Search Results (174)

Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy where endogenous steroid excess may foster immune evasion. However, whether this hormonal axis directly modulates the antigen presentation machinery remains unclear. Methods: We applied an immunoinformatics approach to the TCGA-ACC cohort (n = 79) to investigate relationships among steroid phenotype, HLA expression, tumor microenvironment (TME), and patient outcome. Key findings were assessed in an independent validation cohort (ENSAT-ACC, n = 44) using C1A/C1B molecular subtypes corresponding to the steroid phenotypes. Results: Stratification by steroid phenotype revealed two distinct immunological profiles. The high steroid production (HSP) phenotype was associated with suppressed HLA expression and a lymphocyte-depleted “cold” TME. In contrast, the low steroid production (LSP) phenotype displayed elevated HLA expression, enriched T-cell infiltration, and upregulation of immune checkpoints (e.g., PDCD1, CTLA4), consistent with an inflamed but exhausted TME. The core signature of HLA downregulation in the HSP-like phenotype (C1A) and the significant survival advantage of the LSP-like phenotype (C1B) were confirmed in the validation cohort, demonstrating biological robustness despite platform and sample size differences. Conclusions: These findings identify the steroid phenotype as a critical regulator of immune escape in ACC. Our results support incorporating this stratification as a biomarker for patient selection, identifying LSP tumors as the subgroup most likely to benefit from immune checkpoint blockade due to their “hot” yet exhausted microenvironment. Full article

The adrenocorticotropic hormone (ACTH) is a key regulator of adrenal cortex function, promoting glucocorticoid synthesis and modulating cell proliferation. However, the role of extracellular steroid availability in shaping ACTH responses is still not fully defined. In this study, the functional and transcriptomic effects of ACTH were investigated in primary rat adrenocortical cells cultured under standard conditions and under simulating serum starvation (charcoal-stripped serum). The cells were treated with ACTH (10 nM), and proliferation was monitored using xCELLigence RTCA, while corticosterone secretion was assessed via ELISA. The RNA extracted from these samples was then utilised for the purpose of microarray-based gene expression profiling. The present study revealed that charcoal-stripped serum markedly improved ACTH-induced corticosterone output, suggesting that the absence of endogenous steroids sensitises cells to ACTH stimulation possibly by removing negative feedback constraints. This enhanced steroidogenic response was accompanied by a significant suppression of proliferation, confirming that the stimulation of specialised functions (such as steroid secretion) reduces proliferative capacity of adrenocortical cells. Transcriptomic data revealed that the steroids stimulating effect on corticosterone output was mainly mediated via steroid biosynthetic and lipid metabolic processes while inhibitory effect on proliferation rate was mediated mainly by cell adhesion molecules. These results suggest that, in primary culture of rat adrenocortical cells, the stimulatory effect of ACTH on their specialised function (corticosteroid secretion) simultaneously reduces their basal function, which is their proliferation process. Changes in this type are also observed in cells cultured in steroid-depleted conditions. Full article

Background: Maple syrup urine disease (MSUD) is a genetic disorder caused by mutations in the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, leading to toxic buildup of branched-chain amino acids (BCAAs) and their ketoacid derivatives. While newborn screening (NBS) and molecular testing are standard diagnostic tools, they face challenges such as delayed results and false positives. Untargeted metabolomics has emerged as a complementary approach, offering comprehensive metabolic profiling and potential for novel biomarker discovery. We previously applied untargeted metabolomics to neonates with MSUD, identifying distinct metabolic signatures. Objective: This follow-up study investigates metabolic changes and biomarkers in pediatric MSUD patients and explores shared dysregulated metabolites between neonatal and pediatric MSUD. Methods: Dried blood spot (DBS) samples from pediatric MSUD patients (n = 14) and matched healthy controls (n = 14) were analyzed using LC/MS-based untargeted metabolomics. Results: In pediatric MSUD, 3716 metabolites were upregulated and 4038 downregulated relative to controls. Among 1080 dysregulated endogenous metabolites, notable biomarkers included uric acid, hypoxanthine, and bilirubin diglucuronide. Affected pathways included sphingolipid, glycerophospholipid, purine, pyrimidine, nicotinate, and nicotinamide metabolism, and steroid hormone biosynthesis. Seventy-two metabolites overlapped with neonatal MSUD cases, some exhibiting inverse trends between age groups. Conclusion: Untargeted metabolomics reveals that the metabolic profiling of MCUD pediatric patients different from that of their controls. Also, there are valuable age-specific and shared metabolic alterations in MSUD, enhancing the understanding of disease progression in MSUD patients. This supports its utility in improving diagnostic precision and developing personalized treatment strategies across developmental stages. Full article

The Nile tilapia (Oreochromis niloticus), a key aquaculture species, displays marked sexual growth dimorphism, with males growing faster than females. This process is governed by intricate interactions between antagonistic regulators, including transcription factors, growth factors, and steroid hormones, operating through sex-specific developmental pathways. While circular RNAs (circRNAs) are known to modulate gene expression by sponging microRNAs (miRNAs), their role in teleost sex differentiation remains poorly understood. To address this gap, we profiled circRNA expression in tilapia gonads by constructing six circRNA libraries from testes and ovaries of 180 days after hatching (dah) fish, followed by high-throughput sequencing. We identified 6564 gonadal circRNAs distributed across all 22 linkage groups, including 226 differentially expressed circRNAs (DECs; 108 testis-biased, 118 ovary-biased). Functional enrichment analysis linked their host genes to critical pathways such as cAMP signaling, cell adhesion molecules, and—notably—sexual differentiation processes (e.g., estrogen signaling, oocyte meiosis, and steroid hormone biosynthesis). Furthermore, we deciphered competing endogenous RNA (ceRNA) networks, uncovering circRNA–miRNA–mRNA interactions targeting germ cell determinants, sex-specific transcription factors, and steroidogenic enzymes. This study provides the first systematic exploration of circRNA involvement in tilapia sex differentiation and gonadal differentiation, offering novel insights into the post-transcriptional regulation of sexual dimorphism. Our findings advance the understanding of circRNA biology in fish and establish a framework for future studies on aquaculture species with similar reproductive strategies. Full article

The increasing demand for sustainable alternatives to synthetic agrochemicals underscores the need for novel, naturally derived plant growth regulators (PGRs) with high specificity and minimal environmental impact. In this study, we propose agavenin (AG), a steroidal saponin from Agave species, as a promising candidate and evaluate its potential role in plant growth regulation through a comprehensive in silico approach. Using molecular docking, molecular dynamics simulations, ADME profiling, and FTIR spectroscopy, we analyzed the interaction of AG with three key protein receptors (KPRs) that regulate major hormonal pathways: GA3Ox2 (gibberellin), IAA7 (auxin), and BRI1 (brassinosteroid). AG showed strong and stable binding to GA3Ox2 and IAA7, with affinities comparable to their endogenous ligands, while exhibiting low interaction with BRI1—suggesting receptor selectivity. Molecular dynamics confirmed the stability of AG–GA3Ox2 and AG–IAA7 complexes over 100 ns, and ADME profiling highlighted favorable properties for bioavailability and transport. Collectively, these findings indicate that AG could function as a selective, receptor-targeted modulator of gibberellin and auxin signaling pathways. Beyond demonstrating the molecular basis of AG’s bioactivity, this work establishes a computational foundation for its future experimental validation and potential development as a sustainable, naturally derived growth regulator for plant biotechnology and agriculture. Full article

Cardiotonic steroids (CTS), including the endogenous compound ouabain, modulate neuronal Na/K-ATPase (NKA) activity in a concentration-dependent manner, affecting neuronal survival and function. While high concentrations of ouabain are neurotoxic, endogenous levels of 0.1–1 nM exert neuroprotective effects and influence intracellular signaling. However, the effects of physiologically relevant ouabain concentrations on excitatory synaptic transmission remain unclear. In this study, we examined how 1 nM ouabain affects synaptic responses in rat hippocampal CA1 neurons. Using whole-cell patch-clamp recordings of evoked excitatory postsynaptic currents (EPSCs) and extracellular recordings of field excitatory postsynaptic potentials (fEPSPs), we found that ouabain enhances excitatory synaptic transmission, increasing EPSC amplitude and fEPSP slope by 35–50%. This effect was independent of NMDA receptor (NMDAR) activity. Ouabain reduced the magnitude of NMDAR-dependent long-term potentiation (LTP), but still augmented fEPSPs when applied after LTP induction. This implies separate additive mechanisms. These observations exhibit that ouabain, at concentrations corresponding to endogenous levels, facilitates basal excitatory synaptic transmission while partially suppressing LTP. We propose that ouabain exerts dual modulatory effects in hippocampal networks via distinct synaptic mechanisms. Full article

(1) Objective: This study aimed to systematically elucidate the molecular mechanisms by which gypenosides (GP), a major active component of Gynostemma pentaphyllum, ameliorate hypercholesterolemia by modulating the hepatic steroidogenesis pathway, and to identify key therapeutic targets. (2) Methods: We established a high-fat diet (HFD)-induced hypercholesterolemia (HC) mouse model and performed GP intervention. An integrated multi-omics approach, combining transcriptomics and proteomics, was utilized to comprehensively analyze GP’s effects on the expression of genes and proteins associated with hepatic cholesterol synthesis, transport, and steroid hormone metabolism. (3) Results: HFD induced significant dysregulation, with 48 steroidogenesis pathway-related genes and 35 corresponding proteins exhibiting altered expression in HC mouse livers. GP treatment remarkably reversed these HFD-induced abnormalities, significantly restoring the expression levels of 42 genes and 14 proteins. Multi-omics integration identified seven critical genes/proteins—Cyp3a25, Fdft1, Tm7sf2, Hmgcs1, Fdps, Mvd, and Pmvk—that were consistently and significantly regulated by GP at both transcriptional and translational levels. Furthermore, correlation analyses demonstrated that Cyp3a25 was significantly negatively correlated with serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), whereas Fdft1, Tm7sf2, Hmgcs1, Fdps, Mvd, and Pmvk showed significant positive correlations. (4) Conclusions: GP effectively ameliorates cholesterol dyshomeostasis through a multi-targeted mechanism in the liver. It inhibits endogenous cholesterol synthesis by downregulating key enzymes (Hmgcs1, Fdft1, Pmvk, Mvd, Fdps, Tm7sf2), promotes cholesterol efflux and transport (upregulating Abca1, ApoB), and accelerates steroid hormone metabolism (upregulating Cyp3a11, Cyp3a25). These findings provide robust scientific evidence for the development of GP as a safe and effective novel therapeutic agent for hypercholesterolemia. Full article

Sickle cell disease (SCD) is a prevalent genetic disorder caused by a mutation in the beta-globin gene. Hyperhemolysis (HS) is a severe complication involving the rapid destruction of both transfused and endogenous red blood cells, commonly found in SCD. This literature review explores the clinical presentation, diagnosis, pathogenesis, and management of HS in SCD. HS can manifest acutely or in a delayed manner, complicating diagnosis due to overlapping symptoms and varying reticulocyte responses. Immunohematological assessments often reveal delayed positivity in direct antiglobulin tests and antibody screens. HS typically presents severe anemia, jaundice, hemoglobinuria, and hemodynamic instability. Diagnostic markers include elevated bilirubin and lactate dehydrogenase levels alongside a reduced reticulocyte count. The management of HS is primarily empirical, with no clinical trials to support standardized treatment protocols. First-line treatments involve steroids and intravenous immunoglobulins (IVIG), which modulate immune responses and mitigate hemolysis. Refractory cases may require additional agents such as rituximab, eculizumab, tocilizumab, and, in some instances, plasma exchange or erythropoietin-stimulating agents. Novel therapeutic approaches, including bortezomib and Hemopure, have shown promise but require further investigation. Current management strategies are empirical, underscoring the need for robust clinical trials to establish effective treatment protocols that ultimately improve outcomes for SCD patients experiencing HS. Full article

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, treats type 2 diabetes by blocking renal glucose reabsorption and promoting urinary glucose excretion. This mechanism lowers blood glucose concentrations independently of insulin. The resulting caloric loss also contributes to weight reduction. Although these effects are well documented in patients with diabetes, their magnitude and underlying mechanisms in healthy individuals remain poorly understood. Background/Objectives: We investigated metabolic alterations after a single 10 mg dose of dapagliflozin in healthy adults with normal body-mass indices (BMIs) using untargeted metabolomics. Methods: Thirteen healthy volunteers completed this study. Plasma was collected before and 24 h after dosing. Untargeted metabolic profiling was performed with ultra-high-performance liquid chromatography–quadrupole time-of-flight/mass spectrometry. Results: Twenty-five endogenous metabolites were annotated; ten were putatively identified. Eight metabolites increased significantly, whereas two decreased. Up-regulated metabolites included phosphatidylcholine (PC) species (PC O-36:5, PC 36:3), phosphatidylserine (PS) species (PS 40:2, PS 40:3, PS 36:1, PS 40:4), lysophosphatidylserine 22:1, and uridine. Dehydroepiandrosterone sulfate and bilirubin were down-regulated. According to the Human Metabolome Database, these metabolites participate in glycerophospholipid, branched-chain amino acid, pyrimidine, and steroid-hormone metabolism. Conclusions: Dapagliflozin may affect pathways related to energy metabolism and homeostasis beyond glucose regulation. These data provide a reference for future investigations into energy balance and metabolic flexibility in metabolic disorders. Full article

Neuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone (EpiP) in wild-type mice using behavioral assessment of hypnosis (loss of righting reflex, LORR) and in vivo electrophysiological recordings. Specifically, local field potentials (LFPs) were recorded from the central medial thalamus (CMT) and electroencephalogram (EEG) signals were recorded from the barrel cortex. We found that EpiP-induced LORR exhibited clear sex differences, with females showing increased sensitivity. Spectral power analysis and thalamocortical (TC) and corticocortical (CC) phase synchronization further supported enhanced hypnotic susceptibility in female mice. Our findings reveal characteristic sex-dependent effects of EpiP on the synchronized electrical activity in both thalamus and cortex. These results support renewed exploration of endogenous NAS as clinically relevant anesthetic agents. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Background: Estrogens play a protective role during the early stages of life. However, endogenous 17β-estradiol (E2) can accelerate atherosclerosis progression. Aim: The purpose of this study was to test for the significance of the sex-specific associations of gonadal hormones with the extent of the inflammatory response, myocardial damage, and ventricular arrhythmia risk in acute myocardial infarction (MI). Materials and Methods: Study design: single-center cohort study. Blood samples for the assessment of sex steroids (E2, total testosterone [T]), oxidized low-density lipoproteins, high-sensitivity C-reactive protein (CRP), white blood cell (WBC) counts, and cardiac enzymes were collected 48 h after the onset of symptoms (and within 6 h after PCI) from 111 patients (37% women) with acute MI. Coronary disease severity, left ventricular systolic function (LV), and indices of ventricular repolarization were assessed using coronary angiography, echocardiography, and a conventional electrocardiogram, respectively. Results: In men with acute MI, peak cardiac enzyme levels were predicted by post-percutaneous coronary intervention (PCI) E2 plasma levels, peak WBC count, and peak CRP plasma levels. T levels and the E2/T ratio were associated with post-PCI CRP in these men. For women, peak WBC count was a marker of highest testosterone, and only WBC count was a significant indicator of myocardial injury extent. The incidence of acute ventricular tachycardia detected in AMI was significantly associated with left ventricular ejection fraction and with peak WBC count (as a tendency) regardless of sex. A longer duration of cardiac repolarization prior to PCI was predicted by lower ejection fractions in men and by age, CRP, and testosterone levels in female patients. Conclusions: During acute MI, elevated endogenous estradiol levels in men and increased leukocytes in women indicate acute myocardial damage. Post-PCI plasma inflammatory markers are sex-specific confounding factors for acute endogenous E2 levels, T levels, and the E2/T ratio. LV systolic function in men and, characteristically, the acute inflammatory response and testosterone levels in women are predictors of longer ventricular repolarization and arrhythmia risk. Full article

Hormone-dependent phosphorylation of steroid receptors is a mechanism for modulating glucocorticoid receptor (GR) transcriptional responses. Evidence indicates that GR phosphorylation can influence receptor transcriptional activation in a gene-specific manner, which could have positive or negative impacts, where the relative level of phosphorylation is an important determinant of overall GR function. This review provides insights into the regulatory mechanism of GR phosphorylation in the brain, cellular and molecular specificity affecting neurovascular function, and the impact of GR phosphorylation in neurological disorders. Furthermore, the role of various endogenous and exogenous factors and sex-dependent associations with GR functional changes due to phosphorylation and other interlinking mechanisms are considered. Finally, we highlight the potential therapeutic approaches which have been evaluated, while challenging GR phosphorylation and the overall influence on the activity of GR in brain disorders. Full article

Background: Ozone therapy is used for its immunomodulatory, antioxidant, and analgesic properties in several fields. It can be useful in the rehabilitation of musculoskeletal disorders. Studies showed that O₂-O₃ therapy can reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis. Only a few studies have been published about the efficacy of this treatment in upper limb disease. Objective: The aim of this study is to investigate the use of ozone therapy in upper limb pathologies, evaluating its quantity, quality, and reported results in upper limb musculoskeletal disease, supraspinatus tendinopathy, shoulder impingement, adhesive capsulitis, chronic epicondylitis, and carpal tunnel syndrome. O₂-O₃ reduces inflammation by stimulating anti-inflammatory cytokines and inactivating pro-inflammatory molecules, relieves pain by interacting with pain receptors and improving blood circulation, promotes the regeneration of damaged tissues by stimulating growth factors and improving vascularization, and, finally, activates endogenous antioxidant defense systems by protecting cells from oxidative damage. Methods: A comprehensive search was conducted on PubMed and Scopus using the following MeSH terms: ozone therapy, infiltration joint, musculoskeletal disease, rehabilitation, upper limb, shoulder, wrist, hand, elbow, including English papers published in the last five years. Results: Five papers have been selected: four randomized controlled trials and one retrospective cohort study. The RCTs compared the effectiveness of intra-articular ozone injection with steroid injection alone or with other conservative treatments in shoulder diseases; one paper studied the effectiveness of ozone injection and orthoses in carpal tunnel syndrome compared to orthoses alone; one paper used ozone injections compared with steroid injection in patients with chronic lateral epicondylitis. A total of 218 patients were studied in these trials. Conclusions: Ozone treatment seemed to improve pain and function as well as other therapies in upper limb musculoskeletal disease. However, the trials’ protocols and the upper limb areas treated are different. Further studies are needed to define the effectiveness of ozone therapy in upper limb diseases in rehabilitation fields. Full article

The mineralocorticoid receptor (MR) is a steroid hormone receptor that plays a key role in regulating sodium and water homeostasis and blood pressure. MR antagonists are a guideline recommended for therapy for the treatment of hypertension and cardiovascular disease but can cause hyperkalaemia. Modelling was performed for binding of the endogenous ligands aldosterone and cortisol and MR antagonist spironolactone to the ligand binding domain (LBD) of the MR. A molecular docking screen of compounds that were structurally similar to known antagonists was performed, leading to the identification of two novel compounds, C79 and E67. Molecular dynamics (MD) assessed the dynamic interactions with C79, E76, endogenous ligands, and spironolactone with the MR ligand binding domain (LBD). Analysis of the protein backbone showed modest changes in the overall structure of the MR LBD in response to binding of antagonists, with movement in helix 12 consistent with previous observations. All ligands tested maintained stable binding within the MR LBD throughout the simulations. Hydrogen bond formation played a more prominent role in the binding of endogenous ligands compared to antagonists. MM-PBSA binding free energy calculations showed that all ligands had similar binding affinities, with binding facilitated by key residues within the binding site. The novel antagonists demonstrated similar binding properties to spironolactone, warranting further evaluation. This study provides insights into the molecular mechanisms of MR activation and inhibition, which can aid in the development of novel therapeutic strategies for cardiovascular diseases. Full article