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1.
Sci Rep ; 14(1): 11077, 2024 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745015

RESUMO

Postoperative intra-abdominal adhesions represent a significant post-surgical problem. Its complications can cause a considerable clinical and cost burden. Herein, our study aimed to investigate the effect of Everolimus on peritoneal adhesion formation after inducing adhesions in rats. In this experimental study, adhesion bands were induced by intraperitoneal injection of 3 ml of 10% sterile talc solution in 64 male albino rats. The first group served as the control group. The second one received oral Prednisolone (1 mg/kg/day), the third received Everolimus (0.1 mg/kg/day), and group four received both drugs with similar dosages for four consecutive weeks. The formation of adhesion bands was qualitatively graded according to the Nair classification. The rats in the control group had extensive adhesions between the abdominal wall and the organs. Regarding substantial adhesion formation, 50% (8/16) of animals in the control group had substantial adhesions, while this rate in the groups receiving Prednisolone, Everolimus, and combination treatment was 31%, 31%, and 31%, respectively. Also, 68.75% (5/11) of the Prednisolone recipients had insubstantial adhesions, the same as Everolimus recipients, while in the combination group, 66.66% (10/15) rats had insubstantial adhesions. Everolimus demonstrated satisfactory results in reducing the rates of induced peritoneal adhesion in an experimental model, similar to Prednisolone and superior to a combination regime.


Assuntos
Everolimo , Prednisolona , Animais , Everolimo/farmacologia , Everolimo/administração & dosagem , Aderências Teciduais/tratamento farmacológico , Aderências Teciduais/prevenção & controle , Aderências Teciduais/patologia , Prednisolona/farmacologia , Prednisolona/administração & dosagem , Ratos , Masculino , Quimioterapia Combinada , Modelos Animais de Doenças , Peritônio/patologia , Peritônio/efeitos dos fármacos , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/patologia , Doenças Peritoneais/prevenção & controle , Doenças Peritoneais/etiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/tratamento farmacológico
2.
Eur J Surg Oncol ; 49(9): 106963, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37394316

RESUMO

INTRODUCTION: Cytoreductive surgery is a key point in ovarian cancer treatment. Substantial morbidity may be consecutive to this major radical surgery. However, the objective of no residual tumor (CC-0) had demonstrated its clear improvement of prognosis. Could macroscopically-driven interval debulking surgery (IDS) overestimate active cancer cells and be unnecessarily morbid? MATERIALS AND METHODS: This retrospective cohort study was conducted in Center Leon Berard Cancer Center between 2000 and 2018. We included women with advanced epithelial ovarian cancer who received neoadjuvant chemotherapy and underwent an IDS including resection of peritoneal metastases on the diaphragmatic domes. The primary endpoint was the pathological outcome of peritoneal resections of diaphragmatic domes. RESULTS: Peritoneal resections of diaphragmatic domes consisted of 117 patients. 75 patients required resection of nodules from the right cupola only, 2 patients from the left cupola only, and 40 patients bilaterally. Pathological analysis of the diaphragmatic domes found that 84.6% of samples demonstrated the presence of malignant cells, and only 12.8% found no tumor involvement. Pathology analysis could not be performed for 3 patients (2.6%) (vaporization). CONCLUSION: Surgical evaluation after neoadjuvant chemotherapy in ovarian cancer does not often overestimate peritoneal involvement by active carcinomatosis. Potential surgical morbidity due to peritoneal resection in IDS is admissible.


Assuntos
Neoplasias Ovarianas , Doenças Peritoneais , Cirurgiões , Humanos , Feminino , Procedimentos Cirúrgicos de Citorredução , Estudos Retrospectivos , Neoplasias Ovarianas/patologia , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/patologia , Terapia Neoadjuvante , Quimioterapia Adjuvante , Estadiamento de Neoplasias
4.
Hematol Oncol Clin North Am ; 36(3): 569-582, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35577709

RESUMO

Colorectal cancer with peritoneal involvement is traditionally recognized as having a poor prognosis, with treatment initially limited to palliative systemic chemotherapy alone. The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy drastically altered the course of this disease entity and has demonstrated improvements in survival outcomes. Recent evidence has shown benefit of CRS but did not show benefit of HIPEC. Under the guidance of a multidisciplinary team and for appropriately selected patients, CRS is a key component of treatment that can positively alter the course of disease outcomes for patients with peritoneal involvement.


Assuntos
Neoplasias Colorretais , Hipertermia Induzida , Doenças Peritoneais , Neoplasias Peritoneais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Humanos , Doenças Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/terapia , Prognóstico , Taxa de Sobrevida
5.
J Surg Oncol ; 125(7): 1176-1182, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35481913

RESUMO

Gastric cancer (GC) is an aggressive malignancy with a high burden of peritoneal disease. Evidence regarding the use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to improve outcomes has been growing. However, given multiple limitations, there remains a lack of international consensus regarding the optimal treatment paradigm. This review article discusses the burden of peritoneal disease in GC patients and the role of CRS + HIPEC in all treatment intents-curative, prophylactic, and palliative.


Assuntos
Hipertermia Induzida , Doenças Peritoneais , Neoplasias Peritoneais , Neoplasias Gástricas , Procedimentos Cirúrgicos de Citorredução , Humanos , Hipertermia Induzida/efeitos adversos , Quimioterapia Intraperitoneal Hipertérmica , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/etiologia , Neoplasias Peritoneais/cirurgia , Neoplasias Gástricas/patologia
6.
J Surg Res ; 276: 168-173, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35344743

RESUMO

INTRODUCTION: Peritoneal adhesion formation is a challenging postoperative complication. We aim to evaluate the effect of orally administered sirolimus, prednisolone, and their combination to prevent this entity. METHODS: Eighty female albino underwent intraperitoneal injection of 3 mL of 10% sterile talc solution to induce peritoneal adhesion, and were subsequently and randomly divided into four groups (each n = 20); including a control group; 1 mg/kg oral prednisolone daily in the morning; 0.1 mg/kg oral sirolimus daily; and a combination group which received both drugs, with the same dosage. On the 29th day, abdominal cavities were explored, and classification was done based on Nair classification. RESULTS: All rats were healthy on the 29th day, in which exploration was performed. The rats in the control group had extensive intra-abdominal adhesions, while 17 (85%) rats in the control group had substantial adhesion; however, the prednisolone, sirolimus, and combination group had lesser adhesion formation. Also, 14 (70%) rats of prednisolone group, 13 (65%) of sirolimus group, and 16 (80%) of combination group had insubstantial adhesion. The decrease in the grade of peritoneal adhesion bands was highly significant in the combination group (P > 0.001). CONCLUSIONS: The combination of sirolimus and prednisolone was effective for preventing peritoneal adhesions in rats.


Assuntos
Cavidade Abdominal , Doenças Peritoneais , Animais , Modelos Animais de Doenças , Feminino , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/etiologia , Doenças Peritoneais/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Prednisolona , Ratos , Sirolimo/uso terapêutico , Aderências Teciduais/complicações , Aderências Teciduais/prevenção & controle
7.
PLoS One ; 17(2): e0263614, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35130311

RESUMO

OBJECTIVE: Endometriosis is a common benign disease in women of reproductive age. Qu's formula (QUF) is a patented Chinese herbal medicine for treating endometriosis that has been proven to be effective in treating and preventing the recurrence of endometriosis. This study is aimed to discover its molecular mechanism and to explore the potential drug targets. METHODS: A QUF target and endometriosis-related gene set was identified by the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) databases and five disease-gene databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed, and a protein-protein interaction (PPI) network was established to discover the potential mechanism. MalaCards was searched for targets and signaling pathways related to endometriosis, and the search results were also used to identify the key factors in QUF. Molecular docking was performed to visualize the interactions between the effective molecules and proteins encoded by critical genes. Cell experiments and molecular dynamics (MD) simulations were used to further validate the therapeutic effects of the active compounds in QUF on endometriosis. RESULTS: A compound-target network with 117 nodes (94 genes and 23 active compounds) and 224 edges was generated. The results of GO and KEGG analyses indicated that QUF could act by regulating the immune response, apoptosis and proliferation, oxidative stress, and angiogenesis. VEGFA, CXCL8, CCL2, IL1B and PTGS2 were selected for molecular docking analysis from two critical subnetworks with high correlation scores in MalaCards, and the active compounds of QUF had binding potential and high affinity for them. The mRNA expression levels of CCL2, IL1B and PTGS2 significantly decreased after treatment with quercetin. MD simulations showed that the combinations of quercetin and these proteins were relatively stable. CONCLUSION: The network pharmacological strategy integrates molecular docking to unravel the molecular mechanism by which QUF protects against endometriosis. Our findings not only confirm the clinical effectiveness of QUF but also provide a foundation for further experimental study.


Assuntos
Medicamentos de Ervas Chinesas , Endometriose/tratamento farmacológico , Doenças Peritoneais/tratamento farmacológico , Algoritmos , Células Cultivadas , Biologia Computacional , Bases de Dados de Compostos Químicos , Descoberta de Drogas/métodos , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Endometriose/patologia , Feminino , Ontologia Genética , Humanos , Medicina Tradicional Chinesa/métodos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Farmacologia em Rede , Doenças Peritoneais/patologia , Mapas de Interação de Proteínas , Transdução de Sinais/efeitos dos fármacos
10.
Reprod Biomed Online ; 43(3): 379-393, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34330642

RESUMO

RESEARCH QUESTION: Can preoperative or perioperative intervention reduce the risk of recurrence of endometriosis caused by either incomplete excision or spillage and dissemination? DESIGN: A mouse model of endometriosis recurrence caused by spillage and dissemination was first established using 24 female Balb/c mice. The spillage and dissemination model was used to test the efficacy of preoperative use of ketorolac, perioperative use of aprepitant and combined use of propranolol and andrographolide in a prospective, randomized mouse experiment involving 75 mice. The efficacy of these preoperative and perioperative interventions in a mouse recurrence model caused by incomplete excision was also tested using 72 mice. In all experiments, the baseline body weight and hotplate latency of all mice were measured and recorded before the induction of endometriosis, before the primary surgery and before sacrifice. In addition, all lesions were excised, weighed and processed for quantification and immunohistochemistry analysis of E-cadherin, α-SMA, VEGF, ADRB2 and putative markers of recurrence PR-B, p-p65, as well as Masson trichrome staining. RESULTS: All interventions substantially and significantly suppressed the outgrowth of endometriotic lesions and reduced the risk of recurrence caused by either spillage and dissemination or incomplete excision (P = 0.0007 to 0.042). These interventions also significantly attenuated the generalized hyperalgesia, inhibited the staining of α-SMA, p-p65, VEGF and ADRB2 but increased staining of E-cadherin and PR-B, resulting in reduced fibrosis. CONCLUSION: Given the excellent safety profiles of these drugs, these data strongly suggest that preoperative and perioperative intervention may potentially reduce the risk of endometriosis recurrence effectively.


Assuntos
Endometriose/cirurgia , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Doenças Peritoneais/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Prevenção Secundária/métodos , Animais , Aprepitanto/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Modelos Animais de Doenças , Diterpenos/administração & dosagem , Quimioterapia Combinada , Endometriose/tratamento farmacológico , Endometriose/patologia , Feminino , Procedimentos Cirúrgicos em Ginecologia/métodos , Cetorolaco/farmacologia , Cetorolaco/uso terapêutico , Margens de Excisão , Camundongos , Camundongos Endogâmicos BALB C , Assistência Perioperatória/métodos , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/patologia , Cuidados Pré-Operatórios/métodos , Propranolol/administração & dosagem , Recidiva
12.
Naunyn Schmiedebergs Arch Pharmacol ; 394(2): 317-336, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32979062

RESUMO

Postoperative peritoneal adhesion (PPA) is a serious clinical condition that affects the high percentage of patients after abdominal surgery. In this review, we have tried to focus on pathophysiology and different underlying signal pathways of adhesion formation based on recent progress in the molecular and cellular mechanisms. Also, the strategies, developed based on traditional herbal and modern medicines, to prevent and treat the PPA via regulation of the molecular mechanisms were investigated. The search engines such as Google Scholar, PubMed, Scopus, and Science Direct have been used to evaluate the current literature related to the pathogenesis of adhesion formation and novel products. Recently, different mechanisms have been defined for adhesion formation, mainly categorized in fibrin formation and adhesion fibroblast function, inflammation, and angiogenesis. Therefore, the suppression of these mechanisms via traditional and modern medicine has been suggested in several studies. While different strategies with encouraging findings have been developed, most of the studies showed contradictory results and were performed on animals. The herbal products have been introduced as safe and effective agent which can be considered in future preclinical and clinical studies. Although a wide range of therapeutics based on traditional and modern medicines have been suggested, there is no agreement in the efficacy of these methods to prevent or treat adhesion formation after surgeries. Further basic and clinical researches are still needed to propose the efficiency of recommended strategies for prevention and treatment of PPA.


Assuntos
Doenças Peritoneais , Complicações Pós-Operatórias , Animais , Humanos , Medicina Tradicional , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/etiologia , Doenças Peritoneais/prevenção & controle , Peritônio/patologia , Fitoterapia , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Aderências Teciduais/tratamento farmacológico , Aderências Teciduais/etiologia , Aderências Teciduais/prevenção & controle
13.
Asian J Endosc Surg ; 14(3): 561-564, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33063435

RESUMO

Solitary primary pelvic intraperitoneal hydatid cysts are rare. We report the case of a 22-year-old women who presented with a dull ache in her lower abdomen for 2 years and increased urinary frequency over 3 months. Ultrasonography and CT indicated a solitary primary peritoneal pelvic hydatid cyst. Hydatid serology was positive. Perioperative albendazole was prescribed and laparoscopic cystectomy planned. Intraoperatively, dense adhesions to the omentum, urinary bladder, and left fallopian tube were taken down laparoscopically. A small Pfannenstiel incision was made to separate the bladder's left lateral edge and deliver the cyst externally. This report details our experience of managing this case and reviews pertinent literature.


Assuntos
Equinococose , Doenças Peritoneais , Albendazol/uso terapêutico , Anticestoides/uso terapêutico , Equinococose/diagnóstico por imagem , Equinococose/tratamento farmacológico , Equinococose/cirurgia , Feminino , Humanos , Pelve/diagnóstico por imagem , Pelve/cirurgia , Doenças Peritoneais/diagnóstico por imagem , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/cirurgia , Ultrassonografia , Adulto Jovem
14.
Int Immunopharmacol ; 90: 107242, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33307514

RESUMO

Colonic patches, the counterparts of Peyer's patches in the small intestine, are dynamically regulated lymphoid tissues in the colon that have an important role in defensing against microbial infections. Berberine is an isoquinoline alkaloid extracted from medicinal herbs including Rhizoma coptidis and has long been used for the treatment of infectious gastroenteritis, but its impact on the colonic lymphoid tissues (such as colonic patches) is unknown. In this study, we aimed to investigate whether berberine had any influences on the colonic patches in mice with bacterial infection. The results showed that oral berberine administration in bacterial infected mice substantially enhanced the hypertrophy of colonic patches, which usually possessed the features of two large B-cell follicles with a separate T-cell area. Moreover, the colonic patches displayed follicular dendritic cell networks within the B-cell follicles, indicative of mature colonic patches containing germinal centers. Concomitant with enlarged colonic patches, the cultured colon of infected mice treated with berberine secreted significantly higher levels of interleukin-1ß (IL-1ß), IL-6, TNF-α, and CCL-2, while NLRP3 inhibitor MMC950 or knockout of NLRP3 gene abrogated berberine-induced hypertrophy of colonic patches, suggesting the involvement of the NLRP3 signaling pathway in this process. Functionally, oral administration of berberine ameliorated liver inflammation and improved formed feces in the colon. Altogether, these results indicated that berberine was able to augment the hypertrophy of colonic patches in mice with bacterial infection probably through enhancing local inflammatory responses in the colon.


Assuntos
Infecções Bacterianas/patologia , Berberina/uso terapêutico , Colo/efeitos dos fármacos , Tecido Linfoide/efeitos dos fármacos , Doenças Peritoneais/patologia , Animais , Linfócitos B/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/metabolismo , Colo/crescimento & desenvolvimento , Colo/patologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Gastroenterite/tratamento farmacológico , Tecido Linfoide/crescimento & desenvolvimento , Tecido Linfoide/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/metabolismo , Linfócitos T/efeitos dos fármacos
15.
Gynecol Endocrinol ; 36(sup1): 7-11, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33305662

RESUMO

OBJECTIVE: The present study was to find a pathogenic evidence for dopamine agonist application in patients with endometriosis associated pain syndrome. PATIENTS AND TECHNIQUE: The study involved 227 patients of reproductive age with histologically confirmed genital endometriosis (GE) of I-III degree according to ASRM classification. The control group included 12 women with no laparoscope detected gynecologic pathology. The levels of prolactin (PRL), peripheral blood (PB), and peritoneal fluid (PF) were evaluated by chemiluminescence immune assay. The pain syndrome was measured by McGill visual analogue scale. Statistica10 program (StatSoft, Inc., Tulsa, OK) was applied for obtained data processing. RESULTS: A correlation was established between GE rate and levels of PRL and PB (Rs = 0.28, p < .05) as well as a correlation of PRL in PB and PF (Rs = 0.29, p < .05). Patients receiving cabergoline combined with hormone therapy standard schemes manifested considerable pain syndrome relief. CONCLUSIONS: PRL involvement in GE pathogenesis and more intense therapeutic impact on pain syndrome in case of combined administration of dopamine and standard hormone therapy prove cabergoline application in clinical practice.


Assuntos
Agonistas de Dopamina/uso terapêutico , Endometriose/tratamento farmacológico , Doenças Peritoneais/tratamento farmacológico , Adulto , Líquido Ascítico/química , Líquido Ascítico/metabolismo , Cabergolina/uso terapêutico , Quimioterapia Combinada , Endometriose/complicações , Endometriose/metabolismo , Endometriose/patologia , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Terapia de Alvo Molecular/métodos , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Dor Pélvica/metabolismo , Doenças Peritoneais/complicações , Doenças Peritoneais/metabolismo , Doenças Peritoneais/patologia , Prolactina/sangue , Federação Russa , Síndrome , Resultado do Tratamento
16.
Gynecol Endocrinol ; 36(sup1): 16-19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33305665

RESUMO

OBJECTIVE: Genital endometriosis (GE) is a widespread gynecological disease which requires its further pathogenesis investigation and search for new effective treatments. The known data of oxytocin receptor presence in endometrioid heterotopy smooth muscle cells give some grounds to assume oxytocin participation in the pathogenesis of endometriosis. The present study objective was to evaluate oxytocin level in peripheral blood (PB) in patients with endometriosis associated pain syndrome and to estimate the efficacy of oxytocin receptor inhibitors (IOXTR) administration based on animal endometriosis model. MATERIALS AND METHODS: The basic group comprised 61 patients with endometriosis associated pain syndrome, while 21 patients formed the control group. VAS, MPQ, and BBS objective tests were applied for pain syndrome evaluation. Oxytocin level in PB was measured by immunoenzyme method. After confirmation of endometriosis experimental model formation in rats and further randomization, a daily IOXTR intra-abdominal injection was performed in a dose of 0.35 mg/kg/24 h in the basic group (n = 12) or saline solution administration in the control (n = 12). On the final stage, endometrioid heterotopy size measuring was performed along with histological examination. RESULTS: Oxytocin level in PB was authentically higher in patients with GE compared to the control: 51.45 (35.54-62.76) pg/mL and 27.64 (23.23-34.12) pg/mL, respectively (p<.001). Positive correlation between oxytocin PB level and pain syndrome expression was established in patients with GE: VAS (r = 0.76; p<.001), MPQ (r = 0.52; p<.001), and BBS (r = 0.57; p<.001). Based on the experimental disease model authentical decrease of endometrioid heterotopy average area was observed after IOXTR therapy compared to the control (7.3 ± 1.8 mm2 and 22.2 ± 1.2 mm2, respectively, p<.05). CONCLUSIONS: The obtained results confirm the oxytocin role in the pathogenesis of endometrioid associated pain syndrome. The high efficacy of IOXTR administration based on animal model of surgically induced endometriosis allows viewing this method as a perspective therapy.


Assuntos
Endometriose/tratamento farmacológico , Doenças Peritoneais/tratamento farmacológico , Receptores de Ocitocina/antagonistas & inibidores , Vasotocina/análogos & derivados , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Endometriose/sangue , Endometriose/complicações , Endometriose/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Ocitocina/análogos & derivados , Ocitocina/sangue , Dor Pélvica/sangue , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Dor Pélvica/patologia , Doenças Peritoneais/sangue , Doenças Peritoneais/complicações , Doenças Peritoneais/patologia , Ratos , Ratos Wistar , Síndrome , Vasotocina/uso terapêutico , Adulto Jovem
18.
Int J Mol Sci ; 21(11)2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532126

RESUMO

In chronic peritoneal diseases, mesothelial-mesenchymal transition is determined by cues from the extracellular environment rather than just the cellular genome. The transformation of peritoneal mesothelial cells and other host cells into myofibroblasts is mediated by cell membrane receptors, Transforming Growth Factor ß1 (TGF-ß1), Src and Hypoxia-inducible factor (HIF). This article provides a narrative review of the reprogramming of mesothelial mesenchymal transition in chronic peritoneal diseases, drawing on the similarities in pathophysiology between encapsulating peritoneal sclerosis and peritoneal metastasis, with a particular focus on TGF-ß1 signaling and estrogen receptor modulators. Estrogen receptors act at the cell membrane/cytosol as tyrosine kinases that can phosphorylate Src, in a similar way to other receptor tyrosine kinases; or can activate the estrogen response element via nuclear translocation. Tamoxifen can modulate estrogen membrane receptors, and has been shown to be a potent inhibitor of mesothelial-mesenchymal transition (MMT), peritoneal mesothelial cell migration, stromal fibrosis, and neoangiogenesis in the treatment of encapsulating peritoneal sclerosis, with a known side effect and safety profile. The ability of tamoxifen to inhibit the transduction pathways of TGF-ß1 and HIF and achieve a quiescent peritoneal stroma makes it a potential candidate for use in cancer treatments. This is relevant to tumors that spread to the peritoneum, particularly those with mesenchymal phenotypes, such as colorectal CMS4 and MSS/EMT gastric cancers, and pancreatic cancer with its desmoplastic stroma. Morphological changes observed during mesothelial mesenchymal transition can be treated with estrogen receptor modulation and TGF-ß1 inhibition, which may enable the regression of encapsulating peritoneal sclerosis and peritoneal metastasis.


Assuntos
Transição Epitelial-Mesenquimal , Moduladores de Receptor Estrogênico/farmacologia , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/patologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Doença Crônica , Células Epiteliais/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Flavonoides/farmacologia , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Humanos , NF-kappa B/metabolismo , Doenças Peritoneais/metabolismo , Fibrose Peritoneal/tratamento farmacológico , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/patologia , Peritônio/citologia , Receptores de Estrogênio/metabolismo , Tamoxifeno/uso terapêutico , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral/efeitos dos fármacos
19.
Hum Reprod Update ; 26(4): 565-585, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32412587

RESUMO

BACKGROUND: Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis. OBJECTIVE AND RATIONALE: We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments. SEARCH METHODS: We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment. OUTCOMES: Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response. WIDER IMPLICATIONS: Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.


Assuntos
Endometriose/tratamento farmacológico , Ligantes , Doenças Peritoneais/tratamento farmacológico , Receptores de Progesterona/agonistas , Endometriose/epidemiologia , Endometriose/metabolismo , Endométrio/anormalidades , Feminino , Fármacos para a Fertilidade Feminina/uso terapêutico , Humanos , Doenças Peritoneais/epidemiologia , Doenças Peritoneais/metabolismo , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Receptores de Progesterona/metabolismo , Resultado do Tratamento , Doenças Uterinas/tratamento farmacológico
20.
Phytomedicine ; 69: 153193, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32120245

RESUMO

BACKGROUND: Although mechanical barriers and modern surgical techniques have been developed to prevent postoperative adhesion formation, high incidence of adhesions still represents an important challenge in abdominal surgery. So far, there has been no available therapeutic drug in clinical practice. PURPOSE: In this study, we explored the efficacy of sodium aescinate (AESS) treatment against postoperative peritoneal adhesions, the potential molecular mechanism was also investigated. STUDY DESIGN AND METHODS: Sixty male Sprague-Dawley rats were randomly divided into 6 groups for the study: the blank, vehicle, positive control and three AESS administration groups (0.5, 1 and 2 mg/kg/d, intravenous administration for 7 days). Adhesions were induced by discretely ligating peritoneal sidewall. An IL-1ß-induced HMrSV5 cell model was also performed to explore possible functional mechanism. RESULTS: The results indicated that the incidence and severity of peritoneal adhesions were significantly lower in the AESS-treated groups than that in the vehicle and positive control group. AESS-treated groups showed that the secretion, activity, and expression of tPA in rat peritoneum were notably increased. The FIB levels in rat plasma were decreased. The immunohistochemical staining analysis demonstrated that collagen I and α-SMA deposition were significantly attenuated in AESS-treated peritoneal tissues. Besides, we found that AESS treatment reduced the protein levels of p-MYPT1. To further explore the mechanisms of AESS, both activator and inhibitors of RhoA/ROCK pathway were employed in this study. It was found that AESS-induced up-regulation of tPA was reversed by activator of ROCK, but the effects of ROCK inhibitors were consistent with AESS. CONCLUSION: Taken together, the findings of in vivo and in vitro experiments proved that AESS could significantly suppress postoperative peritoneal adhesion formation through inhibiting the RhoA/ROCK signaling pathway. Our researches provide important pharmacological basis for AESS development as a potential therapeutic agent on peritoneal adhesions.


Assuntos
Doenças Peritoneais/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Saponinas/farmacologia , Triterpenos/farmacologia , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Linhagem Celular , Colágeno Tipo I/metabolismo , Fibrinogênio/metabolismo , Humanos , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Masculino , Doenças Peritoneais/patologia , Doenças Peritoneais/prevenção & controle , Peritônio/citologia , Peritônio/cirurgia , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/prevenção & controle , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Aderências Teciduais
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