RESUMO
We herein describe a case of primary leiomyosarcoma of descending mesocolon mesentery in a pregnant woman. A 31-year-old woman was referred to our clinic for the presence of a suspicious mass (solid heterogenous lesion with lobulated margins) detected during routine obstetric ultrasonography (USG), growing throughout her term. Imaging in her third trimester showed a considerable increase in the size of the mass and was suspected to be malignancy of uterine origin. Tru-cut biopsy performed post-partum indicated leiomyosarcoma. She underwent neoadjuvant chemotherapy with six cycles of dacarbazine and doxorubicin with partial response. Subsequently, she underwent surgery, and the tumor was found to be present in sigmoid colon mesentery extending in retroperitoneum involving 5 cm of ureter. The mass was resected along with part of the colon and ureter that was involved by disease. Patient had uneventful recovery post-surgery. Considering moderate response to chemotherapy and discussion in tumor board, she was not given adjuvant chemotherapy. At follow-up of 15 months, the patient is disease-free with a normal, healthy baby.
Assuntos
Leiomiossarcoma/patologia , Mesentério/patologia , Terapia Neoadjuvante/métodos , Complicações Neoplásicas na Gravidez/patologia , Gestantes , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Feminino , Humanos , Leiomiossarcoma/tratamento farmacológico , Mesentério/efeitos dos fármacos , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológicoRESUMO
Here, we tested the hypothesis that TNAP (tissue nonspecific alkaline phosphatase) modulates vascular responsiveness to norepinephrine. In the isolated, Tyrode's-perfused rat mesentery, 50 µmol/L of L-p-bromotetramisole (L-p-BT; selective TNAP inhibitor, Ki=56 µmol/L) significantly reduced TNAP activity and caused a significant 9.0-fold rightward-shift in the norepinephrine concentration versus vasoconstriction relationship. At 100 µmol/L, L-p-BT further reduced mesenteric TNAP activity and caused an additional significant right-shift of the norepinephrine concentration versus vasoconstriction relationship. A higher concentration (200 µmol/L) of L-p-BT had no further effect on either mesenteric TNAP activity or norepinephrine-induced vasoconstriction. L-p-BT did not alter vascular responses to vasopressin, thus ruling-out nonspecific suppression of vascular reactivity. Since in the rat mesenteric vasculature α1-adrenoceptors mediate norepinephrine-induced vasoconstriction, these finding indicate that TNAP inhibition selectively interferes with α1-adrenoceptor signaling. Additional experiments showed that the effects of TNAP inhibition on norepinephrine-induced vasoconstriction were not mediated by accumulation of pyrophosphate or ATP (TNAP substrates) nor by reduced adenosine levels (TNAP product). TNAP inhibition significantly reduced the Hillslope of the norepinephrine concentration versus vasoconstriction relationship from 1.8±0.2 (consistent with positive cooperativity of α1-adrenoceptor signaling) to 1.0±0.1 (no cooperativity). Selective activation of A1-adenosine receptors, which are known to participate in coincident signaling with α1-adrenoceptors, reversed the suppressive effects of L-p-BT on norepinephrine-induced vasoconstriction. In vivo, L-p-BT administration achieved plasma levels of ≈60 µmol/L and inhibited mesenteric vascular responses to exogenous norepinephrine and sympathetic nerve stimulation. TNAP modulates vascular responses to norepinephrine likely by affecting positive cooperativity of α1-adrenoceptor signaling via a mechanism involving A1 receptor signaling.
Assuntos
Fosfatase Alcalina/metabolismo , Proteínas de Membrana/metabolismo , Mesentério/efeitos dos fármacos , Norepinefrina/farmacologia , Tetramizol/análogos & derivados , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Antagonistas do Receptor A1 de Adenosina/farmacologia , Fosfatase Alcalina/antagonistas & inibidores , Fosfatase Alcalina/genética , Animais , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Mesentério/metabolismo , Ratos , Tetramizol/farmacologia , Xantinas/farmacologiaRESUMO
We tested the effect of low-frequency ultrasound (LUS, 20 kHz, 4 W/cm2) on the function of rat mesentery and human pulmonary arteries with wire myography. The vessels were induced to contract with either noradrenaline or physiologic saline solution (PSS) with a high potassium concentration (KPSS) and then incubated with capsaicin (2.1â¯×â¯10-7 M, TRPV1 [transient receptor potential vanilloid 1] activator), dopamine (1â¯×â¯10-4 M, dopamine and α2-receptor activator), or fenoldopam (dopamineA1 receptor agonist, 1â¯×â¯10-4 M) with and without glibenclamide (1 µM, KATP [adenosine triphosphate {sensitive potassium channel (ATP)}-sensitive potassium channel] inhibitor and α2-receptor modulator), and insonated. Vessels were incubated in Ca2+-free PSS and induced to contract with added extracellular Ca2+ and noradrenaline. Pulmonary arteries were induced to contract with KPSS and dopamine. Then the vessels were insonated. LUS inhibited the influx of external Ca2+, inhibited the dopamine-induced vasoconstriction in the KPSS (glibenclamide reversible), reduced the capsaicin-induced vasorelaxation, increased the gentamicin-induced vasorelaxation and increased the dopamine-induced contraction in the KPSS in human pulmonary arteries.
Assuntos
Mesentério/efeitos dos fármacos , Mesentério/efeitos da radiação , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/efeitos da radiação , Ondas Ultrassônicas , Animais , Humanos , Miografia , Ratos , Ratos WistarRESUMO
EGISTs originating outside the gastrointestinal tract share some similarities with the GISTs regarding their immunohistochemical features including the positive expression of CD117 and CD34. The majority of EGISTs carry activating mutations of the C-KIT or PDGFRA genes. However, there is no precedent in the literature where the two mutations occur in one case of EGISTs to date. We describe herein, a 52-year-old female who presented as mesenteric and pelvic regions masses showing positive immunoreactivity for CD117, DOG-1, CD34. Mutation analysis identified two mutations that located in the exon 13 of C-KIT and in the exon 18 of PDGFRA. The patient was treated sequentially with imatinib, sunitinib, sorafenib, and regorafenib. However, the prognosis was undesirable. Previous research has shown that expression of members of Bcl-2 family may be helpful in predicting prognosis, the survival time, and the resistance to chemotherapeutic agents. IHC was performed to detect the expression of BCL-2 family. The results show that high BCL-2 expression and low BAX expression in both specimens. In conclusion, our case may suggest that the presence of both C-KIT and PDGFRA mutations in EGISTs patients may indicate a very poor prognosis; and the expression level of BCL-2 and BAX could predict clinical outcome.
Assuntos
Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/secundário , Mesentério/patologia , Recidiva Local de Neoplasia/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesentério/efeitos dos fármacos , Mesentério/metabolismo , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , PrognósticoAssuntos
Cardiomiopatias/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adenina/análogos & derivados , Idoso , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/fisiopatologia , Humanos , Linfoma de Célula do Manto/complicações , Linfoma de Célula do Manto/patologia , Masculino , Mesentério/efeitos dos fármacos , Mesentério/patologia , Piperidinas , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagemAssuntos
Doenças do Mediastino/diagnóstico por imagem , Mesentério/diagnóstico por imagem , Pneumatose Cistoide Intestinal/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Doenças do Mediastino/induzido quimicamente , Mesentério/efeitos dos fármacos , Pessoa de Meia-Idade , Pneumatose Cistoide Intestinal/induzido quimicamenteRESUMO
Membrane anatomy is in broad sense the anatomy of the mesentery and its bed, both of which are consisted of fascia membrane or/and serous membrane. Although the traditional mesentery has the definition of mesentery, people unconsciously identify them according to their "fan-shaped" and "free" characteristics. The "generalized mesentery" we propose refers to the fascia and/or serosa, envelope-like organs and their blood vessels, suspending to the posterior wall of the body, regardless of its shape, free or not. So the main points of the anatomy are as follows.(1) Organs or tissues with their feeding structures are enveloped by the fascia membrane or/and serous membrane, suspending to posterior wall of the body, to form different shapes of the mesentery in broad sense, and most of them are buried in the mesentery bed. (2) Cancer metastasis type V of in the gut moves in the envelop of the mesentery in broad sense.(3) Intraoperative breach of the envelop membrane not only results in intraoperative bleeding, but also cancer cell leakage from the mesentery. (4) The cancer of gut can be divided into cancer in the mesentery, cancer out of the mesentery and cancer at edge of the mesentery based on this anatomy. Radical tumor resection is effective for cancer in the mesentery, which should not be artificially breached into those of cancer out of the mesentery. The essence of neoadjuvant chemoradiation is to push cancer at edge of the mesentery back inside the mesentery.(5) Based on such anatomy, radical gut tumor operations are divided into D2/D3 procedure, without emphasizing the integrity of the mesentery during lymphatic dissection; CME procedure, which emphasizes the integrity of the mesentery but does not strictly define the extent of lymphatic dissection; D2/D3 + CME procedure, which strictly defines the integrity of the mesentery and the extent of lymphatic dissection.(6)For gastrointestinal tumors of the same T stage, shorter mesentery indicates worse prognosis.(7) For gastrointestinal tumors with the same T stage and the same length of mesentery, the more mesentery buried in the mesentery bed, the worse prognosis. (8) The above seven principles are universal in the organs of the body cavity (and even all internal organs).Membrane anatomy, unlike traditional "plane surgery" , is completely different from the "anatomy of the membrane..." described by Japanese scholars, but mainly bases on generalized mesentery and mesentery bed, meanwhile inherent life events can be accurately defined and confirmed.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Sistema Digestório/patologia , Neoplasias do Sistema Digestório/cirurgia , Mesentério/patologia , Antineoplásicos/uso terapêutico , Dissecação , Fáscia/patologia , Humanos , Mesentério/anatomia & histologia , Mesentério/efeitos dos fármacos , Mesentério/cirurgia , Estadiamento de Neoplasias , Prognóstico , Membrana Serosa/patologiaRESUMO
We previously demonstrated the protective effect of MSCs in an adaptive transfer mouse model. However, their therapeutic potential in an allogeneic immunocompetent setting mimicking clinical context of islet transplantation remained unknown. The aim of this study was to determine whether MSCs therapy, either by itself, or combined with Rapamycin could benefit the allograft survival of fully MHC-mismatched mouse islet transplant. Combination therapy of MSCs and low-dose Rapamycin significantly prolonged the survival of islet allografts, whereas treatment of MSCs, or Rapamycin alone, had no impact. Interestingly, this protective effect was associated with an induced expansion of regulatory T cells in islet grafts and draining lymph nodes, a skewed T-cell differentiation toward immunotolerance, and a profound suppression of alloreactivity against donor antigen. Our study suggests that a combination therapy of MSCs and low-dose Rapamycin can prolong the survival and preserve the function of islet allograft in the MHC-mismatched mouse model of islet transplantation.
Assuntos
Aloenxertos/imunologia , Sobrevivência de Enxerto/imunologia , Transplante das Ilhotas Pancreáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Sirolimo/farmacologia , Linfócitos T Reguladores/imunologia , Aloenxertos/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Terapia Combinada , Relação Dose-Resposta a Droga , Sobrevivência de Enxerto/efeitos dos fármacos , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Mesentério/efeitos dos fármacos , Mesentério/patologia , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/patologia , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
It is theorized that toxic agents are transported from the hyperpermeable gut of burn victims through the lymph, to the systemic circulation, causing global injury. We believe that immune cells respond to leakage of "toxic lymph" following trauma causing the attraction of these cells to the perilymphatic space. To test this, we utilized a model of burn on rats to examine changes in a single immune cell population associated with mesenteric lymphatic dysfunction. We examined the ability of serum from these animals to increase permeability in lymphatic endothelial monolayers and disrupt cellular junctions. We also treated burn animals with doxycycline, an inhibitor of microvascular permeability, and observed the effects on immune cell populations, morphometry, and lymphatic endothelial permeability. Burn injury increased the number of MHCII+ immune cells along the vessel (>50%). The size and shape of these cells also changed significantly following burn injury. Serum from burn animals increased lymphatic endothelial permeability (â¼1.5-fold) and induced breaks in VE-cadherin staining. Doxycycline treatment blocked the accumulation of immune cells along the vessel, whereas serum from doxycycline-treated animals failed to increase lymphatic endothelial permeability. The size of cells along the vessel in doxycycline-treated burn animals was not affected, suggesting that the cells already present on the lymphatic vessels still respond to substances in the lymph. These findings suggest that factors produced during burn can induce lymphatic endothelial barrier disruption and lymph produced during traumatic injury can influence the attraction and morphology of immune cell populations along the vessel.
Assuntos
Células Apresentadoras de Antígenos/efeitos dos fármacos , Queimaduras/tratamento farmacológico , Doxiciclina/farmacologia , Células Endoteliais/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/imunologia , Vasos Linfáticos/efeitos dos fármacos , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/patologia , Antígenos CD/genética , Antígenos CD/imunologia , Biomarcadores/metabolismo , Queimaduras/genética , Queimaduras/imunologia , Queimaduras/patologia , Caderinas/genética , Caderinas/imunologia , Permeabilidade Capilar , Movimento Celular/efeitos dos fármacos , Tamanho Celular , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Linfático/efeitos dos fármacos , Endotélio Linfático/imunologia , Endotélio Linfático/patologia , Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Linfa/citologia , Linfa/efeitos dos fármacos , Linfa/imunologia , Vasos Linfáticos/imunologia , Vasos Linfáticos/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Mesentério/efeitos dos fármacos , Mesentério/imunologia , Mesentério/patologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Carvacrol (CRV) has strong cytoprotective, antioxidant, and anti-inflammatory properties. We aimed to demonstrate the possible protective effects of CRV on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wistar rats were allocated into the following four groups: Sham, CLP, Sham + CRV, and CLP + CRV. The animals were orally administered with CRV (80 mg/kg/day) or vehicle (corn oil; 1 mL/kg/day) for 7 days. At the eighth day, Sham or CLP procedure was applied. Twenty hours after the operations, MBF and contractile responses of isolated aortic preparations to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological assessments. Additionally, survival rates were recorded throughout 96 h. CRV administration improved the mesenteric perfusion, contractile function of aorta, and survival after CLP. CRV substantially prevented the elevations in the levels of LDH, BUN, Cr, and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) but could not prevent the elevations of AST and ALT after CLP. The decreased liver, kidney, and spleen glutathione levels and increased liver, kidney, lung, and spleen malondialdehyde levels induced by CLP were substantially restored by CRV. Also, histopathological protective effects of CRV on multiple organ damage due to CLP were observed. CRV possesses strong ameliorative effects on sepsis due to its protective effects on mesenteric perfusion and aortic function and its antioxidative and anti-inflammatory effects.
Assuntos
Aorta/efeitos dos fármacos , Monoterpenos/farmacologia , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios , Antioxidantes , Aorta/fisiologia , Cimenos , Mesentério/efeitos dos fármacos , Monoterpenos/uso terapêutico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Ratos , Ratos Wistar , Sepse/microbiologiaRESUMO
Angiogenesis, defined as the growth of new blood vessels from existing ones, plays a key role in development, growth, and tissue repair. Its necessary role in tumor growth and metastasis has led to the creation of a new category of anti-angiogenic cancer therapies. Preclinical development and evaluation of potential drug candidates require models that mimic real microvascular networks. Here, we describe the rat mesentery culture model as a simple ex vivo assay that offers time-lapse imaging of intact microvascular network remodeling and demonstrate its application for anti-angiogenic drug testing.
Assuntos
Inibidores da Angiogênese/farmacologia , Mesentério/citologia , Microvasos/ultraestrutura , Técnicas de Cultura de Tecidos/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Mesentério/irrigação sanguínea , Mesentério/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Modelos Biológicos , Ratos , Ratos Wistar , Imagem com Lapso de TempoRESUMO
Vertical sleeve gastrectomy (VSG) is becoming more and more popular among the world. Despite its dramatic efficacy, however, the mechanism of VSG remains largely undetermined. This study aimed to test interferon (IFN)-γ secretion n of mesenteric lymph nodes in obese mice (ob/ob mice), a model of VSG, and its relationship with farnesoid X receptor (FXR) expression in the liver and small intestine, and to investigate the weight loss mechanism of VSG. The wild type (WT) mice and ob/ob mice were divided into four groups: A (WT+Sham), B (WT+VSG), C (ob/ob+Sham), and D (ob/ob+VSG). Body weight values were monitored. The IFN-γ expression in mesenteric lymph nodes of ob/ob mice pre- and post-operation was detected by flow cytometry (FCM). The FXR expression in the liver and small intestine was detected by Western blotting. The mouse AML-12 liver cells were stimulated with IFN-γ at different concentrations in vitro. The changes of FXR expression were also examined. The results showed that the body weight of ob/ob mice was significantly declined from (40.6±2.7) g to (27.5±3.8) g on the 30th day after VSG (P<0.05). At the same time, VSG induced a higher level secretion of IFN-γ in mesenteric lymph nodes of ob/ob mice than that pre-operation (P<0.05). The FXR expression levels in the liver and small intestine after VSG were respectively 0.97±0.07 and 0.84±0.07 fold of GAPDH, which were significantly higher than pre-operative levels of 0.50±0.06 and 0.48±0.06 respectively (P<0.05). After the stimulation of AML-12 liver cells in vitro by different concentrations of IFN-γ (0, 10, 25, 50, 100, and 200 ng/mL), the relative FXR expression levels were 0.22±0.04, 0.31±0.04, 0.39±0.05, 0.38±0.05, 0.56±0.06, and 0.35±0.05, respectively, suggesting IFN-γ could distinctly promote the FXR expression in a dose-dependent manner in comparison to those cells without IFN-γ stimulation (P<0.05). It was concluded that VSG induces a weight loss in ob/ob mice by increasing IFN-γ secretion of mesenteric lymph nodes, which then increases the FXR expression of the liver and small intestine.
Assuntos
Interferon gama/biossíntese , Intestino Delgado/efeitos dos fármacos , Fígado/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Obesidade/cirurgia , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Peso Corporal , Linhagem Celular , Gastrectomia/métodos , Expressão Gênica , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Interferon gama/metabolismo , Interferon gama/farmacologia , Intestino Delgado/metabolismo , Fígado/metabolismo , Linfonodos/metabolismo , Mesentério/efeitos dos fármacos , Mesentério/metabolismo , Camundongos , Camundongos Obesos , Obesidade/metabolismo , Obesidade/patologia , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Redução de PesoRESUMO
Cancer therapy-induced complications in the bowel and mesentery are fairly common. It is important for clinicians to be aware of these complications and the agents most frequently implicated. Cancer therapy is rapidly evolving and often encompasses both classic cytotoxic drugs and newer molecular targeted agents. Drugs from both broad classes can have numerous adverse effects on the bowel and mesentery that can be detected on imaging. These adverse effects include ileus, various forms of enterocolitis, gastrointestinal perforation, pneumatosis intestinalis, secretory diarrhea, and sclerosing mesenteritis. These complications are diverse and range from relatively benign to life threatening. The management is also variable, but many of these conditions are easily controlled and reversed with supportive care and cessation of the particular cancer therapy. The objective of this pictorial essay is to demonstrate some of the more common cancer therapy-induced complications of the bowel and mesentery, with a focus on the radiographic findings.
Assuntos
Antineoplásicos/efeitos adversos , Enteropatias/induzido quimicamente , Enteropatias/diagnóstico por imagem , Mesentério/efeitos dos fármacos , Mesentério/diagnóstico por imagem , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Humanos , Fatores de RiscoRESUMO
Orthovanadate (OVA), a protein tyrosine phosphatase inhibitor, induces vasoconstriction in a Rho kinase-dependent manner. The aim of this study was to determine the mechanism underlying OVA-induced vasoconstriction of rat mesenteric arteries. OVA-induced constriction of mesenteric arterial rings treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 0.1 mM), a nitric oxide synthase inhibitor, was significantly blocked by the Rho kinase inhibitor Y-27632 (R-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, 10 µM), extracellular signal-regulated kinase 1 and 2 (Erk1/2) inhibitor FR180204 (5-(2-phenyl-pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine, 10 µM), Erk1/2 kinase (MEK) inhibitor PD98059 (2'-amino-3'-methoxyflavone, 10 µM), epidermal growth factor receptor (EGFR) inhibitor AG1478 (4-(3-chloroanilino)-6,7-dimethoxyquinazoline, 10 µM), and Src inhibitor PP2 (4-amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine, 3 µM). However, the myosin light chain kinase inhibitor ML-7 (1-(5-iodonaphthalene-1-sulfonyl)-homopiperazine, 10 µM) did not affect OVA-induced constriction. Phosphorylation of myosin phosphatase target subunit 1 (MYPT1, an index of Rho kinase activity) was abrogated by inhibitors of Src, EGFR MEK, Erk1/2, and Rho kinase. OVA-stimulated Erk1/2 phosphorylation was blocked by inhibitors of EGFR, Src, MEK, and Erk1/2 but not affected by an inhibitor of Rho kinase. OVA-induced Src phosphorylation was abrogated by an Src inhibitor but not affected by inhibitors of EGFR, MEK, Erk1/2, and Rho kinase. In addition, the metalloproteinase inhibitor TAPI-0 (N-(R)-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl-L-naphthylalanyl-L-alanine amide, 10 µM) and an inhibitor of heparin/epidermal growth factor binding (CRM 197, 10 µg/mL) did not affect OVA-induced contraction of rat mesenteric arterial rings. These results suggest that OVA induces vasoconstriction in rat mesenteric arteries via Src, EGFR, MEK, and Erk1/2 activation, leading to the inactivation of myosin light chain phosphatase through phosphorylation of MYPT1.
Assuntos
Sistema de Sinalização das MAP Quinases , Artérias Mesentéricas/efeitos dos fármacos , Mesentério/efeitos dos fármacos , Fosfatase de Miosina-de-Cadeia-Leve/antagonistas & inibidores , Vanadatos/farmacologia , Vasoconstrição/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Animais , Receptores ErbB/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Mesentério/irrigação sanguínea , Mesentério/metabolismo , Fosforilação , Piperazina , Piperazinas/farmacologia , Proteína Fosfatase 1/metabolismo , Ratos Wistar , Transdução de Sinais , Vanádio/metabolismo , Quinases da Família src/metabolismoRESUMO
Biofunctionalized polyethylene glycol maleimide (PEG-MAL) hydrogels were engineered as a platform to deliver pancreatic islets to the small bowel mesentery and promote graft vascularization. VEGF, a potent stimulator of angiogenesis, was incorporated into the hydrogel to be released in an on-demand manner through enzymatic degradation. PEG-MAL hydrogel enabled extended in vivo release of VEGF. Isolated rat islets encapsulated in PEG-MAL hydrogels remained viable in culture and secreted insulin. Islets encapsulated in PEG-MAL matrix and transplanted to the small bowel mesentery of healthy rats grafted to the host tissue and revascularized by 4 weeks. Addition of VEGF release to the PEG-MAL matrix greatly augmented the vascularization response. These results establish PEG-MAL engineered matrices as a vascular-inductive cell delivery vehicle and warrant their further investigation as islet transplantation vehicles in diabetic animal models.
Assuntos
Hidrogéis/administração & dosagem , Ilhotas Pancreáticas/efeitos dos fármacos , Maleimidas/química , Polietilenoglicóis/química , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Alginatos/química , Animais , Colágeno/química , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Hidrogéis/química , Intestino Delgado/irrigação sanguínea , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiologia , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/fisiologia , Transplante das Ilhotas Pancreáticas , Masculino , Mesentério/efeitos dos fármacos , Mesentério/fisiologia , Neovascularização Fisiológica/efeitos dos fármacos , Ratos Endogâmicos Lew , Fator A de Crescimento do Endotélio Vascular/químicaRESUMO
Transformation of epithelial cells into connective tissue cells (epithelial-mesenchymal transition, EMT) is a complex mechanism involved in tumor metastasis, and in normal embryogenesis, while type II EMT is mainly associated with inflammatory events and tissue regenaration. In this study we examined type II EMT at the ultrastructural and molecular level during the inflammatory process induced by Freund's adjuvant treatment in rat mesenteric mesothelial cells. We found that upon the inflammatory stimulus mesothelial cells lost contact with the basal lamina and with each other, and were transformed into spindle-shaped cells. These morphological changes were accompanied by release of interleukins IL-1alpha, -1beta and IL-6 and by secretion of transforming growth factor beta (TGF-ß) into the peritoneal cavity. Mesothelial cells also expressed estrogen receptor alpha (ER-α) as shown by immunolabeling at the light and electron microscopical levels, as well as by quantitative RT-PCR. The mRNA level of ER-α showed an inverse correlation with the secretion of TGF-ß. At the cellular and subcellular levels ER-α was colocalized with the coat protein caveolin-1 and was found in the plasma membrane of mesothelial cells, in caveolae close to multivesicular bodies (MVBs) or in the membrane of these organelles, suggesting that ER-α is internalized via caveola-mediated endocytosis during inflammation. We found asymmetric, thickened, electron dense areas on the limiting membrane of MVBs (MVB plaques) indicating that these sites may serve as platforms for collecting and organizing regulatory proteins. Our morphological observations and biochemical data can contribute to form a potential model whereby ER-α and its caveola-mediated endocytosis might play role in TGF-ß induced type II EMT in vivo.
Assuntos
Cavéolas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptor alfa de Estrogênio/metabolismo , Adjuvante de Freund/farmacologia , Mesentério/efeitos dos fármacos , Mesentério/metabolismo , Animais , Caveolina 1/genética , Caveolina 1/metabolismo , Células Epiteliais/ultraestrutura , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Feminino , Imuno-Histoquímica , Masculino , Ligação Proteica , RatosRESUMO
In the era of highly active antiretroviral therapy, radiologists are increasingly confronted with a progressively aging HIV-infected population with improved immune function and survival, in whom a wide spectrum of infectious and neoplastic opportunistic disorders may be encountered. Furthermore, HIV / AIDS patients commonly have unspecific symptoms and physical signs, multicentric or coexisting diseases, so that diagnostic imaging studies are crucial to correctly identify and stage HIV-related abnormalities. Currently, volumetric multidetector CT (MDCT) provides comprehensive assessment and confident post-treatment follow-up of opportunistic abnormalities involving the mesentery, omentum, and peritoneum. In this pictorial essay, the cross-sectional imaging appearances of opportunistic disorders involving the mesentery, peritoneum, or both compartments in HIV / AIDS patients are reviewed, with emphasis on those MDCT findings that may be helpful for differential diagnosis along with knowledge of the degree of immune suppression as measured by the CD4 lymphocyte count. Familiarity with the varied spectrum of HIV-related opportunistic disorders encountered in antiretroviral - treated patients and their imaging appearances should allow radiologists to improve their confidence in the characterization of abnormal findings observed on abdominal cross-sectional imaging studies.
Assuntos
Antirretrovirais/efeitos adversos , Antirretrovirais/uso terapêutico , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/tratamento farmacológico , Doenças Peritoneais/induzido quimicamente , Doenças Peritoneais/diagnóstico por imagem , Infecções por HIV/complicações , Humanos , Mesentério/diagnóstico por imagem , Mesentério/efeitos dos fármacos , Omento/diagnóstico por imagem , Omento/efeitos dos fármacos , Tomografia Computadorizada por Raios X/tendências , Resultado do TratamentoRESUMO
OBJECTIVES: Mesenteric ischaemia/reperfusion (IR) may lead to liver mitochondrial dysfunction and multiple organ failure. We determined whether gut IR induces early impairment of liver mitochondrial oxidative activity and whether methylene blue (MB) might afford protection. DESIGN: Controlled animal study. MATERIALS AND METHODS: Rats were randomised into three groups: controls (n = 18), gut IR group (mesenteric ischaemia (60 min)/reperfusion (60 min)) (n = 18) and gut IR + MB group (15 mg kg(-1) MB intra-peritoneally) (n = 16). Study parameters were: serum liver function markers, blood lactate, standard histology and DNA fragmentation (apoptosis) on intestinal and liver tissue, maximal oxidative capacity of liver mitochondria (state 3) and activity of complexes II, III and IV of the respiratory chain measured using a Clark oxygen electrode. RESULTS: Gut IR increased lactate deshydrogenase (+982%), aspartate and alanine aminotransferases (+43% and +74%, respectively) and lactate levels (+271%). It induced segmental loss of intestinal villi and cryptic apoptosis. It reduced liver state 3 respiration by 30% from 50.1 ± 3 to 35.2 ± 3.5 µM O(2) min(-1) g(-1) (P < 0.01) and the activity of complexes II, III and IV of the mitochondrial respiratory chain. Early impairment of liver mitochondrial respiration was related to blood lactate levels (r(2) = 0.45). MB restored liver mitochondrial function. CONCLUSIONS: MB protected against gut IR-induced liver mitochondria dysfunction.
Assuntos
Mesentério/irrigação sanguínea , Mesentério/efeitos dos fármacos , Azul de Metileno/farmacologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Citoproteção , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Complexo II de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , L-Lactato Desidrogenase/sangue , Ácido Láctico/sangue , Masculino , Mesentério/patologia , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fatores de TempoRESUMO
The structural peculiarities of the thymus and cranial mesenteric lymph nodes (LN) were examined in 72 neonatal rats born to females, exposed to 15% ethanol solution during pregnancy (n = 34), as well as both during pregnancy and for 1 month preceding it (n = 38). 44 neonatal rats born to intact females, served as a control group. It was shown that the exposure of female rats to ethanol only during pregnancy resulted in more pronounced changes in the mesenteric LN of the offspring than in the thymus. These included the reduction of LN number, cross-sectional area, lymphoid cell relative content, the suppression of mitotic activity, increased reticular cell content and macrophage activity. Pre-gravid ethanol intoxication of females for 1 month in combination with ethanol exposure during pregnancy was shown to have greater effect on the thymus morphogenesis in the offspring. This was manifested by the decrease of its absolute and relative mass, proliferative activity, increase of cell death, appearance of the microcirculatory and dysplastic changes.
Assuntos
Linfonodos/efeitos dos fármacos , Linfa/efeitos dos fármacos , Mesentério/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Etanol/toxicidade , Feminino , Linfonodos/patologia , Gravidez , RatosRESUMO
Recently, steps have been taken to further developments toward increasing gamma-linolenic acid (GLA) concentration and lowering costs in plant seed oils using transgenic technology. Through identification and expression of a fungal delta-6 desaturase gene in the high linoleic acid safflower plant, the seeds from this genetic transformation produce oil with >40% GLA (high GLA safflower oil (HGSO)). The aim of the study was to compare the effects of feeding HGSO to a generally recognized as safe source of GLA, borage oil, in a 90 day safety study in rats. Weanling male and female Sprague-Dawley rats were fed a semi-synthetic, fat free, pelleted diet (AIN93G) supplemented with a 10% (wt/wt) oil blend containing HGSO or borage oil, with equivalent GLA levels. Results demonstrated that feeding diets containing HGSO or borage oil for 90 days had similar biologic effects with regard to growth characteristics, body composition, behavior, organ weight and histology, and parameters of hematology and serum biochemistries in both sexes. Metabolism of the primary n-6 fatty acids in plasma and organ phospholipids was similar, despite minor changes in females. We conclude that HGSO is biologically equivalent to borage oil and provides a safe alternative source of GLA in the diet.