Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

[摘 要] 目的：以MG-63球形细胞作为骨肉瘤干细胞（OSC）富集模型，探讨靶向细胞膜表面HSP90β的单抗2G1对其生物学特征的影响及其与Wnt信号相关蛋白变化的关系。方法：采用无血清悬浮培养人骨肉瘤MG-63细胞获得MG-63球形细胞。通过免疫荧光共定位和免疫共沉淀实验鉴定单克隆抗体2G1识别的靶抗原；采用流式细胞术检测MG-63亲本细胞和MG-63球形细胞膜表面HSP90β的表达水平；通过甲基纤维素成球实验、Transwell迁移和侵袭实验评价单抗2G1对MG-63球形细胞成球、迁移和侵袭能力的影响；采用裸鼠皮下移植瘤模型观察单抗2G1对MG-63球形细胞体内成瘤能力的影响；进一步结合转录组测序、京都基因与基因组百科全书（KEGG）通路富集分析及WB检测，分析单抗2G1处理后相关分子通路及干细胞特性、上皮-间充质转化（EMT）、Wnt/β-catenin信号通路相关蛋白表达变化。结果：免疫荧光共定位和免疫共沉淀结果显示，单抗2G1识别的靶抗原为HSP90β。流式细胞术结果显示，MG-63球形细胞膜表面HSP90β阳性表达细胞比例为（20.77 ± 1.29）%，显著高于MG-63亲本细胞的（2.87 ± 0.33）%（P < 0.001）。与对照组相比，单抗2G1处理后MG-63球形细胞成球数由82.67 ± 4.70降至42.67 ± 4.00，迁移细胞数由117.00 ± 5.57降至78.33 ± 5.03，侵袭细胞数由130.70 ± 5.03降至89.33 ± 5.03（均P < 0.001）。裸鼠移植瘤实验显示，单抗2G1组移植瘤生长受到抑制，瘤质量抑制率和瘤体积抑制率分别为（31.83 ± 16.36）%和（22.00 ± 15.48）%。转录组测序共筛选出698个差异表达基因，其中329个基因上调，369个基因下调；KEGG富集分析显示差异表达基因涉及Wnt信号通路。WB法检测结果显示，与对照组相比，单抗2G1组SOX2、OCT4、N-cadherin、p-β-catenin和c-Myc表达下调，E-cadherin表达上调（均P < 0.001）。结论：细胞膜表面HSP90β在MG-63球形细胞中高表达，靶向HSP90β的单抗2G1可抑制MG-63球形细胞的成球、迁移、侵袭及体内成瘤能力，并影响其干细胞标志物、EMT相关标志物及Wnt/β-catenin信号通路蛋白的表达水平，提示HSP90β可能参与调控MG-63球形细胞的OSC样特征，可作为骨肉瘤靶向治疗的潜在研究靶点。

Hemodynamics numerical simulation,a multidisciplinary research approach integrating fluid dynamics,clinical medicine,and computer simulation techniques,offers an objective and quantitative analysis of cardiovascular blood flow dynamics through calculating data such as flow rate,pressure,resistance,and wall stress.This review provides a comprehensive overview of the modeling methods and characteristics of numerical simulations within the cardiovascular system.Additionally,it also summarizes the research advancements and potential clinical applications of numerical simulations in the context of various cardiovascular diseases,including vascular aneurysms,aortic dissection,atherosclerosis,structural heart diseases,heart failure,ventricular assist devices,cardiogenic shock,and extracorporeal membrane oxygenation.The goal is to facilitate the deep integration of clinical medicine with engineering technologies,thereby fostering innovative solutions for the precise diagnosis and treatment of cardiovascular disease.

The triterpenoid saponins of Centella asiatica, including asiaticoside, madecassoside, asiatic acid, and madecassic acid, are pivotal bioactive compounds of the plant. These constituents exhibit a spectrum of pharmacological activities, such as antioxidant, antitumor, and antidepressant effects, promotion of wound healing, and enhancement of microcirculation. Owing to these therapeutic properties, C. asiatica is widely employed in pharmaceutical and cosmetic industries. However, the escalating global demand for its extracts has led to potential supply shortages, prompting researchers to use multiple strategies such as multi-omics, molecular biology, and synthetic biology to conduct extensive studies. These studies encompass the elucidation of the biosynthetic pathways of triterpenoid saponins in C. asiatica, metabolic regulation, the hormonal induction of secondary metabolite synthesis, and the application of biotechnological strategies for natural product production to increase the yield of secondary metabolites in C. asiatica, or to produce active components via microbial chassis, thus satisfying market demands and promoting the sustainable exploitation of wild C. asiatica resources. This article first introduced the triterpenoid saponins of C. asiatica and their biological activities, then summarized the latest research advancements in their biosynthetic pathways, metabolic regulation, and heterologous biosynthesis, and provided an outlook on future development directions, with the aim of providing reference for comprehensive resource development and biotechnological synthesis of active components from C. asiatica.
Centella/genetics* ; Triterpenes/chemistry* ; Biosynthetic Pathways ; Humans ; Drugs, Chinese Herbal/chemistry* ; Plant Extracts

OBJECTIVE: To investigate the clinical efficacy of thoracoscopic minimally invasive surgery with nickel-titanium shape memory alloy wrap bone plate versus rib periosteal internal fixation in patients with multiple rib fractures (MRF) and flail chest. METHODS: A retrospective analysis was performed on 100 patients with MRF and flail chest treated with thoracoscopic minimally invasive surgery and internal fixation with rib fracture preservation between January 2019 and December 2022, including 54 males and 46 females, aged from 20 to 65 years old, with an average age of (38.0±18.0)years old. The duration of the disease ranged from 8 to 21 days. According to the different surgical methods, the patients were divided into control group and study group, with 50 patients in each group. The control group consisted of 23 males and 27 females, with an average age of (38.35±18.05) years old, who underwent rib preservation periosteal internal fixation. In the study group, there were 31 males and 19 females, with an average age of (38.15±17.99) years old, treated with thoracoscopic nickel-titanium shape memory alloy circumferential bone plate. The pulmonary function indices, electrocardiographic monitoring indices, pain severity, levels of inflammatory factors, complications, rehabilitation indices, and therapeutic efficacy were compared between the two groups before and after treatment. RESULTS: All patients were followed up for 6 months. After 3 days of treatment, the heart rate of both groups was (102.43±13.74) beats per minute vs (86.26±8.06) beats per minute, respiratory rate (28.45±3.40) breaths per minute vs (22.05±2.85) breaths per minute, blood oxygen saturation (89.68±3.66)% vs (98.46±4.84)%, rest pain (3.5±0.5) points vs (2.6±0.6) points, movement pain (3.6±0.5) points vs (2.5±0.5) points, and these differences were statistically significant(P<0.05). The levels of Interleukin-6 (IL-6) (102.30±17.00) pg·ml^-1 vs (85.68±21.20) pg·ml^-1 and tumor necrosis factor-alpha (TNF-α)(33.44±4.85) pg·ml^-1 vs (18.14±4.28) pg·ml^-1 in both groups exhibited an increase post-treatment, while the C-reactive protein (CRP) (75.51±10.54) mg·L^-1 vs (60.75±9.84) mg·L^-1 demonstrated a decrease compared to pre-treatment levels. Furthermore, the study group displayed significantly lower levels than the control group (P<0.05). After 10 days of treatment, the peak expiratory flow rate (3.31±0.52) L·s^-1 vs (5.69±0.74) L·s^-1, forced expiratory volume (1.46±0.29) L vs (2.06±0.38) L, and forced vital capacity (2.68±0.95) L vs (4.26±1.05) L of both groups exhibited significant improvements compared to pre-treatment levels. Moreover, the study group demonstrated significantly higher values than the control group (P<0.05). The incidence of postoperative complications in the study group was significantly lower compared to the control group (6 cases vs 14 cases, P<0.05). Additionally, the duration of bone callus formation(9.50±1.40) days and fracture healing (72.20±8.32) days in the study group was significantly shorter compared to the control group(11.35±2.15) days, (93.70±9.90) days (P<0.001). CONCLUSION Compared with traditional rib-preserving internal fixation, patients with MRF and flail chest treated with minimally invasive internal fixation with thoracoscopic nickel-titanium shape memory alloy surround bone plate have better therapeutic effect, because of less surgical trauma, less pain and inflammatory reaction, fewer postoperative pulmonary complications, faster and better recovery of lung function, and thus promote the recovery of patients.
Humans ; Male ; Female ; Middle Aged ; Adult ; Retrospective Studies ; Rib Fractures/surgery* ; Aged ; Minimally Invasive Surgical Procedures/methods* ; Flail Chest/surgery* ; Thoracoscopy/methods* ; Fracture Fixation, Internal/methods*

Objective:To examine the clinical features and genetic profiles of patients with thyroid peroxidase(TPO) gene mutations and provide diagnostic guidance for clinicians.Methods:A retrospective review of four patients with TPO mutations treated at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, from January 2014 to December 2023. Data on demographics, clinical manifestation, genotypes, treatment, and prognosis of these patients were analyzed.Results:Two males and two females, aged 13 to 27 years at diagnosis, presented with goiter as the initial symptom, with three cases menifesting during puberty. Laboratory findings showed mildly elevated or upper-limit-normal serum thyroid-stimulating hormone(TSH) levels, significantly increased free triiodothyronine/free thyroxine(FT 3/FT 4) ratios, and elevated thyroglobulin(TG) levels. Genetic testing revealed compound heterozygous pathogenic or likely pathogenic TPO mutations. Despite regular levothyroxine(L-T 4) therapy, goiter persisted. Three patients required thyroidectomy due to cosmetic or compressive symptoms, with pathology showing follicular hyperplasia. Conclusion:TPO mutations are characterized by adolescent-onset goiter, elevated FT 3/FT 4 ratios, and normal to high TSH. Genetic testing confirms the diagnosis. L-T 4 offers limited improvement, and surgery is often needed.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

AIM To investigate the protective effect of Sanfeng Tongqiao Dropping Pills against house dust mite(HDM)-induced allergic asthma in mice.METHODS Compared to the intact BALB/c mice in the blank control group,the BALB/c mice randomly assigned into the model group,the dexamethasone group(0.67 mg/kg),and the low-dose,medium-dose,and high-dose Sanfeng Tongqiao Dropping Pills groups(15,30 and 60 mg/kg),were induced into acute allergic asthma models via weekly intraperitoneal sensitization with 0.1 mL HDM solution(0.5 mg/mL)for three weeks followed by three consecutive daily intranasal challenges with 10 μL HDM solution(2.5 mg/mL)starting in the third week.The drug administered continuously 7 days after the last excitation.The mice had their airway reactive Penh value detected,their pulmonary pathological changes observed by HE staining,their blood eosinophils(EOS)counted,their Th2 cytokines in lung tissue and serum IgE levels detected by ELISA,and their number of peripheral blood mononuclear cells(PBMC)and pulmonary Th2 cells detected by flow cytometry.Chronic allergic asthma was induced in grouped BALB/c mice through repeated intranasal challenges with 10 μL HDM solution(2.5 mg/mL)administered five times weekly for five consecutive weeks.Drug treatment continued for 14 days following the final challenge.After the final treatment,the mice had their pulmonary pathological changes observed by HE staining,and their levels of Th2 cytokines in B ALF and lung tissue and serum IgE detected by ELISA.RESULTS Compared to the blank control group,the acute allergic asthma model group exhibited increases in Penh value,EOS count and IgE level in serum,IL-4 and IL-5 levels in lung tissue(P＜0.01);obvious pulmonary inflammatory cells infiltration,and thickened airway wall;and increase in pulmonary number of Th2 cells(P＜0.01).Compared to the model group,the groups intervened with Sanfeng Tongqiao Dropping Pills demonstrated decreased Penh value,serum EOS count,IgE level and IL-5 level in lung tissue(P＜0.05,P＜0.01);reduced pulmonary inflammatory infiltration and alleviated airway wall thickening;and decreased number of pulmonary Th2 cells.Compared to the blank group,the chronic allergic asthma model group showed obvious pulmonary inflammatory infiltration and airway wall thickening;and increased EOS count and IgE level in serum,IL-4 and IL-13 in lung tissue and IL-14 in BALF(P＜0.05,P＜0.01).Compared to the model group,the groups intervened with either medium-dose or high-dose Sanfeng Tongqiao Dropping Pills demonstrated reduced pulmonary inflammatory infiltration;and decreased serum EOS count,IgE level,IL-13 in lung tissue and IL-14 in BALF(P＜0.05,P＜0.01).CONCLUSION Sanfeng Tongqiao Dropping Pills reduce Th2 cells in peripheral blood and lung tissue,suppress type 2 inflammation,and thereby alleviate allergic asthma.

AIM To investigate the protective effect of Sanfeng Tongqiao Dropping Pills against house dust mite(HDM)-induced allergic asthma in mice.METHODS Compared to the intact BALB/c mice in the blank control group,the BALB/c mice randomly assigned into the model group,the dexamethasone group(0.67 mg/kg),and the low-dose,medium-dose,and high-dose Sanfeng Tongqiao Dropping Pills groups(15,30 and 60 mg/kg),were induced into acute allergic asthma models via weekly intraperitoneal sensitization with 0.1 mL HDM solution(0.5 mg/mL)for three weeks followed by three consecutive daily intranasal challenges with 10 μL HDM solution(2.5 mg/mL)starting in the third week.The drug administered continuously 7 days after the last excitation.The mice had their airway reactive Penh value detected,their pulmonary pathological changes observed by HE staining,their blood eosinophils(EOS)counted,their Th2 cytokines in lung tissue and serum IgE levels detected by ELISA,and their number of peripheral blood mononuclear cells(PBMC)and pulmonary Th2 cells detected by flow cytometry.Chronic allergic asthma was induced in grouped BALB/c mice through repeated intranasal challenges with 10 μL HDM solution(2.5 mg/mL)administered five times weekly for five consecutive weeks.Drug treatment continued for 14 days following the final challenge.After the final treatment,the mice had their pulmonary pathological changes observed by HE staining,and their levels of Th2 cytokines in B ALF and lung tissue and serum IgE detected by ELISA.RESULTS Compared to the blank control group,the acute allergic asthma model group exhibited increases in Penh value,EOS count and IgE level in serum,IL-4 and IL-5 levels in lung tissue(P＜0.01);obvious pulmonary inflammatory cells infiltration,and thickened airway wall;and increase in pulmonary number of Th2 cells(P＜0.01).Compared to the model group,the groups intervened with Sanfeng Tongqiao Dropping Pills demonstrated decreased Penh value,serum EOS count,IgE level and IL-5 level in lung tissue(P＜0.05,P＜0.01);reduced pulmonary inflammatory infiltration and alleviated airway wall thickening;and decreased number of pulmonary Th2 cells.Compared to the blank group,the chronic allergic asthma model group showed obvious pulmonary inflammatory infiltration and airway wall thickening;and increased EOS count and IgE level in serum,IL-4 and IL-13 in lung tissue and IL-14 in BALF(P＜0.05,P＜0.01).Compared to the model group,the groups intervened with either medium-dose or high-dose Sanfeng Tongqiao Dropping Pills demonstrated reduced pulmonary inflammatory infiltration;and decreased serum EOS count,IgE level,IL-13 in lung tissue and IL-14 in BALF(P＜0.05,P＜0.01).CONCLUSION Sanfeng Tongqiao Dropping Pills reduce Th2 cells in peripheral blood and lung tissue,suppress type 2 inflammation,and thereby alleviate allergic asthma.