Journal of Endocrinology最新文献

Prostate cancer is a leading cause of death. As a hormone-driven cancer, prostate cancer is often treated with drugs (luteinizing hormone receptor agonists; LHRHa) or surgical approaches (orchidectomy; ORX) with the goal of reducing androgens. These approaches cause side effects such as bone loss. It is unclear if the side effects of these approaches are due to loss of androgens or loss of estrogens, as these approaches reduce both. We seek to evaluate if LHRHa and ORX have equivalent effects on bone, if the bone loss can be ameliorated by estrogen supplementation, and if estrogen supplementation alone is sufficient to improve bone mass while reducing androgen production. Herein, we evaluated bone microarchitecture, mechanical properties, and the cellular mechanism of LHRHa with subsequent hormone add-back on bone. We find that LHRHa negatively affects bone microarchitecture but has more mild effects on bone than ORX. Estrogen supplementation - but not androgen supplementation - improves bone mass and strength in mice treated with LHRHa. Estrogen supplementation alone is also sufficient to improve bone mass and strength while also reducing androgen production. However, estrogen supplementation also increases osteoblast and osteoclast activity, which may promote prostate cancer metastasis in bone. Future studies should evaluate estrogen as a modulator of the metastatic niche.

Triptolide (TP), a bioactive compound, demonstrates efficacy in ameliorating diabetic nephropathy (DN). This study aimed to investigate the role of TP in renal tubular injury during DN and elucidate the underlying mechanism involving acyl-CoA synthetase long-chain family member 1 (ACSL1) and parkin (PRKN). DN model was induced in HK2 cells by high glucose (HG, 30 mmol/L). Cell counting kit-8, EdU assay, flow cytometry were used to assess cell viability, proliferation, and apoptosis. Inflammatory cytokines were measured via enzyme-linked immunosorbent assay. Ferroptosis was assessed by detecting reactive oxygen species (ROS), lipid peroxidation (MDA), Fe2+, and glutathione (GSH) using kits. The mRNA and protein examination was performed by real-time quantitative PCR and western blotting. Co-immunoprecipitation assay was conducted for protein interaction and ubiquitination detection. DN in mice was established by high-fat diet and streptozocin injection. The effects of TP on mice were analyzed by histopathology analysis, biochemical analysis, and protein detection. TP mitigated HG-induced apoptosis, inflammation, and ferroptosis in HK2 cells. The protective effects of TP against HG-induced injury in HK2 cells were mediated by the inhibition of ACSL1. PRKN promoted ubiquitination of ACSL1 to reduce the protein level of ACSL1. PRKN/ACSL1 inhibited HG-induced HK2 cell dysfunction. The protective effect of TP in HG-stimulated HK2 cells was mediated by the upregulation of PRKN. TP activated anti-ferroptosis NRF2/SLC7A11/GPX4 pathway by targeting ACSL1. TP could ameliorate kidney injury in DN mice through modulating PRKN, ACSL1, and NRF2/SLC7A11/GPX4 pathway. All these discoveries suggested that TP protected HK2 cells from HG-triggered kidney injury through upregulating PRKN that further promoted ubiquitination of ACSL1.

Type 2 diabetes (T2DM) significantly increases the risk of dementia due to overlapping metabolic, molecular, and genetic factors. This review comprehensively analyzes the pathophysiological links between diabetes and cognitive decline, focusing on chronic hyperglycemia, insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, and cerebrovascular complications. Key genetic and epigenetic contributors to diabetes-associated dementia (DAD), including variations in APOE, PICALM, SORL1, and GSK3B, are discussed. The roles of pathological proteins such as amyloid-beta (Aβ) and hyperphosphorylated tau in neurodegeneration are also highlighted. Preclinical and clinical evidence supports targeting insulin signaling pathways, oxidative damage, and inflammatory responses as potential therapeutic strategies. Promising therapies, including GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and anti-inflammatory drugs, are reviewed alongside emerging approaches such as gene therapy, stem cell therapy, and immunomodulation. Despite encouraging advances, the clinical translation of these therapies remains challenging due to the complexity of DAD pathogenesis. This review aims to advance understanding of diabetes-induced cognitive impairment and guide the development of personalized dementia therapies by integrating molecular, genetic, and clinical insights. Future research should focus on elucidating the precise molecular mechanisms of DAD progression and on developing targeted, patient-specific therapeutic interventions to overcome translational barriers.

Abstract: The neuropeptide Y1 receptor (Y1R) plays a key role in metabolic regulation, and its peripheral antagonism has shown promise in promoting weight loss and improving glucose metabolism. However, most studies are conducted at room temperature (RT, 21-22°C), where mild cold stress stimulates sympathetic nervous system (SNS) activation. The impact of Y1R blockade under thermoneutral (TN, 30°C) conditions, which eliminate cold stress, remains unclear. In this study, we investigated the effects of BIBO3304 on body weight, energy expenditure (EE), and glucose metabolism in chow- and high-fat diet (HFD)-fed mice housed at TN and compared the results with RT. We found that at RT, BIBO3304 significantly reduced body weight gain and fat mass while increasing EE and fat oxidation. These effects were abolished under TN, where SNS activation is minimized, leading to no changes in body composition or EE. Despite this, BIBO3304 improved glucose tolerance at TN, particularly in the early phase (week 2), independent of insulin sensitivity. However, these glucose-lowering effects diminished by week 6, suggesting a potential SNS-dependent mechanism for long-term benefits. TN-housed mice exhibited greater glucose excursions and reduced insulin sensitivity compared to RT-housed mice, highlighting the impact of ambient temperature on metabolic regulation. In summary, these findings suggest that BIBO3304's effects on energy balance are SNS-dependent, whereas its glucose-lowering benefits persist transiently at TN. This highlights the need to consider environmental temperature in the evaluation of pharmacological interventions for obesity and diabetes, with potential implications for climate-adjusted dosing strategies.

Plain language summary: Peripheral Y1R blockade-induced reductions in body weight and enhancements in energy expenditure at room temperature are abolished under thermoneutrality, irrespective of dietary fat content.Glucose-lowering effects of peripheral Y1R antagonism persist under thermoneutrality, independent of changes in body weight and insulin sensitivity.Chronic thermoneutrality blunts the ability of peripheral Y1R blockade to ameliorate fat-induced glucose intoleranceThese findings emphasize the temperature-dependent efficacy of metabolic drugs and the need for climate-adjusted therapeutic strategies.

This research intended to identify the genes related to PCOS (polycystic ovary syndrome) and verify the regulatory function of miR-486-5p as well as its target PTEN in granulosa cells (GCs). RT-qPCR was used to detect the expression of miR-486-5p in the serum, follicular fluid (FF), and GCs of PCOS patients and normal subjects. ROC curve analysis indicated strong diagnostic performance. Bioinformatic analysis via miRDB and ENCORI databases predicted PTEN as a potential target of miR-486-5p; this prediction was validated through dual-luciferase reporter gene assays. Meanwhile, a series of functional assays were performed. Cellular proliferation capacity was quantitatively assessed using the CCK8 assay, while flow cytometry was used to determine cell apoptosis ratio. The secretion of pro-inflammatory mediators was quantitatively measured employing an ELISA kit. miR-486-5p was found to be reduced in serum from patients, as well as in patient FF and GCs. The enhanced expression of miR-486-5p strengthened the proliferation of GCs and suppressed apoptotic activity, while concurrently attenuating pro-inflammatory cytokine secretion. Conversely, miR-486-5p inhibitor yielded opposing effects. Further investigation revealed that PTEN functioned as a negative regulatory factor of miR-486-5p. The increase of miR-486-5p caused a significant down-regulation of PTEN mRNA expression. Forced expression of PTEN reversed the cellular effects induced by miR-486-5p, including the enhanced proliferation rate, suppressed apoptosis, and attenuated inflammatory response. miR-486-5p can inhibit cell apoptosis and secretion of inflammatory factors by negatively regulating the expression of target gene PTEN, suggesting that miR-486-5p may be a potential target for PCOS.

Mitochondrial dysfunction is a key feature of type 2 diabetes and is closely linked to ageing, a major risk factor for the disease. This study investigated islet cell composition and mitochondrial oxidative phosphorylation protein expression in pancreatic tissue from older donors (≥62 years) with and without type 2 diabetes, matched for age, sex, and BMI. Fixed human pancreatic tissue sections were immunolabelled for insulin, glucagon, NDUFB8 (complex I), MTCO1 (complex IV), and VDAC1 (a mitochondrial mass marker) to quantify islet composition and mitochondrial protein levels. A machine learning-based single-cell segmentation pipeline enabled high-resolution profiling of individual cell populations within islets. In type 2 diabetes, islets exhibited an increased alpha:beta cell ratio, altered spatial organisation with fewer beta-beta and more alpha-alpha interactions, and a significantly higher proportion of bi-hormonal cells co-expressing insulin and glucagon. Within beta cells, we observed significant changes in mitochondrial protein expression, including reduced complex I and elevated complex IV levels. Unsupervised clustering of mitochondrial expression patterns identified three distinct beta cell expression clusters. Donors with type 2 diabetes showed a marked shift in the distribution of beta cells across clusters, with increased proportions of beta cells exhibiting low complex I and high complex IV expression. These results highlight significant alterations in islet architecture and mitochondrial protein expression associated with type 2 diabetes, providing new insights into the mechanisms underlying type 2 diabetes.

Abstract: The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.

Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia and the associated comorbidities. Type 2 diabetes is also associated with the dysfunction of liver, kidney and nervous system. In addition, an altered microbiota is frequently observed in subjects with type 2 diabetes. In this study, a db/db (diabetic) mouse model of type 2 diabetes was used to elucidate the beneficial effects of the probiotic Lactobacillus johnsonii N6.2. To evaluate metabolic effects, we performed metabolomics on liver samples, and RNA-seq from the liver and visceral adipose tissue, followed by qRT-PCR validation. Using L. johnsonii N6.2 extracellular vesicles, we evaluated lipid accumulation in hepatocytes. Finally, the gut microbiome of db/db mice was profiled using 16S rRNA sequencing. We observed that administration of the probiotic improved glycemic levels and decreased diabetes scores and type 2 diabetes-associated injury to the pancreas, liver and kidneys. Liver metabolomic and transcriptome analyses identified biomarkers of L. johnsonii N6.2 activity, including modulation of the vitamin K pathway, upregulation of FGF21, a key regulator of glucose and lipid metabolism, and alternations in selected circadian genes. This study elucidates the beneficial effects of L. johnsonii N6.2, against the common symptoms of type 2 diabetes, highlighting its potential as an adjuvant therapeutic agent.

TIMELESS is considered a molecular hinge linking circadian rhythms and the cell cycle. We recently identified TIMELESS as one of the upregulated core circadian clock genes during thyroid cancer dedifferentiation, but its expression and significance in thyroid cancer remain unclear. To address this, we assessed TIMELESS expression in thyroid neoplasms using bioinformatics analysis, immunoblotting, and immunohistochemistry. TIMELESS expression progressively increased from normal thyroid tissue to differentiated thyroid cancer and then to anaplastic thyroid cancer. Silencing TIMELESS expression in thyroid cancer cells reduced clonogenicity and spheroid formation, induced G2/M cell cycle arrest, and impeded xenograft growth in NOD SCID mice. In The Cancer Genome Atlas, TIMELESS expression was negatively correlated with recombination proficiency scores. Knocking down TIMELESS increased sensitivity to doxorubicin in thyroid cancer cells and upregulated the mRNA expression of NKX2-1 and SLC5A5. In conclusion, the overexpression of TIMELESS is associated with thyroid cancer dedifferentiation and may serve as a potential target for combination therapies.