OBJECTIVE: To delineate the clinical and genetic features of a Chinese girl harboring a rare de novo variant of SYNGAP1 associated with Mental retardation, autosomal dominant 5 (MRD5), and to conduct a comprehensive genotype-phenotype correlation analysis within the Chinese population through an extensive literature review. METHODS: A 5-year-old girl presenting with seizures without an obvious cause was enrolled in September 2020. Genomic DNA was extracted from the patient and her parents. Whole exome sequencing (WES) was performed on the proband to identify suspected pathogenic variants based on her clinical phenotype. Sanger sequencing was used for validation, followed by bioinformatic analysis of the variant. Additionally, data from 54 previously reported Chinese cases with SYNGAP1 variants were integrated to summarize the distribution of variant types and clinical characteristics. Ethical approval was obtained from the Ethics Committee of Kunming Children's Hospital (Ethics No.: 2021-03-055-K01). RESULTS: WES identified a heterozygous nonsense variant, SYNGAP1 c.725G>A (p.Trp242*), in the proband. Sanger sequencing confirmed it was a de novo variant. According to the ACMG guidelines, this variant was classified as pathogenic (PVS1+PS2). Based on the clinical manifestations, the patient was diagnosed with MRD5. Bioinformatic analysis suggested that this variant introduces a premature stop codon at tryptophan 242, disrupting the PH domain and leading to the loss of the C2, Ras-GAP, and C-terminal domains. The pooled analysis of Chinese cases revealed that nonsense (38.2%) and frameshift (36.4%) variants were the predominant types. Intellectual disability/developmental delay was present in 100.0% of patients, epilepsy in 83.6%, and autism spectrum disorder in 41.3%. The incidence of epilepsy differed significantly among variant types (P = 0.045). Exons 8 and 15 were identified as mutation hotspots. CONCLUSION This study has identified a SYNGAP1 c.725G>A variant in the Chinese population and confirmed it as a potential cause of MRD5, which expanded the mutational spectrum of this disorder.
Humans ; Female ; Child, Preschool ; Intellectual Disability/genetics* ; ras GTPase-Activating Proteins/genetics* ; Phenotype ; Exome Sequencing ; Genetic Association Studies

OBJECTIVE: To analyze the clinical characteristics of patients with 11q23 rearrangement acute lymphoblastic leukemia (ALL) with non-KMT2A::AFF1 fusion genes. METHODS: The clinical data of 10 patients with KMT2A fusion gene positive and partner gene non-AFF1 ALL admitted to Henan Cancer Hospital from December 2016 to December 2024 were retrospectively summarized. The immunophenotype, molecular genetic characteristics, clinical manifestations and disease prognosis of these patients were analyzed. This research has been approved by the Medical Ethics Committee of Henan Cancer Hospital (Ethics No.: 2019342). RESULTS: Among the 10 patients, the fusion genes were KMT2A::MLLT1 in 7 cases, KMT2A::MLLT4, KMT2A::MLLT3 and KMT2A::MLLT10 in 1 case each. The European Group for the Immunological Classification of Leukemias (EGIL) classification included 6 cases of T-ALL, 2 cases of pro-B-ALL, 1 case of Common-B-ALL and 1 case of pre-B-ALL. 4 cases of B-ALL all expressed CD19, cCD79a, CD38 and HLA-DR, and some expressed CD34 and CD22, without expression or weak expression of CD10, without expression of CD20. One case was accompanied by myeloid marker CD15 expression. 6 cases of T-ALL all expressed CD34, CD7, most expressed CD38, and some expressed CD3, CD5, CD2, CD4 and CD8, and 1 case expressed CD4 and CD8 together. Chromosomal abnormalities were detected in 3 cases, 5 cases were positive for WT1 fusion gene, and 6 cases had gene alterations. 9 patients achieved the first complete remission (CR1) during chemotherapy, and 1 patient relapsed within 6 months after CR1. At the last follow up, 1 patient (the fusion gene was KMT2A::MLLT4) remained unrelieved. There were 2 cases of KMT2A rearrangement (KMT2A-r) persistent positive (+/+) and 8 cases of KMT2A-r negative (+/-). The overall survival (OS) rate and leukemia-free survival (LFS) rate of patients with KMT2A-r persistent positive were significantly lower than those of patients with negative change, and the differences were statistically significant (P values were all < 0.05). Among the 3 patients who received chemotherapy+allogeneic hematopoietic stem cell transplantation (allo-HSCT), no relapse was observed until the follow up day. The OS rate and LFS rate of patients with KMT2A::MLLT1 and chemotherapy+allo-HSCT were higher than those of non-KMT2A::MLLT1 and single chemotherapy patients, and the differences were not statistically significant (P values were all ≥ 0.05). There was no significant difference in OS rate and LFS rate between T-ALL and B-ALL patients (P values were all ≥ 0.05). The median LFS time of the 10 patients was 32 (0 ~ 100) months, and the median OS time was 36 (1 ~ 101) months. CONCLUSION The 11q23 rearrangement ALL with non-KMT2A::AFF1 transcript is mainly KMT2A::MLLT1, T-ALL is more common, and the rate of chromosomal karyotype detection is relatively low. Persistent positive KMT2A-r is unfavorable for patient survival, and allo-HSCT during the CR1 period may improve patient survival.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Female ; Male ; Myeloid-Lymphoid Leukemia Protein/genetics* ; Histone-Lysine N-Methyltransferase/genetics* ; Adult ; Adolescent ; Chromosomes, Human, Pair 11/genetics* ; Child ; Transcriptional Elongation Factors/genetics* ; Gene Rearrangement ; Oncogene Proteins, Fusion/genetics* ; Retrospective Studies ; Young Adult ; Middle Aged ; Prognosis ; Child, Preschool ; DNA-Binding Proteins/genetics*

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

OBJECTIVE: To analyze the clinical characteristics, treatment, and prognosis of seven pediatric patients with Acute myeloid leukemia (AML) positive for the t(16;21)(p11;q22) FUS::ERG fusion gene. METHODS: A retrospective analysis was carried out on the clinical data, treatment, and prognosis of seven AML patients with t(16;21)(p11;q22) FUS::ERG fusion gene admitted to Henan Children's Hospital between June 2015 and November 2024. Relevant literature was also reviewed. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-102-001). RESULTS: Among 297 pediatric patients with AML, 7 cases (2.36%) were positive for the t(16;21)(p11;q22) FUS::ERG fusion gene, including 3 males and 4 females, with a median age of 11 years (range: 3 ~ 12 years). According to the FAB classification, these included 1 case of M2, 3 cases of M5, and 3 cases of AML-not otherwise specified (non-M3). All 7 patients were found to harbor the t(16;21)(p11;q22) translocation, with 3 cases showing additional chromosomal abnormalities. Immunophenotyping revealed universal expression of CD13, CD33, CD34, and CD117, with partial expression of CD56, CD4, CD64, CD123, CD15, CD38, CD11b, HLA-DR, cMPO, and CD16. One patient achieved complete remission (CR) after the first course of DAE (cytarabine + daunorubicin + etoposide) induction chemotherapy but relapsed and discontinued the treatment. Six patients received DAH (cytarabine + daunorubicin + homoharringtonine) induction therapy, of whom 2 achieved CR after two courses and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), resulting in an overall CR rate of 42.86%. Five children did not receive allo-HSCT and had a median overall survival of 9 months (range: 6 ~ 18 months). Two children who underwent transplantation achieved bone marrow morphological and molecular biological relapse at 6 and 9 months post-transplantation, respectively. After receiving combined chemotherapy and donor lymphocyte infusion, one child failed to achieve remission and died at 22 months post-transplantation, while the other has been followed up to date with positive fusion gene status. Their overall survival was 25 months and 30 months, respectively. CONCLUSION The t(16;21)(p11;q22) FUS::ERG fusion gene is rare in pediatric AML and associated with poor prognosis. Allo-HSCT may mitigate the adverse prognostic impact of the FUS::ERG fusion gene and contribute to prolonged survival.
Humans ; Male ; Child ; Female ; Leukemia, Myeloid, Acute/drug therapy* ; Oncogene Proteins, Fusion/genetics* ; Translocation, Genetic ; Retrospective Studies ; RNA-Binding Protein FUS/genetics* ; Chromosomes, Human, Pair 16/genetics* ; Adolescent ; Child, Preschool ; Chromosomes, Human, Pair 21/genetics* ; Prognosis ; Treatment Outcome

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with Hereditary spastic paraplegia type 3A (SPG3A) and the genotype-phenotype correlation. METHODS: A three-generation pedigree presented at Huantai Maternal and Child Health Care Hospital in March 2021 was selected as the study subject. Whole-exome sequencing (WES) and pedigree analysis was carried out. Candidate variant was validated by Sanger sequencing of the members from the pedigree. Haplotype analysis was used to trace the origin of the variant, and pathogenicity was rated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2025-12). RESULTS: A c.1024C>T (p.Pro342Ser) variant of the ATL1 was identified in the four affected members, including the proband, but none of the three unaffected relatives. Haplotype analysis suggested that the variant was derived from the proband's mother and has co-segregated with the disease phenotype. Based on the guidelines of the ACMG, it was classified as likely pathogenic. CONCLUSION The ATL1 c.1024C>T (p.Pro342Ser) variant probably underlay the pathogenesis in this pedigree. Above finding has enriched the mutational spectrum of ATL1 and phenotypic spectrum of SPG3A in the Chinese population, and enabled genetic counseling for this pedigree.
Humans ; Pedigree ; Spastic Paraplegia, Hereditary/genetics* ; Male ; Female ; Asian People/genetics* ; Adult ; Haplotypes ; Membrane Proteins/genetics* ; Exome Sequencing ; GTP-Binding Proteins/genetics* ; Mutation ; Middle Aged ; China ; Genetic Association Studies ; East Asian People

BACKGROUND

Traditional and alternative medicine (TAM) is increasingly recognized for its potential to complement conventional medicine. However, its acceptance and perspectives among medical doctors remain underexplored, particularly in Zamboanga City.

To assess the level of acceptance, perspectives, and reasons influencing medical doctors’ willingness or hesitancy to advise TAM.

Descriptive cross-sectional study conducted among 230 medical doctors from public and private institutions. Data were collected using a validated questionnaire and in-depth interviews. Quantitative data were analyzed using descriptive statistics, and qualitative data underwent thematic analysis.

74.8% of respondents exhibited high acceptance of TAM, 21.3% were neutral, and 3.9% showed low acceptance. Most believed TAM could enhance patient satisfaction (53.48%) and improve quality of life (62.61%). However, 61.3% reported slight-to-moderate comfort in discussing TAM, and 43.91% rarely initiated such conversations. A majority (55.65%) supported TAM services being delivered by physicians trained in TAM alongside Department of Health-registered professionals, preferably integrated in primary care (38.26%) or hospital-based settings (30%). Willingness to advise TAM was driven by professional development opportunities (58.7%) and improved regulation (57.39%), whereas hesitancy stemmed from concerns about insufficient scientific evidence (65.65%) and lack of regulation (61.3%). Interest in TAM training was high (63.48%), particularly in acupuncture and herbal medicine. Thematic analysis identified key barriers (limited evidence, regulatory gaps, and training deficits) and facilitators (education, policy standardization, research, and educational curriculum integration).

Strong interest in TAM integration exists, contingent on training and regulatory improvements. Findings highlight the need for targeted education, policy reforms, and evidence generation to support evidence-based TAM inclusion in Philippine healthcare.

OBJECTIVE: Diabetes-induced gastrointestinal (GI) motility disorders are increasingly prevalent. Damage to the enteric nervous system (ENS), composed primarily of enteric neurons and glial cells, is an essential mechanism involved in these disorders. Although electroacupuncture (EA) has shown the potential to mitigate enteric neuronal loss, its mechanism is not fully understood. Additionally, the effects of EA on enteric glial cells have not been investigated. Enteric neural precursor cells (ENPCs) contribute to the structural and functional integrity of the ENS, yet whether EA enhances their differentiation into enteric neurons and glial cells remains unexplored. This study investigates whether EA promotes ENS repair through enhancing ENPC-derived neurogenesis and gliogenesis and elucidates the potential molecular mechanisms involved. METHODS: Transgenic mice were used to trace Nestin⁺/nerve growth factor receptor (Ngfr)⁺ ENPCs labeled with green fluorescent protein (GFP) in vivo. Mice were randomly divided into four groups: control, diabetes mellitus (DM), DM + sham EA, and DM + EA. The effects of EA on diabetic mice were evaluated by GI motility, ENS structure, and ENPC differentiation. Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling was detected to clarify the underlying molecular mechanisms. RESULTS: EA alleviated diabetes-induced GI motility disorders, as indicated by reduced whole gut transit time, shortened colonic bead expulsion time, and enhanced smooth muscle contractility. Furthermore, EA attenuated diabetes-induced losses of enteric neurons and glial cells, thereby restoring ENS integrity. Notably, EA reversed the diabetes-induced decrease in ENPCs and significantly increased the absolute number and the proportion of ENPC-derived enteric neurons. However, immunofluorescence analyses revealed no colocalization between EA-induced glial fibrillary acidic protein⁺ glial cells and GFP-labeled ENPCs. Mechanistically, GDNF/Ret signaling was elevated in intestinal tissues and upregulated in ENPCs in EA-treated diabetic mice. CONCLUSION EA facilitates ENS repair by promoting Nestin⁺/Ngfr⁺ ENPC differentiation into enteric neurons via upregulation of GDNF/Ret signaling, and driving enteric gliogenesis from non-Nestin⁺/Ngfr⁺ ENPCs. These findings highlight EA's role in ameliorating diabetes-induced GI dysmotility through ENPC-derived ENS restoration. Please cite this article as: Guo JL, Liu S, Ding SJ, Yang X, Du F. Electroacupuncture at ST36 improves gastrointestinal motility disorders by promoting enteric nervous system regeneration through GDNF/Ret signaling in diabetic mice. J Integr Med. 2025; 23(5):548-559.
Animals ; Electroacupuncture ; Enteric Nervous System/physiology* ; Gastrointestinal Motility/physiology* ; Glial Cell Line-Derived Neurotrophic Factor/metabolism* ; Diabetes Mellitus, Experimental/therapy* ; Signal Transduction ; Mice ; Gastrointestinal Diseases/physiopathology* ; Proto-Oncogene Proteins c-ret/metabolism* ; Mice, Transgenic ; Male ; Nerve Regeneration ; Neural Stem Cells ; Mice, Inbred C57BL ; Acupuncture Points

OBJECTIVE: Glucocorticoid-induced osteoporosis (GIOP) is a common complication of prolonged glucocorticoid therapy. Chlorogenic acid (CGA), a polyphenol with antioxidant properties that is extracted from traditional Chinese medicines such as Eucommiae Cortex, has potential anti-osteoporotic activity. This study aimed to investigate the possible effects of CGA on GIOP in mice and murine long bone osteocyte Y4 (MLO-Y4) cells and explore the underlying molecular mechanisms. METHODS: The protective effects of CGA were initially evaluated in the GIOP mouse model induced by dexamethasone (Dex). The micro-computed tomography, hematoxylin-eosin staining, silver nitrate staining, and serum detection were used to assess the efficacy of CGA for improving bone formation in vivo. Then, network pharmacology analysis was used to predict the potential targets and molecular mechanisms underlying the therapeutic efficacy of CGA against GIOP. After that, 2',7'-dichlorofluorescein diacetate staining, flow cytometry, real-time quantitative reverse transcription polymerase chain reaction, and Western blotting were used to verify the mechanisms of CGA against GIOP in vitro. RESULTS: Animal experiments showed that CGA treatment effectively attenuated Dex-induced decreases in bone mass and strength and improved disrupted osteocyte morphology in mice. The protein-protein interaction analysis highlighted erb-b2 receptor tyrosine kinase (ERBB2), which is also known as human epidermal growth factor receptor 2 (HER2), caspase-3, kinase insert domain receptor, matrix metallopeptidase 9, matrix metallopeptidase 2, proto-oncogene tyrosine-protein kinase Src, and epidermal growth factor receptor as core targets. The Kyoto Encyclopedia of Genes and Genomes analysis revealed several significantly enriched pathways (P < 0.05), including the ERBB, phosphoinositide 3 kinase-AKT serine/threonine kinase 1 (AKT), and mechanistic target of rapamycin kinase (mTOR) pathways. Cellular experiments verified that CGA enhanced bone formation and promoted autophagy while inhibiting apoptosis in MLO-Y4 cells exposed to Dex, which was associated with the upregulated expression of HER2 and activation of the HER2/AKT/mTOR signaling pathway. CONCLUSION CGA exerted anti-osteoporotic effects against GIOP, partially through targeting osteocytes and modulating the HER2/AKT/mTOR signaling pathway. Please cite this article as: Xie AN, Zhang SZY, Zhang Y, Cao JL, Wang CL, Wang LB, Wu HJ, Zhang J, Dai WW. Chlorogenic acid mitigates glucocorticoid-induced osteoporosis via modulation of HER2/AKT/mTOR signaling pathway. J Integr Med. 2025; 23(6):670-682.
Animals ; Chlorogenic Acid/therapeutic use* ; Osteoporosis/metabolism* ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Mice ; Glucocorticoids/adverse effects* ; Receptor, ErbB-2/metabolism* ; Proto-Oncogene Mas ; Dexamethasone/adverse effects* ; Osteocytes/drug effects* ; Osteogenesis/drug effects* ; Male ; Cell Line ; Mice, Inbred C57BL ; Humans

OBJECTIVE: Peritoneal fibrosis (PF) is an adverse event that occurs during long-term peritoneal dialysis, significantly impairing treatment efficiency and adversely affecting patient outcomes. Astragaloside IV (AS-IV), a principal active component derived from Astragalus membranaceus (Fisch.) Bunge, has exhibited anti-inflammatory and antifibrotic effects in various settings. This study aims to investigate the potential therapeutic efficacy and mechanism of AS-IV in the treatment of PF. METHODS: The PF mouse model was established by intraperitoneal injection of 4.25% peritoneal dialysis fluid (100 mL/kg). The epithelial-mesenchymal transition (EMT) of HMrSV5 cells was induced by the addition of 10 ng/mL transforming growth factor β (TGF-β). The differentially expressed genes in HMrSV5 cells treated with AS-IV were screened using transcriptome sequencing analysis. The potential targets of AS-IV were screened using network pharmacology and analyzed using molecular docking and molecular dynamics simulations. RESULTS: Administration of AS-IV at doses of 20, 40, or 80 mg/kg effectively mitigated the increase in peritoneal thickness and the development of fibrosis in mice with PF. The expression of the fibrosis marker α-smooth muscle actin in the peritoneum was significantly decreased in AS-IV-treated mice. The treatment of AS-IV (10, 20, and 40 μmol/L) significantly delayed the EMT of HMrSV5 cells induced by TGF-β, as demonstrated by the decreased number of 5-ethynyl-2'-deoxyuridine-positive cells, reduced migrated area, and decreased expression of fibrosis markers. A total of 460 differentially expressed genes were detected in AS-IV-treated HMrSV5 cells through transcriptome sequencing, with notable enrichment in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase 1 (AKT) signaling pathway. The reduced levels of phosphorylated PI3K (p-PI3K) and p-AKT were detected in HMrSV5 cells with AS-IV treatment. Epidermal growth factor receptor (EGFR) was predicted as a direct target of AS-IV, exhibiting strong hydrogen bond interactions. The activation of the PI3K-AKT pathway by the compound 740Y-P, and the activation of the EGFR pathway by NSC 228155 each partially counteracted the inhibitory effect of AS-IV on the EMT of HMrSV5 cells. CONCLUSION AS-IV delayed the EMT process in peritoneal mesothelial cells and slowed the progression of PF, potentially serving as a therapeutic agent for the early prevention and treatment of PF. Please cite this article as: Huang Y, Chu CL, Qiu WH, Chen JY, Cao LX, Ji SY, Zhu B, Wang GK, Shen QQ. Astragaloside IV delayed the epithelial-mesenchymal transition in peritoneal fibrosis by inhibiting the activation of EGFR and PI3K-AKT pathways. J Integr Med. 2025; 23(6):694-705.
Epithelial-Mesenchymal Transition/drug effects* ; Animals ; Saponins/pharmacology* ; Triterpenes/pharmacology* ; Mice ; Peritoneal Fibrosis/pathology* ; Proto-Oncogene Proteins c-akt/metabolism* ; ErbB Receptors/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Signal Transduction/drug effects* ; Male ; Humans ; Molecular Docking Simulation ; Cell Line ; Mice, Inbred C57BL

Stem-leaf saponins from Panax notoginseng (SLSP) comprise numerous PPD-type saponins with diverse pharmacological properties; however, their role in Parkinson's disease (PD), characterized by microglia-mediated neuroinflammation, remains unclear. This study evaluated the effects of SLSP on suppressing microglia-driven neuroinflammation in experimental PD models, including the 1-methyl-4-phenylpyridinium (MPTP)-induced mouse model and lipopolysaccharide (LPS)-stimulated BV-2 microglia. Our findings revealed that SLSP mitigated behavioral impairments and excessive microglial activation in models of PD, including MPTP-treated mice. Additionally, SLSP inhibited the upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) and attenuated the phosphorylation of PI3K, protein kinase B (AKT), nuclear factor-κB (NFκB), and inhibitor of NFκB protein α (IκBα) both in vivo and in vitro. Moreover, SLSP suppressed the production of inflammatory markers such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) in LPS-stimulated BV-2 cells. Notably, the P2Y2R agonist partially reversed the inhibitory effects of SLSP in LPS-treated BV-2 cells. These results suggest that SLSP inhibit microglia-mediated neuroinflammation in experimental PD models, likely through the P2Y2R/PI3K/AKT/NFκB signaling pathway. These novel findings indicate that SLSP may offer therapeutic potential for PD by attenuating microglia-mediated neuroinflammation.
Animals ; Panax notoginseng/chemistry* ; Saponins/pharmacology* ; Microglia/immunology* ; Mice ; NF-kappa B/immunology* ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/immunology* ; Phosphatidylinositol 3-Kinases/genetics* ; Male ; Parkinson Disease/immunology* ; Mice, Inbred C57BL ; Disease Models, Animal ; Plant Leaves/chemistry* ; Neuroinflammatory Diseases/drug therapy* ; Humans