Search Results (165)

Background: Spectrin proteins are critical cytoskeleton components that maintain cellular structure and mediate intracellular transport. Pathogenic variants in SPTBN1, encoding βII-spectrin, have been associated with various neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorder, and epilepsy. Here we report a Korean infant with infantile epileptic spasms syndrome (IESS) and an SPTBN1 mutation and provide a review of this mutation. Methods: The genomic data of the patient were analyzed by whole exome sequencing. A comprehensive literature review was conducted to identify and analyze all reported SPTBN1 variants, resulting in a dataset of 60 unique mutations associated with neurodevelopmental phenotypes. Case Presentation: A 10-month-old Korean female presented with IESS associated with a de novo heterozygous SPTBN1 mutation (c.785A>T; p.Asp262Val). The patient exhibited global developmental delay, microcephaly, hypotonia, spasticity, and MRI findings of diffuse cerebral atrophy and corpus callosum hypoplasia. Electroencephalography revealed hypsarrhythmia, confirming the diagnosis of IESS. Seizures persisted despite initial treatment with vigabatrin and steroids. Genetic analysis identified a likely pathogenic variant within the calponin homology 2 (CH2) domain of SPTBN1. Conclusions: This is the first report of an association between IESS and an SPTBN1 CH2 domain mutation in a Korean infant. This finding expands the clinical spectrum of SPTBN1-related disorders and suggests domain-specific effects may critically influence phenotypic severity. Further functional studies are warranted to elucidate the pathogenic mechanisms of domain-specific variants. Full article

This study aims to clarify the dose–response relationship between dietary β-carotene levels and gonadal pigment deposition and regulation mechanisms related to the carotenoid synthesis of Strongylocentrotus intermedius based on a 60-day feeding trial and subsequent transcriptome analysis. Adult sea urchins (initial weight: 9.33 ± 0.21 g) of three cages were given one of the dry feeds with different doses of β-carotene (0 mg/kg, 150 mg/kg, 300 mg/kg) or fresh kelp (Saccharina japonica). The results indicated that the weight gain rate (WGR) of sea urchins increased with the addition of β-carotene, with that of the C300 group being markedly higher than that of the C0 group. The addition of β-carotene significantly improved the redness (a*) and yellowness (b*) values of the gonads, with sea urchins in the C300 group exhibiting closest gonad coloration to those in the kelp-fed group. Meanwhile, β-carotene and echinenone in the gonads of the C300 group showed the highest contents, reaching 1.96 μg/kg and 11.97 μg/kg, respectively. Several differential genes, enriched in the pathways of steroid biosynthesis, oxidative phosphorylation, and ubiquitination, were screened based on transcriptome analysis. Real-time PCR further demonstrated that β-carotene significantly upregulated the expression of cholesterol 25-hydroxylase (CH25H), NADH dehydrogenase subunit 1 (ND1), NADH dehydrogenase subunit 2 (ND2), and NADH dehydrogenase subunit 4 (ND4) while it downregulated the expression of 24-dehydrocholesterol reductase (DHCR24). These results showed that 300 mg/kg β-carotene significantly increased the WGR, redness, and yellowness values, as well as the contents of β-carotene and echinenone in the gonads of S. intermedius. On the one hand, dietary β-carotene increased NADH enzyme activity, which participates in echinenone synthesis by donating electrons for the transformation of β-carotene to echinenone synthesis. On the other hand, the addition of β-carotene inhibited cholesterol synthesis by increasing the expression of CH25H and decreasing the expression of DHCR24, which could in turn increase the fluidity and permeability of the cell membranes and the transport efficiency of β-carotene and echinenone from the digestive tract to the gonads. These results provided fundamental insights into the production of sea urchin gonads with market-favored colors. Full article

Male contraception remains an unmet need. Na,K-ATPase α4 (NKA α4), a specific Na⁺/K⁺ transporter of the sperm flagellum, is an attractive target for male contraception. NKA α4 is critical for sperm motility and fertility, and its deletion in male mice causes complete infertility. Our previous structure–activity relationship (SAR) studies on a cardenolide scaffold identified a highly selective, safe NKAα4 inhibitor, but its complex, heavily hydroxylated structure posed challenges for modification and optimization. To address this, we employed a structural simplification strategy to synthesize novel steroidal and non-steroidal analogs and examined their effects on NKAα4 inhibition and sperm motility. Both series reduced sperm motility (up to ~50%), with IC₅₀ values in the picomolar range. Compounds 13 and 45 displayed specificities for NKAα4 over NKAα1, did not affect sperm viability, and showed no reversibility in vitro. Notably, 45, featuring a hexahydronaphthalene core and a benzyltriazole moiety at C5, exhibited potent, highly selective NKAα4 inhibition, reduced sperm motility in vitro and in vivo, and blocked fertilization in vitro. This highlights 45 as a promising lead for non-hormonal male contraception and indicates that the newly generated series of compounds possess the key characteristics needed for further development as potential non-hormonal male contraceptive agents. Full article

Background/Objective: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity. Methods: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids. Results: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment. Conclusions: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment. Full article

Background: Glucocorticoid insensitivity is a problem for the therapy of chronic inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Both are non-communicable chronic inflammatory lung diseases with worldwide increasing incidences. Only symptoms can be controlled by inhaled or systemic glucocorticoids, often combined with β2 agonists and/or muscarinic receptor antagonists. The therapeutic effect of glucocorticoids varies between individuals, and a significant number of patients do not respond well. It is believed that only protein-free circulating unbound glucocorticoids can enter cells by diffusion and achieve their therapeutic effect by binding to the intracellular glucocorticoid receptor (GR), encoded by the NR3C1 gene, for which over 3000 single-nucleotide polymorphisms have been described. In addition, various GR protein isoforms result from 11 transcription start sites, and differential mRNA splicing leads to further GR protein variants; each can be modified post-translational and alter steroid response. To add more variety, some GR isoforms are expressed cell-type specific or in a sub-cellular location. The GR only functions when it forms a complex with other intracellular proteins that regulate ligand binding, cytosol-to-nuclear transport, and nuclear and cytosolic action. Importantly, the timing of the GR activity can be cell type, time, and condition specific. These factors are rarely considered when assessing disease-specific loss or reduced GR response. Conclusions: Future studies should analyze the timing of the availability, activity, and interaction of all components of the glucocorticoid signaling cascade(s) and compare these factors between non-diseased and diseased probands, applying the combination of all omics methods (250). Full article

Withanolides are a class of naturally occurring C-28 ergostane steroidal lactones with an abundance of biological activities, and their members are promising candidates for antineoplastic drug development. The ADMET properties of withanolides are still largely unknown, and in silico predictions can play a crucial role highlighting these characteristics for drug development, shortening time and resources spent on the development of a drug lead. In this work, ADMET properties of promising antitumoral withanolides were assessed. Each chemical structure was submitted to the prediction tools: SwissADME, pkCSM–pharmacokinetics, admetSAR v2.0, and Molinspiration Cheminformatics. The results indicate a good gastrointestinal absorption rate, inability to cross the blood–brain barrier, CYP3A4 metabolization, without inhibition of other P450 cytochromes, high interaction with nuclear receptors, and a low toxicity. It was also predicted for the inhibition of pharmacokinetics transporters and some ecotoxicity. This demonstrates a viability for oral drug development, with low probabilities of side effects. Full article

Placental development plays a pivotal role in ensuring successful pregnancy outcomes, yet its molecular regulatory mechanisms in sheep remain poorly characterized. This study aimed to systematically investigate stage-specific proteomic dynamics and functional adaptations in ovine placental tissues across gestation to elucidate molecular drivers of placental maturation. Using data-independent acquisition proteomics, we identified 7774 proteins in Hu sheep placental tissues at gestational days 50, 80, and 120. Comparative analysis revealed 1450, 1026, and 1964 differentially expressed proteins (DEPs) in the 50 d vs. 80 d, 80 d vs. 120 d, and 50 d vs. 120 d comparisons, respectively. DEPs were functionally enriched in biological processes including cell proliferation, apoptosis, angiogenesis, nutrient transport, and steroid synthesis, with prominent involvement of the PI3K-Akt, MAPK, and estrogen signaling pathways. Protein interaction networks identified SRC, MAP3K1, KRAS, and TJP1 as central regulators exhibiting dynamic expression patterns across gestation. Temporal expression trends showed progressive upregulation of tight junction, immune response, and glucose metabolism proteins, contrasting with downregulation of endoplasmic reticulum protein processing and proteasome components. Validation experiments confirmed elevated proliferation/transport gene expression at 80 d versus 50 d, followed by increased apoptosis/transport genes and decreased proliferation markers at 120 d. This comprehensive proteomic profiling reveals stage-specific regulatory networks governing placental development in sheep, highlighting coordinated shifts in proliferative, metabolic, and structural remodeling processes. These findings advance our understanding of placental adaptation mechanisms and provide valuable insights for improving reproductive management in livestock species. Full article

Burnout syndrome, which significantly impacts both individual and societal quality of life, is primarily characterized by three key criteria: depersonalization, emotional exhaustion, and low personal accomplishment, all linked to work-related stress. Purpose: Comparative evaluation of urine metabolite patterns that may discriminate the burnout levels and the effects of night shifts on healthcare professionals. The Maslach Burnout Inventory survey was administered to 64 physicians and nurses working day and night shifts, with scores for each criterion recorded. Methods: Urine samples were collected, and metabolomic patterns were analyzed using UHPLC-QTOF-ESI+-MS technology. This analysis employed both untargeted and semi-targeted metabolomics, coupled with multivariate and ANOVA statistics, utilizing the online Metaboanalyst 6.0 platform. Partial Least Squares Discriminant Analysis (PLSDA) was performed, along with VIP values, Random Forest graphs, and heatmaps based on 79 identified metabolites. These were further complemented by biomarker analysis (AUC ranking) and pathway analysis of metabolic networks. Results: The findings highlighted the biochemical effects of night shifts and their correlation with burnout scores from each dimension. Conclusions: This study demonstrated the involvement of three major metabolic pathways in diagnosing burnout: lipid metabolism, particularly related to steroid hormones (cortisol, cortisone, and androsterone metabolites); energetic metabolism, involving long-chain acylated carnitines as transporters of free fatty acids, which play a role in burnout control; and a third pathway affecting catecholamine metabolism (neurotransmitters derived from tyrosine, such as dopamine, adrenaline, and noradrenaline), as well as tryptophan metabolism (serotonin and melatonin metabolites) and amino acid metabolism (including aspartate, arginine, and valine). Full article

Background/Objectives: Sepsis continues to be a significant global health issue, with current treatments primarily focused on antibiotics, fluid resuscitation, vasopressors, or steroids. Recent studies have started to explore mitochondrial transplantation as a potential treatment for sepsis. This study aims to evaluate the effects of enhanced mitochondrial transplantation on sepsis. Methods: We examined various mitochondrial-targeting drugs (formoterol, metformin, CoQ10, pioglitazone, fenofibrate, and elamipretide) to improve mitochondrial function prior to transplantation. Mitochondrial function was assessed by measuring the oxygen consumption rate (OCR) and analyzing the expression of genes related to mitochondrial biogenesis. Additionally, the effects of enhanced mitochondrial transplantation on inflammation were investigated using an in vitro sepsis model with THP-1 cells. Results: Formoterol significantly increased mitochondrial biogenesis, as evidenced by enhanced oxygen consumption rates and the upregulation of mitochondrial-associated genes, including those related to biogenesis (PGC-1α: 1.56-fold, p < 0.01) and electron transport (mt-Nd6: 1.13-fold, p = 0.16; mt-Cytb: 1.57-fold, p < 0.001; and mt-Co2: 1.44-fold, p < 0.05). Furthermore, formoterol-enhanced mitochondrial transplantation demonstrated a substantial reduction in TNF-α levels in LPS-induced hyperinflammatory THP-1 cells (untreated: 915.91 ± 12.03 vs. formoterol-treated: 529.29 ± 78.23 pg/mL, p < 0.05), suggesting its potential to modulate immune responses. Conclusions: Mitochondrial transplantation using drug-enhancing mitochondrial function might be a promising strategy in sepsis. Full article

HIV-associated neurocognitive disorders are prevalent despite antiretroviral intervention. Some HIV virotoxins, such as the trans-activator of transcription (Tat), are not targeted by antiretrovirals, and their neurotoxic actions may be exacerbated by opioids. Both Tat and morphine disrupt mitochondrial function, which may promote neurotoxicity, but the mechanisms are poorly understood. Herein, we assess the capacity of HIV Tat and morphine to alter the fundamental ability of mitochondria to generate and transfer energy along the electron transport chain (ETC). We find that exposure to Tat inhibits mitochondrial respiration driven by ETC complexes I or II in a concentration-dependent manner. Findings were consistent across models of permeabilized neuroblastoma cells, murine-derived mitoplasts, and mitochondria derived from mice exposed to Tat in vivo. In cell culture models, Tat promoted Ca²⁺ influx and the generation of cytosolic reactive oxygen species (ROS). Acute exposure to morphine exerted no effect on mitochondrial respiration, but morphine modestly offset Tat-mediated effects on complex I and some effects for the generation of ROS. Morphine did not exert any protective effects when acutely administered in vivo. The mitoprotective steroid, allopregnanolone (AlloP), increased mitochondrial respiration in neuroblastoma cells (complex I) or mitoplasts (complex II) and attenuated Tat-mediated impairment of complexes I and II in neuroblastoma cells or mice exposed to Tat in vivo. AlloP further attenuated Tat-mediated intracellular Ca²⁺ influx and cytosolic ROS production. Taken together, these results suggest that HIV Tat compromises mitochondrial function through the impairment of respiratory complexes I and II and that physiological AlloP may exert protective effects. Full article

Despite the availability of several drug classes for the treatment of hypertension, the current approaches to high blood pressure (BP) are not fully satisfying the needs of this patient population. As a result, in recent years, many clinical trials have investigated novel pharmacological approaches for lowering high BP. As overactivity of the renin–angiotensin–aldosterone system is often present in hypertensive patients, especially those with resistant hypertension, several studies have focused on novel strategies to counteract this phenomenon by the use of non-steroidal inhibitors of the mineralocorticoid receptors, aldosterone synthase inhibitors or RNA-targeting therapies to inhibit the hepatic synthesis of angiotensinogen. The latter approach in particular might offer the additional advantage of reducing the daily pill burden of these patients, hence mitigating the common occurrence of non-adherence to treatment. Because obesity and diabetes are common risk factors for hypertension (a high percentage of individuals with resistant hypertension being obese), numerous investigations have analyzed the BP-lowering effects of those agents, such as glucagon-like peptide-1 receptor agonists and sodium–glucose co-transporter-2 inhibitors, which have been shown to reduce body weight and improve cardiovascular outcomes in these patients. Available evidence suggests that these drug classes can indeed afford a clinically meaningful BP decrease and, potentially, reduce the treatment burden. In conclusion, even though the rates of uncontrolled hypertension remain high, several novel therapeutic options are in the offing. As these emerging treatments will compound with many already available agents, future efforts should be directed at better phenotyping patients to tailor the most suitable approach for each one. Full article

Cortisol, a steroid hormone, is closely associated with human mental stress. The rapid, real-time, and continuous detection of cortisol using wearable devices offers a promising approach for individual mental health. These devices must exhibit high sensitivity and long-term stability to ensure reliable performance. This study developed a wearable electrochemical sensor based on molecularly imprinted polymer (MIP) technology for real-time and dynamic monitoring of cortisol in sweat. A flexible gold (Au) electrode with interfacial hydrophilic treatment was employed to construct a highly stable electrode. The integration of a silk fibroin/polyvinylidene fluoride (SF/PVDF) composite membrane facilitates directional sweat transport, while liquid metal bonding enhances electrode flexibility and mechanical anti-delamination capability. The sensor exhibits an ultrawide detection range (0.1 pM to 5 μM), high selectivity (over 100-fold against interferents such as glucose and lactic acid), and long-term stability (less than 3.76% signal attenuation over 120 cycles). Additionally, a gradient modulus design was implemented to mitigate mechanical deformation interference under wearable conditions. As a flexible wearable device for cortisol monitoring in human sweat, the sensor’s response closely aligns with the diurnal cortisol rhythm, offering a highly sensitive and interference-resistant wearable solution for mental health monitoring and advancing personalized dynamic assessment of stress-related disorders. Full article

Water environments contaminated with arsenic (As) have become a significant environmental concern. Previous research has highlighted the detrimental effects of As on fish, but limited knowledge exists regarding its impacts on endocrine systems. To address this gap, zebrafish embryos were exposed to various concentrations (0, 25, 50, 75, and 150 μg/L) of arsenate (AsV) for 120 h post-fertilization (hpf). Our findings indicate that exposure to AsV significantly increases cortisol- and thyroid-stimulating hormone (TSH) levels while decreasing estradiol (E2) and testosterone (T) levels. Additionally, it initially decreases and then increases thyroxine (T4) contents. Furthermore, several key genes relevant to these endocrine systems also show significant influences. The results from principal component analysis demonstrate that TRH, TSH, TRHRb, and TRβ primarily affect the level of T4 while Cyp11b, StAR, hmgrb MC2R, and GR mainly influence cortisol levels. On the other hand, Cyp19a, Cyp17, 17βhsd, ERβ, LHR, hmgrb, and AR predominantly impact E2 and T levels. Transcriptomics and enrichment analysis reveal that these pathways are primarily associated with steroid hormone synthesis and transport. Furthermore, it was found that AsV stimulates the cAMP signaling pathway through a compensation mechanism. These results suggest that AsV may potentially act as environmental endocrine-disrupting chemicals with non-negligible interference effects on the endocrine system in zebrafish. This study holds theoretical value in assessing the environmental risk posed by As overall as well as providing an important basis for addressing human health issues and implementing preventive measures. Full article

PEG400 is widely used as a pharmaceutical excipient in the biomedical field. Increasing evidence suggests that PEG400 is not an inert drug carrier; it can influence the activity of various drug-metabolizing enzymes and transporters, thereby affecting the in vivo process of drugs. It can also alleviate obesity and adipose tissue inflammation induced by a high-fat diet. In this study, we employed proteomics to investigate the impact of PEG400 on hepatic protein expression in rats. We found that over 40 metabolic enzymes were altered, with UDP-glucuronosyltransferase 1a9 (Ugt1a9) showing the most significant upregulation. This observation is consistent with our previous findings. KEGG pathway enrichment analysis revealed that PEG400 influences retinol metabolism, steroid hormone biosynthesis, drug metabolism, bile secretion, fatty acid degradation, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and pentose and glucuronate interconversions. Western blot and molecular docking were used to quantitatively analyze related proteins. The results demonstrated that PEG400 promotes the metabolism of retinol to produce retinoic acid; enhances bile secretion by upregulating bile acid synthesis and transporter proteins; and activates the PPARα signaling pathway to regulate the expression of fat metabolism-related proteins, thereby reducing lipid accumulation. Furthermore, as natural ligands for nuclear receptors, retinoic acid and bile acids may activate nuclear receptors and initiate the regulation of target gene expression. We found upregulation of the nuclear receptors PPARα, retinoid X receptor alpha (RXRα), and pregnane X receptor (PXR). RXRα can form a dimer with PPARα or PXR to regulate the expression of target genes, which may explain the changes in the expression of numerous metabolic enzymes. This study provides a comprehensive understanding of the effects of PEG400 on liver metabolism in rats, reveals its potential biological functions, and offers new insights into the application and development of PEG400. Full article

Macular telangiectasia type 2 (MacTel) is a slowly progressive macular disorder that is often diagnosed late due to the gradual onset of vision loss. Recent advances in diagnostic techniques have facilitated earlier detection and have shown that MacTel is more common than initially thought. The disease is genetically complex, and multiple variants contribute incrementally to the overall risk. The familial occurrence of the disease prompted the investigation of the genetic background of MacTel. To better understand the molecular milieu of the disease, a literature review of the clinical reports and publications investigating the genetic factors of MacTel was performed. To date, disease-associated variants have been found in genes involved in amino acid (glycine/serine) metabolism and transport, urea cycle, lipid metabolism, and retinal vasculature and thickness. Variants in genes implicated in sphingolipid metabolism and fatty acid/steroid/retinol metabolism have been found in patients with neurological disorders who also have MacTel. Retinal metabolism involves complex biochemical processes that are essential for maintaining the high energy requirements of the retina. Genetic alterations can disrupt key metabolic pathways, leading to retinal cell degradation and the subsequent vision loss that characterizes several retinal disorders, including MacTel. This review article summarizes genetic findings that may allow MacTel to be further investigated as an inherited retinal disorder. Full article