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.

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

Objective:To explore the efficacy and safety of endovascular intervention combined with preoperative laparoscopic exploration in the treatment of patients with acute mesenteric artery ischemia.Methods:This was a prospective cohort study (NCT04686981). The study enrolled 31 patients with acute mesenteric artery ischemia from Oct 1, 2020 to Oct 1, 2022. Among them, 26 patients (84%) were male, with a mean age of (67±13) years and a mean time to onset of (21±8) hours. All patients underwent laparoscopic exploration in the hybrid operating room. If the presence of intestinal necrosis or suspected necrosis was clearly determined, the patient would undergo open surgery (mesenteric artery embolization, intestinal resection and intestinal double stoma) as the treatment by gastrointestinal surgeon. If intestinal necrosis or suspected necrosis was not found by laparoscopy, the patient would undergo endovascular intervention by vascular surgeon. The primary observational endpoints of this study were the proportion of patients who were not dependent on total parenteral nutrition and all-cause mortality within 30 days after operation. The secondary observational endpoints were the rate of mesenteric vascular patency within 30 days and the proportion of interventions that were converted to open surgery.Results:Six patients underwent open surgery and 25 patients underwent endovascular intervention, including 13 cases of thrombus reduction alone, 3 cases of stent implantation during the same period after reduction, and 9 cases of stent implantation alone. Twenty-four patients (77%) were completely weaned from the TPN within 30 days after the procedure, and all-cause mortality was observed in 3 cases (9.7%). The patency rate of the mesenteric artery within 30 days after the procedure was 82.1%. The rate of conversion to open surgery after intervention was 16%.Conclusions:Endovascular intervention combined with preoperative laparoscopic exploration can clarify intestinal ischemia in acute mesenteric patients as early as possible, and individualized treatment strategies for each patient by multidisciplinary care team can potentially improve the prognosis of such patients.

Stroke is the second leading cause of death worldwide,and oxidative stress plays a crucial role.Celastrol exhibits strong antioxidant properties in several diseases;however,whether it can affect oxidation in cerebral ischemic-reperfusion injury(CIRI)remains unclear.This study aimed to determine whether celastrol could reduce oxidative damage during CIRI and to elucidate the underlying mechanisms.Here,we found that celastrol attenuated oxidative injury in CIRI by upregulating nuclear factor E2-related factor 2(Nrf2).Using alkynyl-tagged celastrol and liquid chromatography-tandem mass spectrometry,we showed that celastrol directly bound to neuronally expressed developmentally downregulated 4(Nedd4)and then released Nrf2 from Nedd4 in astrocytes.Nedd4 promoted the degradation of Nrf2 through K48-linked ubiquitination and thus contributed to astrocytic reactive oxygen species production in CIRI,which was significantly blocked by celastrol.Furthermore,by inhibiting oxidative stress and astrocyte activation,celastrol effectively rescued neurons from axon damage and apoptosis.Our study uncovered Nedd4 as a direct target of celastrol,and that celastrol exerts an antioxidative effect on as-trocytes by inhibiting the interaction between Nedd4 and Nrf2 and reducing Nrf2 degradation in CIRI.

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Objective:To analyze the effect of endovascular therapy (including balloon dilation, debulking and anti-restenosis technique) for below-the-ankle atherosclerotic lesions in chronic limb threatening ischemic patients.Methods:A retrospective analysis was performed on the clinical data of 465 patients (570 limbs) with below-the-ankle atherosclerosis who were consecutively admitted to Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University from April 2018 to December 2021. All patients received balloon dilatation below the ankle artery as basic treatment, including 67 patients in debulking subgroup, 82 patients in anti-restenosis subgroup and 11 patients in the triple therapy subgroup. The reocclusion rate, target lesion reintervention rate at 1, 3, 6 and 12 months after surgery were compared; The wound healing rate at 3 months, limb salvage rate at 6 and 12 months and mortality at 12 months in the Global Limb Anatomic Staging System (GLASS) grading groups P0, P1 and P2 were compared.Results:The technical success rate of this group was 76.0%(433 limbs/570 limbs). The follow-up rates of 6 and 12 months after operation were 85.4%(370 limbs/433 limbs) and 75.3%(326 limbs/433 limbs), respectively. The length of treated lesions was (3.6±1.3)cm; The reocclusion rates were 5.5%(23 limbs/420 limbs), 8.2%(33 limbs/403 limbs), 14.9%(55 limbs/370 limbs) and 23.6%(77 limbs/326 limbs) at 1, 3, 6 and 12 months after operation; The reintervention rate of target lesions in 6, 12 months was 7.6%(28 limbs/370 limbs) and 12.0%(39 limbs/326 limbs) respectively; The wound healing rate in groups P0, P1 and P2 within 3 months was 87.3%(192 limbs), 70.5%(62 limbs) and 10.5%(2 limbs) respectively ( P<0.001), the limb salvage rate in 6 months was 96.2%(200 limbs), 84.7%(127 limbs) and 33.3%(4 limbs) respectively ( P<0.001), and the limb salvage rate in 12 months was 78.7%(170 limbs), 54.5%(55 limbs) and 22.2%(2 limbs) respectively ( P<0.001). The mortality was 6.9%(32/465) 12 months after operation. Conclusions:Endovascular therapy below-the-ankle is feasible and has high technical success rate. The constitute integrity of pedal-plantar loop in limb- threatening phase is related to 3-month wound healing rate and limb salvage rate.

Chronic limb threatening ischemia (CLTI) is a severe condition of peripheral artery disease with high amputation and mortality. Pain and infection cause insufficient nutrient intake and protein loss in CLTI patients,while malnutrition is very prevalent in patients with CLTI and associated with poor prognosis.More and more studies have shown that malnutrition increases the risk of amputation and mortality,delays the time of wound healing.Moderate and severe malnutrition are independent risk factors for amputation and mortality in CLTI patients undergoing surgical or endovascular revascularization.Nutritional screening tools such as Geriatric nutritional risk index,Mini Nutritional Assessment and Controlling nutritional status can help to stratify patients with nutritional risk.Identification of patients with nutritional risk and nutritional intervention can improve the prognosis of CLTI patients.

The outbreak of coronavirus disease 2019 (COVID-19) was declared a global public health emergency on 31 January 2020. Emergency medicine procedures in Emergency Department should be optimized to cope with the current COVID-19 pandemic by providing subspecialty services, reducing the spread of nosocomial infections, and promoting its capabilities to handle emerging diseases. Thus, the Chinese Society of Emergency Medicine and Wuhan Society of Emergency Medicine drafted this consensus together to address concerns of medical staffs who work in Emergency Department. Based on in-depth review of COVID-19 diagnosis and treatment plans, literatures, as well as management approval, this consensus proposes recommendations for improving the rationalization and efficiency of emergency processes, reducing the risk of nosocomial infections, preventing hospital viral transmission, and ensuring patient safety.

Chronic limb threatening ischemia (CLTI) is a severe condition of peripheral artery disease with high amputation and mortality. Pain and infection cause insufficient nutrient intake and protein loss in CLTI patients,while malnutrition is very prevalent in patients with CLTI and associated with poor prognosis.More and more studies have shown that malnutrition increases the risk of amputation and mortality,delays the time of wound healing.Moderate and severe malnutrition are independent risk factors for amputation and mortality in CLTI patients undergoing surgical or endovascular revascularization.Nutritional screening tools such as Geriatric nutritional risk index,Mini Nutritional Assessment and Controlling nutritional status can help to stratify patients with nutritional risk.Identification of patients with nutritional risk and nutritional intervention can improve the prognosis of CLTI patients.

The error-related negativity (ERN) is the medical frontal lobe component of event-related potentials caused by the individual incorrect response. It is an important indicator that reflects the function of performance monitoring. This article reviewed the characteristics and influencing factors of ERN in patients with obsessive-compulsive disorder (OCD), and also discussed the relationship between ERN and the clinical symptoms of OCD, the changes of ERN during treatment, the underlying neurological basis, and the possibility of ERN as an endophenotype of the disorder, thereby providing a new perspective on understanding the pathological mechanisms of OCD.