Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system. METHODS: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB-/- mice were generated, and relevant in vivo experiments were performed. RESULTS: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage. CONCLUSION: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.

Clinical factors influencing the success rate of radioiodine treatment for Graves' disease.

AIMS: To investigate the impact of various clinical factors associated with Graves' disease on the success rate of radioiodine (RAI) therapy for Graves' disease within 3 years, and to determine the optimal range of iodine dosage per unit volume that yields the highest cure rate for Graves' disease within 1 year. MATERIALS AND METHODS: This retrospective study included patients diagnosed with Graves' disease who underwent RAI therapy at the Second Affiliated Hospital of Anhui Medical University between October 2012 and October 2022. The cumulative success rate was analysed using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were employed to evaluate factors associated with successful treatment of Graves' disease. Outcomes were categorized as either success or failure for all patients. RESULTS: Overall, 1994 patients were enrolled in this study, including 594 (29.8%) male and 1399 (70.2%) female patients. The success and failure groups comprised 1645 (82.4%) and 349 patients (17.6%), respectively, after a 3-year follow-up period. Multivariate regression analysis demonstrated that sex, antithyroid drug (ATD) use before RAI therapy, age, thyroid receptor antibody (TRAb) levels, iodine dose, thyroid mass, and early ATD use before RAI therapy were independent influencing factors for Graves' disease cure. CONCLUSIONS: We found that female patients and those with TRAbs ≥31.83 IU/L and thyroid mass ≥ 73.42 g had a lower cure rate. Therefore, thyroid size, disease severity, and duration of disease should be comprehensively considered when making treatment decisions and iodine dose selection in clinical practice.

All-optical deaggregation from 8PSK to 3×BPSK based on FWM in HNLF.

A scheme is proposed for all-optical deaggregation from one 30 G-bit/s eight-phase-shift-keying (8PSK) signal to three 10 G-bit/s binary-phase-shift-keying (BPSK) signals based on four-wave mixing (FWM) in high nonlinear fiber (HNLF) without information loss or redundancy. The coded information of three BPSK signals after the deaggregation represents every bit of the coded information of the input 8PSK signal. We conducted theoretical analyses and simulations of the proposal. The error-vector-magnitude (EVM), bit-error rate (BER), and constellations were analyzed for system performance evaluation. The results show that when the optical signal-to-noise ratio (OSNR) of the input 8PSK signal is 18 and 30 dB, the phase standard deviations of output BPSK signals decrease about 6.5° and 1.5°, respectively, after the deaggregation. The OSNR-BER performance of the extracted BPSK signals almost coincides with the ideal BPSK signal, with 21 and 12 dB receiver OSNR difference, respectively, at the BER of 10-3, indicating a larger noise tolerance compared to the input 8PSK signal. The scheme provides an effective method of all-optical deaggregation from 8PSK to BPSK, suitable for future dynamically reconfigurable optical networks, and makes it easier and more effectual for the receiving terminal which doesn't have the matching 8PSK receiver.

A small-molecule Fenton reagent for self-augmented chemodynamic therapy by intelligently regulating intracellular acidosis.

A small-molecule Fenton reagent, integrating ferrocene with a carbonic anhydrase inhibitor, was designed to intelligently regulate intracellular acidosis for self-augmented chemodynamic therapy. Acidosis coupled with up-regulated ROS levels demonstrated potent cytotoxicity and effective tumor suppression.

Recent progress of oxidative stress associated biomarker detection.

Oxidative stress denotes the imbalance between the generation of reactive oxygen species (ROS) and antioxidant defenses in living organisms, participating in various pathophysiological processes and mediating the occurrence of diseases. Typically, the excessive production of ROS under oxidative stress elicits oxidative modification of biomacromolecules, including lipids, proteins and nucleic acids, leading to cell dysfunction and damage. Therefore, the analysis and detection of oxidative stress-associated biomarkers are of considerable importance to accurately reflect and evaluate the oxidative stress status. This review comprehensively elucidates the recent advances and applications of imaging probes for tracking and detecting oxidative stress-related biomarkers such as lipid peroxidation, and protein and DNA oxidation. The existing challenges and future development directions in this field are also discussed.

Predictive values of metabolic score for insulin resistance on risk of major adverse cardiovascular events and comparison with other insulin resistance indices among Chinese with and without diabetes mellitus: Results from the 4C cohort study.

AIMS/INTRODUCTION: To investigate the relationship between the metabolic score for insulin resistance (METS-IR) index and major adverse cardiac events (MACEs) and to compare its ability to predict MACEs with other IR indices including homeostatic model assessment for IR (HOMA-IR) and triglyceride glucose (TyG) index-related parameters. MATERIALS AND METHODS: We conducted a cohort study enrolling 7,291 participants aged ≥40 years. Binary logistic regression and restricted cubic splines were performed to determine the association between METS-IR and MACEs, and the receiver operating curve (ROC) was utilized to compare the predictive abilities of IR indices and to determine the optimal cut-off points. RESULTS: There were 348 (4.8%) cases of MACEs during a median follow-up of 3.8 years. Compared with participants with a METS-IR in the lowest quartile, the multivariate-adjusted RRs and 95% CIs for participants with a METS-IR in the highest quartile were 1.47 (1.05-2.77) in all participants, 1.42 (1.18-2.54) for individuals without diabetes, and 1.75 (1.11-6.46) for individuals with diabetes. Significant interactions were found between the METS-IR and the risk of MACEs by sex in all participants and by age and sex in individuals without diabetes (all P values for interaction < 0.05). In the ROC analysis, the METS-IR had a higher AUC value than other indices for predicting MACEs in individuals with diabetes and had a comparable or higher AUC than other indices for individuals without diabetes. CONCLUSIONS: The METS-IR can be an effective clinical indicator for identifying MACEs, as it had superior predictive power when compared with other IR indices in individuals with diabetes.

Associations between metabolic score for visceral fat and the risk of cardiovascular disease and all-cause mortality among populations with different glucose tolerance statuses.

AIMS: To investigate the associations between metabolic score for visceral fat (METS-VF) and clinical outcomes among populations with different glucose tolerance statuses. METHODS: We analysed 6827 participants aged ≥ 40 years with different glucose tolerance statuses from a cohort study. The associations between METS-VF and cardiovascular disease (CVD) events and all-cause mortality were assessed using Cox regression, restricted cubic spline and receiver operating characteristic curves. RESULTS: During a follow-up of 5.00 years, there were 338 CVD events and 307 subjects experienced all-cause death. The METS-VF quartile (Quartile 4 versus 1) was significantly related to CVD events [adjusted HRs and 95% CIs: 5.75 (2.67-12.42), 2.80 (1.76-4.48), and 3.31 (1.28-8.54) for subjects with normal glucose tolerance, prediabetes and diabetes, respectively] and all-cause mortality [adjusted HRs and 95% CIs: 2.80 (1.43-5.49), 4.15 (2.45-7.01), and 4.03 (1.72-9.42), respectively]. Restricted cubic spline suggested a dose-response association of METS-VF with the risk of CVD events and all-cause mortality. The area under curve for CVD events and all-cause mortality was higher for METS-VF than for the other obesity and IR indexes in subjects with different glucose tolerance statuses. CONCLUSIONS: The METS-VF was associated with an increased risk of CVD events and all-cause mortality and could be used as a predictive index of the risk of CVD events and all-cause mortality among populations with different glucose tolerance statuses.

LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis.

Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

An endoperoxide-containing covalent organic framework as a singlet oxygen reservoir for cancer therapy.

A porphyrin-based COF containing a dialkylnaphthalene derivative was constructed to deliver extracellular singlet oxygen (1O2) into cancer cells through the Diels-Alder/retro-Diels-Alder reaction between dialkylnaphthalene and 1O2 to realize light- and oxygen-independent oxidative damage for cancer therapy.

Imaging strategies for monitoring the immune response.

Real-time monitoring of the immune response can be used to evaluate the immune status of the body and to distinguish immune responders and non-responders, so as to better guide immunotherapy. Through direct labelling of immune cells and imaging specific biomarkers of different cells, the activation status of immune cells and immunosuppressive status of tumor cells can be visualized. The immunotherapeutic regimen can then be adjusted accordingly in a timely manner to improve the efficacy of immunotherapy. In this review, various imaging methods, immune-related imaging probes, current challenges and opportunities are summarized and discussed.