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Cureus Mar 2024Nonclassic congenital adrenal hyperplasia (NCAH) is a genetic disorder characterized by mutations in the genes encoding enzymes involved in cortisol production, most...
Nonclassic congenital adrenal hyperplasia (NCAH) is a genetic disorder characterized by mutations in the genes encoding enzymes involved in cortisol production, most commonly the 21-hydroxylase enzyme. Unlike classic congenital adrenal hyperplasia (CAH), NCAH typically presents later in life with milder symptoms. The diagnosis of NCAH can be challenging due to its nonspecific symptoms and variable presentation. Early detection is crucial for timely intervention and management, particularly in families with a history of the condition. We report a case of NCAH in a patient from the Central-East Region of Tunisia, in whom the subsequent genetic testing revealed a Val281Leu (V281L) mutation in the CYP21A2 gene. A 26-year-old female presented with facial hirsutism and irregular menstrual cycles. Physical examination revealed mild hirsutism and laboratory tests showed elevated levels of testosterone and 17-hydroxyprogesterone (17-OHP). A provisional diagnosis of NCAH was made, subsequently confirmed by an adrenocorticotropic hormone (ACTH) stimulation test demonstrating an exaggerated 17-OHP response. Genetic testing revealed heterozygosity for the V281L mutation. Family testing showed the patient's mother to be homozygous and the father heterozygous for the mutation. This report highlights the importance of recognizing subtle symptoms of NCAH for early diagnosis and management. Genetic testing aids in confirming the diagnosis and identifying carriers within families. Treatment with glucocorticoids aims to suppress adrenal androgen production and manage symptoms. Regular follow-up is essential to monitor treatment response and adjust medication as needed. NCAH can present with subtle symptoms, necessitating a high index of suspicion for a proper diagnosis. Genetic testing plays a crucial role in confirming the diagnosis and identifying carriers within families. Early intervention and regular follow-up improve outcomes in affected individuals. This report also underscores the significance of genetic testing in the management of NCAH and highlights the need for increased awareness about this condition among healthcare providers.
PubMed: 38681304
DOI: 10.7759/cureus.57124 -
The Journal of Steroid Biochemistry and... Jul 2024Mud crab (Scylla paramamosain) has become an important mariculture crab along the southeast coast of China due to its strong adaptability, delicious taste, and rich...
Mud crab (Scylla paramamosain) has become an important mariculture crab along the southeast coast of China due to its strong adaptability, delicious taste, and rich nutrition. Several vertebrate steroid hormones and their synthesis-related genes and receptors have been found in crustaceans, but there are few reports on their synthesis process and mechanism. 3-beta-hydroxysteroid dehydrogenase (HSD3B) is a member of the Short-chain Dehydrogenase/Reductase (SDR) family, and an indispensable protein in vertebrates' steroid hormone synthesis pathway. In this study, the SpHsd3b gene sequence was obtained from the transcriptome data of S. paramamosain, and its full-length open reading frame (ORF) was cloned. The spatial and temporal expression pattern of SpHsd3b was performed by quantitative real-time PCR (qRT-PCR). SpHsd3b dsRNA interference (RNAi) and HSD3B inhibitor (trilostane) were used to analyze the function of SpHSD3B. The results showed that the SpHsd3b gene has an 1113 bp ORF encoding 370 amino acids with a 3β-HSD domain. SpHSD3B has lower homology with HSD3B of vertebrates and higher homology with HSD3B of crustaceans. SpHsd3b was expressed in all examined tissues in mature crabs, and its expression was significantly higher in the testes than in the ovaries. SpHsd3b expression level was highest in the middle stage of testicular development, while its expression was higher in the early and middle stages of ovarian development. RNAi experiment and trilostane injection results showed that SpHSD3B had regulatory effects on several genes related to gonadal development and steroid hormone synthesis. 15-day trilostane suppression could also inhibit ovarian development and progesterone level of hemolymph. According to the above results, crustaceans may have steroid hormone synthesis pathways like vertebrates, and the Hsd3b gene may be involved in the gonadal development of crabs. This study provides further insight into the function of genes involved in steroid hormone synthesis in crustaceans.
Topics: Animals; Brachyura; Female; Male; Phylogeny; Amino Acid Sequence; 3-Hydroxysteroid Dehydrogenases; Ovary; Cloning, Molecular; RNA Interference; Dihydrotestosterone
PubMed: 38670516
DOI: 10.1016/j.jsbmb.2024.106529 -
Frontiers in Oncology 2024Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in...
INTRODUCTION
Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT).
METHODS
Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage.
RESULTS
The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother.
DISCUSSION
In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction.
PubMed: 38665954
DOI: 10.3389/fonc.2024.1377103 -
Journal For Immunotherapy of Cancer Apr 2024Androgen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized...
Myeloid-derived suppressor cells attenuate the antitumor efficacy of radiopharmaceutical therapy using Y-NM600 in combination with androgen deprivation therapy in murine prostate tumors.
RATIONALE
Androgen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized disease. However, for metastatic castration-resistant prostate cancer, EBRT is typically only used in the palliative setting, because of the inability to radiate all sites of disease. Systemic radiation treatments that preferentially irradiate cancer cells, known as radiopharmaceutical therapy or targeted radionuclide therapy (TRT), have demonstrable benefits for treating metastatic prostate cancer. Here, we explored the use of a novel TRT, Y-NM600, specifically in combination with ADT, in murine prostate tumor models.
METHODS
6-week-old male FVB mice were implanted subcutaneously with Myc-CaP tumor cells and given a single intravenous injection of Y-NM600, in combination with ADT (degarelix). The combination and sequence of administration were evaluated for effect on tumor growth and infiltrating immune populations were analyzed by flow cytometry. Sera were assessed to determine treatment effects on cytokine profiles.
RESULTS
ADT delivered prior to TRT (ADT→TRT) resulted in significantly greater antitumor response and overall survival than if delivered after TRT (TRT→ADT). Studies conducted in immunodeficient NRG mice failed to show a difference in treatment sequence, suggesting an immunological mechanism. Myeloid-derived suppressor cells (MDSCs) significantly accumulated in tumors following TRT→ADT treatment and retained immune suppressive function. However, CD4+ and CD8+ T cells with an activated and memory phenotype were more prevalent in the ADT→TRT group. Depletion of Gr1+MDSCs led to greater antitumor response following either treatment sequence. Chemotaxis assays suggested that tumor cells secreted chemokines that recruited MDSCs, notably CXCL1 and CXCL2. The use of a selective CXCR2 antagonist, reparixin, further improved antitumor responses and overall survival when used in tumor-bearing mice treated with TRT→ADT.
CONCLUSION
The combination of ADT and TRT improved antitumor responses in murine models of prostate cancer, however, this was dependent on the order of administration. This was found to be associated with one treatment sequence leading to an increase in infiltrating MDSCs. Combining treatment with a CXCR2 antagonist improved the antitumor effect of this combination, suggesting a possible approach for treating advanced human prostate cancer.
Topics: Animals; Male; Myeloid-Derived Suppressor Cells; Mice; Prostatic Neoplasms; Radiopharmaceuticals; Humans; Cell Line, Tumor; Yttrium Radioisotopes; Disease Models, Animal; Androgen Antagonists; Combined Modality Therapy
PubMed: 38663936
DOI: 10.1136/jitc-2023-008760 -
Ecotoxicology and Environmental Safety Jun 2024Mono-2-ethylhexyl phthalic acid (MEHP) is the most toxic metabolite of the plasticizer di-2-ethylhexyl phthalic acid (DEHP), and studies have shown that MEHP causes...
Mono-2-ethylhexyl phthalic acid (MEHP) is the most toxic metabolite of the plasticizer di-2-ethylhexyl phthalic acid (DEHP), and studies have shown that MEHP causes serious reproductive effects. However, its exact mechanisms of action remain elusive. In this study, we aimed to investigate the reproductive effects of MEHP and preliminarily explore its underlying molecular mechanisms. We found that TM3 cells gradually secreted less testosterone and intracellular free cholesterol with increasing MEHP exposure. MEHP exposure inhibited lipophagy and the Sirt1/Foxo1/Rab7 signaling pathway in TM3 cells, causing aberrant accumulation of intracellular lipid droplets. Addition of the Sirt1 agonist SRT1720 and Rab7 agonist ML-098 alleviated the inhibition of lipophagy and increased free cholesterol and testosterone contents in TM3 cells. SRT1720 alleviated the inhibitory effect of MEHP on the Sirt1/Foxo1/Rab7 signaling pathway, whereas ML-098 only alleviated the inhibition of Rab7 protein expression by MEHP and had no effect on Sirt1 and Foxo1 protein expression. This suggests that MEHP inhibits lipophagy in TM3 cells by suppressing the Sirt1/Foxo1/Rab7 signaling pathway, ultimately leading to a further decrease in cellular testosterone secretion. This study improves our current understanding of the toxicity and molecular mechanisms of action of MEHP and provides new insights into the reproductive effects of phthalic acid esters.
Topics: Testosterone; Sirtuin 1; Signal Transduction; Animals; Mice; rab7 GTP-Binding Proteins; Diethylhexyl Phthalate; Cell Line; rab GTP-Binding Proteins; Forkhead Box Protein O1; Plasticizers; Cholesterol
PubMed: 38663197
DOI: 10.1016/j.ecoenv.2024.116394 -
JCEM Case Reports May 2024Most adrenal incidentalomas are benign neoplasms of the adrenal cortex. While the majority are nonfunctional, many secrete cortisol. Androgen- or estrogen-secreting...
Most adrenal incidentalomas are benign neoplasms of the adrenal cortex. While the majority are nonfunctional, many secrete cortisol. Androgen- or estrogen-secreting adenomas are rare. A 44-year-old female, with history of hypertension and prediabetes, presented with worsening acne, hirsutism, secondary amenorrhea for 2 years, and a 40-pound weight gain. Laboratory evaluation showed high 24-hour urine free cortisol, suppressed adrenocorticotropic hormone (ACTH) level, indicative of ACTH independent Cushing syndrome, and elevated testosterone and androstenedione. Abdominal computed tomography (CT) revealed a 6.3 × 5.2 × 5.6 cm left adrenal mass. Patient underwent left open adrenalectomy. Pathology revealed benign adrenocortical adenoma. Postoperatively there was a significant improvement in her blood pressure and blood sugar levels, resumption of menses, and complete resolution of hyperandrogenism and hypercortisolism. We describe a patient with an adrenal adenoma cosecreting cortisol and androgen, leading to Cushing syndrome and significant virilization. Adrenal masses secreting androgens are less common and concerning for adrenocortical carcinoma (ACC). Patients with adrenal masses cosecreting multiple hormones should undergo workup expediently since ACC confers poor outcomes.
PubMed: 38660483
DOI: 10.1210/jcemcr/luae045 -
Korean Circulation Journal May 2024Myocardial ischemia-reperfusion injury (MIRI) refers to the damage of cardiac function caused by restoration of blood flow perfusion in ischemic myocardium. However,...
BACKGROUND AND OBJECTIVES
Myocardial ischemia-reperfusion injury (MIRI) refers to the damage of cardiac function caused by restoration of blood flow perfusion in ischemic myocardium. However, long non-coding RNA prostate androgen regulated transcript 1 (PART1)'s role in MIRI remain unclear.
METHODS
Immunofluorescence detected LC3 expression. Intermolecular relationships were verified by dual luciferase reporter assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry and transferase-mediated dUTP nick-end labeling (TUNEL) assays analyzed cell viability and apoptosis. The release of lactate dehydrogenase was tested via enzyme-linked immunosorbent assay (ELISA). Left anterior descending coronary artery surgery induced a MIRI mouse model. Infarct area was detected by 2,3,5-triphenyltetrazolium chloride staining. Hematoxylin and eosin staining examined myocardial injury. ELISA evaluated myocardial marker (creatine kinase MB) level.
RESULTS
PART1 was decreased in hypoxia/reoxygenation (H/R) induced AC16 cells and MIRI mice. PART1 upregulation attenuated the increased levels of Bax, beclin-1 and the ratio of LC3II/I, and enhanced the decrease of Bcl-2 and p62 expression in H/R-treated cells. PART1 upregulation alleviated H/R-triggered autophagy and apoptosis via miR-302a-3p. Mechanically, PART1 targeted miR-302a-3p to upregulate transcription factor activating enhancer-binding protein 2C (TFAP2C). TFAP2C silencing reversed the protected effects of miR-302a-3p inhibitor on H/R treated AC16 cells. We further established TFAP2C combined to dual-specificity phosphatase 5 (DUSP5) promoter and activated DUSP5. TFAP2C upregulation suppressed H/R-stimulated autophagy and apoptosis through upregulating DUSP5. Overexpressed PART1 reduced myocardial infarction area and attenuated MIRI in mice.
CONCLUSION
PART1 improved the autophagy and apoptosis in H/R-exposed AC16 cells through miR-302a-3p/TFAP2C/DUSP5 axis, which might provide novel targets for MIRI treatment.
PubMed: 38654453
DOI: 10.4070/kcj.2023.0131 -
Toxicon : Official Journal of the... May 2024Flutamide is frequently used in the management of prostate cancer, hirsutism, and acne. It is a non-steroidal anti-androgenic drug and causes hepatotoxicity. The current...
Flutamide is frequently used in the management of prostate cancer, hirsutism, and acne. It is a non-steroidal anti-androgenic drug and causes hepatotoxicity. The current study's objective is to evaluate sophorin's hepatoprotective effectiveness against flutamide-induced hepatotoxicity in Wistar rats. Sophorin is a citrus flavonoid glycoside, also known as rutin, which is a low molecular weight polyphenolic compound with natural antioxidant properties and reported to have promising hepatoprotective efficacy. In this study, sophorin was used at a dose of 100 mg/kg body weight in purified water via oral route for 4 week daily whereas, flutamide was used at a dose of 100 mg kg/b.wt for 4 weeks daily in 0.5% carboxy methyl cellulose (CMC) through the oral route for the induction of hepatotoxicity. Flutamide administration leads to enhanced reactive oxygen species (ROS) generation, an imbalance in redox homeostasis and peroxidation of lipid resulted in reduced natural antioxidant level in liver tissue. Our result demonstrated that sophorin significantly abrogate flutamide induced lipid peroxidation, protein carbonyl (PC), and also significantly increasesed in enzymatic activity/level of tissue natural antioxidant such as reduced glutathione(GSH), glutathione reductase(GR), catalase, and superoxide dismutase(SOD). Additionally, sophorin reduced the activity of cytochrome P450 3A1 in liver tissue which was elevated due to flutamide treatment. Furthermore, sophorin treatment significantly decreased the pro-inflammatory cytokines (TNF-α and IL-6) level. Immunohistochemical analysis for the expression of inflammatory proteins (iNOS and COX-2) in hepatic tissue was decreased after sophorin treatment against flutamide-induced hepatotoxicity. Moreover, sophorin suppressed the infiltration of mast cells in liver tissue which further showed anti-inflammatory potential of sophorin. Our histological investigation further demonstrated sophorin's hepatoprotective function by restoring the typical histology of the liver. Based on the aforementioned information, we are able to come to the conclusion that sophorin supplementation might benefit wistar rats with flutamide-induced hepatic damage by reducing oxidative stress and hepatocellular inflammation.
Topics: Animals; Rats, Wistar; Flutamide; Rats; Chemical and Drug Induced Liver Injury; Male; Liver; Oxidative Stress; Antioxidants; Lipid Peroxidation; Reactive Oxygen Species; Androgen Antagonists
PubMed: 38653393
DOI: 10.1016/j.toxicon.2024.107722 -
Journal of Receptor and Signal... Feb 2024Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such...
Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 μg), kisspeptin + astressin 2B (1 μg), and kisspeptin + atosiban (300 ng/rat) ( = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.
Topics: Animals; Male; Kisspeptins; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Rats; Rats, Wistar; Peptide Fragments; Luteinizing Hormone; Corticosterone; Vasotocin; Testosterone; Injections, Intraventricular; Gonads; Pituitary Gland; Gonadotropin-Releasing Hormone; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Oligopeptides
PubMed: 38647103
DOI: 10.1080/10799893.2024.2333470 -
Journal of Ethnopharmacology Aug 2024Prostate cancer (PCa) is the most common malignancy of the male genitourinary system and currently lacks effective treatment. Semen Impatientis, the dried ripe seed of...
ETHNOPHARMACOLOGICAL RELEVANCE
Prostate cancer (PCa) is the most common malignancy of the male genitourinary system and currently lacks effective treatment. Semen Impatientis, the dried ripe seed of Impatiens balsamina L., is described by the Chinese Pharmacopoeia as a traditional Chinese medicine (TCM) and is used in clinical practice to treat tumors, abdominal masses, etc. In our previous study, the ethyl acetate extracts of Semen Impatientis (EAESI) was demonstrated to be the most effective extract against PCa among various extracts. However, the biological effects of EAESI against PCa in vivo and the specific antitumor mechanisms involved remain unknown.
AIM OF THE STUDY
In this study, we aimed to investigate the antitumor effect of EAESI on PCa in vitro and in vivo by performing network pharmacology analysis, transcriptomic analysis, and experiments to explore and verify the underlying mechanisms involved.
MATERIALS AND METHODS
The antitumor effect of EAESI on PCa in vitro and in vivo was investigated via CCK-8, EdU, flow cytometry, and wound healing assays and xenograft tumor models. Network pharmacology analysis and transcriptomic analysis were employed to explore the underlying mechanism of EAESI against PCa. Activating transcription factor 3 (ATF3) and androgen receptor (AR) were confirmed to be the targets of EAESI against PCa by RT‒qPCR, western blotting, and rescue assays. In addition, the interaction between ATF3 and AR was assessed by coimmunoprecipitation, immunofluorescence, and nuclear-cytoplasmic separation assays.
RESULTS
EAESI decreased cell viability, inhibited cell proliferation and migration, and induced apoptosis in AR and AR PCa cells. Moreover, EAESI suppressed the growth of xenograft tumors in vivo. Network pharmacology analysis revealed that the hub targets of EAESI against PCa included AR, AKT1, TP53, and CCND1. Transcriptomic analysis indicated that activating transcription factor 3 (ATF3) was the most likely critical target of EAESI. EAESI downregulated AR expression and decreased the transcriptional activity of AR through ATF3 in AR PCa cells; and EAESI promoted the expression of ATF3 and exerted its antitumor effect via ATF3 in AR and AR PCa cells.
CONCLUSIONS
EAESI exerts good antitumor effects on PCa both in vitro and in vivo, and ATF3 and AR are the critical targets through which EAESI exerts antitumor effects on AR and AR PCa cells.
Topics: Male; Animals; Humans; Prostatic Neoplasms; Network Pharmacology; Activating Transcription Factor 3; Receptors, Androgen; Acetates; Mice, Nude; Cell Line, Tumor; Xenograft Model Antitumor Assays; Antineoplastic Agents, Phytogenic; Mice; Apoptosis; Cell Proliferation; Plant Extracts; Transcriptome; Mice, Inbred BALB C; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 38643863
DOI: 10.1016/j.jep.2024.118228