The doublecortin (DCX) gene encodes DCX, a microtubule-associated protein that plays a crucial role in brain development. DCX variants can disrupt microtubule binding and stabilization, interfere with intracellular transport, and affect post-translational modifications. A correlation exists between variant types and clinical severity. Animal models and induced pluripotent stem cell (iPSC) models simulating DCX deficiency revealed the dynamic progression of the disease, which has provided a powerful tool for investigating disease mechanisms and screening therapeutic agents. Currently there is no cure for DCX variants, with treatment primarily relying on anti-epileptic drugs and symptom management. Basic research is now offering new avenues for future therapeutic approaches. This article has summarized the potential pathogenic mechanisms and therapeutic strategies for the DCX variants, with an aim to provide insights for clinical treatment.
Humans ; Doublecortin Protein ; Doublecortin Domain Proteins ; Animals ; Neuropeptides/metabolism* ; Microtubule-Associated Proteins/metabolism* ; Mutation

BACKGROUND: Generalized pustular psoriasis (GPP), a rare and recurrent autoinflammatory disease, imposes a substantial burden on patients and society. Awareness of GPP in China remains limited. METHODS: This cross-sectional survey, conducted between September 2021 and May 2023 across 14 hospitals in China, included GPP patients of all ages and disease phases. Data collected encompassed demographics, clinical characteristics, economic impact, disease severity, quality of life, and treatment-related complications. Risk factors for GPP recurrence were analyzed. RESULTS: Among 127 patients (female/male ratio = 1.35:1), the mean age of disease onset was 25 years (1st quartile [Q1]-3rd quartile [Q3]: 11-44 years); 29.2% had experienced GPP for more than 10 years. Recurrence occurred in 75.6% of patients, and nearly half reported no identifiable triggers. Younger age at disease onset ( P  = 0.021) and transitioning to plaque psoriasis ( P  = 0.022) were associated with higher recurrence rates. The median diagnostic delay was 8 months (Q1-Q3: 2-41 months), and 32.3% of patients reported misdiagnoses. Comorbidities were present in 53.5% of patients, whereas 51.1% experienced systemic complications during treatment. Depression and anxiety affected 84.5% and 95.6% of patients, respectively. During GPP flares, the median Dermatology Life Quality Index score was 19.0 (Q1-Q3: 13.0-23.5). This score showed significant differences between patients with and without systemic symptoms; it demonstrated correlations with both depression and anxiety scores. Treatment costs caused financial hardship in 55.9% of patients, underscoring the burden associated with GPP. CONCLUSIONS The substantial disease and economic burdens among Chinese GPP patients warrant increased attention. Patients with early onset disease and those transitioning to plaque psoriasis require targeted interventions to mitigate the high recurrence risk.
Humans ; Male ; Female ; Psoriasis/pathology* ; Adult ; Cross-Sectional Studies ; Adolescent ; Child ; Young Adult ; Quality of Life ; Middle Aged ; China/epidemiology* ; Recurrence ; Risk Factors ; Surveys and Questionnaires ; East Asian People

Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are linked to numerous chronic conditions, including cardiovascular disease, atherosclerosis, chronic kidney disease, and type II diabetes. Previous research identified the natural flavonoid diosmin, derived from Chrysanthemum morifolium, as a regulator of glucose metabolism. However, its effects on lipid metabolism and underlying mechanisms remained unexplored. The AMP-activated protein kinase (AMPK) pathway serves a critical function in glucose and lipid metabolism. The relationship between diosmin and the AMPK pathway has not been previously documented. This investigation examined diosmin's capacity to reduce lipid content through AMPK pathway activation in hepatoblastoma cell line G2 (HepG2) and 3T3-L1 cells. The study revealed that diosmin inhibits lipogenesis, indicating its potential as an anti-obesity agent in obese mice. Moreover, diosmin demonstrated effective MASLD alleviation in vivo. These findings suggest that diosmin may represent a promising therapeutic candidate for treating obesity and MASLD.
Diosmin/administration & dosage* ; Animals ; AMP-Activated Protein Kinases/genetics* ; Humans ; Non-alcoholic Fatty Liver Disease/enzymology* ; Mice ; Obesity/enzymology* ; Hep G2 Cells ; Male ; 3T3-L1 Cells ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Lipid Metabolism/drug effects* ; Chrysanthemum/chemistry* ; Lipogenesis/drug effects*

Objective:To study the correlation of TCM syndrome elements of large artery atherosclerosis (LAA) cerebral infarction with the new four thrombotic markers and cerebrovascular disease risk factors.Methods:Retrospective analysis was conducted for the baseline data and four diagnosis of 174 patients with LAA cerebral infarction in Department of Neurology, Shanxi Provincial People's Hospital from August 2022 to September 2023. These patients were classified into six TCM syndrome elements: internal wind, qi deficiency, internal fire, blood stasis, yin deficiency, and phlegm-dampness. Thrombomodulin (TM), fibrin-α2 antifibrinolytic inhibitor complex (PIC), thrombin-antithrombinogen complex (TAT), and tissue-type plasminogen activator-plasminogen activator inhibitor complex (t-PAIC) tests were performed in 24 h. Correlation analysis was conducted between the TCM syndrome typing of LAA stroke patients and baseline data, as well as the results of four thrombotic tests.Results:Among the 174 patients with LAA cerebral infarction, 49 (28.16%) were in the internal wind type, 37 (21.26%) in the phlegm-dampness type, 37 (21.26%) in the qi deficiency type, 16 (9.20%) in the internal fire type, 18 (10.35%) in the yin deficiency type, and 17 (9.77%) in the blood stasis type. Comparison of plasma TM ( P=0.003), PIC ( P=0.022), TAT ( P<0.001) and t-PAIC ( P=0.007) levels of each TCM syndrome element showed statistically significant differences ( P<0.05). Logistic regression analysis showed that gender was an influencing factor for the internal wind syndrome element and qi deficiency syndrome element [ OR (95% CI)=0.140 (0.037-0.536)] and blood stasis syndrome element [ OR (95% CI)=0.185 (0.042-0.820)] in TCM; TM was an influencing factor for the internal wind syndrome element and yin deficiency syndrome element [ OR (95% CI)=0.617 (0.423-0.900)], and blood stasis syndrome element [ OR (95% CI)=0.693 (0.496-0.968) ]; TAT was an influencing factor for internal wind syndrome element and phlegm-dampness syndrome element [ OR (95% CI)=2.143 (1.364-3.367)], qi deficiency syndrome element [ OR (95% CI)=1.937 (1.221-3.073)], and internal fire syndrome element [ OR (95% CI)=1.937 (1.221-3.073)], internal fire evidence element [ OR (95% CI)=2.949 (1.796-4.842)], and blood stasis evidence element [ OR (95% CI)=2.118 (1.246-30 600)]; t-PAIC was an influential factor for internal wind syndrome element and qi deficiency syndrome element [ OR (95% CI)=1.140 (1.033-1.258)] ( P<0.05). The ROC curve suggested that a TM level of 8.05 TU/ml had a diagnostic performance of 71.8% for the yin deficiency syndrome; a TAT level of 2.45 ng/L had a diagnostic performance of 71.2% for the internal wind syndrome; a TAT level of 1.65 ng/L had a diagnostic performance of 72.6% for the internal fire syndrome; and a t-PAIC level of 17.55 ng/L had a diagnostic performance of 70.4% for the qi deficiency syndrome. The diagnostic performance of t-PAIC was 70.4% at a t-PAIC level of 17.55 ng/L. Conclusion:Plasma TM, TAT, and t-PAIC levels are independent risk factors for different syndrome elements in patients with LAA cerebral infarction and can be used as markers for early determination of different syndrome elements.

Osteoarthritis(OA)is a common concern over the world.Garlic is a kind of natural herbal medicine,and its active ingredients have shown some anti-inflammatory,antioxidant,anti-catabolic,analgesic and other phar-macological effects.Garlic and its active components alleviate the inflammatory response of OA by inhibiting the ex?pression of inflammatory factors and signal pathways such as NF?κB and PI3K/Akt.They slow down the progression of OA by inhibiting the expression of extracellular matrix(ECM)degrading enzymes.Additionally,they reduce the oxidative damage of joints by upregulating the expression of antioxidant enzymes.Moreover,the active components of garlic can relieve OA pain by activating the potassium ion pathway(Kv7),ATP?sensitive potassium channel(K?ATP),and the nuclear factor erythroid 2?related factor 2(Nrf2)/heme oxygenase 1(HO?1)?NAD(P)H:qui?none oxidoreductase 1(NQO1)signaling pathway.

AIM: To compare the changes of exotropia deviation in children with basic type of intermittent exotropia before and after monocular occlusion test.METHODS: Prospective clinical study. A total of 258 children with basic type of intermittent exotropia who underwent strabismus correction in our hospital from July 2021 to September 2022 were selected, including 122 males and 136 females, aged from 5 to 12 years, with an average age of 8.0±3.1 years. The exotropia deviation was measured at distance(6 m)and near(33 cm)fixation by prism alternating occlusion method, and the exotropia deviation was checked again after covering the non-dominant eyes of children for 40 min.RESULTS: Before and after the monocular occlusion test, the exotropia deviation at distance(6 m)fixation was 28.23△±10.79△ and 29.79△±10.85△, respectively(t=-0.903, P=0.368), while the exotropia deviation at near(33 cm)fixation was 33.14△±8.89△ and 36.90△±10.76△, respectively(t=-2.377, P=0.019).CONCLUSIONS: Monocular occlusion test has a great impact on the exotropia deviation at near(33 cm)fixation in children with basic type of intermittent exotropia before surgery. It can expose the maximum exotropia deviation, reduce the rate of undercorrection after strabismus surgery, and provide a reliable surgical plan.

Asymptomatic carotid artery stenosis (aCAS) is one of the important causes of ischemic stroke. The imaging evaluation of carotid artery plaques is of great significance for selecting the best treatment in patients with aCAS. This article reviews the plaque composition, plaque morphology, and hemodynamic evaluation of aCAS, aiming to provide a basis for developing personalized medical strategies.