AIM: To explore the effect of dihydroquercetin on visual function in mice with form deprivation myopia based on the NOD-like receptor thermoprotein domain-related protein 3(NLRP3)inflammasome pathway.METHODS: The C57BL/6 mice were randomly divided into control group and form deprivation myopia model group, and the form deprivation myopia model group was constructed by covering the right eye with a translucent eye patch. After successful modeling, the mice in the model group of form deprivation myopia were randomly divided into model group, low-, medium- and high-dose dihydroquercetin groups, and high-dose dihydroquercetin + NLRP3 agonist group. The diopter and axial length of mice in each group were detected. The kit was used to detect the levels of superoxide dismutase(SOD)and malondialdehyde(MDA)in retinal tissue. RT-qPCR was used to detect the mRNA expressions of NLRP3, apoptosis-associated spot-like protein(ASC), Caspase-1, IL-1β and IL-18 in retinal tissues. Western blot was used to detect the expression of NLRP3, ASC, cleaved Caspase-1, IL-1β and IL-18 proteins in retinal tissues. TUNEL staining was used to detect apoptosis in retinal tissue.RESULTS: Compared with the control group, the diopter of the mice in the model group decreased, and axial length increased, and the SOD decreased whereas MDA, NLRP3, ASC, Caspase-1, IL-1β, IL-18 increased, and the rate of apoptosis in retinal tissue increased(all P<0.05). Compared with the model group, the diopter of mice in the low-, medium- and high-dose dihydroquercetin groups increased, axial length shortened, the SOD increased, whereas MDA, NLRP3, ASC, Caspase-1, IL-1β, IL-18 decreased, and the rate of apoptosis in retinal tissue decreased(all P<0.05). Compared with the high-dose dihydroquercetin group, the high-dose dihydroquercetin+NLRP3 agonist group had reduced diopter, increased axial length, decreased SOD levels, elevated MDA, NLRP3, ASC, Caspase-1, IL-1β, and IL-18 levels, as well as increased apoptosis rate in retinal tissue(all P<0.05).CONCLUSION: Dihydroquercetin can improve visual function in mice with form deprivation myopia by inhibiting pyroptosis and oxidative stress responses, which may be related to the suppression of NLRP3 inflammasome. NLRP3 agonists can partially mitigate the effects of high-dose dihydroquercetin on form deprivation myopia in mice.

ObjectiveTo delineate imaging findings using an imaging platform and investigate the correlation between MRI characteristics of spinal cord atrophy and clinical diagnosis in children with spinal cord injury (SCI). MethodsImaging data of 150 children with SCI admitted to Beijing Bo'ai Hospital, China Rehabilitation Research Center, from January, 2002 to March, 2024 were collected and imported into the imaging platform. The anteroposterior and transverse diameters of the middle part of the spinal cord at the cross-section with the most severe atrophy were measured, and the relevant indicators of the previous normal spinal cord segment were measured as controls; the radiomic features were extracted. Clinical data of the children including gender, age, cause of injury, sensory level, motor level, spinal cord injury level, injury severity and disease course were collected. ResultsSpinal cord atrophy was identified in 81 cases (54%), among which 78 cases (96%) were American Spinal Injury Association Impairment Scale (AIS) grade A and 3 cases (4%) were AIS grade C. The upper boundary of the spinal cord atrophy site strongly correlated with the injury level, motor level and sensory level (r > 0.8, P < 0.001). ConclusionMore than half of children with SCI may develop secondary spinal cord atrophy, the vast majority of whom suffer from complete spinal cord injury; the upper boundary of spinal cord atrophy is correlated with the injury level.

[This corrects the article DOI: 10.1016/j.apsb.2024.09.010.].

Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe-S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.

Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To investigate the local hemodynamic spatial distribution of internal carotid artery stenosis and its correlation with plaque characteristics using high-resolution vessel wall imaging (HR-VWI) combined with computational fluid dynamics.Methods:This was a cross-sectional study. A retrospective analysis was conducted on the clinical and imaging data of 70 patients with moderate to severe stenosis at the initiation of the internal carotid artery in First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and Tianjin First Central Hospital from March 2018 to June 2020. All patients underwent HR-VWI and CT angiography examinations. The parameters related to plaque characteristics, such as plaque length, maximum wall thickness, plaque volume, wall volume percentage and intraplaque hemorrhage (IPH) were measured and evaluated on HR-VWI images. CT angiography images were used to construct a local hemodynamic vascular model to measure various wall shear stress (WSS) derived parameters, such as time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and transverse wall shear stress (transWSS), at the narrowest, proximal, and distal parts of the lesion. The Friedman test was used to analyze the difference of hemodynamic parameters in different parts of the lesion. Spearman correlation analysis was performed to assess the correlation between plaque burden and local hemodynamic parameters. Univariate and multivariate logistic regression analyses were used to explore the independent risk factors for predicting IPH.Results:Among the 70 patients, 25 patients with IPH and 45 patients without IPH. The overall differences in TAWSS, OSI, RRT and transWSS at the narrowest, proximal, and distal parts of the lesion in 70 patients were statistically significant ( P<0.05). The TAWSS and transWSS at the narrowest parts were significantly higher than those at the proximal and distal parts ( P<0.05). The OSI at the distal part was significantly higher than that at the narrowest and the proximal parts ( P<0.05). The RRT at the proximal part was significantly lower than that at the narrowest and the distal parts ( P<0.05). Spearman correlation analysis showed RRT at the distal part was correlated with plaque volume ( r s=0.249, P=0.044) and wall volume percentage ( r s=0.286, P=0.016), respectively. In a multivariate logistic regression showed plaque length ( OR=1.315, 95% CI 1.073-1.612, P=0.008) and TAWSS at the narrowest part ( OR=1.631, 95% CI 1.308-1.854, P=0.008) were independent risk factors for predicting IPH. Conclusions:The spatial distribution of local hemodynamics of moderate to severe stenosis at the initiation of the internal carotid artery is different, and the WSS parameters in different parts of the lesion have different effects on plaque volume, wall volume percentage and IPH.

Prostate cancer(PCa)is one of the common malignant tumors of the genitourinary system in men.It is generally believed that the serum prostate-specific antigen(PSA)level exceeding 4.0 ng/mL has potential diagnostic value for PCa.However,there are many cases of PCa with low PSA levels in clinical practice,specifically between 0-4.0 ng/mL.These cases may be missed or even misdiagnosed due to low PSA levels,leading to delays in treatment and missing the optimal clinical window for diagnosis and treatment.This review provides a com-prehensive summary of the clinicopathological characteristics of PCa patients with PSA levels below 4.0 ng/mL,including their baseline and clinical features,histological characteristics,imaging features,neuroendocrine prostate cancer(NEPC)and prognostic factors,aiming to en-hance the understanding of this type of PCa.

Objective To explore the prognostic value of plasma sST2 in the population of coronary heart disease(CHD)complicated with chronic kidney disease(CKD).Methods A total of 326 elderly patients with CHD or CKD undergoing physical examination in the Second Medical Center of Chinese PLA General Hospital from April 2021 to July 2022 were continuously enrolled,and according to whether having CHD or CKD,they were divided into a CHD-CKD comorbidity group(n=117),a CHD group(n=124),and a CKD group(n=85).Their baseline data were compared,and the plasma concentration of sST2 was detected using chemiluminescence assay.Multiple linear regression analysis was used to identify the relevant factors of sST2.Kaplan-Meier survival curve and Cox proportional hazards regression analyses were applied to determine the impact of plasma sST2 on all-cause mortality and major adverse cardiovascular events(MACE).Results There were significant differences among the three groups in terms of age,sST2 and NT-proBNP levels,Log(NT-proBNP),eGFR,ratios of hyperuricemia,cerebral infarction,tumors,and using anti-platelet drugs and statins,PR interval,LVEF,and TC,TG,HDL-C and Hb levels(P＜0.05,P＜0.01).Multiple linear regression analysis showed that the sST2 level was positively correlated with logNT-proBNP and negatively with Hb level in the comorbidity group(t=2.266,P=0.025;t=-2.235,P=0.021).Kaplan-Meier survival curve analysis indicated that during a median fol-low-up of 31.5(22.0,32.2)months,the comorbidity group had a lower survival rate than the two single-disease groups(P＜0.05,P＜0.01),and higher incidence of MACEs than the CKD group(P＜0.01).ROC curve analysis suggests that the AUC value of sST2 in predicting all-cause mor-tality in the comorbid group was 0.692.Cox proportional hazards regression model revealed that after adjustment for cofounders,sST2 was still an independent risk factor for all-cause mortality in the comorbid patients(HR=4.461,95％CI:1.640-8.399,P=0.024),although this prognos-tic value may be influenced by NT-proBNP.Conclusion sST2 can independently predict the risk of mortality in elderly patients with CHD-CKD comorbidity.