RESUMEN
ETHNOPHARMACOLOGY RELEVANCE: Traditional herbal medicines have been considered as a novel and effective way to treat many diseases. Lizhong decoction (LZD), a classical prescription composed of Zingiber officinale Rosc., Panax ginseng C. A. Mey., Atractylodes macrocephala Koidz., and Glycyrrhiza uralensis Fisch., has been used to treat gastrointestinal disorders in clinical practices for thousands of years. However, the mechanism of LZD in alleviating ulcerative colitis (UC) is still unclear. AIM OF THE STUDY: The purpose of this study was to clarify the potential molecular mechanism of LZD in improving UC. MATERIALS AND METHODS: The amelioration of LZD on dextran sodium sulfate (DSS)-induced UC mice was evaluated by body weight, colon length, pathology of colon tissues, pro-inflammatory cytokines, and intestinal tight junction (TJ) proteins. Moreover, the gene expression profiles of UC patients were extracted to investigate potential pathological mechanisms of UC. The influence of LZD on ferroptosis was analyzed by iron load, malondialdehyde (MDA), and the expression of ferroptosis-associated proteins. Meanwhile, the inhibition of LZD on oxidative stress (OS) was assessed by the superoxide dismutase (SOD) activity, as well as the expression levels of glutathione (GSH) and glutathione disulfide (GSSG). Furthermore, the influence of LZD on ferroptosis was assessed by inhibiting nuclear factor (erythroid-derived-2)-like 2 (Nrf2). RESULTS: LZD showed significant therapeutic effects in UC mice, including reduction of intestinal injury and inflammation. Moreover, LZD treatment notably upregulated the expression of TJ proteins. Further investigation indicated that LZD significantly inhibited the ferroptosis of enterocytes by decreasing iron load and MDA, and increasing the expression levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in colon tissues. Furthermore, the decreased activity of SOD, reduced level of GSH, and increased content of GSSG in UC mice were notably reversed by LZD. Consistent with in vivo results, LZD could markedly inhibit ferroptosis and OS in RSL3-induced Caco-2 cells. Mechanistically, LZD alleviated ferroptosis by suppressing OS through the activation of Nrf2 signaling. CONCLUSIONS: Collectively, LZD remarkably improved intestinal pathological injury in UC mice, and its potential mechanism was the suppression of ferroptosis in enterocytes by the Nrf2/SLC7A11/GPX4 pathway.
Asunto(s)
Colitis Ulcerosa , Colitis , Ferroptosis , Humanos , Animales , Ratones , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Enterocitos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Factor 2 Relacionado con NF-E2 , Disulfuro de Glutatión , Células CACO-2 , Glutatión , Hierro , Superóxido Dismutasa , Sulfato de Dextran/toxicidad , Ratones Endogámicos C57BL , Sistema de Transporte de Aminoácidos y+RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Lizhong decoction (LZD), a classical herbal prescription recorded by Zhang Zhongjing in Treatise on Febrile and Miscellaneous Diseases, has been extensively used to treat ulcerative colitis (UC) in clinical practice for thousands of years. However, its material basis and underlying mechanism are not yet clear. AIM OF THE STUDY: This study aims to explore the material basis and potential mechanism of LZD against UC based on the spectrum-effect relationship and network pharmacology. MATERIALS AND METHODS: First, LZD was extracted by a systematic solvent extraction method into four parts. Ultra-high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) technique was used to identify the compounds from different polar parts, and dextran sulfate sodium (DSS)-induced colitis model was used to evaluate the efficacy of each fraction. Then, the spectrum-effect analyses of compounds and efficacy indicators were established via grey relational analysis (GRA), bivariate correlation analysis (BCA) and partial least squares regression (PLSR). Finally, the potential mechanism of LZD for UC therapy was explored by network pharmacology, and the results were further verified by molecular docking and reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: 66 chemical components of LZD were identified by UPLC-Q-TOF-MS/MS technology. The pharmacodynamic results showed that extraction parts of LZD had different therapeutic effects on UC, among which ethyl acetate and n-butanol extracts had significant anti-colitis effects, which might be the main effective fractions of LZD. Furthermore, the spectrum-effect analyses indicated that 21 active ingredients such as liquiritin apioside, neolicuroside, formononetin, ginsenoside Rg1, 6-gingesulfonic acid, licoricesaponin A3, liquiritin, glycyrrhizic acid were the main material basis for LZD improving UC. Based on the above results, network pharmacology suggested that the amelioration of LZD on UC might be closely related to the PI3K-Akt signaling pathway. Additionally, molecular docking technology and RT-qPCR further verified that LZD could markedly inhibit the PI3K-Akt signaling pathway. CONCLUSION: Overall, our study first identified the chemical compositions of LZD by using UPLC-Q-TOF-MS/MS. Furthermore, the material basis and potential mechanism of LZD in improving UC were comprehensively elucidated via spectrum-effect relationships, network pharmacology, molecular docking and experimental verification. The proposed strategy provided a systematic approach for exploring how herbal medicines worked. More importantly, it laid the solid foundation for further clinical application and rational development of LZD.
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Colitis Ulcerosa , Colitis , Medicamentos Herbarios Chinos , Humanos , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Farmacología en Red , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Espectrometría de Masas en Tándem , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Four new stilbenes (1-4) and one new flavonoid (5), named cajanines D-H, together with three known stilbenes (6-8) were isolated from the leaves of Cajanus cajan (L.) Millsp. (pigeon pea). The structures of these compounds were elucidated unambiguously on the basis of IR, 1D, and 2D NMR, as well as HRESIMS data. Structurally, stilbenes 1-4 bore an isopentyl side chain, and further hydroxylation of compounds 1-3 generated a greater variety of structural forms. Compound 5 was a flavonoid owning an isopentyl side chain. Besides, antibacterial activity of the isolated compounds against Staphylococcus aureus, Bacillus cereus, and Escherichia coli was studied in vitro. Compounds 1-8 were endowed with profound antibacterial activity. Among them, the MIC values of compounds 4, 6, and 7 against S. aureus were 1.56, 0.78, and 0.78 µg/mL, respectively, among which 6 and 7 had better antibacterial activity than the positive control Vancomycin with the MIC values of 1.56 µg/mL. Additionally, the anti-SARS-CoV-2 main protease activity of all the isolated compounds was evaluated, and it was worth mentioning that the IC50 values of compounds 5-7 were 8.27, 4.65, and 8.30 µM, respectively, being comparable to the positive control Ebselen. Our findings may provide valuable guidance for the application of stilbenes as lead compounds in the future for the development of drugs with antibacterial or anti-COVID-19 activity.
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COVID-19 , Cajanus , Estilbenos , Flavonoides/farmacología , Cajanus/química , Staphylococcus aureus , Estilbenos/química , SARS-CoV-2 , Antibacterianos/farmacologíaRESUMEN
The extract of the whole plant of Carpesium abrotanoides L. yielded five new sesquiterpenes including four eudesmanes (1-4) and one eremophilane (5). The new compounds were characterized by spectroscopic analysis especially 1D and 2D NMR spectroscopy and HRESIMS data. Structurally, both compounds 1 and 2 were sesquiterpene epoxides and 2 owned an epoxy group at C-4/C-15 position to form a spiro skeleton. Compounds 4 and 5 were two sesquiterpenes without lactones and 5 possessed a carboxy group in the molecule. Additionally, all the isolated compounds were preliminarily evaluated for the inhibitory activity against SARS-CoV-2 main protease. As a result, compound 2 showed moderate activity with an IC50 value of 18.79 µM, while other compounds were devoid of noticeable activity (IC50 > 50 µM).
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Asteraceae , COVID-19 , Sesquiterpenos de Eudesmano , Sesquiterpenos , Estructura Molecular , Sesquiterpenos Policíclicos , SARS-CoV-2 , Sesquiterpenos de Eudesmano/farmacología , Espectroscopía de Resonancia Magnética , Asteraceae/químicaRESUMEN
Eurya chinensis has been recorded as a folk medicine traditionally used for treatment of a variety of symptoms. However, the phytochemical and pharmacological investigations of this plant are still scarce. A novel phenolic glycoside named Euryachincoside (ECS) was isolated by chromatographic separation from E. chinensis, and its chemical structure was identified by analysis of HRMS and NMR data. Its anti-hepatic fibrosis effects were evaluated in both HSC-T6 (rat hepatic stellate cells) and carbon tetrachloride (CCl4)-induced mice with Silybin (SLB) as the positive control. In an in vitro study, ECS showed little cytotoxicity and inhibited transforming growth factor-beta (TGF-ß)-induced Collagen I (Col1) along with alpha-smooth muscle actin (α-SMA) expressions in HSC-T6. An in vivo study suggested ECS significantly ameliorated hepatic injury, secretions of inflammatory cytokines, and collagen depositions. Moreover, ECS markedly mediated Smad2/3, nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways both in vitro and vivo. These present findings confirmed that ECS is a novel phenolic glycoside from E. chinensis with promising curative effects on hepatic fibrosis, and its mechanisms may include decreasing extracellular matrix accumulation, reducing inflammation and attenuating free radicals via Smad2/3, NF-κB and Nrf2 signaling pathways, which may shed light on the exploration of more effective phenolic glycoside-based anti-fibrotic agents.
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Glicósidos , FN-kappa B , Ratas , Ratones , Animales , FN-kappa B/metabolismo , Glicósidos/farmacología , Glicósidos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor de Crecimiento Transformador beta , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Hígado , Factor de Crecimiento Transformador beta1/metabolismo , Tetracloruro de Carbono/efectos adversos , Tetracloruro de Carbono/metabolismo , Colágeno/metabolismo , Células Estrelladas HepáticasRESUMEN
Two new withaphysalin-type withanolides (18-O-ethylwithaphysalin R and 5-O-ethylphysaminimin C, 1 and 2), along with twelve known withanolides (3-14), were purified and identified from Physalis peruviana L. The chemical structures of these new isolates were elucidated through analyzing spectroscopic and HRESIMS data. All the obtained metabolites were appraised for their potential antiproliferative activity against the human breast cancer cell line MCF-7. Compound 7 was discovered to exhibit potent activity with an IC50 value of 3.51 µM and compounds 2, 6 and 14 showed weak cytotoxic effect.
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Antineoplásicos , Physalis , Witanólidos , Humanos , Physalis/química , Witanólidos/química , Extractos Vegetales/químicaRESUMEN
A two-stage study was carried out to test the mechanism of arginase in ammonia detoxification of yellow catfish. At stage 1, fish was injected lethal half concentration ammonium acetate and 0.9% sodium chloride respectively every 12 h in six replicates for 72 h. The result found that no significant different in serum ammonia contents of fish in ammonium acetate group at hours 12, 24, 36, 48, 60 and 72. At stage 2, ammonium acetate group was split in two, one continued to injected with ammonium acetate (NH3 group) and the other with ammonium acetate and valine (an inhibitor of arginase; Val group); Sodium chloride group also was split in two, one continued to injected with sodium chloride (NaCl group) and the other with sodium chloride and valine (NaCl + Val group). The experiment continued for 12 h. Serum ammonia and liver arginine contents of fish in Val group were higher than those of fish in NH3 group; Compared with NaCl group, arginase activity and ARG 1 expression in liver of fish in Val group were lower; Fish in NaCl and NaCl + Val groups had the lowest serum superoxide dismutase activities, malondialdehyde, tumor necrosis factor-α, interleukin 1 and 8 contents, TNF-α, IL-1 and IL-8 expressions than fish in NH3 and Val groups, and had the higher lysozyme activities, complement 3 and 4 contents. This study indicates that ammonia poisoning would lead to oxidative damage, immunosuppression and inflammation in yellow catfish; Arginase may be an important target of ammonia toxicity in yellow catfish; Exogenous arginine supplementation might alleviate the symptoms of ammonia poisoning in yellow catfish.