A High-Quality Photoswitchable Probe that Selectively and Potently Regulates the Transcription Factor RORγ.

Retinoic acid receptor-related orphan receptor γ (RORγ) is a nuclear hormone receptor with multiple biological functions. As an experimental therapeutic target in inflammation and immunity, there is great interest in spatially-localised RORγ inhibition; and its cyclic temporal role in circadian rhythms also makes it an intriguing target for time-resolved pharmacology. To create tools that can study RORγ biology with appropriate spatial and temporal resolution, we designed light-dependent inverse RORγ agonists by building azobenzene photoswitches into ligand consensus structures. Optimizations gave photoswitchable RORγ inhibitors with a large degree of potency photocontrol, plus remarkable on-target potency, plus excellent selectivity over related off-target receptors. This still-rare, but urgently-needed combination of performance features, distinguishes them as high quality photopharmaceutical probes; and they can now serve as high precision tools to study the spatial and dynamic intricacies of RORγ action in signaling and in inflammatory disorders.

Transcriptional profiling of mucus production in rhesus macaque endocervical cells under hormonal regulation.

OBJECTIVE: Endocervical mucus production is a key regulator of fertility throughout the menstrual cycle. With cycle-dependent variability in mucus quality and quantity, cervical mucus can either facilitate or block sperm ascension into the upper female reproductive tract. This study seeks to identify genes involved in the hormonal regulation of mucus production, modification, and regulation through profiling the transcriptome of endocervical cells from the non-human primate, the rhesus macaque (Macaca mulatta). INTERVENTION: We treated differentiated primary endocervical cultures with estradiol (E2) and progesterone (P4) to mimic peri-ovulatory and luteal-phase hormonal changes. Using RNA-sequencing, we identified differential expression of gene pathways and mucus producing and modifying genes in cells treated with E2 compared to hormone-free conditions and E2 compared to E2-primed cells treated with P4. MAIN OUTCOME MEASURES: We pursued differential gene expression analysis on RNA-sequenced cells. Sequence validation was done using qPCR. RESULTS: Our study identified 158 genes that show significant differential expression in E2-only conditions compared to hormone-free control, and 250 genes that show significant differential expression in P4-treated conditions compared to E2-only conditions. From this list, we found hormone-induced changes in transcriptional profiles for genes across several classes of mucus production, including ion channels and enzymes involved in post-translational mucin modification that have not previously been described as hormonally regulated. CONCLUSION: Our study is the first to use an in vitro culture system to create an epithelial-cell specific transcriptome of the endocervix. As a result, our study identifies new genes and pathways altered by sex-steroids in cervical mucus production.

Different Effects of Obesity and Fasting on the Expression of Type 3 Deiodinase and Thyroid Hormone Receptors in the Liver and Visceral Adipose Tissue of C57BL/6 Male Mice.

Introduction: Energy status can alter thyroid hormone signalling in different tissues. Little is known about the effect of fasting on the local thyroid hormone metabolism under high-fat diet (HFD)-induced obesity. We aimed to investigate the fasting effect on deiodinase type 3 (DIO3) and thyroid hormone receptors (TRs) expression in liver and visceral adipose tissue (VAT) of HFD-induced obese mice. Methods: The 30 male C57BL/6 mice were divided into three groups (n = 10/group): control (CON) group, obese (OB) group, and fasted obese (OBF) group. Materials: In a 14-week study, the expression levels of DIO3 and TRs in the liver and VAT of mice were measured by real-time polymerase chain reaction. Gene expression results were shown as fold changes defined by 2-ΔΔct. Comparison between groups was performed by using one-way-ANOVA or Kruskal-Wallis ANOVA test. Results: In the liver, there was a significantly lower expression of DIO3 and higher expression of TRs in obese fasted mice compared to obese mice. Compared to the lean mice, OBF mice had significantly lower expression of DIO3 and higher expression of TRß. In the VAT, mRNA expression of DIO3 was significantly increased in OBF and OB groups compared to the CON group. There were no significant differences in the mRNA expression of TRs between groups. Conclusion: Our findings suggest that fasting may be more effective in improving thyroid hormone metabolism in the liver rather than the VAT of obese mice.

Sex steroid hormones: an overlooked yet fundamental factor in oral homeostasis in humans.

Sex steroid hormones (SSH) are extremely versatile molecules with a myriad of physiological functions. Next to their well-known role in sexual development and reproduction, SSH play active roles in practically every tissue in the human body, including the oral cavity. It has long been demonstrated that periodontal tissues express SSH receptors and therefore are responsive to the presence of SSH. Interestingly, SSH not only interact with the periodontal tissues but also with other tissues in the oral cavity such as dental enamel, pulp, cementum, oral mucosa, and salivary glands. Questions concerning the possible physiological functions of these receptors and their role in maintenance of oral health, remain unanswered. The purpose of this scoping review was to gather and summarize all the available evidence on the role of SSH in physiological processes in the oral cavity in humans. Two comprehensive literature searches were performed. References were screened and selected based on title, abstract and full text according to our inclusion criteria. Both searches yielded 18,992 results of which 73 were included. Results were divided into four categories: (1) Periodontium; (2) Dental structure; (3) Mucosa; and (4) Salivary glands. The interaction of these tissues with progestagens, androgens and estrogens are summarized. Sex steroid hormones are an overlooked yet fundamental factor in oral homeostasis. They play important roles in the development and function of the periodontium, dental structure, mucosa and salivary glands. Dentists and healthcare providers should consider these hormonal factors when assessing and treating oral health conditions.

Effect of thyroid disruption on ovarian development following maternal exposure to Bisphenol S.

Thyroid hormones play a crucial role in numerous physiological processes, including reproduction. Bisphenol S (BPS) is a structural analog of Bisphenol A known for its toxic effects. Interference of this substitute with normal thyroid function has been described. To investigate the effect of thyroid disruption on ovarian development following maternal exposure to BPS, female rats were exposed, daily, to either AT 1-850 (a thyroid hormone receptor antagonist) (10 nmol/rat) or BPS (0.2 mg/kg) during gestation and lactation. The effects on reproductive outcome, offspring development, histological structures, hormone levels, oxidative status, cytoskeleton proteins expression, and oocyte development gene expression were examined. Our results are in favor of offspring ovarian development disruption due to thyroid disturbance in adult pregnant females. During both fetal and postnatal stages, BPS considerably altered the histological structure of the thyroid tissue as well as oocyte and follicular development, which led to premature ovarian failure and stimulation of oocyte atresia, being accompanied with oxidative stress, hypothalamic-pituitary-ovarian axis disorders, and cytoskeletal dynamic disturbance. Crucially, our study underscores that BPS may induce reproductive toxicity by blocking nuclear thyroid hormone receptors, evidenced by the parallelism and the perfect meshing between the data obtained following exposure to AT 1-850 and those after the treatment by this substitute.

Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components.

Objective: In this study, we investigated pivotal molecular markers in human high-grade breast ductal carcinoma in situ (DCIS). Expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) was measured among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched and triple-negative). Methods: In total, 357 DCIS cases were classified into respective subtypes, according to the 2013 St. Gallen guidelines. Each subtype was categorized into three subcategories: "Pure" (those without an invasive component), "W/invasive" (those with an invasive component), and "All" (the entire group of the given subtype). ER and PR expression were registered as intervals. Equivocal HER2 immunohistochemistry (IHC) cases (2+) were further investigated using dual-color in situ hybridization. Results: The majority of patients (71%) were over the age of 50. We discovered no significant differences in the proportion of age between the "Pure" and "W/invasive" groups. There was no significant difference in ER/PR expression between "Pure" luminal subtypes of DCIS and "W/invasive" cases. We compared the HER2 IHC scores of "0", "1+", and "2+" among LumA and LumB HER2 subtypes and identified no statistically significant differences between "Pure" and "W/invasive" (p = 0.603). ER and PR expression ≥ 50% cutoff value was present in > 90% of all LumA cases. The incidences of cases with ER expression at cutoff values of < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). The proportion of cases with PR expression < 20% showed significant differences in the various luminal subtypes. In luminal B subtypes, low PR expression (< 20%) was significantly associated with both strong HER2 expression (3+) and the presence of an invasive component (p = 0.0001 and p = 0.0365, respectively). Conclusions: ER and PR expression at ≥ 50% cutoff values were found in more than 90% of LumA cases. Samples with ER < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). Low PR expression in high-grade DCIS was strongly associated with HER2 overexpression (3+) and an invasive component (p = 0.0001 and p = 0.0365, respectively).

Hepatocyte vitamin D receptor functions as a nutrient sensor that regulates energy storage and tissue growth in zebrafish.

Vitamin D receptor (VDR) has been implicated in fatty liver pathogenesis, but its role in the regulation of organismal energy usage remains unclear. Here, we illuminate the evolutionary function of VDR by demonstrating that zebrafish Vdr coordinates hepatic and organismal energy homeostasis through antagonistic regulation of nutrient storage and tissue growth. Hepatocyte-specific Vdr impairment increases hepatic lipid storage, partially through acsl4a induction, while simultaneously diminishing fatty acid oxidation and liver growth. Importantly, Vdr impairment exacerbates the starvation-induced hepatic storage of systemic fatty acids, indicating that loss of Vdr signaling elicits hepatocellular energy deficiency. Strikingly, hepatocyte Vdr impairment diminishes diet-induced systemic growth while increasing hepatic and visceral fat in adult fish, revealing that hepatic Vdr signaling is required for complete adaptation to food availability. These data establish hepatocyte Vdr as a regulator of organismal energy expenditure and define an evolutionary function for VDR as a transcriptional effector of environmental nutrient supply.

Intrahepatic hypothyroidism in MASLD: Role of liver-specific thyromimetics including resmetirom.

BACKGROUND AND AIMS: Thyroid hormones are important regulators of hepatic lipid homeostasis and whole-body energy expenditure. Recent evidence suggests that euthyroid individuals with metabolic dysfunction-associated steatohepatitis (MASH) develop intrahepatic hypothyroidism that promotes progression of MASH. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases from inception till March 2024, using the following keywords: hypothyroidism and nonalcoholic fatty liver disease; MASLD and thyroid function; intrahepatic hypothyroidism; TRß agonists; and resmetirom. Relevant studies were extracted that described pathogenesis of MASH in the context of thyroid functions. RESULTS: In euthyroid individuals with MASH, there is decreased conversion of prohormone thyroxine (T4) to bioactive tri-iodothyronine (T3) and increased conversion of T4 to inactive metabolite reverse T3 (rT3). Consequently, reduced levels of T3 results in impaired intrahepatic TRß signaling, a state of intrahepatic hypothyroidism, which promotes progression of MASH. Hepatic TRß activation leads to metabolically beneficial effects in the liver including mitochondrial fatty acid uptake and ß-oxidation, mitochondrial biogenesis, increasing surface low-density lipoprotein (LDL) receptor density and lowering of circulatory LDL-cholesterol. In recent years, selective thyroid hormone mimetics that exhibit TRß-selective binding and liver-selective uptake have been designed. Resmetirom, a liver-specific thyromimetic, improves intrahepatic TRß signaling and in clinical trials significantly improved liver inflammation, fibrosis and lipid profile in patients with MASH. CONCLUSIONS: In euthyroid individuals with MASH, development of intrahepatic hypothyroidism results in further progression of the disease. In clinical trials, resmetirom treatment results in a significant improvement in steatosis, inflammation and fibrosis and is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of noncirrhotic MASH with moderate to advanced fibrosis.

Changes in expression of breast cancer tumor biomarkers between primary tumors and corresponding metastatic sites: common patterns and relationships with survival.

PURPOSE: In metastatic breast cancer, differences in expression patterns of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) between the primary tumor (PT) and metastatic site (MET) have been reported. However, there is limited understanding of the relationship of tumor subtype discordance and overall survival (OS). We evaluated patterns of ER/PR/HER2 in PTs and corresponding METs and assessed the relationship between these patterns and OS. METHODS: Patients diagnosed at our center with metastatic breast cancer (2011-2020) were included. ER/PR were stratified as < 1%/1-10%/ > 10% by immunohistochemistry and HER2 as positive/negative by immunohistochemistry/FISH. Tumor subtypes were classified as ER or PR + /HER2-, HER2+ , or triple-negative. Biomarker discordance data from PTs to METs were analyzed for expression patterns. OS was assessed. RESULTS: Of 254 patients, 41 (16.1%) had synchronous and 213 (83.9%) had metachronous METs. Category change of ER/PR/HER2 expression was observed in 56 (22.0%), 117 (40.5%), and 30 (11.8%) patients, respectively. Tumor subtype changed in 56 (22.0%) patients. We identified a difference between PT and MET from ER > 10% to ER < 1% (n = 28,16.2% p < 0.01); PR > 10% to PR < 1% (n = 54,48.2%, p < 0.001); PR > 10% to PR 1-10% (n = 18,16.1%, p < 0.001), and ER or PR+/HER2- to triple-negative (n = 19,13.0%, p = 0.03). In log-rank analysis, change from an ER or PR+/HER2- (5-year OS 88.6%) PT to a HER2+(67.5%) or triple-negative (54.6%) MET was associated with decreased survival (p < 0.01); however, in multivariate analysis, discordant biomarker expression was not associated with decreased survival (p > 0.05). CONCLUSION: Tumor expression of ER/PR/HER2 can differ between the PT and MET. Loss of ER/PR expression is common and may be related to worse survival. Routine assessment of MET tumor markers could inform prognosis and therapeutic decision-making.

Development of new steroid-based hydrazide and (thio)semicarbazone compounds with anticancer properties.

Most breast and prostate cancers are caused by abnormal production or action of steroidal hormones. Hormonal drugs based on steroid scaffolds represent a significant class of chemotherapeutics that are routinely used in chemotherapy. In this study, the synthesis of new 17a-homo lactone and 17α-(pyridine-2-ylmethyl) androstane derivatives with hydrazide and semicarbazone motifs is presented. All compounds were screened for their effect on cell viability against a panel of five cancer cell lines and one healthy cell line. Two compounds showed significant cytotoxicity against cancer cells, with low toxicity against healthy cells. The relative binding affinities of compounds for the ligand-binding domains of estrogen receptor α, estrogen receptor ß, androgen receptor and glucocorticoid receptor were tested using a fluorescence screen in yeast. Potential for inhibition of aldo-keto reductase 1C3 and 1C4 activity was measured in vitro. Experimental results are analyzed in the context of molecular docking simulations. Our results could help guide design of steroid compounds with improved anticancer properties against androgen- and estrogen-dependent cancers.

Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model.

Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, and it is associated with alterations in the expression of hormone receptors and inflammation. Estetrol (E4) is a weak estrogen that recently has been approved for contraception. We evaluated the effect of E4 on the growth of endometriotic-like lesions and the expression of TNF-α, estrogen receptors (ERs), and progesterone receptors (PRs) in an in vivo murine model. Endometriosis was induced surgically in female C57BL/6 mice. E4 was delivered via Alzet pump (3 mg/kg/day) from the 15th postoperative day for 4 weeks. E4 significantly reduced the volume (p < 0.001) and weight (p < 0.05) of ectopic lesions. Histologically, E4 did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) (p < 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, p < 0.05) and increased lipid peroxidation (TBARS/MDA, p < 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-α decreased (p < 0.05) and mRNA expression of Esr2 reduced (p < 0.05), in contrast with the increased expression of Esr1 (p < 0.01) and Pgr (p < 0.05). The present study demonstrates for the first time that E4 limited the development and progression of endometriosis in vivo.

Immunophenotypic analysis of angiomyolipoma with epithelial cysts, comparison to mixed epithelial and stromal tumors and epithelial and stromal elements of normal kidney and ovaries.

Angiomyolipoma with epithelial cysts (AMLEC) is a rare variant of renal angiomyolipoma (AML). It is characterized by a conventional AML component admixed with epithelial cysts within an "ovarian-like" stroma. Mixed epithelial and stromal tumor (MEST) is another renal neoplasm featuring epithelial cysts and "ovarian-like" stroma. While there is consensus that in MEST the epithelial and stromal components are neoplastic, in AMLEC it has been hypothesized that the epithelial component may represent renal tubular entrapment or ovarian-like transdifferentiation of tumor cells. The aim of this study was to compare the immunophenotypes of the epithelial-stromal components of AMLEC and MEST, with normal kidney and ovary to provide additional insights into the pathogenesis and relationships of these entities. In this study, we analyzed eight cases of AMLEC and 14 cases of MEST from 2003 to 2023. We used tissue microarrays, full sections, or unstained slides with an immunohistochemical panel including renal and ovarian markers: SF1, ER, PR, AR, PAX8, WT1, GATA3, CA-IX, p16, inhibin A, and BCL2. We compared these cases with ten non-neoplastic ovary and kidney samples. Our findings indicate that the epithelial component of AMLEC and MEST resembles hormone receptor positive renal tubular epithelium (AR + /ER - /PR -). AMLEC's stromal component resembled hormone receptor positive renal stroma, while MEST's resembled ovarian stroma, supporting mullerian transdifferentiation. Our study showed that the epithelial and stromal components of AMLEC and MEST are immunophenotypically different and also differ from normal tissues. Our findings suggest that in AMLEC, the epithelial-stromal component represents a hormonally driven proliferation of non-neoplastic renal elements within a dysregulated tumor microenvironment.

Global untargeted and individual targeted plasma metabolomics of breast cancer recurrence modified by hormone receptors.

BACKGROUND: Breast cancer is a heterogeneous and complex etiological disease. Understanding perturbations of circulating metabolites could improve prognosis. METHODS: We recruited breast cancer patients from Kaohsiung Medical University (KMU) to perform untargeted (case-control design) and targeted (patient cohort) metabolomics analyses in the discovery and validation phases to evaluate interaction effects between clinical factors and plasma metabolites using multivariable Cox proportional hazards model. RESULTS: In the discovery phase, partial least squares-discriminant analysis (PLS-DA) showed that plasma metabolites were significantly different between recurrent and non-recurrent breast cancer patients. Metabolite set enrichment analysis (MSEA) and metabolomic pathway analysis (MetPA) showed that valine, leucine, and isoleucine degradation was the significant pathway, and volcano plot showed significant ten upregulated and two downregulated metabolites between recurrent and non-recurrent cases. Combined with receiver operating characteristic (ROC) curve and biological significance, creatine, valine, methionine, and mannose were selected for the validation phase. In this patient cohort with 41 new-recurrent vs. 248 non-recurrent breast cancer cases, followed for 720.49 person-years, compared with low level of valine, high valine level was significantly negatively associated with recurrent breast cancer (aHR: 0.36, 95% CI: 0.18-0.72, P = 0.004), especially in ER-negative and PR-negative status. There were interaction effects between valine and ER (Pinteraction = 0.006) as well as PR (Pinteraction = 0.002) on recurrent breast cancer. After Bonferroni correction, stratification effects between valine and hormone receptors were still significant. CONCLUSION: Our study revealed that plasma metabolites were significantly different between recurrent and non-recurrent patients, proposing therapeutic insights for breast cancer prognosis.

Synthesis, in vitro and in silico anticancer evaluation of novel pyridin-2-yl estra-1,3,5(10)-triene derivatives.

Aim: The aim of this study was the synthesis of steroid compounds with heterocyclic rings and good anticancer properties. Materials & methods: The synthesis, in silico and in vitro anticancer testing of novel pyridin-2-yl estra-1,3,5(10)-triene derivatives was performed. Results: All synthesized compounds have shown promising results for, antiproliferative activity, relative binding affinities for the ligand binding domains of estrogen receptors α, ß and androgen receptor, aromatase binding potential, and inhibition of AKR1C3 enzyme. Conclusion: 3-Benzyloxy (17E)-pycolinilidene derivative 9 showed the best antitumor potential against MDA-MB-231 cell line, an activity that can be explained by its moderate inhibition of AKR1C3. Molecular docking simulation indicates that it binds to AKR1C3 in a very similar orientation and geometry as steroidal inhibitor EM1404.

The series of pyridine-containing estra-1,3,5(10)-triene derivatives was synthesized. One novel derivative stood out by its excellent activity against the MDA-MB-231 cell line. This activity can be explained by its moderate inhibition of the AKR1C3 enzyme.

Influence of tumor microenvironment on the different breast cancer subtypes and applied therapies.

Despite the significant improvements made in breast cancer therapy during the last decades, this disease still has increasing incidence and mortality rates. Different targets involved in general processes, like cell proliferation and survival, have become alternative therapeutic options for this disease, with some of them already used in clinic, like the CDK4/6 inhibitors for luminal A tumors treatment. Nevertheless, there is a demand for novel therapeutic strategies focused not only on tumor cells, but also on their microenvironment. Tumor microenvironment (TME) is a very complex and dynamic system that, more than surrounding and supporting tumor cells, actively participates in tumor development and progression. During the last decades, it has become clear that the cellular and acellular components of TME differ between the various breast cancer subtypes and shape the differences regarding their severity and prognosis. The pivotal role of the TME in controlling tumor growth and influencing responses to therapy represents a potential source for novel targets and therapeutic strategies. In this review, we present a description of the multiple therapeutic options used for different breast cancer subtypes, as well as the influence that the TME may exert on the development of the disease and on the response to the distinct therapies, which in some cases may explain their failure by the occurrence of relapses and resistance. Furthermore, the ongoing studies focused on the use of TME components for developing potential cancer treatments are described.

Estrogen α and ß Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model.

Glioblastoma multiforme (GBM) is a malignant tumor with a higher prevalence in men and a higher survival rate in transmenopausal women. It exhibits distinct areas influenced by changing environmental conditions. This study examines how these areas differ in the levels of estrogen receptors (ERs) which play an important role in the development and progression of many cancers, and whose expression levels are often correlated with patient survival. This study utilized two research models: an in vitro model employing the U87 cell line and a second model involving tumors resected from patients (including tumor core, enhancing tumor region, and peritumoral area). ER expression was assessed at both gene and protein levels, with the results validated using confocal microscopy and immunohistochemistry. Under hypoxic conditions, the U87 line displayed a decrease in ERß mRNA expression and an increase in ERα mRNA expression. In patient samples, ERß mRNA expression was lower in the tumor core compared to the enhancing tumor region (only in males when the study group was divided by sex). In addition, ERß protein expression was lower in the tumor core than in the peritumoral area (only in women when the study group was divided by sex). Immunohistochemical analysis indicated the highest ERß protein expression in the enhancing tumor area, followed by the peritumoral area, and the lowest in the tumor core. The findings suggest that ER expression may significantly influence the development of GBM, exhibiting variability under the influence of conditions present in different tumor areas.

An Integrated Approach of Bioassays and Non-Target Screening for the Assessment of Endocrine-Disrupting Activities in Tap Water and Identification of Novel Endocrine-Disrupting Chemicals.

The safety of drinking water is a significant environmental issue of great concern for human health since numerous contaminants are often detected in drinking water and its sources. Boiling is a common household method used to produce relatively high-quality drinking water in some countries and regions. In this study, with the aid of an integrated approach of in vitro bioassays and non-target analysis based on high-resolution mass spectrometry coupled with liquid chromatography, alterations in endocrine-disrupting activities in tap water samples without and with boiling were revealed, as well as the potential endocrine-disrupting chemicals (EDCs) contributing to these alterations were identified. The organic extracts of tap water had no significant (ant)agonistic activities against an estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) at enrichment concentrations of ≤10 times, posing no immediate or acute health risk to humans. However, the presence of agonistic activities against PR and MR and antagonistic activities against ER, PR, GR, and MR in OEs of tap water at relatively higher enrichment concentrations still raise potential health concerns. Boiling effectively reduced antagonistic activities against these steroid hormone receptors (SHRs) but increased estrogenic and glucocorticoid activities in drinking water. Four novel potential EDCs, including one UV filter (phenylbenzimidazole sulfonic acid, PBSA) and three natural metabolites of organisms (beta-hydroxymyristic acid, 12-hydroxyoctadecanoic acid, and isorosmanol) were identified in drinking water samples, each of which showed (ant)agonistic activities against different SHRs. Given the widespread use of UV filters in sunscreens to prevent skin cancer, the health risks posed by PBSA as an identified novel EDC are of concern. Although boiling has been thought to reduce the health risk of drinking water contamination, our findings suggest that boiling may have a more complex effect on the endocrine-disrupting activities of drinking water and, therefore, a more comprehensive assessment is needed.

Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study.

Dihydroxylated polybrominated diphenyl ethers (DiOH-PBDEs) could be the metabolites of PBDEs of some organisms or the natural products of certain marine bacteria and algae. OH-PBDEs may demonstrate binding affinity to thyroid hormone receptors (TRs) and can disrupt the functioning of the systems modulated by TRs. However, the thyroid hormone disruption mechanism of diOH-PBDEs remains elusive due to the absence of diOH-PBDEs standards. This investigation explores the potential disruptive effects of OH/diOH-PBDEs on thyroid hormones via competitive binding and coactivator recruitment with TRα and TRß. At levels of 5000 nM and 25,000 nM, 6-OH-BDE-47 demonstrated significant recruitment of steroid receptor coactivator (SRC), whereas none of the diOH-PBDEs exhibited SRC recruitment within the range of 0.32-25,000 nM. AutoDock CrankPep (ADCP) simulations suggest that the conformation of SRC and TR-ligand complexes, particularly their interaction with Helix 12, rather than binding affinity, plays a pivotal role in ligand agonistic activity. 6,6'-diOH-BDE-47 displayed antagonistic activity towards both TRα and TRß, while the antagonism of 3,5-diOH-BDE-100 for TRα and TRß was concentration-dependent. 3,5-diOH-BDE-17 and 3,5-diOH-BDE-51 exhibited no discernible agonistic or antagonistic activities. Molecular docking analysis revealed that the binding energy of 3,3',5-triiodo-L-thyronine (T3) surpassed that of OH/diOH-PBDEs. 3,5-diOH-BDE-100 exhibited the highest binding energy, whereas 6,6'-diOH-BDE-47 displayed the lowest. These findings suggest that the structural determinants influencing the agonistic and antagonistic activities of halogen phenols may be more intricate than previously proposed, involving factors beyond high-brominated PBDEs or hydroxyl group and bromine substitutions. It is likely that the agonistic or antagonistic propensities of OH/diOH-PBDEs are instigated by protein conformational changes rather than considerations of binding energy.

The value of oestrogen receptor, progesterone receptor and keratins 5 and 14 immunohistochemistry in the evaluation of epithelial proliferations at cauterised margins in breast-conserving surgery specimens.

In breast conservative surgery, it is sometimes difficult to decide whether the cauterised tissue at the inked margin represents normal / hyperplastic or neoplastic tissue. We retrospectively assessed the value of ER, PR, CK5 and CK14 IHC in clarifying the nature of cauterised tissues at the margins concerning 34 lesions of 23 patients. 27 cases belonged to lesions that could not be adequately classified on the basis of the HE stains. Two thirds of them could be classified as non-neoplastic or neoplastic and two thirds of the remaining could be favourised as neoplastic or non-neoplastic, with 3/27 cases remaining uncertain. All 4 IHC reactions were helpful in classifying the lesions in almost half of the cases. However, 3 or 4 immunostains were supportive of the classification in 19/27. The most useful stains were the keratins, generally demonstrating a matching pattern of cell labelling with CK5 and CK14. ER and PR were somewhat less useful in classifying uncertain lesions. Considering all the 27 questionable lesions, IHC with ER, PR, CK5 and CK14 clarified the lesions at the cauterised margins in 23 cases. Taken all these considerations into account, CK5, CK14, PR and ER IHC may help in distinguishing between cautery damaged neoplastic and non-neoplastic tissues. All four IHC may yield the best support for decision making, but CK5 and/or CK14 may be sufficient in their own. The essential approach is that the results must be interpreted with caution, in the context of the given patient's disease, to avoid misinterpretations.

Epigenetic Switches in Retinal Homeostasis and Target for Drug Development.

Retinal homeostasis, a tightly regulated process maintaining the functional integrity of the retina, is vital for visual function. Emerging research has unveiled the critical role of epigenetic regulation in controlling gene expression patterns during retinal development, maintenance, and response to mutational loads and injuries. Epigenetic switches, including DNA methylation, histone modifications, and non-coding RNAs, play pivotal roles in orchestrating retinal gene expression and cellular responses through various intracellular, extracellular, and environmental modulators. This review compiles the current knowledge on epigenetic switches in retinal homeostasis, providing a deeper understanding of their impact on retinal structural integrity and function and using them as potential targets for therapeutic interventions.