An integral role of mitochondrial function in the pathophysiology of preeclampsia.

Preeclampsia (PE) is associated with high maternal and perinatal morbidity and mortality. The development of effective treatment strategies remains a major challenge due to the limited understanding of the pathogenesis. In this review, we summarize the current understanding of PE research, focusing on the molecular basis of mitochondrial function in normal and PE placentas, and discuss perspectives on future research directions. Mitochondria integrate numerous physiological processes such as energy production, cellular redox homeostasis, mitochondrial dynamics, and mitophagy, a selective autophagic clearance of damaged or dysfunctional mitochondria. Normal placental mitochondria have evolved innovative survival strategies to cope with uncertain environments (e.g., hypoxia and nutrient starvation). Cytotrophoblasts, extravillous trophoblast cells, and syncytiotrophoblasts all have distinct mitochondrial morphology and function. Recent advances in molecular studies on the spatial and temporal changes in normal mitochondrial function are providing valuable insight into PE pathogenesis. In PE placentas, hypoxia-mediated mitochondrial fission may induce activation of mitophagy machinery, leading to increased mitochondrial fragmentation and placental tissue damage over time. Repair mechanisms in mitochondrial function restore placental function, but disruption of compensatory mechanisms can induce apoptotic death of trophoblast cells. Additionally, molecular markers associated with repair or compensatory mechanisms that may influence the development and progression of PE are beginning to be identified. However, contradictory results have been obtained regarding some of the molecules that control mitochondrial biogenesis, dynamics, and mitophagy in PE placentas. In conclusion, understanding how the mitochondrial morphology and function influence cell fate decisions of trophoblast cells is an important issue in normal as well as pathological placentation biology. Research focusing on mitochondrial function will become increasingly important for elucidating the pathogenesis and effective treatment strategies of PE.

Role of the mitophagy-apoptosis axis in the pathogenesis of polycystic ovarian syndrome.

AIM: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by menstrual irregularities, androgen excess, and polycystic ovarian morphology, but its pathogenesis remains largely unknown. This review focuses on how androgen excess influences the molecular basis of energy metabolism, mitochondrial function, and mitophagy in granulosa cells and oocytes, summarizes our current understanding of the pathogenesis of PCOS, and discuss perspectives on future research directions. METHODS: A search of PubMed and Google Scholar databases were used to identify relevant studies for this narrative literature review. RESULTS: Female offspring born of pregnant animals exposed to androgens recapitulates the PCOS phenotype. Abnormal mitochondrial morphology, altered expression of genes related to glycolysis, mitochondrial biogenesis, fission/fusion dynamics, and mitophagy have been identified in PCOS patients and androgenic animal models. Androgen excess causes uncoupling of the electron transport chain and depletion of the cellular adenosine 5'-triphosphate pool, indicating further impairment of mitochondrial function. A shift toward mitochondrial fission restores mitochondrial quality control mechanisms. However, prolonged mitochondrial fission disrupts autophagy/mitophagy induction due to loss of compensatory reserve for mitochondrial biogenesis. Disruption of compensatory mechanisms that mediate the quality control switch from mitophagy to apoptosis may cause a disease phenotype. Furthermore, genetic predisposition, altered expression of genes related to glycolysis and oxidative phosphorylation, or a combination of these factors may also contribute to the development of PCOS. CONCLUSION: In conclusion, fetuses exposed to a hyperandrogenemic intrauterine environment may cause the PCOS phenotype possibly through disruption of the compensatory regulation of the mitophagy-apoptosis axis.

Current understanding of the pathogenesis of placenta accreta spectrum disorder with focus on mitochondrial function.

AIM: The refinement of assisted reproductive technology, including the development of cryopreservation techniques (vitrification) and ovarian stimulation protocols, makes frozen embryo transfer (FET) an alternative to fresh ET and has contributed to the success of assisted reproductive technology. Compared with fresh ET cycles, FET cycles were associated with better in vitro fertilization outcomes; however, the occurrence of pregnancy-induced hypertension, preeclampsia, and placenta accreta spectrum (PAS) was higher in FET cycles. PAS has been increasing steadily in incidence as a life-threatening condition along with cesarean rates worldwide. In this review, we summarize the current understanding of the pathogenesis of PAS and discuss future research directions. METHODS: A literature search was performed in the PubMed and Google Scholar databases. RESULTS: Risk factors associated with PAS incidence include a primary defect of the decidua basalis or scar dehiscence, aberrant vascular remodeling, and abnormally invasive trophoblasts, or a combination thereof. Freezing, thawing, and hormone replacement manipulations have been shown to affect multiple cellular pathways, including cell proliferation, invasion, epithelial-to-mesenchymal transition (EMT), and mitochondrial function. Molecules involved in abnormal migration and EMT of extravillous trophoblast cells are beginning to be identified in PAS placentas. Many of these molecules were also found to be involved in mitochondrial biogenesis and dynamics. CONCLUSION: The etiology of PAS may be a multifactorial genesis with intrinsic predisposition (e.g., placental abnormalities) and certain environmental factors (e.g., defective decidua) as triggers for its development. A distinctive feature of this review is its focus on the potential factors linking mitochondrial function to PAS development.

Molecular mechanism of autophagy and apoptosis in endometriosis: Current understanding and future research directions.

Background: Endometriosis is a common gynecological condition, with symptoms including pain and infertility. Regurgitated endometrial cells into the peritoneal cavity encounter hypoxia and nutrient starvation. Endometriotic cells have evolved various adaptive mechanisms to survive in this inevitable condition. These adaptations include escape from apoptosis. Autophagy, a self-degradation system, controls apoptosis during stress conditions. However, to date, the mechanisms regulating the interplay between autophagy and apoptosis are still poorly understood. In this review, we summarize the current understanding of the molecular characteristics of autophagy in endometriosis and discuss future therapeutic challenges. Methods: A search of PubMed and Google Scholar databases were used to identify relevant studies for this narrative literature review. Results: Autophagy may be dynamically regulated through various intrinsic (e.g., PI3K/AKT/mTOR signal transduction network) and extrinsic (e.g., hypoxia and iron-mediated oxidative stress) pathways, contributing to the development and progression of endometriosis. Upregulation of mTOR expression suppresses apoptosis via inhibiting the autophagy pathway, whereas hypoxia or excess iron often inhibits apoptosis via promoting autophagy. Conclusion: Endometriotic cells may have acquired antiapoptotic mechanisms through unique intrinsic and extrinsic autophagy pathways to survive in changing environments.

Tissue factor pathway inhibitor 2: Current understanding, challenges, and future perspectives.

AIM: Tissue factor pathway inhibitor 2 (TFPI2) is a structural homolog of tissue factor pathway inhibitor 1 (TFPI1). Since TFPI2 is a placenta-derived protein, dynamic changes in TFPI2 levels may be related to pregnancy-related diseases. Furthermore, TFPI2 has been reported to be a novel serum biomarker for detecting ovarian cancer, especially clear cell carcinoma (CCC). This review aims to summarize the current knowledge on the biological function of TFPI2, highlight the major challenges that remain to be addressed, and discuss future research directions. METHODS: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this review. We also provide novel complementary information to what is known about the action of TFPI2. RESULTS: Since TFPI2 concentrations in the blood of pregnant women, preeclampsia patients, and cancer patients vary greatly, its pathophysiological functions have attracted attention. Downregulation of TFPI2, a tumor-suppressor gene, by hypermethylation may contribute to the progression of several cancers. On the other hand, TFPI2 overexpressed in CCC is a risk factor for the development of thrombosis, possibly through inhibition of plasmin activity. However, agreement on the biological function of TFPI2 is still lacking and there are many scientific questions to be addressed. In particular, the lack of international standardization for the quantification of TFPI2 concentrations makes it difficult for researchers and clinicians to evaluate, pool, and compare data from different studies across countries. DISCUSSION: This review summarizes current understandings and challenges in TFPI2 research and discusses future perspectives.

The role of mitochondrial dynamics in the pathophysiology of endometriosis.

AIM: Endometriosis is a chronic disease of reproductive age, associated with pelvic pain and infertility. Endometriotic cells adapt to changing environments such as oxidative stress and hypoxia in order to survive. However, the underlying mechanisms remain to be fully elucidated. In this review, we summarize our current understanding of the pathogenesis of endometriosis, focusing primarily on the molecular basis of energy metabolism, redox homeostasis, and mitochondrial function, and discuss perspectives on future research directions. METHODS: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this narrative literature review. RESULTS: Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production and cellular redox homeostasis. Under hypoxia, endometriotic cells favor glycolysis and actively produce pyruvate, nicotinamide adenine dinucleotide phosphate (NADPH), and other metabolites for cell proliferation. Mitochondrial fission and fusion dynamics may regulate the phenotypic plasticity of cellular energy metabolism, that is, aerobic glycolysis or OXPHOS. Endometriotic cells have been reported to have reduced mitochondrial numbers, increased lamellar cristae, improved energy efficiency, and enhanced cell proliferation and survival. Increased mitochondrial fission and fusion turnover by hypoxic and normoxic conditions suggests an activation of mitochondrial quality control mechanisms. Recently, candidate molecules that influence mitochondrial dynamics have begun to be identified. CONCLUSION: This review suggests that unique energy metabolism and redox homeostasis driven by mitochondrial dynamics may be linked to the pathophysiology of endometriosis. However, further studies are needed to elucidate the regulatory mechanisms of mitochondrial dynamics in endometriosis.

Clinicopathological characteristics and imaging findings to identify adenomyosis-related symptoms.

PURPOSE: The study aims to identify the clinicopathological risk factors and magnetic resonance (MR) imaging findings for adenomyosis-related symptoms, including menorrhagia, dysmenorrhea, and infertility. METHODS: This was an observation-based cross-sectional study using data from the adenomyosis cohort study. The authors evaluated the clinicopathological variables and various MR imaging findings. RESULTS: Two hundred twenty patients with histologically confirmed adenomyosis were included in this study. Multivariate analysis showed that a middle/retroflexed uterus and adenomyosis lesions of 21 mm or more were significant independent predictors of dysmenorrhea. The history of dysmenorrhea and the maximum length from the cervix to the uterine fundus ≥103 mm were independent risk factors of menorrhagia. One of the key factors associated with non-infertility included the absence of deep infiltrating endometriosis (DIE) and/or superficial peritoneal disease (SUP). CONCLUSIONS: This study identified clinicopathological risk factors and imaging findings associated with adenomyosis-related symptoms. The maximum length from the cervix to the uterine fundus and adenomyosis lesion thickness are independent predictors for the presence of menorrhagia and dysmenorrhea, respectively. Infertility may be associated with the coexistence of endometriosis rather than adenomyosis itself. This result is from an analysis of a small number of infertility patients and requires further study.

Skin-mucous membrane disorder and therapeutic effect of pegylated liposomal doxorubicin in recurrent ovarian cancer.

AIM: Hand-foot syndrome (HFS) induced by chemotherapy and molecule-targeting drugs is correlated with treatment efficacy. We conducted a retrospective analysis to evaluate the relationship between HFS and efficacy of pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer. METHODS: Patients were treated with PLD between July 2009 and May 2014. We evaluated patient characteristics, incidence of adverse events, clinical benefit (rate of complete response, partial response, and stable disease), progression-free survival, and overall survival. RESULTS: Twenty-seven patients were included in the study. Median age was 63 years (range, 41-77 years). The median number of cycles of PLD was 3 (range, 1-6). The clinical benefit rate was 33.3%, and progressive disease was noted in 18 patients (66.7%). Median overall survival was 6.7 months (range, 1.1-41 months). Compared with patients with grade 0/1 HFS and oral mucositis, patients with grade 2-4 toxicity (n = 9, 33.3%) had a significantly higher rate of clinical benefit (11.1% vs 77.7%; P < 0.001) and a longer median overall survival (3.7 months vs 20.8 months; P < 0.001). CONCLUSIONS: Severity of HFS and mucositis may be a predictive marker of PLD efficacy. The prevention and management of HFS and mucositis are important for continued treatment.

Design and Preclinical Validation of the Composite-Type Optical Fiberscope for Minimally Invasive Procedures of Intrauterine Disease.

STUDY OBJECTIVE: Because of the rapid growth of minimally invasive surgical procedures, we developed an ultrathin fiberscopic imaging system for laser surgery that could be an important instrument for clinical use in an office setting. METHODS AND MAIN RESULTS: A new device, consisting of a custom 1.1-mm diameter flexible fiberscope and ytterbium laser-supported ablation system (composite-type optical fiberscope), has been developed to achieve accurate laser irradiation for minimally invasive procedures of intrauterine disease. This system was validated ex vivo with successful laser ablation under observation. This study provides the design, characterization, performance, and preclinical validation of an optimized composite-type optical fiberscope system. The validation of this fiberscope for endometrial ablation was performed in 12 hysterectomy samples. The irradiated spot diameter and depth were (mean ± SD) 2.80 ± 0.28 mm and 1.53 ± 0.58 mm, respectively, in the range of 185 to 400 J. The effects of the laser on endometrial tissue depended strongly on the combined effects of the output power density and duration of irradiation. The new device makes it possible to perform accurate ablation, because our technology concentrated on combining the 2 subsystems into a single prototype capable of simultaneously observing both the endometrial lesion and the laser spot on a monitor. CONCLUSIONS: In conclusion, the feasibility and performance of the composite-type fiberscope system were demonstrated in preclinical studies.

Inhibition of cell death and induction of G2 arrest accumulation in human ovarian clear cells by HNF-1ß transcription factor: chemosensitivity is regulated by checkpoint kinase CHK1.

OBJECTIVE: Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1ß (HNF-1ß) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1ß in regulation of the cell cycle in CCA. METHODS: To clarify the effects of HNF-1ß on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1ß had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1ß (+) cells were arrested in G2 phase because of DNA damage. RESULTS: HNF-1ß (-) cells died because of a checkpoint mechanism. G2 arrest of HNF-1ß (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1ß (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage-induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. CONCLUSIONS: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1ß. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.

Towards an understanding of the molecular mechanism of endometriosis: unbalancing epithelial-stromal genetic conflict.

OBJECTIVES: Despite the high incidence of endometriosis, the etiology is poorly understood. Much work has been carried out to elucidate the genetic basis of endometriosis owing to the advent of genomic analysis and new network-based analysis methods. METHODS: This article reviews the English literature for (epi)genome-wide profiling and association studies on the pathogenesis and pathophysiology of endometriosis. RESULTS: The characteristic 82 up- and 45 down-regulated unique genes in endometriosis included genes encoding cell cycle, growth factors, signal transduction, transcription factors, hormones, cytokines, chemokines and (pro)inflammation, proteases, cell adhesion and motility, stress response and detoxification, immune response, metabolism and others. There appear to be at least two types of genes: some genes (n = 50) may evolve mainly for the benefit of the endometrial growth, and the other genes (n = 55) evolve as a protective mechanism for the endometrial decidualization. The present review has shed new light on the overlapping genetic signatures between endometriosis development and decidualization process. CONCLUSION: In conclusion, insufficient decidualization due to unbalancing epithelial-stromal genetic conflict may result in future endometriosis.

Predictor of mortality in patients with amniotic fluid embolism.

AIM: The purpose of this study was to evaluate the possibility of establishing predictors of mortality in women with amniotic fluid embolism. METHODS: Our previous report identified eight factors associated with amniotic fluid embolism (AFE) fatality: dyspnea, cardiac arrest, loss of consciousness, serum sialyl Tn greater than 47 U/mL, serum interleukin-8 greater than 100 pg/mL, vaginal delivery, multiparity and term delivery. The ratio of the number of positive fatal factors to the number of possible fatal factors in the same case was calculated as the abundance ratio, which was used because information regarding all eight factors was not retrievable for all the patients at the time of registration. The patient group was divided into four quartiles based on this abundance ratio, and the mortality rate in each quartile was compared with the overall mortality rate among the 130 patients with AFE enrolled between 1992 and 2006. The validity of this approach was confirmed in another dataset from a cohort of 38 patients with AFE in 2007. RESULTS: A statistically significant positive correlation was observed between the abundance ratio and the mortality in each quartile (P<0.01) for the patients with AFE enrolled between 1992 and 2006. This result was also found in the AFE patients enrolled in 2007 (P<0.05). Thus, an increased in the abundance ratio of the eight fatal factors resulted in an increased case fatality rate. CONCLUSION: These data suggested that the abundance ratio of fatal factors may be a useful predictor of mortality and therefore may be expected to improve prognostic accuracy in the future.

Altered Energy Metabolism, Mitochondrial Dysfunction, and Redox Imbalance Influencing Reproductive Performance in Granulosa Cells and Oocyte During Aging.

Female fertility decreases during aging. The development of effective therapeutic strategies to address the age-related decline in oocyte quality and quantity and its accurate diagnosis remain major challenges. In this review, we summarize our current understanding of the study of aging and infertility, focusing primarily on the molecular basis of energy metabolism, mitochondrial function, and redox homeostasis in granulosa cells and oocytes, and discuss perspectives on future research directions. Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production, cellular redox homeostasis, aging, and senescence. Young granulosa cells favor glycolysis and actively produce pyruvate, NADPH, and other metabolites. Oocytes rely on oxidative phosphorylation fueled by nutrients, metabolites, and antioxidants provided by the adjacent granulosa cells. A reduced cellular energy metabolism phenotype, including both aerobic glycolysis and mitochondrial respiration, is characteristic of older female granulosa cells compared with younger female granulosa cells. Aged oocytes become more susceptible to oxidative damage to cells and mitochondria because of further depletion of antioxidant-dependent ROS scavenging systems. Molecular perturbations of gene expression caused by a subtle change in the follicular fluid microenvironment adversely affect energy metabolism and mitochondrial dynamics in granulosa cells and oocytes, further causing redox imbalance and accelerating aging and senescence. Furthermore, recent advances in technology are beginning to identify biofluid molecular markers that may influence follicular development and oocyte quality. Accumulating evidence suggests that redox imbalance caused by abnormal energy metabolism and/or mitochondrial dysfunction is closely linked to the pathophysiology of age-related subfertility.

Role of autophagy and ferroptosis in the development of endometriotic cysts (Review).

It is considered that the etiology of endometriosis is retrograde menstruation of endometrial tissue. Although shed endometrial cells are constantly exposed to a challenging environment with iron overload, oxidative stress and hypoxia, a few cells are able to survive and continue to proliferate and invade. Ferroptosis, an iron­dependent form of non­apoptotic cell death, is known to play a major role in the development and course of endometriosis. However, few papers have concentrated on the dynamic interaction between autophagy and ferroptosis throughout the progression of diseases. The present review summarized the current understanding of the mechanisms underlying autophagy and ferroptosis in endometriosis and discuss their role in disease development and progression. For the present narrative review electronic databases including PubMed and Google Scholar were searched for literature published up to the October 31, 2023. Autophagy and ferroptosis may be activated at early stages in endometriosis development. On the other hand, excessive activation of intrinsic pathways (e.g., estrogen and mechanistic target of rapamycin) may promote disease progression through autophagy inhibition. Furthermore, suppression of ferroptosis may cause further progression of endometriotic lesions. In conclusion, the autophagy and ferroptosis pathways may play a dual role in disease initiation and progression. The present review discussed the temporal transition of non­apoptotic cell death regulation during disease progression from retrograde endometrium to early lesions to established lesions.

Tissue Factor Pathway Inhibitors as Potential Targets for Understanding the Pathophysiology of Preeclampsia.

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy that causes maternal and perinatal morbidity and mortality worldwide. Preeclampsia is associated with complex abnormalities of the coagulation and fibrinolytic system. Tissue factor (TF) is involved in the hemostatic system during pregnancy, while the Tissue Factor Pathway Inhibitor (TFPI) is a major physiological inhibitor of the TF-initiated coagulation cascade. The imbalance in hemostatic mechanisms may lead to a hypercoagulable state, but prior research has not comprehensively investigated the roles of TFPI1 and TFPI2 in preeclamptic patients. In this review, we summarize our current understanding of the biological functions of TFPI1 and TFPI2 and discuss future directions in preeclampsia research. METHODS: A literature search was performed from inception to 30 June 2022 in the PubMed and Google Scholar databases. RESULTS: TFPI1 and TFPI2 are homologues with different protease inhibitory activities in the coagulation and fibrinolysis system. TFPI1 is an essential physiological inhibitor of the TF-initiated extrinsic pathway of coagulation. On the other hand, TFPI2 inhibits plasmin-mediated fibrinolysis and exerts antifibrinolytic activity. It also inhibits plasmin-mediated inactivation of clotting factors and maintains a hypercoagulable state. Furthermore, in contrast to TFPI1, TFPI2 suppresses trophoblast cell proliferation and invasion and promotes cell apoptosis. TFPI1 and TFPI2 may play important roles in regulating the coagulation and fibrinolytic system and trophoblast invasion to establish and maintain successful pregnancies. Concentrations of TF, TFPI1, and TFPI2 in maternal blood and placental tissue are significantly altered in preeclamptic women compared to normal pregnancies. CONCLUSIONS: TFPI protein family may affect both the anticoagulant (i.e., TFPI1) and antifibrinolytic/procoagulant (i.e., TFPI2) systems. TFPI1 and TFPI2 may function as new predictive biomarkers for preeclampsia and navigate precision therapy.

Current Understanding of and Future Directions for Endometriosis-Related Infertility Research with a Focus on Ferroptosis.

BACKGROUND: To date, the development of therapy for endometriosis and disease-related infertility remains a major challenge. Iron overload caused by periodic bleeding is a hallmark of endometriosis. Ferroptosis is an iron- and lipid-reactive oxygen species-dependent type of programmed cell death that is distinct from apoptosis, necrosis, and autophagy. This review summarizes the current understanding of and future directions for the research and treatment of endometriosis and disease-related infertility, with the main focus on the molecular basis of ferroptosis in endometriotic and granulosa cells. METHODS: Papers published between 2000 and 2022 in the PubMed and Google Scholar databases were included in this review. RESULTS: Emerging evidence suggests that ferroptosis is closely linked to the pathophysiology of endometriosis. Endometriotic cells are characterized by ferroptosis resistance, whereas granulosa cells remain highly susceptible to ferroptosis, suggesting that the regulation of ferroptosis is utilized as an interventional target for research into the treatment of endometriosis and disease-related infertility. New therapeutic strategies are urgently needed to efficiently kill endometriotic cells while protecting granulosa cells. CONCLUSIONS: An analysis of the ferroptosis pathway in in vitro, in vivo, and animal research enhances our understanding of the pathogenesis of this disease. Here, we discuss the role of ferroptosis modulators as a research approach and potential novel treatment for endometriosis and disease-related infertility.

A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.

Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.

Molecular mechanisms linking endometriosis under oxidative stress with ovarian tumorigenesis and therapeutic modalities.

Inflammation plays a role in the pathogenesis of endometriosis. Endometriosis-associated ovarian carcinogenesis might be promoted through oxidative stress-induced increased genomic instability, aberrant methylation, and aberrant chromatin remodeling, as well as mutations of tumor suppressor genes. Aberrant expression of ARID1A, PIK3CA, and NF-kB genes has been recognized as the major target genes involved in oxidative stress-induced carcinogenesis. HNF-1beta appears to play a key role in anti-oxidative defense mechanisms. We discuss the pathophysiologic roles of oxidative stress as somatic mutations as well as highly specific agents that effectively modulate these targets.

The dichotomy in the histogenesis of endometriosis-associated ovarian cancer: clear cell-type versus endometrioid-type adenocarcinoma.

The histogenesis of endometriosis and endometriosis-associated ovarian cancer is one of the most mysterious aspects of pathology. To better understand the histogenesis of endometriosis and endometriosis-associated ovarian cancer, we analyzed the possibility of a link of endometrium, ovarian surface epithelium, and a cortical inclusion cyst to ovarian endometriosis and endometriosis-associated ovarian cancer by immunohistochemistry using the epithelial membrane antigen (an epithelial marker), calretinin (a mesothelial marker), and hepatocyte nuclear factor (HNF)-1ß (a clear cell carcinoma-specific transcription factor). During ovarian surface epithelium invagination, cortical inclusion cyst epithelial cells may, in some cases, undergo mesothelial-epithelial transition and subsequently differentiate into endometriosis. This case of endometriosis that has undergone Müllerian metaplasia arises from the HNF-1ß-negative cells. The remaining endometriosis may develop from the late secretory and menstrual endometria, with HNF-1ß-positive staining, by retrograde menstruation. Endometrioid adenocarcinoma and clear cell carcinoma arise from the HNF-1ß-negative and HNF-1ß-positive epithelial cells of endometriosis, respectively. It has been proposed that clear cell and endometrioid-type adenocarcinomas arise from distinct types of endometriosis with different cells of origin.

A potential link of oxidative stress and cell cycle regulation for development of endometriosis.

BACKGROUND: The roles of molecular alteration such as genomic instability and cell survival are debated aspects of the pathogenesis of endometriosis. To review the contemporary literature on potential factors and their signaling pathways that support prolonged survival of endometriotic cells. METHODS: This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis. This review is focused on the association of hepatocyte nuclear factor (HNF)-1ß with endometriosis. RESULTS: The iron-induced oxidative stress plays a fundamental role for the pathogenesis of endometriosis. Oxidative stress, secondary to influx of iron during retrograde menstruation, modifies lipids and proteins, leading to cell and DNA damage. Recent studies demonstrated HNF-1ß overexpression in endometriotic foci. HNF-1ß increases the survival of endometriotic cells under iron-induced oxidative stress conditions possibly through the activation of forkhead box (FOX) transcription factors and/or endometriosis-specific expression of microRNAs. Endometriotic cells expressing HNF-1ß also display cell cycle checkpoint pathways required to survive DNA damaging events. CONCLUSIONS: HNF-1ß in endometriosis might be a factor that controls the cell cycle and DNA damage checkpoints.