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Asari Radix et Rhizoma （AR） is a traditional Chinese medicine with a history of more than 2 000 years of medication and has been included in ancient herbal works in the past dynasties. It is effective in releasing the exterior， dispersing cold， dispelling wind， relieving pain， opening orifices， warming the lung， and resolving fluids， and is still widely used in the clinical treatment of influenza， coronavirus disease-2019 （COVID-19） pneumonia， asthma， allergic rhinitis， eye pain， headache， toothache， oral ulcer， eczema， etc. Modern pharmacological studies have shown that AR has antipyretic， anti-inflammatory， analgesic， antibacterial， antiviral， relieving cough and asthma， anti-allergy， and other effects. AR contains a variety of chemical components， in which essential oil is not only associated with functions such as dispelling cold， relieving heat， relieving pain， and resisting inflammation and allergy， but is also toxic. AR also contains lignans， flavonoids， amides， phenanthrenes， alkaloids， and other non-volatile oil components， which play an important role in immunity regulation， anti-inflammation， pain relief， heart strengthening， and blood vessel expansion. The phenanthrene compounds are mainly aristolochic acid analogues， such as aristolochic acid Ⅳa and aristolochic lactam Ⅰ. Aristolochic acid Ⅳa has been proven to have a significant anti-inflammatory effect. The toxicity of AR is related to safrole， aristolochic acids and their analogues， and is also affected by many factors， such as preparation method， dosage， origin， collection time， medicinal part， and decocting time， which should be comprehensively considered in clinical application. Based on the relevant literature in China and abroad， the present study reviewed the correlation of chemical composition and pharmacological and toxicological effects of AR， and the safety of AR， aristolochic acid， safrole， and other components to provide a new perspective for an objective understanding of AR safety， as well as references for rational clinical application， production risk prevention and control， and drug scientific supervision of AR.
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ObjectiveThrough the review of the literature about Asari Radix et Rhizoma， we extracted the key information affecting the toxicity of Asari Radix et Rhizoma， aiming to provide a basis for the rational application of Asari Radix et Rhizoma in the classical prescriptions. MethodThe bibliometric method was employed to analyze the ancient and modern literature and thus reveal the relationship of Asari Radix et Rhizoma toxicity with the medicinal plants， medicinal part， processing method， dosage form， prescription compatibility， medication method， and patients' physical factors. ResultThe dosage of Asari Radix et Rhizoma in Danggui Sinitang and Houpo Mahuangtang was 9 g and 6 g， respectively， and the decocting time should be longer than 120 min. The single dosage of Asari Radix et Rhizoma in Xinyisan， Sanbitang， Daqinjiao Tang， and Qingshang Juantongtang were 0.8， 1.2， 0.9， and 1.1 g， respectively. The rhizome of Asarum heterotropoides var. mandshuricum or A. sieboldii var. seou1ense should be selected for Danggui Sinitang， Houpo Mahuangtang， and Qingshang Juantongtang， while that of A. siebodii var. seou1ense should be selected for Xinyisan. In terms of processing， Asari Radix et Rhizoma can be processed with wine when being used in Danggui Sinitang， Houpo Mahuangtang， Sanbitang， and Daqinjiaotang， and it can be stir-fried when being used in Xinyisan and Qingshang Juantongtang. In addition， the toxicity of Asari Radix et Rhizoma is associated with the compatibility of drugs and the physical conditions of patients. ConclusionBy reviewing the literature on Asari Radix et Rhizoma toxicity， we obtained the key information affecting the toxicity of Asari Radix et Rhizoma and explored the effective ways to avoid the toxicity. This study provides a sufficient basis for the rational development and safe application of the classical prescriptions containing Asari Radix et Rhizoma.
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Objective: Although some studies have linked Asari Radix et Rhizoma (Asari Radix) administration to hepatocellular carcinoma (HCC), few studies have examined the association between the development of HCC and use of Asari Radix among patients in mainland China. This study aimed to evaluate the real-world association between Asari Radix and HCC in patients to strengthen the understanding of Asari Radix safety. Methods: A retrospective cohort study among hepatitis B virus (HBV)-monoinfected patients and non-HBV-monoinfected patients were performed. Patients over 18 years of age were eligible for inclusion. Prescription records of inpatients and outpatients were inquired to distinguish Asari Radix users and nonusers. The risk of developing HCC among Asari Radix users and nonusers in the HBV cohort and the non-HBV cohort was analyzed. Results: There were 49 500 HBV and 133 148 non-HBV patients involved in the two cohorts. Among HBV patients (2 901 users; 46 599 nonusers), the prevalence of HCC in Asari Radix users was lower than that in nonusers (145.70 vs. 265.43 per 10
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ObjectiveTo investigate the effects of Asari Radix et Rhizoma-Zingiberis Rhizoma herb pair （XGHP） on lung and liver lipid metabolism in rats with chronic obstructive pulmonary disease （COPD）. MethodForty SD male rats were divided into a normal group （10 rats） and a model group （30 rats）. The method of cigarette smoke + tracheal injection of lipopolysaccharide（LPS） + cold stimulation was used to replicate COPD model with the syndrome of cold phlegm obstruction in lung. A COPD group， a XGHP group （5.4 g·kg-1·d-1）， and an aminophylline group （0.5 g·kg-1·d-1） were established after successfully inducing the model， with 10 rats in each group. After treatment， the serum triglyceride （TG）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C） levels of rats in each group were measured. Gas chromatography-mass spectrometer （GC-MS） was used to detect the differential metabolites in the lung and liver tissues of rats in each group， and the relevant targets of the differential metabolites were predicted by network pharmacology. Molecular docking was used to verify the binding ability of key components in XGHP to the relevant targets in network pharmacology. The mRNA and protein expression levels of peroxisome proliferator-activated receptor α （PPARα） and fatty acid binding protein 4 （FABP4） in lung and liver tissues of rats in each group were detected by real-time polymerase chain reaction （PCR） and Western blot. ResultXGHP significantly increased the levels of TG， TC， and LDL-C in serum （P<0.05）， and decreased the level of HDL-C （P<0.05） in rats with COPD. GC-MS results showed that there were 8 lung differential metabolites and 17 liver differential metabolites in the COPD group and XGHP group. Network pharmacology predicted 59 common targets for the two differential metabolites， mainly enriched in the PPAR signaling pathway. Molecular docking results showed that the main components in XGHP were well combined with both PPARα and FABP4. Real-time PCR showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 mRNA （P<0.05）， and Western blot showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 proteins （P<0.05） in lung and liver tissues of rats with COPD. ConclusionXGHP effectively improves the blood lipid levels of rats with COPD， which may be related to the increase of the expression levels of PPARα and FABP4 mRNA and proteins in the PPAR signaling pathway， thus regulating lung and liver lipid metabolism.
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ObjectiveTo investigate the effects of Asari Radix et Rhizoma-Zingiberis Rhizoma herb pair （XGHP） on lung and liver lipid metabolism in rats with chronic obstructive pulmonary disease （COPD）. MethodForty SD male rats were divided into a normal group （10 rats） and a model group （30 rats）. The method of cigarette smoke + tracheal injection of lipopolysaccharide（LPS） + cold stimulation was used to replicate COPD model with the syndrome of cold phlegm obstruction in lung. A COPD group， a XGHP group （5.4 g·kg-1·d-1）， and an aminophylline group （0.5 g·kg-1·d-1） were established after successfully inducing the model， with 10 rats in each group. After treatment， the serum triglyceride （TG）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C） levels of rats in each group were measured. Gas chromatography-mass spectrometer （GC-MS） was used to detect the differential metabolites in the lung and liver tissues of rats in each group， and the relevant targets of the differential metabolites were predicted by network pharmacology. Molecular docking was used to verify the binding ability of key components in XGHP to the relevant targets in network pharmacology. The mRNA and protein expression levels of peroxisome proliferator-activated receptor α （PPARα） and fatty acid binding protein 4 （FABP4） in lung and liver tissues of rats in each group were detected by real-time polymerase chain reaction （PCR） and Western blot. ResultXGHP significantly increased the levels of TG， TC， and LDL-C in serum （P<0.05）， and decreased the level of HDL-C （P<0.05） in rats with COPD. GC-MS results showed that there were 8 lung differential metabolites and 17 liver differential metabolites in the COPD group and XGHP group. Network pharmacology predicted 59 common targets for the two differential metabolites， mainly enriched in the PPAR signaling pathway. Molecular docking results showed that the main components in XGHP were well combined with both PPARα and FABP4. Real-time PCR showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 mRNA （P<0.05）， and Western blot showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 proteins （P<0.05） in lung and liver tissues of rats with COPD. ConclusionXGHP effectively improves the blood lipid levels of rats with COPD， which may be related to the increase of the expression levels of PPARα and FABP4 mRNA and proteins in the PPAR signaling pathway， thus regulating lung and liver lipid metabolism.
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Asari Radix et Rhizoma （ARR） is a traditional Chinese medicine for relieving exterior syndrome， and its roots and stems contain rich chemical components， including volatile oils （terpenoids， aromatics and aliphatics）， lignans， flavonoids， etc. Clinically， it has been traditionally used for the treatment of diseases such as phlegm and cough， anemofrigid cold， rheumatic arthralgia due to its ability to spread cold. Modern pharmacological studies have shown that ARR played beneficial roles in analgesic， anti-inflammatory， antitussive， antiasthmatic， antiviral， antibacterial， sedative， antioxidative， and antidepressant responses， antihypertension， as well as tumor suppression. The current studies on the chemical composition of ARR mainly focused on volatile components， and little information is available for the occurrence and pharmacological effects of non-volatile components. In addition， there is a lack of clear classification of chemical components and the distribution of chemical components in medicinal parts and the origin of species. Therefore， in this study， the authors reviewed a large number of literature on the chemical compositions and pharmacological effects of ARR， and hoping to provide a reference for further pharmacological research and the new drug development of ARR.
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Objective:To analyze the known mechanism of toxicology and predict the unknown toxicity in Asari Radix et Rhizoma sinensis by establishing the network relationship of compound, protein, gene and toxicant reaction. Method:After comparing the Asari Radix et Rhizoma candidate compounds obtained from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) database and the toxicological information obtained from the Comparative Toxicogenomics Database(CTD) database, we screened out 13 toxic components from Asari Radix et Rhizoma. And use the Pharm Mapper Server website to find the detailed information of target proteins of the 13 components. The network structure of these 13 chemical components and their corresponding target proteins were drawn by using Cytospace software, and several target proteins with the highest degree of association were found. ClueGO+CluePedia plug-in of Cytospace software was applied in gene ontology(GO) enrichment analysis of genes and kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis, so as to determine the pathways through which toxic substances in Asari Radix et Rhizoma might be harmful to human body. Result:The toxic substances in Asari Radix et Rhizoma may induce tumor and cancer formation through p53 signaling pathway, interleukin(IL)-17 signaling pathway, nuclear factor(NF)-kappa B signaling pathway, tumor necrosis factor(TNF)-signaling pathway. Asari Radix et Rhizoma could inhibit the central nervous system by regulating apoptosis pathways and neurons, and may also cause other autoimmune diseases by IL-17, TNF-α pathway and apoptosis regulation. Conclusion:This study preliminarily explores related mechanisms of toxicity of Asari Radix et Rhizoma,this method can be used to predict toxicity and explain toxicity mechanism of traditional Chinese medicine.
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Objective: To verify the feasibility of vapor-permeable membrane technology for the separation of water bodies containing essential oil of Asari Radix et Rhizoma (ARR) essential oil, and then to apply vapor permeate technology to the separation of more essential oils of traditional Chinese medicine. Methods: The polydimethylsiloxane/polyvinylidene fluoride (PDMS/PVDF) composite flat membrane and polyvinylidene fluoride (PVDF) flat membrane were collected as the membrane material. The oil-bearing water body of ARR volatile oil was separated by vapor permeate technology, and the oil penetration rate of two kinds of membranes was calculated. At the same time, the changes of the composition and content of the essential oil before and after the membrane were analyzed by gas chromatography-mass spectrometry (GC-MS). Results: The results showed that the essential oil penetration rate was significantly higher than that of PDMS/PVDF membrane when PVDF membrane was used as membrane material. GC-MS qualitative analysis results showed that the composition of the essential oil in the penetrants of the two membranes was basically the same as that of the essential oil obtained by the traditional steam distillation method. The content of α-pinene, β-pinene, 3,5-dimethoxytoluene, and methyl eugenol were determined by double internal standard method. The results showed that the content of each component in the PVDF membrane permeation was significantly higher than that of the PDMS/PVDF membrane permeation solution. Conclusion: It is feasible to separate the oil containing water from the essential oil of ARR by vapor permeation membrane technology. Compared with the PDMS/PVDF membrane, the PVDF membrane is more suitable for separating the oil containing water of the essential oil of ARR.
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Asari Radix et Rhizoma has been used for more than 2000 years with wide application in medicine. In recent years, there are many poisoning cases of Asari Radix et Rhizoma being reported in clinic, the rational application in clinic of Asarum Radix et Rhizoma has been widely concerned due to its poisonous componets of safrole and aristolochic acid. The present paper traces the historical evolution of Asari Radix et Rhizoma through accessing Web of Science and multiple databases for biomedicinal sciences, and analyzes the characteristics of its toxic reaction, and discusses the matters needing attention in its rational application from the perspective of chemical composition, so as to promote the safe and reasonable application of Asari Radix et Rhizoma.
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Objective To establish the fingerprint of Magnoliae Flos and Asari Radix et Rhizoma of Liujing Toutong Tablets (LTT), provide the basis for the evaluation of the quality of LTT. Methods Aglient DB-WAX (20 m × 0.18 mm, 180 μm) gas chromatography column, select the appropriate temperature conditions, the determination of the 11 batch of Magnoliae Flos, Asari Radix et Rhizoma, the use of SPSS clustering analysis and chromatographic fingerprint evaluation system (2004A version) the establishment of Xinyi medicine fingerprints, and through the Agilent 7890A-5975C gas quality for instrument on the common peaks were identified. Results The 11 batches of samples were measured and SPSS cluster analysis of 10 batches of medicinal materials were clustered into one group, and the establishment of Xinyi medicine GC fingerprint, the similarity was more than 0.9, a total of 22 common peaks, which belongs to the whole party into 14 components, medicinal unique ingredients 8; 10 batches of Asarum medicinal materials were clustered into one group, and the establishment of Asarum GC fingerprint, the similarity was more than 0.9, a total of 11 common peaks, which belongs to the whole Party composition for 4, 7 for a particular component of medicinal materials. Conclusion This method has strong specificity, high accuracy, good repeatability, and provide the basis for quality control of Herba Magnoliae Flos and Asari Radix et Rhizoma.
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Setting Li Dai Zhong Yao Pao Zhi Zi Liao Ji Yao as clue, this article searched each edition of China Pharmacopoeia, National Processing Standard of Traditional Chinese Medicine issued in 1988, and relevant materials of local processing standards and modern processing study, and concluded and combed the contents about Asari Radix et Rhizoma processing in ancient and modern literature. There are records about Asari Radix et Rhizoma processing methods in history, including net processing, cutting processing, heating processing and processing excipient. However, Asari Radix et Rhizoma processing methods in modern time are relatively simple. In addition to the version of the Processing Standard of Traditional Chinese Medicines in Shanghai issued in 2008, containing the honey Asari Radix et Rhizoma, other editions of China Pharmacopoeia and processing standards only recorded net processing and cutting processing. Recent research showed that processing methods of modern stir frying processing, alkali processing, wine processing, low temperature ultrafine comminution processing and so on, can effectively reduce the toxicity of Asari Radix et Rhizoma and enhance the safety of clinical application. This article summarized the history and research progress of Asari Radix et Rhizoma processing, and provided a reference for the study on modern processing.
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Objective To investigate the influence of β-cyclodextrin (β-CD ) inclusion and its cataplasma on the transdermal permeability of volatile oil extracted from Chuanxiong Rhizoma and Asari Radix et Rhizoma by means of percutaneous penetration test of four preparations containing of the volatile oil. Methods Using the modified Franz diffusion pool as equipment,with 40% ethanol solution as absorption solution and SD rat skin coated with the volatile oil,aβ-CD inclusion complex of the volatile oil,a cataplasma of theβ-CD inclusion complex of the volatile oil,and a cataplasma of the mixture of the volatile oil andβ-CD,respectively,as experimental skin,the transdermal penetration test was carried out.The cumulative penetrative amounts of volatile oil in the absorption liquid were measured by GC-MS in order to evaluate the differences in the percutaneous permeability. Results The percutaneous penetration rate constant size order of four preparations containing the volatile oil is as follows:the volatile oil directly coated on the skin > the cataplasma of β-CD inclusion complex of the volatile oil > the β-CD inclusion complex of the volatile oil directly coated on the skin > the cataplasma of the mixture of the volatile oil and β-CD. Conclusion The compositions of the volatile oil retrieved from the β-CD inclusion complex are no significant changes. The percutaneous permeability of the cataplasma of β-CD inclusion complex of the volatile oil is better than that of the cataplasma of the mixture of volatile oil and β-CD.
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A headspace-solid phase microextraction-gas chromatography-mass spectrometry method（HS-SPME-GC-MS） was adopted for the quantitative study of 4-allylanisole, methyl eugenol, 2,3,5-trimethoxytoluene, 3,4,5-trimethoxytoluene, sarisan, 3,5-dimethoxytoluene and safrole in mice brain, liver tissues and blood after intragastric administration of Asari Radix et Rhizoma. A VF-WAXms (30 m×0.25 mm, 0.25 μm film thickness) capillary column and SPME fiber coated with 65 μm polydimethylsiloxane/divinylbenzene (PDMS/DVB) were used. The calibration curves of seven volatile constituents were established to validate the method's stability (RSD<15%), repeatability (RSD<9.5%), accuracy (RSD<22%), relative recovery (87.0%-108%) and extraction recovery (74.9%-102%). The validated HS-SPME-GC-MS assay was applied to determine the concentrations of seven constituents in liver, brain and blood. The detected contents were 0.22,0.14 μg•g⁻¹,0.25 mg•L⁻¹ (4-allylanisole), 1.1, 0.39 μg•g⁻¹, 0.69 mg•L⁻¹ (methyl eugenol), 0.45, 0.13 μg•g⁻¹, 0.54 mg•L⁻¹ (2,3,5-trimethoxytoluene), 0.51, 0.15 μg•g⁻¹, 0.45 mg•L⁻¹ (3,4,5-trimethoxytoluene), 0.48, 0.039 μg•g⁻¹, 0.69 mg•L ⁻¹ (sarisan), 2.2, 1.2 μg•g⁻¹, 1.5 mg•L⁻¹ (3,5-dimethoxytoluene) and 1.3, 0.67 μg•g⁻¹, 1.1 mg•L⁻¹ (safrole) respectively. This HS-SPME-GC-MS method is rapid and convenient, with a small sample size, and applicable for the analysis and determination of volatile constituents in traditional Chinese medicines, which provides scientific data for further studies on effective substances and toxic substances in Asari Radix et Rhizoma.
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Objective: To study the effect of processing techniques on reducing the contents of safrole and aristolochic acid A in Asari Radix et Rhizoma. Methods: The contents of safrole and aristolochic acid A between raw herb and processed products were determined by HPLC, and the differences in the contents of toxic components between raw herb and processed products were used to evaluate the detoxification efficiency. Results: The linear ranges of safrole and aristolochic acid A were 169.2-846.0 μg (r = 0.9996) and 11.6-58.0 ng (r = 0.9996), respectively. And the average recovery rates were 99.83% (RSD = 1.67%) and 101.43% (RSD = 1.25%). The removal rate of safrole in order was as follows: salt system > fried coke > rice water system > alkali > liquorice > vinegar > ginger > wine > alkali-vinegar > honey and the removal rate of aristolochic acid A was in ordor as: fried coke > alkali-vinegar > salt system > alkali > vinegar > rice water system > liquorice > wine > honey > ginger. The removal rate of aristolochic acid A in Asari Radix et Rhizoma by fried coke was over 60%. Conclusion: The contents of safrole and aristolochic acid A in Asari Radix et Rhizoma could be decreased to different extent by processing techniques. Among the processing methods, processing by fried coke is the best method.
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Objective: To explore the underlying reasons why Asari Radix et Rhizoma (ARR) should be processed by Shanxi aged vinegar when used in Guilingji. Methods: 1H-NMR-based metabolomic approach combined with multivariate statistical analysis was used to investigate the differential chemical components among the raw and two vinegar-baked ARR. Results: More than 30 metabolites were identified in the 1H-NMR spectra of ARR. Raw and two vinegar-baked ARR could be separated obviously, and the rice vinegar-baked ARR and the Shanxi aged vinegar-baked ARR also differed to each other, in which the priamary metabolites showed bigger difference than that of secondary metabolites. Conclusion: This study laid a basis for the modern research of the special processing technology for Guilingji.
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Objective: To study the analgesic effects of aqueous extract from Asari Radix et Rhizoma (ARR) combined with Nimodipine and its mechanism. Methods: Forty healthy male Wistar rats were r andomly divided into control, model, ARR, Nimodipine, and ARR+Nimodipine groups. Except the control group, the neuropathic pain models of rats were produced in the rest groups by the ligation of sciatic nerve. Rats in each group were ig administered for two weeks after operation. The aqueous extract (200 mg/kg) from ARR was given to rats in ARR group, Nimodipine (40 mg/kg) was given to rats in Nimodipine group, and the aqueous extract (200 mg/kg) from ARR was given to rats after 30 min administration of Nimodipine (40 mg/kg) in ARR+Nimodipine group, and physiological saline was given to rats in the control and model groups. Thermal paw withdrawal latency and mechanical paw withdrawal reflex threshold of rats in each group were measured on one day before operation and on the days 1, 3, 5, 9, and 14 after 30 min of administration. Results: The thermal paw withdrawal latency and mechanical paw withdrawal reflex threshold of rats in each group were not significantly different before and after the operation (P>0.05). The thermal paw withdrawal latency and mechanical paw withdrawal reflex threshold of rats in the model group were significantly lower than those in the control group at various time points after the operation (P<0.05 and 0.01). The thermal paw withdrawal latency and mechanical paw withdrawal reflex threshold of rats in ARR and Nimodipine groups were significantly higher than those in the model group from the day 5 after the operation (P<0.05 and 0.01). The thermal paw withdrawal latency and mechanical paw withdrawal reflex threshold of rats in ARR+Nimodipine group were significantly higher than those in the model group from the day 3 after the operation (P<0.05 and 0.01), and were significantly higher than those of both in ARR and Nimodipine groups from the day 5 after the operation (P<0.05 and 0.01). Analgesic effects of ARR+Nimodipine group were better than those of separate ARR and Nimodipine groups. Conclusion: The aqueous extract from ARR combined with Nimodipine has the ideal analgesic effects.