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Due to the sustained proliferative potential of cancer cells, inducing cell death is a potential strategy for cancer therapy. Paraptosis is a mode of cell death characterized by endoplasmic reticulum (ER) and/or mitochondrial swelling and cytoplasmic vacuolization, which is less investigated. Considerable evidence shows that paraptosis can be triggered by various chemical compounds, particularly in cancer cells, thus highlighting the potential application of this non-classical mode of cell death in cancer therapy. Despite these findings, there remain significant gaps in our understanding of the role of paraptosis in cancer. In this review, we summarize the current knowledge on chemical compound-induced paraptosis. The ER and mitochondria are the two major responding organelles in chemical compound-induced paraptosis, which can be triggered by the reduction of protein degradation, disruption of sulfhydryl homeostasis, overload of mitochondrial Ca2+, and increased generation of reactive oxygen species. We also discuss the stumbling blocks to the development of this field and the direction for further research. The rational use of paraptosis might help us develop a new paradigm for cancer therapy.
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Neoplasias , Paraptose , Linhagem Celular Tumoral , Morte Celular , Espécies Reativas de Oxigênio/metabolismo , Retículo Endoplasmático/metabolismo , Apoptose , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the main cause of chronic liver disease. Baicalin (Bai), a bioactive molecule found in Scutellaria baicalensis Georgi, possesses antioxidant and antiinflammatory properties. These activities suggest Bai could be a promising therapeutic agent against NAFLD; however, its specific effects and underlying mechanism are still not clear. This study aims to explore the effect of Bai to attenuate MAFLD and associated molecular mechanisms. Bai (50, 100 or 200 mg/kg) was orally administered to db/db mice with MAFLD for 4 weeks or db/m mice as the normal control. Bai markedly attenuated lipid accumulation, cirrhosis and hepatocytes apoptosis in the liver tissues of MAFLD mice, suggesting strong ability to attenuate MAFLD. Bai significantly reduced proinflammatory biomarkers and enhanced antioxidant enzymes, which appeared to be modulated by the upregulated p62-Keap1-Nrf2 signalling cascade; furthermore, cotreatment of Bai and all-trans-retinoic acid (Nrf2 inhibitor) demonstrated markedly weakened liver protective effects by Bai and its induced antioxidant and antiinflammatory responses. The present study supported the use of Bai in attenuating MAFLD as a promising therapeutic agent, and its strong mechanism of action in association with the upregulating the p62-keap1-Nrf2 pathway.
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Huangqin is the dried root of Scutellaria baicalensis Georgi, which has been widely utilized for heat-clearing (Qingre) and dewetting (Zaoshi), heat-killed (Xiehuo) and detoxifying (Jiedu) in the concept of Traditional Chinese Medicine and is used for treating inflammation and cancer in clinical formulas. Neobaicalein (NEO) is of flavonoid isolated from Huangqin and has been reported to possess prominent anti-inflammatory effects in published work. Th17/Treg balance shift to Th17 cells is an essential reason for autoimmune inflammatory diseases. However, the role NEO plays in Th17 and Treg and the underlying mechanism has not been elucidated yet. Network pharmacology-based study revealed that NEO predominantly regulated IL-17 signaling pathway. Moreover, our result shown that NEO (3-30 µmol/L) down-regulated Th17 differentiation and cellular supernatant and intracellular IL-17A level and tumor necrosis factor α production in a concentration-dependent manner. The further mechanism research revealed that NEO also specifically inhibited phosphorylation of STAT3(Tyr725) and STAT4 (Y693) without influence on activation of STAT5 and STAT6 in splenocytes. Immunofluorescence results illuminated that NEO effectively blocked STAT3 translocated into nucleus. Interestingly, NEO at appreciated dose could only inhibit Th17 cell differentiation and have no effect on Treg differentiation. The present study revealed that NEO effectively inhibited Th17 cell differentiation through specifically blocking the activation of STAT3 signaling without inactivation of STAT5 and STAT6. Additional inhibitory effect on activation of STAT4 by NEO also suggested the potential for antagonism against Th1 differentiation. All work suggested that NEO may be a potential candidate for immunoregulation and treating autoimmune inflammatory diseases through inhibiting immune cell viability and T cell differentiation.
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Doenças Autoimunes , Células Th17 , Humanos , Fator de Transcrição STAT5/metabolismo , Linfócitos T Reguladores , Diferenciação Celular , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Doenças Autoimunes/metabolismoRESUMO
The aim of this paper was to study the effect and mechanism of fucoxanthin on insulin resistance of obese mice induced by high-fat diet. Fifty C57 BL/6 J male mice were randomly divided into control group and high-fat diet group. The insulin resistance model was induced with high-fat diet for 12 weeks, and model mice were randomly divided into model group, fucoxanthin-0.2% group, fucoxanthin-0.4% group and metformin group. After dietary treatment for 6 weeks, the body weight and epididymal fat weight in each group were measured. Fasting blood glucose(FBG), fasting insulin(FINS), total cholesterol(TC), triglyceride(TG), low-density lipoprotein(LDL-C) and high-density lipoprotein(HDL-C) were measured, and insulin resistance index(HOMA-IR) was calcula-ted. The pathological morphology in liver was observed by hematoxylin eosin staining, and the expressions of some key proteins in insulin receptor substrate 1(IRS-1)/posphoinositide 3-kinase(PI3 K)/serine-threonine kinase(Akt) and peroxisome proliferators-activated receptor-γ(PPARγ)/sterol regulatory element binding protein-1(SREBP-1)/fatty acid synthetase(FAS) pathways in liver were detected by Western blot. According to the findings, compared with the model group, levels of body weight, epididymal fat weight, FBG, FINS, TC, TG, LDL-C and HOMA-IR, as well as protein expressions of PPARγ, SREBP-1 and FAS in liver were significantly reduced(P<0.05 or P<0.01), while level of HDL-C and protein expressions of p-IRS-1, IRS-1, PI3 K and p-Akt in liver were signi-ficantly increased after treatment with fucoxanthin(P<0.05 or P<0.01). And the pathological changes of liver tissue in fucoxanthin-treated mice were also improved obviously. The results showed that fucoxanthin could improve obesity, hyperglycemia and hyperlipidemia, and alleviate insulin resistance in obese mice, and its mechanism is possibly related to the regulation of IRS-1/PI3 K/Akt and PPARγ/SREBP-1/FAS pathways.
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Resistência à Insulina , Animais , Dieta Hiperlipídica/efeitos adversos , Insulina , Fígado , Masculino , Camundongos , Camundongos Obesos , XantofilasRESUMO
Alismatis rhizoma (AR), the dried rhizoma of Alisma orientale Juzepzuk (Alismataceae), is a traditional Chinese medicine. AR is an important part of many prescriptions and is commonly used as a diuretic agent in Asia. This study aimed to evaluate the diuretic effects of total triterpene extract (TTE) and triterpene component compatibility (TCC, the mixture of alisol B 23-acetate, alisol B, alisol A 24-acetate, alisol A, and alisol C 23-acetate) of AR in saline-loaded rats. The optimal diuretic TCC of AR was optimized using a uniform design. Different doses (5, 20, and 40 mg/kg) of TTE and TCC groups (N1-N8) were orally administered to rats. Urinary excretion rate, pH, and electrolyte excretion were measured in the urine of saline-loaded rats. Results showed that TTE doses increased urine volume and electrolyte excretion compared with the control group. All uniformly designed groups of TCC also increased urine excretion. In addition, optimal diuretic TCC was calculated (alisol B 23-acetate: alisol B: alisol A 24-acetate: alisol A: alisol C 23-acetate 7.2:0.6:2.8:3.0:6.4) and further validated by saline-loaded rats. This study demonstrated that TTE presented a notable diuretic effect by increasing Na⁺, K⁺, and Cl − displacements. The most suitable TTC compatible proportion of alisol B 23-acetate: alisol B: alisol A 24-acetate: alisol A: alisol C 23-acetate for diuretic activity was validated, and triterpenes were the material basis for the diuretic activity of AR.
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Alisma/química , Diuréticos/química , Rizoma/química , Triterpenos/química , Animais , Diuréticos/farmacologia , Relação Dose-Resposta a Droga , Íons/química , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Triterpenos/farmacologiaRESUMO
BACKGROUND/AIMS: Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism. METHODS: Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks. RESULTS: Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver. CONCLUSION: Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.
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Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Dislipidemias/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Transdução de Sinais , Animais , Benzofuranos/química , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/genética , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Glicogênio Sintase/metabolismo , Glicólise/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Hiperinsulinismo/tratamento farmacológico , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , PPAR alfa/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Saponins are glycosides with triterpenoid or spirostane aglycones that demonstrate various pharmacological effects against mammalian diseases. To promote the research and development of anticancer agents from saponins, this review focuses on the anticancer properties of several typical naturally derived triterpenoid saponins (ginsenosides and saikosaponins) and steroid saponins (dioscin, polyphyllin, and timosaponin) isolated from Chinese medicines. These saponins exhibit in vitro and in vivo anticancer effects, such as anti-proliferation, anti-metastasis, anti-angiogenesis, anti-multidrug resistance, and autophagy regulation actions. In addition, related signaling pathways and target proteins involved in the anticancer effects of saponins are also summarized in this work.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias/tratamento farmacológico , Plantas Medicinais/química , Saponinas/farmacologia , Animais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
In order to explore the differences of chemical constituents of Paeoniae Radix Alba and Paeoniae Radix Rubra, a qualitative analytical method of liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS) was developed for identification of multi-constituents and an HPLC-DAD analytical method was developed for simultaneously determining 14 major compounds (gallic acid, protocatechuic acid, paeoniflorin sulfonate, protocatechuic aldehyde, methyl gallate, oxypaeoniflorin, catechin, albiflorin, and paeoniflorin, ethyl gallate, benzoic acid, pentagaloylglucose, benzoyl-paeoniflorin, and paeonol) in Paeoniae Radix Alba and Paeoniae Radix Rubra. Q-TOF/MS qualitative analysis was performed under negative ion mode and inferred 38 components of Paeoniae Radix Alba and 30 components of Paeoniae Radix Rubra. HPLC-DAD quantitative method result showed the contents of 8 ingredients were different between Paeoniae Radix Alba and Paeoniae Radix Rubra. The results indicated that the new approach was applicable in qualitative and quantitative quality control of Paeoniae Radix Alba and Paeoniae Radix Rubra.
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Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Paeonia/química , Espectrometria de Massas em Tandem/métodos , Hidrocarbonetos Aromáticos com Pontes/química , Glucosídeos/química , Estrutura Molecular , Monoterpenos/química , Paeonia/classificaçãoRESUMO
BACKGROUND: Hepatic fibrosis (HF) runs through multiple stages of liver diseases and promotes these diseases progression. Oxysophoridine (OSR), derived from Sophora alopecuroides l., is a bioactive alkaloid that has been reported to antagonize alcoholic hepatic injury. However, whether OSR suppresses HF and the mechanisms involved in Nrf2 remain unknown. PURPOSE: Since the dysregulation of inflammation and oxidative stress is responsible for the excessive accumulation of extracellular matrix (ECM) and fibrosis in the liver. We hypothesized that OSR may attenuate HF by inhibiting inflammation and oxidative stress through activating Nrf2 signaling. METHODS: In this study, we employed LPS-stimulated HSC-T6 cells, RAW264.7 cells, and a CCl4-induced C57BL/6 mouse fibrotic model to evaluate its suppressing inflammation and oxidative stress, as well as fibrosis. RESULTS: The result showed that OSR significantly reduced α-SMA and TGF-ß1 at a low dose of 10 µM in vitro and at a dose of 50 mg/kg in vivo, which is comparable to Silymarin, the only Chinese herbal active ingredient that has been marketed for anti-liver fibrosis. Moreover, OSR effectively suppressed the expression of iNOS at a dose of 10 µM and COX-2 at a dose of 40 µM, respectively. Furthermore, OSR demonstrated inhibitory effects on the IL-1ß, IL-6, and TNF-α in vitro and almost extinguished cytokine storm in vivo. OSR exhibited antioxidative effects by reducing MDA and increasing GSH, thereby protecting the cell membrane against oxidative damage and reducing LDH release. Moreover, OSR effectively upregulated the protein levels of Nrf2, HO-1, and p62, but decreased p-NF-κB p65, p-IκBα, and Keap1. Alternatively, mechanisms involved in Nrf2 were verified by siNrf2 interference, siNrf2 interference revealed that the anti-fibrotic effect of OSR was attributed to its activation of Nrf2. CONCLUSION: The present study provided an effective candidate for HF involved in both activation of Nrf2 and blockage of NF-κB, which has not been reported in the published work. The present study provides new insights for the identification of novel drug development for HF.
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Alcaloides , Cirrose Hepática , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , NF-kappa B , Estresse Oxidativo , Transdução de Sinais , Sophora , Animais , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Cirrose Hepática/tratamento farmacológico , Alcaloides/farmacologia , NF-kappa B/metabolismo , Células RAW 264.7 , Masculino , Transdução de Sinais/efeitos dos fármacos , Sophora/química , Inflamação/tratamento farmacológico , Tetracloreto de Carbono , Ratos , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The aim of this study is to prepare self-microemulsifying drug delivery system (SMEDDS) of the mixture of paeonol (Pae) and borneol (Bor). Solubility test, ternary phase diagrams and simplex lattice method were employed to screen and optimize the formulation of the mixture of Pae and Bor-loaded SMEDDS. After formed into microemulsions, the particle diameter (PD) was determined and a TEM was employed to observe the microemulsions' morphology. The contents of Pae and Bor were determined by gas chromatography. As a result, while ethyl oleate (EO) as the oil phase, cremophor EL35 (EL35) as surfactant and Transcutol HP (HP) as cosurfactant, the range of the microemulsion on the ternary phase diagram was larger than other combinations. And at a ratio of 20:45:35, the microemulsions' PD was about 34 nm and the polydispersity index (PI) was about 0.2. There were 16% of Pae, 2% of Bor, 16% of EO, 37% of EL35 and 29% of HP in the prepared SMEDDS. The preparation process of the Pae and Bor-loaded SMEDDS based on Xingbi Fang is simple and feasible. This study provides a reference for the researches on the related traditional Chinese medicine and the related components.
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Acetofenonas/administração & dosagem , Canfanos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Acetofenonas/toxicidade , Administração Intranasal , Animais , Bufonidae , Canfanos/toxicidade , Cílios/efeitos dos fármacos , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/toxicidade , Emulsões , Etilenoglicóis/química , Feminino , Masculino , Mucosa Nasal/efeitos dos fármacos , Ácidos Oleicos/química , Tamanho da Partícula , Polietilenoglicóis/química , Solubilidade , Tensoativos/químicaRESUMO
The applications accepted and approved by general program, young scientist fund and fund for less developed region of national natural science funds in the discipline of Chinese materia medica, NSFC in 2012 have been introduced. The research contents of the funded projects in the popular research areas have been summarized and the problems in the applications have been analyzed to give a reference to the scientists in the field of Chinese materia medica.
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Organização do Financiamento/organização & administração , Materia Medica/química , Medicina Tradicional Chinesa/economia , Disciplinas das Ciências Naturais/economia , China , Humanos , Pessoal de Laboratório/economia , Disciplinas das Ciências Naturais/organização & administração , Recursos HumanosRESUMO
OBJECTIVE: Multiple sclerosis (MS) is an immune disease in the central nervous system (CNS) associated with Th17 cells. Moreover, STAT3 initiates Th17 cell differentiation and IL-17A expression through facilitating RORγt in MS. Here, we reported that magnolol, isolated from Magnolia officinalis Rehd. Et Wils, was regarded as a candidate for MS treatment verified by both in vitro and in vivo studies. METHODS: In vivo, experimental autoimmune encephalomyelitis (EAE) model in mice was employed to evaluate the alleviation of magnolol on myeloencephalitis. In vitro, FACS assay was employed to evaluate the effect of magnolol on Th17 and Treg cell differentiation and IL-17A expression; network pharmacology-based study was applied to probe the involved mechanisms; western blotting, immunocytochemistry, and luciferase reporter assay was used to further confirm the regulation of magnolol on JAK/STATs signaling pathway; surface plasmon resonance (SPR) assay and molecular docking were applied to manifest affinity with STAT3 and binding sites; overexpression of STAT3 was employed to verify whether magnolol attenuates IL-17A through STAT3 signaling pathway. RESULTS: In vivo, magnolol alleviated loss of body weight and severity of EAE mice; magnolol improved lesions in spinal cords and attenuated CD45 infiltration, and serum cytokines levels; correspondingly, magnolol focused on inhibiting Th17 differentiation and IL-17A expression in splenocyte of EAE mice; moreover, magnolol selectively inhibited p-STAT3(Y705) and p-STAT4(Y693) of both CD4+ and CD8+ T cells in splenocyte of EAE mice. In vitro, magnolol selectively inhibited Th17 differentiation and IL-17A expression without impact on Treg cells; network pharmacology-based study revealed that magnolol perhaps diminished Th17 cell differentiation through regulating STAT family members; western blotting further confirmed that magnolol inhibited p-JAK2(Y1007) and selectively antagonized p-STAT3(Y705) and slightly decreased p-STAT4(Y693); magnolol antagonized both STAT3 nucleus location and transcription activity; magnolol had a high affinity with STAT3 and the specific binding site perhaps to be at SH2 domain; overexpression of STAT3 resulted in failed inhibition of magnolol on IL-17A. CONCLUSION: Magnolol selectively inhibited Th17 differentiation and cytokine expression through selectively blocking of STAT3 resulting in decreased the ratio of Th17/Treg cells for treating MS, suggesting that the potential of magnolol for treating MS as novel STAT3 inhibitor.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Esclerose Múltipla/tratamento farmacológico , Células Th17 , Interleucina-17/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Simulação de Acoplamento Molecular , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Células Th1RESUMO
In situ fragmentation bioleaching is a promising way to perform deep mining safely, economically, and in an environmentally friendly manner, where oxygen plays a critical role in microbial growth and mineral dissolution. However, the lack of oxygen limits the implementation of in-situ fragmentation bioleaching. To overcome this limitation, aeration was proposed, with saturated dissolved oxygen concentration as an important indicator. Orthogonal experiments were conducted to measure saturated dissolved oxygen concentration at various temperature, pH, and electrolyte (ferrous sulfate, ferric sulfate, copper sulfate, and sulfuric acid) concentration conditions. Experimental data were analyzed by Python programming language and least squares method to obtain a saturated dissolved oxygen concentration model. Results showed that temperature had the most significant effect on oxygen solubility, which was concluded by comparing the results of surface fitting based on the least squares method. At 30-40°C, the saturated dissolved oxygen concentration decreased faster as metal ions concentration increased. The conjoint effect of the five variables on oxygen solubility showed that pH was linearly negatively related to oxygen solubility. Additionally, a mathematical model was also proposed to predict the saturated dissolved oxygen concentration in in situ fragmentation bioleaching of copper sulfide ores. This work enables bioleaching processes to be modeled and controlled more effectively.
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Objective: This study assessed the anti-arthritic effect and protection of Gedunin (GDN) on joint tissues and revealed the possible mechanism in suppressing rheumatoid arthritis (RA). Methods: LPS-induced macrophages and TNF-α-stimulated synovial fibroblasts (MH7A) or IL-1ß-stimulated primary rheumatoid arthritis synovial fibroblasts (RASFs) were used to evaluate the antiinflammatory effect of GDN. In addition, CIA-induced arthritis was employed here to evaluate the anti-arthritic effect. MTT and BRDU assays were utilized to evaluate the cell viability and proliferation, Q-PCR was conducted to detect the mRNA expression of cytokines, FACS was adopted to monitor ROS production, while western blotting (WB) and siRNA interference were applied in confirming the anti-arthritic effects of GDN via the Nrf2 signaling. Results. In vitro, cell viability was inhibited in macrophages and MH7A cells, but not in RASFs; but the proliferation of RASFs was significantly suppressed in time- and dose-dependent manners. GDN suppressed cytokine levels in LPS-stimulated macrophages and TNF-α-stimulated MH7A cells or RASFs. GDN suppressed ROS expression. Furthermore, GDN treatment notably dose-dependently decreased the mRNA and protein expression of iNOS in LPS-induced macrophages. sip62 interference results showed that GDN cause the less expression of HO-1 and Keap1 and also fail to inhibit cytokines after sip62 interference. In vivo, GDN effectively inhibited paw swelling, arthritis score, and arthritis incidence and cytokines. Conclusions: Our study suggested that GDN exhibited strong antagonistic effect on arthritis both in vitro and in vivo via activation of Nrf2 signaling. Our work will provide a promising therapeutic strategy for RA.
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Artrite Reumatoide , Fator 2 Relacionado a NF-E2 , Artrite Reumatoide/tratamento farmacológico , Citocinas/metabolismo , Fibroblastos/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Limoninas , Lipopolissacarídeos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.
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Hunting for natural compounds that can modulate the structure of the intestinal flora is a new hotspot for colitis-associated cancer (CAC) prevention or treatment. Alisol B 23-acetate (AB23A) is a natural tetracyclic triterpenoid found in Alismatis rhizoma which is well known for dietary herb. Alismatis rhizoma is often used clinically to treat gastrointestinal diseases in China. In this study, we investigated the potential prevention of AB23A in male mouse models of azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CAC. AB23A intervention alleviated the body weight loss, disease activity index, colon tumor load, tissue injury, and inflammatory cytokine changes in CAC mice. AB23A intervention leads to remarkable reductions in the activation of TLR, NF-κB and MAPK. AB23A significantly decreased the phosphorylation of p38, ERK, and JNK and up-regulated mucin-2 and the expression of tight junction proteins. The gut microbiota of AB23A-interfered mice was characterized with high microbial diversity, the reduced expansion of pathogenic bacteria, such as Klebsiella, Citrobacter, and Akkermansia, and the increased growth of bacteria including Bacteroides, Lactobacillus, and Alloprevotella. These data reveal that AB23A has the potential to be used to treat CAC in the future.
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Neoplasias Associadas a Colite , Colite , Microbioma Gastrointestinal , Animais , Azoximetano , China , Colestenonas , Sulfato de Dextrana , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , SulfatosRESUMO
Alismatis rhizoma (AR), which is the dried rhizome of Alisma orientale (Sam.) Juz. (Alismataceae), is an important component of many famous Chinese formulas for hypoglycemic. This study aimed to evaluate the insulin resistance (IR) alleviating effects of AR triterpenes (ART) and ART component compatibility (ARTC, the mixture of 16-oxo-alisol A, 16-oxo-alisol A 23-acetate, 16-oxo-alisol A 24-acetate, alisol C, alisol C 23-acetate, alisol L, alisol A, alisol A 23-acetate, alisol A 24-acetate, alisol L 23-acetate, alisol B, alisol B 23-acetate, 11-deoxy-alisol B and 11-deoxy-alisol B 23-acetate) in high-fat diet-induced IR mice and plamitate-treated IR C2C12 cells, respectively. A dose of 200 mg/kg of ART was orally administered to IR mice, and different doses (25, 50, and 100 µg/ml) of ARTC groups were treated to IR C2C12 cells. IPGTT, IPITT, body weight, Hb1AC, FFA, TNF-α, MCP-1, and IR-associated gene expression (p-AMPK, p-IRS-1, PI3K, p-AKT, p-JNK, and GLUT4) were measured in IR mice. Glucose uptake, TNF-α, MCP-1, and IR-associated gene expression were also measured in IR C2C12 cells. Results showed that ART alleviated high-fat diet-induced IR in the skeletal muscle of mice, and this finding was further validated by ARTC. This study demonstrated that ART presented a notable IR alleviating effect by regulating IR-associated gene expression, and triterpenes were the material basis for the IR alleviating activity of AR.
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Platycodonis Radix, the root of Platycodon grandiflorum (Jacq.) A. DC., is a well-known edible herbal medicine. It is a common vegetable used for the preparation of side dish, kimchi, dessert, and tea. Besides, it has been used to treat respiratory disease including cough, excessive phlegm, and sore throat for a long history. In the past decades, the bioactive components and the pharmacological activities of Platycodonis Radix have been widely investigated. Thereinto, platycodins, the oleanane-type triterpenoid saponins were demonstrated to be the main bioactive components in Platycodonis Radix, and more than 70 platycodins have been identified up to date. This paper mainly reviewed the phytochemistry, pharmacological activities (apophlegmatic, anti-tussive, anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, immunomodulatory, cardiovascular protective, and hepatoprotective activities, etc.), toxicology and pharmacokinetics of platycodins isolated from Platycodonis Radix, aiming to promote further investigation on therapeutic potential of these platycodins.
Assuntos
Platycodon/química , Saponinas/química , Saponinas/farmacologia , Animais , Humanos , Fitoterapia , Saponinas/farmacocinética , Saponinas/toxicidadeRESUMO
OBJECTIVE: To explore the effect of compound decoction on notoginsenosides in Panax notoginseng. METHOD: Notoginsenoside R1, Rg1, Re, Rb1 and pH were used as the parameters to investigate the changes on the content of notoginsenosides in different compound extractions by heating for two hours and their correlation with pH. RESULT: When the pH values of solution of P. notoginseng with Fructus ligustri, P. notoginseng with Eupolyphaga seu steleophaga, P. notoginseng with Pheretima asiatica, and Zhitangjiang Fang (free of Hirudo) were rept higher than 5.7, the reserved rate (RR) of notoginsenside were higher than 90%; When the pH values of decoetion of P. notoginseng with Salvia miltiorrhiza, P. notoginseng with Paeonia lactiflora, P. notoginseng with Platycodon grandiflorum, P. notoginseng with Arctium lappa were kept 4.5-5.5, their RR of notoginsenside were 60% - 85%; When the pH values of the decotction of P. notoginseng with Hirudo nipponica was decreased to 3.4, its RR of of notoginsenside was 38.4%; When the pH values of Zhitangjiang Fang extraction was regulated by 0.1% NaOH solution to pH 6. 3, and the RR of notoginsenside increased to 97%. CONCLUSION: The pH of other Chinese herbal medicines extraction with P. notoginseng compound is a critical effect on the stability and yields of notoginsensides.
Assuntos
Medicamentos de Ervas Chinesas/química , Ginsenosídeos/análise , Panax/química , Animais , Arctium/química , Baratas/química , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/isolamento & purificação , Hirudo medicinalis/química , Temperatura Alta , Concentração de Íons de Hidrogênio , Ligustrum/química , Materia Medica/química , Materia Medica/isolamento & purificação , Oligoquetos/química , Paeonia/química , Platycodon/química , Salvia miltiorrhiza/químicaRESUMO
BACKGROUND: Ovarian cancer is the first leading cause of death among gynecologic malignancies worldwide. Discovery of new chemotherapeutic drugs is still imperative for the improvement of the survival rate. PURPOSE: This study aims to investigate the anti-cancer potential of alisol B 23-acetate (AB23), a protostane-type triterpene isolated from the Alismatis Rhizoma, in the parental and paclitaxel-resistant ovarian cancer cells. METHODS: MTT assay was performed to evaluate cell viability after treatment with AB23, along with flow cytometry for apoptosis and cell cycle analysis. Western blotting was conducted to determine the relative protein level. Wound healing and transwell assays were performed to investigate the effect of AB23 on cell migration and invasion. RESULTS: AB23 obviously inhibited proliferation of the three ovarian cancer cell lines, down-regulated the protein levels of CDK4, CDK6, and cyclin D1, and blocked the cell cycle progressions in G1 phase. Meanwhile, AB23 induced accumulation of the sub-G1 phase in the three cell lines in a concentration dependent manner. The protein levels of cleaved poly ADP-ribose polymerase (PARP) and the ratio of Bax/Bcl-2 were up-regulated after treatment with AB23. Further study showed that AB23 induced endoplasmic reticulum stress through IRE1 signaling pathway and silencing of IRE1α partially enhanced AB23-induced apoptosis. Wound healing and transwell assays showed that AB23 could also suppress the migration and invasion of HEY cells. Moreover, it down-regulated the protein levels of matrix metalloproteinases MMP-2 and MMP-9. CONCLUSION: AB23 possessed anti-proliferation, anti-migration and anti-invasion activities as a single agent on ovarian cancer cells.