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Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by cognitive decline and learning/memory impairment associated with neuronal cell loss. Estrogen-related receptor α (ERRα) and ERRγ, which are highly expressed in the brain, have emerged as potential AD regulators, with unelucidated underlying mechanisms. Here, we identified genome-wide binding sites for ERRα and ERRγ in human neuronal cells. They commonly target a subset of genes associated with neurodegenerative diseases, including AD. Notably, Dickkopf-1 (DKK1), a Wnt signaling pathway antagonist, was transcriptionally repressed by both ERRα and ERRγ in human neuronal cells and brain. ERRα and ERRγ repress RNA polymerase II (RNAP II) accessibility at the DKK1 promoter by modulating a specific active histone modification, histone H3 lysine acetylation (H3K9ac), with the potential contribution of their corepressor. This transcriptional repression maintains Wnt signaling activity, preventing tau phosphorylation and promoting a healthy neuronal state in the context of AD. [ABSTRACT FROM AUTHOR]

ObjectiveSkeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen-related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function.MethodsWe assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity.ResultsERRs were induced in human skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRβ and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis.ConclusionsOur findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles.

Estrogen-related receptors (ERRs) belong to a large class of orphan receptors in the nuclear receptor (NR) family. Bisphenol A (BPA) is known as an endocrine disruptor and xenoestrogen with a high affinity for the human estrogen-related receptor (ERRγ). Insects lack estrogen receptors (ER), and their ERR is orthologous to ERRγ. This study was intended to examine whether BPA does not affect the ovarian expression of orphan nuclear ERR in queen honey bees (Apis mellifera L.). The amERR gene was amplified by polymerase chain reaction (PCR) from the cDNA of bees. The amERR protein was harvested and purified with the recombinant vector amERR/pET-32a. Using RT-qPCR and Western blot (WB), the levels of amERR gene and protein expression in the ovaries of control and treated bees were determined. The results indicated that both 3 µg and 10 µg doses suppressed the ovarian expression of amERR, with 6H inhibition being the most significant. Furthermore, AutoDockVina was utilized for simulating molecular docking between the tertiary structure of amERR predicted by I-TASSER and BPA. It hinted that BPA could conjugate with the ligand-binding pocket (LBP) of amERR. Thus, BPA might arrest amERR activation through binding. The results showed that BPA might impact the transcription and protein expression levels of the amERR gene. It may be correlated with the potential specific binding of BPA and amERR. [ABSTRACT FROM AUTHOR]

Energy metabolism is a fundamental process in all organisms. During silkworm (Bombyx mori) embryonic development, there is a high demand for energy due to continuous cell proliferation and differentiation. Estrogen-related receptors (ERRs) are transcriptional regulatory factors that play crucial roles in mammalian energy storage and expenditure. Although most insects have one ERR gene, it also participates in the regulation of energy metabolism, including carbohydrate metabolism in Drosophila, Aphid, and Silkworm. However, no study has reported the direct impact of energy metabolism on embryonic development in silkworms. In this study, we used transgenic technology to increase silkworm (B. mori; Bm) BmERR expression during embryonic development and explored the impact of energy on embryonic development. We found no significant change in the quality of silkworm eggs compared to that of wild-type silkworms. However, there was an increase in the consumption of vitellin, a major nutrient in embryos. This resulted in a decrease in glucose content and a significant increase in ATP content. These findings provide evidence that the acceleration of energy metabolism promotes embryonic development and enhances the motility of hatched silkworms. In addition, these results provide a novel perspective on the relationship between energy metabolism and embryonic development in other insects. [ABSTRACT FROM AUTHOR]

While estrogens are well known for their pivotal role in the female reproductive system, they also play a crucial function in regulating physiological processes associated with learning and memory in the brain. Moreover, they have neuroprotective effects in the pathogenesis of Alzheimer's disease (AD). Importantly, AD has a higher incidence in older and postmenopausal women than in men, and estrogen treatment might reduce the risk of AD in these women. In general, estrogens bind to and activate estrogen receptors (ERs)- mediated transcriptional machineries, and also stimulate signal transduction through membrane ERs (mERs). Estrogen-related receptors (ERRs), which share homologous sequences with ERs but lack estrogen-binding capabilities, are widely and highly expressed in the human brain and have also been implicated in AD pathogenesis. In this review, we primarily provide a summary of ER and ERR expression patterns in the human brain. In addition, we summarize recent studies on their role in learning and memory. We then review and discuss research that has elucidated the functions and importance of ERs and ERRs in AD pathogenesis, including their role in Ab clearance and the reduction of phosphorylated tau levels. Elucidation of the mechanisms underlying ER- and ERR-mediated transcriptional machineries and their functions in healthy and diseased brains would provide new perspectives for the diagnosis and treatment of AD. Furthermore, exploring the potential role of estrogens and their receptors, ERs, in AD will facilitate a better understanding of the sex differences observed in AD, and lead to novel sex-specific therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background. Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound B), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one order of magnitude higher TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds A and B may inhibit the signaling pathway of estrogen-related receptors. [ABSTRACT FROM AUTHOR]

Estrogen is an essential sex steroid hormone that functions primarily in female reproductive system, as well as in a variety of tissues and organs with pleiotropic effects, such as in cardiovascular, nervous, immune, and musculoskeletal systems. Women with low estrogen, as exemplified by those in postmenopause, are therefore prone to suffer from various disorders, i.e., cardiovascular disease, dementia, metabolic syndrome, osteoporosis, sarcopenia, frailty, and so on. Estrogen regulates the expression of its target genes by binding to its cognate receptors, estrogen receptors (ERs) α and β. Notably, the estrogen-related receptors (ERRs) α, β, and γ are originally identified as orphan receptors that share substantial structural homology and common transcriptional targets with ERs. Accumulating evidence suggests that ERs and ERRs play crucial roles in skeletal muscles, such as muscle mass maintenance, muscle exercise physiology, and muscle regeneration. In this article, we review potential regulatory roles of ERs and ERRs in muscle physiology, particularly with regard to mitochondrial function and metabolism. [ABSTRACT FROM AUTHOR]

Estrogen-related receptor (ERR) is an orphan nuclear receptor that was first discovered in animals, and play an important role in metabolism, development, and reproduction. Despite extensive research on the function of ERR, its transcriptional regulation mechanism remains unclear. In this study, we obtained the upstream region of Bombyx mori ERR (BmERR) and confirmed the promoter activity of this region. Interestingly, we found that 10 and 50 nM 20-hydroxyecdysone (20E) up-regulated the transcriptional activity of BmERR promoter. In addition, eight putative ecdysone response elements (EcREs) were predicted in the upstream sequence of BmERR. Based on their positions, the upstream sequence of BmERR was truncated into different fragments. Finally, an EcRE-like sequence (5′-AGTGCAGTAAACTGT-3′) was identified. Electrophoretic mobility shift assay (EMSA) and cell transfection experiments confirmed that this motif specifically binds to the complex formed between ecdysone receptor (BmEcR) and the ultraspiracle (BmUSP), a key complex in the 20E signaling pathway. Interference of BmERR or BmEcR mRNA in the embryonic cells of Bombyx mori significantly affected the expression of BmEcR and BmUSP. Overall, these results suggested that an EcRE element was identified from BmERR, and this will help understanding the detailed regulatory mechanism of ERR in insects. [ABSTRACT FROM AUTHOR]

Estrogen-related receptor (ERR) is an orphan nuclear receptor that was first discovered in animals, and play an important role in metabolism, development, and reproduction. Despite extensive research on the function of ERR, its transcriptional regulation mechanism remains unclear. In this study, we obtained the upstream region of Bombyx mori ERR (BmERR) and confirmed the promoter activity of this region. Interestingly, we found that 10 and 50 nM 20-hydroxyecdysone (20E) up-regulated the transcriptional activity of BmERR promoter. In addition, eight putative ecdysone response elements (EcREs) were predicted in the upstream sequence of BmERR. Based on their positions, the upstream sequence of BmERR was truncated into different fragments. Finally, an EcRE-like sequence (5′-AGTGCAGTAAACTGT-3′) was identified. Electrophoretic mobility shift assay (EMSA) and cell transfection experiments confirmed that this motif specifically binds to the complex formed between ecdysone receptor (BmEcR) and the ultraspiracle (BmUSP), a key complex in the 20E signaling pathway. Interference of BmERR or BmEcR mRNA in the embryonic cells of Bombyx mori significantly affected the expression of BmEcR and BmUSP. Overall, these results suggested that an EcRE element was identified from BmERR, and this will help understanding the detailed regulatory mechanism of ERR in insects.

The Estrogen-Related Receptor (ERR) family of nuclear receptors (NRs) serve key roles in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, ERR activity promotes TAG storage during the post-embryonic growth phase, with loss-of-function mutations in mouse Esrra and Drosophila melanogaster dERR inducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation within adipose tissue remains poorly understood, as previous transcriptomic and metabolomic studies relied on whole animal analyses. Here we address this shortcoming by using tissue-specific approaches to examine the role of dERR in regulating lipid metabolism within the Drosophila larval fat body. We find that dERR autonomously promotes TAG accumulation within fat body cells and regulates expression of genes involved in glycolysis, β-oxidation, and mevalonate metabolism. As an extension of these results, we not only discovered that dERR mutant fat bodies exhibit decreased expression of known dHNF4 target genes but also found that dHNF4 activity is decreased in dERR mutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with developmental growth and hint at a conserved mechanism by which ERR and HNF4 homologs coordinately regulate metabolic gene expression.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by cognitive decline and learning/memory impairment associated with neuronal cell loss. Estrogen-related receptor α (ERRα) and ERRγ, which are highly expressed in the brain, have emerged as potential AD regulators, with unelucidated underlying mechanisms. Here, we identified genome-wide binding sites for ERRα and ERRγ in human neuronal cells. They commonly target a subset of genes associated with neurodegenerative diseases, including AD. Notably, Dickkopf-1 (DKK1), a Wnt signaling pathway antagonist, was transcriptionally repressed by both ERRα and ERRγ in human neuronal cells and brain. ERRα and ERRγ repress RNA polymerase II (RNAP II) accessibility at the DKK1 promoter by modulating a specific active histone modification, histone H3 lysine acetylation (H3K9ac), with the potential contribution of their corepressor. This transcriptional repression maintains Wnt signaling activity, preventing tau phosphorylation and promoting a healthy neuronal state in the context of AD., Competing Interests: Competing interests statement:The authors declare no competing interest.

Estrogen-related receptors (ERRs) are known to function in mammalian kidney as key regulators of ion transport-related genes; however, a comprehensive understanding of the physiological functions of ERRs in vertebrate body fluid ionic homeostasis is still elusive. Here, we used medaka (Oryzias melastigma), a euryhaline teleost, to investigate how ERRs are involved in ion regulation. After transferring medaka from hypertonic seawater to hypotonic freshwater (FW), the mRNA expression levels of errγ2 were highly upregulated, suggesting that Errγ2 may play a crucial role in ion uptake. In situ hybridization showed that errγ2 was specifically expressed in ionocytes, the cells responsible for Na+/Cl- transport. In normal FW, ERRγ2 morpholino knockdown caused reductions in the mRNA expression of Na+/Cl- cotransporter (Ncc), the number of Ncc ionocytes, Na+/Cl- influxes of ionocytes, and whole-body Na+/Cl- contents. In FW with low Na+ and low Cl-, the expression levels of mRNA for Na+/H+ exchanger 3 (Nhe3) and Ncc were both decreased in Errγ2 morphants. Treating embryos with DY131, an agonist of Errγ, increased the whole-body Na+/Cl- contents and ncc mRNA expression in Errγ2 morphants. As such, medaka Errγ2 may control Na+/Cl- uptake by regulating ncc and/or nhe3 mRNA expression and ionocyte number, and these regulatory actions may be subtly adjusted depending on internal and external ion concentrations. These findings not only provide new insights into the underpinning mec hanism of actions of ERRs, but also enhance our understanding of their roles in body fluid ionic homeostasis for adaptation to changing environments during vertebrate evolution. [ABSTRACT FROM AUTHOR]

Until recently, chemical pesticides were one of the most effective means of controlling agricultural pests; therefore, the search for insecticide targets for agricultural pests has been an ongoing problem. Estrogen-related receptors (ERRs) are transcription factors that regulate cellular metabolism and energy homeostasis in animals. Silkworms are highly sensitive to chemical pesticides, making them ideal models for pesticide screening and evaluation. In this study, we detected ERR expression in key organs involved in pesticide metabolism in silkworms (Bombyx mori), including the fat body and midgut. Using ChIP-seq technology, many estrogen- related response elements were identified in the 2000-bp promoter region upstream of metabolism-related genes, almost all of which were potential ERR target genes. The ERR inhibitor, XCT-790, and the endocrine disruptor, bisphenol A, significantly inhibited expression of the ERR target genes, BmTreh-1 , BmTret-1 , BmPK , BmPFK , and BmHK , in the fat bodies of silkworms, resulting in pupation difficulties in silkworm larvae that ultimately lead to death. In addition, based on the clarification that the ERR can bind to XCT-790, as observed through biofilm interferometry, its three-dimensional spatial structure was predicted, and using molecular docking techniques, small-molecule compounds with a stronger affinity for the ERR were identified. In summary, utilizing the powerful metabolic regulatory function of ERR in Lepidoptera pests, the developed small molecule inhibitors of ERR can be used for future control of Lepidoptera pests. [Display omitted] • The BmERR commonly regulates genes related to silkworm metabolism. • XCT-790/BPA has an affinity for the BmERR. • XCT-790/BPA inhibits the expression of ERR target genes in silkworms. • XCT-790/BPA can impact the development of silkworms. • Presence of small-molecule compounds identified with higher affinity for the BmERR. [ABSTRACT FROM AUTHOR]

Abstract Background The obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age. Methods Body composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA. Results Siah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1α, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels. Conclusions The most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females.

Background:Metabolic flexibility is the capacity of a system to adjust fuel (primarily glucose and fatty acids) oxidation based on nutrient availability. Pyruvate Dehydrogenase Kinase 4 (PDK4) is one of the main enzymes that play a critical role in metabolic flexibility. In current study, we examined PDK4 inhibition along with exercise training (ET) on the gene expression of Estrogen related-receptor alpha (ERRα), medium-chain acyl-CoA dehydrogenase (MCAD), carnitine palmitoyl transferase-1b (CPT-1b), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PDK4 and citrate synthase (CS) in skeletal muscle. Method:Sixty-four male Wistar rats (8 week-old) were randomly divided into 8 groups (n=8); 1- untreated control, 2- STZ-induced diabetic, 3- PDK4 inhibition, 4- endurance training (ET), 5- diabetic + PDK4 inhibition, 6- diabetic + ET, 7- PDK4 inhibition + ET, and 8- diabetic +ET + PDK4 inhibition. ERRα, MCAD, CPT-1b, PGC-1α, PDK4 and CS genes expressions were measured by Real-Time PCR and quantified by 2-ΔΔCt method. Results:ERRα, MCAD, CPT-1b, PGC-1α, PDK4, and CS expressions were significantly higher in non-diabetic+ Endurance Training group compared to the control group. The expressions of CPT-1b, MCAD and CS genes were significantly lower in the non-diabetic+ endurance training/PDK4 inhibition compared to the non-diabetic+ endurance training group, and the expressions of ERRα, CPT-1b and MCAD were significantly lower in the diabetic + PDK4 inhibition group compared to the diabetic group. Conclusion:In sum, PDK4 inhibition has negative effects on lipid metabolism in healthy rats, but in animals with diabetes, PDK4 inhibition can be used for improving lipid metabolism (over-expression of CS and PGC-1α). [ABSTRACT FROM AUTHOR]

Estrogen‐related receptors (ERRs) play indispensable roles in development, energy metabolism, and cancers and are metabolic switches in Drosophila. However, the mechanism underlying their metabolic role is unknown in insects. This study analysed the expression profiles of Bombyx mori ERR (BmERR), hexokinase (BmHK), pyruvate kinase (BmPK) and phosphofructokinase (BmPFK) during embryonic development. The expression of BmERR tended to be similar to that of the other genes. We observed a regulatory association between BmERR and glycolytic rate‐limiting enzymes by BmERR overexpression, RNA interference (RNAi), and ERR inhibitors in B. mori embryo cells. Subsequently, ERR cis‐regulation elements (ERREs) were predicted and identified in the BmPFK promoter. Transfection assays, electrophoretic mobility shift assays and chromatin immunoprecipitation showed that BmERR can bind to one of these elements to regulate the expression of BmPFK. ERREs were also predicted in the BmHK and BmPK promoters. In the eggs, the expression of glycolytic rate‐limiting enzyme genes was suppressed when the expression of BmERR was interference by double‐stranded BmERR, the glucose levels also was increased. Meanwhile, the development of silkworm embryos was delayed by about 1 day. These results indicate that BmERR can bind to the ERREs of glycolytic gene promoters and regulate the expression of glycolytic genes, ultimately affecting embryonic development in silkworms. [ABSTRACT FROM AUTHOR]

Aphids are a major problem in agriculture, horticulture, and forestry by feeding on leaves and stems, causing discoloration, leaf curling, yellowing, and stunted growth. Although urushiol, a phenolic compound containing a catechol structure, is known for its antioxidant and anticancer properties, using small molecules to control aphids via catechol-mediated mechanisms is poorly understood. In this study, we investigated the effects of 3-methylcatechol (3-MC) on Myzus persicae fecundity. Our results showed that treatment with 3-MC significantly reduced the intrinsic transcriptional activity of the aphid estrogen-related receptor (MpERR), which regulates the expression of glycolytic genes. Additionally, 3-MC treatment suppressed the promoter activity of MpERR-induced rate-limiting enzymes in glycolysis, such as phosphofructokinase and pyruvate kinase, by inhibiting MpERR binding. Finally, 3-MC also suppressed MpERR-induced glycolytic gene expression and reduced the number of offspring produced by viviparous female aphids. Overall, our findings suggest that 3-MC has the potential to be used as a new strategy for managing aphid populations by controlling their offspring production. [Display omitted] • 3-methylcatechol inhibits aphid ERR transcriptional activity. • 3-methylcatechol reduces ERR-mediated gene expression of glycolytic enzymes, PK and PFK. • 3-methylcatechol reduces the number of offspring by aphids [ABSTRACT FROM AUTHOR]

The function of estrogen-related receptor (ERR) in testicular cells is at the beginning of exploration. Our previous findings showed that expression pattern of estrogen-related receptor (ERR) in mouse Leydig cell depends on physiological status of the cell. Exogenous hormones/hormonally active chemicals affect ERR expression. In Leydig cells in vitro, ERRα and ERRγ show opposing regulatory properties. The aim of this study was to examine the role of ERR in epigenetic processes in cells with altered level of secreted estrogens; mouse tumor Leydig cells and bank vole Leydig cells, respectively. In Leydig cells, ERRα and ERRγ were silenced via siRNA. mRNA and protein expression and protein localization of molecules required for miRNA biogenesis and function (Exportin 5, Dicer, Drosha and Argonaute 2; Ago2) were studied with the use of qRT-PCR, Western blotting, and immunohistochemistry. Global DNA methylation and histone deacetylation status together with estradiol secretion were determined with fluorometric, and immunoenzymatic assays. Regardless of ERR type knockdown in tumor Leydig cells, downregulation (P < 0.05; P < 0.01; P < 0.001) of Exportin5, Dicer, Drosha but not Ago2 was revealed while at protein level only Drosha was downregulated (P < 0.01) by both ERRα and ERRγ. Oppositely, Exportin5, Dicer and Ago2 showed ERR type-dependent regulation (downregulation; P < 0.01 by ERRα and upregulation; P < 0.01; P < 0.001 by ERRγ). In ERR-silenced vole Leydig cells, expression of Exportin5, endonucleases and Ago2 was not changed. Immunolocalization of Dicer and Ago2 was independent of the cell origin in contrast to localization of Exportin5 and Drosha which was dependent on the cell origin and ERR type knockdown. Absence of ERR effected on cell methylation status (ERRα increased it; P < 0.01 while ERRγ decreased it; P < 0.01, P < 0.001) but it not changed histone deacetylates activity. ERRα and ERRγ silencing decreased (P < 0.01, P < 0.001) estradiol secretion in both tumor and vole Leydig cells. In mouse and bank vole Leydig cell, Exportin5, Dicer, Drosha and Ago2 expression as well as methylation status are regulated by ERR in a manner related to receptor type, molecule type, cell origin and level of secreted estrogen. • Drosha, Exportin5, Dicer and Argonaute2 are expressed in bank vole and mouse tumor (MA-10) Leydig cells. • In MA-10 cells, proteins required for miRNA biogenesis and function are regulated by estrogen-related receptor (ERR). • In bank vole Leydig cells, ERRα and γ do not regulate protein expression of Drosha, Exportin5, Dicer and Argonaute2. • In Leydig cell, DNA methylation is dependent on cell origin, secreted estrogen level and type of ERR. • In bank vole and mouse tumor Leydig cells, histone deacetylation is controlled neither by ERR nor estrogen level. [ABSTRACT FROM AUTHOR]

Purpose: The estrogen-related receptor (ERR) α is structurally similar to classical estrogen receptors (ERs), but is considered to be an orphan nuclear receptor. We previously found that ERRα regulates uterine endometrial cancer progression. Here, we investigated the efficacy of XCT790, a selective inverse agonist of ERRα, on endometrial cancer cells in vitro and in vivo. Methods: HEC-1A and KLE, ERα-negative endometrial cancer cells exhibiting high ERRα expression levels, and HEC-1A cell-derived xenograft model mice were treated with XCT790. Transcriptional activity and cell proliferation were examined using luciferase, WST-8 and colony formation assays, respectively. Cell cycle progression was evaluated using flow cytometry, immunofluorescence cytochemistry and Western blotting. Apoptosis was evaluated using a caspase-3/7 activity assay. Results: We found that XCT790 significantly inhibited ERRα-induced in vitro transcriptional activity, including that of the vascular endothelial growth factor (VEGF) gene, in a concentration-dependent manner (p < 0.05). We also found that XCT790 suppressed colony formation and cell proliferation in a concentration and time-dependent manner (p < 0.01) without cytotoxicity, and induced apoptosis (p < 0.01). XCT790 was found to cause cell cycle arrest at the mitotic phase. Akt and mTOR phosphorylation was found to be inhibited by XCT790, but PI3K levels were not found to be significantly affected. Combination therapy of XCT790 with paclitaxel elicited a synergistic inhibitory effect. Additionally, we found that XCT790 significantly inhibited in vivo tumor growth and angiogenesis, and induced apoptosis without a reduction in body weight, in xenograft models (p < 0.01). Conclusions: From our data we conclude that XCT790 has an anti-tumor effect on endometrial cancer cells in vitro and in vivo. As such, it may serve as a novel therapeutic agent for endometrial cancer. [ABSTRACT FROM AUTHOR]

Telocytes (TCs), a novel type of interstitial cells, are involved in tissue homeostasis maintenance. This study aimed to investigate TC presence in the interstitium of mouse testis. Additionally, inactivation of the G-coupled membrane estrogen receptor (GPER) in the testis was performed to obtain insight into TC function, regulation, and interaction with other interstitial cells. Mice were injected with a GPER antagonist (G-15; 50 μg/kg bw), and the GPER-signaling effect on TC distribution, ultrastructure, and function, as well as the interstitial tissue interaction of GPER with estrogen-related receptors (ERRs), was examined. Microscopic observations of TC morphology were performed with the use of scanning and transmission electron microscopes. Telocyte functional markers (CD34; c-kit; platelet-derived growth factor receptors α and β, PDGFRα and β; vascular endothelial growth factor, VEGF; and vimentin) were analyzed by immunohistochemistry/immunofluorescence and Western blot. mRNA expression of CD34 as well as ERR α, β, and γ was measured by qRT-PCR. Relaxin and Ca2+ concentrations were analyzed by immunoenzymatic and colorimetric assays, respectively. For the first time, we reveal the presence of TCs in the interstitium together with the peritubular area of mouse testis. Telocytes were characterized by specific features such as a small cell body and extremely long prolongations, constituting a three-dimensional network mainly around the interstitial cells. Expression of all TC protein markers was confirmed. Based on scanning electron microscopic observation in GPER-blocked testis, groups of TCs were frequently seen. No changes were found in TC ultrastructure in GPER-blocked testis when compared to the control. However, tendency to TC number change (increase) after the blockage was observed. Concomitantly, no changes in mRNA CD34 expression and increase in ERR expression were detected in GPER-blocked testes. In addition, Ca2+ was unchanged; however, an increase in relaxin concentration was observed. Telocytes are an important component of the mouse testicular interstitium, possibly taking part in maintaining its microenvironment as well as contractile and secretory functions (via themselves or via controlling of other interstitial cells). These cells should be considered a unique and useful target cell type for the prevention and treatment of testicular interstitial tissue disorders based on estrogen-signaling disturbances. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) such as superoxide anion (O2•−) and hydrogen peroxide (H2O2) are generated endogenously by processes such as mitochondrial oxidative phosphorylation, or they may arise from exogenous sources like bacterial invasion. ROS can be beneficial (oxidative eustress) as signaling molecules but also harmful (oxidative distress) to cells when ROS levels become unregulated in response to physiological, pathological or pharmacological insults. Indeed, abnormal ROS levels have been shown to contribute to the etiology of a wide variety of diseases. Transcriptional control of metabolic genes is a crucial mechanism to coordinate ROS homeostasis. Therefore, a better understanding of how ROS metabolism is regulated by specific transcription factors can contribute to uncovering new therapeutic strategies. A large body of work has positioned the estrogen-related receptors (ERRs), transcription factors belonging to the nuclear receptor superfamily, as not only master regulators of cellular energy metabolism but, most recently, of ROS metabolism. Herein, we will review the role played by the ERRs as transcriptional regulators of ROS generation and antioxidant mechanisms and also as ROS sensors. We will assess how the control of ROS homeostasis by the ERRs can be linked to physiology and disease and the possible contribution of manipulating ERR activity in redox medicine.

• PvFOXO expression levels depended on caste and developmental stage. • PvFOXO plays an important role in insect molting, pupation and phenotype development. • PvERR has a very important interdependence with the IIS pathway. • PvERR regulates the biosynthesis of 20E via the IIS signaling pathway to control development. Estrogen-related receptor (ERR) is a key regulator of insect growth, development, and metabolic processes in insects; however, the molecular mechanisms underlying its effects are not fully understood. We investigated roles of 20-hydroxyecdysone (20E) and insulin/insulin-like signaling/target of rapamycin (IIS/TOR) signaling pathways in the effects of PvERR on larval development, metamorphosis, and adult growth in ant Polyrhachis vicina Roger. PvFOXO expression levels depended on caste and developmental stage. PvERR RNAi significantly reduced the expression levels of IIS/TOR signaling pathway genes and 20E signaling pathway genes in fourth-instar larvae, pupae, females, and workers and significantly increased the expression levels of IIS/TOR signaling pathway genes PvFOXO and PvAkt in males. PvFOXO RNAi resulted in developmental defects and increased mortality. After PvFOXO RNAi, the expression of PvERR , 20E signaling pathway genes, and IIS/TOR signaling pathway genes decreased significantly in pupae, females, and workers and increased significantly in fourth-instar larvae. Exogenous 20E attenuated expression changes induced by PvFOXO RNAi in a sex- and stage-specific manner. These results indicate that ERR interacts with 20E and IIS/TOR signaling pathways to regulate caste determination, metamorphosis, and male fertility in P. vicina and that correlations between PvERR and PvFOXO are caste- and stage-specific. [ABSTRACT FROM AUTHOR]

Estrogen-related receptors (ERR) are an orphan nuclear receptor sub-family that play a critical role in regulating gene transcription for several physiological processes including mitochondrial function, cellular energy utilization and homeostasis. They have also been implicated to play a role in several pathological conditions. Herein, we report the identification, synthesis, structure-activity relationships and pharmacological evaluation of a new chemical series of potent pan-ERR agonists. This template was designed for ERRγ starting from the known acyl hydrazide template and compounds such as agonist GSK-4716 employing a structure-based drug design approach. This led to the preparation of a series of 2,5-disubstituted thiophenes from which several were found to be potent agonists of ERRγ in cell-based co-transfection assays. Additionally, direct binding to ERRγ was established through 1H NMR protein-ligand binding experiments. Compound optimization revealed that the phenolic or aniline groups could be replaced with a boronic acid moiety, which was able to maintain activity and demonstrated improved metabolic stability in microsomal in vitro assays. Further pharmacological evaluation of these compounds showed that they had roughly equivalent agonist activity on ERR isoforms α and β representing an ERR pan-agonist profile. One potent agonist, SLU-PP-915 (10s), which contained a boronic acid moiety was profiled in gene expression assays and found to significantly upregulate the expression of ERR target genes such as peroxisome-proliferator activated receptor γ co-activators-1α, lactate dehydrogenase A, DNA damage inducible transcript 4 and pyruvate dehydrogenase kinase 4 both in vitro and in vivo. [Display omitted] • Identified a novel series of 2,5-disubstiuted thiophenes that act as potent pan-ERR nuclear receptor agonists. • Compound 10s (SLU-PP-915), contains a boronic acid moiety that acts as a hydrogen-bond donor replacing a phenol group. • Compounds with the boronic acid moiety gave improved microsomal stability as compared to the corresponding aniline or phenol. • Performed ligand-protein NMR experiments to highlight binding of key compounds to the Ligand-binding domain of ERRγ. • Compound 10s significantly up-regulates known ERR target genes in vitro and in vivo and increases exercise capacity in mice. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER) α, but the expression of estrogen receptors ERβ and G protein-coupled estrogen receptor 1 (GPER-1) is able to trigger estrogen-responsivity in TNBC. Estrogen signaling in TNBC can also be activated and modulated by the constitutively active estrogen-related receptors (ERRs). In this review article, we discuss the role of ERβ and GPER-1 as mediators of E2 action in TNBC as well as the function of ERRs as activators and modulators of estrogen signaling in this cancer entity. For this purpose, original research articles on estrogen actions in TNBC were considered, which are listed in the PubMed database. Additionally, we performed meta-analyses of publicly accessible integrated gene expression and survival data to elucidate the association of ERβ, GPER-1, and ERR expression levels in TNBC with survival. Finally, options for endocrine therapy strategies for TNBC were discussed.

Graphical abstract Highlights • The key structural changes underlying the transition from ERRs to vertebrate SRs are not known. • Extant SRs, exemplified by ERα, contain a site for cysteine fatty-acylation (principally palmitate) that is reported to promote both membrane association and receptor activity. • Comparative sequence analysis reveals that the fatty-acylation motif is present in SRs but is absent from all ERRs. • Molecular modeling indicates that palmitate locates to a groove in the surface of the ligand-binding domain, at a site that may modulate the 3D structure of the receptor. • Other potential interactions with the key cysteine residue include second-site steroid ligand and metalloestrogen binding. • Because the fatty-acylation sequence accurately demarcates SRs from ERRs, this modification may have played a role in the emergence of vertebrate receptors responding to steroids. Abstract Present-day nuclear receptors (NRs) responding to adrenal and sex steroids are key regulators of reproduction and growth in mammals, and are thought to have evolved from an ancestral NR most closely related to extant estrogen-related receptors (ERRs). The molecular events (and ligands) that distinguish steroid-activated NRs (SRs) from their inferred ancestor, that gave rise to both the ERRs and SRs, remain unknown. We report that target sequences for fatty-acylation (palmitoylation) at a key cysteine residue (corresponding to Cys447 in human estrogen receptor ERα) in helix 8 of the ligand-binding domain accurately demarcate SRs from ERRs. Docking studies are consistent with the hypothesis that palmitate embeds into a key groove in the receptor surface. The implications of lipidation, and of potential alternative ligands for the key cysteine residue, for receptor function and the evolution of SRs are discussed. [ABSTRACT FROM AUTHOR]

The estrogen-related receptor (ERR) gene is a member of the nuclear receptor subfamily. Previous studies have indicated that ERR plays important roles in regulating insect growth and development. How ERR is associated with ant caste specificities remains unclear. In this study, we attempted to identify the role of ERR in the regulation of different adult caste specificities of Polyrhachis vicina Roger. Significant variations were detected in the ants including PvERR expressions, some physiological indexes and morphological traits including survival rate, body weight, body length, head width and abdominal appearance by different techniques. The results revealed that when PvERR expressions is up-regulated, boundaries of the abdominal segments were indistinct on the ventral side of the abdomen in males. Down-regulation of PvERR expressions caused abdominal swelling in males and a distended ventral abdomen in females and workers. Variation in PvERR expressions led to a remarkable decline in ant survival rates, particularly for males. These results indicated that different caste adults appeared to have different degrees of sensitivity in physiological response and morphological changes caused by variation in PvERR expressions. Thus, our data demonstrate that PvERR plays an important role in regulating the different adult caste specificities of P. vicina. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) has been widely prescribed for patients with advanced prostate cancer (PC) to control key signaling pathways via androgen receptor (AR) and AR-collaborative transcriptional factors; however, PC gradually acquires a lethal phenotype and results in castration-resistant PC (CRPC) during ADT. Therefore, new therapeutic strategies are required in clinical practice. In addition, ARs; estrogen receptors (ERs; ERRα and ERRβ); and estrogen-related receptors (ERRs; ERR, ERR, and ERR ) have been reported to be involved in the development or regulation of PC. Recent investigations have revealed the role of associated molecules, such as KLF5, FOXO1, PDGFA, VEGF-A, WNT5A, TGFb1, and micro-RNA 135a of PC, via ERs and ERRs. Selective ER modulators (SERMs) have been developed. Recently, estrogen and androgen blockade (EAB) using a combination of toremifene and ADT has been demonstrated to improve biochemical recurrence rate in treatment-naïve bone metastatic PC. In the future, the suitability of ADT alone or EAB for individuals may be evaluated by making clinical decisions on the basis of information obtained from RT-PCR, gene-panel, or liquid biopsy to create a "personalized medicine" or "precision medicine". In this review, we summarize ER and ERR signaling pathways, molecular diagnosis, and SERMs as candidates for advanced PC treatment. [ABSTRACT FROM AUTHOR]

Most nuclear receptors (NRs) bind DNA as dimers, either as hetero- or as homodimers on DNA sequences organized as two half-sites with specific orientation and spacing. The dimerization of NRs on their cognate response elements (REs) involves specific protein–DNA and protein–protein interactions. The estrogen-related receptor (ERR) belongs to the steroid hormone nuclear receptor (SHR) family and shares strong similarity in its DNA-binding domain (DBD) with that of the estrogen receptor (ER). In vitro, ERR binds with high affinity inverted repeat REs with a 3-bps spacing (IR3), but in vivo, it preferentially binds to single half-site REs extended at the 5′-end by 3 bp [estrogen-related response element (ERREs)], thus explaining why ERR was often inferred as a purely monomeric receptor. Since its C-terminal ligand-binding domain is known to homodimerize with a strong dimer interface, we investigated the binding behavior of the isolated DBDs to different REs using electrophoretic migration, multi-angle static laser light scattering (MALLS), non-denaturing mass spectrometry, and nuclear magnetic resonance. In contrast to ER DBD, ERR DBD binds as a monomer to EREs (IR3), such as the tff1 ERE-IR3, but we identified a DNA sequence composed of an extended half-site embedded within an IR3 element (embedded ERRE/IR3), where stable dimer binding is observed. Using a series of chimera and mutant DNA sequences of ERREs and IR3 REs, we have found the key determinants for the binding of ERR DBD as a dimer. Our results suggest that the sequence-directed DNA shape is more important than the exact nucleotide sequence for the binding of ERR DBD to DNA as a dimer. Our work underlines the importance of the shape-driven DNA readout mechanisms based on minor groove recognition and electrostatic potential. These conclusions may apply not only to ERR but also to other members of the SHR family, such as androgen or glucocorticoid, for which a strong well-conserved half-site is followed by a weaker one with degenerated sequence.

Estrogen-related receptor gene ( ERR) and ecdysone receptor gene ( EcR) belong to the nuclear receptor gene superfamily, both of which are associated with the regulation of insect reproductive development. However, the relationship between ERR and EcR and whether ERR participates in the 20E signal pathway during male reproduction are unclear. In this paper, adult male crickets Teleogryllus emma Ohmschi & Matsumura were divided into the experimental group, negative group, and control group. Crickets of the experimental group were injected with TeERR or TeEcR-dsRNA, and those in the negative group received EGFP-dsRNA. The efficiency of TeERR and TeEcR-RNAi was detected in the experimental group. Furthermore, the transcription level, morphological characteristics as well as weight were analyzed in the TeERR or TeEcR knocked-down testis. Results showed that the expression level of TeERR or TeEcR was significantly down-regulated ( P < 0.05) when treated with 2000 ng TeERR or TeEcR-dsRNA for 48 h. The expression level of TeERR could be down-regulated ( P < 0.05) using TeEcR-RNAi and vice versa. TeERR and TeEcR-RNAi caused morphological changes in testes, but they had no obvious effect on weight ( P > 0.05). These results indicate that TeERR and TeEcR are intimately related to each other. In addition, TeERR may be involved in the 20E signal pathway and maintain the function of adult cricket testis. [ABSTRACT FROM AUTHOR]

Most nuclear receptors (NRs) bind DNA as dimers, either as hetero- or as homodimers on DNA sequences organized as two half-sites with specific orientation and spacing. The dimerization of NRs on their cognate response elements (REs) involves specific protein-DNA and protein-protein interactions. The estrogen-related receptor (ERR) belongs to the steroid hormone nuclear receptor (SHR) family and shares strong similarity in its DNA-binding domain (DBD) with that of the estrogen receptor (ER). In vitro, ERR binds with high affinity inverted repeat REs with a 3-bps spacing (IR3), but in vivo, it preferentially binds to single half-site REs extended at the 5'-end by 3 bp [estrogen-related response element (ERREs)], thus explaining why ERR was often inferred as a purely monomeric receptor. Since its C-terminal ligand-binding domain is known to homodimerize with a strong dimer interface, we investigated the binding behavior of the isolated DBDs to different REs using electrophoretic migration, multi-angle static laser light scattering (MALLS), non-denaturing mass spectrometry, and nuclear magnetic resonance. In contrast to ER DBD, ERR DBD binds as a monomer to EREs (IR3), such as the tff1 ERE-IR3, but we identified a DNA sequence composed of an extended half-site embedded within an IR3 element (embedded ERRE/IR3), where stable dimer binding is observed. Using a series of chimera and mutant DNA sequences of ERREs and IR3 REs, we have found the key determinants for the binding of ERR DBD as a dimer. Our results suggest that the sequence-directed DNA shape is more important than the exact nucleotide sequence for the binding of ERR DBD to DNA as a dimer. Our work underlines the importance of the shape-driven DNA readout mechanisms based on minor groove recognition and electrostatic potential. These conclusions may apply not only to ERR but also to other members of the SHR family, such as androgen or glucocorticoid, for which a strong well-conserved half-site is followed by a weaker one with degenerated sequence. [ABSTRACT FROM AUTHOR]

Aim The transcriptional cofactor receptor-interacting protein 140 ( RIP140) is known as a deleterious regulator of cardiac mitochondrial function and energy metabolic homeostasis. This study revealed that RIP140 repressed Sirtuin 3 ( SIRT3), a mitochondrial deacetylase that plays an important role in regulating cardiac function. Methods RIP140 was overexpressed by adenovirus infection or was knocked down by RNA interference in neonatal rat cardiomyocytes. Results RIP140 overexpression repressed, while RIP140 silencing elevated the expression and activity of SIRT3. Ad- RIP140 enhanced the expressions of the cardiac hypertrophic markers and increased cardiomyocyte surface area, whereas SIRT3 overexpression prevented the effect of Ad- RIP140. Additionally, SIRT3 overexpression reversed Ad- RIP140-induced mitochondrial dysfunction and energy metabolic dysfunction, such as increase in oxidative stress, decrease in mitochondrial membrane potential and ATP production, as well as downregulation of mitochondrial DNA-encoded genes and genes related to mitochondrial genome replication and transcription, mitochondrial oxidative phosphorylation and fatty acid oxidation. In contrast, SIRT3 silencing exacerbated RIP140-induced cardiomyocyte hypertrophy and mitochondrial dysfunction. Furthermore, the repression of SIRT3 by RIP140 was dependent on estrogen-related receptor-α ( ERRα). The involvement of peroxisome proliferator-activated receptor-γ coactivator-1α ( PGC-1α) was ruled out of SIRT3 suppression by RIP140. RIP140 and PGC-1α might act as functional antagonists on the regulation of SIRT3. Conclusion This study indicates that suppression of SIRT3 by RIP140 facilitates the development of cardiomyocyte hypertrophy, mitochondrial dysfunction and energy metabolic dysfunction. Strategies targeting inhibition of RIP140 and upregulation of SIRT3 might improve cardiac energy metabolism and suggest therapeutic potential for heart diseases. [ABSTRACT FROM AUTHOR]

Mechanisms underlying the development of idiopathic dilated cardiomyopathy (DCM) remain poorly understood. Using transcription factor expression profiling, we identified estrogen-related receptor-β (ESRRβ), a member of the nuclear receptor family of transcription factors, as highly expressed in murine hearts and other highly oxidative striated muscle beds. Mice bearing cardiac-specific deletion of ESRRβ (MHC-ERRB KO) develop DCM and sudden death at ~10 mo of age. Isolated adult cardiomyocytes from the MHC-ERRB KO mice showed an increase in calcium sensitivity and impaired cardiomyocyte contractility, which preceded echocardiographic cardiac remodeling and dysfunction by several months. Histological analyses of myocardial biopsies from patients with various cardiomyopathies revealed that ESRRβ protein is absent from the nucleus of cardiomyocytes from patients with DCM but not other forms of cardiomyopathy (ischemic, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy). Taken together these observations suggest that ESRRβ is a critical component in the onset of DCM by affecting contractility and calcium balance. [ABSTRACT FROM AUTHOR]

L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncometabolite that is capable of inhibiting enzymes involved in metabolism, chromatin modification, and cell differentiation. However, despite the ability of L-2HG to interfere with a broad range of cellular processes, this molecule is often characterized as a metabolic waste product. Here, we demonstrate that Drosophila larvae use the metabolic conditions established by aerobic glycolysis to both synthesize and accumulate high concentrations of L-2HG during normal developmental growth. A majority of the larval L-2HG pool is derived from glucose and dependent on the Drosophila estrogen-related receptor (dERR), which promotes L-2HG synthesis by up-regulating expression of the Drosophila homolog of lactate dehydrogenase (dLdh). We also show that dLDH is both necessary and sufficient for directly synthesizing L-2HG and the Drosophila homolog of L-2-hydroxyglutarate dehydrogenase (dL2HGDH), which encodes the enzyme that breaks down L-2HG, is required for stage-specific degradation of the L-2HG pool. In addition, dLDH also indirectly promotes L-2HG accumulation via synthesis of lactate, which activates a metabolic feedforward mechanism that inhibits dL2HGDH activity and stabilizes L-2HG levels. Finally, we use a genetic approach to demonstrate that dLDH and L-2HG influence position effect variegation and DNA methylation, suggesting that this compound serves to coordinate glycolytic flux with epigenetic modifications. Overall, our studies demonstrate that growing animal tissues synthesize L-2HG in a controlled manner, reveal a mechanism that coordinates glucose catabolism with L-2HG synthesis, and establish the fly as a unique model system for studying the endogenous functions of L-2HG during cell growth and proliferation. [ABSTRACT FROM AUTHOR]

While estrogens are well known for their pivotal role in the female reproductive system, they also play a crucial function in regulating physiological processes associated with learning and memory in the brain. Moreover, they have neuroprotective effects in the pathogenesis of Alzheimer's disease (AD). Importantly, AD has a higher incidence in older and postmenopausal women than in men, and estrogen treatment might reduce the risk of AD in these women. In general, estrogens bind to and activate estrogen receptors (ERs)-mediated transcriptional machineries, and also stimulate signal transduction through membrane ERs (mERs). Estrogen-related receptors (ERRs), which share homologous sequences with ERs but lack estrogen-binding capabilities, are widely and highly expressed in the human brain and have also been implicated in AD pathogenesis. In this review, we primarily provide a summary of ER and ERR expression patterns in the human brain. In addition, we summarize recent studies on their role in learning and memory. We then review and discuss research that has elucidated the functions and importance of ERs and ERRs in AD pathogenesis, including their role in Aβ clearance and the reduction of phosphorylated tau levels. Elucidation of the mechanisms underlying ER- and ERR-mediated transcriptional machineries and their functions in healthy and diseased brains would provide new perspectives for the diagnosis and treatment of AD. Furthermore, exploring the potential role of estrogens and their receptors, ERs, in AD will facilitate a better understanding of the sex differences observed in AD, and lead to novel sex-specific therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sato, Takayama and Inoue.)