1.Discovery and proof-of-concept study of a novel highly selective sigma-1 receptor agonist for antipsychotic drug development.
Wanyu TANG ; Zhixue MA ; Bang LI ; Zhexiang YU ; Xiaobao ZHAO ; Huicui YANG ; Jian HU ; Sheng TIAN ; Linghan GU ; Jiaojiao CHEN ; Xing ZOU ; Qi WANG ; Fan CHEN ; Guangying LI ; Chaonan ZHENG ; Shuliu GAO ; Wenjing LIU ; Yue LI ; Wenhua ZHENG ; Mingmei WANG ; Na YE ; Xuechu ZHEN
Acta Pharmaceutica Sinica B 2025;15(10):5346-5365
Sigma-1 receptor (σ 1R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K i < 4 nmol/L) and selective σ 1R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ 1R in relation to σ 2R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ 1R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.
2.Utidelone induces apoptosis and autophagy in small cell lung cancer cells through the ROS/AMPK signaling pathway
Xiaoqian MU ; Chaonan YU ; Yanqiu ZHAO ; Xiufeng HU ; Hongbo WU
Chinese Journal of Oncology 2025;47(8):703-714
Objective:To investigate the effects and underlying molecular mechanisms of Utidelone (UTD1) in small cell lung cancer (SCLC).Methods:The study utilized small cell lung cancer H446 and H1048 cell lines along with animal models. Cell proliferation, cell cycle progression, apoptosis, autophagy, and related activities following UTD1 treatment were assessed using Cell Counting Kit-8 (CCK-8), flow cytometry, immunofluorescence staining, reactive oxygen species (ROS) generation assay, and Western blot analysis. The involvement of the ROS/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway was also examined. Data analysis was performed using GraphPad Prism version 8 software.Results:UTD1 inhibited the viability of H446 and H1048 cells in a dose- and time-dependent manner. The half inhibitory concentrations (IC 50) of UTD1 for H446 and H1048 cells were 0.675 and 0.439 μg/ml, respectively. The proportion of cells in the G 2/M phase for H446 and H1048 cells in the UTD1 group at 6 h, 12 h, and 24 h was [(53.86±4.54)%, (68.59±5.49)%, (60.89±3.26)%] and [(46.83±2.20)%, (60.67±3.44)%, (57.88±5.11)%], which were significantly higher than that in the control group, except for the proportion of H1048 cells at 6 h [(38.99±2.60)% vs. (40.73±2.50)%, P<0.05]. The apoptosis rates were [(23.57±0.12)%, (35.79±1.59)%, and (46.15±4.57)%] for H446 cells and [(23.05±2.70)%, (37.73±2.97)%, and (43.39±3.31)% for H1048 cells], all of which were significantly higher than those in the control group [(6.44±0.96)%, (6.31±0.75)%, respectively; all P<0.05]. The number of LC3 fluorescent spots was [(56±11), (69±8), and (66±8)] for H446 cells and [(39±7), (56±12), and (50±11)] for H1048 cells, both significantly higher than those in the control group [(13±6) and (12±5), respectively; both P<0.05]. The relative fluorescence intensity of ROS was 2.54±0.48, 2.85±0.68, and 5.03±0.72 for H446 cells and 2.26±0.51, 4.17±0.35, and 4.66±0.51 for H1048 cells, which were also significantly higher than those in the control group ( P<0.05). The expression levels of cyclin B1, cyclin A2, and P21 of H446 cells in the three time points were [(0.63±0.07, 0.33±0.05, 0.23±0.04), (0.68±0.08, 0.46±0.03, 0.27±0.06), and (0.64±0.03, 0.32±0.05, 0.22±0.03), respectively], all significantly lower compared to the control group ( P<0.05). The apoptosis rates of H446 and H1048 cells in the UTD1+Z-VAD-FMK group were (19.97±3.19)% and (17.68±3.14)%, both lower than those in the UTD1 group [(40.73±3.35)% and (39.82±2.45)%, respectively; all P<0.05]. The absorbance values of H446 and H1048 cells in the UTD1+3-MA group were significantly higher than those in the UTD1 group at 6h, 12h, and 24h (all P<0.05). The levels of p-AMPKα/AMPKα, LC3-II expression, and the percentage of apoptotic cells in the H446 and H1048 cells of the UTD1+NAC group were [(1.33±0.09, 1.33±0.11), (1.49±0.16, 1.55±0.05), (17.24±2.15)%, and (19.40±4.28)%], all of which were lower than those observed in the UTD1 group [(1.98±0.17, 2.23±0.23), (2.81±0.19, 2.49±0.38), (38.07±3.53)%, and (41.20±1.87)%, all P<0.05]. The number of LC3 fluorescence points and the percentage of apoptotic cells in the H446 and H1048 cells of the UTD1+si-AMPKα group [(24±5, 23±3), (18.35±1.15)%, and (19.15±3.46)%] were all lower than those in the UTD1+si-NC group [(46±6, 36±6), (39.34±1.77)%, and (39.50±2.15)%, all P<0.05]. The tumor inhibition rates in small cell lung cancer tumor-bearing nude mice for the 2.5 mg/kg UTD1 group and the 5 mg/kg UTD1 group were 46.43% and 58.33%, respectively. Furthermore, the proportions of apoptosis-positive cells and p-AMPKα-positive cells in the UTD1 group were significantly higher compared to the control group, while the levels of Ki-67 positivity were significantly reduced. Conclusion:UTD1 inhibits SCLC cell proliferation, induces G 2/M phase arrest, and promotes cell apoptosis and autophagy through the activation of the ROS/AMPK signaling pathway.
3.Clinical value of puncture biopsy in the diagnosis of hepatocellular carcinoma subtypes
Xueqin TIAN ; Jiapeng WU ; Lu LI ; Chuan PANG ; Chaonan CHEN ; Jie YU ; Ping LIANG
Chinese Journal of Hepatobiliary Surgery 2025;31(6):426-432
Objective:To investigate the clinical value of puncture biopsy for the diagnosis of vessels that encapsulate tumor clusters (VETC) and macrotrabecular-massive (MTM) subtypes of hepatocellular carcinoma (HCC).Methods:One hundred and eighty-four patients with HCC who underwent surgical resection at the Fifth Medical Centre of Chinses PLA General Hospital from November 2023 to July 2024 were prospectively collected, including 154 males and 30 females, aged (57.1±8.6) years. By simulating the clinical puncture procedure, puncture biopsy tissue specimens were obtained postoperatively from the patient's isolated tumors. The puncture biopsies and surgical resection specimens were stained with HE and CD34, and evaluated for VETC and MTM. Patients were divided into two groups based on the histopathological VETC results of surgically resected specimens: the VETC-positive group ( n=41) and the VETC-negative group ( n=143); and two groups based on the histopathological MTM results of surgically resected specimens: the MTM-positive group ( n=39) and the MTM-negative group ( n=145). Clinical data such as gender, age, tumor length, and alpha-fetoprotein (AFP) were recorded. Logistic regression analysis was performed to screen the risk factors of VETC and MTM. Evaluating the diagnostic efficacy of puncture biopsy for VETC and MTM. Results:The results of multivariable logistic analysis showed that puncture biopsy VETC-positive ( OR=63.97, 95% CI: 16.28-251.29), grade of M2 microvascular invasion ( OR=5.07, 95% CI: 1.31-19.59) and tumor length ≥5 cm ( OR=3.42, 95% CI: 1.11-10.52) were the risk factors for VETC-positive (all P<0.05); whereas the risk factors for MTM-positive were only puncture biopsy MTM-positive ( OR=34.78, 95% CI: 12.06-100.29, P<0.001). Puncture biopsy correctly diagnosed VETC subtype in 163 patients with a diagnostic accuracy of 0.89, sensitivity of 0.61, specificity of 0.97, positive predictive value (PPV) of 0.83, and negative predictive value (NPV) of 0.90; MTM subtype was correctly diagnosed in 164 patients with a diagnostic accuracy of 0.89, sensitivity of 0.72, specificity of 0.94, PPV of 0.76, and NPV of 0.93. Using the three indicators of puncture biopsy diagnosis, tumor length and AFP level as a combined indicator, the accuracy to diagnose VETC was 0.83, sensitivity was 0.71, specificity was 0.87, PPV was 0.60, and NPV was 0.91; and the combined indicator diagnosis of MTM had a diagnostic accuracy of 0.85, a sensitivity of 0.82, specificity of 0.86, PPV of 0.68 and NPV of 0.95. Conclusion:Puncture biopsy has high specificity and accuracy in the diagnosis of VETC and MTM subtypes, but the sensitivity is relatively limited, and the role of puncture combined with clinical factors in improving diagnostic efficacy is limited.
4.Characteristics of injury cases in Longhua District
CHEN Shaoyun ; CAO Sijing ; HUO Yongqi ; GU Chaonan ; YAN Xinfeng ; YU Chuanning
Journal of Preventive Medicine 2025;37(9):950-954,958
Objective:
To understand the characteristics of injury cases in Longhua District, Shenzhen City, Guangdong Province from 2021 to 2024, so as to provide the evidence for the development of injury prevention and control measures.
Methods:
The data of injury cases in the first visit due to injury in the sentinel hospitals of Longhua District from 2021 to 2024 were collected from the Shenzhen Injury Surveillance System. The time, cause, place, activity, intention, nature, position, severity, and outcome of injury were described.
Results:
From 2021 to 2024, a total of 167 524 injury cases were reported in Longhua District, with a male-to-female ratio of 1.89∶1. The incidence of injuries was higher in cases aged 30-<45 years (49 957 cases, 29.82%). Injuries mainly occurred from July to August (31 272 cases, 18.67%). The main cause of injury was falls (52 048 cases, 31.07%). Injuries mainly occurred at home (64 110 cases, 38.27%). Leisure activities were the main activities when injuries occurred (79 008 cases, 47.16%). Most of the injuries were unintentional (159 173 cases, 95.02%). The main type of injury was contusion/abrasion (71 900 cases, 42.92%). The main injury site was upper limb (64 247 cases, 38.35%). Most injuries were mild (131 369 cases, 78.42%). The main injury outcome was discharge after treatment, 160 882 cases (96.04%). The second cause of male injury was blunt force injury (30 140 cases, 27.49%), and the second cause of female injury was animal injury (14 648 cases, 25.31%). Fall was the leading cause of injury in people aged 0-<15 years and ≥65 years, and blunt force injury was the leading cause of injury in people aged 15-<65 years. The second place for male injuries was industrial and construction places (23 722 cases, 21.64%), and for female injuries was school/public places (9 644 cases, 16.66%). The first place for injuries in people aged 45-<65 years was in industrial and construction places. The proportions of fractures, moderate injuries, and hospitalizations increased with age (all P<0.05).
Conclusions
The main injury cases in Longhua District were males and people aged 30-<45 years. July and August were a period of high risk for injuries. People aged 0-<15 years and ≥65 years were the high-risk groups of falls. More attention should be paid to the fracture risk in the elderly.
5.Integrated multi-parameter monitoring for optimizing low-molecular-weight heparin treatment in intensive care unit patients: a clinical value assessment
Qin LI ; Liqin LING ; Xiaomei LI ; Chaonan LIU ; Xunbei HUANG ; Shuang WANG ; Zhiyu YU ; Jing ZHOU
Chinese Journal of Laboratory Medicine 2025;48(8):1008-1014
Objective:To explore the clinical value of multi-parameter combined monitoring in guiding low-molecular-weight heparin (LMWH) therapy for intensive care unit (ICU) patients.Methods:A retrospective case-control study was conducted. A total of 381 patients who received LMWH therapy with anti-Ⅹa activity monitoring in the ICU of West China Hospital, Sichuan University between January 31st, 2022, and November 30th, 2023, were enrolled in this study. The cohort comprised 264 males and 117 females, with the age of 58 (48, 71) years old. Clinical data and relevant laboratory parameters were collected, including anti-Ⅹa activity, antithrombin activity (AT), thrombin-antithrombin complex (TAT), plasmin-antiplasmin complex (PIC), conventional coagulation parameters such as activated partial thromboplastin time (APTT), and indicators of hepatic/renal impairment such as alanine aminotransferase (ALT) and creatinine( CREA). Patients were stratified into three groups based on thrombotic event: thrombosis-controlled, progressive thrombosis, and bleeding group. Single-factor and adjusted multifactorial Logistic regression analysis were used to identify independent predictors of anti-xa activity levels.Results:Among 381 patients, thrombosis was controlled in 213 (55.9%) patients, progressed in 81 (21.3%) patients , and bleeding events occurred in 87 (22.8%) patients. The patients whose anti-Ⅹa activity levels lay entirely within the target range(0.2-0.4 IU/ml): Only 35 (16.4%) cases in the thrombosis-controlled group, 16 (19.7%) cases in the progressive thrombosis group, and 16 (18.4%) in the bleeding group. No significant differences in anti-Ⅹ a levels activity among the three groups ( H=1.678, P=0.432). Both single-factor and adjusted multifactorial Logistic regression identified low AT activity as an independent risk factor for failure to achieve target anti-Ⅹ a activity levels (AT nadir, OR=1.031,95% CI 1.016-1.046, P<0.05). Compared with the progressive thrombosis and bleedinggroup, the thrombosis-controlled group exhibited significantly higher proportion of TAT values below the cut-off value ( H=8.519, P=0.014), and a higher proportion of TAT/PIC ratios below the cut-off ( H=15.56, P<0.001). Patients with bleeding demonstrated significantly lower AT activity ( H=14.968, P=0.001), prolonged APTT ( H=6.815, P=0.033), higher ALT ( H=13.774, P=0.001), and higher CREA ( H=14.068, P=0.001) compared with the thrombosis-controlled or progressive thrombosis group. Conclusion:Laboratory monitoring is required for low-molecular-weight heparin (LMWH) therapy in ICU patients. While anti-Ⅹa activity reflects the anticoagulant effect of LMWH, the utility of anti-Ⅹ a activity for predicting thrombotic or hemorrhagic risks in LMWH treated ICU patients is limited. Reductions in TAT levels and TAT/PIC ratios are associated with a lower risk of thrombotic progression. Furthermore, abnormalities in conventional coagulation tests and standard hepatic/renal function parameters occur more frequently in patients experiencing hemorrhagic events.
6.The Effects of Prone Position Ventilation in Patients Receiving Extracorporeal Membrane Oxygenation:a Meta-analysis
Lili LI ; Jing WU ; Junhui WANG ; Hangyan YE ; Chaonan WO ; Miaojie YU ; Fei LI ; Huiping YAO
Chinese Circulation Journal 2025;40(10):999-1005
Objectives:To analyze the effects of prone position ventilation in patients receiving extracorporeal membrane oxygenation(ECMO).Methods:A systematic search was conducted in databases including CNKI,Wanfang Data,China Biomedical Literature Database,PubMed,Embase,Cochrane Library,and Web of Science,from the inception of each database to October 2024,to identify studies on prone position ventilation for ECMO patients.Two researchers independently screened the literature,extracted data,and assessed the quality of the studies.Meta-analysis was performed using RevMan 5.4 software.Results:A total of 10 studies were included in this analysis,comprising 2 randomized controlled trials and 8 cohort studies.A total of 1 513 patients were included,674 were in the prone position ventilation group and 839 were in the supine position ventilation group.Analysis results of 6 studies showed that compared with supine position ventilation,prone position ventilation could increase the successful weaning rate of ECMO(OR=1.47,95%CI:1.07-2.01,P=0.02).Analysis results of 8 studies showed that compared with supine position ventilation,prone position ventilation could prolong the duration of ECMO treatment(mean difference[MD]=4.86 days,95%CI:0.95-8.77,P=0.01).Analysis results of 6 studies showed that the length of stay in the intensive care unit in the prone position ventilation group was significantly longer than that in the supine position ventilation group(MD=5.16 days,95%CI:1.08-9.25,P=0.01).Analysis results of 5 studies showed that the total length of hospital stay in the prone position ventilation group was significantly longer than that in the supine position ventilation group(MD=7.72 days,95%CI:2.10-13.34,P<0.01).Analysis results of 6 studies showed that compared with supine position ventilation,prone position ventilation could prolong the duration of mechanical ventilation(MD=6.06 days,95%CI:0.63-11.49,P=0.03).Prone position ventilation had no obvious advantage in improving patient survival rate.Conclusions:Prone position ventilation can improve the successful weaning rate from ECMO and prolong the duration of ECMO treatment as well as the duration of mechanical ventilation,but it has no significant impact on patient survival rate.Due to the generally small sample size in the studies,further research with larger sample sizes is needed to confirm the effective impact of prone position ventilation in patients receiving ECMO treatment.
7.The Effects of Prone Position Ventilation in Patients Receiving Extracorporeal Membrane Oxygenation:a Meta-analysis
Lili LI ; Jing WU ; Junhui WANG ; Hangyan YE ; Chaonan WO ; Miaojie YU ; Fei LI ; Huiping YAO
Chinese Circulation Journal 2025;40(10):999-1005
Objectives:To analyze the effects of prone position ventilation in patients receiving extracorporeal membrane oxygenation(ECMO).Methods:A systematic search was conducted in databases including CNKI,Wanfang Data,China Biomedical Literature Database,PubMed,Embase,Cochrane Library,and Web of Science,from the inception of each database to October 2024,to identify studies on prone position ventilation for ECMO patients.Two researchers independently screened the literature,extracted data,and assessed the quality of the studies.Meta-analysis was performed using RevMan 5.4 software.Results:A total of 10 studies were included in this analysis,comprising 2 randomized controlled trials and 8 cohort studies.A total of 1 513 patients were included,674 were in the prone position ventilation group and 839 were in the supine position ventilation group.Analysis results of 6 studies showed that compared with supine position ventilation,prone position ventilation could increase the successful weaning rate of ECMO(OR=1.47,95%CI:1.07-2.01,P=0.02).Analysis results of 8 studies showed that compared with supine position ventilation,prone position ventilation could prolong the duration of ECMO treatment(mean difference[MD]=4.86 days,95%CI:0.95-8.77,P=0.01).Analysis results of 6 studies showed that the length of stay in the intensive care unit in the prone position ventilation group was significantly longer than that in the supine position ventilation group(MD=5.16 days,95%CI:1.08-9.25,P=0.01).Analysis results of 5 studies showed that the total length of hospital stay in the prone position ventilation group was significantly longer than that in the supine position ventilation group(MD=7.72 days,95%CI:2.10-13.34,P<0.01).Analysis results of 6 studies showed that compared with supine position ventilation,prone position ventilation could prolong the duration of mechanical ventilation(MD=6.06 days,95%CI:0.63-11.49,P=0.03).Prone position ventilation had no obvious advantage in improving patient survival rate.Conclusions:Prone position ventilation can improve the successful weaning rate from ECMO and prolong the duration of ECMO treatment as well as the duration of mechanical ventilation,but it has no significant impact on patient survival rate.Due to the generally small sample size in the studies,further research with larger sample sizes is needed to confirm the effective impact of prone position ventilation in patients receiving ECMO treatment.
8.Clinical value of puncture biopsy in the diagnosis of hepatocellular carcinoma subtypes
Xueqin TIAN ; Jiapeng WU ; Lu LI ; Chuan PANG ; Chaonan CHEN ; Jie YU ; Ping LIANG
Chinese Journal of Hepatobiliary Surgery 2025;31(6):426-432
Objective:To investigate the clinical value of puncture biopsy for the diagnosis of vessels that encapsulate tumor clusters (VETC) and macrotrabecular-massive (MTM) subtypes of hepatocellular carcinoma (HCC).Methods:One hundred and eighty-four patients with HCC who underwent surgical resection at the Fifth Medical Centre of Chinses PLA General Hospital from November 2023 to July 2024 were prospectively collected, including 154 males and 30 females, aged (57.1±8.6) years. By simulating the clinical puncture procedure, puncture biopsy tissue specimens were obtained postoperatively from the patient's isolated tumors. The puncture biopsies and surgical resection specimens were stained with HE and CD34, and evaluated for VETC and MTM. Patients were divided into two groups based on the histopathological VETC results of surgically resected specimens: the VETC-positive group ( n=41) and the VETC-negative group ( n=143); and two groups based on the histopathological MTM results of surgically resected specimens: the MTM-positive group ( n=39) and the MTM-negative group ( n=145). Clinical data such as gender, age, tumor length, and alpha-fetoprotein (AFP) were recorded. Logistic regression analysis was performed to screen the risk factors of VETC and MTM. Evaluating the diagnostic efficacy of puncture biopsy for VETC and MTM. Results:The results of multivariable logistic analysis showed that puncture biopsy VETC-positive ( OR=63.97, 95% CI: 16.28-251.29), grade of M2 microvascular invasion ( OR=5.07, 95% CI: 1.31-19.59) and tumor length ≥5 cm ( OR=3.42, 95% CI: 1.11-10.52) were the risk factors for VETC-positive (all P<0.05); whereas the risk factors for MTM-positive were only puncture biopsy MTM-positive ( OR=34.78, 95% CI: 12.06-100.29, P<0.001). Puncture biopsy correctly diagnosed VETC subtype in 163 patients with a diagnostic accuracy of 0.89, sensitivity of 0.61, specificity of 0.97, positive predictive value (PPV) of 0.83, and negative predictive value (NPV) of 0.90; MTM subtype was correctly diagnosed in 164 patients with a diagnostic accuracy of 0.89, sensitivity of 0.72, specificity of 0.94, PPV of 0.76, and NPV of 0.93. Using the three indicators of puncture biopsy diagnosis, tumor length and AFP level as a combined indicator, the accuracy to diagnose VETC was 0.83, sensitivity was 0.71, specificity was 0.87, PPV was 0.60, and NPV was 0.91; and the combined indicator diagnosis of MTM had a diagnostic accuracy of 0.85, a sensitivity of 0.82, specificity of 0.86, PPV of 0.68 and NPV of 0.95. Conclusion:Puncture biopsy has high specificity and accuracy in the diagnosis of VETC and MTM subtypes, but the sensitivity is relatively limited, and the role of puncture combined with clinical factors in improving diagnostic efficacy is limited.
9.Integrated multi-parameter monitoring for optimizing low-molecular-weight heparin treatment in intensive care unit patients: a clinical value assessment
Qin LI ; Liqin LING ; Xiaomei LI ; Chaonan LIU ; Xunbei HUANG ; Shuang WANG ; Zhiyu YU ; Jing ZHOU
Chinese Journal of Laboratory Medicine 2025;48(8):1008-1014
Objective:To explore the clinical value of multi-parameter combined monitoring in guiding low-molecular-weight heparin (LMWH) therapy for intensive care unit (ICU) patients.Methods:A retrospective case-control study was conducted. A total of 381 patients who received LMWH therapy with anti-Ⅹa activity monitoring in the ICU of West China Hospital, Sichuan University between January 31st, 2022, and November 30th, 2023, were enrolled in this study. The cohort comprised 264 males and 117 females, with the age of 58 (48, 71) years old. Clinical data and relevant laboratory parameters were collected, including anti-Ⅹa activity, antithrombin activity (AT), thrombin-antithrombin complex (TAT), plasmin-antiplasmin complex (PIC), conventional coagulation parameters such as activated partial thromboplastin time (APTT), and indicators of hepatic/renal impairment such as alanine aminotransferase (ALT) and creatinine( CREA). Patients were stratified into three groups based on thrombotic event: thrombosis-controlled, progressive thrombosis, and bleeding group. Single-factor and adjusted multifactorial Logistic regression analysis were used to identify independent predictors of anti-xa activity levels.Results:Among 381 patients, thrombosis was controlled in 213 (55.9%) patients, progressed in 81 (21.3%) patients , and bleeding events occurred in 87 (22.8%) patients. The patients whose anti-Ⅹa activity levels lay entirely within the target range(0.2-0.4 IU/ml): Only 35 (16.4%) cases in the thrombosis-controlled group, 16 (19.7%) cases in the progressive thrombosis group, and 16 (18.4%) in the bleeding group. No significant differences in anti-Ⅹ a levels activity among the three groups ( H=1.678, P=0.432). Both single-factor and adjusted multifactorial Logistic regression identified low AT activity as an independent risk factor for failure to achieve target anti-Ⅹ a activity levels (AT nadir, OR=1.031,95% CI 1.016-1.046, P<0.05). Compared with the progressive thrombosis and bleedinggroup, the thrombosis-controlled group exhibited significantly higher proportion of TAT values below the cut-off value ( H=8.519, P=0.014), and a higher proportion of TAT/PIC ratios below the cut-off ( H=15.56, P<0.001). Patients with bleeding demonstrated significantly lower AT activity ( H=14.968, P=0.001), prolonged APTT ( H=6.815, P=0.033), higher ALT ( H=13.774, P=0.001), and higher CREA ( H=14.068, P=0.001) compared with the thrombosis-controlled or progressive thrombosis group. Conclusion:Laboratory monitoring is required for low-molecular-weight heparin (LMWH) therapy in ICU patients. While anti-Ⅹa activity reflects the anticoagulant effect of LMWH, the utility of anti-Ⅹ a activity for predicting thrombotic or hemorrhagic risks in LMWH treated ICU patients is limited. Reductions in TAT levels and TAT/PIC ratios are associated with a lower risk of thrombotic progression. Furthermore, abnormalities in conventional coagulation tests and standard hepatic/renal function parameters occur more frequently in patients experiencing hemorrhagic events.
10.Utidelone induces apoptosis and autophagy in small cell lung cancer cells through the ROS/AMPK signaling pathway
Xiaoqian MU ; Chaonan YU ; Yanqiu ZHAO ; Xiufeng HU ; Hongbo WU
Chinese Journal of Oncology 2025;47(8):703-714
Objective:To investigate the effects and underlying molecular mechanisms of Utidelone (UTD1) in small cell lung cancer (SCLC).Methods:The study utilized small cell lung cancer H446 and H1048 cell lines along with animal models. Cell proliferation, cell cycle progression, apoptosis, autophagy, and related activities following UTD1 treatment were assessed using Cell Counting Kit-8 (CCK-8), flow cytometry, immunofluorescence staining, reactive oxygen species (ROS) generation assay, and Western blot analysis. The involvement of the ROS/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway was also examined. Data analysis was performed using GraphPad Prism version 8 software.Results:UTD1 inhibited the viability of H446 and H1048 cells in a dose- and time-dependent manner. The half inhibitory concentrations (IC 50) of UTD1 for H446 and H1048 cells were 0.675 and 0.439 μg/ml, respectively. The proportion of cells in the G 2/M phase for H446 and H1048 cells in the UTD1 group at 6 h, 12 h, and 24 h was [(53.86±4.54)%, (68.59±5.49)%, (60.89±3.26)%] and [(46.83±2.20)%, (60.67±3.44)%, (57.88±5.11)%], which were significantly higher than that in the control group, except for the proportion of H1048 cells at 6 h [(38.99±2.60)% vs. (40.73±2.50)%, P<0.05]. The apoptosis rates were [(23.57±0.12)%, (35.79±1.59)%, and (46.15±4.57)%] for H446 cells and [(23.05±2.70)%, (37.73±2.97)%, and (43.39±3.31)% for H1048 cells], all of which were significantly higher than those in the control group [(6.44±0.96)%, (6.31±0.75)%, respectively; all P<0.05]. The number of LC3 fluorescent spots was [(56±11), (69±8), and (66±8)] for H446 cells and [(39±7), (56±12), and (50±11)] for H1048 cells, both significantly higher than those in the control group [(13±6) and (12±5), respectively; both P<0.05]. The relative fluorescence intensity of ROS was 2.54±0.48, 2.85±0.68, and 5.03±0.72 for H446 cells and 2.26±0.51, 4.17±0.35, and 4.66±0.51 for H1048 cells, which were also significantly higher than those in the control group ( P<0.05). The expression levels of cyclin B1, cyclin A2, and P21 of H446 cells in the three time points were [(0.63±0.07, 0.33±0.05, 0.23±0.04), (0.68±0.08, 0.46±0.03, 0.27±0.06), and (0.64±0.03, 0.32±0.05, 0.22±0.03), respectively], all significantly lower compared to the control group ( P<0.05). The apoptosis rates of H446 and H1048 cells in the UTD1+Z-VAD-FMK group were (19.97±3.19)% and (17.68±3.14)%, both lower than those in the UTD1 group [(40.73±3.35)% and (39.82±2.45)%, respectively; all P<0.05]. The absorbance values of H446 and H1048 cells in the UTD1+3-MA group were significantly higher than those in the UTD1 group at 6h, 12h, and 24h (all P<0.05). The levels of p-AMPKα/AMPKα, LC3-II expression, and the percentage of apoptotic cells in the H446 and H1048 cells of the UTD1+NAC group were [(1.33±0.09, 1.33±0.11), (1.49±0.16, 1.55±0.05), (17.24±2.15)%, and (19.40±4.28)%], all of which were lower than those observed in the UTD1 group [(1.98±0.17, 2.23±0.23), (2.81±0.19, 2.49±0.38), (38.07±3.53)%, and (41.20±1.87)%, all P<0.05]. The number of LC3 fluorescence points and the percentage of apoptotic cells in the H446 and H1048 cells of the UTD1+si-AMPKα group [(24±5, 23±3), (18.35±1.15)%, and (19.15±3.46)%] were all lower than those in the UTD1+si-NC group [(46±6, 36±6), (39.34±1.77)%, and (39.50±2.15)%, all P<0.05]. The tumor inhibition rates in small cell lung cancer tumor-bearing nude mice for the 2.5 mg/kg UTD1 group and the 5 mg/kg UTD1 group were 46.43% and 58.33%, respectively. Furthermore, the proportions of apoptosis-positive cells and p-AMPKα-positive cells in the UTD1 group were significantly higher compared to the control group, while the levels of Ki-67 positivity were significantly reduced. Conclusion:UTD1 inhibits SCLC cell proliferation, induces G 2/M phase arrest, and promotes cell apoptosis and autophagy through the activation of the ROS/AMPK signaling pathway.


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