ObjectiveThe exacerbating trend of global population aging poses profound socioeconomic and public health challenges, making the comprehensive elucidation of biological aging mechanisms and the discovery of effective anti-aging interventions an urgent priority in the life sciences. Based on our previous serum metabolomics findings that dimethylglycine, an intermediate metabolite of amino acid metabolism naturally present in the human body, was significantly enriched in the serum of longevity families, this study aimed to systematically investigate the anti-aging effects of dimethylglycine both in living organisms and in controlled laboratory environments, and to preliminarily elucidate its underlying molecular mechanisms. While existing literature indicates that dimethylglycine possesses antioxidant and immunomodulatory properties, its direct anti-aging efficacy and the specific molecular pathways through which it operates remain largely unexplored. MethodsTo comprehensively evaluate the anti-aging properties of dimethylglycine, we utilized replicative senescent human embryonic lung fibroblasts, specifically the WI-38 cell line, as an experimental model in a controlled laboratory environment. Cell viability and safety were thoroughly assessed using Cell Counting Kit-8 and lactate dehydrogenase release assays across various concentrations of dimethylglycine. The impact of dimethylglycine on cellular senescence phenotypes, oxidative stress, and proliferative capacity was evaluated via senescence-associated beta-galactosidase staining, reactive oxygen species fluorescence detection, and 5-ethynyl-2'-deoxyuridine incorporation assays. Furthermore, the molecular alterations of senescence-associated secretory phenotype factors and core senescence signaling pathways were quantified using quantitative reverse transcription polymerase chain reaction for the messenger RNA levels of interleukin-6, interleukin-8, p21, and matrix metalloproteinase-1, and enzyme-linked immunosorbent assay for the measurement of p16 and p21 protein expression levels. For the living organism model, the wild-type nematode Caenorhabditis elegans was used to evaluate systemic physiological effects. We conducted a comprehensive lifespan analysis at 20°C, heat stress resistance survival assays at 35℃, senescence-associated beta-galactosidase staining, lipofuscin accumulation tracking, intracellular reactive oxygen species measurement, and Oil Red O staining to ascertain systemic lipid accumulation. Additionally, network pharmacology bioinformatics tools, including PharmMapper and STRING databases, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were utilized to predict target pathways, alongside highly detailed molecular docking simulations utilizing SwissDock and Protein-Ligand Interaction Profiler to examine interactions with the cytochrome P450 family 2 subfamily C member 9 protein. ResultsThe experimental outcomes robustly demonstrate the potent anti-aging capabilities of dimethylglycine. At the cellular level, toxicity analyses firmly confirmed that dimethylglycine is highly safe; continuous treatment with 50 mol/L and 70 mol/L of dimethylglycine for 5 d did not induce any cellular membrane damage or cytotoxicity, but rather actively promoted cellular proliferation. Utilizing the optimal standardized concentration of 50 mol/L, dimethylglycine treatment significantly ameliorated senescent phenotypic markers in human embryonic lung fibroblasts, which was evidenced by a drastic and highly significant reduction in the senescence-associated beta-galactosidase positive cell percentage (P<0.000 1) and intracellular reactive oxygen species levels (P<0.000 1), alongside a marked increase in the 5-ethynyl-2'-deoxyuridine-positive proliferation rate (P=0.003 5). On a molecular expression scale, dimethylglycine significantly downregulated the messenger RNA expression of multiple core senescence-associated secretory phenotype inflammatory factors, including interleukin-6, interleukin-8, p21, and matrix metalloproteinase-1. Concurrently, it effectively suppressed the protein expression of critical cell cycle arrest markers, diminishing p16 protein levels by 57.3% (P=0.000 4) and p21 protein levels by 27.2% (P=0.000 7). In the nematode Caenorhabditis elegans animal model, dimethylglycine significantly extended the mean lifespan from 20.402 d to an impressive 23.066 d (P<0.000 1) and notably enhanced overall survival rates under severe heat stress environmental conditions (P=0.017). Furthermore, systemic dimethylglycine intervention significantly mitigated age-related physiological decline by decreasing bodily lipofuscin accumulation (P<0.000 1), significantly reducing senescence-associated beta-galactosidase activity, lowering systemic reactive oxygen species fluorescence (P=0.008), and effectively alleviating overall fat accumulation (P<0.000 1). Mechanistically, extensive network pharmacology and Kyoto Encyclopedia of Genes and Genomes analyses strongly revealed that the potential targets of dimethylglycine are significantly enriched in fundamental drug metabolism and oxidative stress response pathways. Precision molecular docking simulations conclusively demonstrated that dimethylglycine forms highly stable structural interactions with the cytochrome P450 family 2 subfamily C member 9 protein, specifically highlighting the definitive formation of 5 stable hydrogen bonds involving serine 365, leucine 366, and serine 429 residues, as well as two critical salt bridge formations with arginine 97 and histidine 368 residues. It is additionally predicted to interact favorably with glutathione S-transferase family proteins. ConclusionDimethylglycine exhibits a profoundly significant and multifaceted anti-aging activity at both the cellular and entire living animal levels. By powerfully alleviating oxidative stress, heavily suppressing the core p16 and p21-dependent cellular senescence signaling pathways, and substantially mitigating the detrimental senescence-associated secretory phenotype, dimethylglycine effectively delays fundamental cellular senescence processes and drastically extends whole-organism lifespan. The biological mechanisms driving these robust protective effects are highly likely closely associated with its direct stable interactions with crucial metabolic and detoxifying enzyme systems, such as cytochrome P450 family 2 subfamily C member 9 and glutathione S-transferase family proteins, thereby systemically improving metabolic dysregulation and restoring critical redox homeostasis. This comprehensive study provides highly solid experimental evidence supporting dimethylglycine as a highly potent and safe potential anti-aging intervention agent, while simultaneously offering a clear molecular mechanistic explanation for the previously documented high abundance of dimethylglycine observed within exceptionally long-lived human populations.

Ferroptosis is a form of cell death that occurs when there is an excess of reactive oxygen species(ROS),lipid peroxidation,and iron accumulation.The precise regulation of metabolic pathways,including iron,lipid,and amino acid metabolism,is crucial for cell survival.This type of cell death,which is associated with oxidative stress,is controlled by a complex network of signaling molecules and pathways.It is also implicated in various respiratory diseases such as asthma,chronic obstructive pulmonary disease(COPD),acute lung injury(ALI),lung cancer,pulmonary fibrosis(PF),and the coronavirus disease 2019(COVID-19).To combat drug resistance,it is important to identify appropriate biological markers and treatment targets,as well as intervene in respiratory disorders to either induce or prevent ferroptosis.The focus is on the role of ferroptosis in the development of respiratory diseases and the potential of targeting ferroptosis for prevention and treatment.The review also explores the interaction between immune cell ferroptosis and inflammatory mediators in respiratory diseases,aiming to provide more effective strategies for managing cellular ferroptosis and respiratory disorders.

OBJECTIVE: To investigate the clinical characteristics and genetic etiology of a child with Cortical dysplasia, complex, with other brain malformations 4 (CDCBM4) and epilepsy due to a TUBG1 gene variant. METHODS: A child diagnosed with CDCBM4 and epilepsy at the Children's Medical Center of the Affiliated Hospital of Guangdong Medical University in May 2024 was selected as the study subject. Clinical data were retrospectively analyzed. Peripheral venous blood samples were collected from the child and her parents for genomic DNA extraction. Trio-based whole-exome sequencing (WES) was performed, and candidate variants were validated by Sanger sequencing. According to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG), candidate variants were classified for pathogenicity. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Guangdong Medical University (Ethics No.: PJ2021-097). RESULTS: The child, a 4-month-old female infant, had no special facial features, normal limb muscle strength, and increased muscle tone of infantile onset, with generalized tonic-clonic seizures as the main manifestation. During seizures, she exhibited head retroflexion, tightly closed eyes, and tonic convulsions of the limbs, occurring approximately 2-3 times per day. Electroencephalogram suggested bilateral anterior predominant medium-to-high amplitude 7-8 Hz mixed rhythm discharges. Head MRI revealed ventricular system dilatation and pachygyria. Trio-WES results indicated that the child has harbored a TUBG1 gene variant of c.776C>T (p.Ser259Leu). Sanger sequencing verification showed that neither of her parents had carried the same variant, confirming it as de novo in origin. According to the ACMG guidelines, the variant was rated as pathogenic (PS2+PS3+PM2_Supporting+PP3). Combining the child's clinical phenotype, the child was diagnosed as CDCBM4 with epilepsy. CONCLUSION Children with CDCBM4 and epilepsy due to TUBG1 gene variants may show pachygyria or agyria and commonly present with intellectual and motor developmental delays and seizure disorders of variable severity. The heterozygous TUBG1 c.776C>T (p.Ser259Leu) variant is likely the genetic etiology underlying this disorder. The results of this study has expanded the mutational spectrum of the TUBG1 gene associated with CDCBM4 and epilepsy.
Humans ; Female ; Epilepsy/genetics* ; Malformations of Cortical Development/genetics* ; Infant ; Phenotype ; Exome Sequencing ; Microtubule-Associated Proteins/genetics*

OBJECTIVE: To explore the clinical phenotype and genetic etiology of a child with Ehlers-Danlos syndrome, spondylodysplastic type 2 (EDSSPD2). METHODS: A child who was admitted to the Children's Medical Center of the Affiliated Hospital of Guangdong Medical University in July 2024 for "delayed motor development for 1 and a half year" was selected as the study subject. Clinical data of the child was collected, including medical history, family history, and results of auxiliary examinations. Peripheral venous blood samples were collected from the child and his two brothers and both parents. Genomic DNA was extracted from the child and his family members and subjected to whole-exome sequencing (WES) and copy number variation (CNV) analysis. Sanger sequencing was used to verify the parental origin of the candidate variants. Multiple protein function prediction software tools, including SIFT, PolyPhen-2, and REVEL, were used to assess the impact of candidate variants on the protein function. Based on protein database information from UniProt, a two dimensional structural schematic of the target protein was generated. The pathogenicity of the variants was classified based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Relevant literature on the B3GALT6 gene variants leading to EDSSPD2 was retrieved from CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases. The procedures followed in this study were reviewed and approved by the Medical Ethics Committee of Affiliated Hospital of Guangdong Medical University (Ethics No.：PJ2021-097). RESULTS: The proband was a 2-year-old male with an onset in infancy. The main clinical manifestations included loose skin, scoliosis and kyphosis, generalized hypermobility of joints, and motor developmental delay. WES has revealed two compound heterozygous variants of the B3GALT6 gene (NM_080605.4): c.766C>T (p.Arg256Trp) and c.962G>A (p.Cys321Tyr). Sanger sequencing verification showed that the c.766C>T and c.962G>A variants were respectively derived from his phenotypically normal father and mother. Bioinformatics analysis showed that for the c.766C>T (p.Arg256Trp) variant, the Arg256 site is located within the galactosyltransferase catalytic domain (GalT domain) of the β3GalT6 protein. According to the ACMG guidelines, the c.766C>T variant was classified as a likely pathogenic (PS3+PM2_supporting+PM3+PP3), and the c.962G>A was classified as a variant of unknown significance (PM2_Supporting+PM3+PP3). By following the pre-set literature retrieval strategy, a total of 12 articles related to B3GALT6 gene variants were identified (11 English and 1 Chinese), which involved a total of 71 patients. Among these, 4 reports (involving 20 patients) involved B3GALT6 gene variants leading to EDSSPD2. Among the 18 live-born EDSSPD2 patients (including the proband in this study), common clinical manifestations have included scoliosis (88.9%, 16/18), generalized hypotonia (83.3%, 15/18), and soft and lax skin (66.7%, 12/18). Some patients already showed skeletal abnormalities on prenatal ultrasound scan (22.2%, 4/18), while a few presented with cervical instability (16.7%, 3/18). One child had deceased at 18 months of age due to hypoxia caused by tracheomalacia and tracheal compression due to scoliosis. Among the 23 reported EDSSPD2 related B3GALT6 variant sites, missense variants were the most common (78.3%, 18/23), followed by nonsense variants (21.7%, 5/23). CONCLUSION Above finding has enriched the clinical and mutational spectra of EDSSPD2. Early genetic testing has important clinical value for the diagnosis, differential diagnosis, and genetic counseling of this disease.
Humans ; Male ; Ehlers-Danlos Syndrome/genetics* ; Pedigree ; N-Acetylgalactosaminyltransferases/genetics* ; Asian People/genetics* ; DNA Copy Number Variations ; Exome Sequencing ; Female ; Child ; Child, Preschool ; Phenotype ; Mutation ; China ; East Asian People ; Galactosyltransferases

ObjectiveTo analyze the diversity and structural characteristics of microbial communities in the rhizosphere soil of healthy and diseased Andrographis paniculata and to explore the interactions of soil， plants， and microorganisms during the occurrence of diseases. MethodsThe physicochemical properties of the rhizosphere soil of healthy and diseased A.paniculata were determined， and the composition and diversity of bacterial and fungal communities in the rhizosphere soil were analyzed by Illumina high-throughput sequencing. Furthermore， the correlations between physicochemical properties and microorganisms of the rhizosphere soil were explored. ResultsThe content of total nitrogen， total potassium， and available potassium in the rhizosphere soil of diseased A. paniculata was significantly higher than that of healthy A. paniculata. The alpha diversity and richness （operational taxonomic units） of bacterial and fungal communities in the rhizosphere soil of diseased plants decreased compared with those of healthy plants. The microbial communities in the rhizosphere soil of healthy and diseased A. paniculata showed similar composition but different relative abundance. At the phylum level， the relative abundance of Proteobacteria and Chytridiomycota significantly increased， while that of Bacteroidota significantly decreased in the rhizosphere soil of diseased plants. At the genus level， the relative abundance of Sphingomonas， Pseudomonas， and Bryobacter significantly increased， while that of RB41 showed a significant decrease in the rhizosphere soil of diseased plants. The correlation analysis showed different correlations of microbial phyla with physicochemical properties of the rhizosphere soil between healthy and diseased plants. Organic matter， alkaline nitrogen， available phosphorus， and total potassium were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of healthy plants， while available nitrogen and total phosphorus were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of diseased plants. ConclusionThere are differences in the diversity and richness of microbial communities in the rhizosphere soil of healthy and diseased A. paniculata. The physicochemical properties of soil may have an impact on the rhizosphere microorganisms of A. paniculata， leading to the development of diseases. The results provide a scientific basis for the prevention and ecological management of A. paniculata diseases.

ObjectiveTo analyze the diversity and structural characteristics of microbial communities in the rhizosphere soil of healthy and diseased Andrographis paniculata and to explore the interactions of soil， plants， and microorganisms during the occurrence of diseases. MethodsThe physicochemical properties of the rhizosphere soil of healthy and diseased A.paniculata were determined， and the composition and diversity of bacterial and fungal communities in the rhizosphere soil were analyzed by Illumina high-throughput sequencing. Furthermore， the correlations between physicochemical properties and microorganisms of the rhizosphere soil were explored. ResultsThe content of total nitrogen， total potassium， and available potassium in the rhizosphere soil of diseased A. paniculata was significantly higher than that of healthy A. paniculata. The alpha diversity and richness （operational taxonomic units） of bacterial and fungal communities in the rhizosphere soil of diseased plants decreased compared with those of healthy plants. The microbial communities in the rhizosphere soil of healthy and diseased A. paniculata showed similar composition but different relative abundance. At the phylum level， the relative abundance of Proteobacteria and Chytridiomycota significantly increased， while that of Bacteroidota significantly decreased in the rhizosphere soil of diseased plants. At the genus level， the relative abundance of Sphingomonas， Pseudomonas， and Bryobacter significantly increased， while that of RB41 showed a significant decrease in the rhizosphere soil of diseased plants. The correlation analysis showed different correlations of microbial phyla with physicochemical properties of the rhizosphere soil between healthy and diseased plants. Organic matter， alkaline nitrogen， available phosphorus， and total potassium were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of healthy plants， while available nitrogen and total phosphorus were correlated with the relative abundance of some dominant bacterial and fungal phyla in the rhizosphere soil of diseased plants. ConclusionThere are differences in the diversity and richness of microbial communities in the rhizosphere soil of healthy and diseased A. paniculata. The physicochemical properties of soil may have an impact on the rhizosphere microorganisms of A. paniculata， leading to the development of diseases. The results provide a scientific basis for the prevention and ecological management of A. paniculata diseases.

Ulcerative colitis(UC) is a recurrent, chronic, nonspecific inflammatory bowel disease. The longer the course of the disease, the higher the risk of cancerization. In recent years, the incidence and mortality rates of colon cancer in China have been increasing year by year, seriously threatening the life and health of patients. Therefore, studying the mechanism of "inflammation cancer transformation" in UC and conducting early intervention is crucial. The "Kenang" theory is an important component of traditional Chinese medicine(TCM) theory of phlegm and blood stasis. It is based on the coexistence of phlegm and blood stasis in the body and deeply explores the pathogenic syndromes and characteristics of phlegm and blood stasis. Kenang is a pathological product formed when long-term Qi stagnation leads to the internal formation of phlegm and blood stasis, which is hidden deep within the body. It is characterized by being hidden, progressive, and difficult to treat. The etiology and pathogenesis of "inflammation cancer transformation" in UC are consistent with the connotation of the "Kenang" theory. The internal condition for the development of UC "inflammation cancer transformation" is the deficiency of healthy Qi, with Qi stagnation being the key pathological mechanism. Phlegm and blood stasis are the main pathogenic factors. Phlegm and blood stasis accumulate in the body over time and can produce cancer toxins. Due to the depletion of healthy Qi and a weakened constitution, the body is unable to limit the proliferation and invasion of cancer toxins, eventually leading to cancer transformation in UC. In clinical treatment, the focus should be on removing phlegm and blood stasis, with syndrome differentiation and treatment based on three basic principles: supporting healthy Qi to strengthen the body's foundation, resolving phlegm and blood stasis to break up the Kenang, and regulating Qi and blood to smooth the flow of energy and resolve stagnation. This approach helps to dismantle the Kenang, delay, block, or even reverse the cancerization process of UC, reduce the risk of "inflammation cancer transformation", improve the patient's quality of life, and provide new perspectives and strategies for early intervention in the development of colon cancer.
Humans ; Colitis, Ulcerative/immunology* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use* ; Cell Transformation, Neoplastic

Fusion variations of neurotrophic receptor tyrosine kinase (NTRK) are oncogenic drivers in various solid tumors such as breast cancer, salivary gland carcinoma, infant fibrosarcoma, etc. Gene rearrangements involving NTRK1/2/3 lead to constitutive activation of the tropomyosin receptor kinase (TRK) domain, and the expressed fusion proteins drive tumor growth and survival. NTRK fusions are estimated to occur at a frequency of approximately 0.1% to 1% in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations are prevalent in NSCLC, but the frequency of EGFR G719A mutation is relatively low (about 2%), and EGFR mutations are typically mutually exclusive with NTRK fusion variants. The study presented the first documented case of lung adenocarcinoma harboring both EGFR G719A mutation and LMNA-NTRK1 fusion. A review of the literature was conducted to elucidate the role of NTRK fusion mutations in NSCLC and their relationship with EGFR mutations, aiming to enhance the understanding of NTRK fusion mutations in NSCLC.
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Humans ; Adenocarcinoma/genetics* ; Adenocarcinoma of Lung ; ErbB Receptors/genetics* ; Lamin Type A/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Oncogene Proteins, Fusion/genetics* ; Receptor, trkA/metabolism*

Ovarian tumor (OT) is the most lethal form of gynecologic malignancy, with minimal improvements in patient outcomes over the past several decades. Metastasis is the leading cause of ovarian cancer-related deaths, yet the underlying mechanisms remain poorly understood. Psychological stress is known to activate the glucocorticoid receptor (NR3C1), a factor associated with poor prognosis in OT patients. However, the precise mechanisms linking NR3C1 signaling and metastasis have yet to be fully elucidated. In this study, we demonstrate that chronic restraint stress accelerates epithelial-mesenchymal transition (EMT) and metastasis in OT through an NR3C1-dependent mechanism involving nuclear protein 1 (NUPR1). Mechanistically, NR3C1 directly regulates the transcription of NUPR1, which in turn increases the expression of snail family transcriptional repressor 2 (SNAI2), a key driver of EMT. Clinically, elevated NR3C1 positively correlates with NUPR1 expression in OT patients, and both are positively associated with poorer prognosis. Overall, our study identified the NR3C1/NUPR1 axis as a critical regulatory pathway in psychological stress-induced OT metastasis, suggesting a potential therapeutic target for intervention in OT metastasis.