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1.
Biomed Pharmacother ; 125: 109999, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32070876

RESUMO

The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.

10.
Front Pharmacol ; 10: 843, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31402869

RESUMO

Metabolic reprogramming is thought to be one of the initiators in cancer drug resistance. It has been shown that CTAB is capable of interfering the efficiency of cancer therapy by regulation of cell metabolic reprogramming. In this study, we hypothesized that AMPK as a key metabolic regulator plays a crucial role in regulation of breast cancer drug resistance, which could be alleviated by treatment of CTAB. We observed that CTAB can improve the DOX sensitivity of the breast cancer cells by inhibition of the ATP-dependent drug-efflux pump P-gp complex through activation of the AMPK-HIF-1α-P-gp cascades. The CTAB effect was also confirmed in vivo showing low systemic toxicity. Taken together, our results showed that CTAB sensitized drug resistance of breast cancer to DOX chemotherapy by activating AMPK signaling cascades both in vitro and in vivo, suggested that CTAB may be developed as a promising and novel chemosensitizer and chemotherapeutic candidate for breast cancer treatment.

14.
Oncol Rep ; 41(1): 270-278, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30542707

RESUMO

Acute pancreatitis (AP) is an aseptic inflammation characterized with an annual incidence rate, and ~20% patients progressing to severe AP (SAP) with a high mortality rate. Although Qingyi decoction has been frequently used for SAP treatment over the past 3 decades in clinic, the actual mechanism of its protective effects remains unknown. As the major active ingredient of Qingyi decoction, emodin was selected in the present study to investigate the effect of emodin against severe acute pancreatitis (SAP) in rats through NOD­like receptor protein 3 (NLRP3) inflammasomes. The rats were randomly divided into a sham operation group, an SAP model group induced by a standard retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct, and low­dose (30 mg/kg) and high­dose (60 mg/kg) emodin­treated groups. At 12 h after the event, the plasma amylase, lipase, interleukin (IL)­1ß, IL­18 and myeloperoxidase (MPO) activities were examined. Furthermore, the pathological scores of pancreases were evaluated by hematoxylin and eosin staining. The expression levels of P2X ligand­gated ion channel 7 (P2X7), NLRP3, apoptosis­associated speck­like protein containing a C­terminal caspase recruitment domain and caspase­1 were also analyzed by western blot analysis. The data demonstrated that, compared with the SAP group, emodin could significantly relieve the pancreatic histopathology and acinar cellular structure injury, and notably downregulate the plasma amylase and lipase levels, as well as the MPO activities in pancreatic tissues, in a dose­dependent manner. Furthermore, emodin inhibited the P2X7/NLRP3 signaling pathway followed by the decrease of pro­inflammatory factors, and the latter is beneficial for the recovery of SAP. Collectively, the data indicated that emodin may be an efficient candidate natural product for SAP treatment.


Assuntos
Emodina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pancreatite/tratamento farmacológico , Substâncias Protetoras/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Emodina/uso terapêutico , Humanos , Masculino , Pancreatite/induzido quimicamente , Pancreatite/diagnóstico , Pancreatite/patologia , Peroxidase/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Sprague-Dawley , Rheum/química , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Ácido Taurocólico/toxicidade , Resultado do Tratamento
15.
Pharmacol Res ; 137: 259-269, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30315966

RESUMO

Currently, the numbers of patients with cancer, fibrosis, diabetes, chronic kidney disease, stroke and osteoporosis are increasing fast and fast. It's critical necessary to discovery lead compounds for new drug development. Dioscin, one active compound in some medicinal plants, has anti-inflammation, immunoregulation, hypolipidemic, anti-viral, anti-fungal and anti-allergic effects. In recent years, dioscin has reached more and more attention with its potent effects to treat liver, kidney, brain, stomach and intestine damages, and metabolic diseases including diabetes, osteoporosis, obesity, hyperuricemia as well as its anti-cancer activities through adjusting multiple targets and multiple signals. Therefore, dioscin is a promising multi-target candidate to treat various diseases. This review paper summarized the progress on pharmacological activities and mechanisms of dioscin, which may provide useful data for development and exploration of this natural product in the further.


Assuntos
Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Diosgenina/análogos & derivados , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais , Diosgenina/uso terapêutico , Humanos
17.
Pharmacol Res ; 137: 56-63, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30240824

RESUMO

Oxidative stress plays important roles in intestinal ischemia-reperfusion (II/R) injury, and exploration of effective lead compounds against II/R injury via regulating oxidative stress is necessary. In this study, the effects and possible mechanisms of dioscin against hypoxia-reoxygenation (H/R) injury in IEC-6 cells and II/R injury in mice were investigated. The results showed that dioscin markedly increased cell viability, and reduced ROS level caused by H/R injury in IEC-6 cells. in vivo, dioscin significantly reduced the levels of MDA, MPO and chiu' score, increased SOD level, and improved pathological changes caused by II/R injury in mice. Mechanism investigation showed that dioscin markedly up-regulated the expression levels of Sirt6 by decreasing miR-351-5p levels, decreased the expression levels of p-FoxO3α via activating AMPK, and increased the expression levels of MnSOD and CAT. In addition, miR-351-5p mimic in IEC-6 cells and agomir in mice increased ROS levels and aggravated II/R injury. MiR-351-5p inhibitor in IEC-6 cells and antagomir in mice alleviated these actions by adjusting Sirt6 signal pathway. MiR-351-5p interference experiment further confirmed that dioscin increased Sirt6 expression level by down- regulating miR-351-5p level to inhibit oxidative stress and reduce II/R injury. Furthermore, we also demonstrated that dioscin inhibited the expression level of miR-351-5p via reducing TRBP expression level during the generation of miR-351-5p mature body. Dioscin showed protective effect against II/R injury via adjusting miR- 351-5/Sirt6 signal to reduce oxidative stress, which should be considered as one potent candidate to treat II/R injury. In addition, miR-351-5/Sirt6 could be one effective drug target against II/R injury.


Assuntos
Diosgenina/análogos & derivados , MicroRNAs/genética , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/genética , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diosgenina/farmacologia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo
18.
Foods ; 7(6)2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29890650

RESUMO

We previously reported the effects of the total flavonoids (TFs) from Rosa laevigata Michx fruit against carbon tetrachloride-induced liver damage, non-alcoholic fatty liver disease, and liver ischemia-reperfusion injury. However, there have been no papers reporting the role of R. laevigata TFs against lipopolysaccharide (LPS)-induced liver injury. In this paper, liver injury in mice was induced by LPS, and R. Laevigata extract was intragastrically administered to the mice for 7 days. Biochemical parameters in serum and liver tissue were examined, and pathological changes were observed by transmission electron microscopy, hematoxylin and eosin (H&E) and Oil Red O staining. The results showed that the TFs markedly reduced serum ALT (alanine transferase), AST (aspartate transaminase), TG (total triglyceride), and TC (total cholesterol) levels and relative liver weights and improved liver pathological changes. In addition, the TFs markedly decreased tissue MDA (malondialdehyde) level and increased the levels of SOD (superoxide dismutase) and GSH-Px (glutathione peroxidase). A mechanistic study showed that the TFs significantly increased the expression levels of Nrf2 (nuclear erythroid factor2-related factor 2), HO-1 (heme oxygenase-1), NQO1 (NAD(P)H dehydrogenase (quinone 1), GCLC (glutamate-cysteine ligase catalytic subunit), and GCLM (glutamate-cysteine ligase regulatory subunit) and decreased Keap1 (Kelch-like ECH-associated protein 1) level by activating FXR (farnesoid X receptor) against oxidative stress. Furthermore, the TFs markedly suppressed the nuclear translocation of NF-κB (nuclear factor-kappa B) and subsequently decreased the expression levels of IL (interleukin)-1β, IL-6, HMGB-1 (high -mobility group box 1), and COX-2 (cyclooxygenase-2) by activating FXR and FOXO3a (forkhead box O3) against inflammation. Besides, the TFs obviously reduced the expression levels of SREBP-1c (sterol regulatory element-binding proteins-1c), ACC1 (acetyl-CoA carboxylase-1), FASN (fatty acid synthase), and SCD1 (stearoyl-coenzyme A desaturase 1), and improved CPT1 (carnitine palmitoyltransferase 1) level by activating FXR to regulate lipid metabolism. Our results suggest that TFs exhibited protective effect against LPS-induced liver injury by altering FXR-mediated oxidative stress, inflammation, and lipid metabolism, and should be developed as an effective food and healthcare product for the therapy of liver injury in the future.

19.
Br J Pharmacol ; 175(17): 3594-3609, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29952043

RESUMO

BACKGROUND AND PURPOSE: Intestinal ischaemia-reperfusion (II/R) injury is a serious clinical problem. Here we have investigated novel mechanisms and new drug targets in II/R injury by searching for microRNAs regulating such injury. EXPERIMENTAL APPROACH: We used hypoxia/reoxygenation (H/R) of IEC-6 cell cultures and models of II/R models in rats and mice. Microarray assays were used to identify target miRNAs from rat intestinal. Real-time PCR, Western blot and dual luciferase reporter assays, and agomir and antagomir in vitro and in vivo were used to assess the effects of the target miRNA on II/R injury. KEY RESULTS: The miR-351-5p was differentially expressed in our models and it targeted MAPK13 and sirtuin-6. This miRNA reduced levels of sirtuin-6 and AMP-activated protein kinase phosphorylation, and activated forkhead box O3 (FoxO3α) phosphorylation to cause oxidative stress. Also, miR-351-5p markedly reduced MAPK13 level, activated polycystic kidney disease 1/NF-κB signal and increased NF-κB (p65). Moreover, miR-351-5p up-regulated levels of Bcl2-associated X, cytochrome c, apoptotic peptidase activating factor 1, cleaved-caspase 3 and cleaved-caspase 9 by reducing sirtuin-6 levels to promote apoptosis. In addition, miR-351-5p mimic in IEC-6 cells and agomir in mice aggravated these effects, and miR-351-5p inhibitor and antagomir in mice alleviated these actions. CONCLUSIONS AND IMPLICATIONS: Our data showed that miR-351-5p aggravated II/R injury by promoting intestinal mucosal oxidative stress, inflammation and apoptosis by targeting MAPK13 and sirtuin-6.These data provide new insights into the mechanisms regulating II/R injury, and of miR-351-5p could be considered as a novel therapeutic target for such injury.


Assuntos
Intestinos/irrigação sanguínea , MicroRNAs/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Sirtuínas/metabolismo , Animais , Apoptose , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Ratos Wistar , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
20.
Redox Biol ; 16: 189-198, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29524841

RESUMO

Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX-treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity. Furthermore, dioscin significantly inhibited myocardial oxidative insult through adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px in vitro and in vivo. Our data also indicated that dioscin activated Nrf2 and Sirt2 signaling pathways, and thereby affected the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a through decreasing miR-140-5p expression level. In addition, the level of intracellular ROS was significantly increased in H9C2 cells treated by DOX after miR-140-5p mimic transfection, as well as the down-regulated expression levels of Nrf2 and Sirt2, which were markedly reversed by dioscin. In conclusion, our data suggested that dioscin alleviated DOX-induced cardiotoxicity through modulating miR-140-5p-mediated myocardial oxidative stress. This natural product should be developed as a new candidate to alleviate cardiotoxicity caused by DOX in the future.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Diosgenina/análogos & derivados , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Diosgenina/administração & dosagem , Doxorrubicina/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas de Neoplasias/genética , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Ratos
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