Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1α, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a ‘hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.

Purpose Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.

The objective of this study was to test the hypothesis that older reproductive aged women ovulate at a smaller follicle diameter and are more likely to produce multiple follicles during their menstrual cycle compared with midreproductive aged women. We performed a comparative study of 16 midreproductive aged women (MRA; 22-34 yr old) and 34 older reproductive aged women (ORA; >45 yr old). Women underwent serial transvaginal ultrasounds to follow follicular growth over 1 menstrual cycle. A subset of women (nine MRA and 19 ORA) had daily blood sampling. Scans were initiated within 1 wk of menses and were performed at least 3 times/wk until evidence of follicular collapse was observed. If there was no evidence of follicle growth beyond 10 mm by 20 d, observations (ultrasounds and blood sampling) were ended. Follicle growth was organized backward from maximum presumed preovulatory diameter. Hormones were standardized to d 0, the day when progesterone levels exceeded 2 ng/ml. Group comparisons were performed using ANOVA with Mann-Whitney post hoc testing and Kruskal-Wallis testing for integrated hormones. The main outcome measures were peak follicle diameter, follicle growth patterns, and circulating LH, F OLLICLE GROWTH PATTERNS in the menstrual cycles of reproductive aged women have been characterized using ultrasonographic evaluation. Several small studies, with up to 25 women, documented similar findings (1-3). Follicles in spontaneous cycles of midreproductive aged (MRA) women grow at a rate of between 2-6 mm daily, and ovulation has been reported to occur at a mean follicle diameter of 16 -27 mm. The latter estimates were from a study that used transabdominal scanning, which may have resulted in larger estimates of follicle size (2). Nonetheless, follicle dynamics have been noted to be consistent in populations of normally cycling women. Some recent studies have described the ovarian morphology and patterns of follicle growth associated with reproductive aging. Ovarian volume has been reported to decrease with age in a population of 13,963 women undergoing ovarian cancer screening (4). The inclusion of women in the age group between 30 -50 yr who were already naturally menopausal may have contributed disproportionately to these results, however, and the menopausal status of the younger women in this study is not provided. The number of antral follicles (i.e. Ͼ2 mm) in the ovaries has been reported to be significantly decreased in women over an age range of 22-42 yr old (5). These differences in follicle counts were independent of the stage of the menstrual cycle. Another study of 162 women that was confined to the early follicular phase alone (6) reported a mean yearly decline of antral follicle counts of about 5%, which increased to almost 12% after the age of 37 yr. Taken together, these data suggest that follicles in various stages of growth constitute the bulk of ovarian volume and that declining numbers of observable follicles occur concomitant with reproductive aging.Others have observed the patterns of f...

Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.