Combating endometriosis by blocking proteasome and nuclear factor- B pathways

Çelik, Önder; Hasçalık, Şeyma; Elter, Koray; Tağluk, M. Emin; Gürateş, Bilgin; Aydın, Engin

doi:10.1093/humrep/den246

Cited by 55 publications

(56 citation statements)

References 38 publications

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“…Upcoming experiments will study the interactions of the sperm proteasome with MFGE8, spermadhesins, and other acrosomal proteins that copurify with sperm proteasomes. In addition to the study of fertilization, the PSMA1-GFP pig model might be used to study a variety of reproductive technologies and disorders, such as germ cell transplantation (38), ovarian/oocyte function (39), and endometriosis (40). The transgenic animal model described in the present study is available through the National Institutes of Health-sponsored NSRRC and may be used to study the functioning of the UPS in a variety of cellular pathways and pathologies, such as Alzheimer's disease, Huntington disease, Parkinson disease, cancer, immune and inflammatory disorders, and liver cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Transgenic pig carrying green fluorescent proteasomes

Miles

O’Gorman

Zhao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Among its many functions, the ubiquitin-proteasome system regulates substrate-specific proteolysis during the cell cycle, apoptosis, and fertilization and in pathologies such as Alzheimer's disease, cancer, and liver cirrhosis. Proteasomes are present in human and boar spermatozoa, but little is known about the interactions of proteasomal subunits with other sperm proteins or structures. We have created a transgenic boar with green fluorescent protein (GFP) tagged 20S proteasomal core subunit α-type 1 (PSMA1-GFP), hypothesizing that the PSMA1-GFP fusion protein will be incorporated into functional sperm proteasomes. Using direct epifluorescence imaging and indirect immunofluorescence detection, we have confirmed the presence of PSMA1-GFP in the sperm acrosome. Western blotting revealed a protein band corresponding to the predicted mass of PSMA1-GFP fusion protein (57 kDa) in transgenic spermatozoa. Transgenic boar fertility was confirmed by in vitro fertilization, resulting in transgenic blastocysts, and by mating, resulting in healthy transgenic offspring. Immunoprecipitation and proteomic analysis revealed that PSMA1-GFP copurifies with several acrosomal membrane-associated proteins (e.g., lactadherin/milk fat globule E8 and spermadhesin alanine-tryptophan-asparagine). The interaction of MFGE8 with PSMA1-GFP was confirmed through cross-immunoprecipitation. The identified proteasome-interacting proteins may regulate sperm proteasomal activity during fertilization or may be the substrates of proteasomal proteolysis during fertilization. Proteomic analysis also confirmed the interaction/coimmunoprecipitation of PSMA1-GFP with 13/14 proteasomal core subunits. These results demonstrate that the PSMA1-GFP was incorporated in the assembled sperm proteasomes. This mammal carrying green fluorescent proteasomes will be useful for studies of fertilization and wherever the ubiquitin-proteasome system plays a role in cellular function or pathology.

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Section: Discussionmentioning

confidence: 99%

Transgenic pig carrying green fluorescent proteasomes

Miles

O’Gorman

Zhao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…A study in p50 knockout mice showed a reduction in endometriotic implants size relative to endometriotic implants in wild type mice (84). Other animal studies have shown diminished endometriotic lesion development and cell proliferation in response to NFkB inhibition (71,80,85). In endometriotic cells in culture, inhibition of NF-kB reduced cell proliferation and stimulated apoptosis by down-regulating IL-8, macrophagemigration inhibitory factor, survivin, B-cell lymphoma/leukemia 2 (Bcl-2) and Bcl-XL (antiapoptotic proteins at the mitochondrial level), and by activating caspase 3, caspase 8, and caspase 9 (54,58,59,69,74,75).…”

Section: Nf-kb-regulated Cell Proliferation and Apoptosis In Endometrmentioning

confidence: 97%

“…Table 1 shows NF-kB-modulated genes (proteins) that have been shown to participate in endometriosis inflammatory reaction. Using NF-kB inhibitors in endometrial and endometriotic cell cultures and in endometriosis animal models has resulted in a reduction of the expression of most of the NF-kB-regulated cytokines mentioned in Table 1 (11,31,39,50,53,56,57,59,60,69,74,(77)(78)(79)(80)(81).…”

Section: Nf-kb-modulated Inflammation In Endometriosismentioning

confidence: 99%

Nuclear factor–kappaB: a main regulator of inflammation and cell survival in endometriosis pathophysiology

González-Ramos

Defrère

Devoto

2012

Fertility and Sterility

111

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“…It is believed that nuclear factor-kappa B (NF-kB) is a critical early regulator of the inflammatory response in endometriotic tissues (Celik et al 2008). Activation of NF-kB mediates cell proliferation and angiogenesis, which was observed through increases in the vascularized areas of newly-formed microvascular networks and the increased expression of cell proliferation markers in these endometriotic lesions (Wang et al 2005).…”

Section: Discussionmentioning

confidence: 99%

The Expression of Cyclophilin A in Ovarian Endometrioma: Its Correlation with Recurrence and Vascularity

Usta

Turan

Adalı

2017

Tohoku J. Exp. Med.

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Endometriosis is defined as the presence of functional endometrial tissues outside of the uterine cavity. Ovarian endometrioma is the most common type of endometriosis. It is an estrogen-dependent inflammatory disease that frequently causes infertility and chronic pelvic pain. Cyclophilin A (CyPA) is secreted from various types of cells in response to inflammatory stimuli. Many previous studies have shown that the increased expression and/or heightened plasma levels of CyPA exacerbates inflammation. The aim of this study is to evaluate CyPA immunoreactivity in ovarian endometrioma cyst wall. In this cross-sectional study, CyPA immunoreactivity in endometrial tissue samples obtained from uterine cavity and in endometrioma cyst walls of 44 consecutive women with ovarian endometrioma were compared with control endometrial tissue samples obtained from uterine cavity of 40 women without endometrioma. All endometrioma samples were confirmed via histopathological examination. Finally, the relationship between CyPA immunoreactivity and the clinicopathological findings related to endometrioma were evaluated. The CyPA expression rates in glandular cells, stromal cells, and the capillary endothelium were significantly higher in endometrioma cyst walls of women with ovarian endometrioma than in the control endometrial tissue of women without endometrioma (p = 0.0002, p = 0.0417 and p = 0.0067, respectively). The correlation analysis demonstrated that glandular CyPA expression was correlated with endometrioma recurrence (p = 0.0267). However, stromal and vascular endothelial CyPA expression were correlated with dysmenorrhea recurrence (p = 0.0023 and p = 0.0003, respectively). In conclusion, the increased expression of CyPA in ectopic endometrial tissue is associated with endometrioma recurrences and vascularity.

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Combating endometriosis by blocking proteasome and nuclear factor- B pathways

Abstract: PDTC and bortezomib may represent a novel therapeutic strategy for treatment of endometriosis.

Cited by 55 publications

References 38 publications

Transgenic pig carrying green fluorescent proteasomes

Transgenic pig carrying green fluorescent proteasomes

Nuclear factor–kappaB: a main regulator of inflammation and cell survival in endometriosis pathophysiology

The Expression of Cyclophilin A in Ovarian Endometrioma: Its Correlation with Recurrence and Vascularity

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