Journal of molecular endocrinology最新文献

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy of thyroid C-cells characterized by the secretion of several circulating biomarkers, including calcitonin (CT), procalcitonin (PCT), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and pro-gastrin-releasing peptide (proGRP). These analytes substantially contribute to the diagnosis, postoperative monitoring, and prognostic stratification of MTC. Nevertheless, their optimal use remains limited by analytical, pre-analytical, and biological factors that can compromise result reliability and clinical interpretation. Despite improvements in assay technology, significant inter-method variability persists for CT and CA 19-9, while heterophile antibodies, macro-analyte formation, renal dysfunction, and pharmacologic influences may cause spurious or misleading results. Moreover, a lack of harmonized reference intervals and clinical decision thresholds complicates longitudinal follow-up and inter-laboratory comparison. This review systematically addresses current laboratory challenges affecting MTC biomarkers, summarizes the main sources of false-positive or unreliable results, and discusses the complementary diagnostic roles of CT, PCT, and emerging analytes such as ProGRP. Emphasis is placed on standardization needs, verification of analytical performance, and the importance of consistent assay use in patient follow-up. Ultimately, the effective management of MTC biomarkers requires active engagement of clinical chemists and pathologists within multidisciplinary teams to ensure accurate interpretation, resolve analytical ambiguities, and integrate biochemical data into evidence-based therapeutic decision-making.

Renal sodium balance is important for blood pressure homeostasis and is regulated by corticosteroids, chiefly aldosterone but also glucocorticoids. Abundance of these hormones in functional subregions of the kidney is unknown, previous work being limited to measurements in plasma and urine, and in microdialysate from kidney medulla. Here mass spectrometry imaging (MSI) was applied to map corticosteroids in kidney to understand how their distribution overlays with functional targets. Male C57BL6 mice, aged 10 weeks, were fed diets containing 0.03%, 0.3% or 3% w:w sodium for two weeks and kidneys harvested at cull. Steroids were localised as Girard T derivatives on cryosections using Matrix assisted laser desorption ionisation Fourier transform ion cyclotron MSI, with confirmation by liquid extraction surface analysis. Co-registration was performed on sections stained with hematoxylin and eosin. Corticosterone localised along the papilla, medulla and inner cortex, whereas 11-dehydrocorticosterone was concentrated in the medulla. Higher amounts of aldosterone were present in medulla and outer cortex. Distribution patterns were unchanged by dietary salt, but amounts of corticosterone were elevated, particularly in outer cortex with low salt diet. MSI holds great promise to dissect corticosteroid signalling in functional zones of the kidney.

Novel biomarkers are imperative for predicting radioactive iodine (RAI) avidity in metastatic lesions of differentiated thyroid carcinoma, and mechanisms regulating RAI uptake remain incompletely understood. This study aimed to identify distinct serum metabolic profiles in papillary thyroid carcinoma (PTC) patients with non-131I-avid disease and elucidate underlying molecular mechanisms. Serum samples from 94 PTC patients were analyzed using gas chromatography-time-of-flight mass spectrometry. Patients were stratified into the non-131I-avid pulmonary metastases group (n = 30), the 131I-avid pulmonary metastases group (n = 31), and the remnant ablation group (n = 33). Principal component analysis and orthogonal partial least squares-discriminant analysis was employed for classification and biomarker identification. Differential metabolites were visualized via heatmap and evaluated for diagnostic potential using receiver operating characteristic curve analysis. Pathway enrichment analysis utilized the KEGG database. Sixty metabolites were significantly dysregulated between non-131I-avid and 131I-avid groups: 54 elevated (fold change (FC) range: 1.17-4.81) and 6 reduced (FC range: 0.31-0.82) in the non-131I-avid cohort. Ten metabolites demonstrated a high predictive power for non-131I-avid pulmonary metastatic PTC (AUC > 0.9; P < 0.001). Pathway analysis identified linoleic acid (LA) metabolism as the most significantly altered pathway (impact factor = 1.0). Mechanistically, LA competitively inhibited the binding of the endoplasmic reticulum (ER) stress-responsive transcription factor ATF4 to the sodium-iodide symporter (NIS) promoter, suppressing NIS transcription. Serum metabolomic profiling effectively discriminates PTC patients with pulmonary metastases based on 131I avidity. Our findings demonstrate that LA attenuates NIS expression by inhibiting ER stress-mediated ATF4 activation in PTC. This work provides novel mechanistic insights into non-131I-avid metastatic PTC development and identifies potential diagnostic biomarkers and therapeutic targets.

Thyroid eye disease (TED), a major extrathyroidal manifestation of Graves' disease, is driven by the underlying autoimmune responses. This study aimed to elucidate the pathological role of IL-11 in TED and evaluate the therapeutic potential of LASN01, a potent, fully human antibody that targets IL-11 receptor alpha (IL-11Rα). IL-11 (P < 0.001) and IL-11Rα (P = 0.003) mRNA were significantly elevated in TED orbital tissues (n = 15) compared to normal controls (n = 15) by quantitative real-time polymerase chain reaction (RT-qPCR). IL-11 expressions in both TED and normal orbital fibroblasts (OFs) were upregulated after treatment with either transforming growth factor-beta (TGF-β) or insulin-like growth factor 1 (IGF-1). Furthermore, IL-11 exerted a synergistic stimulatory effect on hyaluronan production in TED OFs when combined with either TGF-β (3.21-fold, P < 0.001) or IGF-1 (2.83-fold, P < 0.001). Notably, the combination of IL-11 and TGF-β induced greater procollagen production (6.17-fold, P < 0.001). Blocking IL-11R with LASN01 effectively reduced both hyaluronan (94% reduction, P < 0.001) and procollagen production (36% reduction, P = 0.002) in ELISA under various stimulation conditions. Finally, Western blot analysis showed that LASN01 blocked STAT3 and ERK phosphorylation in TED OFs, which are known as downstream effectors of IL-11 signaling. This study systematically analyzed how IGF-1 and TGF-β promote IL-11 expression in OFs and examined the downstream effects of IL-11 on hyaluronan and procollagen production, highlighting the central role of IL-11 in TED-associated tissue expansion and fibrosis. The inhibitory effects of LASN01 on hyaluronan and procollagen production suggest that targeting IL-11R could represent an effective therapeutic option for TED, providing a foundation for future clinical applications.

Differentially altered expression of transcripts of retinoic acid receptors α, β, γ (Rarα, β, γ), which mediate the actions of all-trans retinoic acid (RA), is observed in glomeruli of nephrotic syndrome (NS) patients vs normal individuals, with Rarβ reduced and both RARα and RARγ increased. Thus, we generated a mouse model (PCRB) with Rarβ specifically deleted in podocytes to define the glomerular actions of Rarβ. Rarβ deletion in PCRB mice results in podocyte loss, podocyte foot process effacement, glomerular basement membrane (GBM) thickening, reduced podocyte adhesion to the GBM, lipid accumulation in glomeruli, and hyperfiltration leading to albuminuria. Genome-wide transcriptomics and proteomics studies of glomeruli revealed that Rarβ deletion increased Mogat, Dgat, and Hmgcs mRNAs, which catalyze triglyceride and cholesterol synthesis, and Slc27a2 and Cd36, which mediate fatty acid uptake, recapitulating NS symptoms. Surprisingly, podocyte-specific Rarβ deletion also increased key mRNAs and proteins involved in fatty acid uptake and lipid biosynthesis in the liver, promoting steatohepatitis and systemic hyperlipidemia. These data indicate that Rarβ signaling in the kidney has a profound impact on both kidney and liver functions and suggest that Rarβ plays an important role in regulating kidney-liver crosstalk. PCRB mice may be a useful model of NS.

Extracellular vesicle (EV) miRNAs play pivotal roles in metabolic disorders. This study aimed to describe the plasma EV miRNA profiling of type 2 diabetes mellitus (T2DM) and evaluate the association between differentially expressed miRNAs and T2DM. The subjects were from the Henan Rural Cohort. The miRNA profiling of plasma EVs was quantified by the next-generation sequencing of RNA in the discovery sets to identify differentially expressed miRNAs. The association between differentially expressed miR-3120-5p and T2DM was validated in 75 pairs of newly diagnosed T2DM and controls using logistic regression and a generalized linear model. In vitro experiments were performed in HepG2 cells to explore the mRNA and protein expression levels of glucose-related transcription factors and glucose consumption by transfecting miR-3120-5p mimic or inhibitor. We found that in the discovery set, the first phase identified 73 upregulated and 44 downregulated miRNAs, followed by 41 upregulated and 23 downregulated miRNAs in the second phase. miR-3120-5p showed upregulation in the two phases. In the validation set, the miR-3120-5p level in plasma EVs was positively associated with the risk of T2DM (OR: 1.22, 95% CI: 1.05, 1.44). In vitro experiments demonstrated that glucose consumption was reduced in HepG2 cells overexpressing miR-3120-5p compared to mimic negative controls, and that expression of the glucose uptake factor GLUT2 protein was also decreased. We conclude that plasma EV miR-3120-5p was associated with T2DM in the rural populations with limited resources, and might contribute to the pathological process by directly or indirectly inhibiting hepatocyte GLUT2 expression and glucose consumption.

Prenatally androgenised (PA) sheep are a clinically realistic model of polycystic ovary syndrome (PCOS). They have dysfunctional subcutaneous adipose tissue (SAT) with reduced adipogenesis in adolescence and enlarged adipocytes with increased inflammation in adulthood. We hypothesised that analysis of SAT in young adults, after adipogenesis is complete but before inflammation is apparent, would give insights into the evolution of adipose tissue dysfunction. Pregnant sheep were treated intramuscularly with 100 mg testosterone propionate or vehicle control (C) twice weekly from day 62-102 of gestation. Weight-matched female offspring (PA = 10; C = 10) were studied up to 22 months of age. Glucose tolerance testing was performed, and at sacrifice SAT was fixed for histological analysis and frozen for RNA sequencing (RNAseq) and gene expression analysis. There was no difference in the average size of SAT adipocytes between PA and C young adults. There were no differences in the expression of the adipogenesis markers PPARG, CEBPA and CEBPB, or the inflammatory markers TNF and IL6, although PA sheep were already hyperinsulinaemic. RNAseq identified 792 potentially differentially expressed (P < 0.05) genes in PA sheep SAT (406 upregulated; 386 downregulated). Ingenuity Pathway Analysis highlighted upregulation of fibrotic pathways in the SAT of PA sheep. POSTN, associated with tissue fibrosis, and COL1A1, COL1A2 and COL3A1 were significantly elevated, and histochemistry showed significantly increased SAT fibrosis in PA sheep. Early fibrotic changes in SAT occur before inflammatory gene expression in PA sheep. A fibrotic barrier to healthy adipocyte expansion may have a mechanistic role in the development of inflammation in PCOS.

Type 2 diabetes mellitus (DM) is closely associated with cellular senescence (SnC), a state of irreversible cell cycle arrest marked by functional decline. Preventing cellular senescence in already diagnosed DM patients is crucial for limiting disease progression and the onset of co-morbidities. The relationship between oxidative stress, DNA damage, and telomere shortening provides a mechanistic framework for elucidating the role of cellular senescence in the pathogenesis and progression of type 2 DM. This senescence-driven model of metabolic dysfunction not only accounts for impaired β-cell function and insulin resistance but also for the systemic complications observed in DM patients. The accumulation of senescent cells, particularly in metabolically active tissues such as adipose tissue, is increasingly recognised as both a cause and a consequence of the chronic inflammatory environment that characterises diabetes. Evidence from in vitro and preclinical studies highlights the detrimental effects of the senescence-associated secretory phenotype, reinforcing tissue damage through paracrine and autocrine signalling mechanisms. Despite its complexity, approaches targeting the senescent phenotype offer a promising avenue for adjunct therapies. Senotherapeutics, such as senomorphic agents that protect cells from cytotoxic damage and mitigate oxidative stress, can potentially protect against disease onset, whereas senolytic agents have the potential to eliminate senescent cells to limit metabolic disease progression, mitigate complications, and ultimately improve patient outcomes. There is, however, an urgent need to translate the preclinical findings into clinical trials to assess the safety, efficacy, and long-term effects of senotherapeutic agents.

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by single-gene mutations. MODY3, the most common subtype, results from mutations in the hepatocyte nuclear factor 1-alpha (HNF1α) gene. HNF1α is a transcription factor essential for pancreatic β-cell function and insulin production. Clinically, β-cells in MODY3 patients generally retain intact sulfonylurea receptor function, making sulfonylureas the preferred treatment. However, a novel loss-of-function variant, HNF1α-Q125ter, has been shown to induce sulfonylurea insensitivity in MODY3 patients. This study aimed to investigate the role and mechanism of HNF1α-Q125ter-mediated mitochondrial dysfunction and impaired mitophagy in new variant-induced β-cell dysfunction. Mitophagy-related protein and transcription levels were analysed by Western blotting and reverse transcription-quantitative PCR (RT-qPCR). Mitochondrial morphology was examined by transmission electron microscopy. Ins-1 cells were transfected with overexpression constructs for HNF1α-Q125ter or short hairpin RNA targeting HNF1a (shHNF1α) to assess its effects on mitochondrial function and mitophagy. Ins-1 cells expressing HNF1α-Q125ter showed decreased mitochondrial number, oxygen consumption, and energy metabolism. Correspondingly, mitochondrial morphology was damaged in an hnf1a+/- zebrafish model. HNF1α-Q125ter also inhibited mitophagy by suppressing the mRNA expression of PTEN-induced kinase 1 (PINK1), pyruvate dehydrogenase E1 subunit α1 (PDHA1), and Parkin RBR E3 ubiquitin-protein ligase (Parkin). Mechanistically, HNF1α-Q125ter impaired autophagy by downregulating phosphorylated mammalian target of rapamycin (p-mTOR) (Ser2448) and phosphorylated-70 kDa ribosomal protein S6 kinase (p-p70S6K) (Thr389). In conclusion, our findings suggest that HNF1α-Q125ter induces mitophagy dysfunction by suppressing the p-mTOR(ser2448)/p-p70S6K(Thr389) signalling pathway, providing novel insights into the mechanisms underlying sulfonylurea insensitivity in patients with this variant.

Insulin resistance is often characterized as the factor that contributes to the emergence of metabolic diseases. Hepatic microRNAs (miRNAs) played critical roles in the development of metabolic-associated steatotic liver disease (MASLD) and insulin resistance. To investigate the effects of hepatic miR-411-5p in regulating insulin resistance, the present study utilized primary mouse hepatocytes and mice with MASLD. Suppression of miR-411-5p decreased hepatocyte glycogen production and phosphorylation of AKT, but miR-411-5p mimic improved insulin sensitivity. Mechanistically, 3'-UTR of transcription factor Sp2 was one of the binding sites of miR-411-5p. Treatment of miR-411-5p mimic suppressed the Sp2 mRNA and protein levels, enhancing the insulin signaling activity in the primary mouse hepatocytes. Hepatocyte-specific overexpression of Sp2 induced hepatic lipid accumulation and activation of related metabolic pathways. In contrast, inhibition of miR-411-5p reversely upregulated the expression of Sp2 and exaggerated insulin resistance in primary hepatocytes and the mouse model. Similarly, miR-411-5p mimic decreased obesity-induced hyperinsulinemia, glucose intolerance, insulin intolerance, and pyruvate intolerance. Furthermore, the parameters of MASLD, including lipid deposits, inflammation, and fibrosis, were improved after miR-411-5p replenishment, but co-administration with adeno-associated virus (AAV)-Sp2 abolished these benefits in the obese mouse model. Taken together, these findings demonstrated that Sp2-dependent miR-411-5p action regulates insulin resistance and MASLD, which provides a therapeutic approach toward resolving insulin resistance.