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1.
Biochem Biophys Res Commun ; 528(4): 732-739, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32522342

RESUMO

Based on the lately identified role for the interstitial cells of Cajal (ICCs) of mouse prostate in catecholamine production, as well as the well-established role for the master coregulator metastasis-associated protein 1 (MTA1) in inflammation, we probed into the functional link between aberrant MTA1 expression and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using both a MTA1-/- mouse model of experimental autoimmune prostatitis (EAP) and an in vitro chronic prostatitis model in cultured murine ICCs. EAP-induced MTA1 expression was enriched in ICCs of mouse prostate. EAP resulted in a higher increase in the pelvic pain response in MTA1-/- mice compared to WT mice. Consistently, the ICCs from MTA1-/- mice produced higher levels of catecholamines upon induction of in vitro chronic prostatitis. Mechanistically, MTA1 could directly suppress the transcription of Aadc, a rate-limiting enzyme during catecholamine synthesis, in a HDAC2-depdendent manner. Importantly, treatment with AADC inhibitor NSD-1015 significantly ameliorated EAP-elicited pain response and catecholamine overactivity in MTA1-/- mice. Taken together, our findings reveal an inherent regulatory role of the MTA1/AADC pathway in the maintenance of catecholamine production homeostasis in prostate ICCs, and also point to a potential use of HDAC inhibitors and/or AADC inhibitors to treat CP/CPPS.


Assuntos
Descarboxilases de Aminoácido-L-Aromático/genética , Catecolaminas/imunologia , Células Intersticiais de Cajal/imunologia , Prostatite/imunologia , Proteínas Repressoras/imunologia , Transativadores/imunologia , Animais , Descarboxilases de Aminoácido-L-Aromático/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doença Crônica , Regulação para Baixo , Deleção de Genes , Células Intersticiais de Cajal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Próstata/imunologia , Próstata/patologia , Prostatite/genética , Prostatite/patologia , Proteínas Repressoras/genética , Transativadores/genética , Ativação Transcricional
2.
Medicina (Kaunas) ; 55(2)2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30781716

RESUMO

In recent years, the interstitial cells telocytes, formerly known as interstitial Cajal-like cells, have been described in almost all organs of the human body. Although telocytes were previously thought to be localized predominantly in the organs of the digestive system, as of 2018 they have also been described in the lymphoid tissue, skin, respiratory system, urinary system, meninges and the organs of the male and female genital tracts. Since the time of eminent German pathologist Rudolf Virchow, we have known that many pathological processes originate directly from cellular changes. Even though telocytes are not widely accepted by all scientists as an individual and morphologically and functionally distinct cell population, several articles regarding telocytes have already been published in such prestigious journals as Nature and Annals of the New York Academy of Sciences. The telocyte diversity extends beyond their morphology and functions, as they have a potential role in the etiopathogenesis of different diseases. The most commonly described telocyte-associated diseases (which may be best termed "telocytopathies" in the future) are summarized in this critical review. It is difficult to imagine that a single cell population could be involved in the pathogenesis of such a wide spectrum of pathological conditions as extragastrointestinal stromal tumors ("telocytomas"), liver fibrosis, preeclampsia during pregnancy, tubal infertility, heart failure and psoriasis. In any case, future functional studies of telocytes in vivo will help to understand the mechanism by which telocytes contribute to tissue homeostasis in health and disease.


Assuntos
Homeostase/fisiologia , Células Intersticiais de Cajal/patologia , Telócitos/patologia , Antígenos CD34/imunologia , Humanos , Imunofenotipagem , Células Intersticiais de Cajal/imunologia , Neovascularização Fisiológica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/imunologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/imunologia , Regeneração , Transdução de Sinais , Telócitos/imunologia
3.
Eur Rev Med Pharmacol Sci ; 23(1): 312-320, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30657572

RESUMO

OBJECTIVE: Irritable bowel syndrome (IBS) is a common functional disorder in the gastrointestinal tract. Inflammatory response has been found to participate in the pathogenesis of IBS. This study aimed to explore the effects of long non-coding RNA taurine upregulated gene 1 (TUG1) on tumor necrosis factor alpha (TNF-α)-induced interstitial cells of Cajal (ICC) inflammatory injury, which was relevant to the pathogenesis of IBS. PATIENTS AND METHODS: The expression levels of TUG1 and microRNA-127 (miR-127) were analyzed by qRT-PCR. Viability, apoptosis and the expression of apoptosis-associated factors were analyzed by CCK-8 assay, flow cytometry and Western blot, respectively. The mRNA and protein levels of pro-inflammatory cytokines were detected by qRT-PCR and Western blot, respectively. Finally, activations of nuclear factor kappa-B (NF-κB) and Notch pathways were evaluated by Western blot. RESULTS: TNF-α treatment inhibited ICC viability, induced ICC apoptosis and promoted an inflammatory response in ICC. TUG1 was downregulated in TNF-α-treated ICC. TUG1 overexpression protected ICC from TNF-α-induced apoptosis and pro-inflammatory cytokines expression. TUG1 suppression showed opposite effects. MiR-127 was negatively regulated by TUG1 and implicated in the action of TUG1 in ICC. MiR-127 up-regulation largely reversed the effects of TUG1 on TNF-α-treated ICC. Mechanistically, TUG1 inhibited TNF-α-induced activation of NF-κB and Notch pathways in ICC by down-regulating miR-127. CONCLUSIONS: TUG1 attenuated TNF-α-caused apoptosis and inflammatory response in ICC by down-regulating miR-127 and then inactivating NF-κB and Notch pathways.


Assuntos
Células Intersticiais de Cajal/imunologia , Síndrome do Intestino Irritável/genética , MicroRNAs/genética , RNA Longo não Codificante/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose/genética , Apoptose/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Humanos , Células Intersticiais de Cajal/patologia , Síndrome do Intestino Irritável/imunologia , Síndrome do Intestino Irritável/patologia , Camundongos , MicroRNAs/metabolismo , Cultura Primária de Células , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Receptores Notch/imunologia , Receptores Notch/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima
4.
Rom J Morphol Embryol ; 56(1): 133-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25826497

RESUMO

Adenomyosis and endometriosis are lesions which have aroused the interest for the investigation of antibodies specific to the structures from the composition, but also for the cause behind the appearance of these lesions in completely different structures. The impact they have on fertility is not known entirely, for they are difficult to diagnose. Endometriosis causes infertility and it is a hard to treat lesion. The research performed in the last years has been focused on the so-called linkage analysis, or reverse genetics. It refers to identifying the genes which are prone to developing this affection. We investigated clinically 40 female inpatients (n=40) who had underwent genital surgery and received a variegate diagnosis in the "Sf. Ioan" Emergency Hospital, Bucharest, Romania, between January-September 2014 and also their histopathology and immunohistochemistry. We proceeded with the histopathology examination in order to establish a diagnosis in respect to the admission diagnosis and then, using the ABC (Avidin-Biotin complex) method, we analyzed the immunohistochemistry of the following markers: S100 protein (for detection of ganglia and nerve cells), CD117÷c-kit (selective detection of interstitial Cajal cells - ICC), desmin and vimentin (intermediary filaments for detecting ICC-like cells, which cohabit with uterine myocytes and are not contractile cells) and CD10 (a sensitive and useful immunomarker in the diagnosis of endometrial stroma and, in some cases, of neoplasia). Our study, regarding the immunoprofile of some markers of adenomyosis÷endometriosis lesions, supports the hypothesis that the interstitial Cajal cells are non-reactive, they are not in relationship with investigated lesions, but CD10 is a very useful marker to highlight the endometrial stroma in query cases.


Assuntos
Adenomiose/imunologia , Endometriose/imunologia , Células Intersticiais de Cajal/imunologia , Adenomiose/cirurgia , Adulto , Idoso , Endometriose/cirurgia , Endométrio/imunologia , Endométrio/cirurgia , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Células Intersticiais de Cajal/metabolismo , Pessoa de Meia-Idade , Neprilisina/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas S100/metabolismo , Células Estromais/citologia , Vimentina/metabolismo
5.
Gastroenterology ; 148(5): 978-90, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25637652

RESUMO

BACKGROUND & AIMS: After allogeneic transplantation, murine stem cells (SCs) for interstitial cells of Cajal (ICCs), electrical pacemaker, and neuromodulator cells of the gut, were incorporated into gastric ICC networks, indicating in vivo immunosuppression. Immunosuppression is characteristic of bone marrow- and other non-gut-derived mesenchymal stem cells (MSCs), which are emerging as potential therapeutic agents against autoimmune diseases, including inflammatory bowel disease. Therefore, we investigated whether gut-derived ICC-SCs could also mitigate experimental colitis and studied the mechanisms of ICC-SC-mediated immunosuppression in relation to MSC-induced pathways. METHODS: Isolated ICC-SCs were studied by transcriptome profiling, cytokine assays, flow cytometry, mixed lymphocyte reaction, and T-cell proliferation assay. Mice with acute and chronic colitis induced by dextran sulfate sodium and T-cell transfer, respectively, were administered ICC-SCs intraperitoneally and evaluated for disease activity by clinical and pathological assessment and for ICC-SC homing by live imaging. RESULTS: Unlike strain-matched dermal fibroblasts, intraperitoneally administered ICC-SCs preferentially homed to the colon and reduced the severity of both acute and chronic colitis assessed by clinical and blind pathological scoring. ICC-SCs profoundly suppressed T-cell proliferation in vitro. Similar to MSCs, ICC-SCs strongly expressed cyclooxygenase 1/2 and basally secreted prostaglandin E2. Indomethacin, a cyclooxygenase inhibitor, countered the ICC-SC-mediated suppression of T-cell proliferation. In contrast, we found no role for regulatory T-cell-, programmed death receptor-, and transforming growth factor-ß-mediated mechanisms reported in MSCs; and transcriptome profiling did not support a relationship between ICC-SCs and MSCs. CONCLUSIONS: Murine ICC-SCs belong to a class different from MSCs and potently mitigate experimental colitis via prostaglandin E2-mediated immunosuppression.


Assuntos
Colite/prevenção & controle , Colo , Dinoprostona/metabolismo , Imunidade Celular , Células Intersticiais de Cajal/transplante , Transplante de Células-Tronco , Transferência Adotiva , Animais , Proliferação de Células , Células Cultivadas , Colite/induzido quimicamente , Colite/imunologia , Colite/metabolismo , Colite/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Sulfato de Dextrana , Perfilação da Expressão Gênica , Marcadores Genéticos , Proteínas de Homeodomínio/genética , Hospedeiro Imunocomprometido , Células Intersticiais de Cajal/imunologia , Células Intersticiais de Cajal/metabolismo , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Fatores de Tempo
6.
Arch Gynecol Obstet ; 288(6): 1295-300, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23700252

RESUMO

PURPOSE: The aim of the study was to observe alterations of pacemaker cells termed cajal-like type of tubal interstitial cells (t-ICC) in oviduct from early-stage EMs and tEP, discuss underlying mechanisms and potential role in tubal factor infertility (TFI). METHODS: Ten patients with early-stage EMs, 10 with unruptured tEP and 10 control subjects were included in this retrospective comparative study, received adnexectomy (salpingectomy) and/or hysterectomy. Paraffin-embedded full-thickness isthmic segment of oviduct specimens received immunohistochemistry with c-kit/CD117 antibody. Network distribution and area density of cells with features of t-ICC were analyzed. RESULTS: t-ICC was detected mainly in lamina propria and smooth muscle layers. t-ICC lost its network integrity, became less densely stained, sparse and almost invisible with relatively very rare connections in EMs and tEP, apparently differing in morphology of t-ICC from control, which demonstrated rich t-ICC immunostaining and intact network. Further quantitative analysis showed the area density of t-ICC decreased significantly in early-stage EMs and tEP compared with the control (73.9 ± 8.8 vs. 156 ± 18.3 mm(2); and 76 ± 7.4 vs. 156 ± 18.3 mm(2); both P < 0.001). CONCLUSIONS: We revealed that t-ICC underwent certain degree of cell damage, suggested that decreased expression of t-ICC network may be involved in early development of EMs and tEP, and might serve as an explanation for TFI in these patients.


Assuntos
Endometriose/patologia , Tubas Uterinas/metabolismo , Células Intersticiais de Cajal/metabolismo , Gravidez Tubária , Adulto , Animais , Estudos de Casos e Controles , Tubas Uterinas/química , Feminino , Histocitoquímica , Humanos , Imuno-Histoquímica , Células Intersticiais de Cajal/imunologia , Mucosa/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-kit/imunologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Estudos Retrospectivos
7.
Hepatogastroenterology ; 59(119): 2147-50, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23435133

RESUMO

BACKGROUND/AIMS: In Chagasic megacolon, there is a reduction in the population of interstitial cells of Cajal. It was aimed to evaluate density of Cajal cells in the resected colon of Chagasic patients compared to control patients and to verify possible association between preoperative and postoperative bowel function of megacolon patients and cell count. METHODOLOGY: Sixteen megacolon patients (12 female; mean age 54.4 (31-73)) were operated on. Pre- and postoperative evaluation using Cleveland clinic constipation score was undertaken. Resected colons were examined. Cajal cells were identified by immunohistochemistry (anti-CD117). The mean cell number was compared to resected colons from 16 patients (7 female; mean age 62.8 (23-84)) with non-obstructive sigmoid cancer. Association between pre- and postoperative constipation scores and cell count for megacolon patients was evaluated using the Pearson test (r). RESULTS: A reduced number of Cajal cells (per field: 2.84 (0-6.6) vs. 9.68 (4.3-13); p<0.001) were observed in the bowel of megacolon patients compared to cancer patients. No correlation between constipation score before (r=- 0.205; p=0.45) or after surgery (r=0.291; p=0.28) and cell count in megacolon was observed. CONCLUSIONS: Patients with megacolon display marked reduction of interstitial cells of Cajal. An association of constipation severity and Cajal cells depopulation was not demonstrated.


Assuntos
Doença de Chagas/patologia , Colo/patologia , Células Intersticiais de Cajal/patologia , Megacolo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Estudos de Casos e Controles , Contagem de Células , Doença de Chagas/parasitologia , Doença de Chagas/fisiopatologia , Doença de Chagas/cirurgia , Colo/imunologia , Colo/parasitologia , Colo/fisiopatologia , Colo/cirurgia , Constipação Intestinal/parasitologia , Constipação Intestinal/patologia , Constipação Intestinal/fisiopatologia , Defecação , Feminino , Humanos , Imuno-Histoquímica , Células Intersticiais de Cajal/imunologia , Células Intersticiais de Cajal/parasitologia , Laparoscopia , Masculino , Megacolo/parasitologia , Megacolo/fisiopatologia , Megacolo/cirurgia , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-kit/análise , Resultado do Tratamento , Adulto Jovem
8.
Gastroenterology ; 139(3): 942-52, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20621681

RESUMO

BACKGROUND & AIMS: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor alpha (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kit(low) ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST. METHODS: Isolated Kit(low)Cd44(+)Cd34(+) cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The Kit(low)Cd44(+)Cd34(+) cells' responsiveness to Kit activation and blockade was studied by enumerating them in Kit(K641E) mice (a GIST model), in mice with defective Kit signaling, and pharmacologically. RESULTS: Single isolated Kit(low)Cd44(+)Cd34(+) cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The Kit(low)Cd44(+)Cd34(+) cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In Kit(K641E) mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of Kit(low)Cd44(+)Cd34(+) cells and increased their sensitivity to imatinib. CONCLUSIONS: Kit(low)Cd44(+)Cd34(+) progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Tumores do Estroma Gastrointestinal/patologia , Células Intersticiais de Cajal/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Antígenos CD34/análise , Benzamidas , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Células Clonais , Relação Dose-Resposta a Droga , Regulação para Baixo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Receptores de Hialuronatos/análise , Hiperplasia , Mesilato de Imatinib , Células Intersticiais de Cajal/imunologia , Células Intersticiais de Cajal/metabolismo , Células Intersticiais de Cajal/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Mutação , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piranos/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Tempo , Carga Tumoral
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