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BACKGROUND AND AIM: Clinical evidence for early identification and diagnosis of liver cirrhosis (LC) caused by different types of liver disease is limited. We investigated this topic through a meta-analysis of quantitative metabolomics. METHODS: Four databases were searched until October 31, 2022 for studies comparing metabolite levels between patients with different types of liver disease and control individuals. A random-effects model was applied for the meta-analysis. RESULTS: This study included 55 studies with 8266 clinical participants, covering 348 metabolites. In LC related to drug-induced liver injury (DILI), hepatitis B virus (HBV) infection, and non-alcoholic fatty liver disease (NAFLD), the primary bile acid biosynthesis (taurocholic acid: SMD, 1.08[0.81, 1.35]; P < 0.00001; glycocholic acid: SMD, 1.35[1.07, 1.62]; P < 0.00001; taurochenodeoxycholic acid: SMD, 1.36[0.94, 1.78]; P < 0.00001; glycochenodeoxycholic acid: SMD, 1.49[0.93, 2.06]; P < 0.00001), proline and arginine (l-proline: SMD, 1.06[0.53, 1.58]; P < 0.0001; hydroxyproline: SMD, 0.81[0.30, 1.33]; P = 0.002), and fatty acid biosynthesis (palmitic acid: SMD, 0.44[0.21, 0.67]; P = 0.0002; oleic acid: SMD, 0.46[0.19, 0.73]; P = 0.0008; stearic acid: SMD, 0.37[0.07, 0.68]; P = 0.02) metabolic pathways were significantly altered. CONCLUSION: We identified key biomarkers and metabolic characteristics for distinguishing and identifying LC related to different types of liver disease, providing a new perspective for early diagnosis, disease monitoring, and precise treatment.
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Cinnamomi ramulus (CR) is a common Chinese herbal medicine with a long history. It is often used to treat exogenous wind-cold diseases in clinic, but its chemical compositions remain to be studied. In this study, CR was extracted with 75% ethanol, and UPLC-Q-Orbitrap-MS combined with data post-processing method was used to identify the chemical components in the extract. Through this technology, the components in CR can be separated and accurately identified. A total of 61 compounds were identified, including 14 simple phenylpropanoids, 3 coumarins, 5 lignans, 14 flavonoids, 10 benzoic acids, 8 organic acids, and 7 others. This study confirmed the existence of these compounds in CR and speculated the cleavage pathways of each compound, which enriched the mass spectrometry data and cleavage rules. This study can provide a reference for CR and other research.
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Cumarinas , Medicamentos Herbarios Chinos , Flavonoides , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/análisis , Cumarinas/química , Cumarinas/análisis , Flavonoides/análisis , Flavonoides/química , Lignanos/análisis , Lignanos/química , Espectrometría de Masas/métodos , Cinnamomum/química , Espectrometría de Masas en Tándem/métodosRESUMEN
RATIONALE: This study developed a method for the rapid classification and identification of the chemical composition of Qingyan dropping pills (QDP) to provide the theoretical basis and data foundation for further in-depth research on the pharmacological substance basis of the formula and the selection of quality control indexes. METHODS: Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and data postprocessing technology were used to analyze the chemical composition of QDP. The fragmentation information on possible characteristic fragments and related neutral losses was summarized based on the literature and was compared with the MS data obtained from the assay, and thus a rapid classification and identification of chemical components in QDP could be achieved. RESULTS: A total of 73 compounds were identified, namely 24 flavonoids, 14 terpenoids, 30 organic acids and their esters, 3 alkaloids, and 2 phenylpropanoids. CONCLUSIONS: In this study, UHPLC-Q-TOF-MS and data postprocessing technology were used to realize the rapid classification and identification of the chemical constituents of QDP, which provided a comprehensive, efficient, and fast qualitative analysis method, a basis for further quality control and safe medication of QDP.
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Medicamentos Herbarios Chinos , Espectrometría de Masas , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/análisis , Espectrometría de Masas/métodos , Flavonoides/análisis , Flavonoides/química , Alcaloides/análisis , Alcaloides/química , Terpenos/análisis , Terpenos/químicaRESUMEN
Huai Yam (Dioscoreae Rhizoma) contains many active ingredients such as flavonoids, saponins, and amino acids. In this study, an efficient method for the classification and rapid identification of yam components was established based on UPLC-Q-Exactive-MS and data post-processing techniques. First, the mass spectrometry information including the characteristic fragmentations (CFs) and neutral losses (NLs) of yam reported in the literature were summarised and a database of compounds was established. Then, the mass spectrometry data detected by the yam sample are compared with those described in database for rapid identification of target compounds. Finally, 60 compounds were identified, including 18 flavones, 2 saponins, 10 amino acids, 7 organic acids, 3 carbohydrates, 8 fatty acids and 12 others. A new strategy for identifying target constituents based on CFs and NLs was successfully established, laying the foundation for further research on yam and promoting the development of composition analysis of Traditional Chinese Medicine (TCM).
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Ochratoxin A (OTA) is a common fungal toxin frequently detected in food and human plasma samples. Currently, the physiologically based toxicokinetic (PBTK) model plays an active role in dose translation and can improve and enhance the risk assessment of toxins. In this study, the PBTK model of OTA in rats and humans was established based on knowledge of OTA-specific absorption, distribution, metabolism, and excretion (ADME) in order to better explain the disposition of OTA in humans and the discrepancies with other species. The models were calibrated and optimized using the available kinetic and toxicokinetic (TK) data, and independent test datasets were used for model evaluation. Subsequently, sensitivity analyses and population simulations were performed to characterize the extent to which variations in physiological and specific chemical parameters affected the model output. Finally, the constructed models were used for dose extrapolation of OTA, including the rat-to-human dose adjustment factor (DAF) and the human exposure conversion factor (ECF). The results showed that the unbound fraction (Fup) of OTA in plasma of rat and human was 0.02-0.04% and 0.13-4.21%, respectively. In vitro experiments, the maximum enzyme velocity (Vmax) and Michaelis-Menten constant (Km) of OTA in rat and human liver microsomes were 3.86 and 78.17⯵g/g min-1, 0.46 and 4.108⯵g/mL, respectively. The predicted results of the model were in good agreement with the observed data, and the models in rats and humans were verified. The PBTK model derived a DAF of 0.1081 between rats and humans, whereas the ECF was 2.03. The established PBTK model can be used to estimate short- or long-term OTA exposure levels in rats and humans, with the capacity for dose translation of OTA to provide the underlying data for risk assessment of OTA.
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Modelos Biológicos , Ocratoxinas , Toxicocinética , Ocratoxinas/toxicidad , Ocratoxinas/farmacocinética , Animales , Ratas , Humanos , Medición de Riesgo , MasculinoRESUMEN
Zanthoxylum, as a medicinal and edible herbal medicine, has a long history and complex chemical composition. There are many varieties of Zanthoxylum, and there are differences in composition between varieties. In this study, a rapid classification and identification method for the main components of Zanthoxylum was established using ultra-high-performance-liquid chromatography quadrupole-orbitrap-mass spectrometry. The components of Shandong Zanthoxylum bungeanum, Wudu Zanthoxylum bungeanum, and Zanthoxylum schinifolium were identified by studying the characteristic fragmentations and neutral losses of characteristic components. A total of 48 common components and 24 different components were identified and the fragmentation patterns of the main components, such as flavonoids, alkaloids, and organic acids were summarized. These findings provided a reference for the study of pharmacodynamic substance basis and quality control of different varieties of Zanthoxylum.
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Alcaloides , Medicamentos Herbarios Chinos , Plantas Medicinales , Zanthoxylum , Zanthoxylum/química , Plantas Medicinales/química , Medicamentos Herbarios Chinos/química , Espectrometría de Masas , Cromatografía Liquida , Cromatografía Líquida de Alta PresiónRESUMEN
The Chinese herb Qianghuo is an antiphlogistic herb with many effects and complex components. In this study, the chemical composition of Qianghuo and its components in rat plasma after oral administration were investigated using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). The extracts, blank plasma, and plasma containing the drug were analyzed by mass spectrometry, and data collected in both positive and negative ion modes were analyzed using Masslynx software, and the structures were confirmed by combining the compound fragment ions and mass spectrometry cleavage pathways. A total of 62 in vitro chemical components were identified, including 27 coumarins, 18 organic acids, 5 amino acids, 5 glycosides, 2 flavonoids, 4 nucleotides, and 1 ester, which were summarized from the obtained compounds in terms of their possible cleavage patterns. Among the identified 31 compounds in rat plasma, 21 were prototypes, mostly coumarins, organic acids, and flavonoids, and 10 were metabolites, which were mainly generated via hydroxylation and methylation pathways. Based on these, this study provides a theoretical foundation for quality control and basic research on Qianghuo medicinal substances.
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Medicamentos Herbarios Chinos , Espectrometría de Masas en Tándem , Ratas , Animales , Espectrometría de Masas en Tándem/métodos , Medicamentos Herbarios Chinos/química , Cromatografía Líquida de Alta Presión/métodos , Estructura Molecular , Flavonoides/análisis , Ácidos , Cumarinas/análisisRESUMEN
Leonurus japonicus Houtt (LJH) is a bulk medicinal material commonly used in clinical practice, but its complex constituents have not been completely understood, posing challenges to pharmacology, pharmacokinetic research, and scientific and rational drug use. As a result, it is critical to develop an efficient and accurate method for classifying and identifying the chemical composition of LJH. In this study, ultra-performance liquid chromatography-quadrupole electrostatic field-orbital trap high resolution mass spectrometry (UPLC-Q-Orbitrap-MS) was successfully established, along with two data post-processing techniques, characteristic fragmentations (CFs) and neutral losses (NLs), to quickly classify and identify the chemical constituents in LJH. As a result, 44 constituents of LJH were identified, including four alkaloids, 20 flavonoids, two phenylpropanoids, 17 organic acids, and one amino acid. The method in this paper enables classification and identification of chemical compositions rapidly, providing a scientific foundation for further research on the effective and toxic substances of LJH.
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Medicamentos Herbarios Chinos , Leonurus , Medicamentos Herbarios Chinos/química , Leonurus/química , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Extractos Vegetales/químicaRESUMEN
As a compound preparation of traditional Chinese medicine, Jianwei Xiaoshi Tablets (JXT) is made from five Chinese herbs: Taizishen (Pseudostellariae Radix), Chenpi (Citri Reticulatae Pericarpium), Shanyao (Dioscoreae Rhizoma), Maiya (Hordei Fructus Germinatus) and Shanzha (Crataegi Fructus). It is mainly used to treat dyspepsia. However, the chemical composition of JXT is complex and unclear. In this study, ultra performance liquid chromatography-quadrupole-orbitrap-mass spectrometry and data post-processing technologies were used to analyse the samples of JXT. Firstly, the mass spectrometric information of the main components of five traditional Chinese herbs in JXT was summarised and a compound database was established. Then, the mass spectrometric data detected by the prepared samples was compared with the database. Finally, 93 chemical components were successfully identified, including 6 amino acids, 34 flavonoids, 18 alkaloids, 15 organic acids, 9 cyclic peptides and 11 other components, and the rapid classification and identification of chemical components of JXT were realised.
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Schisandra chinensis is a traditional Chinese medicine, which has played an important role in the field of medicine and food. In this study, ultra-high-performance liquid chromatography quadrupole-orbitrap-mass spectrometry was used to rapidly classify and identify the chemical compositions. Note that 32, 28, and 30 kinds of compounds were successfully identified from northern Schisandra chinensis, vinegar-processed Schisandra chinensis, and wine-processed Schisandra chinensis, respectively. The cleavage patterns of various components including lignans, organic acids, flavonoids, and terpenoids were summarized, and the effects of different processing methods on Schisandra chinensis were analyzed through chemical composition. This method realized the rapid classification and identification of raw Schisandra chinensis and two different processed products, and provided references for improving the traditional processing methods, strengthening quality control, and ensuring safe clinical application.
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Medicamentos Herbarios Chinos , Lignanos , Schisandra , Cromatografía Líquida de Alta Presión/métodos , Schisandra/química , Lignanos/análisis , Medicamentos Herbarios Chinos/análisis , Espectrometría de Masas en Tándem/métodosRESUMEN
Hugan tablet is a Chinese medicine preparation. It is composed of Bupleuri Radix, Artemisiae Scopariae Herba, Isatidis Radix, Schisandrae Chinensis Fructus, Suis Fellis Pulvis, and Vigna radiata L. It has the effects of dispersing stagnated liver qi, strengthening the spleen and eliminating food to be used for the treatment of chronic hepatitis and early cirrhosis. However, the chemical composition of Hugan tablet is complex and not fully understood, which hampers the research in pharmacology. In this study, a reliable method for the rapid analysis and identification of the chemical components in Hugan tablet by their characteristic fragments and neutral losses using ultra-performance liquid chromatography-quadrupole-exactive orbitrap mass spectrometry was developed. A total of 144 chemical components were tentatively identified, including 57 organic acids, 19 flavonoids, 23 alkaloids, 18 lignans, 7 saponins, and 20 others. These components may be the active ingredients of Hugan tablet. The established method can systematically and rapidly analyze the chemical components in Hugan tablet, which provides a basis for the pharmacodynamic substance study and is meaningful for the quality control of Hugan tablet.
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Introduction: YiYiFuZi powder (YYFZ) is a classical formula in Chinese medicine, which is commonly used clinically for the treatment of Chronic Heart Disease (CHD), but it's pharmacological effects and mechanism of action are currently unclear. Methods: An adriamycin-induced CHD model rat was established to evaluate the pharmacological effects of YYFZ on CHD by the results of inflammatory factor level, histopathology and echocardiography. Metabolomic studies were performed on rat plasma using UPLC-Q-TOF/MS to screen biomarkers and enrich metabolic pathways; network pharmacology analysis was also performed to obtain the potential targets and pathways of YYFZ for the treatment of CHD. Results: The results showed that YYFZ significantly reduced the levels of TNF-α and BNP in the serum of rats, alleviated the disorder of cardiomyocyte arrangement and inflammatory cell infiltration, and improved the cardiac function of rats with CHD. The metabolomic analysis identified a total of 19 metabolites, related to amino acid metabolism, fatty acid metabolism, and other metabolic pathways. Network pharmacology showed that YYFZ acts through PI3K/Akt signaling pathway, MAPK signaling pathway and Ras signaling pathway. Discussion: YYFZ treatment of CHD modulates blood metabolic pattern and several protein phosphorylation cascades but importance specific changes for therapeutic effect require further studies.
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Psoraleae Fructus (PF) is one of the most frequently used traditional Chinese medicine, which has good efficacy in warming kidney to activate yang, promoting inspiration to relieve asthma and warming spleen to stop diarrhea. However, the chemical composition of PF is complex, which makes it difficult to determine its active and toxic components. In order to rapidly classify and identify the chemical components of the extracts from PF, this research was processed with CNKI, PubMed, and PubChem databases and data post-processing technique basing on ultrahigh performance liquid chromatography quadrupole orbitrap mass spectrometry (UPLC-Q-Orbitrap MS) technique. Finally, 73 chemical components were discriminated, including 44 flavonoids, 18 coumarins, and 11 terpenoids, with the cleavage rules of each chemical component summarized. This study established a UPLC-Q-Orbitrap MS method for the separation and discrimination of the chemical constituents of PF, which can lay a foundation for the further study of its medicinal substances and quality control.
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Medicamentos Herbarios Chinos , Medicamentos Herbarios Chinos/química , Cromatografía Líquida de Alta Presión/métodos , Medicina Tradicional China , Cromatografía Liquida , Espectrometría de MasasRESUMEN
Doxorubicin (DOX) is a broad-spectrum chemotherapeutic drug used in clinical treatment of malignant tumors. It has a high anticancer activity but also high cardiotoxicity. The aim of this study was to explore the mechanism of Tongmai Yangxin pills (TMYXPs) in ameliorating DOX-induced cardiotoxicity through integrated metabolomics and network pharmacology. In this study, first, an ultrahigh-performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry (UPLC-Q-TOF/MS) metabonomics strategy was established to obtain metabolite information and potential biomarkers were determined after data processing. Second, network pharmacological analysis was used to evaluate the active components, drug-disease targets, and key pathways of TMYXPs to alleviate DOX-induced cardiotoxicity. Targets from the network pharmacology analysis and metabolites from plasma metabolomics were jointly analyzed to select crucial metabolic pathways. Finally, the related proteins were verified by integrating the above results and the possible mechanism of TMYXPs to alleviate DOX-induced cardiotoxicity was studied. After metabolomics data processing, 17 different metabolites were screened, and it was found that TMYXPs played a role in myocardial protection mainly by affecting the tricarboxylic acid (TCA) cycle of myocardial cells. A total of 71 targets and 20 related pathways were screened out with network pharmacological analysis. Based on the combined analysis of 71 targets and different metabolites, TMYXPs probably played a role in myocardial protection through regulating upstream proteins of the insulin signaling pathway, MAPK signaling pathway, and p53 signaling pathway, as well as the regulation of metabolites related to energy metabolism. They then further affected the downstream Bax/Bcl-2-Cyt c-caspase-9 axis, inhibiting the myocardial cell apoptosis signaling pathway. The results of this study may contribute to the clinical application of TMYXPs in DOX-induced cardiotoxicity.
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As a multi-base source traditional Chinese medicine, the hepatotoxicity of Uncariae Ramulus Cum Uncis (URCU) has been reported repeatedly in recent years. The lack of clarity of toxic components and toxicity mechanisms is a key issue that needs to be addressed. In this article, a "component-target-pathway" network strategy was established to firstly predicting the hepatotoxic components and the toxicity mechanism of URCU. Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and data post-processing technology were used to classify and identify the main components in Uncaria rhynchophylla (Miq.) Miq. ex Havil. (UR) and Uncaria sinensis (Oliv.) Havil. (US). Then, the potential hepatotoxic components were screened by network pharmacology and molecular docking. As a result, 40 components and 39 ingredients were identified in UR and US, respectively. Cadambine, rhynchophylline, corynoxeine, isocorynoxeine, strictosamide and mitraphylline were screened as the potential hepatotoxic ingredients contained both in UR and US. The network pharmacology showed that the potential hepatotoxic components could affect the IL-17 signaling pathway by regulating related targets such as MAPK1 and MAPK14, which might lead to the occurrence of liver injury. This study not only provided a reasonable strategy for the rapid screening of hepatotoxic components in URCU, but also supplied reference and guidance for the rational clinical application and scientific supervision of URCU.
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Medicamentos Herbarios Chinos , Uncaria , Uña de Gato , Medicamentos Herbarios Chinos/química , Medicina Tradicional China , Simulación del Acoplamiento Molecular , Extractos Vegetales , Uncaria/química , Uncaria/metabolismoRESUMEN
In this study, a new enantioseparation method was established for the quantitative analysis of the oxypeucedanin enantiomers by using cellulose tris(3,5-dichlorophenyl carbamate) stationary phase column Chiralpak IC. For this method, enantiomeric separation of oxypeucedanin was achieved with the mobile phase consisting of acetonitrile-water (60:40, v/v) at a flow rate of 0.5 mL/min by changing the type and proportion of mobile phase. And the quantitative determination of racemic oxypeucedanin in Angelica Dahuricae Radix (in vitro) and rat plasma (in vivo) were performed on above-mentioned condition by High PerformanceLiquid Chromatography combined with diode arrangement detector (HPLC-DAD) and mass spectrometry (HPLC-MS/MS). The precision, repeatability, stability, recovery were within the acceptance criteria. And the method was validated in the concentration range of 1-400 µg/mL for the two enantiomers in vitro and 0.2-600 ng/mL in vivo. After validation, the established method was successfully applied to the stereoselective analysis of racemic oxypeucedanin in Angelica dahurica from different regions and the stereoselective pharmacokinetic investigation in rat. Results showed that the (+)-oxypeucedanin was at a relative high level in Angelica dahuricae Radix and (-)-oxypeucedanin performed a higher plasma concentration, which demonstrated the difference of oxypeucedanin enantiomers both in vitro and in vivo.
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Angelica , Furocumarinas , Angelica/química , Animales , Cromatografía Líquida de Alta Presión/métodos , Ratas , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: The interaction of small molecules with direct targets constitutes the molecular initiation events of drug efficacy and toxicity. Aconitine, an active compound of the Aconitum species, has various pharmacological effects but is strongly toxic to the heart. The direct targets of aconitine-induced cardiotoxicity remain unclear. METHODS: We predicted the toxic targets of aconitine based on network pharmacology and followed a novel proteomic approach based on the "drug affinity responsive target stability" technology combined with LC-MS/MS to identify the direct targets of aconitine. The identified targets were analysed from the perspective of multilevel and multidimensional bioinformatics through a network integration method. The binding sites were investigated via molecular docking to explore the toxicity mechanism and predict the direct targets of aconitine. Finally, atomic force microscopy (AFM) imaging was performed to verify the affinity of aconitine to the direct targets. RESULTS: PTGS2, predicted by network pharmacology as a toxic target, encodes cyclooxygenase 2 (COX-2), which is closely related to myocardial injury. Furthermore, cytosolic phospholipase A2 (cPLA2) is the upstream signal protein of PTGS2, and it is a key enzyme in the metabolism of arachidonic acid during an inflammatory response. We determined cPLA2 as a direct target, and AFM imaging verified that aconitine could bind to cPLA2 well; thus, aconitine may cause the expression of PTGS2/COX-2 and release inflammatory factors, thereby promoting myocardial injury and dysfunction. CONCLUSION: We developed a complete set of methods to predict and verify the direct targets of aconitine, and cPLA2 was identified as one. Overall, the novel strategy provides new insights into the discovery of direct targets and the molecular mechanism of toxic components that are found in traditional Chinese medicine.
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Aconitina/efectos adversos , Medicamentos Herbarios Chinos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Fosfolipasas A2 Citosólicas/antagonistas & inhibidores , Aconitina/química , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Inhibidores Enzimáticos/química , Medicina Tradicional China , Conformación Molecular , Simulación del Acoplamiento Molecular , Farmacología en Red , Fosfolipasas A2 Citosólicas/análisis , Fosfolipasas A2 Citosólicas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Heart failure is a common systemic disease with high morbidity and mortality worldwide. Doxorubicin (DOX) is a commonly used anthracycline broad-spectrum antitumor antibiotic with strong antitumor effect and definite curative effect. However, cardiotoxicity is the adverse reaction of drug dose cumulative toxicity, but the mechanism is still unclear. In this study, proteomics and metabonomics techniques were used to analyze the tissue and plasma of DOX-induced heart failure (HF) in rats and to clarify the molecular mechanism of the harmful effects of DOX on cardiac metabolism and function in rats from a new point of view. The results showed that a total of 278 proteins with significant changes were identified by quantitative proteomic analysis, of which 118 proteins were significantly upregulated and 160 proteins were significantly downregulated in myocardial tissue. In the metabonomic analysis, 21 biomarkers such as L-octanoylcarnitine, alpha-ketoglutarate, glutamine, creatine, and sphingosine were detected. Correlation analysis showed that DOX-induced HF mainly affected phenylalanine, tyrosine, and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, phenylalanine metabolism, biosynthesis of unsaturated fatty acids, and other metabolic pathways, suggesting abnormal amino acid metabolism, fatty acid metabolism, and glycerol phospholipid metabolism. It is worth noting that we have found the key upstream target of DOX-induced HF, PTP1B, which inhibits the expression of HIF-1α by inhibiting the phosphorylation of IRS, leading to disorders of fatty acid metabolism and glycolysis, which together with the decrease of Nrf2, SOD, Cytc, and AK4 proteins lead to oxidative stress. Therefore, we think that PTP1B may play an important role in the development of heart failure induced by doxorubicin and can be used as a potential target for the treatment of heart failure.
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Triptolide (TP), the main active ingredient of Tripterygium wilfordii Hook F., has great potential in the treatment of autoimmune diseases. However, it has been found that the side effects of TP involve multiple organs and systems, of which the most serious side effects relate to the kidney. The mechanism of nephrotoxicity caused by TP requires further investigation. In the present study, we integrated proteomic and metabolomic methods to identify proteins and small molecule metabolites associated with TP-induced nephrotoxicity. There was a significant difference (p value <0.05) in the expression changes of 357 proteins for quantitative proteomics. In addition, high resolution metabolomic data showed significant changes in the levels of 9 metabolites, including hypoxanthine, PC(22:0/18:4), sphingosine, phenylalanine, etc. Finally, based on the Kyoto Encyclopaedia of Genes and Genomes (KEGG) database for network analysis, it was determined that the 7 differentially expressed proteins were highly correlated with these 9 metabolites. Enrichment analysis revealed that the metabolic pathways involved purine and pyrimidine metabolism, glycerol and phospholipid metabolism, sphingolipid metabolism, and amino acid metabolism. The key target proteins were verified by Western blot technology, and the mechanism of TP-induced nephrotoxicity was further elucidated to provide a basis for safe and rational application.
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Diterpenos/toxicidad , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Riñón/efectos de los fármacos , Fenantrenos/toxicidad , Aminoácidos/metabolismo , Animales , Compuestos Epoxi/toxicidad , Glicerol/metabolismo , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/patología , Masculino , Metabolómica , Fosfolípidos/metabolismo , Proteómica , Purinas/metabolismo , Pirimidinas/metabolismo , Ratas Wistar , Esfingolípidos/metabolismoRESUMEN
PURPOSE: A novel brain targeting drug delivery system based on OX26 antibody conjugation on PEGylated cationic solid lipid nanoparticles (OX26-PEG-CSLN) was prepared. METHODS: The Baicalin-loaded PEGylated cationic solid lipid nanoparticles modified by OX26 antibody (OX26-PEG-CSLN) were prepared by emulsion evaporation-solidification at low temperature method. The immune-gold labeled OX26-PEG-CSLN was visualized by transmission electron microscopy. The mean diameter and zeta potential of OX26-PEG-CSLN, PEG-CSLN and CSLN were determined using a Zetasizer. The entrapment efficiency of OX26-PEG-CSLN, PEG-CSLN and CSLN was determined by ultrafiltration centrifugation method. And the solid-state characterization of OX26-PEG-CSLN and CSLN were analyzed by X-ray. Pharmacokinetics studies were conducted by in vivo microdialysis in rat cerebrospinal fluid. RESULTS: The results showed that the OX26-PEG-CSLN, PEG-CSLN and CSLN had average diameters of 47.68 ± 1.65, 27.20 ± 1.70 and 33.89 ± 5.74 nm, Zeta potentials of -0.533 ± 0.115 mV, 11.200 ± 0.500 mV and 11.080 ± 1.170 mV and entrapment efficiencies of 83.03 ± 0.01%, 92.90 ± 3.50% and 97.83 ± 0.19%, respectively. In the pharmacokinetics studies, the AUC value of OX26-PEG-CSLN was11.08-fold higher than that of the Baicalin solution (SOL) (p<0.01), and 1.12-fold higher than that of the CSLN (p>0.05); the Cmax value of OX26-PEG-CSLN was 7.88-fold higher than that of SOL (p<0.01) and 1.12-fold (p<0.01) higher than that of the CSLN, respectively. CONCLUSION: These results demonstrated OX26-PEG-CSLN could be a promising carrier to deliver drugs across the BBB for the treatment of brain diseases.