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1.
Zhongguo Zhong Yao Za Zhi ; 47(7): 1932-1941, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35534264

RESUMO

This study aims to explore the toxicity mechanism of Rhododendri Mollis Flos(RMF) based on serum metabolomics and network toxicology. The toxic effect of RMF on normal rats was evaluated according to the symptoms, serum biochemical indexes, and histopathology. Serum metabolomics was combined with multivariate statistical analysis to search endogenous differential metabolites and related metabolic pathways. The toxic components, targets, and signaling pathways of RMF were screened by network toxicology technique, and the component-target-metabolite-metabolic pathway network was established with the help of serum metabolomics. The result suggested the neurotoxicity, hepatotoxicity, and cardiotoxicity of RMF. A total of 31 differential metabolites and 10 main metabolic pathways were identified by serum metabolomics, and 11 toxic components, 332 related target genes and 141 main signaling pathways were screened out by network toxicology. Further analysis yielded 7 key toxic components: grayanotoxin Ⅲ,grayanotoxinⅠ, rhodojaponin Ⅱ, rhodojaponin Ⅴ, rhodojaponin Ⅵ, rhodojaponin Ⅶ, and kalmanol, which acted on the following 12 key targets: androgen receptor(AR), albumin(ALB), estrogen receptor ß(ESR2), sex-hormone binding globulin(SHBG), type 11 hydroxysteroid(17-beta) dehydrogenase(HSD17 B11), estrogen receptor α(ESR1), retinoic X receptor-gamma(RXRG), lactate dehydrogenase type C(LDHC), Aldo-keto reductase(AKR) 1 C family member 3(AKR1 C3), ATP binding cassette subfamily B member 1(ABCB1), UDP-glucuronosyltransferase 2 B7(UGT2 B7), and glutamate-ammonia ligase(GLUL). These targets interfered with the metabolism of gamma-aminobutyric acid, estriol, testosterone, retinoic acid, 2-oxobutyric acid, and affected 4 key metabolic pathways of alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism, steroid hormone biosynthesis, and retinol metabolism. RMF exerts toxic effect on multiple systems through multiple components, targets, and pathways. Through the analysis of key toxic components, target genes, metabolites, and metabolic pathways, this study unveiled the mechanism of potential neurotoxicity, cardiotoxicity, and hepatotoxicity of RMF, which is expected to provide a clue for the basic research on toxic Chinese medicinals.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Animais , Cardiotoxicidade , Medicamentos de Ervas Chinesas/toxicidade , Hormônios , Metabolômica , Ratos
2.
Zhongguo Zhong Yao Za Zhi ; 47(8): 1989-1994, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35531713

RESUMO

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.


Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Medicamentos de Ervas Chinesas/toxicidade , Projetos de Pesquisa
3.
Zhongguo Zhong Yao Za Zhi ; 47(4): 1085-1094, 2022 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-35285209

RESUMO

This study systematically searched CNKI and Web of Science(WoS) for the research papers on the toxicity of Tripterygium wilfordii included from database inception to August 31, 2021, and visually displayed the authors, research institutions, keywords, and other contents using bibliometrics and CiteSpace 5.8.3. Furthermore, the current situation and research progress on T. wilfordii safety were also analyzed based on information extraction to find the research hotspot, evolution path, and development trend, and to provide references for future research. A total of 1 876 Chinese papers and 243 English papers were included in the study. The analysis of authors showed that WANG Qi and ZHANG Luyong had the most publications in Chinese and English papers, respectively. According to the analysis of research institutions, National Institutes for Food and Drug Control and China Pharmaceutical University possessed the largest number of Chinese and English papers, respectively, but there was less cooperation between them. The analysis of keywords in Chinese and English papers showed that the research contents of the safety of T. wilfordii mainly focused on clinical monitoring, mechanism, dosage form improvement, quality standard, component analysis, monomer research, efficiency and toxicity reduction, etc. Metabonomics, tripterine, and the underlying mechanism of toxicity were the research hotspots in the future. At present, the research on the toxicity of T. wilfordii is still under development. It is necessary to highlight the in-depth research and strengthen the inter-group and inter-region cooperation of authors or institutions to provide references for the research on the toxicity of T. wilfordii.


Assuntos
Medicamentos de Ervas Chinesas , Tripterygium , Bibliometria , China , Medicamentos de Ervas Chinesas/toxicidade , Humanos
4.
Toxicol In Vitro ; 80: 105324, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35101544

RESUMO

In this study, the inhibitory effect of components from Chinese Herb Medicine (CHMs) with potential hepatotoxicity was assessed by human bile salt export pump (hBSEP) vesicles with and without S9 metabolism. Sixty-three compounds from 22 hepatoxicity CHMs were selected as the test articles. In hBSEP vesicles, eighteen of them were found to have moderate or strong inhibitory effect towards BSEP. Further studies were performed to determine the IC50 values of strong inhibitors. For the compounds belong to CHMs reported to cause cholestasis and strong inhibitors defined in hBSEP vesicles, their relative transport activities of Taurocholic acid (TCA) were evaluated in hBSEP vesicles as well as hBSEP vesicles with S9 system (S9/hBSEP vesicles). The differences of their relative transport activities of TCA between the above two system were compared to reveal the net effect of metabolism on BSEP's activity. It was found that the inhibitory effect of Saikogenin A (SGA), Saikogenin D (SGD), Diosbulbin B (DB) and rhein were significantly increased; while the inhibitory effect of isobavachalcone, saikosaponin d and saikosaponin b2 were significantly decreased after S9 metabolizing. Identification of metabolic pathways suggested that CYP3A4 was responsible for aggravating inhibitory effect of SGA and SGD against BSEP.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Medicamentos de Ervas Chinesas/toxicidade , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Colestase/metabolismo , Humanos , Fígado/metabolismo
5.
Zhongguo Zhong Yao Za Zhi ; 47(3): 611-627, 2022 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-35178943

RESUMO

A total of 33 pesticides have been banned from Chinese medicinal materials and decoction pieces(plants) according to Chinese Pharmacopoeia(2020 edition). According to the chemical structures, they are mainly divided into seven categories: organophosphorus compounds, organochlorines, carbamates, amidines, sulfonylureas, phenylpyrazoles, and ethers. These banned pesticides exhibit neurotoxicity, reproductive toxicity, immune system toxicity, teratogenicity, carcinogenesis, and mutagenesis, seriously damaging human and animal health. They affect not only the quality and safety of traditional Chinese medicines and resulting products, but also their competitiveness in the international market. Due to the numerous varieties of traditional Chinese medicines and their complex substrates, it is necessary to establish a universal and highly sensitive method for pesticide residue detection. This review systematically summarized the residual status, toxicity, and analytical methods of banned pesticides in traditional Chinese medicines, and forecasted the prospects of different analytical techniques, so as to provide reference for further safety and risk assessment of banned pesticide residues in traditional Chinese medicines, thus ensuring the safe production of traditional Chinese medicines.


Assuntos
Medicamentos de Ervas Chinesas , Resíduos de Praguicidas , Praguicidas , China , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Medicina Tradicional Chinesa , Compostos Organofosforados , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/toxicidade , Praguicidas/análise
6.
Zhongguo Zhong Yao Za Zhi ; 47(2): 511-527, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35178996

RESUMO

In this study, the toxicological/pharmacological research method of "quantity-weight-evidence" network was first proposed and practiced to supplement the existing methodology of network toxicology. We transformed the traditional qualitative network into a quantitative network in this study by attributing weights to toxic component content and target frequency, which improved the reliability of data and provided a research idea for the systematic safety evaluation and toxicological research of Chinese medicinal herbs. Firstly, 50% ethanol extract of Dysosma versipellis(DV) was administrated to rats via gavage and the potential hepatotoxic components were identified by serum pharmacochemistry. Then, the component targets were obtained from SwissTargetPrediction, PharmMapper and other online databases, and the target weights were given according to the relative content of components and target fishing frequency. Meanwhile, the targets of hepatotoxicity were predicted from online databases such as Comparative Toxicology Database(CTD) and GeneCards. Subsequently, protein-protein interaction analysis and KEGG pathway enrichment were performed with the STRING database. Finally, the quantitative network of "toxic components-weighted targets-pathways" was constructed. Eleven potential toxic compounds were predicted, including podophyllotoxin, podophyllotoxone, deoxypodophyllotoxin, and 6-methoxypodophyllotoxin. A total of 106 hepatotoxic targets and 65 weighted targets(e.g., Cdk2, Egfr, and Cyp2 c9) were identified. The results of Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment showed that these targets could act on PI3 K-AKT, MAPK, and Ras signaling pathways to play a role in inflammatory response and oxidative stress. However, traditional network toxicology showed that 51 targets such as AKT1, Alb, and Stat3 may lead to hepatotoxicity by mediating inflammation and cell proliferation. In conclusion, we proposed "quantity-weight-evidence" network toxicology in this study and used it to study the mechanism of DV-induced hepatotoxicity in rats. This study confirms the feasibility of this new methodology in toxicological evaluation and further improves the systematic evaluation of the safety of Chinese medicinal herbs.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/toxicidade , Etanol , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Ratos , Reprodutibilidade dos Testes
7.
J Ethnopharmacol ; 289: 115053, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35104575

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Houttuynia cordata Thunb., a plant belonging to the family of Saururaceae, has been used as a traditional Chinese medicine for more than 1500 years. Because of its various pharmacological activities, it was widely used as antipyretic, detoxification, anti-inflammatory drugs. Houttuynia cordata (HC) injection was prepared using contemporary methods to extract effective components from H. cordata Thunb. However, the adverse event reports of HC injection are accumulating remarkably with the HC injection clinical applications increased. Previous studies demonstrated that the major side effects of HC injection were anaphylactoid reactions. Our work might shed the light on the role of Mas-related G-protein coupled receptor-X2 (MRGPRX2) in modulating drug-induced anaphylactoid reactions. AIM OF THE STUDY: We aimed to investigate the role of the mouse Mas-related G-protein coupled receptor B2 (Mrgprb2) (the orthologous gene of human MRGPRX2) in anaphylactoid reactions induced by HC injection. MATERIALS AND METHODS: Mrgprb2 related anaphylactoid reactions induced by HC injection were investigated by histamine/ß-hexosaminidase releasing, mast cell degranulation, and hind paw swelling assays by using a Mrgprb2 knockout mouse model. Furthermore, the transcriptomic profiles of the anaphylactoid reaction induced by HC injection was analyzed by RNA sequencing. RESULTS: Mice without Mrgprb2 exhibited significantly decreasing in mast cell degranulation, serum histamine release, and hind paw swelling degrees. The RNA sequencing results indicated that Mrgprb2 could play a pivotal role in HC injection induced anaphylactoid reaction mediated by mTOR/AMPK pathway. Intriguingly, our results showed that Mrgprb2 might involve in Compound 48/80 induced anaphylactoid reactions mediated by Reelin/E-cadherin axis, which suggested different roles of Mrgprb2 in anaphylactoid reactions induced by HC injection and C48/80. CONCLUSION: Our studies reported effects and underlying mechanisms of Mrgprb2 in the anaphylactoid reaction induced by HC injection.


Assuntos
Anafilaxia/etiologia , Medicamentos de Ervas Chinesas/toxicidade , Houttuynia/química , Receptores Acoplados a Proteínas G/genética , Anafilaxia/genética , Animais , Degranulação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Liberação de Histamina/efeitos dos fármacos , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , p-Metoxi-N-metilfenetilamina/toxicidade
8.
Biomed Chromatogr ; 36(5): e5321, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34984711

RESUMO

To evaluate the detoxification effect of a combination of Radix Glycyrrhizae (GU) and Semen Strychni (SN) from toxicokinetics and drug tissue distribution perspectives, decoctions of processed SN and codecoction of SN and GU (SGN) were prepared, and an HPLC-ESI-MS/MS method was developed to monitor the severe exposure level in 1-month toxicokinetics and tissue distribution experiments to detect brucine and strychnine in rats. The toxicokinetic characteristics and tissue distribution before and after the addition of GU were analyzed. The method was successfully applied to evaluate the toxicokinetics and tissue distribution before and after the combination of SN and GU. The results show that GU decreased the blood concentration of toxic components in SN, and a double peak was observed in the drug time curve. The results of tissue distribution show that a combination of GU and SN significantly decreased the accumulation of toxic substances in metabolic organs and accelerated the clearance of toxic substances in the brain. These results provide a reference for the toxicity reduction mechanism of GU combined with SN.


Assuntos
Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , Administração Oral , Animais , Medicamentos de Ervas Chinesas/toxicidade , Ratos , Sementes , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual , Toxicocinética
9.
Toxicol Lett ; 357: 84-93, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35017030

RESUMO

The association of herb medicine Cortex Dictamni (CD) with severe even fatal hepatotoxicity has been widely reported. Recently, we demonstrated that the metabolic activation of at least ten furanoids in CD was responsible for the liver injury caused by the ethanol extract of CD (ECD) in mice. Protein adduction by reactive metabolites is considered to initiate the process of liver injury. Unlike single chemicals, the mode of and the details of protein modification by multiple components in an herb is unclear. This study aimed to characterize protein adductions derived from the reactive metabolite of furanoids in ECD-treated mice and define the association of protein adduction with liver injury. The hepatic cysteine- and lysine-based protein adducts derived from epoxide or cis-enedione of at least six furanoids were identified in mice. The furanoids with an earlier serum content Tmax were mainly to bind with hepatic glutathione and no protein adducts were formed except for dictamnine. The hepatic proteins were modified by the later absorbed furanoids. The levels of hepatic protein adduct were correlated with the degree of liver injury. In addition, the reactive metabolites of different furanoids can simultaneously bind to the model peptide by the identical reactive moiety, indicating the additive effects of the individual furanoids in the modification of hepatic proteins. In conclusion, hepatic protein adduction by multiple furanoids may play a role in ECD-induced liver injury. The earlier absorbed furanoids were mainly to bind with glutathione whereas the hepatic proteins were modified by the later furanoids.


Assuntos
Dictamnus/química , Furanos/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Plantas Medicinais/toxicidade , Proteínas/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas , Cisteína/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Etanol/química , Glutationa/metabolismo , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Extratos Vegetais/efeitos adversos , Plantas Medicinais/química
10.
Toxicol Lett ; 354: 1-13, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34718095

RESUMO

Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-α (Tnf-α) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-α and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1ß, IL-1ß and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B p65 (NF-κB p65), in the female mouse livers. In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-κB inhibition.


Assuntos
Antraquinonas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Peixe-Zebra/metabolismo , Animais , Cassia/química , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Humanos , Larva/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacos
11.
J Ethnopharmacol ; 285: 114798, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34780984

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Arisaema belongs to the family Araceae, which includes Chinese herbal medicines with wide-ranging pharmacological functions, including those useful for the treatment of stubborn phlegm, cough, epilepsy, tetanus, snakebite, rheumatoid arthritis, and other ailments. AIM OF THE STUDY: The current study aimed to comprehensively review the botany, uses, phytochemistry, pharmacology, toxicity, quality control and pharmacokinetics of plants in the genus Arisaema and to provide novel insights to develop future research in this field. MATERIALS AND METHODS: Relevant information on the genus Arisaema was obtained from published scientific materials (including materials from PubMed, Elsevier, Web of Science, Google Scholar, Baidu Scholar, CNKI, and Wiley) and other literature sources (e.g., the Chinese Pharmacopoeia, 2020 edition; Chinese herbal books and PhD and MSc thesis). RESULTS: The application information complied with this review and included processing techniques, traditional uses, clinical applications and classic prescriptions. Approximately 260 compounds, including flavonoids, alkaloids, saccharides, steroids, fatty acids, amino acids and volatile oils, have been separated and identified from the genus Arisaema. The isolated compounds exhibit wide-ranging pharmacological activities such as antitumor activity, analgesic and sedative activity, antioxidant activity and anti-inflammatory activity. The toxicity and irritant impacts, quality control, and pharmacokinetics are also discussed in this review. CONCLUSIONS: Plants in the genus Arisaema are valuable resources with therapeutic potential for a broad spectrum of ailments. Based on the limited literature, this review comprehensively and systematically summarizes current knowledge regarding the genus Arisaema for the first time. However, there have been insufficient studies on the active ingredients and germplasm and insufficient in-depth mechanistic studies. Therefore, isolation and identification of additional effective components and through research on the germplasm, pharmacodynamic mechanisms, and toxicology should be conducted to assess effectiveness and safety and to ensure the quality of the related drugs.


Assuntos
Arisaema , Medicamentos de Ervas Chinesas , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/toxicidade , Etnofarmacologia , Humanos , Medicina Tradicional Chinesa/métodos
12.
J Ethnopharmacol ; 283: 114735, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34637969

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Qing' E Formula (QEF) is a compound preparation that was originally recorded in the 'Prescriptions of the Bureau of Taiping People's Welfare Pharmacy' during the Song Dynasty (10th century CE). It consists of four Chinese medicinal herbs, Eucommiae Cortex (Eucommia ulmoides), Psoraleae Fructus (Psoralea corylifolium), Juglandis Semen (Juglans regia), and Garlic Rhizoma. According to traditional Chinese medicine (TCM), QEF has the ability to tonify the kidney and strengthen muscle and bone. According to the 'kidney governing bone' theory in TCM, QEF is also used to treat the symptoms of climacteric syndrome, especially osteoporosis caused by reduced production of estrogen during the perimenopausal period; however, the therapeutic roles of the individual components of the QEF and their compatibility within the formula has not been investigated. AIM OF THE STUDY: In this study, the compatibility mechanism and estrogen-like action properties of the four herbal components in the QEF was elucidated according to the organizing principle of Chinese medicine formulas using both in vitro and in vivo models. MATERIALS AND METHODS: The estrogen-like effects of QEF and its herbal components were investigated in MCF7 and HEK293 cells as well as ovariectomized (OVX) rats. The estrogen-like effects of the QEF and its components were analyzed in vitro using Cell Counting Kit-8 and Luciferase reporter gene assays. In the in vivo studies, the blood plasma levels of hormones, lipids, neurotransmitters, aromatase, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured through enzyme-linked immunosorbent assays (ELISAs). The histological morphologies of the target organs after exposure to QEF were investigated by HE staining and immunohistochemical methods. The expression levels of estrogen pathway-related proteins and genes in the OVX rats were measured by Western blotting and real time quantitative PCR (RT-qPCR), respectively. RESULTS: The in vitro results showed that the QEF, Eucommia (EC) and Psoralea (PF) promoted the proliferation of MCF-7 cells and upregulated the expression of ERα, ERß and pS2 genes in the MCF-7 cells. Notably, the QEF demonstrated the most active estrogen-like effects compared to the individual ingredients. The in vivo results showed that the QEF, EC, and PF increased the uterine coefficient, upregulated the expression of both ERs (ERα and ERß) in the uterus, and increased blood serum hormone levels. QEF and its individual components ameliorated menopausal-derived lipid metabolism dysfunction, increased neurotransmitter production by stimulating the adrenal glands, enhanced the antioxidant activity in the serum by increasing the concentration of SOD, reversed ovariectomy-derived atrophy in the uterus, and reduced the weight gain associated with estrogen reduction in the OVX rats. The QEF also antagonize the loss of appetite of OVX animals caused by feeding Psoralea alone, which could explain the compatibility mechanism of Qing' E Formula with reducing toxicity and increasing efficiency. CONCLUSIONS: The estrogen-like effects of Eucommia and Psoralea were mainly mediated through activation of ERα and ERß. The phytoestrogen components regulated hormone production and the expression of related proteins and genes, which indicated that these components exhibited estrogen-like therapeutic effects. However, the QEF showed the greatest estrogen-like effects compared to the individual components. Overall, this corroborated the therapeutic prowess of the QEF and clarified the pharmacodynamic interactions between the different components extracts in the QEF.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Menopausa/efeitos dos fármacos , Fitoestrógenos/farmacologia , Animais , Antioxidantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Células HEK293 , Humanos , Células MCF-7 , Ovariectomia , Fitoestrógenos/química , Fitoestrógenos/toxicidade , Ratos , Ratos Sprague-Dawley
13.
J Ethnopharmacol ; 282: 114638, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34530096

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has been applied for more than 2000 years. However, modern basic research on the safety of TCMs is limited. Establishing safety evaluation technology in line with the characteristics of TCM and conducting large-scale basic toxicity research are keys to comprehensively understand the toxicity of TCMs. In recent years, zebrafish has been used as a model organism for toxicity assessment and is increasingly utilized for toxicity research of TCMs. Yet, a comprehensive review in using zebrafish as a toxicological model for TCMs is lacked. AIM OF THE STUDY: We aim to summarize the progress and limitation in toxicity evaluation of TCMs using zebrafish and put forward the future research ideas. MATERIALS AND METHODS: The scientific databases, including Springer, Science Direct, Wiley, Pubmed and China Knowledge Resource Integrated (CNKI) were searched using the key words of zebrafish, toxicology, traditional Chinese medicine, acute toxicity, liver injury, cardiotoxicity, kidney toxicity, developmental toxicity, neurotoxicity, gastrointestinal irritation, immunotoxicity, ototoxicity, and osteotoxicity. RESULTS: Zebrafish assays are low experimental cost and short cycle, easily achieving high-throughput toxicity screening, and exemption from ethical legislation up to 5 dpf. It has been widely used to evaluate the acute toxicity, liver toxicity, cardiotoxicity, nephrotoxicity, developmental toxicity, neurotoxicity, gastrointestinal irritation, immunotoxicity, and ototoxicity caused by TCMs, although some physiological difference limited its application. CONCLUSIONS: Zebrafish is a powerful model for TCMs toxicity evaluation, but it is not flawless. The toxicity testing criterion and high throughput assays are urgent to be established. This review provides references for future studies.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Modelos Animais , Testes de Toxicidade/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Medicina Tradicional Chinesa , Peixe-Zebra
14.
J Pharm Biomed Anal ; 208: 114471, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34814080

RESUMO

Yunaconitine (YAC), crassicauline A (CCA), 8-deacetylyunaconitine (DYA), and 8-deacetylcrassicauline A (DCA), as hidden toxic Aconitum alkaloids, are detected in some products of processed Aconitum carmichaelii lateral root and poisoning cases. The distribution and toxicity of these four components in Aconitum herbs should be further systematically studied for medication safety. This study developed a new UHPLC-QQQ-MS/MS method to determine ten Aconitum alkaloids, including aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, benzoylhypaconine, YAC, CCA, DYA, and DCA, for Aconitum herbs simultaneously. YAC and CCA were founded in some samples of unprocessed A. carmichaelii lateral root (7.04%), A. carmichaelii root (9.43%), A. brachypodum root (6.00%), and A. ouvrardianum root (100%). Four hidden toxic Aconitum alkaloids were detected in processed A. carmichaelii lateral root (2.56%) and A. vilmorinianum root (100%). Four hidden toxic Aconitum alkaloids played significant roles in the classification of Aconitum herbs by OPLS-DA analysis. The acute toxicity test was performed by up-and-down procedure (UDP). The oral administration of the half lethal dose (LD50) of YAC, CCA, DYA, and DCA to female ICR mice was 2.37 mg/kg, 5.60 mg/kg, 60.0 mg/kg, and 753 mg/kg, respectively. The LD50 by intravenous injection was 0.200 mg/kg, 0.980 mg/kg, 7.60 mg/kg, and 34.0 mg/kg, respectively. The LD50 of unprocessed A. carmichaelii lateral root, A. vilmorinianum root, and A. brachypodum root to mice orally was 1.89 g/kg, 0.950 g/kg, and 0.380 g/kg, respectively. Symptoms of Aconitum alkaloid poisoning in mice were decreased activity, fur erect, palpebral edema, vomiting, polypnea, and convulsions. The main change of organs was flatulence. No poisoning or death occurred in mice at the maximum dosage (27.0 g/kg) of A. ouvrardianum root orally. To better control the quality and safety of Aconitum herbs, this study provides favorable support for improving the existing standards to strengthen the supervision of the four hidden toxic Aconitum alkaloids.


Assuntos
Aconitum , Alcaloides , Medicamentos de Ervas Chinesas , Aconitina/toxicidade , Alcaloides/toxicidade , Animais , Medicamentos de Ervas Chinesas/toxicidade , Camundongos , Camundongos Endogâmicos ICR , Raízes de Plantas , Espectrometria de Massas em Tandem
15.
Parasitol Int ; 87: 102532, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34933121

RESUMO

Plasmodium falciparum, the most virulent human malaria parasite, causes serious diseases among the infected patients in the world and is particularly important in African regions. Although artemisinin combination therapy is recommended by the WHO for treatment of P. falciparum-malaria, the emergence of artemisinin-resistant parasites has become a serious issue which underscores the importance of sustained efforts to obtain novel chemotherapeutic agents against malaria. As a part of such efforts, thirty-nine herbal extracts from traditional Chinese medicine (TCM) were assayed for their anti-malarial activity using 3D7 strain of P. falciparum. Three herbal supplements appeared to possess higher specific anti-malarial activity than the others. One of them (D3) was separated by two sequential fractionations with reverse-phase (the first step) and normal-phase (the second step) liquid chromatography, in which some fractions resulted in higher specific activities than those of D3 or the previous fractions. Cell toxicity assay was performed with the fractions of the first fractionation and demonstrated no obvious cell toxicity. These results suggest that structure determination of the major compound for the anti-malarial activity in D3 may help the development of more potent chemicals in the future.


Assuntos
Antimaláricos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Inonotus/química , Malária Falciparum/tratamento farmacológico , Panax notoginseng/química , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Resistência a Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Células HeLa , Humanos , Concentração Inibidora 50 , Japão
16.
J Ethnopharmacol ; 287: 114940, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-34968665

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sanren decoction (SRD) is a well-known traditional Chinese medicine prescription containing eight kinds of materials. SRD has been used mainly in China for more than 200 years for the treatment of respiratory disorders that co-occur with a bad fever after midday. AIM OF THE STUDY: To evaluate the acute and 28-day subacute toxicity of an aqueous extract of SRD using in vivo methods. MATERIALS AND METHODS: To determine acute toxicity, SRD was administered by gavage at a dosage of 58.5 g/kg/day to male and female mice for 7 days. To determine subacute toxicity, SRD was administered at 3.3, 6.5, or 13 g/kg/day to male and female rats for 28 days. The general behavior, body weight, biochemical and hematological parameters, organ coefficients and pathological morphology of the treated animals were analyzed. RESULTS: Neither acute nor subacute concentrations of SRD caused significant changes in the body weights, general behavior, hematology and biochemical parameters, organ weights, or histopathological appearances of the liver, kidney, spleen, brain, lung or heart in mice or rats. CONCLUSIONS: The administration of SRD can be considered safe within the conditions of this study.


Assuntos
Peso Corporal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/toxicidade , Tamanho do Órgão/efeitos dos fármacos , Animais , Animais não Endogâmicos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
17.
Pharm Biol ; 59(1): 1359-1368, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34915801

RESUMO

CONTEXT: Jiang Zhi Granule (JZG) is known to improve hepatic function, reduce liver fat deposition and inflammation in non-alcoholic fatty liver disease (NAFLD). OBJECTIVE: To determine the protective mechanism of JZG on immunological barrier of intestinal mucosa in rats with diet-induced non-alcoholic steatohepatitis (NASH). MATERIALS AND METHODS: A Sprague-Dawley (SD) model of NASH was established using a high-fat diet and 1% dextran sulphate sodium (DSS) through drinking water. The rats were randomized into four groups and treated for four weeks, respectively, including normal control (NC), model control (MC), positive control (PC) and JZG. Mesenteric lymph nodes (MLNs) cells were isolated and cultured to assess a potential disruption of the enteric immune barrier. Also, investigation of intestinal mucosal dendritic cell-toll-like-receptor-myeloid differentiation primary response 88 (DC-TLR-MyD88) signalling pathway in vitro was examined. RESULTS: The lethal concentration 50 (LD50) of JZG was greater than 5 g/kg, while its inhibitory concentration 50 (IC50) was 1359 µg/mL in HepG2. In JZG group, the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST), malondialdehyde (MDA), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG) and serum endotoxin were significantly (p < 0.01) reduced. In contrast, plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and superoxide dismutase (SOD) were increased. Furthermore, proinflammatory factor, interferon-γ (IFN-γ)+ from CD4+ T cells in DSS-induced NASH rats increased significantly (p < 0.01) compared to NC group. Importantly, JZG treatment substantially decreased (p < 0.01) the relative expressions of TLR-44 and MyD88. CONCLUSIONS: JZG treatment may protect immunological barrier of intestinal mucosa in NASH individual.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Sulfato de Dextrana , Dieta Hiperlipídica , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Células Hep G2 , Humanos , Concentração Inibidora 50 , Mucosa Intestinal/imunologia , Dose Letal Mediana , Masculino , Fator 88 de Diferenciação Mieloide/genética , Hepatopatia Gordurosa não Alcoólica/imunologia , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética
18.
Phytomedicine ; 93: 153518, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34735910

RESUMO

BACKGROUND: The hepatotoxicity of Chinese herbal medicine (CHM) is an important reason for its restrictive application. Psoraleae Fructus (PF), a commonly used CHM for treatment of osteoporosis and vitiligo etc., has caused serious concern due to the frequent occurrence of liver injury incidents. To date, its hepatotoxic equivalent markers (HEMs) and potential mechanisms are still unclear. PURPOSE: To discover and validate the HEMs of PF and further explore the potential mechanisms of hepatotoxicity. METHODS: Multi-parametric cellular imaging was performed by high content screening, and multi-component quantitative profiling was conducted by ultra-high performance liquid chromatography coupled with triple-quadrupole mass spectrometry. The correlations between hepatotoxic features and component contents were modeled by chemometrics including partial least square regression, back propagation-artificial neural network, and hierarchical cluster analysis. Then the candidate HEMs of PF were screened out and subjected to hepatotoxic equivalence assessment in primary hepatocytes, zebrafish, and mice, and the hepatotoxic mechanisms of PF were investigated. RESULTS: The chemical combination of psoralen and isopsoralen was discovered as the HEMs of PF through pre-screening and verifying process. PF was demonstrated to induce oxidative stress, mitochondrial dysfunction and cellular apoptosis. CONCLUSIONS: This study not only provides a rational strategy for screening HEMs from CHMs like PF, but also contributes to understanding the underlying mechanisms of PF hepatotoxicity.


Assuntos
Medicamentos de Ervas Chinesas , Animais , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/toxicidade , Frutas , Fígado , Camundongos , Peixe-Zebra
19.
Sci Rep ; 11(1): 23083, 2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845218

RESUMO

In recent decades, herbal medicines have played more and more important roles in the healthcare system in the world because of the good efficacy. However, with the increasing use of herbal medicines, the toxicity induced by herbal medicines has become a global issue. Therefore, it is needed to investigate the mechanism behind the efficacy and toxicity of herbal medicines. In this study, using Aconiti Lateralis Radix Praeparata (Fuzi) as an example, we adopted a systems pharmacology approach to investigate the mechanism of Fuzi in treating rheumatoid arthritis and in inducing cardiac toxicity and neurotoxicity. The results showed that Fuzi has 25 bioactive compounds that act holistically on 61 targets and 27 pathways to treat rheumatoid arthritis, and modulation of inflammation state is one of the main mechanisms of Fuzi. In addition, the toxicity of Fuzi is linked to 32 compounds that act on 187 targets and 4 pathways, and the targets and pathways can directly modulate the flow of Na+, Ca2+, and K+. We also found out that non-toxic compounds such as myristic acid can act on targets of toxic compounds and therefore may influence the toxicity. The results not only reveal the efficacy and toxicity mechanism of Fuzi, but also add new concept for understanding the toxicity of herbal medicines, i.e., the compounds that are not directly toxic may influence the toxicity as well.


Assuntos
Aconitum/metabolismo , Artrite Reumatoide/tratamento farmacológico , Diterpenos/farmacologia , Diterpenos/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Algoritmos , Química Farmacêutica/métodos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Medicina Tradicional Chinesa/métodos , Extratos Vegetais/farmacologia , Plantas Medicinais/metabolismo , Mapeamento de Interação de Proteínas
20.
Artigo em Inglês | MEDLINE | ID: mdl-34800750

RESUMO

Euodiae Fructus (EF), the dried unripe scented fruit of Euodia rutaecarpa (Juss.) Benth., was reported to show anti-hypertensive, antitumor, and anti-obesity effects. The main alkaloids of EF were reported as the reason for toxicity of EF by metabolic activation majority through CYP3A. Up till the present moment, the cytotoxicity mechanisms of EF have not yet to be fully clarified. For the purposes of this article, the influence of CYP3A inducer and inhibitor on cytotoxicity of EF and metabolism in L02 cells of five alkaloids related to toxicity of EF were evaluated. The results indicated that CYP3A inducer aggravated the toxicity and CYP3A inhibitor alleviated the toxicity. UPLC-Q-Exactive-MS was used for the identification of five alkaloids of EF in L02 cells. A total of 13 metabolites were detected in L02 cells. In general, five alkaloids were widely metabolized in L02 cells such as oxygenation, demethylation, dehydrogenation, and etc. In addition, oxygenation was the main metabolic pathway. It was inferred that the toxicity of EF was closely related to the CYP3A and the metabolic intermediate might be one of the reasons for the toxicity of EF. Hence, the choice of optimal dose might be critical to avoid the adverse reactions owing to combination of EF and CYP3A inducer.


Assuntos
Alcaloides/química , Inibidores do Citocromo P-450 CYP3A/toxicidade , Medicamentos de Ervas Chinesas/toxicidade , Evodia/toxicidade , Fígado/efeitos dos fármacos , Alcaloides/metabolismo , Alcaloides/toxicidade , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/metabolismo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Evodia/química , Evodia/metabolismo , Frutas/química , Frutas/metabolismo , Frutas/toxicidade , Humanos , Fígado/enzimologia , Espectrometria de Massas
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