Mechanisms underlying the protective effect of montelukast in prevention of endometrial hyperplasia in female rats

Abdelzaher, Walaa Yehia; Bahaa, Haitham Ahmed; Toni, Nisreen D. M.; Sanad, Ahmad Sameer

doi:10.1016/j.intimp.2018.07.008

Cited by 14 publications

(4 citation statements)

References 40 publications

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“…Protein PTEN is a tumor suppressor protein; its loss in the endometrial tissue indicates cellular atypia in EH and endometrial carcinoma. 33 Here, PTEN expression was nearly lost in the uteri of the EV group while epithelial atypia was observed and vascularity increased; this is in line with Abdelzaher et al 16 The necessary role of PTEN in the development of complex atypical hyperplasia was assessed in our study by determining its downstream pathway PI3K/Akt. The current results revealed the upregulation of PI3K and Akt genes expression in the uteri of the EV group in line with Gao et al and their drop with febuxostat treatment.…”

Section: Discussionsupporting

confidence: 88%

“…The doses were selected according to our preliminary data and the previous published studies, respectively. 15,16 At the end of the experimental period, the animals were sacrificed by decapitation after anesthetized underuse of intraperitoneal injection of urethane hydrochloride (1 g/kg) anesthesia 17 and the uterus was gently dissected and cleaned with cold saline. Parts of the uterus were put in liquid nitrogen and then kept at À80 C for biochemical analysis.…”

Section: Methodsmentioning

confidence: 99%

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PTEN/PI3K/VEGF signaling pathway involved in the protective effect of xanthine oxidase inhibitor febuxostat against endometrial hyperplasia in rats

et al. 2020

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Endometrial hyperplasia (EH) is a medical condition that affects many females as it increases their uterine carcinogenic potential. EH results from entangling hormonal imbalance and inflammatory response. The study examined the role of a xanthine oxidase inhibitor, febuxostat, in a rat model of EH. Adult female Wistar albino rats were subjected to estradiol valerate (EV) 2 mg/kg for 10 days to induce EH. Another group was treated concomitantly with febuxostat 10 mg/kg for the same period. The uterine malondialdehyde, reduced glutathione (GSH), and superoxide dismutase (SOD) were assessed by chemical methods. Gene expressions of phosphatidylinositol-3-kinase (PI3K), Akt, and hypoxia-inducible factor 1 alpha were assessed by the quantitative real-time polymerase chain reaction. Moreover, the vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay. Histopathology and immunohistochemical techniques were used for the detection of phosphatase and tensin homolog (PTEN). The results revealed that EV administration induced complex EH with focal atypia and loss of PTEN expression by the histological examination. Uteri of the EV group showed a significant drop in GSH content and SOD activity and rise in the expressions of PI3K, Akt, VEGF, and IL-6. Febuxostat administration significantly improved the uterine GSH and SOD levels. It decreased the expressions of PI3K, Akt, VEGF, and IL-6. The endometrium showed a regression of the proliferative epithelium with the restoration of PTEN expression and the absence of the atypical features. In conclusion, febuxostat protected the endometrium against estrogen-induced EH and may be beneficial in the management along with the hormonal therapy.

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

PTEN/PI3K/VEGF signaling pathway involved in the protective effect of xanthine oxidase inhibitor febuxostat against endometrial hyperplasia in rats

et al. 2020

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“…TNFα can contribute to the pathogenesis of EB-induced EH through induction of oxidative stress [ 35 ], generation of angiogenic factors [ 36 ], increase estrogen production [ 37 ], and activation of NF-κB-induced anti-apoptotic genes (Bcl-2 and survivin), inflammatory responses, and cyclooxygenase-2 [ 4 ]. In the present study, the increase in uterine TNFα is in harmony with the results of Abdelzaher et al [ 38 ] who reported a significant increase in TNFα in estradiol valerate-induced EH in rats. In contrast, the expression of the IL10 gene did not change in patients with EH [ 39 ], although in the current study, EH was associated with decreased IL10 expression.…”

Section: Discussionsupporting

confidence: 92%

Protective Effects of Irbesartan, an Angiotensin Receptor Blocker with PPARγ Agonistic Activity, against Estradiol Benzoate-Induced Endometrial Hyperplasia and Atypia in Female Rats via Modulation of TNFα/Survivin Pathway

et al. 2021

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Endometrial hyperplasia (EH) is a common gynecological problem and may progress to carcinoma. Early detection and management of EH are mandatory for the prevention of endometrial cancer. Activation of the renin–angiotensin system and angiotensin II signaling are involved in the progression of precancerous and cancerous lesions. However, no studies have evaluated the role of this system in estradiol benzoate (EB)-induced EH and atypia. Irbesartan (IRB), an angiotensin II receptor blocker with peroxisome proliferator-activated receptor gamma (PPARγ) agonistic activity was administered (30 mg/kg/d) in EB-treated (60 µg/100 g bodyweight, intramuscularly, three times per week) or untreated rats for 4 weeks. Uterine weight changes, malondialdehyde, superoxide dismutase (SOD), tumor necrosis factor-alpha (TNFα), survivin, cleaved caspase 3, interleukin-10 (IL10), and PPARγ were measured in addition to undergoing histopathological examination. Results showed that EB-induced EH and atypia significantly increased the uterine body weight, malondialdehyde, TNFα, and survivin, accompanied with significantly decreased SOD, cleaved caspase 3, IL10, and PPARγ, with typical histopathological changes of EH and atypia. Coadministration of IRB significantly prevented EB-induced biochemical and histopathological changes. The protective effects of IRB may be attributed to its anti-inflammatory and antioxidant properties, reduction of survivin, and increased levels of cleaved caspase 3.

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“…The dose of OV was chosen based on our preliminary study and literature search. [19][20][21] Plant material M. indica leaves were purchased and authenticated at the Botany Department, University of Ibadan, Nigeria, with voucher number UIH 22555.…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

Amelioration of oestradiol valerate-induced endometrial hyperplasia in female rats by methanol fraction ofMangifera indicaLinn. through modulation of oestrogen receptor signalling pathway

Olowofolahan

Tobih

Olorunsogo

2021

IJPP

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Objectives: Mangifera indica is a medicinal plant that is folklorically used in the treatment of certain disorders connected with women reproductive organs, especially, uterine fibroids. This study investigated the effect of methanol fraction of M. indica (MFMI) extract on oestradiol valerate (OV)-induced endometrial hyperplasia (EH). Materials and Methods: The animals were randomly divided into four groups of seven rats each. These include a control group, an MFMI-alone group, a model (OV-alone) group and MFMI treatment (OV+MFMI) group. The EH was induced by intraperitoneal injection of OV. The levels of oestrogen (E2), progesterone (PG) and total cholesterol (TC) were determined using ELISA technique. The uterine histological and immunohistochemical assessments of oestrogen receptor, β-catenin and Ki-67 were carried out. Fibroblast cell count/μm2 using histomorphometry as well as gas chromatography–mass spectrometry (GCMS) analysis of MFMI was carried out. Results: Severe EH was induced on oestradiol valerate administration. The MFMI was able to improve the pathological features of the animal model. Furthermore, the levels of oestrogen, PG and TC were reduced by MFMI. The immune reactive expression of oestrogen receptor alpha, β-catenin and Ki-67 was downregulated by MFMI coadministration. The histomorphometric analysis of the fibroblast cell count/μm2 showed increased cell count density in the OV-treated group which was significantly ameliorated by MFMI coadministration. The GC– MS analysis revealed the presence of some pharmacologically relevant phytochemicals. Conclusion: This study suggests that MFMI contains phytochemicals that can ameliorate OV-induced EH in female Wistar and the possible mechanism of action involves modulation of oestrogen signalling pathway.

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Mechanisms underlying the protective effect of montelukast in prevention of endometrial hyperplasia in female rats

Cited by 14 publications

References 40 publications

PTEN/PI3K/VEGF signaling pathway involved in the protective effect of xanthine oxidase inhibitor febuxostat against endometrial hyperplasia in rats

PTEN/PI3K/VEGF signaling pathway involved in the protective effect of xanthine oxidase inhibitor febuxostat against endometrial hyperplasia in rats

Protective Effects of Irbesartan, an Angiotensin Receptor Blocker with PPARγ Agonistic Activity, against Estradiol Benzoate-Induced Endometrial Hyperplasia and Atypia in Female Rats via Modulation of TNFα/Survivin Pathway

Amelioration of oestradiol valerate-induced endometrial hyperplasia in female rats by methanol fraction ofMangifera indicaLinn. through modulation of oestrogen receptor signalling pathway

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