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

The pathogenesis of Parkinson's disease is closely related to genetic factors. This article has systematically reviewed the research progress of molecular genetic mechanism on Parkinson's disease by focusing on the role of six high-penetrance pathogenic genes (SNCA, LRRK2, PRKN, PINK1, PARK7, and VPS35) and some risk genes (such as GBA1). These genetic variants eventually converge in three core pathogenic biological pathways, including lysosomal-autophagy pathway disorder, mitochondrial quality control disorder and α-synuclein metabolic abnormality. In-depth understanding of these molecular mechanisms is of great significance for the development of targeted therapy and realization of precision medicine for this disease.
Humans ; Parkinson Disease/metabolism* ; alpha-Synuclein/genetics* ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics* ; Genetic Predisposition to Disease ; Protein Kinases/genetics* ; Animals ; Glucosylceramidase/genetics* ; Ubiquitin-Protein Ligases/genetics*

OBJECTIVE: To elucidate the epidemiological characteristics and genetic variant profile of Short-chain acyl-CoA dehydrogenase deficiency (SCADD) among newborns from Hainan Province and evaluate its significance within the local neonatal disease screening panel. METHODS: A total of 84 184 newborns born in Hainan Province from February to December 2024 were included. Tandem mass spectrometry (MS/MS) was employed to detect butyrylcarnitine (C4) and propionylcarnitine (C3) levels in dried blood spots. Screening thresholds were set at C4 > 0.43 μ mol/L and C4/C3 ratio > 0.28. Suspected cases underwent confirmatory testing via urinary ethylmalonic acid analysis by gas chromatography-mass spectrometry and whole-exome sequencing for ACADS gene variants. This study was approved by the Medial Ethics Committee of the hospital (Ethics No.: HNWCMC-2024-55). RESULTS: Six SCADD cases (male-to-female ratio = 1:1) were diagnosed, with all carrying compound heterozygous variants at two loci, yielding a prevalence of 7.13 per 100,000 live births. Four known ACADS gene variants were identified, with both c.322G>A and c.625G>A detected at a frequency of 41.7%. Regular follow-up (as of January 2026) revealed that all diagnosed cases have remained asymptomatic with normal growth and development. CONCLUSION The prevalence of SCADD among newborns in Hainan Province is relatively high, with c.322G>A and c.625G>A as the hotspot variants in the region. Given the absence of clinical phenotypes in all screen-detected cases during long-term follow-up, it is recommended to remove this condition from the routine neonatal screening program for this region to reduce unnecessary anxiety and medical cost.
Humans ; Infant, Newborn ; Neonatal Screening/methods* ; Female ; Male ; Lipid Metabolism, Inborn Errors/epidemiology* ; Acyl-CoA Dehydrogenase/genetics* ; China/epidemiology* ; Follow-Up Studies

Non-invasive prenatal testing (NIPT) based on fetal free DNA is a non-invasive technique to screen for common fetal aneuploidies by analyzing cell-free fetal DNA (cffDNA) in the peripheral blood of pregnant women. This technique has opened a new era of prenatal screening for its high safety and reliability. In recent years, it has been shown that NIPT can not only screen for fetal aneuploidies, but may also reveal maternal genomic abnormalities. The incidental detection of maternal tumors has aroused widespread concern in the clinical settings. The aim of this review is to systematically summarize the research progress of NIPT technique in incidental detection of maternal tumors, and to discuss its clinical significance, technical challenges, and future development direction. It has been found that multiple chromosome aneuploidies (MCAs) in NIPT detection is one of the important biomarkers suggesting occult maternal malignant tumors. In this paper, the relevant progress of NIPT technique in the incidental discovery of maternal tumors were reviewed in order to provide a reference for individualized and standardized application of NIPT technique in maternal health monitoring.
Humans ; Female ; Pregnancy ; Cell-Free Nucleic Acids/blood* ; Prenatal Diagnosis/methods* ; Incidental Findings ; Neoplasms/genetics* ; Noninvasive Prenatal Testing/methods* ; Aneuploidy ; Fetus/metabolism*

OBJECTIVES: To investigate the mechanism by which circ_EPHB4 regulates temozolomide (TMZ) sensitivity of glioma cells through the miR-424-5p/Wnt3 signal axis. METHODS: We detected the expression levels of circ_EPHB4, miR-424-5p and Wnt3 mRNA in glioma specimens from 25 patients with primary glioma and 25 patients experiencing relapse following temozolomide-based chemotherapy and in TMZ-sensitive and -resistant glioma A172 and SHG44 cells with circ_EPHB4 knockdown using qRT-PCR, and Wnt3 protein expression level was detected with Western blotting. Cell viability, colony-forming ability, and apoptosis of the cells with circ_EPHB4 knockdown were assessed, and the targeted regulation relationship between circ_EPHB4, miR-424-5p, and Wnt3 was verified by dual luciferase reporter assay and RNA immunoprecipitation (RIP) experiments. The effect of circ_EPHB4 knockdown on tumorigenesis of glioma cells was evaluated in subcutaneous tumor-bearing nude mouse models. RESULTS: The expression of circ_EPHB4 was significantly increased in glioma tissues and cells as compared with normal neural tissues and astrocytes (P=0.014). In TMZ-resistant glioma cells, circ_EPHB4 knockdown resulted in an obvious reduction of IC50 value of TMZ, inhibited cell colony formation, and promoted cell apoptosis, and these effects were reversed by miR-424-5p knockdown. The expressions of miR-424-5p and circ_EPHB4 were negatively correlated in glioma tissues (P=0.011). MiR-424-5p knockdown also attenuated the effect of circ_EPHB4 knockdown on expressions of PCNA, P-gp, MRP1 and bax. CONCLUSIONS Circ_EPHB4 regulates Wnt3 expression through "sponge adsorption" of miR-424-5p, thereby modulating TMZ-resistant glioblastoma cell clonogenesis, apoptosis, and TMZ sensitivity, suggesting the potential of circ_EPHB4 as a therapeutic target for reversing drug resistance of gliomas.
MicroRNAs/genetics* ; Humans ; Temozolomide ; Glioma/genetics* ; Animals ; Mice, Nude ; Cell Line, Tumor ; Wnt3 Protein/metabolism* ; Mice ; Apoptosis ; RNA, Circular ; Drug Resistance, Neoplasm ; Brain Neoplasms/pathology* ; Signal Transduction

OBJECTIVES: To elucidate the molecular mechanism by which villin-like protein VILL (VILL) inhibits proliferation of nasopharyngeal carcinoma (NPC) cells. METHODS: Co-immunoprecipitation (CO-IP) assay, mass spectrometry, Western blotting, immunofluorescence staining, and GST pull-down assay were employed to identify and confirm the protein interacting with VILL that had the highest abundance in NPC cell lines. Transgenic experiments were conducted in both NPC cell lines and nude mice to validate the regulatory role of VILL and its target protein in NPC proliferation. Immunohistochemistry was utilized to assess the correlation of the expression levels of VILL and its target protein in clinical tissue specimens of NPC with the clinical features of the patients. RESULTS: In NPC cell lines (HONE1 EBV and S18), VILL was found to interact most abundantly with the E3 ubiquitin ligase LMO7, and both proteins co-localized in the cytoplasm with direct interactions. Overexpression of LMO7 partially counteracted the inhibitory effect of VILL on NPC cell proliferation. The expression of VILL was significantly downregulated in 136 NPC tissue samples compared to 67 non-cancerous nasopharyngeal tissues (P<0.00001) with close correlation with clinical T stage (P=0.04), N stage (P=0.01), and M stage (P=0.013), whereas LMO7 was highly expressed in all the NPC tissues. CONCLUSIONS VILL overexpression inhibits NPC proliferation probably by suppressing the oncogenic function of LMO7.
Nasopharyngeal Neoplasms/metabolism* ; Humans ; LIM Domain Proteins/metabolism* ; Cell Proliferation ; Cell Line, Tumor ; Animals ; Mice ; Nasopharyngeal Carcinoma ; Mice, Nude ; Transcription Factors/metabolism* ; Carcinoma ; Female ; Microfilament Proteins/genetics* ; Male ; Middle Aged

OBJECTIVES: To investigate the mechanism by which the pyramidal neurons of the anterior cingulate cortex (ACC) modulate the effects of enriched environment (EE) for relieving anxiety-like behaviors in mice. METHODS: C57BL/6J mice were randomly divided into control group, restraint stress (RS) group, and RS+EE group (n=8). The mice in the latter two groups were subjected to RS for 2 h daily for 3 days, and those in RS+EE group were housed in an EE during modeling. Anxiety-like behaviors of the mice were evaluated using the elevated plus-maze tests (EPM) and open field test (OFT). Changes in c-Fos expression in the ACC of the mice were detected with immunofluorescence assay, and pyramidal neuron excitability in the ACC (Pyn^ACC) was measured using patch-clamp technique. The miniature excitatory and inhibitory postsynaptic currents (mEPSC and mIPSC, respectively) were analyzed to assess synaptic transmission changes. RESULTS: Behavioral tests showed obvious anxiety-like behaviors in RS mice, and such behavioral changes were significantly improved in RS+EE mice. Immunofluorescence staining revealed significantly increased c-Fos expression in the ACC in RS mice but lowered c-Fos expression in RS+EE group. Compared with the control mice, the RS mice showed increased action potential firing rate of Pyn^ACC, which was significantly reduced in RS+EE group. Compared with the RS mice, the RS+EE mice showed also decreased frequency of mEPSCs of Pyn^ACC, but the amplitude exhibited no significant changes. No obvious changes in the frequency or amplitude of mIPSCs were observed in RS+EE mice. CONCLUSIONS EE reduces excitability of Pyn^ACC to alleviate anxiety-like behaviors induced by RS in mice.
Animals ; Anxiety/physiopathology* ; Gyrus Cinguli ; Mice, Inbred C57BL ; Mice ; Pyramidal Cells/physiology* ; Restraint, Physical ; Stress, Psychological ; Proto-Oncogene Proteins c-fos/metabolism* ; Male ; Behavior, Animal ; Environment ; Excitatory Postsynaptic Potentials

OBJECTIVES: To explore the mechanism of Shenqi Buzhong (SQBZ) Formula for alleviating mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease (COPD) in light of the AMPK/SIRT1/PGC-1α pathway. METHODS: Fifty male SD rat models of COPD, established by intratracheal lipopolysaccharide (LPS) instillation, exposure to cigarette smoke, and gavage of Senna leaf infusion, were randomized into 5 groups (n=10) for treatment with saline (model group), SQBZ Formula at low, moderate and high doses (3.08, 6.16 and 12.32 g/kg, respectively), or aminophylline (0.024 g/kg) by gavage for 4 weeks, with another 10 untreated rats as the control group. Pulmonary function of the rats were tested, and pathologies and ultrastructural changes of the lung tissues were examined using HE staining and transmission electron microscopy. The levels of SOD, ATP, MDA, and mitochondrial membrane potential in the lungs were detected using WST-1, colorimetric assay, TBA, and JC-1 methods. Flow cytometry was used to analyze ROS level in the lung tissues, and the protein expression levels of P-AMPKα, AMPKα, SIRTI, and PGC-1α were detected using Western blotting. RESULTS: The rat models of COPD showed significantly decreased lung function, severe histopathological injuries of the lungs, decreased pulmonary levels of SOD activity, ATP and mitochondrial membrane potential, increased levels of MDA and ROS, and decreased pulmonary expressions of P-AMPKα, SIRTI, and PGC-1α proteins. All these changes were significantly alleviated by treatment with SQBZ Formula and aminophylline, and the efficacy was comparable between high-dose SQBZ Formula group and aminophylline group. CONCLUSIONS SQBZ Formula ameliorates mitochondrial dysfunction in COPD rats possibly by activating the AMPK/SIRT1/PGC-1α pathway.
Animals ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Sirtuin 1/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Rats, Sprague-Dawley ; Male ; Rats ; AMP-Activated Protein Kinases/metabolism* ; Mitochondria/metabolism* ; Disease Models, Animal ; Signal Transduction/drug effects*

OBJECTIVES: To study the mechanism mediating the protective effect of asiaticoside (AS) against myocardial ischemia-reperfusion injury (MIRI) in rats. METHODS: Fifty SD rats were randomized into sham-operated group, MIRI model group and AS treatment group. AS treatment was administered at low, moderate and high doses by daily gavage for 2 weeks before MIRI modeling (n=10). Serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), interleukin-18 (IL-18) and IL-1β, the volume of myocardial infarction and ischemia, and myocardial pathologies of the rats were determined or observed. The protein expression levels of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18 in the myocardial tissues were detected using Western blotting. The changes in the expression levels of these proteins were also detected in H9C2 cells with AS pretreatment prior to hypoxia-reoxygenation (H/R) injury. RESULTS: The rats models of MIRI exhibited significant myocardial infarction and ischemia with increased serum levels of LDH and CK-MB and myocardial expressions of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18. AS pretreatment effectively reduced myocardial infarction volume in the rat models and significantly reduced serum LDH and CK-MB levels and the protein levels in the myocardial tissue in a dose-dependent manner. In the H9C2 cell model of H/R injury, AS pretreatment significantly suppressed the elevation of the protein expressions of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18. Molecular docking studies showed that AS had a strong binding affinity with NLRP3. CONCLUSIONS Asiaticoside can alleviate MIRI in rats possibly by inhibiting NLRP3 inflammasome-mediated pyroptosis.
Animals ; Myocardial Reperfusion Injury/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Pyroptosis/drug effects* ; Rats, Sprague-Dawley ; Rats ; Inflammasomes/metabolism* ; Triterpenes/pharmacology* ; Interleukin-18/metabolism* ; Male ; Interleukin-1beta/metabolism* ; Caspase 1/metabolism*

OBJECTIVES: To investigate the therapeutic mechanism of Huoxue Shufeng Granules (HXSFG) for alleviating central sensitization in a mouse model of chronic migraine (CM). METHODS: We analyzed the main chemical components of HXSFG through literature review and explored their pharmacological mechanisms by bioinformatics analyses. In a male C57BL/6J mouse model of CM established by intraperitoneal injections of nitroglycerin (10 mg/kg) every other day (5 injections), the effects of gavage with low, and high doses of HXSFG or intraperitoneal injections of topiramate for ameliorating central sensitization were evaluated using Von Frey test and a hot plate apparatus; the changes in expressions of inflammatory factors, the proteins in the TLR4/NF‑κB signaling pathway, and activation of c-Fos and CGRP were detected using RT-qPCR, Western blotting and immunofluorescence staining. RESULTS: Network pharmacology analysis suggested that the main active components in HXSFG for alleviating CM included formononetin, paeoniflorin, quercetin, and tanshinone. Gene Ontology (GO) enrichment analysis identified 492 GO entries, comprising 366 biological processes, 46 cellular components, and 80 molecular functions. KEGG pathway enrichment analysis indicated that the Toll-like receptor and NF‑κB signaling pathways were crucial in mediating the therapeutic effects of HXSFG on CM. In the mouse models of CM, both topiramate and HXSFG treatments alleviated the symptoms of central sensitization, evidenced by improved mechanical and thermal pain thresholds in the mice. HXSFG significantly reduced the expression of c-Fos and CGRP, improved inflammatory markers, and downregulated the expressions of TLR4, p-NF‑κB, IL-1β, and TNF‑α proteins in the mouse models. CONCLUSIONS HXSFG effectively alleviates central sensitization in CM mice by modulating the inflammatory pathways and inhibiting the TLR4/ NF-κB signaling pathway, suggesting its potential as a therapeutic option for CM.
Animals ; Toll-Like Receptor 4/metabolism* ; NF-kappa B/metabolism* ; Drugs, Chinese Herbal/therapeutic use* ; Mice ; Male ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Migraine Disorders/metabolism* ; Disease Models, Animal ; Inflammation