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1.
Eur J Clin Invest ; 53(3): e13899, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36346481

ABSTRACT

BACKGROUND: Dysregulated hyaluronic acid (HA) metabolism has been shown to be implicated in several pathologies including endometriosis. 4-Methylumbelliferone (4MU) is an HA synthesis inhibitor with proven antitumour activity. In this study, we aim to evaluate the effect of 4MU on endometriosis development both in vivo and in vitro. METHODS: Endometriosis was surgically induced by uterine tissue auto-transplantation in 32 two-month-old BALB/c mice. Animals were designated into the early or late starting treatment group, which initiated on day 2 or day 15 after surgery, respectively. Within each group, 4MU 200 mg/kg/day or vehicle (Control) were administered by oesophageal gavage for 28 days. After sacrifice, the percentage of developed lesions, lesion size, cell proliferation, vascularization and HA deposition within the endometriotic-like lesions were evaluated. Cell viability was assessed in endometrial epithelial cells (ECC-1) and in endometrial stromal cells (t-HESC); and migration was evaluated in t-HESC. RESULTS: There was a significant reduction in the percentage of developed lesions in mice that started the 4MU treatment on day 2 compared with its respective control group, and compared with those that started treatment on day 15. However, no significant changes were found when analysing endometriotic-like lesion's cell proliferation, vascularization and HA deposition. In vitro, both cell viability and migration were inhibited by 4MU treatment. CONCLUSIONS: The inhibition of HA synthesis could be a beneficial and alternative option to treat endometriosis at the early stage of the disease. Further research is necessary to elucidate 4MU's mechanism of action and better strategies for delivering this promising drug.


Subject(s)
Endometriosis , Humans , Female , Mice , Animals , Endometriosis/drug therapy , Endometriosis/metabolism , Endometriosis/pathology , Hyaluronic Acid/pharmacology , Hyaluronic Acid/therapeutic use , Uterus/metabolism , Uterus/pathology , Neovascularization, Pathologic , Epithelial Cells/metabolism , Cell Proliferation
2.
Food Funct ; 12(20): 9894-9903, 2021 Oct 19.
Article in English | MEDLINE | ID: mdl-34664592

ABSTRACT

Endometriosis is an often painful disease in reproductive-aged women, in which endometrial-like tissue grows outside the uterine cavity. Since the limited current therapeutic alternatives fail in alleviating the symptoms and based on our previous research in in vitro models using the same compounds as the ones used in the present study, we aimed to evaluate the effects of urolithins A (UA) and B (UB) on the growth and survival of endometriotic-like lesions in a murine model of endometriosis. Female BALB/C mice were surgically induced with endometriosis and treated with 2.5 mg kg-1 day-1 intraperitoneal UA or UB. The mice were monitored daily and weighed and the estrous stage was determined. After 28 days of treatment, lesions were counted, measured, excised, and fixed. Both urolithins proved not to affect the estrous cycle or body weight of the mice. UA completely prevented endometriotic-like lesions, while UB diminished the implant volume (p < 0.05). Treatment also reduced epithelial and stromal cell proliferation within the implants (p < 0.001 and p < 0.01, respectively) and apoptosis was enhanced (p < 0.05 and p < 0.01, respectively). These results are promising and reveal that urolithins A and B, separately, have a beneficial effect on the overall endometriotic growth without affecting the body weight or estrous cycle.


Subject(s)
Coumarins/pharmacology , Endometriosis/drug therapy , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Endometriosis/metabolism , Endometriosis/pathology , Endometrium/metabolism , Endometrium/pathology , Estrous Cycle/drug effects , Female , Humans , Mice , Mice, Inbred BALB C
3.
Reprod Biomed Online ; 37(6): 769-782, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30446309

ABSTRACT

RESEARCH QUESTION: Can carnosic acid, (CA) rosmarinic acid (RA) and wogonin (WG) inhibit the growth of cultured human endometrial stromal cells and endometriotic-like lesions induced in a BALB/c model of endometriosis? DESIGN: Primary stromal cell cultures were established from endometrial biopsies from women with endometriosis and controls. The human endometrial stromal cell line T-HESC was also used for in-vitro experiments. Endometriosis was surgically induced in BALB/c mice, which were randomly assigned to CA 2 mg/kg/day (n = 11); CA 20 mg/kg/day (n = 10); RA 1 mg/kg/day (n = 11); RA 3 mg/kg/day (n = 10); WG 20 mg/kg/day (n = 12); intraperitoneal vehicle control (n = 8) or oral vehicle control (n = 11). After surgery, CA and RA were administered intraperitoneally on days 14-28. WG was administered orally by intragastric gavage on days 14-26. RESULTS: CA, RA and WG significantly inhibited in-vitro cell proliferation in primary and T-HESC cell cultures (P < 0.05). CA and WG induced cell cycle arrest of T-HESC at the G2/M phase (P < 0.01). RA reduced intracellular ROS accumulation (P < 0.001), whereas WG increased it (P < 0.05). WG significantly inhibited oestrogen receptor alpha expression in T-HESC (P < 0.01). In-vivo, CA, RA and WG significantly reduced lesions size (P < 0.05). All compounds significantly decreased the percentage of cells in proliferation (P < 0.05) whereas RA and WG further increased the percentage of apoptotic cells (P < 0.05) in endometriotic-like lesions. CONCLUSIONS: The results are promising; further investigation of these compounds as new therapeutics is needed.


Subject(s)
Abietanes/pharmacology , Cinnamates/pharmacology , Depsides/pharmacology , Endometriosis/drug therapy , Flavanones/pharmacology , Rosmarinus/chemistry , Scutellaria baicalensis/chemistry , Abietanes/chemistry , Abietanes/therapeutic use , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Cinnamates/chemistry , Cinnamates/therapeutic use , Depsides/chemistry , Depsides/therapeutic use , Endometriosis/pathology , Female , Flavanones/chemistry , Flavanones/therapeutic use , Humans , Mice , Mice, Inbred BALB C , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Leaves/chemistry , Plant Roots/chemistry , Rosmarinic Acid
4.
PLoS One ; 10(4): e0124900, 2015.
Article in English | MEDLINE | ID: mdl-25915402

ABSTRACT

OBJECTIVES: To evaluate the effect of endometriosis on fertility and the levels of the IL-2 and IFN-γ in the peritoneal fluid in a mouse model; to evaluate the effect of pregnancy on endometriotic lesion growth, apoptosis and cell proliferation. STUDY DESIGN: Two month old C57BL/6 female mice underwent either a surgical procedure to induce endometriosis or a sham surgery. Four weeks after surgery mice were mated and sacrificed at day 18 of pregnancy. Number of implantation sites, fetuses and fetal weight were recorded. Endometriotic lesions were counted, measured, excised and fixed. Apoptosis and cell proliferation were evaluated in lesions by TUNEL and immunohistochemistry for PCNA respectively. Levels of IL-2 and IFN-γ were assessed by ELISA in the peritoneal fluid. RESULTS: Pregnancy rate (i.e. pregnant mice/N) decreased in mice with endometriosis. However there were no significant differences in resorption rate, litter size and pup weight between groups. IFN-γ augmented in endometriosis mice independently of pregnancy outcome. Additionally IFN-γ increased in pregnant endometriosis mice compared to pregnant sham animals. While IFN-γ increased in non pregnant versus pregnant mice in the sham group, IL-2 was increased in non pregnant mice in the endometriosis group. The size of endometriotic lesions increased in pregnant mice while apoptosis increased in the stroma and cell proliferation decreased in the epithelium of these lesions. Additionally, leukocyte infiltration, necrosis and decidualization were increased in the same lesions. CONCLUSIONS: Pregnancy rate is reduced in this mouse model of endometriosis. Levels of IL-2 are increased in the peritoneal fluid of mice with endometriosis suggesting a role of this cytokine in infertility related to this disease. The size of endometriotic lesions is increased in pregnant mice; however pregnancy has a beneficial effect on lesions by decreasing cell proliferation and by increasing apoptosis, decidualization and necrosis.


Subject(s)
Endometriosis/complications , Infertility, Female/etiology , Pregnancy Complications/etiology , Animals , Ascitic Fluid/metabolism , Endometriosis/metabolism , Endometriosis/pathology , Female , Infertility, Female/metabolism , Infertility, Female/pathology , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-2/genetics , Interleukin-2/metabolism , Mice , Mice, Inbred C57BL , Necrosis , Pregnancy , Pregnancy Complications/metabolism , Pregnancy Complications/pathology
5.
Reprod Sci ; 18(7): 614-22, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21266664

ABSTRACT

The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P < .05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P < .01), reduced vascular density (P < .001), as well as increased the apoptotic cell percentage (P < .001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P < .05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Antibodies, Monoclonal/pharmacology , Endometriosis/drug therapy , Endometriosis/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized , Antigens, CD34 , Ascitic Fluid/cytology , Ascitic Fluid/metabolism , Bevacizumab , Cell Proliferation/drug effects , Disease Models, Animal , Female , In Situ Nick-End Labeling , Mice , Mice, Inbred BALB C , Neovascularization, Pathologic/metabolism , Proliferating Cell Nuclear Antigen/metabolism , Vascular Endothelial Growth Factor A/metabolism
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