Steroid Hormones Research Articles

Cell-cycle machinery is critical in regulating uterine steroid hormone for embryo implantation and development

Cell-cycle machinery is critical in regulating uterine steroid hormone for embryo implantation and development

Molecular Interactions of the Plant Steroid Hormone Epibrassinolide on Human Drug-Sensitive and Drug-Resistant Small-Cell Lung Carcinoma Cells

Background: Small-cell lung cancer (SCLC) has a poor prognosis because it is often diagnosed after it has spread and develops multi-drug resistance. Epibrassinolide (EB) is a plant steroid hormone with widespread distribution and physiological effects. In plants, EB-activated gene expression occurs via a GSK-mediated signaling pathway, similar to Wnt-β-catenin signaling in animal cells that is elevated in cancer cells. Methods: This mechanistic parallel prompted investigations of the molecular interactions of EB on drug-sensitive (H69) and multi-drug-resistant (VPA) SCLC cells. Cellular and molecular investigations were performed. Results: Pharmacologic interactions between EB and the Wnt signaling inhibitors IGC-011 and PRI-724 were determined by the combination index method and showed antagonism, indicating that EB acts on the same pathway as these inhibitors. Following incubation of drug-sensitive and drug-resistant SCLC cells with EB, there was a reduction in β-catenin (e.g., 3.8 to 0.7 pg/µg protein), accompanied by a reduction in β-catenin promoter activity, measured by firefly luciferase-coupled promoter element transfection. Cellular β-catenin concentration is regulated by the active form of GSK3β. In Wnt signaling, active GSK3β is converted to inactive pGSK3β, thereby increasing the concentration of β-catenin. After incubation of SCLC cells with EB, there was a reduction in the inactive form (pGSK3β) and a relative increase in the active form (GSK3β). In vitro enzyme assays showed that EB did not inhibit purified GSK3β, but there was non-competitive inhibition when SCLC cell extracts were used as the source of enzyme. This indirect inhibition by EB indicates that it may act on the Wnt pathway by blocking the phosphorylation of GSK3β. The protein levels of three SCLC tumor markers, namely, NSE, CAV1, and MYCL1, were elevated in drug-resistant SCLC cells. EB incubation led to a significant reduction in the levels of the three markers. Two major effects of EB on SCLC cells are the promotion of apoptosis and the reversal of drug resistance. Transcriptional analyses showed that after exposure of SCLC cells to EB, there were increases in the expression of genes encoding apoptotic inducers (e.g., BAX and FAS) and effectors (e.g., CASP3) and reductions in the expression of genes encoding apoptosis inhibitors (e.g., survivin). PGP1 and MRP1, two membrane efflux pumps expressed in SCLC cells, were elevated in drug-resistant cells, but EB incubation did not affect these protein levels. Cellular assays of drug efflux by PGP1 showed an increase in drug-resistant cells, but EB did not alter efflux activity. Following exposure to human liver microsomes, EB was metabolized by NADPH-dependent oxidation and UDPG-dependent glucuronidation, as evidenced by the elimination of EB cytotoxicity against SCLC cells. Conclusions: Taken together, these data indicate that EB, a steroid hormone in plants consumed in the human diet, is pharmacologically active in drug-sensitive and drug-resistant SCLC cells in the Wnt signaling pathway, alters apoptotic gene expression, and is a substrate for microsomal modifications.

Abstract B074: Intrinsic subtypes in Ethiopian breast cancer patients: Implications for better care

Abstract Objective: The recent development of multi-gene assays for gene expression profiling has contributed significantly to the understanding of the clinically and biologically heterogeneous breast cancer (BC) disease. PAM50 is one of these assays used to stratify BC patients and individualize treatment. The present study was conducted to characterize PAM50-based intrinsic subtypes among Ethiopian BC patients. Patients and methods: Formalin-fixed paraffin- embedded tissues were collected from 334 BC patients who attended five different Ethiopian health facilities. All samples were assessed using the PAM50 algorithm for intrinsic subtyping. Results: The tumor samples were classified into PAM50 intrinsic subtypes as follows: 104 samples (31.1%) were luminal A, 91 samples (27.2%) were luminal B, 62 samples (18.6%) were HER2-enriched and 77 samples (23.1%) were basal-like. The intrinsic subtypes were found to be associated with clinical and histopathological parameters such as steroid hormone receptor status, HER2 status, Ki-67 proliferation index and tumor differentiation, but not with age, tumor size or histological type. An immunohistochemistry-based classification of tumors (IHC groups) was found to correlate with intrinsic subtypes. Conclusion: The distribution of the intrinsic subtypes confirms previous immunohistochemistry-based studies from Ethiopia showing potentially endocrine-sensitive tumors in more than half of the patients. Health workers in primary or secondary-level health care facilities can be trained to offer endocrine therapy to improve breast cancer care. Additionally, the findings indicate that PAM50-based classification offers a robust method for the molecular classification of tumors in the Ethiopian context. Citation Format: Zelalem Desalegn Woldesonbet, Meron Yohannes, Martin Porsch, Kathrin Stückrath, Endale Anberber, Pablo Santos, Marcus Bauer, Adamu Addissie, Yonas Bekuretsion, Mathewos Assefa, Yasin Worku, Lesley Taylor, Tamrat Abebe, Eva J Kantelhardt, Martina Vetter. Intrinsic subtypes in Ethiopian breast cancer patients: Implications for better care [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B074.

Progesterone supplemented uterine epithelial cell co-culture improves in vitro quality embryo production in buffalo

Objectives: The present study was conducted to study the effect of progesterone and uterine luminal epithelial cells monolayer on blastocyst development and hatching rate. Material and Methods: The isolation, culture, and characterization of slaughterhouse-derived uterine epithelial cells were done using standard protocol. The steroid hormones estrogen and progesterone were supplemented in embryo developmental media (EDM), and day 04 embryos were cultured in different groups as progesterone supplementation (T1), co-cultured with epithelial cell monolayer (T2), co-cultured with progesterone supplemented epithelial cell monolayer (T3), or without any treatment (control). Finally, the effect of different treatments was analyzed in terms of blastocyst and hatching rate. Results: The isolated epithelial cells depicted compact cuboidal or columnar morphology at the confluence. Immunocytochemical localization and polymerase chain reaction study revealed positive expression of cytokeratin and absence of vimentin. Significantly higher blastocyst and hatching rates were noted in the T3 group, followed by T2, T1, and control groups. Conclusion: The present study revealed improved in vitro embryo production after co-culturing embryos with progesterone-supplemented uterine epithelial cells in buffalo.

Comparative Transcriptome Analysis of Sexual Differentiation in Male and Female Gonads of Nao-Zhou Stock Large Yellow Croaker (Larimichthys crocea)

The Nao-zhou stock large yellow croaker (Larimichthys crocea) is a unique economic seawater fish species in China and exhibits significant dimorphism in both male and female phenotypes. Cultivating all-female seedlings can significantly improve breeding efficiency. To accelerate the cultivation process of all female seedlings of this species, it is necessary to deeply understand the regulatory mechanisms of sexual differentiation and gonadal development. This study used Illumina high-throughput sequencing to sequence the transcriptome of the testes and ovaries of Nao-zhou stock large yellow croaker to identify genes and molecular functions related to sex determination. A total of 10,536 differentially expressed genes were identified between males and females, including 5682 upregulated and 4854 downregulated genes. Functional annotation screened out 70 important candidate genes related to sex, including 34 genes highly expressed in the testis (including dmrt1, foxm1, and amh) and 36 genes highly expressed in the ovary (including gdf9, hsd3b1, and sox19b). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis found that differentially expressed genes were significantly enriched in nine signaling pathways related to sex determination and gonadal development, including steroid hormone biosynthesis, MAPK signaling pathway, and the TGF-beta signaling pathway. By screening sex-related differentially expressed genes and mapping protein–protein interaction networks, hub genes such as dmrt1, amh, and cyp19a1a were found to be highly connected. The expression levels of 15 sex-related genes, including amh, dmrt1, dmrt2a, foxl1, and zp3b, were determined by qRT–PCR and RNA sequencing. This study screened for differentially expressed genes related to sex determination and differentiation of Nao-zhou stock large yellow croaker and revealed the signaling pathways involved in gonad development of male and female individuals. The results provide important data for future research on sex determination and differentiation mechanisms, thereby providing a scientific basis for the cultivation of all-female seedlings.

A roadmap to reduce the incidence and mortality of breast cancer by rethinking our approach to women’s health

Abstract Despite progress, breast cancer remains the most feared disease among women. In the USA alone, the incidence is now almost 300,000 new cancers per year, a rate that has nearly doubled in the last 30 years. Most women survive, but over 40,000 women a year still die of their disease National Cancer Institute [Internet]. [cited 2024 Nov 4]. Cancer of the Breast (Female) - Cancer Stat Facts. Available from: https://seer.cancer.gov/statfacts/html/breast.html. It is the most diagnosed cancer among women and the second leading cause of cancer death. Important disparities exist in breast cancer outcomes among African American women, where women die of breast cancer at higher rates, are diagnosed younger, and at a more advanced stage. We are proposing a radical shift in our thinking about breast cancer prevention with an aspiration to dramatically lower breast cancer incidence. Most breast cancers are driven by steroid hormones. Throughout the life course, women are offered an array of hormonal treatments for menstrual cycle control, family planning, in vitro fertilization, postpartum weaning, and menopausal symptom management. There are mixed data on the extent to which each of these may contribute to increased or decreased risk for breast cancer. These endocrine manipulations could represent a great opportunity to potentially reduce breast cancer incidence and improve quality of life for survivors. To date, they have not been designed to explicitly reduce breast cancer risk. A new holistic approach will require scientists, drug developers, breast oncologists, obstetricians, gynecologists, endocrinologists, radiologists, and family medicine/internists to work together toward the common goal of reducing breast cancer risk while addressing other critical issues in women’s health.

Estrogen Regulates Ca2+ to Promote Mitochondrial Function Through G-Protein-Coupled Estrogen Receptors During Oocyte Maturation

Estrogen is a steroid hormone that plays a key role in regulating many physiological processes, such as follicle activation and development and oocyte maturation in mammals. Ca2+ is crucial in oogenesis, oocyte maturation, ovulation, and fertilization. However, the mechanism by which estrogen regulates Ca2+ during oocyte maturation in mice has not been reported. This study revealed that Ca2+ levels in oocytes significantly increase during the 4–12 h period in vitro. Oocytes treated with 0.1 µM estrogen and 1 µM G1, a G-protein-coupled estrogen receptor (GPER) agonist, showed significantly increased Ca2+ levels, while treatment with 1 µM G15, an antagonist of GPER, significantly decreased Ca2+ levels. Notably, estrogen regulates Ca2+ in oocytes through the GPER pathway and promotes the expression of the Ca2+-producing protein EPAC1. In addition, estrogen alleviates the inhibitory effect of the Ca2+ chelator BAPTA-AM during oocyte maturation by promoting Ca2+ production. Furthermore, estrogen can promote the expression of the mitochondrial generation-associated protein SIRT1 through the GPER pathway, alleviate mitochondrial oxidative damage caused by BAPTA-AM, and restore the mitochondrial membrane potential level. Collectively, this study demonstrates that estrogen can regulate Ca2+ through the GPER-EPAC1 pathway and promote the expression of SIRT1, which promotes oocyte mitochondrial function during oocyte maturation.

DDDR-32. EXPLORING ANDROGENIC MODULATION IN GLIOBLASTOMA: POTENCY AND SELECTIVITY OF NOVEL NORETHINDRONE DERIVATIVES

Abstract BACKGROUND Glioblastoma (GBM) represents the most frequently diagnosed malignant CNS tumor in adults and remains incurable. Despite the identification of several oncogenic drivers contributing to tumor formation, targeted therapy with brain-penetrant inhibitors has afforded little progress in survival outcomes. Interestingly, gender has been shown to increase the incidence of GBM, with men having roughly a 50-60% increase in incidence compared to women in the US. This statistic led to research on the involvement of and subsequent inhibition of androgen synthesis and signaling in cell culture models and tumor samples. METHODS To further investigate the potential involvement of steroidal hormones in GBM proliferation, our lab synthesized a series of norethindrone (NE) derivatives with varied molecular weights, steric bulk, and lipophilicity to modulate the androgenic activity of NE. The small library was tested in several GBM cell lines, including U87, A172, and T98G cells, using cell viability assays. RESULTS One derivative, a lipophilically modified version of NE synthesized via a one-pot click reaction, was shown to have improved potency compared with parental NE (>5-fold). The lipophilic NE derivative had IC50 value of 22 uM, 15 uM, and 35 uM in the U87, A172, and T98G cells, respectively. This molecule was tested in immortalized normal human astrocyte (NHA) cells and found to have an IC50 value of 34 uM suggesting some selectivity. DISCUSSION Given this derivative’s activity in GBM models and modest selectivity, we plan to screen it in additional GBM cell lines (LN-18 and U251) and eventually in glioma stem cell models. Future research will focus on identifying key targets involved in the mechanism of action, including the impact of lipophilic addition to the steroid nucleus and its effect on androgenic activity and downstream signaling. We will investigate these effects using RPPA and co-treatments with androgen receptor antagonists and 5-alpha reductase inhibitors.

Triple-template surface imprinted magnetic polymers for wide-coverage extraction of steroid hormones from human serum

Triple-template surface imprinted magnetic polymers for wide-coverage extraction of steroid hormones from human serum

Responses in organs, sperm, steroid hormones and CYP450 enzyme in male mice treated by quinestrol only or in conjunction with clarithromycin

Pest rodents persistently undermine crop yields and food security. Fertility control could be a viable alternative for managing rodent populations. This study investigates the antifertility effects of various concentrations of clarithromycin combined with 1.0 mg/kg quinestrol on male rodents to determine an effective contraceptive dose that minimizes quinestrol usage, addressing key concerns such as potential environmental residue, which may impact ecological balance, and poor palatability, which could reduce ingestion and limit the sterilant’s effectiveness. Male mice were divided into five groups and administered different doses of clarithromycin or clarithromycin and quinestrol for three consecutive days, while the control group received sunflower seed oil only. After seven days, organ weights, reproductive organ weights, sperm density, serum hormone levels, and CYP3A4 content in small intestinal and liver tissues were measured to assess persistent effects. Compared with the control group, all treatment groups had significant reductions in epididymal weight, seminal vesicle weight, and serum T and LH levels. Higher concentrations of clarithromycin (2 mg/kg and 10 mg/kg) significantly impacted reproductive metrics, including sperm density, organ weights, and serum LH and testosterone levels, though complete sterilization was not achieved, with more than 60 million cauda epididymal spermatozoa remaining. However, the combination demonstrated potential as an effective strategy for male fertility control. The combination of 2.0 mg/kg clarithromycin and quinestrol can mitigate organ enlargement seen with quinestrol alone. This combination also decreased total enzyme content, thereby diminishing quinestrol’s induction of CYP3A4, which may increase the sterilization effectiveness of the treatment.

Susceptibility of Human Spermatozoa to Titanium Dioxide Nanoparticles: Evaluation of DNA Damage and Biomarkers

Nowadays, developing countries have seen a reduction in male reproductive parameters, and it has been linked to the exposure of endocrine disrupting chemicals (EDCs), which are able to mimic or disrupt steroid hormone actions. Also, nanoparticles have shown effects on the male reproductive system, in particular the use of TiO2-NPs in drugs, cosmetics, and food as pigment additives, and, thanks to their small size (1–100 nm), provide themselves the opportunity to be internalized by the body and pass the blood–testis barrier (BTB). Therefore, TiO2-NPs can act on spermatogenesis and spermatozoa. In this study, we carried out an in vitro assay on human spermatozoa to evaluate the effects of TiO2-NPs at the concentrations of 500, 250, 100, and 50 ppm. Exposure did not statistically alter sperm parameters (e.g., motility and viability) but induced damage to sperm DNA and the expression of biomarkers by spermatozoa. This immunofluorescence investigation showed a positivity for biomarkers of stress (HSP70 and MTs) on the connecting piece of spermatozoa and also for sex hormone binding globulin (SHBG) biomarkers. The SHBG protein acts as a carrier of androgens and estrogens, regulating their bioavailability; therefore, its expression in the in vitro assay did not rule out the ability of TiO2-NPs to act as endocrine disruptors.

Ovarian Steroid Cell Tumor About a Case

Tumors of the sex cords and stroma of the ovary are relatively rare, accounting for around 8% of all primary ovarian tumors. Steroid cell tumors of the ovary are rare, accounting for less than 0.1% of all ovarian tumors. The majority of these tumors produce steroid hormones, and only 10-15% of patients are asymptomatic. Although steroid cell tumors are generally benign, there is a risk of malignant transformation. Surgery is the main treatment. We report a case of a steroid cell tumour of the left ovary discovered on anatomopathological examination of the left adnexectomy operative specimen in a 47-year-old hypertensive diabetic patient who clinically presented with virilism with severe hirsutism, muscular and clitoral hypertrophy and frontotemporal baldness, and biologically increased androgens without associated hypercorticism, and in whom an abdomino-pelvic scanner showed a left latero-uterine mass measuring 74x66x64 mm, pelvic MRI showed a polylobed left ovarian mass classified ORADS 5, measuring 53x65x87 mm. After histological confirmation of the diagnosis, the patient was taken back for total surgery with total hysterectomy, right adnexectomy, omentectomy, appendectomy, multiple peritoneal biopsies, with no signs of malignancy on histological examination, simple postoperative follow-up and our patient placed under surveillance.

Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways

AbstractHormone therapy resistance and the ensuing aggressive tumor progression present a significant clinical challenge. However, the mechanisms underlying the induction of tumor malignancy upon inhibition of steroid hormone signaling remain poorly understood. Here, we demonstrate that Drosophila malignant epithelial tumors show a similar reduction in ecdysone signaling, the main steroid hormone pathway. Our analysis of ecdysone-induced downstream targets reveals that overexpression of the nuclear receptor E75, particularly facilitates the malignant transformation of benign tumors. Genome-wide DNA binding profiles and biochemistry data reveal that E75 not only binds to the transcription factors of both Hippo and Notch pathways, but also exhibits widespread co-binding to their target genes, thus contributing to tumor malignancy. We further validated these findings by demonstrating that depletion of NR1D2, the mammalian homolog of E75, inhibits the activation of Hippo and Notch target genes, impeding glioblastoma progression. Together, our study unveils a novel mechanism by which hormone inhibition promotes tumor malignancy, and describes an evolutionarily conserved role of the oncogene E75/NR1D2 in integration of Hippo and Notch pathway activity during tumor progression.

Based on Serum Pharmacochemistry and Metabolomics Studied the Pharmacodynamic Material Basis and Mechanism of Rubi Fructus (Fupenzi) in Improving the Symptom of Kidney-Yang Deficiency.

Rubi fructus (Fupenzi) is the immature fruit of East China Rubi fructus, which is widely used in medicine, food, health food and other fields. Since ancient times, Fupenzi has been considered to be an important medicine for tonifying the kidney in terms of nourishing the liver and kidney, fixing essence and reducing urine, but its effective components and mechanism are not clear. In this paper, the effective components of Rubi fructus were analyzed by detecting the components of Fupenzi in vivo and in vitro. Adenine was used to replicate the model of kidney yang deficiency, and organ index, biochemical index and histopathology were used to evaluate the effect of different doses of Fupenzi on tonifying kidney yang. Metabonomics technique was used to analyze the metabolic regulation mechanism of Fupenzi in improving kidney yang deficiency syndrome. The results showed that 61 chemical constituents of Fupenzi were identified in vitro, including 18 flavonoids, 19 organic acids, 5 coumarins, 8 terpenoids, 7 amino acids and 4 other components. A total of 51 chemical components were identified, including 30 prototype components and 21 metabolic components, which may be the effective components of Fupenzi. The results of pharmacodynamics showed that compared with the model group, the renal index, testicular index and epididymal index of rats in each Fupenzi group were significantly improved (p<0.01), cAMP significantly increased (p<0.05), cGMP decreased (p<0.05) and cAMP/cGMP ratio increased significantly (p<0.05). The content of ACTH in low dose group increased significantly (p<0.05), while the content of ACTH in middle and high dose groups increased, but there was no significant difference. The results of HE staining showed that compared with the model group, the kidney, testis and epididymis of rats in each treatment group were significantly improved. In general, these changes may be mainly through primary bile acid biosynthesis, linoleic acid metabolism, steroid hormone biosynthesis, β-alanine metabolism, glutathione metabolism, porphyrin and chlorophyll metabolism, unsaturated fatty acid biosynthesis, arachidonic acid metabolism, arginine and proline metabolism and other metabolic pathways to improve adenine-induced metabolic disorders in rats with kidney-yang deficiency syndrome.

Integrative analysis of the transcriptome, targeted metabolome, and anatomical observation provides insights into the brassinosteroids-mediated seasonal variation of cambial activity in Chinese fir

Chinese fir (Cunninghamia lanceolata) is widely planted in southern China due to its strong adaptability and fast-growing. Wood formation is derived from the periodic changes of cambial activity that is regulated by environmental cues and phytohormone signals. Brassinosteroids (BRs), a class of plant-specific steroid hormones, play central roles in modulating cambial activity and xylem development. To decipher the regulatory role of BR in the dynamic change of Chinese fir cambium, a comprehensive analysis of the transcriptome, targeted metabolome, and anatomical observation was conducted. The application of 24-epibrassinolide (EBR, 10 μM) significantly increased the cambial cell layers, resulting in the thickening of the secondary xylem. Conversely, brassinazole (Brz) treatment strikingly inhibited the xylem development by attenuating cambial activity. Moreover, 1583 up-regulated differentially expressed genes (DEGs) were shared in stages A (reactivating), C (active), and E (dormant), which were annotated into the xylem formation and BR signaling pathway. Metabolomic profiling of phytohormone indicated that the contents of brassinolide (BL, the most active BR), castasterone (CS), and typhasterol (TY) were distinctly increased in stage C. Furthermore, ClBES1/BZR1, a hub gene in the co-expression network, dramatically activated the expression of ClPAL2 and ClMYB4 by binding to their promotors. Collectively, these results elucidate the potential role of BR in dynamic changes in the cambial zone and provide insight into the regulatory mechanism of wood formation in conifers.

Modification of B-Nor Steroids Mediated by Filamentous Fungus Fusarium culmorum: Focus on 15α-Hydroxylase Activity

The metabolic activities of microorganisms to modify the chemical structures of organic compounds are an effective tool for the production of high-value steroidal drugs or active pharmaceutical ingredients (APIs). The integration of biotransformation into the synthesis of APIs can greatly reduce the number of reaction steps and achieve higher process efficiency, thus enabling their greener production. The current research efforts are focused on either the optimization of existing processes or identification of new potentially useful bioconversions. This study aimed to assess the catalytic abilities of the filamentous fungus Fusarium culmorum AM 282 to transform B-nor analogues (5(6→7)abeo compounds) of steroid hormones: androstenedione (AD), dehydroepiandrosterone (DHEA) and its acetate. Our previous studies have demonstrated that this strain is an active hydroxylating catalyst for many steroidal compounds with diverse structures. The results presented in this work showed that the hydroxylation of B-nor steroids occurred with the regio- and stereoselectivity typical of this strain in relation to the corresponding natural hormones of the standard 6:6 A/B series. After the transformations of B-nor-DHEA and its acetate, 15α-hydroxy-B-nor-DHEA was obtained as the sole product of the reaction, while the transformation of the AD analogue resulted in a mixture of its 15α- and 6α-hydroxy derivatives. A detailed analysis of the transformation course indicated that all the obtained hydroxy derivatives could be the result of the activity of the same enzyme. The presented results may provide a basis for research aimed at understanding the molecular nature of cytochrome P-450 monooxygenase from F. culmorum AM 282 with its ability for 15α-hydroxylation of steroidal compounds. An analysis of the pharmacokinetic and pharmacodynamic properties of the obtained metabolites with cheminformatics tools suggests their potential biological activity.

Hippocampus under pressure: molecular mechanisms of cognitive impairment in shr rats

In clinical studies and in animal experiments, data have been obtained indicating the association of chronic hypertension with the development of cognitive impairment. The review examines structural and biochemical changes in the hippocampus of SHR rats with genetic hypertension, which are used as a model of essential hypertension, as well as vascular dementia. The dysfunction of the hypothalamic-pituitary-adrenocortical system, observed in SHR rats at an early age, may, along with the development of hypertension, be a key factor in the damage to the hippocampus at the structural and molecular levels. Global changes at the body level (hypertension, neurohumoral dysfunction) are associated with the development of vascular pathology and destruction of the blood-brain barrier. Changes in multiple biochemical glucocorticoid-dependent processes in the hippocampus (dysfunction of steroid hormone receptors, disorders of neurotransmitter systems, BDNF deficiency, oxidative stress, neuroinflammation) are accompanied by structural changes including cellular processes of neuroinflammation (microgliosis, astrogliosis), disorders of neurogenesis in the subgranular neurogenic niche, neurodegenerative processes at the level of synapses, axons and dendrites up to neuronal cell death. The consequence of this is dysfunction of the hippocampus, a key structure of the limbic system necessary for the realization of cognitive functions. Summarizing of the available results at various levels, from the level of the organism and the structure of the brain (hippocampus) to the molecular one, allows us to confirm the translational validity of SHR rats for modeling the mechanisms of vascular dementia.

The association between metabolite profiles and impaired bone microstructure in adult growth hormone deficient rats

BackgroundAdult growth hormone deficiency (AGHD) is associated with an increased risk of fractures and impaired bone microstructure. Understanding the metabolic changes accompanying bone deterioration in AGHD might provide insights into mechanisms behind molecular changes and develop new biomarkers or nutritional strategies for bone destruction. Our study aimed to investigate the association between altered metabolite patterns and impaired bone microstructure in adult rats with growth hormone deficiency.MethodsThirty seven-week-aged adult Lewis dwarf homozygous (dw/dw) rats (five females and five males), and adult Lewis dwarf heterozygous (dw/ +) rats (five females and five males) rats were compared. Micro-computed tomography (Micro-CT) was used to examine the bone's microstructure. Hematoxylin and eosin (H&E) staining were used to quantify the histological characteristics. Liquid chromatography-mass spectrometry untargeted serum metabolomic analysis was applied in the study. ELISA was used to measure serum bone turnover markers and IGF-1 levels.ResultsAdult dw/dw rats exhibited great reductions in trabecular volume bone density (Tb.vBMD), bone volume/total volume (BV/TV), and cortical thickness (Ct. Th) compared with adult dw/ + rats (all p values < 0.05), indicating significant impairment in bone microstructure. The serum metabolite profiles revealed substantial differences between the dw/dw rats and dw/ + rats. A total of 134 differential metabolites in positive ion mode and 49 differential metabolites in negative mode were identified. Five metabolites, including Lysophosphatidylcholine(LPC) 20:3, LPC22:6, LPC22:4, cortisol and histamine levels were upregulated in dw/dw rats. The steroid hormone biosynthesis and bile secretion pathways were the main perturbed metabolic pathways. There were significant associations between differential metabolites and the impaired bone microstructure parameters, indicating that the selected metabolites might serve as potential biomarkers for deteriorated bone microstructure in AGHD.ConclusionAdult dw/dw rats exhibit impaired bone microstructure and distinct serum metabolic profiles, and the altered metabolites were significantly associated with bone microstructure destruction. This provides a new insight into understanding the mechanism of bone deterioration in AGHD patients from a metabolic perspective.

Endocannabinoid System and Metabolism: The Influences of Sex

The endocannabinoid system (ECS) is a lipid signaling system involved in numerous physiological processes, such as endocrine homeostasis, appetite control, energy balance, and metabolism. The ECS comprises endocannabinoids, their cognate receptors, and the enzymatic machinery that tightly regulates their levels within tissues. This system has been identified in various organs, including the brain and liver, in multiple mammalian and non-mammalian species. However, information regarding the sex-specific regulation of the ECS remains limited, even though increasing evidence suggests that interactions between sex steroid hormones and the ECS may ultimately modulate hepatic metabolism and energy homeostasis. Within this framework, we will review the sexual dimorphism of the ECS in various animal models, providing evidence of the crosstalk between endocannabinoids and sex hormones via different metabolic pathways. Additionally, we will underscore the importance of understanding how endocrine-disrupting chemicals and exogenous cannabinoids influence ECS-dependent metabolic pathways in a sex-specific manner.

In-utero exposure to real-life environmental chemicals disrupts gene expression within the hypothalamo-pituitary-gonadal axis of prepubertal and adult rams

Environmental chemicals (ECs) have been associated with a broad range of disorders and diseases. Daily exposure to various ECs in the environment, or real-life exposure, has raised significant public health concerns. Utilizing the biosolids-treated pasture (BTP) sheep model, this study demonstrates that in-utero exposure to a real-life EC mixture disrupts hypothalamo-pituitary-gonadal (HPG) axis gene expression and reproductive traits in prepubertal (8-week-old, 8w) and adult (11-month-old) male sheep. Ewes were maintained on either BTP or pastures fertilized with inorganic fertilizer [control (C)] from approximately one month prior to insemination until around parturition. Thereafter, all animals were kept under control conditions. Effects on reproductive parameters including testosterone concentrations and the expression of key genes in the HPG axis were evaluated in eight-week-old and adult male offspring from both C and biosolids-exposed (B) groups. Results showed that, at 8w, relative to C (n = 11), B males (n = 11) had lower body weight, and altered testicular expression of HSD3B1, LHR and HSD17B3, BMP4, ABP, P27kip and CELF1. Principal component analysis (PCA) identified two 8w B subgroups, based on hypothalamic expression of GnRH, ESR1, and AR, and pituitary expression of KISSR. The two subgroups also exhibited different serum testosterone concentrations. The largest biosolids effects were observed in the hypothalamus of adult rams with NKB, ESR1, KISS1, AR, DLK1 and GNRH1 mRNA expression differing between B (n = 10) and C (n = 11) rams. Testicular steroidogenic enzymes CYP11A1 and HSD3B1 mRNA expression also differed between exposure groups. PCA identified two adult B subgroups, with BS1 (n = 6) displaying hypothalamic effects and BS2 (n = 4) both hypothalamic and testicular effects. The subgroups also differed in circulating testosterone concentrations. These findings demonstrate that exposure to a real-life EC mixture may predispose some males to infertility, by disrupting key functional HPG markers before puberty with consequent downstream effects on steroid hormones and spermatogenesis.