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1.
Hepatology ; 75(2): 353-368, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34490644

RESUMO

BACKGROUND AND AIMS: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. APPROACH AND RESULTS: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Hepatopatias Alcoólicas/fisiopatologia , Fígado/fisiopatologia , Neovascularização Patológica/genética , Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Animais , Vasos Sanguíneos/metabolismo , Doença Crônica , Progressão da Doença , Expressão Gênica , Ontologia Genética , Hepatite Alcoólica/patologia , Hepatite Alcoólica/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fígado/metabolismo , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Camundongos , Neovascularização Patológica/patologia , Neovascularização Fisiológica/genética , Proteínas do Tecido Nervoso/metabolismo , Organoides , Gravidade do Paciente , Receptores Imunológicos/metabolismo , Transdução de Sinais/genética , Células-Tronco , Regulação para Cima , Remodelação Vascular , Cicatrização , Proteínas Roundabout
3.
J Tradit Chin Med ; 36(4): 479-85, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-28459512

RESUMO

OBJECTIVE: To study the effect of Lichong decoction (LD) on expression of matrix metalloproteinase- 2 (MMP-2) and metalloproteinase-2 (TIMP-2) in a rat model of uterine leiomyoma (UL). METHODS: UL was induced in rats using exogenous estrogen and progesterone. LD was administered (p.o.) for 4 weeks, and mifepristone (RU-486) used as a control. To observe the effect of LD on the uterine coefficient and uterine transverse diameter, a radioimmunoassay method was used to detect serum levels of sex hormones. Light microscopic analyses of pathologic changes in the tissues of UL rats were evaluated. Expression of the proteins of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in uterine tissues was assessed by immunohistochemical staining and western blotting. RESULTS: A UL model in rats was established successfully. LD reduced uterine weight, uterine coefficient, and uterine transverse diameter compared with untreated controls. LD reduced levels of estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone in our UL models. LD improved the pathologic condition of uterine muscle. Expression of MMP-2 protein decreased to varying extents in LD-treated groups, but TIMP-2 levels were enhanced. LD appears to reduce MMP-2 expression and increase TIMP-2 expression in UL tissue. CONCLUSION: These data suggest that the mechanism of action of LD on ULs may involve reduction of MMP-2 expression and increase in TIMP-2 expression in rats.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Leiomioma/tratamento farmacológico , Metaloproteinase 2 da Matriz/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Neoplasias Uterinas/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Humanos , Leiomioma/enzimologia , Leiomioma/genética , Metaloproteinase 2 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Útero/efeitos dos fármacos , Útero/enzimologia , Útero/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-26417374

RESUMO

Podocyte injury is an important mechanism of diabetic nephropathy (DN). Accumulating evidence suggests that nephrin expression is decreased in podocyte in DN. Moreover, it has been demonstrated that tongxinluo (TXL) can ameliorate renal structure disruption and dysfunction in DN. However, the effect of TXL on podocyte injury in DN and its molecular mechanism is unclear. In order to explore the effect of TXL on podocyte injury and its molecular mechanism in DN, our in vivo and in vitro studies were performed. Our results showed that TXL increased nephrin expression in diabetic rats and in high glucose cultured podocyte. Meanwhile, TXL decreased ICN1 (the intracellular domain of notch), HES1, and snail expression in podocyte in vivo and in vitro. More importantly, we found that TXL protected podocyte from injury in DN. The results demonstrated that TXL inhibited the activation of notch1/snail pathway and increased nephrin expression, which may be a mechanism of protecting effect on podocyte injury in DN.

5.
Invest Ophthalmol Vis Sci ; 56(9): 5210-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26244297

RESUMO

PURPOSE: Recent research has provided novel but contrary insight into the function of Slit2-Robo signaling in angiogenesis. Although the role of Robo in choroidal neovascularization (CNV) has been studied, the effect of its ligand, Slit2, on CNV development is unclear. This study investigated the role of endogenous Slit2 in CNV and the possible mechanisms. METHODS: Laser-induced CNV in Slit2 transgenic and wild-type mice was used to study the effects of endogenous Slit2 on angiogenesis in vivo. Fluorescein angiography was performed to evaluate the leakage area of each lesion. Plasmid-based gene transfer technology was used to increase Slit2 expression and to study its effects on human umbilical vein endothelial cells (HUVECs) in vitro. Cell proliferation, migration, and tube formation were assessed. Quantitative real-time PCR and Western blot were used to measure expression in the extracellular signal-related kinase 1/2 (ERK1/2), protein kinase B (AKT), and p38 mitogen-activated protein kinase (p38 MAPK) molecular pathways. RESULTS: Laser treatment led to more CNV and vascular leakage in Slit2 transgenic mice compared with wild-type mice. Upregulation of Slit2, Robo1, VEGF receptor 2 (VEGFR2), and phosphorylated ERK1/2 (p-ERK1/2) were detected in retina and choroidal tissue of laser-treated transgenic mice. After transfection of HUVECs with a Slit2 overexpression plasmid, cell proliferation, migration, and tube formation capacities were promoted. Slit2, Robo1, VEGFR2, and p-ERK1/2 were elevated in transfected HUVECs. CONCLUSION: Slit2 overexpression promoted angiogenic effects in both a laser-induced CNV mouse model and HUVECs and promoted the biological activity of endothelial cells. Slit2 may promote angiogenesis by upregulating Robo1 and activating the VEGFR2-ERK1/2 pathway.


Assuntos
Neovascularização de Coroide/genética , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas do Tecido Nervoso/genética , RNA/metabolismo , Receptores Imunológicos/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Western Blotting , Movimento Celular , Proliferação de Células , Células Cultivadas , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Proteínas de Drosophila , Feminino , Angiofluoresceinografia , Fundo de Olho , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Receptores Imunológicos/biossíntese , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Proteínas Roundabout
6.
Oncotarget ; 6(9): 6584-96, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25762641

RESUMO

Blood platelets foster carcinogenesis. We found that platelets are accumulated in human tumors. P-selectin deficiency and soluble P-selectin abolish platelet deposition within tumors, decreasing secretion of vascular endothelial growth factor and angiogenesis, thereby suppressing tumor growth. Binding of the P-selectin cytoplasmic tail to talin1 triggers the talin1 N-terminal head to interact with the ß3 cytoplasmic tail. This activates αIIbß3 and recruits platelets into tumors. Platelet infiltration into solid tumors occurs through a P-selectin-dependent mechanism.


Assuntos
Plaquetas/metabolismo , Proliferação de Células , Insulinoma/metabolismo , Melanoma Experimental/metabolismo , Selectina-P/metabolismo , Neoplasias Pancreáticas/metabolismo , Adesividade Plaquetária , Animais , Feminino , Humanos , Insulinoma/sangue , Insulinoma/genética , Insulinoma/patologia , Melanoma Experimental/sangue , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Selectina-P/sangue , Selectina-P/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligação Proteica , Transdução de Sinais , Talina , Fatores de Tempo , Carga Tumoral
7.
Fertil Steril ; 103(4): 990-1000.e8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25681855

RESUMO

OBJECTIVE: To test the hypothesis that P-selectin plays a critical role in the development of endometriosis and that targeting P-selectin has therapeutic potential. DESIGN: Prospective, randomized study. SETTING: Academic facility. ANIMAL(S): The first experiment used 24 each of female adult P-selectin knockout mice and C57BL/6 wild-type mice, and 96 male green fluorescent protein (GFP) transgenic mice. The second experiment used 16 female adult C57BL/6 mice. INTERVENTION(S): In experiment 1, P-selectin knockout and wild-type mice alternately served as donors and recipients for the transplantation of endometrial tissue fragments into the peritoneal cavity to induce endometriosis. Two weeks later all four groups were each randomly divided into two equal-sized subgroups, receiving either green fluorescent protein-expressing platelets or saline infusion. In experiment 2, 2 weeks after the surgical induction of endometriosis, the mice were randomly divided into two groups, one receiving a 2-week treatment with a recombinant P-selectin protein and the other, non-immune IgG, both by intraperitoneal injection. MAIN OUTCOME MEASURE(S): Lesion size, hotplate latency, and immunohistochemistry analysis of platelet aggregation, angiogenesis, transforming growth factor ß1, α-smooth muscle actin, collagen I, and the extent of macrophage infiltration in ectopic implants. The extent of fibrosis also was evaluated in experiment 2. RESULT(S): P-selectin deficiency significantly retarded the development of endometriosis in a mouse model of endometriosis. In addition, soluble P-selectin treatment markedly reduced the lesion size in mouse through decreased platelet aggregation and angiogenesis, improved general hyperalgesia, and reduced the extent of macrophages infiltration, resulting in reduced fibrotic tissue content. CONCLUSION(S): Targeting P-selectin-mediated platelet adhesion onto endometriotic lesions holds promise as a novel therapeutics for treating endometriosis.


Assuntos
Endometriose/tratamento farmacológico , Terapia de Alvo Molecular , Selectina-P , Doenças Peritoneais/tratamento farmacológico , Animais , Endometriose/genética , Endometriose/patologia , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Imunoglobulina G/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia de Alvo Molecular/métodos , Neovascularização Patológica/tratamento farmacológico , Selectina-P/genética , Selectina-P/farmacologia , Selectina-P/uso terapêutico , Doenças Peritoneais/genética , Doenças Peritoneais/patologia , Agregação Plaquetária/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
8.
J Immunol ; 194(4): 1654-64, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25609840

RESUMO

T cell development and homeostasis are both regulated by TCR signals. Protein phosphorylation and dephosphorylation, which are catalyzed by protein kinases and phosphatases, respectively, serve as important switches controlling multiple downstream pathways triggered by TCR recognition of Ags. It has been well documented that protein tyrosine phosphatases are involved in negative regulation of proximal TCR signaling. However, how TCR signals are terminated or attenuated in the distal TCR signaling pathways is largely unknown. We investigated the function of Ser/Thr protein phosphatase (PP) 6 in TCR signaling. T cell lineage-specific ablation of PP6 in mice resulted in enhanced thymic positive and negative selection, and preferential expansion of fetal-derived, IL-17-producing Vγ6Vδ1(+) T cells. Both PP6-deficient peripheral CD4(+) helper and CD8(+) cytolytic cells could not maintain a naive state and became fast-proliferating and short-lived effector cells. PP6 deficiency led to profound hyperactivation of multiple distal TCR signaling molecules, including MAPKs, AKT, and NF-κB. Our studies demonstrate that PP6 acts as a critical negative regulator, not only controlling both αß and γδ lineage development, but also maintaining naive T cell homeostasis by preventing their premature activation before Ag stimulation.


Assuntos
Homeostase/imunologia , Ativação Linfocitária/imunologia , Fosfoproteínas Fosfatases/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Separação Celular , Citometria de Fluxo , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia
9.
Int J Biol Sci ; 10(4): 404-14, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24719558

RESUMO

Insulinomas are rare tumors, and approximately 10% of insulinomas are malignant. Accumulating evidence has implicated that we still lack effective therapy to treat the patients who are diagnosed with rare malignant insulinoma. Previous studies have reported that Andrographolide (Andro) could inhibit cell cycle progression, reduce cell invasion and induce cell apoptosis in many common cancer cells. However, the effects of andro are cell type-dependent. So we emplored the ß-TC-6 cells and the RIP1-Tag2 transgenic mouse model of endogenously growing insulinoma model to elucidate the possible anti-cancer effect of Andro on insulinoma, an uncommon type of malignant cancers in this study. Our experiments revealed that Andro significantly inhibited tumor growth at both the early-stage and the advanced-stage of insulinoma through targeting the TLR4/NF-κB signaling pathway. This work initially provides the evidence that the TLR4/NF-κB signaling pathway might be vital as a potential therapeutic target, and also indispensable in Andro-mediated anti-cancer effect in insulinoma.


Assuntos
Antineoplásicos/uso terapêutico , Diterpenos/uso terapêutico , Insulinoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Humanos , Insulinoma/irrigação sanguínea , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Neovascularização Patológica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
10.
J Immunol ; 192(4): 1525-35, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24453252

RESUMO

Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1(-/-) mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1(-/-) bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency-mediated human immunodeficiency syndrome.


Assuntos
Doenças Autoimunes/imunologia , Fatores de Transcrição Forkhead/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Doenças Autoimunes/genética , Autoimunidade/genética , Autoimunidade/imunologia , Linhagem Celular , Proteína Forkhead Box O1 , Proteína Forkhead Box O3 , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinase 3 , Transdução de Sinais/imunologia , Linfócitos T Reguladores/transplante
11.
Am J Physiol Renal Physiol ; 306(5): F486-95, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24370587

RESUMO

Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies. The epithelial-to-mesenchymal transition (EMT) plays an important role in DN. The physiological role of microRNA-21 (miR-21) was closely linked to EMT. However, it remained elusive whether tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-induced EMT in DN. This study aimed to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-ß1/smads signals. Real-time RT-PCR, cell transfection, in situ hybridization (ISH), and laser confocal microscopy were used, respectively. Here, we revealed that TXL dose dependently lowered miR-21 expression in tissue, serum, and cells. Overexpression of miR-21 can enhance α-smooth muscle actin (SMA) expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression. Interestingly, TXL also increased E-cadherin expression and decreased α-SMA expression by regulating miR-21 expression. More importantly, TXL decreased collagen IV, fibronectin, glomerular basement membrane, glomerular area, and the albumin/creatinine ratio, whereas it increased the creatinine clearance ratio. The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-induced EMT, which was one of the mechanisms to protect against DN, and that miR-21 may be one of the therapeutic targets for TXL in DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MicroRNAs/metabolismo , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Humanos
12.
Nature ; 501(7465): 107-11, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23903657

RESUMO

Cancer research has been rightly and successfully focused on prevention, early detection, and identification of specific molecular targets that distinguish the malignant cells from the neighbouring benign cells. However, reducing lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-stage metastatic cancers remains a key clinical challenge. Here we tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. We found that intestinal stem cells (ISCs) expressed Slit2 and its single-span transmembrane cell-surface receptor roundabout 1 (Robo1). Partial genetic deletion of Robo1 decreased ISC numbers and caused villus hypotrophy, whereas a Slit2 transgene increased ISC numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist) plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumour sensitivity to chemotherapy. Therefore Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Intestinos/citologia , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Trombospondinas/metabolismo , Animais , Linhagem da Célula , Proliferação de Células/efeitos dos fármacos , Feminino , Homeostase/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Intestinos/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/radioterapia , Neoplasias/patologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/farmacologia , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Regeneração/efeitos dos fármacos , Regeneração/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/efeitos da radiação , Taxa de Sobrevida , Trombospondinas/administração & dosagem , Trombospondinas/farmacologia , Proteínas Wnt/metabolismo , Proteínas Roundabout
13.
J Tradit Chin Med ; 33(2): 238-42, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23789224

RESUMO

OBJECTIVE: To study on effects of Lichong decoction on expression of apoptosis-controlling genes, Bcl-2 and Bcl-2-associated X protein (Bax) mRNAs in hysteromyoma tissue of the hysteromyoma model rat. METHODS: Fifty Wistar female rats were randomly divided into a normal group, a model group, a Lichong decoction group, a Guizifuling capsule group and a Mifepristone group. The hysteromyoma rat model was established by intraperitoneal injection of exogenous estrin and progestogens. Pathological examination of uterine tissue, uterine coefficient and uterine transverse diameter were made under optic microscope and expressions of Bcl-2 and Bax mRNAs in uterine tissue in the groups were detected with real-time fluorescent quantitative polymerase chain reaction (PCR) technique. RESULTS: After treatment, under microscope it was found that in the Lichong decoction group myometrium thinned, muscle fiber slightly overgrowth or long and thin, regular arrangement, inserting phenomenon of inner circular muscle and external longitudinal muscle was occasionally or not seen in the Lichong decoction group. The uterine coefficient and the uterine transverse diameter significantly decreased (P < 0.01), and Bcl-2 mRNA expression significantly decreased (P < 0.01) and Bax mRNA expression significantly increased in hysteromyoma tissue (P < 0.01) in the Lichong decoction group as compared with the model group. CONCLUSION: Therapeutic effects of Lichong decoction on hysteromyoma is related with decrease of Bcl-2 mRNA expression and increase of Bax mRNA expression.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Mioma/tratamento farmacológico , Mioma/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genética , Proteína X Associada a bcl-2/genética , Animais , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mioma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Neoplasias Uterinas/metabolismo , Proteína X Associada a bcl-2/metabolismo
14.
Exp Cell Res ; 319(8): 1083-93, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23438940

RESUMO

Formation of the neural tube is the morphological hallmark for development of the embryonic central nervous system (CNS). Therefore, neural tube development is a crucial step in the neurulation process. Slit/Robo signaling was initially identified as a chemo-repellent that regulated axon growth cone elongation, but its role in controlling neural tube development is currently unknown. To address this issue, we investigated Slit/Robo1 signaling in the development of chick neCollege of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH, UKural tube and transgenic mice over-expressing Slit2. We disrupted Slit/Robo1 signaling by injecting R5 monoclonal antibodies into HH10 neural tubes to block the Robo1 receptor. This inhibited the normal development of the ventral body curvature and caused the spinal cord to curl up into a S-shape. Next, Slit/Robo1 signaling on one half-side of the chick embryo neural tube was disturbed by electroporation in ovo. We found that the morphology of the neural tube was dramatically abnormal after we interfered with Slit/Robo1 signaling. Furthermore, we established that silencing Robo1 inhibited cell proliferation while over-expressing Robo1 enhanced cell proliferation. We also investigated the effects of altering Slit/Robo1 expression on Sonic Hedgehog (Shh) and Pax7 expression in the developing neural tube. We demonstrated that over-expressing Robo1 down-regulated Shh expression in the ventral neural tube and resulted in the production of fewer HNK-1(+) migrating neural crest cells (NCCs). In addition, Robo1 over-expression enhanced Pax7 expression in the dorsal neural tube and increased the number of Slug(+) pre-migratory NCCs. Conversely, silencing Robo1 expression resulted in an enhanced Shh expression and more HNK-1(+) migrating NCCs but reduced Pax7 expression and fewer Slug(+) pre-migratory NCCs were observed. In conclusion, we propose that Slit/Robo1 signaling is involved in regulating neural tube development by tightly coordinating cell proliferation and differentiation during neurulation.


Assuntos
Diferenciação Celular/genética , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Tubo Neural/embriologia , Células Neuroepiteliais/fisiologia , Receptores Imunológicos/fisiologia , Animais , Células Cultivadas , Embrião de Galinha , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Tubo Neural/metabolismo , Células Neuroepiteliais/metabolismo , Neurulação/genética , Neurulação/fisiologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais/genética , Proteínas Roundabout
15.
Anat Rec (Hoboken) ; 296(3): 533-43, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23382139

RESUMO

Primitive streak (PS) is the first structure occurring in embryonic gastrulation, in which the epiblast cells undergo the epithelial-mesenchymal transition to become the loose mesoderm cells subsequently. Because the mesoderm cells departing from different portions of PS are blessed with disparate migration trajectory and differentiation fate, one question is when the cell fate is determinated. To understand whether the cell fate and cell migration pattern will be alternated along with the microenvironment transformation, the traditional transplantation technology was used to replace the anterior PS cells in HH4 host embryo using posterior PS tissue labeled by green fluorescent protein (GFP) in the same stage donor embryo, and then, we tracked the migration trajectory of the GFP-positive cells with fluorescence stereomicroscope after incubation, and eventually verified the cell contribution from the transplants with in situ hybridization and immunocytochemistry. The same experimental strategy applied for posterior PS site replacement in host embryo. We found that the transplanted posterior PS cells to anterior part of streak followed the anterior PS cell migration pattern rather than kept its posterior streak cell migration trajectory, and so did vice versa. In addition, the transplants were involved in the contribution to the subsequent organogenesis as the local PS tissues affirmed by specific expression of myocardial or hematopoietic markers. Therefore, our data strongly suggest that the PS cells still keep stem cell plasticity during gastrulation and the eventual cell fate will depend on the spatial gene expression within local microenvironment along with development.


Assuntos
Diferenciação Celular , Linhagem da Célula , Células-Tronco Embrionárias/fisiologia , Linha Primitiva/fisiologia , Nicho de Células-Tronco , Animais , Movimento Celular , Embrião de Galinha , Eletroporação , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/transplante , Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Imuno-Histoquímica , Hibridização In Situ , Microscopia de Fluorescência , Organogênese , Fenótipo , Linha Primitiva/citologia , Linha Primitiva/metabolismo , Fatores de Tempo , Técnicas de Cultura de Tecidos , Transfecção
16.
Reprod Sci ; 20(3): 285-98, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22875847

RESUMO

We recently reported that Slit/Roundabout (ROBO) 1 pathway may be a constituent biomarker for recurrence of endometriosis, likely through promoting angiogenesis. In this study, we sought to determine as whether Slit2 overexpression can facilitate angiogenesis, increase lesion size, and induce hyperalgesia in mice with induced endometriosis. We used 30 Slit2 transgenic (S) and 29 wild-type (W) mice and cross-transplanted endometrial fragments from S to W (group SW) and vice versa (group WS), and also within the S and W (groups SS and WW, respectively), into the peritoneal cavity, inducing endometriosis. We also performed a sham surgery within both S and W mice (groups Sm and Wm, respectively). The size of the ectopic implants, microvessel density (MVD) and immunoreactivity to ROBO1, and vascular endothelial cell growth factor (VEGF) in ectopic and eutopic endometrium, along with hotplate and tail-flick tests in all mice, were then evaluated. We found that the induction of endometriosis resulted in generalized hyperalgesia, which was unaffected by Slit2 overexpression. Slit2 overexpression did increase the lesion size significantly and correlated positively with the MVD in ectopic and eutopic endometrium. Slit2 expression levels appear to correlate with the MVD, but not with VEGF immunoreactivity, in ectopic endometrium. Consequently, we conclude that Slit2 may play an important role in angiogenesis in endometriosis. The increased angiogenesis, as measured by MVD, but not VEGF immunoreactivity, likely resulted in increased lesion size in induced endometriosis. Thus, SLIT2/ROBO1 pathway may be a potential therapeutic target for treating endometriosis.


Assuntos
Endometriose/metabolismo , Endometriose/patologia , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Microvasos/metabolismo , Microvasos/patologia , Proteínas do Tecido Nervoso/biossíntese , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia
17.
PLoS One ; 7(7): e41845, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22844530

RESUMO

Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors that have not been identified. We report here that a lectin from the seeds of Maackia amurensis (MASL) with affinity for O-linked carbohydrate chains containing sialic acid targets PDPN to inhibit transformed cell growth and motility at nanomolar concentrations. Interestingly, the biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular system to inhibit melanoma cell growth, migration, and tumorigenesis. These studies demonstrate how lectins may be used to help develop dietary agents that target specific receptors to combat malignant cell growth.


Assuntos
Movimento Celular/efeitos dos fármacos , Transformação Celular Neoplásica , Glicoproteínas de Membrana/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Lectinas de Plantas/farmacologia , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Maackia/química , Melanoma/irrigação sanguínea , Melanoma/dietoterapia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Dados de Sequência Molecular , Necrose/induzido quimicamente , Neovascularização Patológica/dietoterapia , Lectinas de Plantas/química , Lectinas de Plantas/metabolismo , Quinases da Família src/metabolismo
18.
J Tradit Chin Med ; 32(4): 636-40, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23427402

RESUMO

OBJECTIVE: To study the effect of Lichong Decoction (Lichong Decoction for strengthening anti-pathogenic Qi and eliminating blood stasis) on the expression of insulin-like growth factor-I (IGF-I) and proliferating cell nuclear antigen (PCNA) mRNA in a rat model of uterine leiomyoma. METHODS: Fifty female Wistar rats were randomized into a normal control group, model group, Lichong Decoction group, Guizhifuling Capsule (Capsule containing Cassia Twig and Poria) group, and Mifepristone group. The uterine leiomyoma model was established by peritoneal injections of exogenous estrogen and progesterone hormone. The ultrastructural changes in cells of rat uterine tissues were observed with transmission electron microscopy, and the expression of IGF-I and PCNA mRNA was detected by real-time fluorescent quantitative PCR. RESULTS: Following treatment, cells in the Lichong Decoction group appeared to be arranged normally, the cellular morphology were almost in a normal state, hyperplasia and hypertrophy of the chondriosome was reduced, collagen fibers were arranged in a regular manner, without obvious hyperplasia, and the expression of IGF-I and PCNA mRNA was significantly decreased compared with the model group (P < 0.01). CONCLUSIONS: The effect of Lichong Decoction on uterine leiomyoma is related to its function in reducing the expression of IGF-I and PCNA mRNA.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Fator de Crescimento Insulin-Like I/genética , Leiomioma/tratamento farmacológico , Leiomioma/genética , Antígeno Nuclear de Célula em Proliferação/genética , Animais , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Leiomioma/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar
19.
Immunol Cell Biol ; 90(4): 388-95, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21647172

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-mediated disease of the central nervous system. Serum amyloid P component (SAP) is a highly conserved plasma protein named for its universal presence in amyloid deposits. Here we report that SAP-transgenic mice had unexpectedly attenuated EAE due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35-55 in complete Freund's adjuvant, SAP-transgenic mice showed reduced spinal cord inflammation with lower severity of EAE attacks as compared with control C57BL/6 mice. However, in SAP-Knockout mice, the severity of EAE is enhanced. Adoptive transfer of Ag-restimulated T cells from wild type to SAP-transgenic mice, or transfer of SAP-transgenic Ag-restimulated T cells to control mice, induced milder EAE. T cells from MOG-primed SAP-transgenic mice showed weak proliferative responses. Furthermore, in SAP-transgenic mice, there is little infiltration of CD45-positive cells in the spinal cord. In vitro, SAP suppressed the secretion of interleukin-2 stimulated by P-selectin and blocked P-selectin binding to T cells. Moreover, SAP could change the affinity between α4-integrin and T cells. These data suggested that SAP could antagonize the development of the acute phase of inflammation accompanying EAE by modulating the function of P-selectin.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Integrina alfa4/metabolismo , Componente Amiloide P Sérico/farmacologia , Linfócitos T/metabolismo , Transferência Adotiva , Animais , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Selectina-P , Componente Amiloide P Sérico/uso terapêutico
20.
Acta Pharmacol Sin ; 32(11): 1327-36, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21986575

RESUMO

AIM: To investigate the effect of the axon guidance cue Slit2 on the density of blood vessels and permeability of the blood-brain barrier in mouse brain. METHODS: hSlit2 transgenic mouse line was constructed, and the phenotypes of the mice were compared with wild-type mice in respect to the lateral ventricle (LV), ventricle pressure, and the choroids plexus. An in vivo Miles permeability assay and an amyloid-ß permeability assay were used to assess the permeability of brain blood vessels. Brain vessel casting and intracerebral hemorrhage models were built to investigate vessel density in the transgenic mice. An in vitro permeability assay was used to test whether Slit2 could change the permeability and tight junctions of blood vessel endothelial cells. RESULTS: Hydrocephalus occurred in some transgenic mice, and a significantly larger lateral ventricle area and significantly higher ventricle pressure were observed in the transgenic mice. The transgenic mice displayed changed construction of the choroids plexus, which had more micro vessels, dilated vessels, gaps between epithelial cells and endothelial cells than wild-type mice. Slit2 significantly increased brain vessel density and the permeability of brain vessels to large molecules. These blood vessels were more sensitive to cues that induce brain hemorrhage. At the cellular level, Slit2 disturbed the integrity of tight junctions in blood vessel endothelial cells and improved the permeability of the endothelial cell layer. Thus, it promoted the entry of amyloid-ß peptides from the serum into the central nervous system, where they bound to neurons. CONCLUSION: Slit2 increases vessel density and permeability in the brains of transgenic mice. Thus, Slit2 induces numerous changes in brain vessels and the barrier system.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Permeabilidade Capilar , Endotélio Vascular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/genética , Junções Íntimas/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Regulação para Cima
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