RESUMO
This study aims to investigate the effect and mechanism of Stellera chamaejasme extract(SCL) on multidrug resistance(MDR) in breast cancer. Human triple-negative breast cancer cell line MDA-MB-231 and its adriamycin-resistant cell line MDA-MB-231/ADR were used in the experiment. Cell viability was detected by methyl thiazolyl tetrazolium(MTT) assay, and cell apoptosis was detected by DAPI staining and Annexin-V/Pi double staining. Western blot(WB) was used to detect the expression levels of Keap1, Nrf2, HO-1, Bcl-2, Bax, caspase-9, and caspase-3. Immunofluorescence staining was used to observe the distribution of Nrf2 in the cell, and flow cytometry was used to detect the level of reactive oxygen species(ROS) in the cell. The results showed that the resis-tance factor of SCL was 0.69, and that of adriamycin and paclitaxel was 8.40 and 16.36, respectively. DAPI staining showed that SCL could cause nuclear shrinkage and fragmentation of breast cancer cells. Annexin-V/Pi double staining showed that the average apoptosis rate of the drug-resistant cells was 32.64% and 50.29%, respectively under medium and high doses of SCL. WB results showed that SCL could significantly reduce the expression levels of anti-apoptotic proteins Bcl-2, caspase-9, and caspase-3 and significantly increase the expression level of pro-apoptotic protein Bax. Further studies showed that SCL could significantly promote the expression of Keap1, significantly inhibit the expression of Nrf2 and HO-1, and significantly reduce the expression level of Nrf2 in the nucleus. Correspondingly, flow cytometry showed that the intracellular ROS level was significantly increased. In conclusion, SCL can significantly inhibit the proliferation of MDA-MB-231 multidrug-resistant cells of triple-negative breast cancer and cause cell apoptosis, and the mechanism is related to inhibiting Keap1/Nrf2 signaling pathway, leading to ROS accumulation in drug-resistant cells and increasing the expression of apoptosis-related proteins.
Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Fator 2 Relacionado a NF-E2 , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Feminino , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Thymelaeaceae/química , Medicamentos de Ervas Chinesas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Doxorrubicina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proliferação de Células/efeitos dos fármacos , Células MDA-MB-231RESUMO
This study aims to investigate the regulatory effect of the Spatholobi Caulis extract from ethyl acetate(SEA) on natural killer(NK) cells under physiological conditions and elucidate the underlying mechanism. The C57BL/6 mice were randomized into NC and SEA groups, and NK-92 cells were respectively treated with 0, 25, 50, and 100 µg·mL~(-1) SEA. The body weight and immune organ index of the mice were compared between groups. The lactate dehydrogenase(LDH) assay was employed to examine the cytotoxicity of NK-92 cells treated with SEA and the killing activity of mouse NK cells against YAC-1 cells. The cell-counting kit-8(CCK-8) was used to examine the impact of SEA on the proliferation of NK-92 cells. Flow cytometry was employed to measure the number of NK cells in the peripheral blood as well as the expression levels of natural killer group 2 member A(NKG2A) and natural killer group 2 member D(NKG2D). The enzyme-linked immunosorbent assay(ELISA) was performed to determine the interferon(IFN)-γ secretion in the serum. Semi-quantitative PCR was conducted to determine the mRNA levels of NKG2A, NKG2D, and IFN-γ in spleen cells. Western blot was employed to investigate the involvement of phosphoinositide 3-kinase(PI3K)/extracellular regulated protein kinase 1(ERK1) signaling pathway. The results showed that SEA exhibited no adverse effects on the body, while significantly enhance the number of NK cells and augment the cytotoxicity of NK-92 cells against YAC-1 cells. Moreover, it suppressed the expression of NKG2A, enhanced the expression of NKG2D, promoted IFN-γ secretion, and upregulated the protein levels of PI3K and ERK. The findings suggest that SEA has the potential to enhance the immune recognition and effector function of NK cells by increasing the cell number, modulating the expression of functional receptors, and promoting IFN-γ secretion via the PI3K/ERK signaling pathway.
Assuntos
Acetatos , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Fosfatidilinositol 3-Quinases , Camundongos , Animais , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Células Matadoras NaturaisRESUMO
Shenlian (SL) extract has been proven to be effective in the prevention and treatment of atherosclerosis and myocardial ischemia. However, the function and molecular mechanisms of SL on coronary artery no-reflow have not been fully elucidated. This study was designed to investigate the contribution of SL extract in repressing excessive mitochondrial autophagy to protect the mitochondrial function and prevent coronary artery no-reflow. The improvement of SL on coronary artery no-reflow was observed in vivo experiments and the molecular mechanisms were further explored through vitro experiments. First, a coronary artery no-reflow rat model was built by ligating the left anterior descending coronary artery for 2 hr of ischemia, followed by 24 hr of reperfusion. Thioflavin S (6%, 1 ml/kg) was injected into the inferior vena cava to mark the no-reflow area. Transmission electron microscopy was performed to observe the cellular structure, mitochondrial structure, and mitochondrial autophagy of the endothelial cells. Immunofluorescence was used to observe the microvascular barrier function and microvascular inflammation. Cardiac microvascular endothelial cells (CMECs) were isolated from rats. The CMECs were deprived of oxygen-glucose deprivation (OGD) for 2 hr and reoxygenated for 4 hr to mimic the Myocardial ischemia-reperfusion (MI/R) injury-induced coronary artery no-reflow in vitro. Mitochondrial membrane potential was assessed using JC-1 dye. Intracellular adenosine triphosphate (ATP) levels were determined using an ATP assay kit. The cell total reactive oxygen species (ROS) levels and cell apoptosis rate were analyzed by flow cytometry. Colocalization of mitochondria and lysosomes indirectly indicated mitophagy. The representative ultrastructural morphologies of the autophagosomes and autolysosomes were also observed under transmission electron microscopy. The mitochondrial autophagy-related proteins (LC3II/I, P62, PINK, and Parkin) were analyzed using Western blot analysis. In vivo, results showed that, compared with the model group, SL could reduce the no-reflow area from 37.04 ± 9.67% to 18.31 ± 4.01% (1.08 g·kg-1 SL), 13.79 ± 4.77% (2.16 g·kg-1 SL), and 12.67 ± 2.47% (4.32 g·kg-1 SL). The extract also significantly increased the left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) (p < 0.05 or p < 0.01). The fluorescence intensities of VE-cadherin, which is a junctional protein that preserves the microvascular barrier function, decreased to ~74.05% of the baseline levels in the no-reflow rats and increased to 89.87%(1.08 g·kg-1 SL), 82.23% (2.16 g·kg-1 SL), and 89.69% (4.32 g·kg-1 SL) of the baseline levels by SL treatment. SL administration repressed the neutrophil migration into the myocardium. The oxygen-glucose deprivation/reoxygenation (OGD/R) model was induced in vitro to mimic microvascular ischemia-reperfusion injury. The impaired mitochondrial function after OGD/R injury led to decreased ATP production, calcium overload, the excessive opening of the Mitochondrial Permeability Transition Pore, decreased mitochondrial membrane potential, and reduced ROS scavenging ability (p < 0.05 or p < 0.01). The normal autophagosomes (double-membrane vacuoles with autophagic content) in the sham group were rarely found. The large morphology and autophagosomes were frequently observed in the model group. By contrast, SL inhibited the excessive activation of mitochondrial autophagy. The mitochondrial autophagy regulated by the PINK/Parkin pathway was excessively activated. However, administration of SL prevented the activation of the PINK/Parkin pathway and inhibited excessive mitochondrial autophagy to regulate mitochondrial dysfunction. Results also demonstrated that mitochondrial dysfunction stimulated endothelial cell barrier dysfunction, but Evans blue transmission was significantly decreased and transmembrane resistance was increased significantly by SL treatment (p < 0.05 or p < 0.01). Carbonylcyanide-3-chlorophenylhydrazone (CCCP) could activate the PINK/Parkin pathway. CCCP reversed the regulation of SL on mitochondrial autophagy and mitochondrial function. SL could alleviate coronary artery no-reflow by protecting the microvasculature by regulating mitochondrial function. The underlying mechanism was related to decreased mitochondrial autophagy by the PINK/Parkin pathway.
Assuntos
Vasos Coronários , Traumatismo por Reperfusão Miocárdica , Ratos , Animais , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Carbonil Cianeto m-Clorofenil Hidrazona/metabolismo , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Volume Sistólico , Função Ventricular Esquerda , Autofagia , Mitocôndrias , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/farmacologia , Oxigênio/metabolismo , Trifosfato de Adenosina/metabolismo , Glucose/metabolismoRESUMO
This study explored the effect and underlying mechanism of Stellera chamaejasme extract(SCE) on multidrug resistance of breast cancer. The chemotherapy-sensitive breast cancer cell line MCF-7 and adriamycin(ADR)-resistant cell line MCF-7/ADR were used as experimental subjects. MTT assay was used to detect cell proliferation activity. Pi staining was used to detect the cell cycle. 4',6-Diamidino-2-phenylindole, dihydrochloride(DAPI) staining and flow cytometry were used to detect apoptosis. Dansylcadaverine(MDC) staining and GFP-LC3B-Mcherry adenovirus transfection were used to detect autophagy. The protein expression of Bcl-2, Bax, caspase-9, caspase-3, LC3B, p62, and Beclin-1 was detected by Western blot. The results showed that SCE could significantly inhibit the proliferation of both sensitive and resistant breast cancer cell lines. The drug resistance factor was 0.53, which was significantly lower than 59 of ADR. Meanwhile, the proportion of sensitive/resistant cells in the G_0/G_1 phase increased significantly after SCE treatment. In addition, DAPI staining showed that a series of apoptosis phenomena such as nuclear pyknosis, staining deepening, and nuclear fragmentation appeared in sensitive/resistant cell lines after SCE administration. Moreover, the results of flow cytometry double staining showed that the proportion of apoptotic cells in sensitive/resistant cell lines increased significantly after SCE administration. Besides, Western blot showed that the protein expression levels of caspase-3, caspase-9, and Bcl-2 significantly decreased and the expression level of Bax protein significantly increased in both breast cancer cell lines after SCE administration. Furthermore, SCE could also increase the positive fluorescent spots after MDC staining and yellow fluorescent spots after GFP-LC3B-mcherry transfection, and up-regulate the expression levels of autophagy-related proteins LC3B-â ¡, p62, and Beclin-1 in breast cancer cells. In summary, SCE may play the role of anti-multidrug resistance by blocking the cell cycle of breast cancer multidrug-resistant cells, blocking autophagy flow, and ultimately interfering with the apoptosis resistance of drug-resistant cells.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Células MCF-7 , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Proteína Beclina-1/farmacologia , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proliferação de CélulasRESUMO
Multiple sclerosis(MS) shows the pathological characteristics of "inflammatory injury of white matter" and "myelin repair disability" in the central nervous system(CNS). It is very essential for MS treatment and reduction of disease burden to strengthen repair, improve function, and reduce disability. Accordingly, different from the simple immunosuppression, we believe that key to strengthening remyelination and maintaining the "damage-repair" homeostasis of tissue is to change the current one-way immunosuppression strategy and achieve the "moderate pro-inflammation-effective inflammation removal" homeostasis. Traditional Chinese medicine shows huge potential in this strategy. Through literature research, this study summarized the research on remyelination, discussed the "mode-rate pro-inflammation-effective inflammation removal" homeostasis and the "damage-repair" homeostasis based on microglia, and summed up the key links in remyelination in MS. This review is expected to lay a theoretical basis for improving the function of MS patients and guide the application of traditional Chinese medicine.
Assuntos
Esclerose Múltipla , Remielinização , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Remielinização/fisiologia , Bainha de Mielina/patologia , Inflamação/tratamento farmacológico , HomeostaseRESUMO
(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptoxâ A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.
Assuntos
Ageratina , Neuroblastoma , Sesquiterpenos , Humanos , Ageratina/química , Ciclização , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Estrutura MolecularRESUMO
As a classic prescription, Wuji Pills is composed of Coptidis Rhizoma, Euodiae Fructus Preparata, and stir-fried Paeo-niae Radix Alba at the ratio of 6â¶1â¶6. The practical application of it is limited compared with other famous Chinese medicine prescriptions. Only one company produces Wuji Pills in China. In this study, ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS/MS) was used to analyze and identify 26 identical compounds from Wuji Pills and drug-containing plasma of rats. Based on these components, 46 potential targets were screened out with network pharmacology methods, followed by the component-target network construction, Gene Ontology(GO) term enrichment, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and disease prediction. It was concluded that Wuji Pills acted on core targets such as PTGS2, PTSG1, NCOA2, HSP9 OAD1, and RXRA through magnoflorine, hydroxyevodiamine, daucosterol, and berberine and exerted pharmacodynamic effects through various pathways such as calcium ion signaling pathway, phosphatidylinositol-3-kinase-protein kinase B(PI3 K-Akt) signaling pathway, and vascular endothelial growth factor(VEGF) signaling pathway. Thus, Wuji Pills has therapeutic potential for Alzheimer's disease, diabetes mellitus, myocardial ischemia, and other diseases in addition to the conventional disease(irritable bowel syndrome, IBS). The above research results can provide a reference for the comprehensive interpretation of the pharmacodynamic basis of Wuji Pills and the expansion of clinical application. At the same time, a lot of components in serum and the in vivo transformed and metabolized components of Wuji Pills have similar structure and relative molecular weight. In theory, these components may show additive effects and the competitive/antagonistic effects on the same target. According to the hypothesis of "additive effect of multiple components for a single target" in traditional Chinese medicine, multiple similar components may exert the additive effects on local targets. This study can partly prove the scientificity of this hypothesis and provide laboratory evidence.
Assuntos
Medicamentos de Ervas Chinesas , Animais , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Espectrometria de Massas em Tandem , Farmacologia em Rede , Fator A de Crescimento do Endotélio Vascular , Simulação de Acoplamento MolecularRESUMO
This study aimed to investigate the effect and the possible mechanism of Shenlian( SL) extract on tumor necrosis factor-α( TNF-α)-induced ECV304 injury. After the establishment of TNF-α-induced ECV304 cells injure model,MTT assay was used to detect cell viability and the level of reactive oxygen species( ROS) was measured by flow cytometry. The contents of superoxide dismutase( SOD),malondialdehyde( MDA),nitric oxide( NO),endothelin-1( ET-1) and interleukin-1ß( IL-1ß) in the supernatant were detected by biochemical method and enzyme linked immunosorbent assay( ELISA). The expression levels of apoptosis-related proteins B-lymphoma-2 gene( Bcl-2),Bcl-2 associated X protein( Bax),caspase-3,caspase-9 and nuclear factor E2 associated factor2( Nrf2)/Kelch like epichlorohydrin associated protein-1( Keap1) signaling pathway related proteins Nrf2,Keap1,quinone oxidoreductase( NQO1) and heme oxygenase 1( HO-1) were detected by Western blot. The results showed that 50 µg·L-1 TNF-α significantly damaged ECV304 cells,induced the impairment of cell viability( P<0. 01),the increase of ROS production,the decrease of SOD activity,and the increase of MDA,NO,ET-1 and IL-1ß( P<0. 01),meanwhile,it caused the up-regulation of Keap1,caspase-9 and Bax protein expression,and down-regulation of NQO1 and Bcl-2 protein expression( P<0. 05) compared with the control group.Compared with the model group,SL extract reduced the damage of ECV304 cells induced by TNF-α,improved cell viability,reduced ROS production,increased SOD activity and decreased MDA,NO,ET-1,IL-1ß content( P<0. 01 or P<0. 05). In addition,SL extract also down-regulated the protein expression levels of Keap1,caspase-3,caspase-9 and Bax,and increased the protein expressions of Nrf2,NQO1,HO-1 and Bcl-2( P<0. 01 or P<0. 05). The above results indicate that SL extract can provide protective effect on ECV304 cells injury induced by TNF-α,alleviate oxidative stress injury,inflammation and apoptosis,and its mechanism may be related to regulating Nrf2/Keap1 signaling pathway.
Assuntos
Fator 2 Relacionado a NF-E2 , Fator de Necrose Tumoral alfa , Apoptose , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Extratos Vegetais , Transdução de Sinais , Fator de Necrose Tumoral alfa/genéticaRESUMO
Corona virus disease 2019(COVID-19) has brought untold human sufferings and economic tragedy worldwide. It causes acute myocardial injury and chronic damage of cardiovascular system, which has attracted much attention from researchers. For the immediate strategy for COVID-19, "drug repurposing" is a new opportunity for developing drugs to fight COVID-19. Artemisinin and its derivatives have a wide range of pharmacological activities. Recent studies have shown that artemisinin has clear cardiovascular protective effects. This paper summarizes the research progress on the pathogenesis the pathogenesis of COVID-19 in cardiovascular damage by 2019 novel coronavirus(2019-nCoV) virus from myocardial cell injury directly by 2019-nCoV virus,viral ligands competitively bind to ACE2 and then reduce the protective effect of ACE2 on cardiovascular disease, "cytokine storm" related myocardial damage, arrhythmia and sudden cardiac death induced by the infection and stress, myocardial injury by hypoxemia, heart damage side effects from COVID-19 drugs and summarizing the cardiovascular protective effects of artemisinin and its derivatives have activities of anti-arrhythmia, anti-myocardial ischemia, anti-atherosclerosis and plaque stabilization. Then analyzed the possible multi-pathway intervention effects of artemisinin-based drugs on multiple complications of COVID-19 based on its specific immunomodulatory effects, protective effects of tissue and organ damage and broad-spectrum antiviral effect, to provide clues for the treatment of cardiovascular complications of COVID-19, and give a new basis for the therapy of COVID-19 through "drug repurposing".
Assuntos
Artemisininas , COVID-19 , Doenças Cardiovasculares , Cardiopatias , Humanos , SARS-CoV-2RESUMO
The aim of this paper was to obtain low toxicity and high efficiency anti-tumor Chinese medicine through screening the combination ratios of Momordicae Semen and Epimedii Folium, and to explore the anti-tumor mechanism of the combination of two drugs by observing their effect on apoptosis-related proteins in cancer cells. Methyl thiazolyl tetrazolium(MTT) assay was used to observe the effect of drug combination on the proliferation of tumor cells from different tissue sources. The effects of the combination of the two drugs on tumor cells were analyzed by Compusyn software. Plate cloning assay was used to observe the effect of combination of these two drugs on the proliferation of A549 cells in vitro. The expression of reactive oxygen species(ROS) and apoptotic proteins p53, Bcl-2 and Bax were compared by using ROS kit and Western blot. Lewis lung cancer model was used to observe the anti-tumor effect of drugs in vivo. The results showed that the anti-tumor effect of their ethanol extract was more significant than that of water extract, and the anti-proliferation effect was strongest when the ratio was 1â¶1(P<0.05). Compusyn analysis showed that the combination of the two drugs had synergistic effect. Further studies showed that after combined use, the number of clonogen formation in A549 cells was significantly reduced(P<0.01); ROS production was increased; the expression of apoptosis-related protein p53 was up-regulated, and the ratio of Bcl-2/Bax was decreased. In vivo animal study showed that the tumor inhibition rate was 53.06%(P<0.05) in the high dose group. As compared with the single use of the two drugs, the combination of the two drugs had more significant anti-proliferative effect on tumors, and the optimum ratio was 1â¶1. The combination of the two drugs at a ratio of 1â¶1 inhibited the proliferation of various tumor cells, and had no significant effect on normal liver cells LO2 when compared with other ratios. Therefore, it can be preliminarily inferred that the combination of the two drugs may have the effect of synergism and detoxification. Further studies showed that the combination of the two drugs can significantly inhibit the proliferation of A549 cells, and its mechanism may be related to the activation of endogenous apoptotic pathway. In vivo experiments also showed that the tumor inhibition rate increased with the increase of drug concentration.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Epimedium/química , Neoplasias Pulmonares/tratamento farmacológico , Momordica/química , Células A549 , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Experimentais/tratamento farmacológico , Folhas de Planta/químicaRESUMO
Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.
Assuntos
Apoptose , Artemisininas/uso terapêutico , Heme Oxigenase-1/biossíntese , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/imunologia , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Doenças Inflamatórias Intestinais/enzimologia , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos , Oxazolona , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Ácido TrinitrobenzenossulfônicoRESUMO
Artemisinin was isolated from traditional Chinese herb Artemisia annua for treating malaria. A series of derivatives,like dihydroartemisinin,artesunate,artemether,artether,had the same core chemical structure,and sesquiterpene lactone containing peroxide bridge constitute the basic chemical structure. Besides anti-malaria,artemisinin family drugs were found to ameliorate many different diseases,which have attracted wide attention in recent years. Among different diseases,artemisinin family drugs were found to have T lymphocytes immunomodulation effects,including activation,proliferation,differentiation,apoptosis and subsets function. Because T cell immunologic response is the key point of many diseases,and impact the pathogenic process,therapeutic effect and prognosis,the drug studies with it as the target have become hotspots in recent years. Studies of artemisinin family drug on T cell immunomodulation were still at the initial stage and involved in different disease; furthermore,T cell immune process involves complicated molecular mechanism,it is imperative to summarize the advance of current studies for further systematic explanation and exploration of their characteristics and mechanisms. This article will summarize the research progress of artemisinin family drugs for malaria,autoimmune disease,hypersensitivity reaction,tumor,schistosomiasis and AIDS relating to T cell immune modulation,so as to provide basic and professional reference for related research and application.
Assuntos
Antimaláricos , Artemisia annua , Artemisininas/farmacologia , Imunomodulação , Linfócitos TRESUMO
In the background of the high incidence and high mortality of cardiovascular diseases,atherosclerosis is the main pathological feature of cardiovascular diseases and the core pathological basis for disease progression. In the evolution of atherosclerotic plaques,the rupture of unstable plaques,plaque shedding and formation of thrombosis are the most dangerous parts. In this process,the formation of plaque fibrosis is the core mechanism regulating plaque stability. Additionally,fibrosis reflects dynamic changes in the inflammatory processes and pathological changes. In view of the inflammation regulation and fibrosis regulation,this paper clarified the process of atherosclerotic plaque,explained the roles of relevant inflammatory cells and cytokines in plaque stability,and summed up drug researches related with stable plaque in recent years. In the future,improving the fibrosis will be a new idea for stabilizing plaque in atherosclerosis drug development.
Assuntos
Aterosclerose/tratamento farmacológico , Inflamação , Placa Aterosclerótica/tratamento farmacológico , Trombose/tratamento farmacológico , Aterosclerose/patologia , Citocinas , Fibrose , Humanos , Placa Aterosclerótica/patologia , Trombose/patologiaRESUMO
Human health has been severely threatened by malignant tumors continuously.Rational and effective drug use provides an effective means for the treatment of malignant tumors,and is expected to become an important way to solve the problem of tumor treatment in the future.In recent years,with the escalation of new cancer theories and the emergence of clinical drug resistance,innovative research and development of anti-cancer drugs has always been a hot spot and focus in cancer research.Among them,the discovery of novel anti-cancer drugs from natural compound is of top priority due to its strong anti-cancer efficacy and the abundant drug resources.Therefore,it is imperative to systematically summarize the cutting-edge advancements of the natural products and their potential pharmacological mechanisms according to the characteristics of tumor progression,and put forward the new directions and trends for further development of anti-cancer natural products in the future.Specifically,the research advancements on anti-cancer effect of natural products were reviewed,focusing on both the traditional and innovative application.We hope this review could bring the light on the research path of the natural anti-cancer products clearly and comprehensively,and also provide inspirations for innovative,safer and more effective anti-cancer drug development and exploration.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Neoplasias/tratamento farmacológico , Humanos , PesquisaRESUMO
This paper was mainly to discuss the potential role and mechanism of Lianhua Qingwen Capsules(LHQW) in inhibiting pathological inflammation in the model of acute lung injury caused by bacterial infection. For in vitro study, the mRNA expression of MCP-1 in RAW264.7 cells and THP-1 cells, the content of MCP-1 in cell supernatant, as well as the effect of LHQW on chemotaxis of macrophages were detected. For in vivo study, mice were randomly divided into 7 groups, including normal group, model group(LPS 5 mg·kg~(-1)), LHQW 300, 600 and 1 200 mg·kg~(-1)(low, middle and high dose) groups, dexamethasone 5 mg·kg~(-1) group and penicillin-streptomycin group. Then, the anal temperature was detected two hours later. Dry weight and wet weight of lung tissues in mice were determined; TNF-α and MCP-1 levels in alveolar lavage fluid and MCP-1 in serum were detected. In addition, the infiltration of alveolar macrophages was also observed and the infiltration count of alveolar macrophages was measured by CCK-8 method. HE staining was also used to observe the inflammatory infiltration of lung tissues in mice. Both of the in vitro and in vivo data consistently have confirmed that: by down-regulating the expression of MCP-1, LHWQ could efficiently decrease the chemotaxis of monocytes toward the pulmonary infection foci, thus blocking the disease development in ALI animal model.
Assuntos
Lesão Pulmonar Aguda/microbiologia , Infecções Bacterianas/tratamento farmacológico , Quimiotaxia , Medicamentos de Ervas Chinesas/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar , Cápsulas , Quimiocina CCL2/metabolismo , Humanos , Lipopolissacarídeos , Pulmão , Camundongos , Células RAW 264.7 , Distribuição Aleatória , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Artemisinin (Qinghaosu) and its semi-synthetic derivatives have been demonstrated to alleviate neuroinflammatory response in the central nerve system (CNS). In this review, we summarized that artemisinins are capable to treat neuroinflammtion-related CNS diseases in both direct (via regulating inflammatory process in the CNS, exerting anti-oxidative stress and neuroprotective effect, and preventing Aß accumulation) and indirect (via maintaining BBB integrity, suppressing systemic inflammation and alleviating intestinal inflammtion) manner. However, the precise mechanism of their anti-neuroinflammatory effects and potential neurotoxicity, which hindered further progress in these aspects, remains unclear. We suggest that further understanding of the PK/PD properties and structure-action relationship of atemisinin and its derivatives will facilitate the development of new therapeutics with better curative effects and safety.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Artemisininas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Intestinos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologiaRESUMO
This article proposes a new thought on the study of "main effect" of traditional Chinese medicine (TCM) formulae. The blood concentrations of the pharmacodynamic substances of Chinese material medicaï¼CMMï¼are usually very low, with lower toxic and side effects than western medicine. Therefore, according to a recent hypothesis of additive effect of multiple components for a single target, local targets in multi-component multi-target synergistic effect network of TCM may have the additive effect of similar components. Studies on the disposition of CMM showed that a constituent could bebio-transformed to many metabolites; these compounds with a similar structure are likely to have the same pharmacological effects on the same target, which could provide experimental evidences for the hypothesis of "additive effect". The authors of this article further believe that additive effect of TCM multi-components only comes up under a limited conditions/concentration. Because of the complexity of TCM-organism system, the complex effect of multicomponent addition and competition/antagonism is more likely to appear in single targets of drug effect. This complex effect may be the key to impact the synergistic effect of TCM multi-targets. In theory, choose and create a single target additive effect could realize the scientific compatibility of TCM and improve the curative effect and attenuate toxicity. According to the clinical demand and under the guidance of the above thought, we proposed the "main effect" of TCM formulae. Because traditional Chinese medicine (compounds) have diverse and complex effects, how to better study TCM formulae compatibility mechanism and improve the curative effect? Efforts shall be made to select one or several effects relating to clinical specific syndromes from the complex and diverse effects of TCM as the "main effect". The "main effect" of TCM formulae is the macroscopic manifestation of the synergistic effect of multi-component/multi-target. The study of the Formulae "main effect" can contain at least two aspects: one is the study of pharmacokinetic application of TCM formulae, and another is the study for pharmacodynamics effect. In the study of main effect, there are two main elements. First, which drug targets are directly related to the main effect? This requires identifying the target network. Second, which drug components positively or negatively control the single target of the target network? And what change in single target effect as well as the multi-target synergistic effect will be caused by the regulatory component concentration or the change in number? These two elements is the key to elucidate the mechanism of compound action and compatibility mechanism of Chinese herbal compound formulae. Through the study of the main effect, the clinical curative effect and the mechanism of the TCM formulae shall be improved.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Medicina Tradicional Chinesa , PesquisaRESUMO
In view of the fact that the antimalarial effects of artemisinins are significant but the mechanism has not yet been clarified and there are many different opinions, it is possible that artemisinins can produce high anti-malarial efficacy through various mechanisms and multiple pathways. In addition, the researches on the pathogenesis of malaria "erythrocyte membrane plasmodial surface anion channel (PSAC)" in the past few years have provided more positive findings, which may confirm and discover the new antimalarial mechanism of artemisinins. This paper was as to study the effect of dihydroartemisinin (DHA) in vitro on erythrocyte membrane permeability of HB3 plasmodium infection, with using the mechanism of 5% sorbitol can be used to kill the Plasmodium falciparum in red blood cell membrane selectively, the effectual difference of sorbitol on the killing of P. falciparum with adding DHA or not was detected, so as to investigate whether DHA can affect the permeability of the erythrocyte membrane. Result showed that, Pre-stimulation with 10 nmol·L⻹ DHA (the final concentration of plasmodium in vitro culture system) for 30 min could significantly decrease the killing effect of sorbitol on the HB3 plasmodium in the P. falciparum erythrocytic cycle, and DHA may inhibit the permeability of the erythrocyte membrane for preventing sorbitol through the red blood cell membrane, thereby reducing the killing effect of sorbitol on the P. falciparum.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Permeabilidade da Membrana Celular , Membrana Eritrocítica/efeitos dos fármacos , Células Cultivadas , Eritrócitos , HumanosRESUMO
Cerebral malaria (CM) is the leading cause of death in children under 5 years in Africa, severe neurological sequelae may occur in surviving children. Although artesunate has made breakthrough progress in the clinical treatment of CM, the clinical problems of high mortality and high morbidity have not yet been completely resolved. In this study, an experimental cerebral malaria (ECM) model was established by infecting C57BL/6 mice with Pb ANKA (Plasmodium berghei ANKA) to compare parasitemia level, survival rates, and rapid murine coma behavior scale scores, cerebral microvascular obstruction, haemozoin deposition in the liver, body temperature and weight to investigate the anti-cerebral malaria effect of the artesunate compound combination. The results showed that the artesunate compound combination could improve the survival rate of Pb ANKA-infected mice, reduce the level of parasitemia, effectively improve the symptoms of ECM neurological injury, reduce cerebrovascular obstruction and haemozoin deposition in the liver, and also significantly improve body temperature, weight and other basic indicators. The results showed that the artesunate compound combination improved the pathological changes and neurological damage caused by CM. It is expected to provide a theoretical basis for human cerebral malaria patients in clinical adjuvant therapy.
Assuntos
Antimaláricos/farmacologia , Artesunato/farmacologia , Malária Cerebral/tratamento farmacológico , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium bergheiRESUMO
On October 18th, 2017, a research article named "Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia" was published on Science Translational Medicine. This article pointed out that herbs containing aristolochic acids could cause liver cancer by inducing the specific "aristolochic acids mutational signature". The public was also suggested to avoid the intake of herbs containing aristolochic acids. Since 2000, CFDA has gradually abolished the medicinal standards for herbs containing aristolochic acids such as caulis aristolochiae manshuriensis, aristolochia heterophylla and radix aristolochiae. Related drugs have been strengthened supervision since then. Chinese Pharmacopoeia has also removed the records of a series of related herbs. State Administration of Traditional Chinese Medicine held a conference on the "toxicity" of aristolochic acids as soon as the article was published. After a discussion of the studies on the toxicity of aristolochic acids, experts attending the meeting discovered several problems, including the unclearness of exposure history, tumor-producing dose and latent period, the absence of some key factors such as hepatitis B, the small sample size, miscellaneous factors, incomplete evidence chains, the missing of analyses between data with huge differences, the insufficiency of fundamental research arguments, etc. In order to understand the toxicity of aristolochic acids and the carcinogenic risks, as well as guide clinical safe medication, the experts suggested thatï¼â Complete the systematical evaluation of aristolochic acids carcinogenicity as soon as possible. Scientifically elucidate the relationship between aristolochic acids and the genesis of liver cancer. â¡Establish medication risk warnings of aristolochic acids and strengthen the supervision. â¢Make an in-depth study of the toxicity of traditional Chinese medicine. Find out the adverse effects of all traditional Chinese medicine step by step.