relieving coughs and asthma.Through phytochemical research, at least 366 components have been found from N. domestica to date.Modern pharmacology demonstrates that N. domestica exhibits antitumor, dermatological, anti-inflammatory, antioxidant, antimicrobial, and detoxification activities, as well as effects on respiratory system, etc.These findings validate several traditional uses and clinical applications of TCM.
To further our understanding and utilization of N. domestica, we make the following suggestions.Firstly, nearly half of the components are detected from the volatile oil of N. domestica by GC-MS.The components in the volatile oil exist in the form of mixtures.There have been little investigations on the pharmacological properties of individual components in the volatile oil.Therefore, finding physiologically active natural compounds from the various medicinal portions of N. domestica by chromatographic techniques and in vitro and in vivo pharmacological activity investigations would be useful.Secondly, the existing pharmacological activity studies have focused on the crude extracts or semi-purified constituents of various medicinal parts of N. domestica.There should be a need for an indepth exploration of the pharmacological activities of the chemical constituents isolated from N. domestica.Thirdly, N. domestica is traditionally used for the treatment of asthma, chronic bronchitis, conjunctivitis, whooping cough, pharyngeal tumors, etc. Existing pharmacological activity studies have demonstrated the antitumor, anti-inflammatory, antimicrobial, as well as effect on respiratory system, and so on.Numerous traditional uses of N. domestica have been validated by existing pharmacological activity.Therefore, further research is necessary to determine its precise mechanism.Fourthly, additional toxicity and pharmacokinetic investigations must be conducted on various medicinal parts and active ingredients isolated from N. domestica to validate their safety.Lastly, the quality markers of N. domestica should be determined based on the perspective of traditional application, pharmacological activity, toxicity, chemical composition, and blood components to identify a more rational and precise quality control system.

FIGURE 8
FIGURE 8Pharmacological activities of N. domestica (Red arrows denote upward adjustments, and blue arrows denote downward adjustments).