Search Results (190)

Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product. It plays an appreciable part in the carcinogenesis and pathogenesis of neurodegeneration, such as Alzheimer’s disease and infantile neurodegeneration. This mitochondrial, homo-tetrameric protein is a central hub in various metabolic pathways, e.g., branched-chain amino acid degradation and neurosteroid metabolism. It can bind to other proteins carrying out diverse physiological functions, e.g., tRNA maturation. It has also previously been proposed to be an Aβ-binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ-binding protein (ERAB), although those reports are controversial due to data analyses. For example, the reported k_m value of some substrate of ABAD/ERAB was five times higher than its natural solubility in the assay employed to measure k_m. Regarding any reported “one-site competitive inhibition” of ABAD/ERAB by Aβ, the k_i value estimations were likely impacted by non-physiological concentrations of 2-octanol at high concentrations of vehicle DMSO and, therefore, are likely artefactual. Certain data associated with ABAD/ERAB were found not reproducible, and multiple experimental approaches were undertaken under non-physiological conditions. In contrast, 17β-HSD10 studies prompted a conclusion that Aβ inhibited 17β-HSD10 activity, thus harming brain cells, replacing a prior supposition that “ABAD” mediates Aβ neurotoxicity. Furthermore, it is critical to find answers to the question as to why elevated levels of 17β-HSD10, in addition to Aβ and phosphorylated Tau, are present in the brains of AD patients and mouse AD models. Addressing this question will likely prompt better approaches to develop treatments for Alzheimer’s disease. Full article

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR activation in rat DRG neurons by its endogenous ligand, aldosterone. This study aimed to determine whether MR, its protective enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), its endogenous ligand aldosterone, and the aldosterone-synthesizing enzyme CYP11B2 are expressed in human DRG neurons and whether they colocalize with key pain-associated signaling molecules as potential targets for genomic regulation. To this end, we performed mRNA transcript profiling and immunofluorescence confocal microscopy on human and rat DRG tissues. We detected mRNA transcripts for MR, 11β-HSD2, and CYP11B2 in human DRG, alongside transcripts for key thermosensitive and nociceptive markers such as TRPV1, the TTX-resistant sodium channel Nav1.8, and the neuropeptides CGRP and substance P (Tac1). Immunofluorescence analysis revealed substantial colocalization of MR with 11β-HSD2 and CGRP, a marker of unmyelinated C-fibers and thinly myelinated Aδ-fibers, in human DRG. MR immunoreactivity was primarily restricted to small- and medium-diameter neurons, with lower expression in large neurons (>70 µm). Similarly, aldosterone colocalized with CYP11B2 and MR with nociceptive markers including TRPV1, Nav1.8, and TrkA in human DRG. Importantly, functional studies demonstrated that prolonged intrathecal inhibition of aldosterone synthesis within rat DRG neurons, using an aldosterone synthase inhibitor significantly downregulated pain-associated molecules and led to sustained attenuation of inflammation-induced hyperalgesia. Together, these findings identify a conserved peripheral MR signaling axis in humans and highlight its potential as a novel target for pain modulation therapies. Full article

Lipedema is a chronic, estrogen-sensitive adipose tissue disorder characterized by disproportionate subcutaneous fat accumulation, fibrosis, inflammation, and resistance to fat mobilization. Despite its high prevalence, lipedema remains poorly understood and frequently misdiagnosed. This narrative review proposes a novel pathophysiological model in which menopause acts as a critical turning point in the progression of lipedema, driven by estrogen receptor imbalance (ERβ predominance over ERα), intracrine estrogen excess, and adipose tissue dysfunction. We demonstrate how menopause amplifies adipose tissue dysfunction by suppressing ERα signaling; enhancing ERβ activity; and disrupting mitochondrial function, insulin sensitivity, and lipid oxidation. Concurrently, the upregulation of aromatase and 17β-HSD1, combined with the suppression of 17β-HSD2, sustains localized estradiol excess, perpetuating inflammation, fibrosis, and immune dysregulation. The molecular signature observed in lipedema closely mirrors that of other estrogen-driven gynecological disorders, such as endometriosis, adenomyosis, and uterine fibroids. Understanding these molecular mechanisms highlights the pivotal role of menopause as a catalyst for disease progression and provides a rationale for targeted therapeutic strategies, including hormonal modulation and metabolic interventions. This review reframes lipedema as an estrogen receptor-driven gynecological disorder, offering a new perspective to improve clinical recognition, diagnosis, and management of this neglected condition. Full article

Glehnia littoralis Fr. Schmidt ex Miq. has been cultivated in China for a long time and used as a medicinal plant called “Beishashen” in traditional Chinese medicine and has been traditionally known to have antibacterial and anti-inflammatory effects, but its direct role in periodontitis has not been known. Currently used periodontal treatments require long-term administration, which causes many side effects. Therefore, in this study, we evaluated the effects of G. littoralis extract (GLE) on periodontitis in an experimental periodontitis-induced in vitro and vivo model and understood its potential molecular mechanism. The effect of GLE on periodontitis in vitro was investigated using human periodontal ligament (HPDL) cells mediated by PG-LPS. Additionally, a ligature-induced periodontitis model and a PG-LPS-induced periodontal inflammation model were used to investigate the effect of GLE in vivo. In vitro study results showed that GLE down-regulated the increased inflammatory cytokines and mediators in HPDL cells stimulated with PG-LPS, and simultaneously down-regulated the levels of 11β-HSD1 and glucocorticoid receptor (GR), thereby alleviating periodontal inflammation. At the same time, it restored the lost osteoblast differentiation potential of HPDL cells. In addition, in an in vivo model representatively used for periodontitis research, the periodontal inflammation-alleviating effect and the effect of restoring or protecting damaged periodontal tissue were confirmed. GLE can be considered as a new periodontitis treatment agent through regulating 11β-HSD1. Full article

Background/Objectives: Non-alcoholic steatohepatitis (NASH) carries a high risk of developing hepatic fibrosis. Hugan tablets (HGTs), a traditional Chinese medicine, have exhibited potent anti-hepatic fibrosis effects, though the underlying mechanisms remain unclarified. This study aims to assess the efficacy of HGTs against NASH-related liver fibrosis in mice and investigate the underlying mechanisms via the integration of pseudotargeted metabolomics and microbiomics. Methods: C57BL/6 mice were fed a choline-deficient, ethionine-supplemented (CDE) diet and treated with HGTs. The therapeutic effects of HGTs in CDE mice were assessed. The underlying mechanism of HGTs was investigated by the integration of microbiomics, a pseudo-sterile model, untargeted followed by pseudotargeted metabolomics, and molecular docking. Results: HGTs alleviated NASH-related hepatic fibrosis in CDE mice and restored the composition of the gut microbiota. The depletion of the gut microbiota eliminated the anti-hepatic fibrosis effect of HGTs. HGTs increased intestinal 7-ketolithocholic acid and tauroursodeoxycholic acid via 7α/β-hydroxysteroid dehydrogenase (7α/βHSDH), while reducing deoxycholic acid (DCA) and taurodeoxycholic acid through inhibition of bile acid 7α-dehydratase (BaiE), leading to lower hepatic DCA. Six intestinal components of HGTs interacted with 7αHSDH, 7βHSDH, and BaiE, which are expressed in the bacterial genera altered by HGTs. Conclusions: HGTs alleviate NASH fibrosis by reshaping the gut microbiome, acting on microbial BA-metabolizing enzymes, and regulating the BA metabolism in the liver and gut. Full article

Objectives: HSD17B13 (17β-hydroxysteroid dehydrogenase 13), a lipid droplet-associated enzyme, has emerged as a key regulator of hepatic lipid metabolism and a potential therapeutic target for metabolic-associated fatty liver disease (MAFLD). While its role in lipid homeostasis and liver inflammation has been partially revealed, the impact of HSD17B13 deficiency on lipid metabolism in aged mice remains poorly understood. In this study, we performed comprehensive lipidomic profiling of liver tissues from aged Hsd17b13 gene knockout (Hsd17b13 KO) mice to investigate the effects of Hsd17b13 deletion on hepatic lipid composition and metabolic pathways. Methods: Changes in hepatic lipid profiles were assessed through a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomic analysis. Results: The lipid profiles, including triglycerides (TGs), diglycerides (DGs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs), and ceramides (Cers), exhibited notable alterations in the Hsd17b13 KO mice. Conclusions: HSD17B13 plays a pivotal role in liver lipid metabolism during aging, and it is involved in the regulation of hepatic phospholipid metabolism. Our study highlights the importance of HSD17B13 in maintaining liver lipid homeostasis and its potential as a therapeutic target for age-related liver diseases. Full article

One hazardous material that occurs naturally in the environment and induces oxidative stress is cadmium (Cd). Epidemiological data revealed that exposure to cadmium in the workplace and environment might be linked to many illnesses and serious testicular injuries. Aims: It is taught that antioxidants can protect different organs against environmental toxic compounds. Therefore, the current investigation aims to show the role of antioxidants (gallic acid and selenium) in the protection against cadmium toxicity, including the architecture of the testes, semen properties, steroid hormones, protein expression of cytochrome P450 [CYP 19 and 11A1] contributing to the production of steroid hormones, and antioxidant enzyme activities, in male rabbits. Methods: Male rabbits were given cadmium orally three times/week [1 mg/kg BW] for twelve weeks. In addition, gallic acid (20 mg/kg) or selenium (1 mg/kg BW) was administered two hours before cadmium treatment. This investigation included a spectrophotometer, histopathology, and Western immunoblotting techniques. Results: Cadmium treatment significantly reduced sperm counts, testosterone, and estrogen levels after four, eight, and twelve weeks of treatment. In addition, after a 12-week treatment of rabbits with cadmium, the activity of 17β-hydroxysteroid dehydrogenase and antioxidant enzymes, including catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, as well as the glutathione levels, were inhibited in the testes tissue. On the other hand, following cadmium treatment, rabbit’s testes showed a discernible increase in free radical levels. Interestingly, the activity of antioxidant enzymes and level of free radicals were recovered in rabbits treated with gallic acid or selenium before cadmium treatment. In addition, after 12 weeks of cadmium treatment, the steroidogenic protein expressions of CYP 11A1 and CYP 19 were upregulated and downregulated in the testes, respectively. Interestingly, after pretreatment of rabbits with either gallic acid or selenium for two hours before cadmium administration, the downregulated CYP11A1 was restored to normal levels. In the histopathological investigation, immature spermatozoids and sloughed spermatogonium cells were observed in cadmium-treated rabbits’ testes. On the other hand, pretreatments of rabbits with gallic acid or selenium mitigated and alleviated the adverse effects of cadmium on testes architecture and increased the production of healthy sperm. Conclusions: The lower levels of steroid hormones could be due to the downregulation of CYP11A1, inhibition of 17β-hydroxysteroid dehydrogenase, antioxidant enzyme activities, and the induction of free radical levels. Furthermore, the pretreatment of rabbits with gallic acid or selenium mitigated the adverse effects of cadmium on the tissue architecture of testes and steroid hormone levels. Full article

Gestational diabetes mellitus (GDM) is characterized by an inadequate pancreatic β-cell response to pregnancy-induced insulin resistance, resulting in hyperglycemia. The pathophysiology involves reduced incretin hormone secretion and signaling, specifically decreased glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), impairing insulinotropic effects. Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), impair insulin receptor substrate-1 (IRS-1) phosphorylation, disrupting insulin-mediated glucose uptake. β-cell dysfunction in GDM is associated with decreased pancreatic duodenal homeobox 1 (PDX1) expression, increased endoplasmic reticulum stress markers (CHOP, GRP78), and mitochondrial dysfunction leading to impaired ATP production and reduced glucose-stimulated insulin secretion. Excessive gestational weight gain exacerbates insulin resistance through hyperleptinemia, which downregulates insulin receptor expression via JAK/STAT signaling. Additionally, hypoadiponectinemia decreases AMP-activated protein kinase (AMPK) activation in skeletal muscle, impairing GLUT4 translocation. Placental hormones such as human placental lactogen (hPL) induce lipolysis, increasing circulating free fatty acids which activate protein kinase C, inhibiting insulin signaling. Placental 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overactivity elevates cortisol levels, which activate glucocorticoid receptors to further reduce insulin sensitivity. GDM diagnostic thresholds (≥92 mg/dL fasting, ≥153 mg/dL post-load) are lower than type 2 diabetes to prevent fetal hyperinsulinemia and macrosomia. Management strategies focus on lifestyle modifications, including dietary carbohydrate restriction and exercise. Pharmacological interventions, such as insulin or metformin, aim to restore AMPK signaling and reduce hepatic glucose output. Emerging therapies, such as glucagon-like peptide-1 receptor (GLP-1R) agonists, show potential in improving glycemic control and reducing inflammation. A mechanistic understanding of GDM pathophysiology is essential for developing targeted therapeutic strategies to prevent both adverse pregnancy outcomes and the progression to overt diabetes in affected women. Full article

The role of 11β-HSD1 in Alzheimer’s disease (AD) has garnered significant attention due to its involvement in glucocorticoid metabolism, neuroinflammation, and cognitive decline. This review explores the current understanding of 11β-HSD1 in AD, examining genetic, preclinical, and clinical research. Genetic studies have identified 11β-HSD1 polymorphisms that may influence AD risk, although findings remain inconsistent. Mechanistically, 11β-HSD1 promotes neurodegeneration through the dysregulation of glucocorticoid activity, contributing to hippocampal atrophy, amyloid plaque formation, and tau pathology. Preclinical studies have shown that 11β-HSD1 inhibitors offer neuroprotective effects, including enhanced cognitive function, reduced inflammation, and improved mitochondrial activity. However, clinical trials, including those involving ABT-384 and Xanamem, have produced mixed results, with no substantial cognitive improvements despite effective enzyme inhibition. These inconsistencies highlight the complexity of AD and the challenges in translating preclinical findings into clinical outcomes. Moreover, while 11β-HSD1 inhibition holds therapeutic potential, other strategies targeting neuroinflammation, autophagy, and glucocorticoid signaling are also being explored. Ongoing research is focusing on optimizing 11β-HSD1 inhibitors, identifying biomarkers for patient selection, and investigating combination therapies to enhance treatment efficacy. Ultimately, 11β-HSD1’s role in AD presents a promising therapeutic target, but further studies are required to fully understand its potential in managing the disease. Full article

Trilostane is a drug able to block the synthesis of progesterone from pregnenolone, dependent on the enzyme 3β-hydroxysteroid dehydrogenase/Δ⁵⁻⁴ isomerase. As a consequence of this effect, it is used to treat endocrinological diseases such as Cushing’s syndrome, especially in dogs. Because of the modulatory effects of trilostane on the hypothalamic–pituitary–adrenal axis, trilostane administration causes an increase in brain levels of neurosteroids with anticonvulsant properties, as in the case of allopregnanolone. Allopregnanolone is also of interest in curing depression, suggesting that trilostane might represent a tool to address neurological and psychiatric disorders. In this review, we investigated the historical development of this drug and its current use, mechanisms, and possible developments. By searching the literature from 1978 to 2025, we identified 101 papers describing studies with trilostane. Precisely, 55 were about dogs and trilostane, 3 were on cats, and 23 were with other animals. Some studies (15) were also designed with human patients. The main disease treatment with trilostane was hyperadrenocorticism. However, we also found two preclinical papers on trilostane’s potential use in psychiatric diseases and three on trilostane’s potential use in neurological disorders. Moreover, few clinical and preclinical studies suggested the involvement of neurosteroids modulated by trilostane in different neurological disorders, thus opening a possible new perspective for the use of this drug. Full article

Intrauterine growth restriction (IUGR) is a risk factor for postnatal cardiovascular, metabolic, and psychiatric disorders. In most IUGR models, placental dysfunction that causes reduced 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) activity, which degrades glucocorticoids (GCs) in the placenta, resulting in fetal GC overexposure. This overexposure to GCs continues to affect not only intrauterine fetal development itself, but also the metabolic status and neural activity in adulthood through epigenetic changes such as microRNA change, histone modification, and DNA methylation. We have shown that the IUGR model induced DNA hypomethylation in the paraventricular nucleus (PVN) in the brain, which in turn activates sympathetic activities, the renin–angiotensin system (RAS), contributing to the development of salt-sensitive hypertension. Even in adulthood, strong stress and/or exogenous steroids have been shown to induce epigenetic changes in the brain. Furthermore, DNA hypomethylation in the PVN is also observed in other hypertensive rat models, which suggests that it contributes significantly to the origins of elevated blood pressure. These findings suggest that if we can alter epigenetic changes in the brain, we can treat or prevent hypertension. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a refined categorization of non-alcoholic fatty liver disease (NAFLD), highlighting the intricate relationship between hepatic steatosis and metabolic dysfunction. Abdominal obesity (AO), a key diagnostic criterion for metabolic dysfunction, predominantly results from inappropriate diet and unhealthy dietary habits. To comprehensively investigate which dietary factors contribute to MASLD through AO and to understand the underlying biological mechanisms, we initially conducted a systematic review of meta-analysis articles in the PubMed database from the past decade, summarizing dietary factors that affect AO. Subsequently, we conducted targeted searches in the PubMed database for these dietary factors and provided a narrative review of the mechanisms of how these dietary factors lead to AO and how AO exacerbates MASLD. A diet characterized by excessive intake of energy, carbohydrates, fructose, or ultra-processed foods (UPFs) is considered inappropriate. Inappropriate diet leads to the formation of MASLD and AO by enhancing pathways such as de novo lipid synthesis (DNL) in the liver, insulin resistance (IR), gut–liver dysfunction, and inflammation. Dietary interventions for inappropriate diets can effectively intervene in and improve MASLD and AO. The mechanism of inappropriate diet on abdominal fat deposition is through excessive energy or the activation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) to increase endocortisol secretion. Then, the excessive accumulation of visceral fat facilitates a rapid and augmented flux of free fatty acids (FFAs) to the liver and initiates a series of deleterious effects, including oxidative stress (OS), endoplasmic reticulum stress (ERS), activation of protein kinase C (PKC) pathways, and inflammation. Additionally, FFAs may mediate excessive lipid deposition and hepatocellular damage through the action of hormones. These pathways to liver damage exacerbate MASLD and progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Furthermore, investigating other potential mechanisms by which AO may influence MASLD could offer new recommendations for the treatment guidelines of MASLD. Full article

Background/Objectives: Late-onset hypogonadism (LOH), characterized by declining testosterone levels with age, negatively affects the health of men, causing physical, psychological, and sexual dysfunction. Conventional testosterone replacement therapies have side effects, which has led to interest in natural alternatives. We investigated the effects of a standardized fermented Morinda citrifolia extract (FME) on oxidative stress-induced damage in TM3 Leydig and TM4 Sertoli cells. The cells were treated with H₂O₂ to simulate oxidative stress, followed by the FME treatment. Methods: Cytotoxicity assays, testosterone measurements, and gene and protein expression analyses were conducted to evaluate the restorative properties of FME. Results: The H₂O₂ treatment significantly decreased the cell viability, testosterone production, and the expression of proteins involved in testosterone synthesis and spermatogenesis, and the FME treatment improved testosterone production and restored the luteinizing hormone receptor, steroidogenic acute regulatory protein, CYP11A1, 3β-hydroxysteroid dehydrogenase, 17,20 desmolase, and 17β-hydroxysteroid dehydrogenase levels in the TM3 Leydig cells. It also reduced the expression of testosterone-degrading enzymes, aromatase and 5α-reductase. The FME treatment restored the levels of the androgen receptor and follicle-stimulating hormone receptor in the TM4 Sertoli cells. Conclusions: FME alleviates oxidative stress-induced damage in Leydig and Sertoli cells by promoting testosterone synthesis and spermatogenesis while regulating testosterone metabolism. These findings suggest that FME could be a promising candidate for the management of LOH symptoms. Full article

Testosterone (TS) and its 1(2)-dehydrogenated derivative boldenone (BD) are widely used in medicine, veterinary science and as precursors in organic synthesis of many therapeutic steroids. Green production of these compounds is possible from androstenedione (AD) enzymatically, or from phytosterol (PS) using fermentation stages. In this study, the ascomycete Curvularia sp. VKM F-3040 was shown to convert androstadienedione (ADD, 4 and 10 g/L) to yield 97% and 78% (mol/mol) of BD, respectively. Based on its high 17β-hydroxysteroid dehydrogenase (17β-HSD) activity, a novel cascade biotransformation of PS was developed for production of TS and BD. At the first stage, the strains of Mycolicibacterium neoaurum VKM Ac-1815D or M. neoaurum VKM Ac-1816D converted PS (5 or 10 g/L) into AD or ADD (each in a concentration of 2.5 or 5 g/L), respectively. At the second stage, mycelium of the fungus under the revealed optimal conditions reduced AD or ADD with more than 90% efficiency to form TS or BD, respectively. Based on transcriptome analysis, six candidate genes that might encode 17β-HSDs in the Curvularia sp. genome were revealed. Along with 17β-HSDs, the fungus possessed inducible P450_cur 7-monooxygenase, which led to the accumulation of 7α-hydroxytestosterone (7α-OH-TS) as a major product from AD (up to 83% within 24 h after mycelium addition at the second stage of cascade biotransformation). The presence of protein synthesis inhibitor cycloheximide (CHX) prevented 7α/β-hydroxylation due to inhibition of de novo synthesis of the enzyme in the fungal cells. The results demonstrate the high biotechnological potential of the Curvularia sp. strain and open up prospects for the synthesis of valuable 17β-reduced and 7-hydroxylated steroids by cascade biotransformations. Full article

Steroid hormone imbalance is associated with the pathogenesis of preeclampsia. However, affected enzymes of steroid metabolism and gene and protein expression in serum and placenta have not been elucidated yet. We aimed to investigate steroid hormone profiles and precursor-to-product ratios in preeclamptic women compared to women with healthy pregnancy (controls) to identify potentially affected steroid hormones and their metabolizing enzymes. Also, we aimed to investigate whether the mRNA expression of these enzymes is different between the study groups and whether levels of serum mRNA expression reflect postnatal placental protein expression. Serum levels of 14 steroid hormones were measured at eight time points throughout pregnancy in nine preeclamptic women and 36 controls. Serum mRNA expression of selected steroid-metabolizing enzymes was assessed, and their protein expression was analyzed in additional nine preeclamptic women. Mean levels of sex steroid and corticosteroid hormones were significantly altered in preeclamptic women. Precursor-to-product ratios of 5α-reductase, aromatase and 11β-hydroxysteroid dehydrogenase 1 were significantly increased, those of steroid 17α-hydroxylase, 17β-hydroxysteroid-dehydrogenase, steroid 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase 2 were significantly decreased. Serum mRNA expression and placenta protein expression were comparable between the groups. Results contribute to understanding the heterogeneity of preeclampsia and can thus promote future research in personalized medicine. Full article