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1.
Br J Pharmacol ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33687738

RESUMO

BACKGROUND AND PURPOSE: Pancreatic cancer is an exceptionally fatal disease. However, therapeutic drugs for pancreatic cancer have presented a serious shortage over the past few decades. Signal Transducer and Activator of Transcription-3 (STAT3) is persistently activated in many human cancers where it promotes tumor development and progression. Natural products serve as an inexhaustible source of anticancer drugs. Here, we identified the natural product Trienomycin A (TA), an ansamycin antibiotic, as a potential inhibitor of the STAT3 pathway with potent activity against pancreatic cancer. EXPERIMENTAL APPROACH: Utilizing the STAT3-luciferase (STAT3-luc) reporter system, we found that TA potently inhibits the transcriptional activity of STAT3. We subsequently investigated in vitro and in vivo inhibitory activity of TA against pancreatic cancer and its potential mechanism by using the molecular docking, SPR assay, MTS assay, colony formation assay, transwell migration/invasion assay, flow cytometric analysis, immunofluorescence staining, quantitative real-time PCR, western blotting, tumor xenograft model, H&E staining and immunohistochemistry. KEY RESULTS: TA directly bound to STAT3 and inhibited STAT3 (Tyr705) phosphorylation, leading to the inhibition of the STAT3 pathway. TA significantly inhibited the colony formation, proliferation, migration and invasion of pancreatic cancer cell lines. TA dramatically blocked pancreatic tumor growth. More importantly, TA did not show obvious toxicity at the effective dose in mice. CONCLUSIONS AND IMPLICATIONS: TA exhibits antineoplastic activity by suppressing the STAT3 activation in pancreatic cancer. TA could be a novel therapeutic candidate for pancreatic cancer by blocking the STAT3 pathway.

2.
Sci Rep ; 11(1): 3850, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594167

RESUMO

Fibroblast-like synoviocytes (FLS) play a pathogenic role in rheumatoid arthritis (RA). STAT3 signaling is activated in FLS of RA patients (RA-FLS), which in turn causes RA-FLS hyperproliferation. RL is a traditional remedy for treating inflammatory diseases in China. It comprises Rosae Multiflorae Fructus and Lonicerae Japonicae Flos. A standardized ethanolic extract of RL (RLE) has been shown to exert anti-arthritic effects in collagen-induced arthritis (CIA) rats. Some constituents of RLE were reported to inhibit JAK2/STAT3 signaling in rat FLS. Here, we determined whether RLE inhibits FLS hyperproliferation, and explored the involvement of STAT3 signaling in this inhibition. In joints of CIA rats, RLE increased apoptotic FLS. In IL-6/sIL-6R-stimulated RA-FLS, RLE reduced cell viability and evoked cell apoptosis. In synovial tissues of CIA rats, RLE lowered the protein level of phospho-STAT3. In IL-6/sIL-6R-stimulated RA-FLS, RLE inhibited activation/phosphorylation of STAT3 and JAK2, decreased the nuclear localization of STAT3, and downregulated protein levels of Bcl-2 and Mcl-1. Over-activation of STAT3 diminished RLE's anti-proliferative effects in IL-6/sIL-6R-stimulated RA-FLS. In summary, RLE inhibits hyperproliferation of FLS in rat and cell models, and suppression of STAT3 signaling contributes to the underlying mechanisms. This study provides further pharmacological groundwork for developing RLE as a modern anti-arthritic drug.

3.
BMC Complement Med Ther ; 20(1): 341, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176782

RESUMO

BACKGROUND: Herba Siegesbeckiae (HS), the dried aerial parts of Siegesbeckia orientalis L., S. pubescens Makino, or S. glabrescens Makino, is traditionally used for treating chronic diseases in China. However, there is no information about the chronic toxicity of HS. The objective of this study is to evaluate the 24-week oral dosing toxicities of HS aqueous extract (HSE) in rats. METHODS: S. orientalis-originated HS was reflux-extracted with distilled water. Sprague-Dawley rats were randomly divided into four groups, with 10 males and 10 females in each group. The rats were intragastrically administered with HSE at 5, 1.67 and 0.56 g/kg (experimental groups) or an equal volume of distilled water (control group), 6 days a week, for 24 weeks. The high dose of HSE (5 g/kg) was its maximum tolerated dose. Body weight was recorded every 2 days during the experimental period. Chemical, hematological and histopathological parameters, as well as organ weights, were measured at the end of the experiment. RESULTS: Decreased body weight gain; increased liver and lung relative weights; histopathological alterations in liver and lung tissues; elevated serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were found after HSE treatments. In liver tissues, HSE treatment upregulated levels of three pro-inflammatory cytokines: IL-6, IL-1ß and TNF-α. In lung tissues, HSE treatment caused oxidative stress and activated mitogen-activated protein kinases (MAPKs). CONCLUSION: Long-term oral administration of HSE caused toxicities in rats evidenced by decreased body weight gain, as well as liver and lung damage. Treatment-induced oxidative stress, inflammation and MAPK activation are involved in HSE's toxicities. Caution should be taken when using HS to treat chronic diseases.

4.
Biol Pharm Bull ; 43(8): 1267-1271, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741948

RESUMO

Primary liver cancer is a lethal cancer. The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of liver cancer. Gomisin N (GN), a lignan isolated from the dried fruits of Schisandra chinensis (Turca.) Baill., has been reported to reduce viability of, and induce apoptosis in, HepG2 liver cancer cells. In preadipocytes, GN was found to inhibit Akt activity. In the present study, Akt signaling-related anti-liver cancer mechanisms of GN were investigated. We confirmed that GN reduces cell viability of, and triggers apoptosis in, more liver cancer cell lines. Mechanistic studies revealed that GN lowers protein levels of phospho-PI3K (p85 tyrosine (Tyr)458), phospho-Akt (serine (Ser)473), and Akt downstream molecules Mcl-1 in HepG2 and HCCLM3 cells. Meanwhile, GN activates mTOR and inhibits ULK1 (a negative downstream effector of mTOR) activities. Activation of mTOR has been reported to suppress ULK1 activity and repress autophagy. Indeed, we observed that GN inhibits autophagy in liver cancer cells. In summary, we for the first time demonstrated that GN inhibits the PI3K-Akt pathway and regulates the mTOR-ULK1 pathway in liver cancer cells.

5.
Phytomedicine ; 76: 153254, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32531698

RESUMO

BACKGROUND: Receptor activator of NF-κB ligand (RANKL) facilitates differentiation of osteoclast precursors into osteoclasts, resulting in bone erosion in rheumatoid arthritis (RA) patients. Fibroblast-like synoviocytes (FLS) are the main cells for producing RANKL. Signal transducer and activator of transcription 3 (STAT3) signaling is activated in FLS of RA patients (RA-FLS), which has been linked to RANKL production. A two-herb formula (RL) comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos is traditionally used for treating RA in China. We have found that a standardized ethanolic extract of RL (RLE for short) alleviates bone erosion in collagen-induced arthritis (CIA) rats. PURPOSE: This study aimed to determine whether RLE inhibits RANKL production and osteoclastogenesis in cell and rat models, and to explore the involvement of the STAT3 pathway in this inhibition. STUDY DESIGN AND METHODS: A CIA rat model, interleukin-6/soluble interleukin-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS and a co-culture system (IL-6/sIL-6R-stimulated RA-FLS/peripheral blood mononuclear cells) were used to evaluate the effects of RLE. Micro-computed tomography analysis was used to observe bone erosion in CIA rats. Tartrate-resistant acid phosphatase staining was used to evaluate osteoclastogenesis. Western blotting and ELISA assays were employed to examine protein levels. RT-qPCR was used to detect mRNA levels. STAT3-over-activated RA-FLS were used to investigate the involvement of STAT3 signaling in the anti-osteoclastogenic effects of RLE. RESULTS: RLE alleviated bone erosion in joints of CIA rats. In both synovial tissues of CIA rats and IL-6/sIL-6R-stimulated RA-FLS, RLE downregulated the protein level of RANKL. In the co-culture system, RLE significantly and dose-dependently inhibited IL-6/sIL-6R-induced osteoclastogenesis. Mechanistic studies revealed that RLE lowered the protein level of phospho-STAT3 (Tyr705) in synovial tissues of CIA rats. In IL-6/sIL-6R-stimulated RA-FLS, RLE inhibited the activation/phosphorylation of a STAT3 upstream kinase Janus kinase 2 (Tyr1007/1008) and STAT3 (Tyr705), decreased the nuclear localization of STAT3, lowered mRNA levels of STAT3-transcriptionally regulated genes IL-1ß and TNF-α. RLE's inhibitory effects on RANKL production in RA-FLS gradually decreased when IL-6/sIL-6R doses increased. Over-activation of STAT3 diminished the inhibitory effects of RLE on RANKL production in IL-6/sIL-6R-stimulated RA-FLS, and attenuated the anti-osteoclastogenic effects of RLE in the co-culture system. CONCLUSION: We, for the first time, demonstrated that suppressing STAT3 signaling contributes to the inhibition of RANKL production and osteoclastogenesis, and thereby supports the mechanisms responsible for the reduction in bone erosion in RLE-treated CIA rats. This study provides further pharmacological groundwork for developing RLE as a modern anti-arthritic drug, and supports the notion that targeting STAT3 signaling is a viable strategy for managing bone erosion.

6.
J Ethnopharmacol ; 260: 113065, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32505839

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Si-Jun-Zi-Tang (SJZT) is a traditional Chinese medicine formula used to treat chronic and debilitating diseases including melanoma. SJZT-based therapies have achieved good clinical outcomes in melanoma management. However, the pharmacological basis of SJZT for its clinical use in melanoma treatment is not fully understood. AIM OF THE STUDY: To investigate the anti-melanoma effects and mechanism of action of an ethanolic extract of SJZT. MATERIALS AND METHODS: SJZT was extracted using 50% ethanol. A murine B16 melanoma-bearing mouse model was employed to investigate the anti-melanoma effects of SJZT. microRNA (miRNA) and mRNA levels were examined by RT-qPCR, and protein levels were measured by Western blotting. RESULTS: SJZT significantly inhibited B16 tumor growth in mice. Mechanistic investigations revealed that SJZT elevated miR-34b (a tumor suppressing miRNA), and lowered c-Met (a miR-34b target gene) and ß-catenin (a downstream molecule of c-Met signaling) expression levels in the B16 tumors. CONCLUSIONS: In this study we found, for the first time, that SJZT exerts anti-melanoma effects and regulates the miR-34b/c-Met/ß-catenin pathway in a melanoma mouse model. Our findings provide pharmacological justifications for the clinical use of SJZT in treating melanoma.

7.
Cell Death Dis ; 11(4): 246, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312954

RESUMO

Malignant melanoma is aggressive and has a high mortality rate. Toll-like receptor 4 (TLR4) has been linked to melanoma growth, angiogenesis and metastasis. However, signal transduction mediated by TLR4 for driving melanoma progression is not fully understood. Signal transducer and activator of transcription 3 (STAT3) has been identified as a major oncogene in melanoma progression. We found: that TLR4 expression positively correlates with activation/phosphorylation of STAT3 in human melanoma samples; that TLR4 ligands activate STAT3 through MYD88 and TRIF in melanoma cells; and that intratumoral activation of TLR4 increases STAT3 activation in the tumor and promotes tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT) and the formation of an immunosuppressive tumor microenvironment in mice. Further, we found that the effects mediated by activating TLR4 are weakened by suppressing STAT3 function with a dominant negative STAT3 variant in melanoma. Collectively, our work identifies STAT3 activation as a key event in TLR4 signaling-mediated melanoma progression, shedding new light on the pathophysiology of melanoma.

8.
ACS Med Chem Lett ; 11(4): 451-456, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32292549

RESUMO

Supramolecular aggregation-induced emission (AIE) has become a research hotspot in cell imaging. Herein, supramolecular assembly with AIE effect was constructed in two stages, where adamantane modified tetraphenylethene self-assembly emitted weak fluorescence, and then after adding ß-cyclodextrin modified hyaluronic acid, the formed nanoparticles enhanced AIE fluorescence for targeted cancer cell imaging.

9.
Oncol Lett ; 19(3): 2508-2514, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32194752

RESUMO

Late stage melanoma is associated with a high mortality rate. Signal transducer and activator of transcription 3 (STAT3) is currently a target for melanoma treatment as it is constitutively activated with high frequency in melanoma. Dioscin is a natural steroid saponin that is present in several medical herbs. A previous study demonstrated that dioscin inhibits STAT3 signaling in a cerebral ischemia-reperfusion injury rat model. Furthermore, dioscin has been reported to exert anti-melanoma effects in B16 melanoma cells and a B16 allograft mouse model. The present study investigated whether inhibition of STAT3 signaling is involved in the anti-melanoma effects of dioscin. The results of the present study demonstrated that dioscin significantly decreased viability, induced apoptosis and suppressed migration of human A375 melanoma cells and murine B16F10 melanoma cells. Furthermore, dioscin inhibited the phosphorylation of STAT3 and Src (an upstream kinase of STAT3), and downregulated mRNA levels of STAT3-targeted genes, including B-cell lymphoma-2, cyclin D1 and matrix metalloproteinase-2. In addition, overexpression of STAT3 decreased the anti-proliferative effects of dioscin. Overall, the results of the present study indicate that inhibiting the Src/STAT3 signaling pathway contributes to the anti-melanoma molecular mechanisms of dioscin. These results provide further pharmacological groundwork for developing dioscin as a novel anti-melanoma agent.

10.
Phys Rev Lett ; 124(2): 023603, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-32004058

RESUMO

Exploring the properties and applications of topological quantum states is essential to better understand topological matter. Here, we theoretically study a quasi-one-dimensional topological atom array. In the low-energy regime, the atom array is equivalent to a topological superatom. Driving the superatom in a cavity, we study the interaction between light and topological quantum states. We find that the edge states exhibit topology-protected quantum coherence, which can be characterized from the photon transmission. This quantum coherence helps us to find a superradiance-subradiance transition, and we also study its finite-size scaling behavior. The superradiance-subradiance transition also exists in symmetry-breaking systems. More importantly, it is shown that the quantum coherence of the subradiant edge state is robust to random noises, allowing the superatom to work as a topologically protected quantum memory. We suggest a relevant experiment with three-dimensional circuit QED. Our study may have applications in quantum computation and quantum optics based on topological edge states.

11.
Phytomedicine ; 68: 153173, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31999977

RESUMO

BACKGROUND: Chrysoeriol is a flavone found in diverse dietary and medicinal herbs such as Lonicerae Japonicae Flos (the dried flower bud or newly bloomed flower of Lonicera japonica Thunb.). These herbs are commonly used for treating inflammatory diseases. Herbal extracts containing chrysoeriol have been shown to have anti-inflammatory effects and inhibit nuclear factor-kappa B (NF-κB) signaling. Some of these extracts can inhibit signal transducers and activators of transcription 3 (STAT3) signaling in cancer cells. PURPOSE: This study aimed to determine whether chrysoeriol has anti-inflammatory effects and whether NF-κB and STAT3 pathways are involved in the effects. STUDY DESIGN AND METHODS: A TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ear edema mouse model and LPS-stimulated RAW264.7 cells were used to evaluate the effects of chrysoeriol. Griess reagent was used to measure the production of nitric oxide (NO). Western blot and enzyme-linked immunosorbent assays were employed to detect protein levels. RT-qPCR analyses were used to detect mRNA levels. Haematoxylin and eosin (H&E) staining was employed to examine the pathological conditions in animal tissues. RESULTS: In the mouse model, chrysoeriol ameliorated acute skin inflammation, evidenced by reduced ear thickness, ear weight and number of inflammatory cells in inflamed ear tissues. The compound lowered protein levels of phospho-p65 (Ser536), phospho-STAT3 (Tyr705), inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), IL-1ß and tumor necrosis factor α (TNF-α) in mouse swollen ears. In LPS-stimulated RAW264.7 cells, chrysoeriol also lowered levels of these proteins. In addition, chrysoeriol decreased the production of NO and prostaglandin E2; inhibited the phosphorylation of inhibitor of κB (Ser32), p65 (Ser536) and Janus kinase 2 (Tyr1007/1008); decreased nuclear localization of p50, p65 and STAT3; and down-regulated mRNA levels of pro-inflammatory cytokines IL-6, IL-1ß and TNF-α that are transcriptionally regulated by NF-κB and STAT3 in the cell model. CONCLUSION: We for the first time demonstrated that chrysoeriol ameliorates TPA-induced ear edema in mice, and that inhibition of JAK2/STAT3 and IκB/p65 NF-κB pathways are involved in the anti-inflammatory effects of chrysoeriol. This study provides chemical and pharmacological justifications for the use of chrysoeriol-containing herbs in treating inflammatory diseases, and provides pharmacological groundwork for developing chrysoeriol as a novel anti-inflammatory agent.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Erupção por Droga/tratamento farmacológico , Flavonas/farmacologia , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Erupção por Droga/metabolismo , Erupção por Droga/patologia , Regulação da Expressão Gênica , Proteínas I-kappa B/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/toxicidade
13.
Cancer Biomark ; 26(3): 361-366, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31594211

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor and second most common cause of tumor-related deaths worldwide. Activated platelets play a prominent role in tumor. Platelet distribution width (PDW) indicates platelets activation and is altered in malignancies. The aim of this study was to explore the prognostic value of PDW for overall survival (OS) in HCC patients. METHODS: We retrospectively reviewed 273 HCC patients at a single institution from 2010 to 2014. The relationship between PDW and clinicopathological characteristics was analyzed. Kaplan-Meier curves and multivariate Cox regression analyses were used to evaluate the relationship of PDW with OS. RESULTS: Low PDW levels were observed in 127 (46.5%) out of 273 patients. A significant correlation was found between PDW and liver cirrhosis. Median follow-up was 36 months, survival curves revealed that the patients with increased PDW had significantly shorter survival time than those with normal PDW (p= 0.001). Cox regression analysis demonstrated that PDW was an independent prognostic factor for overall survival (hazard ratio, 2.464; 95% confidence interval [CI], 1.402-4.330, p= 0.001). CONCLUSION: PDW is significantly associated with OS in HCC. This result suggests activated platelet may affect clinical outcome and warrant continued investigation.


Assuntos
Plaquetas/patologia , Carcinoma Hepatocelular/mortalidade , Hepatectomia , Neoplasias Hepáticas/mortalidade , Volume Plaquetário Médio , Adulto , Idoso , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Phytomedicine ; 64: 153084, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31514083

RESUMO

BACKGROUND: Metastasized melanoma is extremely difficult to treat. Activation of C-C chemokine receptor type 7 (CCR7) has been linked to melanoma metastasis. CCR7 can be directly regulated by miR-let-7. We have previously shown that an ethanolic extract of an herbal formula comprising Sophorae Flos and Lonicerae Japonicae Flos (SLE) inhibits melanoma cell migration and invasion. PURPOSE: In this study, we determined whether SLE suppresses melanoma metastasis, and whether regulation of miR-let-7a/f-CCR7 signaling is involved in the effect. STUDY DESIGN AND METHODS: Small RNA sequencing was conducted to compare miRNA expression profiles of B16F10 tumors dissected from SLE-treated or untreated mice. Western blot and RT-qPCR analyses were employed to examine protein and miRNA levels, respectively. A B16F10 melanoma lung metastasis mouse model was used to evaluate the effects of SLE on melanoma metastasis. MiR-let-7a/f-knockdown and CCR7-overexpression cell models were used to investigate the involvement of miR-let-7a/f-CCR7 signaling in the anti-metastatic effects of SLE. RESULTS: It was found that SLE upregulated levels of miR-let-7a/f in B16F10 melanoma tissues. SLE significantly elevated levels of miR-let-7a/f, lowered the protein level of CCR7, inhibited the phosphorylation of CCR7 downstream molecules p38 and JNK in B16F10 and A375 melanoma cells. SLE inhibited B16F10 melanoma lung metastasis in mice. SLE upregulated levels of miR-let-7a/f, and lowered protein levels of CCR7, MMP-2, MMP-9, phospho-p38 (Thr180/Tyr182) and phospho-JNK (Thr183/Tyr185) in melanoma-invaded lung tissues. Knockdown of miR-let-7a/f diminished the effects of SLE on CCR7 signaling in, and invasion of, melanoma cells. Overexpression of CCR7 lessened the effects of SLE in inhibiting the phosphorylation of p38 and JNK in, and the invasive capability of, melanoma cells. CONCLUSION: We for the first time demonstrated that SLE inhibits melanoma metastasis in mice, and that regulation of the miR-let-7a/f-CCR7 pathway contributes to the anti-metastatic mechanisms of SLE. These findings provide a pharmacological basis for developing SLE as a modern agent for treating metastatic melanoma. Additionally and importantly, this study suggests that regulating the miR-let-7a/f-CCR7 pathway is a novel strategy for controlling melanoma metastasis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Melanoma Experimental/tratamento farmacológico , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Receptores CCR7/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Receptores CCR7/genética , Sophora/química
15.
Cochrane Database Syst Rev ; 8: CD013107, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31436846

RESUMO

BACKGROUND: Chronic hepatitis B is a liver disease associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming to reduce the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, as well as to improve health-related quality of life. Acupuncture is being used to decrease discomfort and improve immune function in people with chronic hepatitis B. However, the benefits and harms of acupuncture still need to be established in a rigorous way. OBJECTIVES: To assess the benefits and harms of acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. SEARCH METHODS: We undertook electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry (ChiCTR) for ongoing or unpublished trials until 1 March 2019. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B as defined by the trialists or according to guidelines. We allowed co-interventions when the co-interventions were administered equally to all intervention groups. DATA COLLECTION AND ANALYSIS: Review authors in pairs individually retrieved data from reports and through correspondence with investigators. Primary outcomes were all-cause mortality, proportion of participants with one or more serious adverse events, and health-related quality of life. Secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered not to be serious. We presented the pooled results as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed the risks of bias using risk of bias domains with predefined definitions. We put more weight on the estimate closest to zero effect when results with fixed-effect and random-effects models differed. We evaluated the certainty of evidence using GRADE. MAIN RESULTS: We included eight randomised clinical trials with 555 randomised participants. All included trials compared acupuncture versus no intervention. These trials assessed heterogeneous acupuncture interventions. All trials used heterogeneous co-interventions applied equally in the compared groups. Seven trials included participants with chronic hepatitis B, and one trial included participants with chronic hepatitis B with comorbid tuberculosis. All trials were assessed at overall high risk of bias, and the certainty of evidence for all outcomes was very low due to high risk of bias for each outcome, imprecision of results (the confidence intervals were wide), and publication bias (small sample size of the trials, and all trials were conducted in China). Additionally, 79 trials lacked the necessary methodological information to ensure their inclusion in our review.None of the included trials aim to assess all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. We are uncertain whether acupuncture, compared with no intervention, has an effect regarding adverse events considered not to be serious (RR 0.67, 95% CI 0.43 to 1.06; I² = 0%; 3 trials; 203 participants; very low-certainty evidence) or detectable hepatitis B e-antigen (HBeAg) (RR 0.64, 95% CI 0.11 to 3.68; I² = 98%; 2 trials; 158 participants; very low-certainty evidence). Acupuncture showed a reduction in detectable hepatitis B virus (HBV) DNA (a non-validated surrogate outcome; RR 0.45, 95% CI 0.27 to 0.74; 1 trial, 58 participants; very low-certainty evidence). We are uncertain whether acupuncture has an effect regarding the remaining separately reported adverse events considered not to be serious.Three of the eight included trials received academic funding from government or hospital. None of the remaining five trials reported information on funding. AUTHORS' CONCLUSIONS: The clinical effects of acupuncture for chronic hepatitis B remain unknown. The included trials lacked data on all-cause mortality, health-related quality of life, serious adverse events, hepatitis-B related mortality, and hepatitis-B related morbidity. The vast number of excluded trials lacked clear descriptions of their design and conduct. Whether acupuncture influences adverse events considered not to be serious is uncertain. It remains unclear if acupuncture affects HBeAg, and if it is associated with reduction in detectable HBV DNA. Based on available data from only one or two small trials on adverse events considered not to be serious and on the surrogate outcomes HBeAg and HBV DNA, the certainty of evidence is very low. In view of the wide usage of acupuncture, any conclusion that one might try to draw in the future should be based on data on patient and clinically relevant outcomes, assessed in large, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding.


Assuntos
Terapia por Acupuntura/métodos , Hepatite B Crônica/terapia , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
16.
J Agric Food Chem ; 67(31): 8677-8688, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31293164

RESUMO

Reversed-phase ultrahigh-performance-liquid chromatography-mass spectrometry (UPLC-MS) is the typical method for the lipidomic analysis of most of biological samples, which was rarely used for the comprehensive lipidomic analysis of marine shellfish. Thus, a range of columns, modifiers, and resuspension solvents were evaluated using UPLC-electrospray ionization-quadrupole time-of-flight-MS to facilitate the ionization efficiency in both the positive and negative electrospray ionization (ESI(+)/(-)) modes for abalone lipids. Optimal lipidomic coverage was acquired with 10 mM ammonium formate in both ESI(+)/(-) modes. The selected resuspension solvents also influenced ionization efficiency through the matrix effect, and resuspension in methanol enhanced the signal intensities by reducing ion suppression. Because of the higher glycerophospholipid content in shellfish, bridged ethylene hybrid C8 columns showed clear advantages over charged surface hybrid C18 columns. A series of glycerophospholipids, lyso-glycerophospholipids, glycerolipids, and fatty acids in different shellfish can be annotated and semiquantified in one injection by the optimized method.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Lipídeos/química , Frutos do Mar/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Cromatografia Líquida de Alta Pressão/instrumentação , Ácidos Graxos/química , Glicerofosfolipídeos/química , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas em Tandem
17.
Pharmacol Res ; 142: 115-126, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30797070

RESUMO

A traditional Chinese medicine (TCM) formula (SL) comprising Sophorae Flos and Lonicerae Japonicae Flos was used for treating melanoma in ancient China. We have previously shown that an ethanolic extract of SL (SLE) possesses anti-melanoma effects and suppresses STAT3 signaling in vitro and in vivo. STAT3 has been linked to the development of melanoma immunosuppressive microenvironment. In this work, we investigated whether SLE inhibits melanoma growth by reprogramming the tumor microenvironment in mouse and co-culture cell models. In B16F10 melanoma-bearing mice, we found that intragastric administration of SLE (1.2 g/kg) dramatically inhibited tumor growth. This observation was associated with the downregulation of protein levels of phospho-STAT3 (Tyr 705) and STAT3-regulated immunosuppressive cytokines, and mRNA levels of STAT3-targeted genes involved in tumor growth and immune evasion. We also observed increased Th, Tc and dendritic cells in the melanomas and spleens in SLE-treated mice compared to that in control mice. In a co-culture system composed of B16F10 cells and mouse primary splenic lymphocytes, it was found that SLE not only inhibited STAT3 activation in B16F10 cells, but also downregulated mRNA levels of STAT3-targeted genes in the splenic lymphocytes. In this co-culture setting, SLE decreased the levels of STAT3-regulated immunosuppressive cytokines, increased the percentages of Th, Tc and dendritic cells as well. Furthermore, effects of SLE on STAT3 phosphorylation, cytokine levels and immune cell subtype percentages were significantly weaker in the B16STAT3C cells (stable cells harboring a constitutively active STAT3 variant STAT3C)/splenic lymphocytes co-culture system than in the B16V cells (cells stably transfected with the empty vector)/splenic lymphocytes co-culture system, indicating that STAT3 over-activation diminishes SLE's effects. In summary, our findings indicate that reprograming the immune microenvironment, partially mediated by inhibiting STAT3 signaling, contributes to the anti-melanoma mechanisms of SLE. This study provides further pharmacological groundwork for developing SLE as a modern agent for melanoma prevention/treatment, and supports the notion that reprograming immunosuppressive microenvironment is a viable anti-melanoma strategy.


Assuntos
Antineoplásicos/farmacologia , Melanoma Experimental/imunologia , Extratos Vegetais/farmacologia , Fator de Transcrição STAT3/imunologia , Neoplasias Cutâneas/imunologia , Sophora , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Técnicas de Cocultura , Flores , Linfócitos , Masculino , Medicina Tradicional Chinesa , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Extratos Vegetais/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Microambiente Tumoral/imunologia
18.
J Zhejiang Univ Sci B ; 19(9): 689-698, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30178635

RESUMO

The thioredoxin system plays a role in a variety of physiological functions, including cell growth, differentiation, apoptosis, tumorigenesis, and immunity. We previously confirmed that butaselen (BS), a novel thioredoxin reductase inhibitor, can inhibit the growth of various human cancer cell lines, yet the underlying mechanism remains elusive. In this study, we investigated the anti-tumor effect of BS in vivo through regulating the immune system of KM mice. We found that BS inhibits tumor proliferation by promoting the activation of splenic lymphocytes in mice. BS can elevate the percentage of CD4-CD8+ T lymphocytes and the secretion of downstream cytokines in mice via down-regulating the expression of programmed death-ligand 1 (PD-L1) on the tumor cells' surface in vivo. Further study in HepG2 and BEL-7402 cells showed that decrease of PD-L1 level after BS treatment was achieved by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation. Taken together, our results suggest that BS has a role in promoting the immune response by reducing PD-L1 expression via the STAT3 pathway, and subsequently suppresses tumorigenesis.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Derivados de Benzeno/farmacologia , Compostos Organosselênicos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Derivados de Benzeno/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Compostos Organosselênicos/uso terapêutico , Fator de Transcrição STAT3/fisiologia , Carga Tumoral/efeitos dos fármacos
19.
Sci Rep ; 8(1): 12928, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30131579

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

20.
Food Chem ; 265: 49-56, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29884393

RESUMO

Abalone has been farmed commercially for the last few decades, and the breeding and economic value of abalone have gained extensive attention. In this study, the lipid profile of the foot muscles, viscera, and gonads of male and female Japanese abalone Haliotis discus hannai Ino was explored using ultra performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS), to discuss the effect of lipid composition on its nutritional value. Thirty-four species from ten lipid classes including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, lysophosphatidic acid, triacylglycerol, steroids, terpenoids and fatty acids were annotated by MS-DIAL to obtain all fragment ions for precursors. Glycerophospholipids (GPLs) enriched in unsaturated fatty acids were the major components, which accounted for 52-57% of total lipids. Considering the high-level of GPLs, and their importance in maintaining the integrity and functionality of cell membranes, further utilization of inexpensive tissues, such as viscera and gonads is warranted.


Assuntos
Gastrópodes/química , Lipídeos/química , Espectrometria de Massas por Ionização por Electrospray , Animais , Membrana Celular/química , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Gastrópodes/citologia , Espectrometria de Massas em Tandem
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