BACKGROUND: In China, stroke burden remains severe as it is a major cause of mortality and disability. Detailed analyses across different subtypes will help optimize intervention strategies, enhance resource allocation efficiency, and ultimately reduce the overall disease burden. METHODS: We conducted a descriptive analysis of the incidence, prevalence, mortality, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) of stroke and its subtypes using data (1990-2021) from the Global Burden of Disease (GBD) database. A Joinpoint regression model was applied to quantitatively analyze the indicators and calculate the annual percentage change (APC) and average annual percentage change (AAPC). We applied the Bayesian age-period-cohort (BAPC) model to project trends for 2022-2040. RESULTS: Incidence of stroke increased by 100.64% from 1990 to 2021, with ischemic stroke (IS) exhibiting the largest increase (201.13%) among all the subtypes, and the incidence being consistently higher in males than in females. The YLL/YLD ratio for stroke and its subtypes has decreased, with the YLL/YLD ratio falling from 20.13 to 9.48 in 1990-2021, indicating an increase in non-fatal burden. After adjusting for age, the age-standardized incidence rates (ASIRs) of stroke and its subtypes declined, except for IS. The age-standardized mortality rate (ASMR) for subarachnoid hemorrhage (SAH) decreased significantly (APC: -15.31%; 2000-2004), with the largest reduction in the age-standardized DALY rate (ASDR) also occurring during this period (APC: -14.22%). Furthermore, BAPC projections (2022-2040) indicate that stroke ASIRs in males will slightly decline but increase in females. Meanwhile, the ASIR of IS is expected to continue to rise. Overall, the ASMR and ASDR are projected to decline. CONCLUSIONS Although China has made some progress in stroke prevention and control, several challenges remain. Controlling IS must be prioritized, especially due to the high stroke burden among males.

Objective To construct a targeted drug delivery system, Ang-BEVs@Dox, based on Angiopep-2 peptide-modified bacterial extracellular vesicles （BEVs） loaded with doxorubicin （Dox）, overcome the challenges of blood-brain barrier （BBB） penetration and systemic toxicity in chemotherapy for glioblastoma （GBM）, enhance drug targeting to brain tumors and reduce its toxic side effects. Methods BEVs derived from Escherichia coli were isolated using ultracentrifugation. The targeting ligand Angiopep-2, specific for the LRP-1 receptor, was conjugated onto the surface of BEVs to construct the targeted carrier （Ang-BEVs）. Dox was loaded into Ang-BEVs using low-frequency sonication to form Ang-BEVs@Dox. The physicochemical properties （morphology and size） of the carriers were characterized by transmission electron microscopy （TEM） and dynamic light scattering （DLS）. The BBB-penetrating capability, in vitro/in vivo anti-tumor efficacy, and biosafety of the system were evaluated using cellular uptake assays, 3D tumor spheroid models, and orthotopic tumor-bearing mouse models. Results ① Carrier characterization and in vitro efficacy: Ang-BEVs@Dox exhibited a particle size of approximately 100 nm and maintained structural stability after Dox loading. It significantly enhanced cellular uptake efficiency in U87MG cells and achieved deep penetration within 3D tumor spheroids. Cytotoxicity assays demonstrated synergistic anti-tumor effects between the BEVs and Dox in the Ang-BEVs@Dox system. ② In vivo targeting and anti-tumor efficacy: In orthotopic tumor-bearing mouse models, Ang-BEVs@Dox effectively penetrated the BBB and significantly inhibited tumor growth, extending the median survival time of tumor-bearing mice to 33.5 days （compared to 23.5 days in the blank control group, P<0.001）. Immunohistochemical analysis revealed significant suppression of the tumor cell proliferation marker Ki-67 and enhancement of the apoptosis marker TUNEL staining signals. ③ Biosafety: Major organs from mice in the Ang-BEVs@Dox treatment group showed no observable pathological damage, indicating good biosafety. Conclusion This study successfully constructed an Angiopep-2 peptide-modified engineered BEVs delivery system （Ang-BEVs@Dox）. Through Angiopep-2-mediated BBB penetration and tumor targeting, it significantly enhanced the accumulation and therapeutic efficacy of BEVs at the GBM site. This method combined efficient delivery, low systemic toxicity, and clinical translation potential, which provided an innovative solution to overcome the therapeutic bottleneck in GBM treatment.

The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe²⁺ levels in vitro. Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe²⁺, is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.

Psoriasis is a chronic inflammatory skin disease, and its pathogenesis is largely modulated by abnormal angiogenesis. Previous research has indicated that AlkB homolog 5 (ALKBH5), an important demethylase affecting N⁶-methyladenosine (m⁶A) modification, plays a role in regulating angiogenesis in cardiovascular and eye diseases. Our present study found that ALKBH5 was upregulated and co-localized with cluster of differentiation 31 (CD31) in the skin of IMQ group compared with control group. ALKBH5-deficient mice decreased IMQ-induced psoriatic dermatitis and exhibited histological improvements, including decreased epidermal thickness, hyperkeratosis, numbers of dermal capillary vessels and inflammatory cell infiltration. ALKBH5-KO mice alleviated angiogenesis in psoriatic lesions by downregulating the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Additionally, the expression of ALKBH5 was significantly upregulated in IL-17A-induced human umbilical vein endothelial cells (HUVECs), which further promoted the expression of angiogenesis-related cytokines and endothelial cell proliferation. Cell proliferation and angiogenesis were suppressed in ALKBH5 knockdown group, whereas ALKBH5 overexpression promoted these processes. The regulation of angiogenesis in HUVECs by ALKBH5 was facilitated through the AKT-mTOR pathway. Collectively, ALKBH5 plays a pivotal role in psoriatic dermatitis and angiogenesis, which may offer a new potential targets for treating psoriasis.
Animals ; Psoriasis/chemically induced* ; Mice ; Humans ; Neovascularization, Pathologic/genetics* ; Human Umbilical Vein Endothelial Cells/metabolism* ; AlkB Homolog 5, RNA Demethylase/genetics* ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Cell Proliferation ; Mice, Knockout ; Disease Models, Animal ; Signal Transduction ; Male ; Skin/blood supply* ; Mice, Inbred C57BL ; Angiogenesis

Inflammation plays a pivotal role in the etiology and progression of various diseases. In traditional Chinese medicine, the whole plants of Thesium chinense Turcz. and its preparations (e.g. Bairui Granules) have been employed to manage inflammatory conditions. While flavonoids were previously considered the primary anti-inflammatory components, other potentially active constituents have been largely overlooked and not thoroughly investigated. This study presents a novel finding that the total alkaloids of T. chinense (BC-Alk) are potent active substances underlying the traditional and clinical applications of T. chinense and Bairui Granules as anti-inflammatory agents. UPLC-MS/MS analysis identified the composition of BC-Alk as quinolizidine alkaloids. The anti-inflammatory efficacy of BC-Alk was evaluated using a lipopolysaccharide (LPS)-induced lung inflammation model in mice. Results demonstrated that BC-Alk significantly mitigated LPS-induced lung inflammation, attenuated the overproduction of IL-1β and the overproduction of inflammatory factors (TNF-α), and ameliorated lung tissue hyperplasia in mice in vivo. Mechanistic studies in vitro revealed that BC-Alk upregulated the expression of Nrf2 and its downstream proteins NQO1 and glutamate-cystine ligase and modifier subunit (GCLM), inhibited NF-κB phosphorylation, and suppressed NLRP3 activation. Collectively, these findings indicate that BC-Alk exerts potent inhibitory effects against lung inflammation by modulating Nrf2, NF-κB, and NLRP3 pathways. This study provides new insights into the anti-inflammatory constituents of T. chinense and Bairui Granules.
Animals ; Lipopolysaccharides/adverse effects* ; Alkaloids/pharmacology* ; NF-kappa B/metabolism* ; NF-E2-Related Factor 2/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Mice ; Signal Transduction/drug effects* ; Anti-Inflammatory Agents/pharmacology* ; Male ; Mice, Inbred C57BL ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Pneumonia/genetics*

Objective To establish and verify a mature and stable glioblastoma(GBM)organoid model,so as to provide an accurate and personalized preclinical model for the research and treatment of GBM.Methods Fresh GBM tissues obtained through surgical procedures were initially processed,and then GBM stem cells(GSCs)were isolated using stem cell culture medium and were identified.Subsequently,GSCs were cultured in organoid culture medium for 3D cultivation,and GBM organoids were successfully obtained.The histological morphology of GBM organoids was observed by hematoxylin-eosin(H-E)staining;the stemness and similarity to the parental tumor were identified by immunofluorescence staining;and the in vivo tumorigenic ability of GBM organoids was identified by orthotopic tumorigenesis experiments in nude mice.Results A total of 7 GBM organoids were constructed from 9 human GBM samples,with a morphology resembling"neurosphere",and the average duration for organoid formation was 1 week.H-E staining results showed that the histological morphology of GBM organoids under high-power microscope was very similar to that of GBM tumor tissues;immunofluorescence staining results indicated that the GBM organoids possessed stemness characteristics and histological cellular similarity;and GBM organoids had a stronger tumorigenic ability compared to ordinary GBM cells in nude mice.Conclusion This study presents a stable and reliable method for constructing GBM organoids retaining the histological characteristics of the original GBM tissue,which providing new insights for future GBM research and clinical practice.

WD repeat domain 1(WDR1)is a highly conserved cytoskeleton-associated protein that plays a crucial role in physiological processes such as actin cytoskeleton remodeling,dynamic regulation of intercellular junctions,cell division,and migration.WDR1 exhibits abnormal high ex-pression in various malignant tumors,including breast cancer,ovarian cancer,and thyroid cancer,and has been demonstrated to significantly promote the invasive and migratory capabilities of tumor cells,suggesting its important role in the malignant progression of tumors.Moreover,the expression level of WDR1 is closely related to the clinical prognosis of patients with multiple malignant tumors.Especially in patients with esophageal cancer and osteosarcoma,its high expression often indicates a poor overall survival rate.WDR1 can promote tumor initiation and progression by regulating the Wnt/β-Catenin signaling pathway and the Hippo-YAP signaling pathway.Meanwhile,its expression is also subject to multi-level regulation by transcription activation factors and long non-coding RNAs(lncR-NAs),thereby influencing the proliferation,migration,and other biological behaviors of tumor cells.Additionally,WDR1 can further drive the invasive growth and metastatic potential of tumors by regu-lating the epithelial-mesenchymal transition(EMT)process.This article aimed to systematically re-view the research progress in recent years regarding the biological functions and molecular mechanisms of WDR1 in tumor initiation and development,with a view to providing new theoretical foundations and research directions for the early diagnosis,prognosis assessment,and individualized treatment of clinical tumors.

Objective To analyze the long-term outcome of modified Morrow surgery (interventricular septal cardiomyectomy) in the treatment of hypertrophic obstructive cardiomyopathy (HOCM) in children. Methods The clinical data of the children with HOCM (aged≤14 years) who underwent modified Morrow surgery from January 2010 to August 2022 in Guangdong Provincial People's Hospital were retrospectively analyzed, including changes in hospitalization status, perioperative period, and long-term 15-lead electrocardiogram and echocardiography. Results A total of 29 patients were collected, including 22 males and 7 females, aged 10.00 (5.00, 12.00) years. Five (17.9%) patients had New York Heart Association (NYHA) heart function grade Ⅲ or Ⅳ. Ventricular septal cardiomyectomy was performed in all patients. All 29 patients survived and their cardiac function recovered after operation. Before discharge, right bundle branch block was observed in 2 patients and left bundle branch block in 6 patients. After surgery, in the left ventricular septal cardiomyectomy, the left atrial diameter decreased (P＜0.001), left ventricular end-systolic diameter increased (P=0.009), the peak pressure gradient of left ventricular outflow tract decreased (P＜0.001), and the thickness of ventricular septum decreased (P＜0.001). The systolic anterior motion of mitral valve disappeared and mitral regurgitent jet area decreased (P＜0.001). The flow velocity and peak pressure gradient of right ventricular outflow tract also decreased in the patients who underwent right ventricular septal cardiomyectomy. The average follow-up of the patients was 69.03±10.60 months. All the patients survived with their NYHA cardiac function grading Ⅰ or Ⅱ. No new-onset arrythmia event was found. Echocardiography indicated that the peak pressure gradient of the left ventricular outflow tract remained low (P<0.001). Moderate mitral regurgitation occurred in 2 patients, and left ventricular outflow tract obstruction with moderate mitral regurgitation occurred in 1 patient after simple right ventricular septal cardiomyectomy. Conclusion Right ventricular or biventricular obstruction is frequent in the children with HOCM and they usually have more symptoms before surgery. Modified Morrow surgery can effectively relieve outflow tract obstruction and improve their cardiac function. The long-term outcome is satisfactory. However, the posterior wall of the left ventricle remains hypertrophic. Also, there is an increased risk of a conduction block.

Objective To explore the impact of SARS-CoV-2-positive donors on the prognosis of heart transplant recipients. Methods The Medline, EMbase, CENTRAL, CNKI, Wanfang Data, VIP and China Biology Medicine from inception to May 2023 were searched by computer for studies about impact of SARS-CoV-2-positive donors on the prognosis of heart transplant recipients. The data were extracted from all the relevant literatures, and the quality of the data was assessed using the Newcastle-Ottawa Scale (NOS). All statistical analyses were conducted by the Stata 11.0 software. Results A total of 10 studies (NOS score ranging from 5 to 9 points) involving 643 patients were enrolled. The pooled results demonstrated that the pooled mortality of heart transplant recipients from SARS-CoV-2-positive donors was 4% (95%CI 2% to 5%). And the incidence of composite outcome, regarding graft failure, rejection and death as poor prognosis, was 7% (95%CI 5% to 9%). Besides, compared with recipients from SARS-CoV-2-negative donors, the pooled odds ratio (OR) value of death of SARS-CoV-2-positive donors was 0.68 (95%CI 0.38 to 1.22, Z=1.28, P=0.200). The pooled OR value of rejection rate was 0.41 (95%CI 0.27 to 0.64, Z=3.97, P<0.005). For the composite outcome, the pooled OR value was 0.50 (95%CI 0.37 to 0.69, Z=4.30, P<0.005). In addition, there was no statistical difference in the length of hospital stay between heart transplant recipients from SARS-CoV-2-positive donors and negative donors (SMD=–0.03, 95%CI –0.22 to 0.15, Z=0.36, P=0.720). Conclusion The application of heart from SARS-CoV-2-positive donor for transplantation is safe and feasible. However, further prospective studies with longer follow-up are still needed to verify its impact on long-term outcomes.