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ObjectiveMetabolomics was used to reveal the mechanism of Aconiti Lateralis Radix Praeparata（ALRP） in attenuating toxicity by processing from the aspects of amino acid metabolism， oxidative stress and energy metabolism by analyzing multiple metabolic pathways. MethodTwenty-four rats were randomly divided into control group， raw group and processed group， 8 rats in each group. The raw and processed group were given with 0.64 g·kg-1 of raw ALRP and processed ALRP respectively every day， the control group was given with an equal amount of normal saline once a day. After continuous administration for 7 days， the urine， serum and heart tissue of rats were collected. Pathological examination of the heart was carried out using hematoxylin-eosin（HE） staining， and the activities of lactate dehydrogenase（LDH） and creatine kinase-MB（CK-MB） in serum and cardiac tissues were detected by microplate assay and immunoinhibition assay. The effects of ALRP on rat heart before and after processing were compared and analyzed. Ultra performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS） was used to perform urine metabolomics analysis， and multivariate statistical analysis was used to screen for differential metabolites related to ALRP in attenuating toxicity by processing， and pathway enrichment analysis was carried out to explore the processing mechanism. ResultHE staining showed that no obvious pathological changes were observed in the heart tissue of the control group， while obvious infiltration of inflammatory cells such as plasma cells and granulocytes was observed in the heart tissue of the raw group， indicating that the raw ALRP had strong cardiotoxicity. There was no significant difference in HE staining of heart tissue between the processed group and the control group， indicating that the toxicity of ALRP was significantly reduced after processing. Compared with the control group， the activities of LDH and CK-MB were significantly increased in serum and heart tissue of the raw group， and those were significantly decreased in serum and heart tissue of the processed group， suggesting that the myocardial toxicity of processed ALRP was reduced. A total of 108 endogenous differential metabolites associated with the raw ALRP were screened using multivariate statistical analysis in positive and negative modes， of which 51 differential metabolites were back-regulated by the processed ALRP. Biological analysis of the key regulatory pathways and associated network changes showed that the pathways related to toxicity of ALRP mainly included tryptophan metabolism， arginine and proline metabolism， phenylalanine metabolism， aminoacyl-tRNA biosynthesis， alanine， aspartate and glutamate metabolism， etc. The metabolic pathways related to the attenuation of processed ALRP mainly included aminoacyl-tRNA biosynthesis， tryptophan metabolism， phenylalanine， tyrosine and tryptophan biosynthesis， phenylalanine metabolism and caffeine metabolism. ConclusionThe processing technology of ALRP in Guilingji can significantly attenuate the cardiotoxicity of raw products， the mechanism mainly involves amino acid metabolism， oxidative stress and energy metabolism， which can provide experimental bases for the research related to the mechanism of toxicity reduction of ALRP by processing and its clinical safety applications.
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As the smallest combination unit of Chinese medicinals， herbal pairs serve as the bridge between medicinals and formulas， whose combination theory reflects the basic characteristics of Chinese medicinals combination and the core essence of prescription composition. Simultaneously， as a key combination of medicinals in clinical treatment of diseases， syndromes， and symptoms， herbal pairs are the main form of clinical medication in traditional Chinese medicine （TCM） as well as the characteristic advantage of treating diseases. This article summarized that “mutual complement of medicinals of same or antagonism flavor and nature” theory is the theoretical origin， and efficacy-enhancement and toxicity-attenuation is the core purpose of the combination of herbal pairs. The property theory of Chinese medicinals and the thought of differentiation and treatment are the main basis of the combination of herbal pairs， and pertinence and flexibility are the key points in clinical application. All mentioned above are expected to provide theoretical guidance for the clinical use and modern research of herbal pairs.
ABSTRACT
@#As the smallest combination unit of Chinese medicinals， herbal pairs serve as the bridge between medicinals and formulas， whose combination theory reflects the basic characteristics of Chinese medicinals combination and the core essence of prescription composition. Simultaneously， as a key combination of medicinals in clinical treatment of diseases， syndromes， and symptoms， herbal pairs are the main form of clinical medication in traditional Chinese medicine （TCM） as well as the characteristic advantage of treating diseases. This article summarized that “mutual complement of medicinals of same or antagonism flavor and nature” theory is the theoretical origin， and efficacy-enhancement and toxicity-attenuation is the core purpose of the combination of herbal pairs. The property theory of Chinese medicinals and the thought of differentiation and treatment are the main basis of the combination of herbal pairs， and pertinence and flexibility are the key points in clinical application. All mentioned above are expected to provide theoretical guidance for the clinical use and modern research of herbal pairs.
Subject(s)
Herb-Drug InteractionsABSTRACT
This study explored toxicity attenuation processing technology of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction for the first time, and further explored its detoxification mechanism. Nine processed products of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction were prepared by orthogonal experiment with three factors and three levels. Based on the decrease in the content of the main hepatotoxic component diosbulbin B before and after processing of Rhizoma Dioscoreae Bulbiferae by high-performance liquid chromatography, the toxicity attenuation technology was preliminarily screened out. On this basis, the raw and representative processed products of Rhizoma Dioscoreae Bulbiferae were given to mice by gavage with 2 g·kg~(-1)(equival to clinical equivalent dose) for 21 d. The serum and liver tissues were collected after the last administration for 24 h. The serum biochemical indexes reflecting liver function and liver histopathology were combined to further screen out and verify the proces-sing technology. Then, the lipid peroxidation and antioxidant indexes of liver tissue were detected by kit method, and the expressions of NADPH quinone oxidoreductase 1(NQO1) and glutamate-cysteine ligase(GCLM) in mice liver were detected by Western blot to further explore detoxification mechanism. The results showed that the processed products of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction reduced the content of diosbulbin B and improved the liver injury induced by Rhizoma Dioscoreae Bul-biferae to varying degrees, and the processing technology of A_2B_2C_3 reduced the excessive levels of alanine transaminase(ALT) and aspartate transaminase(AST) induced by raw Rhizoma Dioscoreae Bulbiferae by 50.2% and 42.4%, respectively(P<0.01, P<0.01). The processed products of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction reversed the decrease protein expression levels of NQO1 and GCLM in the liver of mice induced by raw Rhizoma Dioscoreae Bulbiferae to varying degrees(P<0.05 or P<0.01), and it also reversed the increasing level of malondialdehyde(MDA) and the decreasing levels of glutathione(GSH), glutathione peroxidase(GPX), and glutathione S-transferase(GST) in the liver of mice(P<0.05 or P<0.01). In summary, this study shows that the optimal toxicity attenuation processing technology of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction is A_2B_2C_3, that is, 10% of Paeoniae Radix Alba decoction is used for moistening Rhizoma Dioscoreae Bulbiferae and processed at 130 ℃ for 11 min. The detoxification mechanism involves enhancing the expression levels of NQO1 and GCLM antio-xidant proteins and related antioxidant enzymes in the liver.
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Mice , Animals , Antioxidants/analysis , Plant Extracts/pharmacology , Drugs, Chinese Herbal/chemistry , Rhizome/chemistry , Paeonia/chemistry , Glutathione/analysisABSTRACT
Toxicity-attenuating compatibility is an effective measure to ensure the safety of Chinese medicine. Involving the origin, processing method, compatibility mode, and dosage, it faces multiple challenges, such as the uncertainty of toxic substances, toxicity latency, indefinite safe dose, complex toxicity-efficacy relationship, and individual difference. As a result, research on clinical safety of Chinese medicine is limited by the consistency at "molecular-cellular-organ-overall" levels, unclear interaction of multiple medicinals and multiple substances, the "toxicity-efficacy-compatibility-syndrome" correlation, and the "dosage-time-toxicity-efficacy" conversion law. Therefore, following the principle of "starting from the clinical practice, verifying via the theoretical basis, and finally applying in clinical practice", we verified the toxicity at "molecular-cellular-organ-overall" levels, revealed the interaction of multiple medicinals and substances, collected evidence at multiple levels, clarified the "dosage-time-toxicity-efficacy" relationship, and tested the consistency between basic and clinical biomarkers. On this basis, we studied the toxicity-alleviating and efficacy-enhancing(preserving) compatibility characteristics, the fate of one medicinal and multiple medicinals in vivo, the molecular mechanism of toxicity, the "dosage-time-toxicity-efficacy" conversion law, and the clinical characteristics of toxic traditional Chinese medicine based on disease and syndrome. The three mechanisms of toxicity-attenuating compatibility reflect the seven-reaction theory in Chinese medicine compatibility. Finally, the strategies for safe use of Chinese medicine were proposed.
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Drugs, Chinese Herbal/toxicity , Medicine, Chinese Traditional , Research DesignABSTRACT
The research on the processing mechanism of Chinese medicine is the key and core foundation to improve processing technologies of Chinese medicine, formulate the quality standards of Chinese medicinal pieces, enhance the clinical efficacy of Chinese medicine, enrich Chinese medicine processing theories, and promote the development of Chinese medicine processing. Many researc-hers have conducted in-depth exploration on the processing mechanism of Chinese medicine in the 20 years in the 21 st century. Significant progress has been made in the transformation of chemical components during the processing, the change of active components in the body, the law of toxicity attenuation in the processing of toxic Chinese medicine, the mechanism of efficacy enhancement and toxicity attenuation of processing with auxiliary materials, and the application of new biomedical technologies. At present, the processing mechanism of multiple Chinese medicines has been preliminarily clarified, which has greatly promoted the development of Chinese me-dicine processing. The development of the processing mechanism of Chinese medicine reveals that the in vitro transformation of chemical components is combined with the in vivo absorption, transport, and metabolism, and the macroscopic biological effects of the organism are combined with the cells, molecules, targets, and pathways in the study of the processing mechanism of Chinese medicine. More attention has been paid to exploring the processing mechanism from the overall level, and a modern systematic research system on the processing mechanism of Chinese medicine has been initially formed. To further promote the scientific development of Chinese me-dicine processing, the present study proposed that the research on the processing mechanism of Chinese medicine should take Chinese medicine properties into account, focus on the influence of disease condition on the mode of action and effect strength of the drugs, comply with the characteristics of clinical compound compatibility of Chinese medicine, use the holistic view research strategies of systems bio-logy, and deeply explore the processing mechanism of Chinese medicine from traditional Chinese medicine theories and the characteristics of clinical medication of Chinese medicine.
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Drugs, Chinese Herbal/pharmacology , Medicine, Chinese Traditional , Reference Standards , Research Design , TechnologyABSTRACT
The active ingredients in some Tibetan medicinal herbs are toxic components as well,and we need to have a clear understanding of their mechanism and metabolic pathways in use. The endogenous toxic components of highly toxic Tibetan herbal medicines are mainly alkaloids, such as aconitum alkaloids, methyllycaconitine, tropane alkaloids, brucine, strychnine, papaverine and swainso-nine. The majority of endogenous toxic alkaloids in Tibetan medicine herbs exist in roots, fruits and seeds of plants, exerting neurotoxicity or cardiotoxicity as highly toxic inherent chemicals. Most alka-loids are metabolized in phaseⅠvia de-alkylation, hydroxylation, hydrolysis and other reactions, as well as in phaseⅡvia glucuronic acid and sulfonic acid conjugation. They form various metabolites with high polarities and reduced toxicities so as to be easily excreted. The closeness between the therapeutic dose and toxic dose of alkaloids components in Tibetan medicinal herbs leads to their attenuated prep-aration via frying, dairy, highland barley wine soaking, or in combination with Terminalia Chebula to decrease toxicity, as is cited classic books on in Tebitan medicine. Focused on twelve alkaloids of five classes including aconitine, tropane and brucine, we have reviewed the characteristics of their metabo-lism and transformation, as well as their toxicity attenuation and safety evaluation.
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Drug toxicity is commonly divided into intrinsic and idiosyncratic types. The former can be generally uncovered in the preclinical safety evaluation stage by conventional toxicological experiments, while the latter is usually found only in the clinical evaluation stage, which is the main cause of severe adverse reactions and withdrawal of post-marketing drugs. Assessment and prediction of idiosyncratic toxicity is a challenging problem worldwide, and is an essential in the development of translational toxicology and precision medicine. Since traditional Chinese medicines (TCMs) have been applied for thousands of years with long experience in clinical efficacy and safety, idiosyncratic toxicity is regarded as an important factor for traditional "non-toxic" medicines and is associated with multiple individual states including different diseases, syndromes, habitus, etc. However, these individual conditions related to disease are often difficult to be resolved in conventional toxicological experiments, leading to insufficient translation of the experimental results into clinical application. We took an approach of systematic analysis of the differences and similarities in toxic property, medication rule and evaluating requirement between TCMs and chemical synthetic medicines. We present a novel and clinic-associated safety assessment strategy, namely as "disease-syndrome-based toxicology", for TCMs. The strategy is able to access the relativity, susceptibility and controllability of the toxicity of TCMs. The new strategy provides a theoretical and methodological guidance to practice and development of the TCM in favor of precision medicine.
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To study the chemical component groups with toxicity alleviation effect to Realgar in Niuhuang Jiedu tablet based on ¹H-NMR metabonomics. Twenty-four male Wistar rats were divided into four groups： control group, R group (treated with Realgar), RRSPG group (treated with Realgar, the root and rhizoma of Rheum palmatum, the root of Scutellaria baicalensis, the root of Platycodon grandiflorum and the root and rhizoma of Glycyrrhiza uralensis) and RC group (treated with total anthraquinones from the root and rhizoma of R. palmatum, total flavonoids from the root of S. baicalensis, total saponins from the root of P. grandiflorum, total flavonoids and saponins from the root and rhizoma of G. uralensis). Based on ¹H-NMR spectra of urine and serum from rats, PLS-DA was performed to identify different metabolic profiles.The metabolic profiles of R group were different from that of control group, while the metabolic profiles of RC group were almost similar to control group.Total anthraquinones from the root and rhizoma of R. palmatum, total flavonoids from the root of S. baicalensis, total saponins from the root of P. grandiflorum, total flavonoids and saponins from the root and rhizoma of G. uralensis regulated energy, choline and amino acid metabolism and gut flora disorder affected by realgar's toxicity.
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OBJECTIVE:To optimize the toxicity attenuation processing technology of Amorphophallus sinensis Belval.. METH-ODS:With the overall score of taste stimulation and rabbit eye irritation of A. sinensis Belval. as the index,and based on the sin-gle factor method,orthogonal test was designed to investigate the the influences of the amount of saturated calcium hydroxide solu-tion,heating time and heating temperature on the processing effect,and verification tests as well as irratation comparison before and after processing were conducted. RESULTS:The amount of saturated calcium hydroxide solution and heating temperature had significant influence on the processing effect. The optimal processing technology was to add saturated calcium hydroxide solution 30 times as much as the amount of medicinal materials at 100 ℃ and heat it for 30 min. The verification tests showed overall scores of 8.05,8.44 and 8.37(RSD=2.5%,n=3). The average overall scores before and after processing were 0.12 and 8.54(n=10)re-spectively. CONCLUSIONS:The medicinal materials processed by the optimal technology have lower stimulation and irritation. The optimal technology is stable and reliable.
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Objective: To enhance the transformation rate of brucine and strychnine in Strychnos nux-vomica and establish a high efficient microbial transformation system by Cunninghamella blakesleeana. Methods: Based on the growth and metabolic rule of C. blakesleeana, through single-factor experiments, by using brucine sulphate and strychnine nitrate as substrates and the transformation rate of each substrate as index, several influential factors were investigated. Results: The optimal transformation condition was inoculation amount at 4%, fermentation time at 2.5 d, substrate concentration at 20 mg/L, transformation time at 3 d, culture temperature at 28°C, initial pH of medium at 6.5, and shaking speed at 150 r/min. Under the above condition, the average transformation rates of brucine sulphate and strychnine nitrate were approximate 77.75% and 77.10%, respectively. Conclusion: The average transformation rates of brucine sulphate and strychnine nitrate are increased by about 17% and 22%, respectively by C. blakesleeana, and this microbial transformation system could meet the need of the study on "toxicity attenuation and efficacy reservation" of S. nux-vomica.
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Objective To investigate the toxicity attenuation and efficacy potentiation effects of Shiquan Dabu Tang (SDT) on high dose chemotherapy in T739 mice with bladder carcinoma. Methods Mouse bladder carcinoma tissue was inoculated subcutaneously into T739 mice to establish tumor-beating mice model. The tumor-bearing mice were randomly divided into a CTX group (100, 200, 400 mg/Kg respectively), a SDT group (high or low dose respectively), a high-dose SDT combined with 200 mg/Kg CTX group and a control group. The body weight, diameter of tumor nodules and complete blood count were observed subsequently. Results Different doses of SDT could effectively inhibit tumor growth in mice. SDT + CTX treatment significantly prolonged the survival time of mice by 49.4±23.3 days (P<0.01, 0.05, 0.01), compared with high dose SDT treatment (17.4±5.77) days, 200 mg/kg CTX treatment (23±14.02) days and control group (11.75±2.06) days respectively. The peripheral platelet count increased more significantly in mice treated with SDT within a week as compared to mice without SDT treatment (P<0.05). The peripheral RBC count and liB concentration increased more significantly in mice treated with SDT for 2 weeks as compared to mice without SDT treatment (P<0.05). Conclusions SDT could enhance the anti-tumor effects of high dose CTX on tumor-bearing mice and reduce toxicity in its peripheral red blood cells. The results showed that SDT combined with high dose of CTX chemotherapy had toxicity attenuation and efficacy potentiation effects in tumor-beating T739 mice.