Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila (A. muc); however, whether it can alleviate ferroptosis remains unclear. The current study indicates A. muc intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1α axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon A. muc treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that A. muc mediated antiferroptotic effects in the absence of other microbes. These data indicated that A. muc exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid (PUFA) synthesis.

Ferroptosis of chondrocytes is a significant contributor to osteoarthritis (OA), for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis. Here, we screen for anti-ferroptotic drugs in Food and Drug Administration (FDA)-approved drug library via a high-throughput manner in chondrocytes. We identified a group of FDA-approved anti-ferroptotic drugs, among which vitamin K showed the most powerful protective effect. Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix (ECM) degradation in chondrocytes. Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus (DMM) mouse model. Mechanistically, transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6 (Gas6). Furthermore, exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase (AXL)/phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) axis. Together, we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis, indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

Sini Decoction (SNT) is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold. However, elucidating the mechanism of action of SNT remains challenging due to its complex multiple components. This study utilized a synergistic approach combining two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE)-based drug affinity responsive target stability (DARTS) with label-free quantitative proteomics techniques to identify the direct and indirect protein targets of SNT in myocardial infarction. The analysis identified 590 proteins, with 30 proteins showing significant upregulation and 51 proteins showing downregulation when comparing the SNT group with the model group. Through the integration of 2D-DIGE DARTS with proteomics data and pharmacological assessments, the findings indicate that protein disulfide-isomerase A3 (PDIA3) may serve as a potential protein target through which SNT provides protective effects on myocardial cells during myocardial infarction.
Myocardial Infarction/genetics* ; Proteomics/methods* ; Drugs, Chinese Herbal/chemistry* ; Animals ; Protein Disulfide-Isomerases/genetics* ; Male ; Two-Dimensional Difference Gel Electrophoresis/methods* ; Humans ; Rats ; Rats, Sprague-Dawley ; Electrophoresis, Gel, Two-Dimensional

Objective:To investigate factors influencing frequent episodes (≥ 4 episodes within 1 year) in children with moderate-to-severe atopic dermatitis (AD) in China.Methods:A national multicenter cross-sectional study was conducted. Patients under the age of 18 years diagnosed with moderate-to-severe AD were enrolled at dermatology clinics in 18 medical institutions across 12 provinces and municipalities in China between June 12 and August 8, 2023. At the time of the visit, their guardians completed a structured questionnaire covering demographic characteristics, clinical features of AD, personal and family history, factors associated with frequent episodes of moderate-to-severe AD, compliance with treatment, and disease awareness. Statistical analyses included t tests, one-way analysis of variance, rank-sum tests, and chi-square tests, with multiple-response analysis applied for multiple-choice questions. Results:A total of 965 valid questionnaires were collected, and 965 children with moderate-to-severe AD were included. Among them, there were 531 males and 434 females, 678 (70.3%) were aged 2 - < 12 years, 837 (86.7%) were from urban areas, the age at onset was 2.47 ± 3.03 years, and the median frequency of AD episodes in the past year was 4 times. These children were divided into 2 groups based on the median episode frequency: < 4-episode group (439 cases, 45.5%) and ≥ 4-episode group (526 cases, 54.5%). Compared with the < 4-episode group, children in the ≥ 4-episode group showed younger ages at onset (2.22 ± 2.98 years vs. 2.76 ± 3.06 years, P = 0.006) and higher proportions of patients with comorbid allergic diseases in both the children themselves (82.9% [436/526] vs. 69.7% [306/439], χ2 = 23.42, P < 0.001) and their relatives (66.0% [347/526] vs. 57.4% [252/439], χ2 = 7.46, P = 0.006). Children in the ≥ 4- episode group also had higher monthly usage of moisturizers (150 [30, 300] g vs. 60 [6, 200] g) and daily frequency of moisturizer use, greater disease awareness, but more severe fear of medication use (all P < 0.05). The region and the human development index level were both significantly associated with the episode frequency (both P < 0.001), with the highest proportion of children from South China in the ≥ 4- episode group (36.3%, 191/526). Children in the ≥ 4-episode group also had a longer duration of topical glucocorticoid use than those in the < 4-episode group ( Z = -2.21, P = 0.027). External triggers associated with AD episodes mainly included heat exposure (50.36%, 486/965), hot water bathing (40.73%, 393/965), seafood (23.52%, 227/965), and dust mites (33.37%, 322/965) . Conclusion:In children with moderate-to-severe AD in China, factors influencing frequent episodes may include residence in southern or economically developed regions, earlier age at onset, having a personal or family history of allergic diseases, and fear of medication use.

Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in Food and Drug Administration(FDA)-approved drug library via a high-throughput manner in chondrocytes.We identified a group of FDA-approved anti-ferroptotic drugs,among which vitamin K showed the most powerful protective effect.Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix(ECM)degradation in chondrocytes.Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus(DMM)mouse model.Mechanistically,transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6(Gas6).Furthermore,exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase(AXL)/phosphatidylinositol 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)axis.Together,we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis,indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

Objective:To construct a Harvard cancer index-based risk predictive model for perioperative venous thromboembolism (VTE) in elderly patients with femoral neck fracture and assess its predictive effectiveness.Methods:A retrospective cohort study was conducted to analyze the clinical data of 610 elderly patients with femoral neck fracture admitted to Peking Union Medical College Hospital between January 2013 and December 2022, including 193 males and 417 females, aged 60-99 years [(77.3±9.0)years]. The patients were divided into VTE group ( n=125) and non-VTE group ( n=485) according to occurrence of VTE during the perioperative period. The two groups were compared in terms of gender, age, body mass index, smoking status, alcohol consumption, time from fracture to admission, surgical waiting time, comorbidities, perioperative electrolyte disorders, past or present history of malignancy, past history of deep vein thrombosis (DVT) or pulmonary embolism (PE), and preoperative use of oral anticoagulants. Univariate analysis and multivariable stepwise Logistic regression analysis were conducted to evaluate and identify independent risk factors for perioperative VTE in elderly patients with femoral neck fracture. A perioperative VTE risk predictive model for elderly patients with femoral neck fracture was constructed using the Harvard cancer index: (1) assigning a risk score to each variable according to the corresponding conversion criteria of the Harvard cancer index and risk score, based on the magnitude of their ORs; (2) determining the exposure rate of each risk factor based on the population distribution observed in this study; (3) calculating the average population risk score; (4) computing the individual VTE risk score; (5) deriving the ratio (X) of each individual ′s VTE risk score to the population average. Based on the Harvard cancer index classification criteria for disease risk levels, individual VTE risk categories were determined. The predictive performance of the risk stratification was evaluated by comparing the incidence of VTE across different risk levels. The predictive performance of the model was evaluated based on sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC). The calibration of the model was assessed using the Hosmer-Lemeshow (H-L) test and internal validation was performed using the bootstrap resampling method with 1000 iterations. Results:Univariate analysis showed that gender, age, time from fracture to admission, surgical waiting time, previous cerebral infarction, stroke within the past month, Alzheimer′s disease, primary Parkinson′s syndrome, hysterectomy with bilateral adnexectomy, perioperative electrolyte disorders, history of DVT or PE, and preoperative use of oral anticoagulant drug were moderately associated with the occurrence of VTE in elderly patients with femoral neck fracture ( P<0.10). Multivariable stepwise logistic regression analysis demonstrated that female gender ( OR=2.26, 95% CI 1.34, 3.80, P<0.01), time from fracture to admission>1 day ( OR=3.70, 95% CI 2.24, 6.12, P<0.01), surgical waiting time>70 hours ( OR=2.06, 95% CI 1.29, 3.30, P<0.01), previous cerebral infarction ( OR=3.78, 95% CI 1.04, 13.76, P<0.05), stroke within the past month ( OR=11.57, 95% CI 1.21, 110.44, P<0.05), Alzheimer′s disease ( OR=3.26, 95% CI 1.12, 9.49, P<0.05), primary Parkinson ′s syndrome ( OR=3.47, 95% CI 1.22, 9.85, P<0.05), previous hysterectomy with bilateral adnexectomy ( OR=4.75, 95% CI 2.09, 10.80, P<0.01), perioperative electrolyte disorders ( OR=2.73, 95% CI 1.39, 5.35, P<0.01), and preoperative oral anticoagulant use ( OR=3.86, 95% CI 1.18, 12.67, P<0.05) were significantly associated with the occurrence of perioperative VTE in elderly patients with femoral neck fracture. Based on the above 10 risk factors, a perioperative VTE risk predictive model for elderly patients with femoral neck fracture was constructed with the Harvard cancer index. The formula was as follows: X=[10×(female gender)+25×(time from fracture to admission>1 day)+10×(surgical waiting time>70 hours)+25×(previous cerebral infarction)+50×(stroke within the past month)+25×(Alzheimer′s disease)+25×(primary Parkinson′s disease)+25×(previous hysterectomy with bilateral adnexectomy)+10×(perioperative electrolyte disorders)+25×(preoperative use of oral anticoagulant drug)]/33. Individualized VTE risk was classified into five levels: very low, low, moderate, high, and very high, with corresponding VTE rates of 4.8%, 11.8%, 14.9%, 32.3%, and 73.5%, respectively ( χ2=87.71, P<0.01). The VTE risk predictive model demonstrated an AUC of 0.74 (95% CI 0.69, 0.79, P<0.01), with a sensitivity of 63.2% and specificity of 74.8%. The H-L goodness-of-fit test indicated satisfactory model calibration ( P>0.05). The internal validation with the bootstrap method confirmed that the AUC remained 0.74. Conclusions:Female gender, time from fracture to admission>1 day, surgical waiting time>70 hours, previous cerebral infarction, stroke within the past month, Alzheimer′s disease, primary Parkinson′s syndrome, hysterectomy with bilateral adnexectomy, perioperative electrolyte disorders, and preoperative use of oral anticoagulant drug are independent risk factors for perioperative VTE in elderly patients with femoral neck fracture. Based on these factors, the perioperative VTE risk predictive model constructed using the Harvard cancer index demonstrates good clinical predictive value. Individualized VTE risk stratification can effectively identify high-, intermediate-, and low-risk populations, providing a valuable reference for tailoring anticoagulant prophylaxis strategies and enhancing postoperative surveillance.

Objective:To compare the results of plasma samples and histological/cytological samples for detection of lung cancer driver gene by next-generation sequencing (NGS), to provide reference for sampling selection of clinical patients.Methods:A retrospective analysis was performed on 220 patients with lung cancer who were admitted to Quanzhou First Hospital in Fujian Province from May 2017 to May 2024, and NGS detection of lung cancer driver gene was performed on both plasma samples and histological/cytological samples. Histological specimens included biopsy or surgical resection of lung cancer, cervical lymph nodes and pleural metastases; the cytological specimen was pleural fluid cell wax block. Specimens were divided into plasma group (experimental group) and matched histological and cytological group (control group). Eight gene variants recommended by the guidelines were EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600 mutation, RET rearrangement, MET exon 14 jump mutation, KRAS mutation, and NTRK1/2/3 rearrangement. The detection results of the two groups of specimens were compared and analyzed.Results:Among the 220 cases, 183 were adenocarcinoma, 23 were squamous cell carcinoma and 14 were non-small cell lung cancer. There were 4 cases in stage Ⅰ, 3 cases in stage Ⅱ, 24 cases in stage Ⅲ, and 189 cases in stage Ⅳ. In the plasma group, 120 cases were positive, the detection rate was 54.5%; There were 152 positive cases in the control group, the detection rate was 69.1%; the detection rate in the plasma group was lower than that in the control group ( χ2=6.12, P<0.05). The detection rate of plasma in patients with stage Ⅰ/Ⅱ/Ⅲ was 12.9% (4/31), which was significantly lower than that in stage Ⅳ (61.4%; χ2=22.10, P<0.05). In the early clinical stage (stage Ⅰ/Ⅱ) of 7 cases, 3 cases were positive in the control group, while all were negative in the plasma group. There were 24 stage Ⅲ cases, 8 were positive in the control group and 4 were positive in the plasma group. Among the positive cases in the control group, 34 were negative and 4 were not detected in the matched plasma group. In the plasma positive cases, there were 2 negative cases and 4 partial mutations were not detected in the matched control group. Among these 6 cases, 5 were treated patients, and the mean mutation abundance of corresponding plasma positive genes was 1.5%. There were 110 cases with the same positive result (the same mutation site) and 66 cases with the same negative result, with agreement rate of 80.0% (176/220). The sensitivity and specificity of the plasma group were 75.0% (114/152) and 91.7% (110/120), respectively. Conclusions:When NGS is used for lung cancer driver gene detection, the positive rate of plasma samples is lower than that of tissue/cytology samples, but the consistency rate with the latter can reach 80%, and the sensitivity is higher than 70%, which has a good clinical detection efficiency, especially for patients with non-small cell lung cancer stage Ⅳ.

Purpose: Cancer has become a significant major public health concern, making the discovery of new cancer markers or therapeutic targets exceptionally important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression has been observed in certain types of cancer. This project aims to investigate the function of TNFRSF12A in tumors and the underlying mechanisms. Materials and Methods: Various websites were utilized for conducting the bioinformatics analysis. Tumor cell lines with stable knockdown or overexpression of TNFRSF12A were established for cell phenotyping experiments and subcutaneous tumorigenesis in BALB/c mice. RNA-seq was employed to investigate the mechanism of TNFRSF12A. Results: TNFRSF12A was upregulated in the majority of cancers and associated with a poor prognosis. Knockdown TNFRSF12A hindered the colorectal cancer progression, while overexpression facilitated malignancy both in vitro and in vivo. TNFRSF12A overexpression led to increased nuclear factor кB (NF-κB) signaling and significant upregulation of baculoviral IAP repeat containing 3 (BIRC3), a transcription target of the NF-κB member RELA, and it was experimentally confirmed to be a critical downstream factor of TNFRSF12A. Therefore, we speculated the existence of a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer. Conclusion TNFRSF12A is upregulated in various cancer types and associated with a poor prognosis. In colorectal cancer, elevated TNFRSF12A expression promotes tumor growth, potentially through the TNFRSF12A/RELA/BIRC3 regulatory axis.

Purpose: Cancer has become a significant major public health concern, making the discovery of new cancer markers or therapeutic targets exceptionally important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression has been observed in certain types of cancer. This project aims to investigate the function of TNFRSF12A in tumors and the underlying mechanisms. Materials and Methods: Various websites were utilized for conducting the bioinformatics analysis. Tumor cell lines with stable knockdown or overexpression of TNFRSF12A were established for cell phenotyping experiments and subcutaneous tumorigenesis in BALB/c mice. RNA-seq was employed to investigate the mechanism of TNFRSF12A. Results: TNFRSF12A was upregulated in the majority of cancers and associated with a poor prognosis. Knockdown TNFRSF12A hindered the colorectal cancer progression, while overexpression facilitated malignancy both in vitro and in vivo. TNFRSF12A overexpression led to increased nuclear factor кB (NF-κB) signaling and significant upregulation of baculoviral IAP repeat containing 3 (BIRC3), a transcription target of the NF-κB member RELA, and it was experimentally confirmed to be a critical downstream factor of TNFRSF12A. Therefore, we speculated the existence of a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer. Conclusion TNFRSF12A is upregulated in various cancer types and associated with a poor prognosis. In colorectal cancer, elevated TNFRSF12A expression promotes tumor growth, potentially through the TNFRSF12A/RELA/BIRC3 regulatory axis.

Occupational chronic n-hexane poisoning incidents have been effectively curtailed in traditional printing and footwear industries, but its hazards are emerging in new industries. In recent years, two cluster incidents involving eight patients with occupational chronic n-hexane poisoning had occurred in Longgang District, Shenzhen City. Unlike the cleaning processes of electronic components in the electronics industry, these two incidents occurred during cleaning operations of non-electronic products. The rapid on-site detection tubes indicated the presence of n-hexane in the organic solvents used at the work site, and subsequent analysis of volatile components of the organic solvents further confirmed the involvement of n-hexane. Although the n-hexane exposure concentration of short term in the workplace air samples were below its occupational exposure limit, all eight cases were diagnosed as occupational chronic n-hexane poisoning, based on occupational exposure history, clinical manifestations, field investigations, and laboratory test results. These two poisoning incidents highlight that in air-conditioned or enclosed workshops with substandard occupational disease prevention facilities, the use of n-hexane containing organic solvents may result in occupational chronic n-hexane poisoning, even when the air monitoring results do not exceed the occupational exposure limits.