Background Type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor agonist drug in the treatment of T2D, has been demonstrated the therapeutic effects on diabetic encephalopathy (DE). Especially, the Ex-4 ameliorates the tau hyperphosphorylation and cognitive impairment in DE. And these crucial alterations are also important bridge between T2D and AD. However, its unique mechanism is unclear. Methods The db/db mice, high-fat-diet (HFD) / streptozotocin (STZ)—induced diabetic (HF-diabetic) mice, and high-glucose-damaged (HGD) HT-22 hippocampal cells were enrolled to examine the effects of Ex-4 on AD-like changes in T2D. The Novel object recognition test (NORT) and Morris water maze test (MWMT) were conducted to evaluate the cognitive impairment. The Dickkopf-1 (DKK1) was employed to weaken the activation of the Wnt/β-catenin pathway to explore the mechanism of Ex-4 in protecting the brain functions. The JASPAR was based to predict the interaction between NeuroD1 and the promoter region of Ins2 . Moreover, the chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter assays were performed. Results Ex-4 alleviated the tau hyperphosphorylation, increased the brain-derived insulin, and improved the PI3K/AKT/GSK3-β signalling in db/db mice, HF-diabetic mice, and HGD HT-22 hippocampal neuronal cells. The NORT and MWMT indicated that Ex-4 alleviated the learning and memory deficits in HF-diabetic mice. The inhibitor Dickkopf-1 (DKK1) of the Wnt/β-catenin pathway significantly blocked the protective effects of Ex-4. Regarding further molecular mechanisms, NeuroD1 was affected by Ex-4 in vivo and in vitro, and the knockdown or overexpression of NeuroD1 suggested its crucial role in promoting the brain insulin by Ex-4. Meanwhile, the ChIP‒qPCR and luciferase reporter assays confirmed the combination between NeuroD1 and the promoter region of the insulin-encoding gene Ins2 . And this interaction could be promoted by Ex-4. Conclusions Our study proposes that Ex-4 alleviates tau hyperphosphorylation and cognitive dysfunction by increasing Ins2 -derived brain insulin through the Wnt/β-catenin/NeuroD1 signaling in T2D. And its also show new lights on part of the progress and mechanism on treatment targets for the DE in T2D.

Painful diabetic neuropathy (PDN) is a prevalent and debilitating complication of diabetes, characterized by persistent neuropathic pain that severely impairs quality of life. Current management strategies predominantly target peripheral nerve dysfunction and offer only symptomatic relief, with no disease-modifying therapies available. Emerging evidence now underscores the critical role of central nervous system (CNS) glial cells—microglia, astrocytes, and oligodendrocytes, collectively termed the “glial triad”—in driving PDN pathogenesis. This review synthesizes recent advances elucidating how these glial cells contribute to neuroinflammation, metabolic dysregulation, and central sensitization. We detail specific mechanisms including microglial NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation and metabolic reprogramming, astrocytic aquaporin-4 (AQP4) polarity disruption impairing glymphatic function, and oligodendrocyte myelination deficits via Mammalian Target of Rapamycin (mTOR) signaling. Furthermore, we discuss the translational potential of glia-derived biomarkers (e.g., Translocator Protein (TSPO), Glial Fibrillary Acidic Protein (GFAP), myelin basic protein (MBP)) for early diagnosis and patient stratification. Finally, we highlight promising therapeutic avenues that target glial pathways, such as interleukin-35 (IL-35), β-hydroxybutyrate, and metformin, which aim to shift the treatment paradigm from symptomatic control to disease modification. By integrating preclinical and clinical insights, this review proposes the glial triad as a central player in PDN and suggests that targeted glial interventions may represent a promising frontier for future disease-modifying strategies.

Introduction and Objective: Protein lactylation is implicated in MASLD, yet its functional role remains poorly defined. This study investigated the mechanism through which AARS2 regulates SOD2 lactylation to drive MASLD progression. Methods: This study integrated multi-omics data from clinical and preclinical MASLD models to systematically assess AARS2 expression. Lactyl-proteomics identified SOD2 as a key target. Direct AARS2-SOD2 interaction were confirmed by Co-IP, IP-MS, and IF. Site-directed mutagenesis, lactylation-specific antibody and in vitro lactylation assays verified AARS2-specific catalysis of SOD2-K114 lactylation. AARS2-overexpressing/KO mice and SOD2-p.K114R knock-in mice were generated to elucidate the functional role of this modification. Functional consequences were assessed by measuring SOD2 activity, mitochondrial superoxide and respiration. Results: The results showed that AARS2 was upregulated in MASLD patient livers. In vivo, AARS2 overexpression worsened hepatic steatosis, while its knockout attenuated lipid accumulation. Mechanistically, AARS2 directly catalyzed SOD2-K114 lactylation, suppressing its antioxidant function and resulting in mitochondrial superoxide accumulation, metabolic impairment, and accelerated MASLD progression. Conclusion: Our findings unravel the mechanism by which AARS2 regulates SOD2 lactylation and indicate that targeting AARS2-SOD2 Kla may be a promising strategy for MASLD therapy. Disclosure Q. He: None. W. He: None. H. Ren: None. G. Yuan: None.

Introduction and Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health challenge with limited effective pharmacological therapies. Although lysine lactylation has emerged as an important regulator of metabolic homeostasis, whether lactylation of the key glycolytic enzyme phosphofructokinase liver type (PFKL) drives MASLD progression and the underlying mechanisms remain obscure. Methods: Quantitative lactylome and proteomic analyses were performed in HFD-fed mice. Hepatic lactate levels and global Kla were assessed in human and mouse MASLD samples. PFKL lactylation sites and enzymatic activity were analyzed in vitro assays. C57BL/6J mice were injected with AAV9-TBG-PFKL or AAV9-TBG-PFKL-K677R, followed by metabolic phenotyping. Mass spectrometry, co-IP, and ubiquitination assays were conducted to investigate the mechanisms of TRIM25-mediated PFKL degradation. Results: Hepatic lactate levels and global Kla were markedly elevated in patients with MASLD and in HFD- or MCD-fed mice, correlating with disease progression. Integrated lactylome and proteomic analyses identified PFKL as a key glycolytic regulator with increased expression and lactylation at lysine 677, dynamically regulated by PCAF. K677 lactylation enhanced PFKL enzymatic activity and protein stability by attenuating its interaction with the E3 ligase TRIM25, thereby preventing proteasomal degradation. Liver-specific expression of delactylation-mimic PFKL mutants conferred resistance to HFD-induced steatosis, insulin resistance, inflammation, and apoptosis. Elevated PFKL abundance promoted glycolytic flux and lactate accumulation, forming a positive feedback loop that sustained metabolic reprogramming and hepatic dysfunction. Disruption of this loop by LDHA knockdown or pharmacological inhibition effectively ameliorated MASLD progression. Conclusion: These findings reveal a lactylation-dependent mechanism driving MASLD progression and demonstrate that targeting PFKL lactylation may have therapeutic potential. Disclosure Y. Guo: None. H. Ren: None. G. Yuan: None. Funding National Natural Science Foundation of China (No. 82270855, No. 81974121, No. 82470867, No. 82470908 and No. 82100922)

To develop a deep learning-based multimodal framework for automated segmentation of orbital soft tissues and identify quantitative imaging biomarkers for precise grading of thyroid eye disease (TED). This retrospective multicenter study enrolled 330 TED patients from a primary center for model development and 113 patients from two external centers for validation. From the primary cohort, 182 mild and 138 moderate-to-severe TED were subsequently selected for further analysis. All subjects underwent 3 T MRI with water-fat separation and fat-suppressed (FS) T2 mapping sequences. TED-Net, a deep learning model integrating ConvNeXt and Transformer architectures, was developed to segment orbital structures including the extraocular muscles, lacrimal gland, orbital fat, and eyeball. The model automatically extracted both morphological parameters (volume and volume ratio) and functional parameters (water fraction, fat fraction, and FS T2 relaxation time), enabling quantitative comparison between mild and moderate-to-severe TED. Diagnostic performance for evaluating orbital involvement was assessed using receiver operating characteristic analysis and decision curve analysis. TED-Net achieved Dice similarity coefficients > 0.80 across all orbital structures. Volumetric measurements showed high consistency among different sequences (intraclass correlation coefficient = 0.843). Significant differences in morphological and functional parameters were observed between mild and moderate-to-severe TED (all p < 0.05). The combined volumetric-functional model demonstrated superior diagnostic accuracy (area under the curve [AUC] = 0.982) over the volumetric model (AUC = 0.908). TED-Net enables accurate automated segmentation and multiparametric quantification of orbital soft tissues, providing reliable imaging biomarkers for objective assessment of TED severity. Question MRI-based quantitative metrics are essential for assessing orbital involvement in TED, but effective tools for rapid and accurate parameter extraction are currently lacking. Findings TED-Net achieved precise orbital segmentation and multiparametric quantification; the integration of volumetric and functional parameters yielded an AUC of 0.982 for evaluating orbital involvement. Clinical relevance The proposed TED-Net provides a reliable approach for quantifying orbital soft tissue involvement, and its clinical implementation enables more accurate assessment of TED severity.

ObjectiveThe heterogeneity of extraocular muscles (EOMs) in thyroid eye disease (TED) correlates with response to intravenous glucocorticoid (IVGC) therapy but remains unquantified by current imaging. This study applied habitat imaging to characterize EOM heterogeneity and remodeling patterns. MethodsThis retrospective study included 138 patients with active moderate-to-severe TED (84 responsive; 54 unresponsive), all undergoing water–fat separation imaging before and after IVGC therapy. Four EOM habitat subregions were defined using the Otsu method based on water and fat signal intensity (SI). Volume and volume percentage (VP), including their absolute (Δ) and relative (Δ%) changes post-therapy, were compared between groups. Univariate analysis compared habitat features, while binary logistic regression and receiver operating characteristic (ROC) curve analysis identified valuable parameters for evaluating therapeutic effect. ResultsHabitat imaging identified edema (high SIwater and low SIfat) and myosteatosis (low SIwater and high SIfat) subregions. The responsive group exhibited a higher edema VP (32.64 vs 14.13%, P = 0.008) at baseline. After IVGC treatment, the responsive group had a significant decrease in edema VP (32.64 vs 9.85%, P < 0.001); both groups displayed increased myosteatosis, with more pronounced changes observed in the responders. The combination of Δ volume of myosteatosis region and Δ% volume of whole region demonstrated excellent discriminative ability (AUC = 0.86) with high sensitivity (93.75%) in treatment response assessment. ConclusionsHabitat imaging based on water–fat separation provides quantitative visualization of EOM pathological remodeling, establishing myosteatosis as an adjunctive biomarker for evaluating IVGC therapeutic response.

BACKGROUND:3D T1 may assess the superior ophthalmic vein (SOV) congestion, yet its role in the intravenous glucocorticoid (IVGC) therapy remains unclear. PURPOSE:To evaluate SOV congestion by 3D T1 in thyroid eye disease (TED) and explore its correlation with IVGC therapeutic response. STUDY TYPE:Retrospective. SUBJECTS:One hundred thirty-three TED patients, classified as 80 IVGC responders (45.7 ± 10.9 years, 32 males) and 53 non-responders (47.6 ± 9.7 years, 23 males); 290 healthy controls (HCs) (47.9 ± 16.4 years, 145 males). FIELD STRENGTH/SEQUENCE:3 T; 3D T1-weighted spoiled gradient-recalled echo, T2 iterative decomposition of water and fat with echo asymmetric and least-squares estimation, and fat-suppressed (FS) T2 mapping. ASSESSMENT:The SOV diameter (mm), along with the volume ratio, FS T2 relaxation time (T2RT [ms]), and water fraction (WF [%]) of the extraocular muscles (EOMs) and orbital fat (OF) were manually measured. STATISTICAL TESTS:Student's t-test, Mann-Whitney U test, one-way analysis of variance, interclass correlation coefficient, and correlation analysis. p < 0.05 defined statistical significance. RESULTS:TED patients presented significantly larger SOV diameters than HCs (2.21 ± 0.45 vs. 1.72 ± 0.26). Among them, the responsive group had significantly larger baseline SOV diameters (2.26 ± 0.49 vs. 2.15 ± 0.39), along with higher FS T2RT (71.30 ± 14.32 vs. 67.65 ± 13.33) and WF (79.31 ± 13.68 vs. 75.17 ± 14.47) in the EOMs compared to the nonresponsive group. The SOV diameter demonstrated moderate-to-good positive correlations with FS T2RT (r = 0.59) and WF (r = 0.67) in responders. Following IVGC therapy, a significant reduction in SOV diameter was observed exclusively in the responsive group (2.26 ± 0.49 vs. 1.98 ± 0.47). DATA CONCLUSION:Patients exhibiting more severe SOV congestion showed a better response to IVGC therapy, potentially due to an enhanced inflammatory state in the EOMs. EVIDENCE LEVEL:4. TECHNICAL EFFICACY:Stage 4.

Background:Dysthyroid optic neuropathy (DON) is a vision-threatening complication of thyroid-associated ophthalmopathy (TAO). The underlying pathophysiology is believed to involve compression of the optic nerve at the orbital apex, primarily due to edema and volumetric expansion of orbital soft tissues. Early detection of DON is crucial to prevent irreversible visual loss. However, reliable imaging biomarkers for early diagnosis remain limited. This study aimed to investigate whether orbital soft tissue volume and water fraction (WF), derived from three-dimensional cube fast spin-echo Flex (3D Cube FSE-Flex) magnetic resonance imaging (MRI), can serve as predictive markers for DON in TAO patients. Methods:In this retrospective study, 3D Cube FSE-Flex MRI images and clinical data were analyzed from 60 patients with TAO (27 with DON, 33 without). A total of 116 orbits (53 with DON, 63 without) were included. Quantitative measurements of extraocular muscle volume (EOMV), water fraction of extraocular muscles (EOM-WF), and orbital fat (OF-WF) were obtained using semi-automated segmentation. Group comparisons were performed using appropriate statistical tests. Logistic regression was used to identify risk factors for DON, and receiver operating characteristic (ROC) curve analysis was employed to evaluate diagnostic performance. Correlation analysis was conducted to assess relationships between imaging parameters and clinical activity scores (CAS). Results:DON orbits showed significantly higher EOMV, EOM-WF, and OF-WF compared to non-DON orbits (all P<0.001). Logistic regression revealed that increased EOMV [odds ratio (OR) =1.555; 95% confidence interval (CI): 1.250-1.934] and higher OF-WF (OR =1.190; 95% CI: 1.064-1.332) were independent risk factors for DON. A combined model incorporating EOMV and OF-WF demonstrated good diagnostic performance [area under the curve (AUC) =0.843]. Additionally, both EOMV (P=0.015, r=0.333) and OF-WF (P=0.025, r=0.308) were positively correlated with CAS. Conclusions:Quantitative MRI analysis using 3D Cube FSE-Flex reveals that enlargement and edema of orbital soft tissues-specifically EOMV and OF-WF-are significant risk factors for DON. The combination of these parameters provides a robust imaging biomarker for early identification of DON in TAO patients, with potential clinical utility in risk stratification and treatment planning.

Dysregulated energy metabolism, particularly lipid metabolism disorders, has been identified as a key factor in the development of diabetic cardiomyopathy (DCM). Sirtuin 2 (SIRT2) is a deacetylase involved in the regulation of metabolism and cellular energy homeostasis, yet its role in the progression of DCM remains unclear. We observed significantly reduced SIRT2 expression in DCM model mice. Cardiac-specific overexpression of SIRT2 protected mice from streptozotocin/high-fat diet (STZ/HFD)-induced insulin resistance (IR), cell apoptosis, and cardiac dysfunction, whereas its downregulation exacerbated these conditions. Moreover, we found that SIRT2 regulated cardiac lipid accumulation and fatty acid oxidation (FAO), and identified its localization in cardiac mitochondria. Mechanistically, we determined carnitine palmitoyltransferase 2 (CPT2) as a critical substrate of SIRT2, which is implicated in DCM. SIRT2-mediated deacetylation at K239 enhanced CPT2 ubiquitination, resulting in decreased protein stability and subsequent inhibition of FAO and reactive oxygen species (ROS) production. Taken together, these findings suggest that the SIRT2/CPT2 signaling pathway plays a crucial role in DCM progression.

BACKGROUND:Three-dimensional fast spin echo with 2-point Dixon-based fat suppression (3D-FSE-Dixon) sequence may assess volume and water fraction (WF) of orbit. PURPOSE:To explore the association between 3D-FSE-Dixon based parameters and methylprednisolone pulse therapy (MPPT) efficacy in active moderate-to-severe thyroid-associated ophthalmopathy (TAO). STUDY TYPE:Retrospective. POPULATION:Fifty-nine TAO patients (29 females, 30 males, 49.1 ± 10.9 years) were included: 26 (15 females, 11 males, 48.4 ± 11.1 years) showed improvement and 33 (14 females, 19 males, 49.6 ± 10.9 years) did not. FIELD STRENGTH/SEQUENCE:3D-FSE-Dixon sequence of orbits at 3 T. ASSESSMENT:Manual segmentation delineated bony orbit (BO), whole orbit (WO), globe (GO), lacrimal gland (LG), and optic nerve (ON). Multi-dimensional threshold (MDT) identified orbital fat (OF). Extraocular muscles (ETM) were obtained by subtracting other tissues from WO. WF was calculated from water and in-phase images. Treatment efficacy, the clinical outcome, was assessed within 2 weeks after MPPT. STATISTICAL TESTS:Unpaired t-test and Mann-Whitney U test compared normal and non-normal data, respectively. Paired t-test analyzed parameter changes pre- and post-MPPT. Multivariate logistic regression analysis identified factors independently associated with the efficacy of MPPT. Significance was set at P < 0.05. RESULTS:Responsive group showed significantly higher pre-treatment WF (ETM, 0.86 ± 0.06 vs. 0.82 ± 0.07; OF, 0.21 ± 0.04 vs. 0.19 ± 0.02), with no difference in volume (OF: 21.34 ± 3.33 vs. 21.36 ± 3.46, P = 1.00; ETM: 13.48 ± 2.82 vs. 13.72 ± 3.45, P = 1.00) or volume ratio (OF/GO: 3.23 ± 0.50 vs. 3.26 ± 0.56, P = 1.00; ETM/GO: 2.06 ± 0.58 vs. 2.12 ± 0.64, P = 1.00). WF significantly decreased in responsive group (ETM, 0.86 ± 0.06 vs. 0.79 ± 0.05; OF, 0.21 ± 0.04 vs. 0.17 ± 0.03) but not decreased in unresponsive group (ETM, 0.81 ± 0.07 vs. 0.81 ± 0.07, P = 1.00; OF, 0.19 ± 0.02 vs. 0.190 ± 0.02, P = 1.00). ETM WF and disease duration can assess MPPT efficacy. DATA CONCLUSION:Higher ETM WF demonstrates better MPPT efficacy for TAO. EVIDENCE LEVEL:4 TECHNICAL EFFICACY: Stage 4.

Ferroptosis, an iron-dependent form of programmed cell death, is closely associated with tubular damage in diabetic nephropathy (DN). Glutathione peroxidase 4 (GPX4) is an important anti-oxidant enzyme, and plays a crucial role in protecting against ferroptosis. However, the regulatory mechanism of GPX4 expression levels in renal tubular epithelial cells (RTECs) remains elusive. This study reveals that ferroptosis occurs in the late-stage of DN, and the GPX4 level is significantly downregulated in DN patients, animal models and cell models. By applying database predictions, luciferase reporter assays and chromatin immunoprecipitation, we find that vitamin D receptor (VDR) transcription factor promotes GPX4 expression and plays a key role in inhibiting ferroptosis of RTECs. VDR knockout exacerbates ferroptosis in RTECs and worsens renal function, while intraperitoneal injection of VDR agonist paricalcitol significantly improves renal injury. Proteomics analysis suggests that E3 ligase PRPF19 mediates ubiquitination degradation of VDR and is an important therapeutic target for DN. Therefore, through molecular docking, targeted fishing technology using high-performance affinity beads, and surface plasmon resonance (SPR), we screen and identify berberine (BBR) as a novel inhibitor of PRPF19, which offers renal protection by inhibiting VDR degradation and tubular ferroptosis. These findings elucidate the role of ferroptosis in DN renal tubular injury, and suggest that PRPF19 is a promising therapeutic target.

BACKGROUND:Obesity is a known risk factor for diabetic peripheral neuropathy (DPN), but the relationship between body mass index (BMI) and DPN remains controversial. AIMS:This study explores the relationship between weight-adjusted waist index (WWI) and DPN in Chinese patients with Type 2 Diabetes Mellitus (T2DM), with the goal of establishing WWI as an effective tool for the early detection and risk stratification of DPN. METHODS:A total of 1790 participants were included. The relationships between WWI, BMI, WC, and DPN were analyzed using logistic regression, restricted cubic spline, and subgroup analysis, with ROC-AUC used to assess the diagnostic performance of the obesity indices. RESULTS:During this cross-sectional study, a total of 895 cases of DPN were recorded. Each 1-SD increase in WWI was associated with an increased risk of DPN in Model 1 (OR: 1.72, 95% CI: 1.37-2.16), Model 2 (OR: 1.41, 95% CI: 1.10-1.80), and Model 3 (OR: 1.37, 95% CI: 1.06-1.77). A linear relationship was observed between WWI and DPN when WWI was greater than 10.757 cm/√kg (OR: 1.375, 95% CI: 1.115-1.7). BMI was nonlinearly associated with DPN (p-nonlinear < 0.05), and age significantly modified the relationship between BMI and DPN. ROC analysis indicated that WWI had superior diagnostic performance compared to BMI and WC. CONCLUSION:WWI is linearly and independently associated with DPN and demonstrates greater stability and predictive value than BMI and WC. Therefore, WWI may serve as a more reliable indicator for identifying individuals at risk for DPN.

The molecular mechanisms of early-onset multigenerational diabetes remain unknown. This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations. From 1296 inpatients with diabetes, we selected individuals who were ≤ 30 years of age and who were clinically suspected of having familial monogenic diabetes. Clinical data were collected from the probands and their family members. Whole-exome sequencing (WES) was used to identify possible causal variants for diabetes. Candidate pathogenic variants were verified by Sanger sequencing, assessed for cosegregation in family members, and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Moreover, missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2. RNAfold was used to predict RNA structural alterations for synonymous variants. Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled. Pathogenic/likely pathogenic variants (p.Gly292fs in HNF1A, p.Gly245Argfs*22 in PDX1, p.Asp329His in KCNJ11, p.Leu734Phe and p.Val606Gly in WFS1) were detected in four patients, who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results. The variants of uncertain significance (ABCC8 c.3039 G > A (p.Ser1013 = Ser), MAPK8IP1 p.Gln144_Gly145insSerGln, and TBC1D4 p.Arg1249Trp) were identified in three probands. Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants. Genetic testing in this population enables precision diagnosis, informs individualized treatment, and facilitates genetic counseling.

PURPOSE:This study explored the link between liver fibrosis and left ventricular hypertrophy (LVH), a good indicator of cardiovascular disease (CVD), and chronic kidney disease (CKD) risk in type 2 diabetes mellitus (T2DM) patients. METHODS:We analyzed data from 2,436 T2DM patients who visited our clinic between 2022 and 2024. Liver fibrosis was evaluated using NAFLD Fibrosis Score (NFS). We applied logistic regression to assess the relationship between liver fibrosis and LVH/CKD risk. RESULTS:Among the 2,436 participants (63.79 % male, mean [SD] age 53.08 [12.65] years), the prevalence of LVH, and CKD was 38.88 %, and 34.69 %. Individuals with NFS-defined advanced fibrosis had significantly higher risks of LVH (OR 1.45, 95 % CI [1.16-1.81]) and CKD (OR 1.94, 95 % CI [1.56-2.41]), after adjusting for established cardiovascular risk markers. Results remained consistent regardless of body mass index (BMI), or lipid profile status. We also observed that worsening liver fibrosis was associated with a higher stage of cardiovascular-kidney-metabolic (CKM) syndrome. CONCLUSIONS:Liver fibrosis is independently associated with increased LVH/CKD risk and CKM stage in T2DM patients. These findings indicate that metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive stage (liver fibrosis) should be introduced into the CKM staging structure to enhance risk stratification.

Insulin resistance and its linked health complications are increasing in prevalence. Recent work has caused the role of Tribbles2 (TRIB2) in metabolism and cellular signaling to be increasingly appreciated, but its role in the progression of insulin resistance has not been elucidated. Here, we explore the functions of TRIB2 in modulating insulin resistance and the mechanism involved in insulin resistance mice and palmitic acid (PA) treated HepG2 cells. We demonstrate that whole-body knockout and hepatic-specific TRIB2 deficiency protect against diet-induced insulin resistance, inflammation and ER stress. Accordingly, upregulation of TRIB2 in the liver aggravates these metabolic disturbances in HFD-induced mice and ob/ob mice. Mechanistically, TRIB2 directly binds to the αγ-SBS domain of PRKAB through its pseudokinase domain, subsequently inhibiting the formation and activity of the AMPK complex. Moreover, the results of intervention against AMPK suggest that the effects of TRIB2 depend on AMPK. Our findings reveal that TRIB2 is a novel target for the treatment of insulin resistance and its associated metabolic complications and clarify the function of TRIB2 as a regulatory component of AMPK activity.

BACKGROUND:Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS:A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS:A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION:CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.

Emerging evidence indicates that transfer RNA (tRNA)-derived small RNAs (tsRNAs), originated from tRNA with high abundance RNA modifications, play an important role in many complex physiological and pathological processes. However, the biological functions and regulatory mechanisms of modified tsRNAs in cancer remain poorly understood. Here, it is screened for and confirmed the presence of a novel m7G-modified tsRNA, m7G-3'-tiRNA LysTTT (mtiRL), in a variety of chemical carcinogenesis models by combining small RNA sequencing with an m7G small RNA-modified chip. Moreover, it is found that mtiRL, catalyzed by the tRNA m7G-modifying enzyme mettl1, promotes bladder cancer (BC) malignancy in vitro and in vivo. Mechanistically, mtiRL is found to specifically bind the oncoprotein Annexin A2 (ANXA2) to promote its Tyr24 phosphorylation by enhancing the interactions between ANXA2 and Yes proto-oncogene 1 (Yes1), leading to ANXA2 activation and increased p-ANXA2-Y24 nuclear localization in BC cells. Together, these findings define a critical role for mtiRL and suggest that targeting this novel m7G-modified tsRNA can be an efficient way for to treat BC.

Background and objectives: The efficacy of rituximab (RTX) in treating steroid-resistant Graves’ orbitopathy (GO) has been limitedly studied in Asians. Moreover, RTX has been considered even less for patients with steroid-resistant dysthyroid optic neuropathy (DON) who failed to undergo orbital decompression surgery for physical or financial reasons, or who responded poorly to the procedure. This study aimed to investigate the efficacy of RTX in treating steroid-resistant active moderate-to-severe and sight-threatening GO in a Chinese population. Methods: Data from 28 patients with steroid-resistant GO prescribed a single dose of 500 mg RTX were retrospectively retrieved. Treatment responses and contributing factors were analyzed. Results: The median follow-up time was 22 (8–34) weeks. 23 (82.1 %) patients had a positive objective outcome recommended by the European Group on Graves’ Orbitopathy (EUGOGO), while 25 (92.6 %) had a decrease in 7-item clinical activity score (CAS) by at least 2. Diplopia, visual dysfunction, and MRI-detected T2 relaxation time of the involved extraocular muscles improved significantly at the last follow-up compared to baseline (81.0 % vs. 47.6 %, 38.9 % vs. 16.7 %, and 87.8 (8.64) vs. 75.8 (10.9) ms, respectively; all p values < 0.05). No significant improvement was seen in terms of proptosis and eye muscle duction. Notably, a higher baseline IgG4 to IgG ratio was a predictor for RTX-induced positive EUGOGO outcomes. After RTX treatment, all 8 patients with DON demonstrated inactivation, and 4 improved in visual acuity by ≥ 1 line. No patient with DON experienced obvious deterioration. Conclusion: A single dose of 500 mg RTX seemed to be an effective and tolerable treatment for steroid-resistant GO. However, larger-scale studies with a control group are required for a more solid conclusion. The role of RTX in steroid-resistant DON management where surgery is unavailable or ineffective should be further explored.

To investigate the value of fat-suppression (FS) T2 relaxation time (T2RT) derived from FS T2 mapping and water fraction (WF) derived from T2 IDEAL to predict the treatment response to intravenous glucocorticoids (IVGC) in patients with thyroid-associated ophthalmopathy (TAO) based on texture analysis. In this study, 89 patients clinically diagnosed with active and moderate-to-severe TAO were enroled (responsive group, 48 patients; unresponsive group, 41 patients). The baseline clinical characteristics and texture features were compared between the two groups. Multivariate analysis was performed to identify the independent predictors of treatment response to IVGC. ROC analysis and the DeLong test were used to assess and compare the predictive performance of different models. The responsive group exhibited significantly shorter disease duration and higher 90th percentile of FS T2RT and kurtosis of WF in the extraocular muscle (EOM) and 95th percentile of WF in the orbital fat (OF) than the unresponsive group. Model 2 (disease duration + WF; AUC, 0.816) and model 3 (disease duration + FS T2RT + WF; AUC, 0.823) demonstrated superior predictive efficacy compared to model 1 (disease duration + FS T2RT; AUC, 0.756), while there was no significant difference between models 2 and 3. The orbital tissues of responders exhibited more oedema and heterogeneity. Furthermore, OF is as valuable as EOM for assessing the therapeutic efficacy of IVGC. Finally, WF derived from T2 IDEAL processed by texture analysis can provide valuable information for predicting the treatment response to IVGC in patients with active and moderate-to-severe TAO. The texture features of FS T2RT and WF are different between responders and non-responders, which can be the predictive tool for treatment response to IVGC.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.