OBJECTIVE: This study aimed to compare 9 perfluoroalkyl sulfonic acids (PFSA) with carbon chain lengths (C4-C12) to inhibit human placental 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1), aromatase, and rat 3β-HSD4 activities. METHODS: Human and rat placental 3β-HSDs activities were determined by converting pregnenolone to progesterone and progesterone secretion in JEG-3 cells was determined using HPLC/MS-MS, and human aromatase activity was determined by radioimmunoassay. RESULTS: PFSA inhibited human 3β-HSD1 structure-dependently in the order: perfluorooctanesulfonic acid (PFOS, half-maximum inhibitory concentration, IC ₅₀: 9.03 ± 4.83 μmol/L) > perfluorodecanesulfonic acid (PFDS, 42.52 ± 8.99 μmol/L) > perfluoroheptanesulfonic acid (PFHpS, 112.6 ± 29.39 μmol/L) > perfluorobutanesulfonic acid (PFBS) = perfluoropentanesulfonic acid (PFPS) = perfluorohexanesulfonic acid (PFHxS) = perfluorododecanesulfonic acid (PFDoS) (ineffective at 100 μmol/L). 6:2FTS (1H, 1H, 2H, 2H-perfluorooctanesulfonic acid) and 8:2FTS (1H, 1H, 2H, 2H-perfluorodecanesulfonic acid) did not inhibit human 3β-HSD1. PFOS and PFHpS are mixed inhibitors, whereas PFDS is a competitive inhibitor. Moreover, 1-10 μmol/L PFOS and PFDS significantly reduced progesterone biosynthesis in JEG-3 cells. Docking analysis revealed that PFSA binds to the steroid-binding site of human 3β-HSD1 in a carbon chain length-dependent manner. All 100 μmol/L PFSA solutions did not affect rat 3β-HSD4 and human placental aromatase activity. CONCLUSION Carbon chain length determines inhibitory potency of PFSA on human placental 3β-HSD1 in a V-shaped transition at PFOS (C8), with inhibitory potency of PFOS > PFDS > PFHpS > PFBS = PFPS = PFHxS = PFDoS = 6:2FTS = 8:2FTS.
Humans ; Pregnancy ; Female ; Rats ; Animals ; Placenta ; Progesterone/pharmacology* ; Aromatase/pharmacology* ; Cell Line, Tumor ; Fluorocarbons ; Alkanesulfonic Acids ; Structure-Activity Relationship ; Hydroxysteroid Dehydrogenases/pharmacology*

OBJECTIVE: To analyze the expression of hydroxysteroid dehydrogenase like 2 (HSDL2) in rectal cancer tissues and the effect of changes in HSDL2 expression level on proliferation of rectal cancer cells. METHODS: Clinical data and tissue samples of 90 patients with rectal cancer admitted to our hospital from January 2020 to June 2022 were collected from the prospective clinical database and biological specimen database. The expression level of HSDL2 in rectal cancer and adjacent tissues was detected by immunohistochemistry, and based on the median level of HSDL2 expression, the patients were divided into high expression group (n=45) and low expression group (n=45) for analysis the correlation between HSDL2 expression level and the clinicopathological parameters. GO and KEGG enrichment analyses were performed to explore the role of HSDL2 in rectal cancer progression. The effects of changes in HSDL2 expression levels on rectal cancer cell proliferation, cell cycle and protein expressions were investigated in SW480 cells with lentivirus-mediated HSDL2 silencing or HSDL2 overexpression using CCK-8 assay, flow cytometry and Western blotting. RESULTS: The expressions of HSDL2 and Ki67 were significantly higher in rectal cancer tissues than in the adjacent tissues (P < 0.05). Spearman correlation analysis showed that the expression of HSDL2 protein was positively correlated with Ki67, CEA and CA19-9 expressions (P < 0.01). The rectal cancer patients with high HSDL2 expressions had significantly higher likelihood of having CEA ≥5 μg/L, CA19-9 ≥37 kU/L, T3-4 stage, and N2-3 stage than those with a low HSDL2 expression (P < 0.05). GO and KEGG analysis showed that HSDL2 was mainly enriched in DNA replication and cell cycle. In SW480 cells, HSDL2 overexpression significantly promoted cell proliferation, increased cell percentage in S phase, and enhanced the expression levels of CDK6 and cyclinD1 (P < 0.05), and HSDL2 silencing produced the opposite effects (P < 0.05). CONCLUSION The high expression of HSDL2 in rectal cancer participates in malignant progression of the tumor by promoting the proliferation and cell cycle progress of the cancer cells.
Humans ; CA-19-9 Antigen ; Ki-67 Antigen/metabolism* ; Prospective Studies ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Rectal Neoplasms/genetics* ; Cell Cycle ; Gene Expression Regulation, Neoplastic ; Hydroxysteroid Dehydrogenases/metabolism*

11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics* ; Humans ; Mineralocorticoid Excess Syndrome, Apparent/genetics* ; Pedigree

Animals ; Autophagy/genetics* ; Cholesterol/metabolism* ; Gene Expression Regulation ; Integrases/metabolism* ; Leydig Cells/metabolism* ; Male ; Mice, Knockout ; Multienzyme Complexes/metabolism* ; Phosphoproteins/metabolism* ; Primary Cell Culture ; Progesterone Reductase/metabolism* ; RNA Splicing Factors/metabolism* ; Scavenger Receptors, Class B/metabolism* ; Sequestosome-1 Protein/metabolism* ; Signal Transduction ; Sirtuin 1/genetics* ; Sodium-Hydrogen Exchangers/metabolism* ; Steroid 17-alpha-Hydroxylase/metabolism* ; Steroid Isomerases/metabolism* ; Testosterone/genetics*

OBJECTIVE: To explore the genetic basis for a sib pair featuring 17beta-hydroxysteroid dehydrogenase type 3 deficiency. METHODS: Genomic DNA was extracted from the proband, her sister, and their parents, and was subjected to sequencing analysis with a gene panel for sexual development. Suspected variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Both the proband and her sister were found to harbor novel compound heterozygous missense variants of the HSD17B3 gene, namely c.839T>C (p.Leu280Pro) and c.239G>T (p.Arg80Leu), which were derived respectively from their mother and father. The variants were unreported previously and predicted to be deleterious by PolyPhen2, MutationTaster and other online software. Based on the American College of Medical Genetics and Genomics standards and guidelines, both c.839T>C(p.Leu280Pro) and c.239G>T (p.Arg80Leu) were predicted to be likely pathogenic (PM2+PP1+PP2+PP3+PP4, PM2+PM5+PP1+PP2+PP3+PP4). CONCLUSION The compound heterogeneous variants of the HSD17B3 gene probably underlay the disease in this sib pair. 17beta-hydroxysteroid dehydrogenase type 3 deficiency may lack specific clinical features and laboratory index, genetic testing can facilitate a definitive diagnosis.
17-Hydroxysteroid Dehydrogenases/genetics* ; Female ; Genetic Testing ; Genomics ; Humans ; Mutation ; Mutation, Missense

A 15-day-old boy was admitted to the hospital due to repeated convulsions for 14 days. The main clinical manifestations were uncontrolled seizures, hypoergia, feeding difficulties, limb hypotonia, and bilateral hearing impairment. Clinical neurophysiology showed reduced brainstem auditory evoked potential on both sides and burst-suppression pattern on electroencephalogram. Measurement of very-long-chain fatty acids in serum showed that C26:0 was significantly increased. Genetic testing showed a pathogenic compound heterozygous mutation, c.101C>T(p.Ala34Val) and c.1448_1460del(p.Ala483Aspfs*37), in the
Genetic Testing ; Humans ; Infant, Newborn ; Male ; Muscle Hypotonia ; Mutation ; Peroxisomal Multifunctional Protein-2/genetics* ; Protein Deficiency/genetics*

OBJECTIVE: To investigate the effects of calcium-sensitive receptors (CaSR) on the expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and cortisol concentration in a neonatal mouse model of persistent pulmonary hypertension (PPH). METHODS: Fifty-six newborn C57BL/6 mice were randomly divided into a control group (n=14), a PPH group (n=14), an agonist group (n=14), and an inhibitor group (n=14). The mice in the PPH, agonist, and inhibitor groups were exposed to a 12% oxygen concentration, and the agonist group and inhibitor group were given CaSR agonist (GdCl3, 16 mg/kg) and CaSR antagonist (NPS2390, 1 mg/kg) intraperitoneally once a day, respectively. The mice in control group were exposed to air, and then injected with an equal volume of normal saline as those in the PPH group every day. All mice were treated for 14 days. Morphological examination of heart and lung tissues was performed using hematoxylin-eosin staining. The expression levels of 11β-HSD2 mRNA and 11β-HSD2 protein in lung tissues were measured by qRT-PCR and Western blot respectively. Brain natriuretic peptide (BNP) and cortisol levels in lung tissues were determined using ELISA. RESULTS: Compared with the control group, the PPH group had significantly increased pulmonary artery wall thickness (WT%), ratio of right to left ventricular thickness (RV/LV), alveolar mean linear intercept, and BNP concentration and a significantly reduced radial alveolar count (P<0.05); compared with the PPH group, the agonist group showed significant increases in WT% and BNP concentration, while the inhibitor group showed significant reductions in the two indicators (P<0.05). Compared with the control group, the PPH group showed significant reductions in the expression levels of 11β-HSD2 mRNA and 11β-HSD2 protein, but a significant increase in cortisol concentration (P<0.05); compared with the PPH group, the agonist group had significantly lower expression levels of 11β-HSD2 mRNA and 11β-HSD2 protein, but a significant higher cortisol concentration, while the inhibitor group showed opposite changes in these indicators (P<0.05). CONCLUSIONS CaSR may control the development and progression of PPH in newborn mice by regulating the expression of 11β-HSD2 and cortisol concentration.
11-beta-Hydroxysteroid Dehydrogenase Type 2 ; Animals ; Animals, Newborn ; Calcium ; Hydrocortisone ; Hypertension, Pulmonary ; Mice ; Mice, Inbred C57BL ; Receptors, Calcium-Sensing

Adipose tissue inflammation is considered a major contributing factor in the development of obesity-associated insulin resistance and cardiovascular diseases. However, the cause of adipose tissue inflammation is presently unclear. The role of mitochondria in white adipocytes has long been neglected because of their low abundance. However, recent evidence suggests that mitochondria are essential for maintaining metabolic homeostasis in white adipocytes. In a series of recent studies, we found that mitochondrial function in white adipocytes is essential to the synthesis of adiponectin, which is the most abundant adipokine synthesized from adipocytes, with many favorable effects on metabolism, including improvement of insulin sensitivity and reduction of atherosclerotic processes and systemic inflammation. From these results, we propose a new hypothesis that mitochondrial dysfunction in adipocytes is a primary cause of adipose tissue inflammation and compared this hypothesis with a prevailing concept that “adipose tissue hypoxia” may underlie adipose tissue dysfunction in obesity. Recent studies have emphasized the role of the mitochondrial quality control mechanism in maintaining mitochondrial function. Future studies are warranted to test whether an inadequate mitochondrial quality control mechanism is responsible for mitochondrial dysfunction in adipocytes and adipose tissue inflammation.
11-beta-Hydroxysteroid Dehydrogenases ; Adipocytes ; Adipocytes, White ; Adipokines ; Adiponectin ; Adipose Tissue ; Anoxia ; Cardiovascular Diseases ; Homeostasis ; Inflammation ; Insulin Resistance ; Metabolism ; Mitochondria ; Nitric Oxide ; Obesity ; Quality Control

At present, there is no reliable in vitro assembled prepubertal testis-like biomimetic organ culture system designed to assess the functional effects of human gonadotropins on Sertoli and Leydig cells. Spermatogenesis is regulated by endocrine, paracrine, and juxtacrine factors (testicular cross-talk), mainly orchestrated by gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that play a pivotal role by stimulating Leydig and Sertoli cells, respectively. The aim of our study was to set up an in vitro prepubertal porcine bioengineered construct as a new model for experimental studies on reassembled Sertoli and Leydig cells. We have evaluated Sertoli and Leydig cells obtained from 15- to 20-day-old neonatal pig testes in terms of purity and function. Subsequently, purified Sertoli and enriched Leydig cells were subjected to coincubation to obtain an in vitro prepubertal porcine testis-like culture system. We performed enzyme-linked immunosorbent assay (ELISA) for anti-Müllerian hormone (AMH), inhibin B, and testosterone secretion in the medium, and Real-Time PCR analysis of AMH, inhibin B, FSH-r, aromatase, LHr, and 3β-HSD mRNA expression levels. This in vitro testis-like system was highly responsive to the effects of human gonadotropins and testosterone. AMH mRNA expression and secretion declined, and inhibin-B increased, while FSH-receptor expression was downregulated upon FSH/LH exposure/treatment. Finally, the production of testosterone was increased selectively upon LH treatment. In summary, our proposed model could help to better determine the action of human gonadotropins on Sertoli and Leydig cells. The potential usefulness of the system for shedding light into male infertility-related issues is evident.
3-Hydroxysteroid Dehydrogenases/metabolism* ; Animals ; Animals, Newborn ; Anti-Mullerian Hormone/metabolism* ; Aromatase/metabolism* ; Cell Culture Techniques ; Enzyme-Linked Immunosorbent Assay ; Follicle Stimulating Hormone/pharmacology* ; Hormones/pharmacology* ; In Vitro Techniques ; Inhibins/metabolism* ; Leydig Cells/metabolism* ; Luteinizing Hormone/pharmacology* ; Male ; Models, Biological ; Real-Time Polymerase Chain Reaction ; Receptors, FSH/metabolism* ; Receptors, LH/metabolism* ; Sertoli Cells/metabolism* ; Swine ; Testis/metabolism* ; Testosterone/metabolism*

Non-alcoholic fatty liver disease (NAFLD) is an epidemic metabolic condition driven by an underlying lipid homeostasis disorder. The lipid droplet (LD), the main organelle involved in neutral lipid storage and hydrolysis, is a potential target for NAFLD therapeutic treatment. In this review, we summarize recent progress elucidating the connections between LD-associated proteins and NAFLD found by genome-wide association studies (GWAS), genomic and proteomic studies. Finally, we discuss a possible mechanism by which the protein 17β-hydroxysteroid dehydrogenase 13 (17β-HSD13) may promote the development of NAFLD.
17-Hydroxysteroid Dehydrogenases ; genetics ; metabolism ; Animals ; Genome-Wide Association Study ; Genomics ; Humans ; Lipid Droplets ; metabolism ; Lipid Metabolism ; genetics ; Non-alcoholic Fatty Liver Disease ; genetics ; metabolism ; Proteomics