Endometrial expression and in vitro modulation of the iron transporter divalent metal transporter-1: implications for endometriosis

Alvarado-Díaz, Carlos Patricio; Núñez, Marco T.; Devoto, Luigi; González-Ramos, Reinaldo

doi:10.1016/j.fertnstert.2016.04.002

Cited by 14 publications

(13 citation statements)

References 76 publications

(99 reference statements)

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“…When their clearance ability is overwhelmed, and in the presence of an excess of free radicals, peripheral macrophages generate, through NF‐κB, multiple inflammatory signals supporting the recruitment of further phagocytes at the site. These events might be specifically involved in the persisting inflammatory status of endometriotic lesions, in which the endometrial tissue still responds to normal hormonal signals, but menstrual blood cannot be eliminated by the normal process of physiological shedding . Generally, oxidative injury occurs when continued delivery of iron to the peritoneal macrophages is associated with inhibition of iron storage in ferritin .…”

Section: Conditions In Which Inflammatory Triggers Are Not Eliminatedmentioning

confidence: 99%

The peritoneum: healing, immunity, and diseases

Capobianco

Cottone

Monno

et al. 2017

The Journal of Pathology

120

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The peritoneum defines a confined microenvironment, which is stable under normal conditions, but is exposed to the damaging effect of infections, surgical injuries, and other neoplastic and non-neoplastic events. Its response to damage includes the recruitment, proliferation, and activation of a variety of haematopoietic and stromal cells. In physiological conditions, effective responses to injuries are organized; inflammatory triggers are eliminated; inflammation quickly abates; and the normal tissue architecture is restored. However, if inflammatory triggers are not cleared, fibrosis or scarring occurs and impaired tissue function ultimately leads to organ failure. Autoimmune serositis is characterized by the persistence of self-antigens and a relapsing clinical pattern. Peritoneal carcinomatosis and endometriosis are characterized by the persistence of cancer cells or ectopic endometrial cells in the peritoneal cavity. Some of the molecular signals orchestrating the recruitment of inflammatory cells in the peritoneum have been identified in the last few years. Alternative activation of peritoneal macrophages was shown to guide angiogenesis and fibrosis, and could represent a novel target for molecular intervention. This review summarizes current knowledge of the alterations to the immune response in the peritoneal environment, highlighting the ambiguous role played by persistently activated reparative macrophages in the pathogenesis of common human diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Conditions In Which Inflammatory Triggers Are Not Eliminatedmentioning

confidence: 99%

The peritoneum: healing, immunity, and diseases

Capobianco

Cottone

Monno

et al. 2017

The Journal of Pathology

120

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“…At the same time, excess iron can act as a catalyst to promote the production of a range of free-radical components through the Fenton reaction, mediating oxidative damage to normal tissue cells. In turn, the inflammatory environment brought about by iron overload and oxidative damage enhance the expression of divalent metal transporter-1 and others in the endometrium of EM patients, leading to the further development of EM [ 26 ]. The current study can be summarized in two ways.…”

Section: Discussionmentioning

confidence: 99%

Huayu Jiedu Fang Protects Ovarian Function in Mouse with Endometriosis Iron Overload by Inhibiting Ferroptosis

Ding

Zhao

Zhou

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Endometriosis (EM) is a common chronic inflammatory disease in women. Sampson’s retrograde menstruation theory is the most widely accepted theory of EM pathogenesis. The periodic bleeding of ectopic lesions is an important pathological feature of this disease, and the occurrence and progression of EM are closely associated with the iron overload caused by ectopic lesions. However, animal models that simulate menstrual-blood reflux and hemorrhage from EM lesions are lacking. In this study, we performed intraperitoneal injection of endometrial fragments and periodic intraperitoneal blood injection to simulate the real cause and disease state of EM and successfully constructed a mouse model of EM iron overload. Our research found that the number, size, and degree of adhesion of EM lesions in the iron-overload model mouse were significantly higher than those in the model mouse. Moreover, the iron concentration in the abdominal fluid and ovary significantly increased, and the level of malondialdehyde (MDA) in the ovary increased. Conversely, GPX4, GSH, and other anti-ferroptosis-related proteins were downregulated, proving the occurrence of ferroptosis. Huayu Jiedu Fang (HYJDF) is an empirical prescription for EM treatment. This study combined animal experiments, UHPLC-QE-MS analysis, and network pharmacology to analyze whether HYJDF can inhibit ferroptosis to slow down the progression of EM and protect ovarian function. Based on the constructed iron-overload model, HYJDF can reduce the volume of EM lesions and the degree of adhesion, downregulate the total iron concentration in the peritoneal fluid and ovary, upregulate GPX4 expression and GSSG in the ovary, downregulate the level of MDA in the ovary, and promote the development of follicles. We further confirmed that HYJDF can inhibit the progression of EM disease and improve the ovarian function of the model mouse by inhibiting ferroptosis. Finally, through UHPLC-QE-MS and network pharmacology analysis, the natural compounds in HYJDF were identified and verified and the regulatory effect of HYJDF on the EM ferroptosis pathway through the IL-6/hepcidin pathway was preliminarily elucidated.

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“…The presence of iron conglomerates in endometriotic lesions inducing oxidative stress in the pelvic cavity may play a crucial role not only in endometriosis pathogenesis but also in disease progression [40][41][42][43]. Iron overload activates proinflammatory signaling, such as NFkB and interleukin (IL)-1β, and triggers proliferation through cell cycle progression [86,87]. Iron chelators have been shown to mitigate iron overload effects, including excessive proliferation, serving as potential treatment options for cancer therapy [88,89] (Table 1).…”

Section: Iron Overloadmentioning

confidence: 99%

Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets?

Cacciottola

Donnez

Dolmans

2021

IJMS

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Endometriosis is a disease of reproductive age characterized by chronic pelvic pain and infertility. Its pathogenesis is complex and still partially unexplained. However, there is increasing evidence of the role of chronic inflammation, immune system dysregulation, and oxidative stress in its development and progression. The latter appears to be involved in multiple aspects of the disease. Indeed, disease progression sustained by a hyperproliferative phenotype can be related to reactive oxygen species (ROS) imbalance, as numerous experiments using drugs to counteract hyperproliferation have shown in recent years. Chronic pelvic pain is also associated with cell function dysregulation favoring chronic inflammation and oxidative stress, specifically involving macrophages and mast cell activation. Moreover, there is increasing evidence of a role for ROS and impaired mitochondrial function not only as deleterious effectors of the ovarian reserve in patients with endometriomas but also in terms of oocyte quality and, hence, embryo development impairment. Targeting oxidative stress looks to be a promising strategy to both curb endometriotic lesion progression and alleviate endometriosis-associated symptoms of chronic pain and infertility. More investigations are nevertheless needed to develop effective therapeutic strategies for clinical application.

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Endometrial expression and in vitro modulation of the iron transporter divalent metal transporter-1: implications for endometriosis

Cited by 14 publications

References 76 publications

The peritoneum: healing, immunity, and diseases

The peritoneum: healing, immunity, and diseases

Huayu Jiedu Fang Protects Ovarian Function in Mouse with Endometriosis Iron Overload by Inhibiting Ferroptosis

Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets?

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