Shanghai Eighth People Hospital

BackgroundOleanolic acid (OA), a pentacyclic triterpenoid abundantly present in various traditional Chinese herbs, exhibits promising anti-psoriatic potential owing to its broad pharmacological activities. Nevertheless, its clinical translation has been hindered by challenges including poor aqueous solubility, limited cutaneous permeation, and rapid systemic clearance, all of which compromise bioavailability when administered topically. To address these limitations, we designed and developed encapsulated and disulfide bonded OA-hyaluronic acid nanoprodrugs (OA-NPs@OA) for topical treatment of psoriasis in this study.ResultsOA-NPs@OA exhibited significantly enhanced cellular uptake via CD44 receptor-mediated endocytosis in keratinocytes, achieving a markedly lower IC50 value compared to free OA and considerably stronger apoptosis induction effects. In the IMQ-induced murine model, topically applied OA-NPs@OA demonstrated superior transdermal penetration with sustained lesional retention, effectively reversing psoriatic phenotypes with remarkably reduced PASI scores and splenomegaly, normalized epidermal thickness, and suppressed immune inflammation and cytokines. OA-NPs@OA exhibited superior effects to free OA and Calcipotriol Ointment. Mechanistically, OA-NPs@OA concurrently suppressed keratinocyte hyperproliferation via blocking the YAP-AREG pathway axis and reduced immune cell infiltration by downregulating chemokine networks, breaking the psoriatic inflammatory loop. Crucially, OA-NPs@OA showed excellent biosafety with no dermal or systemic toxicity following consecutively topical administration.ConclusionsOA-NPs@OA represents a novel targeted nanotherapy that overcomes the limitations of OA in anti-psoriasis by offering enhanced bioavailability, multimodal anti-psoriatic action, and optimized safety profiles.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12951-026-04264-x.

Osteoarthritis (OA) is a prevalent degenerative joint disease largely driven by chondrocyte dysfunction; however, effective disease-modifying therapies remain elusive. Although metabolic reprogramming toward glycolysis and epigenetic modifications are recognized hallmarks of osteoarthritis chondrocytes, the precise epigenetic pathways that immediately regulate these metabolic transitions remain incompletely understood. The role of ATP-structured chromatin remodelers like SWI/SNF-related Matrix-associated Actin-dependent Regulator of Chromatin Subfamily A Member 5 (SMARCA5) in regulating chondrocyte metabolism and function represents a vital knowledge gap. We explored SMARCA5's role in osteoarthritis pathogenesis through an integrated analysis of human osteoarthritis transcriptomic data, invitro experiments in primary chondrocytes exposed to inflammatory stress, mechanistic assays including chromatin immunoprecipitation-quantitative polymerase chain reaction and co-immunoprecipitation mass spectrometry, functional metabolic analysis, and invivo validation using destabilization of the medial meniscus-induced osteoarthritis in chondrocyte-specific Smarca5 conditional knockout mice. SMARCA5 was highly upregulated in osteoarthritis and increased progressively during experimental disease development. Functionally, SMARCA5 enhanced pathological glycolysis, proliferation, and apoptosis in chondrocytes. Mechanistically, Remodeling and Spacing Factor 1 (RSF1) served as an indispensable co-factor, with the SMARCA5-RSF1 complex directly binding to key glycolytic promoters, activating histone H3 lysine 27 acetylation and transcription through an ATPase-dependent process. Chondrocyte-specific Smarca5 ablation attenuated cartilage damage, subchondral bone changes, and joint inflammation. This study establishes SMARCA5 as an essential epigenetic driver connecting chromatin remodeling to pathological glycolysis in osteoarthritis, identifying a novel therapeutic target for treatment.

ObjectiveTo investigate the correlation between red blood cell distribution width to albumin ratio (RAR) and cardiovascular events (CVEs) in maintenance hemodialysis (MHD) patients.MethodsClinical data were retrospectively collected from MHD patients in Tongren Hospital, Shanghai Jiao Tong University School of Medicine from January 1, 2017 to May 31, 2024. The prognostic endpoints in this study were CVEs. Kaplan-Meier survival curve, Cox regression model, restricted cubic spline analyses and subgroup analysis were used to analyze the independent relationship between RAR and CVEs.ResultsA total of 237 MHD patients were included. The median follow-up was 22 (6, 45) months, and CVEs occurred in 100 patients (100/237, 42.2%). The population was divided into Tertile1, 2, and 3 according to the tertiles of baseline RAR levels. Kaplan-Meier survival curve showed a significant difference in the cumulative survival free of CVEs among the tertiles (p=0.0096). Multivariate Cox regression model showed that RAR was an independent risk factor for CVEs in MHD patients (HR=1.336, 95% CI 1.090, 1.638, p=0.005). Compared with Tertile 1 (RAR<3.75), Tertile 3 (RAR≥4.46) was associated with an increased risk of CVEs (HR=1.909, 95% CI 1.074, 3.394, p=0.028). The adjusted restricted cubic spline analysis indicated that the relationship of RAR with CVEs was linear (p for nonlinearity = 0.402). In the subgroup analysis, an interaction effect of RAR and gender was observed.ConclusionElevated RAR is an independent risk factor for CVEs in MHD patients, and RAR may be helpful for early detection of CVEs risk in MHD patients, although sex differences should be taken in account.

Hyperglycemia-induced oxidative stress accelerates bone senescence, presenting a major challenge for diabetic bone regeneration. In this study, we developed a smart hydrogel by crosslinking hyaluronic acid (HA) grafted with 3-aminophenylboronic acid (HA-PBA) and polyvinyl alcohol (PVA) via phenylboronic acid ester bonds, incorporating metformin (Met), and anchoring parathyroid hormone-related peptide-1 (PTHrP-1) onto polydopamine (PDA)–hybridized nanosized zeolitic imidazolate framework-8 (P1@PZIF-8) to improve the osteogenic microenvironment and repair diabetic bone defects. Incorporation of PZIF-8 shortened gelation time and enhanced the mechanical strength of the HPA hydrogel. The system enabled dynamic, spatiotemporal drug release: >80 % of Met was released within 12 days, while PTHrP-1 and Zn2+ were released gradually over 28 days. This controlled release reduced reactive oxygen species (ROS) accumulation, maintained a favorable redox balance, promoted autophagy, prevented bone marrow mesenchymal stem cells (BMSCs) senescence, and enhanced osteogenesis. Additionally, it delayed high-glucose-induced endothelial cell senescence and improved pro-angiogenic activity. Transcriptome sequencing revealed that the hydrogel inhibited BMSCs senescence via the PI3K–AKT–mTOR pathway and promoted osteogenesis through the Wnt/β-catenin pathway. In vivo, it enhanced angiogenesis, osteogenesis, and tissue remodeling while reducing cellular senescence in diabetic bone defects. Thus, the spatiotemporally controlled drug-release platform thus provides a potent therapeutic strategy to accelerate bone regeneration and functional recovery in the diabetic milieu.

Diagnostics for urothelial carcinoma have low sensitivity, thereby negatively impacting diagnostic outcomes. Herein, we present BiovueUro, a machine learning-based urine DNA biomarker tool for urothelial carcinoma detection. We developed BiovueUro to monitor DNA mutation and methylation in urine samples. The study involved 63 patients with malignant urothelial carcinoma, 13 patients with benign lesions, 115 patients with urinary symptoms, and 106 healthy participants undergoing physical check-ups. Detection was performed using real-time fluorescence quantitative polymerase chain reaction. BiovueUro can detect six single nucleotide polymorphism sites in FGFR3, PIK3CA, and TERT, and aberrant methylation in HIST1H4F, NRN1, and POU4F2. Ten machine-learning algorithms were employed to train the data and classify patients and healthy controls. The optional model demonstrated high diagnostic efficacy in distinguishing patients with high-grade urothelial carcinoma from non-patients. In the validation set, the receiver operating characteristic curve, sensitivity, specificity, accuracy, and positive and negative predictive values were 96.1% (95% CI 89.3-100), 94.7%, 99.1%, 98.5%, 94.7%, and 99.1%, respectively. For distinguishing patients with early-stage urothelial carcinoma from non-patients, the values in the training set were 91.7% (95% CI 84.2-99.1), 80%, 98.3%, 95.1%, 90.9%, and 95.8%, and those in the validation set were 92.5% (95% CI 86.6-98.4%), 80%, 95.7%, 93%, 80%, and 95.7%, respectively. The study's limitations include a relatively small cohort size, restricted regional diversity and a lack of long-term follow-up data to assess disease progression and treatment outcomes. In summary, BiovueUro, a machine learning-enhanced multi-analyte liquid biopsy integrating mutation polymorphisms and methylation profiling, demonstrates superior diagnostic accuracy for urothelial carcinoma compared to conventional urinary tests and methylation-based assays. Its robust sensitivity for early-stage tumors, high specificity for high-grade lesions, and non-invasive nature underscore its potential as a clinically actionable tool for urothelial carcinoma detection. Longer-term outcomes and regional diversity should be evaluated.

No study has comprehensively investigated the association between comorbidities, uremic-specific complications (collectively defined as clinical uremic syndrome [CUS]), and mortality in peritoneal dialysis (PD) patients. We conducted a retrospective cohort study including 4,424 incident PD patients from seven centers in China. Comorbidities and complications were each assigned one point: cardiovascular disease, peripheral vascular disease, cerebrovascular disease, diabetes mellitus, hypertension, hyperlipidemia, malnutrition, and anemia. Patients aged 50 years or older received additional points. The total score (CUS score) was calculated to evaluate its association with mortality in PD patients. Over 18,898.4 person-years of follow-up, 1,208 patients (27.3%) died. The median CUS score was 3 (interquartile range [IQR] 2-5; range, 1-11). A nonlinear association between CUS scores and all-cause mortality was observed (nonlinear, p = 0.006). A pre-1point increase in the CUS score was associated with a 1.35-fold increase in the risk of all-cause mortality (95% confidence interval [CI], 1.31-1.39). Compared with patients with CUS scores ≤ 3, those with scores > 3 had a 2.81-fold higher risk of mortality (95% CI, 2.47-3.21). Higher CUS scores were significantly associated with increased all-cause mortality risk in PD patients, particularly those with scores > 3.

Background:The present study aimed to investigate whether the combination of low-intensity pulsed ultrasound (LIPUS) and aerobic exercise (AE) exerts an enhanced therapeutic benefit for patients with knee osteoarthritis.Methods:Participants were allocated into a LIPUS treatment group, an AE treatment group, and a LIPUS combined with AE (LIPUS + AE) treatment group. Numerical rating scale (NRS) and Lequesne index were determined, and gait analysis was performed before treatment and after 12 weeks of treatment.Results:The LIPUS treatment could significantly alleviate NRS score and Lequesne index in patients with knee osteoarthritis. The AE treatment could significantly alleviate NRS score and Lequesne index, accompanied by improvement in stride length, stride speed, and total walking distance. LIPUS + AE treatment further contributed to an improvement in NRS score and Lequesne index, accompanied by improvement in stride length, stride speed, and total walking distance. At the end of treatment, the Lequesne index improvement on LIPUS + AE treatment group was greater than LIPUS or AE group, NRS score improvement on LIPUS + AE treatment group was greater than LIPUS group. The stride speed, stride length, and total walking distance improvements on LIPUS + AE treatment group were greater than either LIPUS or AE group.Conclusion:The study indicates LIPUS + AE treatment is more effective than LIPUS or AE for knee osteoarthritis. LIPUS + AE promises to be a potential rehabilitation therapy for patients with knee osteoarthritis.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that certain of the tumor images shown in Fig. 7B on p. 13 had already appeared in different form in Fig. 2E in a previously published paper in the journal Frontiers in Cell and Developmental Biology written by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been published prior to its submission to International Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 60: 14, 2022; DOI: 10.3892/ijo.2022.5304].

ObjectiveTo investigate the important active sites within the NTFs to affect the in vitro interaction of oxidized low-density lipoprotein (ox-LDL) with its receptor, OLR1.MethodsSimulation analysis online was performed to generate various OLR1 chimeras, truncation mutants, and site-specific mutations. They were transfected in COS-7 cells and subjected to ox-LDL stimulations to observe the different reactions. Immunoprecipitation-mass spectrometry (IP-MS) was performed to show what proteins combined with OLR1 mutants in reaction to ox-LDL. Lipid uptake in human monocytes (THP-1) originated foam cells overexpressing somatic mutant of OLR1 were also determined. Further studies focusing on these regions were conducted using truncation mutants and site-specific mutants such as G43A, V44A, L45A, C46A, and L47A.ResultsAmino acids within the TM were highly conserved, spanning amino acids 35 to 57. The induction of intracellular p-ERK1/2 in response to ox-LDL stimulation was highly promoted in Chimera 3 possessing the TM from OLR1 like OLR1/WT (p < 0.05). Sequence alignment revealed two conserved regions within the TM of OLR1, Leu45-Cys46-Leu47 and Val55-Leu56-Gly57. Western blot showed that most of the TM changes ablated ERK1/2 activation in response to ox-LDL stimulation (p < 0.05). One human somatic mutation at L45F revealed significantly lower p-ERK1/2 levels with enhanced intake of ox-LDL in THP-1-derived foam cells than the control cells (p < 0.05). L45A and C46A molecular complexes were identified. After ox-LDL stimulation, these underlined interactions with keratins, namely KRT2 and KRT6A.ConclusionThese findings emphasize the vital role of the TM in the interactions between OLR1 and ox-LDL and point to an exciting possibility that signal transduction induced by ox-LDL through its receptor OLR1 may involve complex interactions with cytoskeletal proteins.

ABSTRACTDuring ischemia, succinate accumulates and leads to significant damage to the tissues. The specific role of succinate in lung ischemia–reperfusion injury (LIRI) remains unresolved. Differential metabolites in LIRI were identified through untargeted metabolomics using gas chromatography–mass spectrometry (GC–MS). Type II alveolar epithelial cells (AECs) were cultured and subjected to hypoxia/reoxygenation (H/R) in vitro, while an in vivo LIRI model was developed using C57BL/6 mice. Cytokine levels, lung oedema, histopathological alterations and lung functionality were evaluated. Protein levels were analysed through Western blotting. The mitochondrial membrane potential (Δψm) was measured using the JC‐1 fluorescent dye, and mitochondrial morphology in Type II AECs following H/R damage was observed with a transmission electron microscope (TEM). Oxidative stress and apoptosis markers were detected in lung tissues and Type II AECs. Succinate was increased in the peripheral serum of LIRI patients and the C57BL/6 mices model. Succinate pre‐treatment promotes Type II AEC cell apoptosis and oxidative stress, inhibits mitochondrial membrane potential and damages the alveolar epithelial cells' mitochondrial activity after H/R. Meanwhile, succinate may considerably reduce the amounts of acyl‐CoA oxidase 1 (ACOX1) and isocitrate dehydrogenase 2 (IDH2) protein expression. Importantly, N‐acetyl‐L‐cysteine (NAC) was observed to dramatically retard succinate‐induced cell apoptosis, mitochondrial dysfunction and ROS levels in alveolar epithelial cells following H/R in vivo, with succinate‐neutralising antibodies protecting LIRI in vitro. In conclusion, during ischemia, the build‐up of succinate contributes to the advancement of LIRI by enhancing mitochondrial oxidative stress and promoting cell apoptosis, and blocking succinate may be a potential target for LIRI treatment.