Endocrine journal最新文献

Significant overlap in the epidemiology and coinfection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) has been identified, which accelerates the development of severe liver cirrhosis and hepatocellular carcinoma worldwide. Interferon-α (IFN-α), a cytokine with antiviral properties, exerts profound physiological effects on innate immunity by regulating interferon-stimulated genes (ISGs) within cells. However, the underlying mechanism of IFN-α in hepatic inflammation remains to be fully elucidated. Here, we utilized LO2 cells treated with the recombinant IFN-α protein and conducted microRNA (miR) sequencing. MiR-122-3p and miR-122-5p_R+1 were the most enriched miRNAs involved in the pathogenesis of IFN-α-induced inflammatory responses and were significantly downregulated by IFN-α treatment. Furthermore, we identified interferon induced protein with tetratricopeptide repeats 1 (IFIT1) as a potential target gene of miR-122. IFN-α markedly increased the expression of proinflammatory cytokines and fibrogenic genes but decreased the mRNA expression of ISGs. Additionally, IFN-α significantly activated the NF-κB p-p65, MAPK p-p38, and Jak/STAT pathways to trigger inflammation. Importantly, supplementation with a miR-122 mimic significantly alleviated IFN-α-induced inflammation and induced IFIT1 expression in LO2 cells. Conversely, the suppression of miR-122 markedly exacerbated the inflammatory response triggered by IFN-α. Furthermore, silencing IFIT1 via an siRNA elicited an inflammatory response, whereas IFIT1 overexpression ameliorated hepatic inflammation and fibrosis in a manner comparable to that induced by IFN-α treatment. Taken together, our findings suggest that miR-122 and its target, IFIT1, reciprocally regulate the inflammatory response associated with IFN through the Jak/STAT pathway.

Non-high-density lipoprotein cholesterol (non-HDL), a more readily available and reliable lipid parameter, is unclear in its association with type 2 diabetes (T2D). Previous studies assessing the relationship between non-HDL and T2D risk remains inconsistent results. We performed a meta-analysis to systematically evaluate this association. The PubMed, EMBASE, Medline, Web of Science, and Cochrane Library databases were systematically searched to find articles on "non-HDL" and "T2D" from inception to December 6, 2023. A random-effects model was used to calculate the effect estimates and 95% confidence intervals. Subgroup analyses and univariate Meta-regression were performed to explore sources of heterogeneity. The main exposure and outcome were non-HDL and T2D, respectively, in the general population. A total of 8 studies included 251,672 participants who met the inclusion criteria for this study. Meta-analysis showed that higher non-HDL increased the risk of T2D compared with the lower non-HDL group (total effect size: 1.16; 95% CI 1.079-1.251, p < 0.001). Subgroup analyses and Meta-regression of the association between non-HDL and T2D were not affected by region, proportion of men, sample size, or adjustment for confounders (including BMI, hypertension, waist circumference, and family history of diabetes). Higher non-HDL may be associated with an increased risk of T2D. Large prospective cohort studies are needed to validate these findings, and further studies are required in order to elucidate the underlying pathophysiologic mechanisms underlying the association between non-HDL and T2D.

Circular RNAs (circRNAs) play an important role in regulating inflammation and oxidative stress during the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the underlying mechanism is unclear. This study aimed to determine the role of mmu_circ_0009303 in MASLD. We used a bioinformatics approach to identify potential targets and established an in vitro model of MASLD. Oil red O staining, cell transfection and dual-luciferase reporter assay were used to determine the role of mmu_circ_0009303. The results indicated that the mmu_circ_0009303 expression was significantly increased in the MASLD model both in vitro and in vivo and was associated with oxidative stress levels and inflammation. Moreover, bioinformatics analyses revealed that miRNA-182-5p and Foxo3 are targets of mmu_circ_0009303 and miRNA-182-5p, respectively. In the in vitro MASLD model, mmu_circ_0009303 promoted fat deposition in NCTC1469 cells, which was induced by free fatty acid (FFA) through the regulation of miRNA-182-5p/Foxo3. The expression of miRNA-182-5p and Forkhead box O3 (Foxo3) was associated with mmu_circ_0009303 expression in the liver of mice with MASLD, which was induced by a high-fat diet. Furthermore, mmu_circ_0009303 may be involved in regulating the expression of lipid metabolism-related regulatory proteins, such as CPT1A, SLC27A4, ACBD3, SREBP1, FAS, PPARα, and PPARγ. Taken together, mmu_circ_0009303 promotes oxidative stress, inflammation, and excessive fat accumulation in NCTC1469 cells induced by FFA through the regulation of miRNA-182-5p/Foxo3 and lipid metabolism-related regulatory proteins. These findings provide a potential target for the treatment of MASLD.

Ghrelin produced in the stomach promotes food intake and GH secretion, and acts as an anabolic peptide during starvation. Ghrelin binds to the growth hormone secretagogue receptor, a G protein-coupled receptor (GPCR), whose high-resolution complex structures have been determined in the apo state and when bound to an antagonist. Anamorelin, a low-molecular-weight ghrelin agonist, has been launched in Japan for the treatment of cancer cachexia, and its therapeutic potential has attracted attention due to the various biological activities of ghrelin. In 2019, liver-expressed antimicrobial peptide (LEAP2), initially discovered as an antimicrobial peptide produced in the liver, was identified to be upregulated in the stomach of diet-induced obese mice after vertical sleeve gastrectomy. LEAP2 binds to the GHSR and antagonizes ghrelin's activities. The serum concentrations of human LEAP2 are positively correlated with body mass index, body fat accumulation, and fasting serum concentrations of glucose and triglyceride. Serum LEAP2 elevated and ghrelin reduced in obesity. Ghrelin and LEAP2 regulate body weight, food intake, and GH and blood glucose concentrations, and other physiological phenomena through their interactions with the same receptor, GHSR.

Over 70 intragenic copy-number variations (CNVs) of PHEX have been identified in patients with X-linked hypophosphatemia (XLH). However, the underlying mechanism of these CNVs has been poorly investigated. Furthermore, although PHEX undergoes X chromosome inactivation (XCI), the association between XLH in women with heterozygous PHEX variants and skewed XCI remains unknown. In this study, we determined the precise genomic structure and the XCI status of a girl with XLH who showed short stature and bowing of the legs at 2 years old. Laboratory tests revealed low levels of serum phosphate and elevated levels of alkaline phosphatase and fibroblast growth factor 23. Multiplex ligation-dependent probe amplification and targeted long-read sequencing revealed that she carried a 24.6-kb intragenic duplication of PHEX. The duplication was tandemly aligned in a head-to-tail orientation. The duplication breakpoints shared a 2-bp microhomology, indicating that this CNV resulted from a replication-based error. Trio sequencing results showed that the duplication was a de novo CNV that occurred on the paternally-derived allele. DNA methylation analysis demonstrated random XCI. A literature review of 12 previously reported cases of intragenic CNVs of PHEX revealed that the deletions/duplications can be ascribed to replication-based errors. Our findings and those of previous studies indicate that XLH-causative CNVs in PHEX predominantly arise from replication-based errors. Thus, the genomic region surrounding PHEX may be vulnerable to replication-based errors during gametogenesis or early embryogenesis. Our study provides supporting evidence that heterozygous PHEX variants can lead to XLH in women with random XCI.

The ferroptosis of osteoblasts has been demonstrated to play a significant role in the development of steroid-induced osteonecrosis of the femoral head (SONFH). Additionally, microRNAs (miRNAs) have been identified as regulators of SONFH progression. However, the precise role of miRNAs in the regulation of osteoblast ferroptosis remains unclear. This study explored the role of exosomal miR-150-3p, derived from bone marrow mesenchymal stem cells (BMSCs), in osteoblast ferroptosis in SONFH. Dexamethasone (DEX) was used to treat osteoblasts to induce ferroptosis. BMSCs exosomes with different levels of miR-150-3p were introduced into a co-culture with the cells. To verify the targeting relationship between growth factor independence 1 (Gfi1) and the miR-150-3p promoter, as well as between miR-150-3p and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC), respectively, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and dual luciferase assays were employed. It was found that BMSCs-Exos-miR-150-3p mitigated DEX-triggered ferroptosis in osteoblasts. MiR-150-3p directly targeted BTRC, leading to its downregulation in osteoblasts. The BTRC/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the inhibition of DEX-induced osteoblast ferroptosis by BMSCs-Exos-miR-150-3p. Overexpression of BTRC reversed the inhibitory effect of BMSCs-Exos-miR-150-3p. In a SONFH rat model, BMSCs-Exos-miR-150-3p alleviated ferroptosis in osteoblasts through BTRC/Nrf2. In addition, Gfi1 bonded to the miR-150-3p promoter and inhibited its transcription. Gfi1 silencing elevated miR-150-3p levels and improves cell viability of BMSCs. In conclusion, our results suggest that BMSCs-Exos-miR-150-3p alleviates SONFH by suppressing ferroptosis through the regulation of BTRC/Nrf2 and miR-150-3p may be a potential target for SONFH treatment.

Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Liraglutide could improve cognition in AD mouse models, but its precise mechanism remains unclear. In this study, we used STZ-induced diabetic rats and HT-22 cells to investigate the effects of liraglutide. The MWM test, MTT assay, ELISA, western blot, and immunofluorescence were used in this research. Diabetic rats induced by STZ displayed a longer escape latency and entered the target zone less frequently (p < 0.05) in the MWM test. Intraperitoneal injection of liraglutide improved the cognition of diabetic rats (p < 0.05) and reduced Aβ42 expression in the hippocampus (p < 0.05). In vivo experiments showed that HT-22 cell viability decreased in the HG group, but liraglutide (100 nmol/L and 1 μmol/L) enhanced HT-22 cell viability (p < 0.05). Oxidative stress markers were upregulated in HT-22 cells in the HG group, while liraglutide treatment significantly reduced these markers (p < 0.05). Western blot and immunofluorescence analyses demonstrated increased levels of Aβ, BACE1, and γ-secretase in HT-22 cells in the HG group (p < 0.05), whereas these levels were reduced in the liraglutide treatment group (p < 0.05). These effects were reversed by the nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors (p < 0.05). These findings suggest that liraglutide improved the cognition of diabetic rats and might exert its protective effects by reducing oxidative stress, downregulating BACE1 and γ-secretase expression, and decreasing Aβ deposition via the NF-κB and ERK1/2 pathways.

Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the conversion of glutamic acid into γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS). GAD is widely expressed in the CNS and pancreatic β-cells. GABA produced by GAD plays a role in regulating insulin secretion in pancreatic islets. Anti-GAD antibody is an established marker of type 1 diabetes mellitus (T1DM) and is also associated with stiff-person syndrome (SPS) and several other neurological disorders, including ataxia, cognitive impairment, limbic encephalitis, and epilepsy, collectively referred to as GAD antibody-spectrum disorders (GAD-SD). We report the case of a 17-year-old male patient who developed GAD-SD and T1DM after allogeneic hematopoietic cell transplantation (HCT). He presented with memory disorders, including feelings of déjà vu, accompanied by vomiting and headaches, and exhibited abnormal brain magnetic resonance imaging and electroencephalogram results. In addition to elevated fasting plasma glucose and glycated hemoglobin levels, markedly elevated anti-GAD antibody levels were detected in the serum and cerebrospinal fluid. Based on these findings, the patient was diagnosed with GAD-SD and T1DM and treated with methylprednisolone, followed by multiple daily insulin injections. We also reviewed previously reported cases of GAD-SD following HCT and multiple positive islet-related antibodies.

Adolescent and young adult (AYA, 15-39 years old) patients with papillary thyroid carcinoma (PTC) experience significant psychological distress and place great importance on obtaining information regarding the disease; however, their demands remain unmet. We aimed to investigate clinicopathological and molecular features of PTC in AYA patients and compare them to those of PTC in older patients (≥40 years). This retrospective study enrolled 1,677 patients diagnosed with PTC from January 2018 to December 2022, with 400 AYA patients and 1,277 older adults. At the time of diagnosis, AYA patients with PTC had higher rates of presentation in females, larger tumor size (>2.0 cm), lymphatic vessel invasion, chronic thyroiditis, clinical lymph node metastasis, and pathologic lymph node metastasis, but lower rates of multifocality and extrathyroidal extension compared with PTC in older adults. The two groups had no significant differences regarding surgical method and distant metastasis. The prevalences of BRAF p.V600E and TERT promoter mutations of PTC were significantly lower in AYA patients (69.1% vs. 82.6% and 1.3% vs. 18.8%, respectively; both p < 0.001). In conclusion, PTC in AYA patients differed from PTC in older patients. Particularly, BRAF p.V600E and TERT promoter mutations in AYA with PTC were less frequently observed than in older adults.