Activity of estrogen receptor ß expressing neurons in the medial amygdala regulates preference toward receptive females in male mice.

The processing of information regarding the sex and reproductive state of conspecific individuals is critical for successful reproduction and survival in males. Generally, male mice exhibit a preference toward the odor of sexually receptive (RF) over nonreceptive females (XF) or gonadally intact males (IM). Previous studies suggested the involvement of estrogen receptor beta (ERß) expressed in the medial amygdala (MeA) in male preference toward RF. To further delineate the role played by ERß in the MeA in the neuronal network regulating male preference, we developed a new ERß-iCre mouse line using the CRISPR-Cas9 system. Fiber photometry Ca2+ imaging revealed that ERß-expressing neurons in the postero-dorsal part of the MeA (MeApd-ERß+ neurons) were more active during social investigation toward RF compared to copresented XF or IM mice in a preference test. Chemogenetic inhibition of MeApd-ERß+ neuronal activity abolished a preference to RF in "RF vs. XF," but not "RF vs. IM," tests. Analysis with cre-dependent retrograde tracing viral vectors identified the principal part of the bed nucleus of stria terminalis (BNSTp) as a primary projection site of MeApd-ERß+ neurons. Fiber photometry recording in the BNSTp during a preference test revealed that chemogenetic inhibition of MeApd-ERß+ neurons abolished differential neuronal activity of BNSTp cells as well as a preference to RF against XF but not against IM mice. Collectively, these findings demonstrate for the first time that MeApd-ERß+ neuronal activity is required for expression of receptivity-based preference (i.e., RF vs. XF) but not sex-based preference (i.e., RF vs. IM) in male mice.

Renal tubular estrogen ß receptors are expressed at high levels in small vessel vasculitis and are primarily localized in the distal tubule.

This study investigated the possible roles of renal estrogen receptors (ER) in glomerulonephritis associated with small vessel vasculitis. The relationships of ERs were investigated in antineutrophilic cytoplasmic antibody (ANCA)-associated glomerulonephritis and immunoglobulin A (IgA) nephropathy groups, which are small vessel vasculitis subtypes with two different glomerulonephritis development pathophysiologies. The design of this study was prepared as a retrospective cohort study. The study included 42 patients with ANCA-associated vasculitis and 18 with IgA nephropathy in the small vessel vasculitis group. For the control group, intact renal tissues of 28 patients who underwent nephrectomy due to renal cell carcinoma were used. Renal biopsy samples of the groups were stained with ER beta (ß) and ER alpha (α). Tubular ER ß expression score (TERßES) median values were found to be significantly higher in ANCA- associated vasculitis (B = 0.724, OR [95%CI]: 2.064 [1.141-3.731], p = .016) and IgA nephropathy (B = 0.898, OR [95%CI]: 2.454 [1.307-4.609], p = .005) than in intact kidney tissue. It was determined that tubular ERß was most frequently localized in the distal tubule at 57.9% and the second most common in the proximal tubule at 20.4%. The expression of tubular ERß is increased in glomerulonephritis due to small vessel vasculitis. Tubular ERßs are most commonly localized in the distal tubule. Further studies are needed to understand the physiological and pathophysiological effects of altered renal ER levels in small vessel vasculitis.

The AF-2 cofactor binding region is key for the selective SUMOylation of estrogen receptor alpha by antiestrogens.

Antiestrogens (AEs) are used to treat all stages of estrogen receptor (ER)-positive breast cancer. Selective estrogen receptor modulators such as tamoxifen have tissue-specific partial agonist activity, while selective estrogen receptor downregulators such as fulvestrant (ICI182,780) display a more complete antiestrogenic profile. We have previously observed that fulvestrant-induced ERα SUMOylation contributes to transcriptional suppression, but whether this effect is seen with other AEs and is specific to ERα is unclear. Here we show that several AEs induce SUMOylation of ERα, but not ERß, at different levels. Swapping domains between ERα and ERß indicates that the ERα identity of the ligand-binding domain helices 3 and 4 (H3-H4 region), which contribute to the static part of the activation function-2 (AF-2) cofactor binding groove, is sufficient to confer fulvestrant-induced SUMOylation to ERß. This region does not contain lysine residues unique to ERα, suggesting that ERα-specific residues in H3-H4 determine the capacity of the AE-bound ERα ligand-binding domain to recruit the SUMOylation machinery. We also show that the SUMO E3 ligase protein inhibitor of activated STAT 1 increases SUMOylation of ERα and of ERß containing the H3-H4 region of ERα, but not of ERß. Together, these results shed new light on the molecular basis for the differential capacity of selective estrogen receptor modulators and selective estrogen receptor downregulators to suppress transcription by ERα.

Sex-specific vulnerabilities in human astrocytes underpin the differential impact of palmitic acid.

Obesity and neurometabolic diseases have been linked to neurodegenerative diseases. Our hypothesis is that the endogenous estrogenic component of human astrocytes plays a critical role in cell response during lipotoxic damage, given that obesity can disrupt hormonal homeostasis and cause brain inflammation. Our findings showed that high concentrations of palmitic acid (PA) significantly reduced cell viability more in male astrocytes, indicating sex-specific vulnerabilities. PA induced a greater increase in cytosolic reactive oxygen species (ROS) production in males, while female astrocytes exhibited higher superoxide ion levels in mitochondria. In addition, female astrocytes treated with PA showed increased expression of antioxidant proteins, including catalase, Gpx-1 and Nrf2 suggesting a stronger cellular defence mechanism. Interestingly, there was a difference in the expression of estrogenic components, such as estrogen, androgens, and progesterone receptors, as well as aromatase and 5α-reductase enzymes, between males and females. PA induced their expression mainly in females, indicating a potential protective mechanism mediated by endogenous hormones. In summary, our findings highlight the impact of sex on the response of human astrocytes to lipotoxicity. Male astrocytes appear to be more susceptible to cellular damage when exposed to high concentrations of fatty acids.

Cholinergic interneurons in the nucleus accumbens are a site of cellular convergence for corticotropin-releasing factor and estrogen regulation in male and female mice.

Cholinergic interneurons (ChIs) act as master regulators of striatal output, finely tuning neurotransmission to control motivated behaviours. ChIs are a cellular target of many peptide and hormonal neuromodulators, including corticotropin-releasing factor, opioids, insulin and leptin, which can influence an animal's behaviour by signalling stress, pleasure, pain and nutritional status. However, little is known about how sex hormones via estrogen receptors influence the function of these other neuromodulators. Here, we performed in situ hybridisation on mouse striatal tissue to characterise the effect of sex and sex hormones on choline acetyltransferase (Chat), estrogen receptor alpha (Esr1) and corticotropin-releasing factor type 1 receptor (Crhr1) expression. Although we did not detect sex differences in ChAT protein levels in the dorsal striatum or nucleus accumbens, we found that female mice have more Chat mRNA-expressing neurons than males in both the dorsal striatum and nucleus accumbens. At the population level, we observed a sexually dimorphic distribution of Esr1- and Crhr1-expressing ChIs in the ventral striatum that was negatively correlated in intact females, which was abolished by ovariectomy and not present in males. Only in the NAc did we find a significant population of ChIs that co-express Crhr1 and Esr1 in females and to a lesser extent in males. At the cellular level, Crhr1 and Esr1 transcript levels were negatively correlated only during the estrus phase in females, indicating that changes in sex hormone levels can modulate the interaction between Crhr1 and Esr1 mRNA levels.

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough.

In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain-derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain-associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage-Dependent Anion Channel, Insulin-Like Growth Factor 1 Receptor, estrogen-metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERß)-Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along-with this, the association between estrogen, estrogen-metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

Hypertension disrupts the vascular clock in both sexes.

Blood pressure (BP) displays a circadian rhythm and disruptions in this pattern elevate cardiovascular risk. Although both central and peripheral clock genes are implicated in these processes, the importance of vascular clock genes is not fully understood. BP, vascular reactivity, and the renin-angiotensin-aldosterone system display overt sex differences, but whether changes in circadian patterns underlie these differences is unknown. Therefore, we hypothesized that circadian rhythms and vascular clock genes would differ across sex and would be blunted by angiotensin II (ANG II)-induced hypertension. ANG II infusion elevated BP and disrupted circadian patterns similarly in both males and females. In females, an impact on heart rate (HR) and locomotor activity was revealed, whereas in males hypertension suppressed baroreflex sensitivity (BRS). A marked disruption in the vascular expression patterns of period circadian regulator 1 (Per1) and brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (Bmal1) was noted in both sexes. Vascular expression of the G protein-coupled estrogen receptor (Gper1) also showed diurnal synchronization in both sexes that was similar to that of Per1 and Per2 and disrupted by hypertension. In contrast, vascular expression of estrogen receptor 1 (Esr1) showed a diurnal rhythm and hypertension-induced disruption only in females. This study shows a strikingly similar impact of hypertension on BP rhythmicity, vascular clock genes, and vascular estrogen receptor expression in both sexes. We identified a greater impact of hypertension on locomotor activity and heart rate in females and on baroreflex sensitivity in males and also revealed a diurnal regulation of vascular estrogen receptors. These insights highlight the intricate ties between circadian biology, sex differences, and cardiovascular regulation.NEW & NOTEWORTHY This study reveals that ANG II-induced hypertension disrupts the circadian rhythm of blood pressure in both male and female mice, with parallel effects on vascular clock gene and estrogen receptor diurnal patterns. Notably, sex-specific responses to hypertension in terms of locomotor activity, heart rate, and baroreflex sensitivity are revealed. These findings pave the way for chronotherapeutic strategies tailored to mitigate cardiovascular risks associated with disrupted circadian rhythms in hypertension.

The elucidation of species-specific receptor pharmacology: a case study using subtype selective para- and meta-carborane estrogen receptor agonists.

Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) ß is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERß without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERß-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERß-12 for human ERß. However, like others in the meta-carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. Significance Statement This study investigates para- and meta-substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERß compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.

3-epi-18ß-glycyrrhetinic acid or its glucuronide, the metabolites of glycyrrhizinic acid with individual differences, correlated with diagnostic maker for licorice-induced pseudoaldosteronism in humans.

Licorice is a crude drug that is used in traditional Japanese Kampo medicine and is also used as a sweetener. Occasionally, it causes pseudoaldosteronism (PsA) as a side effect. The major symptoms include hypokalemia, hypertension, edema, and low plasma aldosterone levels. PsA might be caused by the metabolites of glycyrrhizinic acid (GL), a component of licorice. The development of PsA markedly varies among individuals; however, the factors that cause these individual differences remain unknown. In this study, 78 patients who consumed Kampo medicines containing licorice were enrolled, and their laboratory data, including serum potassium levels, plasma aldosterone concentrations (PAC), and the concentrations of GL metabolites in the residual blood and/or urine samples were evaluated. Of the 78 participants, 18ß-glycyrrhetinic acid (GA), 3-epi-GA, 3-oxo-GA, 18ß-glycyrrhetinyl-30-O-glucuronide (GA30G), and 3-epi-GA30G were detected in the serum samples of 65, 47, 63, 62, and 3 participants, respectively. Of the 29 urine samples collected, GA30G and 3-epi-GA30G were detected in 27 and 19 samples. 3-epi-GA30G is a newly found GL metabolite. Moreover, 3-epi-GA, 3-oxo-GA, and 3-epi-GA30G were identified in human samples for the first time. High individual differences were found in the appearances of 3-epi-GA in serum and 3-epi-GA30G in urine, and the concentrations of these metabolites were correlated with serum PsA markers. The inhibitory titers of 3-epi-GA, 3-oxo-GA, GA30G, and 3-epi-GA30G on human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) were almost similar. These findings suggest that 3-epi-GA and/or 3-epi-GA30G are associated with individual differences in the development of PsA. Significance Statement In this study, we detected 3-epi-GA in human serum for the first time. We also identified 3-epi-GA30G as a novel GL metabolite in human urine. These GL metabolite levels showed correlations with markers of PsA. Additionally, there are individual differences in whether or not they appear in the serum/urine. In conclusion, 3-epi-GA/3-epi-GA30G correlates with individual differences in the development of PsA.

Protective effects of 17-ß-estradiol on liver injury: The role of TLR4 signaling pathway and inflammatory response.

Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERß) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1ß, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.

The Influence of Sex Hormones and X Chromosome in Immune Responses.

Males and females differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections and cancers. Cellular targets and molecular pathways underlying sexual dimorphism in immunity have started to emerge and appeared multifactorial. It became increasingly clear that sex-linked biological factors have important impact on the development, tissue maintenance and effector function acquisition of distinct immune cell populations, thereby regulating multiple layers of innate or adaptive immunity through distinct mechanisms. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in susceptibility to autoimmune diseases and allergies, and the sex-biased responses in natural immunity and cancer.

Involvement of estrogen receptor activation in kaempferol-3-O-glucoside's protection against aging-related cognition impairment and microglial inflammation.

Estrogens have been demonstrated to inhibit age-related cognitive decline via binding to estrogen receptors (ERs). As a natural flavonoid component of Cuscuta Chinensis Lam., Kaempferol-3-O-glucoside (K-3-G) not only possesses anti-neuroinflammatory potential but also functions as an agonist for ERα and ERß. This study aimed to determine whether K-3-G improved cognition during the aging process, with an emphasis on its effect on microglial inflammation. In vivo, K-3-G (5 or 10 mg/kg/day) was orally given to the senescence-accelerated mouse prone 8 (SAMP8) mice from six to eight-month old. In addition to mitigating the memory and learning deficits of SAMP8 mice, K-3-G upregulated the expression of ERα and ERß in their hippocampal CA1 region, with the higher dose being more effective. Less Iba-1+ microglial cells presented in SAMP8 mice treated with K-3-G. The formation of NLR Family Pyrin Domain Containing 3 (NLRP3) complex, production of pro-inflammatory cytokines and oxidative stress-related markers, as well as expression of pro-apoptotic proteins were reduced by K-3-G. In vitro, BV2 microglial cells exposed to oligomeric amyloid beta (Aß)1-42 were treated with 100 µM K-3-G. K-3-G showed similar anti-inflammatory effects on BV2 cells as in vivo. K-3-G-induced alterations were partly diminished by fulvestrant, an ER antagonist. Moreover, dual-luciferase reporter system demonstrated that K-3-G induced ER expression by activating the transcription of estrogen-response elements (EREs). Collectively, these findings demonstrate that K-3-G may be a novel therapeutic agent for senescence-related cognitive impairment by inhibiting microglial inflammation through its action on ERs.

Atrazine promotes cholangiocarcinoma cell proliferation and migration via GPER-mediated PI3K/Akt/NF-κB pathway.

Atrazine (ATZ), an herbicide widely distributed on a global scale, possess a potential risk for the development of various cancers upon environmental exposure. However, the effect and molecular mechanism of ATZ in cholangiocarcinoma (CCA), is still unclear. This study aimed to investigate the effect of ATZ on the proliferation and migration of CCA cell in vitro. Immortalized human cholangiocytes (MMNK-1) and three CCA cell lines (KKU-055, KKU-100 and KKU-213B) were treated with 0.01 to 100 µM of ATZ and 17ß-estradiol (E2). The results showed that, similar to E2, low doses (0.01 to 1 µM) of ATZ promoted the proliferation of all CCA and MMNK-1 cells. ATZ exposure increased non-genomic G protein-coupled estrogen receptor (GPER) expression in the cell membrane and cytoplasm of KKU-213B and KKU-055 cells via G2/M cell cycle accumulation. This, in turn, promoted the proliferation and migration of CCA cells. ATZ exposure induced the upregulation of GPER and increased expression levels of PI3K, p-PI3K, Akt, p-Akt, NF-κB and PCNA. In contrast, following ATZ treatment, the GPER antagonist G15 significantly downregulated the GPER/PI3K/Akt/NF-κB pathway. These results suggest that ATZ promotes CCA cell proliferation and migration through the GPER/PI3K/Akt/NF-κB pathway. This information can enhance public health awareness regarding ATZ contamination to prevent the relative risk of CCA.

Equol production capability and family history as risk factors for hand osteoarthritis in menopausal and postmenopausal women. Cross-sectional study.

BACKGROUND: Hand disorders are common in menopausal women. Equol is a soy metabolite produced in humans and its production level differs among individuals. The purpose of this research is to investigate the correlative relationship between variables indicating equol production levels and the occurrence of hand disorders in menopausal and postmenopausal women. METHODS: Female subjects were divided into two groups: women 45-70 years of age with hand osteoarthritis (patient group) and women in the same age range without hand osteoarthritis (control group). The equol production level of each subject was estimated by measuring her urine equol concentration. We also surveyed the subjects' family histories of osteoarthritis. RESULTS: Equol levels in the patient group were significantly lower than those in the control group (p < 0.05). This difference was most apparent for women in their 50s. Individuals with family histories of Heberden's and Bouchard's nodes were found to be 48.1 times more likely to develop these conditions than individuals in the control group. CONCLUSIONS: Women with early menopausal hand symptoms (i.e., stiff and arthritic hands) often develop hand osteoarthritis during their late menopausal and postmenopausal periods, which may cause their QoL to significantly deteriorate. Although a link between the probability of women developing hand osteoarthritis and their clinical backgrounds (i.e., family history) had been suspected, it had not been thoroughly investigated. Our survey of women with and without Heberden's nodes and Bouchard's nodes found a significant correlation between the likelihood of women developing osteoarthritis and a family history of this disease. We also found a significant correlation between the likelihood of women developing hand osteoarthritis and their equol production levels. These results indicate that women with family histories of finger osteoarthritis and low equol production have higher risks of developing finger osteoarthritis.

Estrogen Receptors: A New Frontier in Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a long-term neurodegenerative condition that leads to the deterioration of neurons and synapses in the cerebral cortex, resulting in severe dementia. AD is significantly more prevalent in postmenopausal women, suggesting a neuroprotective role for estrogen. Estrogen is now known to regulate a wide array of physiological functions in the body by interacting with three known estrogen receptors (ERs) and with the ß-amyloid precursor protein, a key factor in AD pathogenesis. Recent experimental evidence indicates that new selective ER modulators and phytoestrogens may be promising treatments for AD for their neuroprotective and anti-apoptotic properties. These alternatives may offer fewer side effects compared to traditional hormone therapies, which are associated with risks such as cardiovascular diseases, cancer, and metabolic dysfunctions. This review sheds light on estrogen-based treatments that may help to partially prevent or control the neurodegenerative processes characteristic of AD, paving the way for further investigation in the development of estrogen-based treatments.

Glyphosate Exposure Induces Cytotoxicity, Mitochondrial Dysfunction and Activation of ERα and ERß Estrogen Receptors in Human Prostate PNT1A Cells.

Glyphosate, the active ingredient of several broad-spectrum herbicides, is widely used throughout the world, although many adverse effects are known. Among these, it has been recognized as an endocrine disruptor. This work aimed to test the effects and potential endocrine disrupting action of glyphosate on PNT1A human prostate cells, an immortalized non-tumor epithelial cell line, possessing both ERα and ERß estrogen receptors. The results showed that glyphosate induces cytotoxicity, mitochondrial dysfunction, and rapid activation of ERα and ERß via nuclear translocation. Molecular analysis indicated a possible involvement of apoptosis in glyphosate-induced cytotoxicology. The apoptotic process could be attributed to alterations in mitochondrial metabolism; therefore, the main parameters of mitochondrial functionality were investigated using the Seahorse analyzer. Impaired mitochondrial function was observed in glyphosate-treated cells, with reductions in ATP production, spare respiratory capacity, and proton leakage, along with increased efficiency of mitochondrial coupling. Finally, the results of immunofluorescence analysis demonstrated that glyphosate acts as an estrogen disruptor determining the nuclear translocation of both ERs. Nuclear translocation occurred independent of dose, faster than the specific hormone, and persisted throughout treatment. In conclusion, the results collected show that in non-tumor prostate cells glyphosate can cause cell death and acts as a xenoestrogen, activating estrogen receptors. The consequent alteration of hormonal functions can have negative effects on the reproductive health of exposed animals, compromising their fertility.

Comparison of FGF-8, FGF-10, FGF-Receptor 2, Androgen Receptor, Estrogen Receptor-A and SS in Healthy and Hypospadiac Children.

In this study, we aimed to investigate the levels of Fibroblast Growth Factor-8 (FGF-8), FGF-10, FGF-Receptor-2 (FGFR-2), Androgen receptor (AR), Estrogen receptor alpha and beta (ER-α and ER-ß) in the foreskins of children with and without hypospadias. Methods: Samples from the foreskins of 20 children with hypospadias and 20 skin samples from children without hypospadias between the ages of 14 months and 12 years were taken during circumcision or hypospadias correction surgery for immunohistochemical (IHC) examination of these markers. In IHC examination, it was shown that ER-α, ER-ß and AR receptors were more involved in the foreskin of children with hypospadias than in the fore-skin of without hypospadias children, and FGF-8, FGF-10 and FGFR-2 were lower (p<0.05). ER and AR uptake were higher in hypospadias tissue samples and FGF-8, FGF-10, and FGFR-2 uptakes were lower compared to without hypospadias children's tissue samples, and these factors were supported by affecting each other in the development of hypospadias. The limited number of studies on this subject in the literature and the contradictory results of the findings indicate that more research should be done on this subject in the future.

[Comparative immunohistochemistry study of different antibodies clones for detection of breast cancer markers (estrogen receptor, progesterone receptor, HER2/neu, Ki-67)]. / Sravnitel'noe issledovanie antitel razlichnykh klonov dlya vyyavleniya markerov raka molochnoi zhelezy (retseptorov estrogenov, progesterona, HER2/neu, Ki-67) immunogistokhimicheskim metodom.

OBJECTIVE: A comparative study of detection of breast cancer markers (estrogen receptors, progesterone receptors, HER2/neu, Ki-67) by immunohistochemical method with antibodies produced by PrimeBioMed (Russia) and antibodies produced by Roche Ventana (USA). MATERIAL AND METHODS: Surgical specimens and biopsies from 37 patients with invasive breast cancer were used. Sections were stained with antibodies of clones ER SP1 and GM030, PR 1E2 and PBM-5B8, HER2/neu 4B5 and PBM-46A6, Ki-67 30-9 and GM010. RESULTS: There was a high positive and significant correlation between the immunohistochemistry results and antibodies of the clones ER-SP1 and GM030, PR1E2 and PBM-5B8, HER2/neu4B5 and PBM-46A6, Ki-67 30-9 and GM010. CONCLUSION: The study showed the possibility of using antibodies of clones GM030, HER2/neu 4B5, PBM-46A6, GM010 (PrimeBioMed) on the Ventana Bench Marck Ultra automatic immunostainer using the detection system UltraView Universal DAB Detection Kit.

Dynamic Interplay between miRNAs and the Extracellular Matrix Influences the Tumor Microenvironment.

Expression of miRNAs is critical for the regulation of several cell functions including proliferation, migration, differentiation, and survival, as well as extracellular matrix (ECM) remodeling. The dynamic interplay between miRNAs, ECM macromolecules, and the tumor microenvironment plays critical roles in many aspects of human diseases such as metabolic disorders and cancers. Circulating and secreted miRNAs, via membrane vesicles, affect cell-cell communication and cellular metabolic pathways, underscoring their significance in tumor progression. The primary goal of this article is to highlight the importance of epigenetic regulatory factors, focusing on miRNA-mediated ECM reorganization and their functional relationships, and how matrix-mediated miRNAs affect tumor progression.

Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms.

Women are at twice the risk for anxiety and depression disorders as men are, although the underlying biological factors and mechanisms are largely unknown. In this review, we address this sex disparity at both the etiological and mechanistic level. We dissect the role of fluctuating sex hormones as a critical biological factor contributing to the increased depression and anxiety risk in women. We provide parallel evidence in humans and rodents that brain structure and function vary with naturally-cycling ovarian hormones. This female-unique brain plasticity and associated vulnerability are primarily driven by estrogen level changes. For the first time, we provide a sex hormone-driven molecular mechanism, namely chromatin organizational changes, that regulates neuronal gene expression and brain plasticity but may also prime the (epi)genome for psychopathology. Finally, we map out future directions including experimental and clinical studies that will facilitate novel sex- and gender-informed approaches to treat depression and anxiety disorders.