Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 391
Filtrar
1.
Life Sci ; 240: 117096, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760097

RESUMO

Aim Liver fibrosis represents a massive global health burden with limited therapeutic options. Thus, the need for curative options is evident. Thus, this study aimed to assess the potential antifibrotic effect of honokiol in Concanavalin A (Con A) induced immunological model of liver fibrosis as well the possible underlying molecular mechanisms. METHODS: Male Sprague-Dawley rats were treated with either Con A (20 mg/kg, IV) and/or honokiol (10 mg/kg, orally) for 4 weeks. Hepatotoxicity indices were as well as histopathological evaluation was done. Hepatic fibrosis was assessed by measuring alpha smooth muscle actin (α-SMA) expression and collagen fibers deposition by Masson's trichrome stain and hydroxyproline content. To elucidate the underlying molecular mechanisms, the effect of honokiol on oxidative stress, inflammatory markers as well as transforming growth factor beta (TGF-ß)/SMAD and mitogen-activated protein kinase (MAPK) pathways was assessed. KEY FINDINGS: Honokiol effectively reversed the hepatotoxicity indices elevations and abnormal histopathological changes induced by Con A. Besides, honokiol attenuated Con A-induced liver fibrosis by down-regulation of hydroxyproline levels, α-SMA expression together with a marked decrease in collagen fibers deposition. Mechanistically Con A induced oxidative stress, provocation of inflammatory responses and activation of TGF-ß/SMAD/MAPK pathways. Contrariwise, honokiol co-treatment significantly restored antioxidant defence mechanisms, down-regulated inflammatory cascades and inhibited TGF-ß/SMAD/MAPK signaling pathways. CONCLUSION: The results provide an evidence for the promising antifibrotic effect of honokiol that could be partially due to suppressing oxidative stress and inflammatory processes as well as inhibition of TGF-ß/SMAD/MAPK signaling pathways.


Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Cirrose Hepática/prevenção & controle , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Actinas/metabolismo , Animais , Concanavalina A , Hidroxiprolina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida
2.
Medicine (Baltimore) ; 98(47): e18088, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764844

RESUMO

The objective of this study is to compare the effects of paravertebral nerve block-propofol intravenous general anesthesia (PPA) and sevoflurane inhalation general anesthesia (SGA) on the expression of serum vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-ß) in patients undergoing radical resection of lung cancer.Patients undergoing radical resection of lung cancer were divided into PPA group and SGA group. In PPA group, thoracic paraspinal nerve block was performed with 0.5% ropivacaine (2 mg/kg) before general anesthesia. Anesthesia was maintained with 2.5-3.5 µg/mL TCI of propofol. In SGA group, anesthesia was maintained with 1.0-1.5 MAC sevoflurane. The dosage of opioids during and 24 h after operation, the pain score at 2, 8, 24, 48, and 72 h after operation, and the concentrations of serum VEGF and TGF-ß before and 24 h after operation were observed in the two groups.The intraoperative dosage of remifentanil in PPA group was significantly less than that in SGA group (P < 0.05). The dosage of sufentanil in SGA group was significantly less than that in SGA group at 24 h after operation (P < 0.05). The VAS score at 2, 8, and 24 h after operation was significantly lower than that in SGA group (P < 0.05). The serum VEGF and TGF-ß concentration in PPA group was significantly lower than that in SGA group (P < 0.05).Thoracic paravertebral nerve block-propofol intravenous general anesthesia can reduce the dosage of opioids, improve the effect of postoperative analgesia, and reduce the serum concentration of tumor angiogenesis-related factors in patients undergoing radical resection of lung cancer.


Assuntos
Anestesia Geral/métodos , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Propofol/administração & dosagem , Sevoflurano/administração & dosagem , Sevoflurano/farmacologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Anestesia por Inalação , Anestesia Intravenosa , Anestésicos Inalatórios/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos Paraespinais/inervação , Pneumonectomia/métodos , Propofol/farmacologia , Estudos Prospectivos , Tórax
3.
Inflammation ; 42(4): 1441-1455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31028577

RESUMO

Paraquat (PQ), a widely used potent herbicide, generates superoxide anions and other free radicals, leading to severe toxicity and acute lung injury. PQ induces pulmonary fibrosis through epithelial to mesenchymal transition (EMT) characterized by increased number of myofibroblasts. Time-dependent PQ-induced EMT has been evaluated in present investigation where intracellular ROS levels were significantly enhanced after 24 h of PQ intoxication. Anti-inflammatory effects of curcumin have been studied where alveolar epithelial cells (A549 cells) were incubated with curcumin (30 µΜ) for 1 and 3 h before PQ intoxication (700 µM). Western blot and immunocytochemistry studies revealed that pretreatment of A549 cells with curcumin for 3 h before PQ exposure has maintained E-cadherin expression and inhibited PQ induced α-smooth-muscle actin (α-SMA) expression. Transforming growth factor-ß (TGF-ß) that seems to be involved in PQ-induced EMT was enhanced after PQ intoxication, but curcumin pretreatment has effectively inhibited its expression. Immunostaining studies have shown that curcumin pretreatment has significantly reduced matrix metalloproteinase-9 (MMP-9) expressions, which were elevated after PQ intoxication. These results demonstrate that curcumin can regulate PQ-induced EMT by regulating the expression of TGF-ß.


Assuntos
Curcumina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Paraquat/farmacologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Células A549 , Caderinas/metabolismo , Antagonismo de Drogas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Herbicidas , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Paraquat/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo
4.
Life Sci ; 220: 92-105, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703382

RESUMO

BACKGROUND: Arsenic exposure can cause fibrosis of organs including the liver, heart and lung. It was reported that TGF-ß/Smad pathway played a crucial role in the process of fibrosis. However, the mechanism of arsenic-induced fibrosis through TGF-ß/Smad signaling pathway has remained controversial. OBJECTIVE: A systematic review and meta-analysis was performed to clarify the relationship between arsenic and TGF-ß/Smad pathway, providing a theoretical basis of fibrosis process caused by arsenic. METHODS: A meta-analysis was used to reveal a correlation between arsenic and fibrosis markers of TGF-ß/Smad pathway, including 47 articles of both in vivo and in vitro studies. (Standardized Mean Difference) SMD was employed to compare and analyze the combined effects. When I2 > was 50%, random effect model was selected and subgroup analysis was used to explore the source of heterogeneity. RESULTS: Arsenic exposure up-regulated the expression of TGF-ß1, p-Smad2/3, α-SMA, Collagen1/3 and FN. The dose-response relationship showed that low dose (≤5 µmol/L) arsenic exposure up-regulated the expression of TGF-ß1, whereas high doses had a tendency to down-regulate that of TGF-ß1. Subgroup analysis showed that low or short-term arsenic exposure induced the expression of TGF-ß1 and fibrosis markers. CONCLUSION: The results indicated that arsenic activates the TGF-ß/Smad pathway and induced fibrosis. The mechanism is related to the up-regulation of NADPH oxidase and ROS accumulation. However, high-dose arsenic exposure may inhibit this pathway.


Assuntos
Arsênico/metabolismo , Arsênico/fisiologia , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Fibrose/metabolismo , Fibrose/patologia , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo
5.
Eur J Pharmacol ; 845: 91-98, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30287151

RESUMO

Vitamin D has been suggested to harbor multiple biological activities, among them the potential of vitamin D in the protection of diabetic nephropathy (DN) has attracted special attention. Both animal studies and clinical trials have documented an inverse correlation between low vitamin D levels and DN risk, and supplementation with vitamin D or its active derivatives has been demonstrated to improve endothelial cell injury, reduce proteinuria, attenuate renal fibrosis, and resultantly retard DN progression. Vitamin D exerts its pharmacological effects primarily via vitamin D receptor, whose activation inhibits the renin-angiotensin system, a key culprit for DN under hyperglycemia. The anti-DN benefit of vitamin D can be enhanced when administrated in combination with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. Mechanistic studies reveal that pathways relevant to inflammation participate in the pathogenesis of DN, however, consumption of vitamin D-related products negatively regulates inflammatory response at multiple levels, indicated by inhibiting macrophage infiltration, nuclear factor-kappa B (NF-κB) activation, and production of such inflammatory mediators as transforming growth factor-ß(TGF-ß), monocyte chemoattractant protein 1(MCP-1), and regulated upon activation normal T cell expressed and secreted protein(RANTES). The robust anti-inflammatory property of vitamin D-related products allows them with a promising renoprotective therapeutic option for DN. This review summarizes new advances in our understanding of vitamin D-related products in the DN management.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Proteinúria/tratamento farmacológico , Receptores de Calcitriol/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Vitamina D/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Quimiocina CCL2/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Quimioterapia Combinada , Células Endoteliais/patologia , Humanos , NF-kappa B/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Vitamina D/farmacologia
6.
J Appl Oral Sci ; 27: e20180015, 2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30540068

RESUMO

OBJECTIVES: In this study, the effects of ozonetherapy on secondary wound healing were evaluated histologically and immuno-histochemically. MATERIAL AND METHODS: Material and Methods: 8 healthy pigs were used in this study. Six wounds with 10 mm in diameter were created through the punch technique on the palatinal gingiva of each pig. Ozone gas was applied on only 3 wounds (test group) and the remaining 3 were left to natural healing (control group). Biopsy samples were taken from one of the wounds in each group on the third day, from another wound of each group on the seventh day, and from another one on the tenth day. Routine histological analysis and immuno-histochemical staining were performed to investigate transforming growth factor-beta (TGF-ß) and (VEGF) expressions. RESULTS: Results: No statistical difference was found between the test and control groups in terms of collagen fibers, epithelial formation and inflammation scores. A VEGF expression found in the test group was statistically higher than control group samples taken on the 3rd and 7th day. There was no statistical difference between the test and control groups in terms of TGF-ß expression on any of the sampling days. CONCLUSIONS: Conclusion: The topical application of ozone gas could be effective in the early stages of wound healing by increasing the amount of VEGF expression. Clinical Relevance: Topical application of ozone gas may be effective in the early stages of oral wound healing.


Assuntos
Gengiva/efeitos dos fármacos , Gengiva/patologia , Ozônio/uso terapêutico , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Biópsia , Imuno-Histoquímica , Distribuição Aleatória , Valores de Referência , Reprodutibilidade dos Testes , Suínos , Fatores de Tempo , Fator de Crescimento Transformador beta/análise , Fator de Crescimento Transformador beta/efeitos dos fármacos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
7.
Med Sci Monit ; 24: 7548-7555, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30347408

RESUMO

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive disease with unknow. etiology and a high mortality rate. Oridonin is a diterpenoid isolated from the Rabdosia rubesecens with diverse biological functions. However, whether oridonin possess potential protective activity on IPF is still unclear. MATERIAL AND METHODS The aim of the present study was to explore the therapeutic effects of oridonin on IPF. First, TGF-ß1-induced MRC-5 cells were employed for the evaluation of inhibitory activity in vitro. Then, a bleomycin (BLM)-induced mice pulmonary fibrosis model was used to verify the activity of oridonin in vivo. Several pathological changes, including alveolar space collapse, emphysema, and infiltration of inflammatory cells, were observed in the BLM­treated mice. RESULTS Oridonin could significantly inhibit the mRNA and protein expression levels of α-SMA and COL1A1 in TGF-ß1-induced MRC-5 cells. Oridonin could attenuate pathological changes, including alveolar space collapse, emphysema, and infiltration of inflammatory cells induced by BLM. In addition, oridonin could significantly inhibit BLM-induced upregulation of α-SMA and COL1A1 and the phosphorylation of Smad2/3 in lung tissues of mice. CONCLUSIONS Oridonin could be used as a potential therapeutic agent in treatment for patients with IPF. The mechanisms of anti-fibrosis effect of oridonin might be inhibition of the TGF-ß/Smad pathway.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Miofibroblastos/efeitos dos fármacos , Animais , Bleomicina , Linhagem Celular Tumoral , Diterpenos de Caurano/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/patologia , Camundongos , Fosforilação , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
8.
Clin Immunol ; 197: 118-129, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30248398

RESUMO

Endotoxin tolerance is an important state for the prevention of lethal infection and inflammatory response, which is closely associated with the participation of innate immune cells. Moreover, mesenteric lymph nodes (MLNs)-resident immune cells, such as CD4+Foxp3+ regulatory T (Treg) cells and dendritic cells, play important roles in the maintenance of peripheral immune tolerance. However, the potential roles of these cells in MLNs in the development of endotoxin tolerance remain largely unknown. Recent research work showed that CD4+Foxp3+ Treg cells contributed to the development of endotoxin tolerance. Here, we further analyzed the possible change on CD4+Foxp3+Tregs population in MLNs in murine LPS-induced endotoxin tolerance model. Our data showed that the proportion and absolute number of CD4+Foxp3+Tregs, expressing altered levels of CTLA4 and GITR, significantly increased in MLNs of murine LPS-induced tolerance model. Moreover, the expression level of TGF-ß in MLNs also increased obviously. Furthermore, TGF-ß blockade could obviously reduce the proportion and absolute number of CD4+Foxp3+Tregs in MLNs and subsequently impair the protection effect against LPS rechallenge. Of note, we found that tolerogenic dendritic cell (Tol-DC), expressing lower levels of MHC-II and CD86 molecules, dominantly secreted TGF-ß in MLNs in murine LPS-induced tolerance model. In all, our data provided an unknown phenomenon that the total cell number of CD4+Foxp3+Tregs significantly increased in MLNs in endotoxin tolerance, which was related to MLN-resident TGF-ß secreting CD11c+DCs, providing a new fundamental basis for the understanding on the potential roles of MLN-resident immune cells in the development of endotoxin tolerance.


Assuntos
Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Linfonodos/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Antígenos CD11 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Citocinas/efeitos dos fármacos , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Fatores de Transcrição Forkhead , Proteína Relacionada a TNFR Induzida por Glucocorticoide/efeitos dos fármacos , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Tolerância Imunológica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Mesentério , Camundongos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética
9.
Exp Cell Res ; 370(2): 613-622, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30031128

RESUMO

Fucosyltransferase 2 (FUT2), the enzyme catalyzing α-1,2-fucosylation in mammals, has been implicated in cancer. The up-regulation of FUT2 has been observed in lung adenocarcinoma (LUAD), and FUT2 can enhance the cell migration and invasion of LUAD cell lines. However, the underlying mechanism of FUT2 in LUAD remains largely unknown. Abundant studies have revealed that epithelial-mesenchymal transition (EMT) played a pivotal role during lung cancer metastasis and progression. In the present study, we showed that knocking down FUT2 in LUAD cell lines increased the expression of E-cadherin and reduced the expression of Vimentin, N-cadherin, TßRII, p-Smad2, p-Smad3 and Snail, which were the makers of EMT. Meanwhile, the expression of E-cadherin was decreased, and the expression of Vimentin was increased by restoring the expression of FUT2 in RNA interference FUT2 (RNAi-FUT2) cells, suggesting that FUT2 enhanced the EMT process in LUAD. Additionally, silencing FUT2 expression can up-regulate E-cadherin and down-regulate Vimentin, significantly attenuated EMT in vivo. Treated with the SIS3, a new-type inhibitor of p-Smad3 of TGF-ß signaling, the expression of E-cadherin, Vimentin and Snail were not affected by RNAi-FUT2 cells, indicating that the effect of FUT2 on EMT depended on TGF-ß/Smad signaling. Overall, the current results indicated that FUT2 might promote LUAD metastasis through the EMT initiated by TGF-ß/Smad signaling. Therefore, FUT2 might be a prognostic factor and therapeutic target for LUAD.


Assuntos
Caderinas/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fucosiltransferases/farmacologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Caderinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Vimentina/metabolismo
10.
J Immunother Cancer ; 6(1): 47, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866156

RESUMO

BACKGROUND: TGFß signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFß's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFß pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. RESULTS: In vitro treatment with galunisertib reversed TGFß and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFß and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. CONCLUSIONS: Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy.


Assuntos
Terapia Combinada/métodos , Imunoterapia/métodos , Pirazóis/uso terapêutico , Quinolinas/uso terapêutico , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pirazóis/farmacologia , Quinolinas/farmacologia
11.
Neurochem Res ; 43(3): 760-774, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29423667

RESUMO

Paeoniflorin (PF) is a polyphenolic compound derived from Radix Paeoniae Alba thathas anti-cancer activities in a variety of human malignancies including glioblastoma. However, the underlying mechanisms have not been fully elucidated. Epithelial to mesenchymal transition (EMT), characterized as losing cell polarity, plays an essential role in tumor invasion and metastasis. TGFß, a key member of transforming growth factors, has been demonstrated to contribute to glioblastoma aggressiveness through inducing EMT. Therefore, the present studies aim to investigate whether PF suppresses the expression of TGFß and inhibits EMT that plays an important role in anti-glioblastoma. We found that PF dose-dependently downregulates the expression of TGFß, enhances apoptosis, reduces cell proliferation, migration and invasion in three human glioblastoma cell lines (U87, U251, T98G). These effects are enhanced in TGFß siRNA treated cells and abolished in cells transfected with TGFß lentiviruses. In addition, other EMT markers such as snail, vimentin and N-cadherin were suppressed by PF in these cell lines and in BALB/c nude mice injected with U87 cells. The expression of MMP2/9, EMT markers, are also dose-dependently reduced in PF treated cells and in U87 xenograft mouse model. Moreover, the tumor sizes are reduced by PF treatment while there is no change in body weight. These results indicate that PF is a potential novel drug target for the treatment of glioblastoma by suppression of TGFß signaling pathway and inhibition of EMT.


Assuntos
Movimento Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Invasividade Neoplásica/patologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/metabolismo , Humanos , Camundongos Nus
12.
Clin Sci (Lond) ; 132(4): 437-447, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29343616

RESUMO

Rapamycin, the macrolide immunosuppressant and active pharmaceutic in drug-eluting stents (DES), has a well-recognized antiproliferative action that involves inhibition of the mTOR pathway after binding to the cytosolic protein FKBP12. TGF receptor-type I (TGFRI) spontaneous activation is inhibited by the association with FKBP12. We hypothesized that rapamycin, in addition to inhibition of mTOR signaling, activates TGFRI independent of TGFß. Human umbilical vein endothelial cells (HUVECs) were treated with rapamycin (10 nmol/l) and/or TGFß RI kinase inhibitor (TGFRIi, 100 nmol/l) for 24 h. Rapamycin induced SMAD phosphorylation (SMAD1, SMAD2, and SMAD5) and PAI-1 up-regulation, which was specifically abrogated by SMAD2 knockdown. TGFRIi efficiently blocked phosphorylation of SMAD2, but not SMAD1/5. Interestingly, the inhibitor did not alter cell proliferation arrest induced by rapamycin. Active TGFß secretion was not affected by the treatment. Neutralizing TGFß experiments did not influence SMAD2 phosphorylation or PAI-1 expression indicating that activation of this pathway is independent of the ligand. In addition, rapamycin induction of endothelial-to-mesenchymal transition (EndMT) was potentiated by IL-1ß and efficiently blocked by TGFRIi. In vivo, the prothrombogenic effects of rapamycin and up-regulation of PAI-1 in murine carotid arteries were reduced by TGFRIi treatment. In conclusion, we provide evidence that rapamycin activates TGF receptor independent of its ligand TGFß, in concert with promotion of PAI-1 expression and changes in endothelial phenotype. These undesirable effects, the prothrombogenic state, and activation of EndMT are SMAD2-dependent and independent of the therapeutic rapamycin-induced cell proliferation arrest.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/efeitos dos fármacos , Sirolimo/farmacologia , Proteína Smad2/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos
13.
Chembiochem ; 19(8): 851-864, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29369495

RESUMO

Pentachloropseudilin (PClP) is a chlorinated phenylpyrrole compound that was first isolated from Actinoplanes (ATCC33002), and its structure has been confirmed by chemical synthesis. PClP shows broad antimicrobial activity against Gram-negative and Gram-positive bacteria, protozoa, fungi, and yeast. In mammalian cells, PClP is known to act as a reversible and allosteric inhibitor of myosin 1c (Myo1c). Herein, we report that PCIP is a potent inhibitor of transforming growth factor-ß (TGF-ß)-stimulated signaling. PCIP inhibits TGF-ß-stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor-1 (PAI-1) promoter activation with an IC50 of 0.1 µm in target cells (A549, HepG2, and Mv1Lu cells). In addition, PCIP attenuates TGF-ß-stimulated expression of vimentin, N-cadherin, and fibronectin and, thus, blocks TGF-ß-induced epithelial to mesenchymal transition (EMT) in these cells. Furthermore, cell-surface labeling and immunoblot analysis indicates that PCIP suppresses TGF-ß-stimulated cellular responses by attenuating cell-surface expression of the type II TGF-ß receptor through accelerating caveolae-mediated internalization followed by primarily lysosome-dependent degradation of the receptor, as demonstrated by sucrose density gradient analysis and immune fluorescence staining.


Assuntos
Hidrocarbonetos Clorados/farmacologia , Pirróis/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo II/agonistas , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Linhagem Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Miosina Tipo I/genética , Miosina Tipo I/metabolismo , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo
14.
Eur Urol ; 73(5): 648-652, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29275833

RESUMO

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8+ T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-ß (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8+ T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene (PZ1) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8+ T-cells to be PSMA reactive and insensitive to TGF-ß. Cr51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8+ T-cells was evaluated using an immunodeficient RAG-1-/- mouse model. We found PSMA-specific, TGF-ß insensitive CD8+ T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8+ T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8+ T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8+ T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. PATIENT SUMMARY: We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-ß insensitive CD8+ T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer.


Assuntos
Antígenos de Superfície/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Glutamato Carboxipeptidase II/efeitos dos fármacos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias de Próstata Resistentes à Castração/terapia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Antígenos de Superfície/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glutamato Carboxipeptidase II/imunologia , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica , Antígeno Prostático Específico/efeitos dos fármacos , Antígeno Prostático Específico/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Fator de Crescimento Transformador beta/imunologia , Resultado do Tratamento
15.
Photodiagnosis Photodyn Ther ; 21: 252-256, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29277361

RESUMO

A cohort of 19 patients affected by chronic venous ulcers was recruited from our centre. A 4-mm punch biopsy from wound bed was taken before application of ALA 20% gel and repeated one hour after the first PDT irradiation. We observed a significant and progressive reduction of wounds mean volumes right after three ALA-PDT sessions (once per week; 4479.9 +/- 345.5 mm3 vs 34599 +/- 190.3 mm3, p < .01). On immunofluorescence staining from biopsy specimens, we observed a change in all tested stains of post treatment specimens compared to pre-treatment ones. An increase of plasmacytoid dendritic cells (from 699 +/- 22 cells/0.018 mm2 to 1369 +/- 27 cells/0.018 mm2, p < .0001); MHC-II expression (260.39 +/- 99.7 Red, Green, Blue [RGB 0-255] to 370.2 +/- 162.6 RGB (0-255), p < .01), TNF-alpha positive mast cells expression (49 +/- 0.3 cells/0.018 mm2 to 69 +/- 0.4 cells/0.018 mm2, p < .001), TGF-beta expression (59.89 +/- 23.2 RGB (0-255)/cell vs 137.39 +/- 56.6 RGB (0-255)/cell, p < .01) and CD4+/CD25+ Treg cells (39 +/- 1 cells/0.018 mm2 vs 209 +/- 10 cells/0.018 mm2, p < .001) was observed. An increase of TGF-beta was correlated in a statistical significant manner with a reduction of wounds' mean volumes.


Assuntos
Ácido Aminolevulínico/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Úlcera Varicosa/tratamento farmacológico , Doença Crônica , Células Dendríticas/efeitos dos fármacos , Humanos , Projetos Piloto , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Úlcera Varicosa/patologia
16.
Allergy Asthma Proc ; 39(1): 36-42, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29279058

RESUMO

BACKGROUND: Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody used in the treatment of severe asthma. Its therapeutic efficacy is primarily attributed to reduction of serum-free IgE and in the expression of high-affinity IgE receptor, fc epsilon RI. However, its effect on the low-affinity IgE receptor fc epsilon RII/CD23 in vivo has not been evaluated. AIM: To determine whether CD23 plays a role in the inflammatory process in severe uncontrolled asthma and whether anti-IgE therapy modulates fc epsilon RII/CD23 expression in these patients. METHODS: We evaluated the expression of IgE receptors fc epsilon RI, fc epsilon RII/CD23, and soluble CD23 (sCD23), and the activation state of peripheral blood monocytes (tumor necrosis factor alpha, interleukin (IL) 1-beta, transforming growth factor (TGF) beta expression) in the patients with severe asthma before and after 24 weeks of omalizumab treatment and in the healthy controls. Cytokine expression of monocytes in response to different stimulation (IL-4, IL-4 plus IgE, IL-4 plus IgE plus anti-IgE, and IL-4 plus IgE plus anti-IgE plus anti-CD23 for 72 hours) was determined by enzyme-linked immunosorbent assay. RESULTS: Treatment with omalizumab (for 24 weeks) improved disease control and pulmonary function (forced expiratory volume in the first second of expiration, 64.5 versus 74%; p = 0.021). Mean ± SE expression of fc epsilon RI on monocytes was higher in the patients with asthma versus the controls (45.7 ± 12.2% versus 18.6 ± 5.8%; p = 0.04) and was reduced after omalizumab treatment (45.7 ± 12.2% versus 15.6 ± 4.4%; p = 0.027). Mean ± SE TGF-beta levels in supernatants from monocytes were reduced in the patients treated with omalizumab (211 ± 6 pg/mL versus 184 ± 9 pg/mL; p = 0.036). CONCLUSION: Modulation of the low affinity IgE receptor CD23 in severe asthma is complex, and sCD23 may inversely reflect disease activity. Treatment with omalizumab was associated with reduced monocyte activation.


Assuntos
Asma/tratamento farmacológico , Omalizumab/farmacologia , Receptores de IgE/efeitos dos fármacos , Antiasmáticos/uso terapêutico , Asma/imunologia , Estudos de Casos e Controles , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Monócitos/metabolismo , Omalizumab/uso terapêutico , Fator de Crescimento Transformador beta/efeitos dos fármacos , Resultado do Tratamento
17.
Nat Med ; 23(9): 1036-1045, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28759052

RESUMO

D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-ß activation, which in turn was mediated by upregulation of integrin αvß8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.


Assuntos
Colite/imunologia , Diabetes Mellitus Tipo 1/imunologia , Pneumopatias/imunologia , Pulmão/efeitos dos fármacos , Manose/farmacologia , Pâncreas/efeitos dos fármacos , Hipersensibilidade Respiratória/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Transferência Adotiva , Animais , Colo/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Técnicas In Vitro , Inflamação , Integrinas/efeitos dos fármacos , Integrinas/imunologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/imunologia , Pneumopatias/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Ovalbumina/efeitos adversos , Oxirredução/efeitos dos fármacos , Pâncreas/imunologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Hipersensibilidade Respiratória/induzido quimicamente , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/imunologia , Regulação para Cima
18.
Noise Health ; 19(88): 149-153, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28615545

RESUMO

INTRODUCTION: Infrasound is a mechanical vibration wave with frequency between 0.0001 and 20 Hz. It has been established that infrasound of 120 dB or stronger is dangerous to humans. However, the biological effects of low decibel infrasound are largely unknown. The purpose of this study was to investigate the effects of low decibel infrasound on the cardiac fibroblasts. MATERIALS AND METHODS: The cardiac fibroblasts were isolated and cultured from Sprague-Dawley rats. The cultured cells were assigned into the following four groups: control group, angiotensin II (Ang II) group, infrasound group, and Ang II+infrasound group. The cell proliferation and collagen synthesis rates were evaluated by means of [3H]-thymidine and [3H]-proline incorporation, respectively. The levels of TGF-ß were determined by enzyme-linked immunosorbent assay. Moreover, RNAi approaches were used for the analysis of the biological functions of miR-29a, and the phosphorylation status of Smad3 was detected using western blotting analysis. RESULTS: The results showed that low decibel infrasound significantly alleviated Ang II-induced enhancement of cell proliferation and collagen synthesis. DISCUSSION: Compared with the control, Ang II markedly decreased the expression of miR-29a levels and increased the secretion of TGF-ß and phosphorylation of Smad3, which was partly reversed by the treatment with low decibel infrasound. Importantly, knockdown of miR-29a diminished the effects of infrasound on the cardiac fibroblasts. In conclusion, low decibel infrasound inhibits Ang II-stimulated cardiac fibroblasts via miR-29a targeting TGF-ß/Smad3 signaling.


Assuntos
Angiotensina II/farmacologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Miocárdio/citologia , Vibração , Animais , Células Cultivadas , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Ensaio de Imunoadsorção Enzimática , Fibroblastos/metabolismo , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , Fosforilação/efeitos dos fármacos , Prolina/efeitos dos fármacos , Prolina/metabolismo , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/efeitos dos fármacos , Proteína Smad3/metabolismo , Timidina/metabolismo , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Trítio
19.
Exp Biol Med (Maywood) ; 242(12): 1254-1261, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28537499

RESUMO

OBJECTIVE: The contents of transforming growth factor-ß and insulin-like growth factor-1 in disc of diabetic rats were measured at three different periods after injected with 1,25-Dihydroxyvitamin D3, and compared with that in normal rats. The significance of content changes was also discussed. METHODS: Fourty-five Sprague-Dawley (SD) rats were divided into three groups, namely the experimental group (STZ+calcitriol), control group (STZ+citrate buffer), and normal group (citrate buffer). Complete lumbar discs in these groups were obtained at the second, fourth, sixth week, respectively. After paraffin-embedded sections and HE staining, the structure and morphology changes of disc were observed. The content of transforming growth factor-ß and insulin-like growth factor-1 was measured by immunohistochemical method, and the expression of transforming growth factor-ß and insulin-like growth factor-1 was detected by Western Blot. RESULTS: In hematoxylin-eosin staining, degenerative changes were observed in disc of experimental and control group at three different periods, and there were no changes in disc in normal group. Immunohistochemical method indicated the content of transforming growth factor-ß and insulin-like growth factor-1 in experimental and control group was significantly lower than normal group at three different periods ( P < 0.05). And there were significant differences between experimental and control group at three different periods ( P < 0.05). CONCLUSION: Vitamin D can protect the degeneration of intervertebral disc and improve the content of transforming growth factor-ß and insulin-like growth factor-1 in the intervertebral disc, which provides a new idea for the prevention and treatment of degenerative changes of the intervertebral disc in diabetic patients. Impact statement No researchers reported Vitamin D could protect degeneration of intervertebral disc. That is to say, we found a new method to prevent and treat degenerative changes of the intervertebral disc in diabetic patients. And Vitamin D prevented the discs by improving the content of TGF-ß and IGF-1.


Assuntos
Calcitriol/farmacologia , Diabetes Mellitus Experimental/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Disco Intervertebral/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/metabolismo , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/etiologia , Degeneração do Disco Intervertebral/metabolismo , Vértebras Lombares , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/efeitos dos fármacos
20.
Diabetes ; 66(7): 1914-1927, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28450417

RESUMO

Growth differentiation factor 11 (GDF11) has been implicated in the regulation of islet development and a variety of aging conditions, but little is known about the physiological functions of GDF11 in adult pancreatic islets. Here, we showed that systematic replenishment of GDF11 not only preserved insulin secretion but also improved the survival and morphology of ß-cells and improved glucose metabolism in both nongenetic and genetic mouse models of type 2 diabetes (T2D). Conversely, anti-GDF11 monoclonal antibody treatment caused ß-cell failure and lethal T2D. In vitro treatment of isolated murine islets and MIN6 cells with recombinant GDF11 attenuated glucotoxicity-induced ß-cell dysfunction and apoptosis. Mechanistically, the GDF11-mediated protective effects could be attributed to the activation of transforming growth factor-ß/Smad2 and phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-FoxO1 signaling. These findings suggest that GDF11 repletion may improve ß-cell function and mass and thus may lead to a new therapeutic approach for T2D.


Assuntos
Glicemia/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Apoptose , Glicemia/metabolismo , Western Blotting , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Proteína Forkhead Box O1/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Teste de Tolerância a Glucose , Fatores de Diferenciação de Crescimento/antagonistas & inibidores , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Camundongos , Fosfotransferases (Aceptor do Grupo Álcool)/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores para Leptina/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA