1.Early coagulation function changes of penetrating intestinal firearm injury of pigs in high-altitude environment
Jiu SUN ; Xue YANG ; Jinquan QU ; Xinyue YANG ; Caifu SHEN ; Jiajia LI ; Yanchao XING ; Jiangwei LIU
Chinese Journal of Trauma 2024;40(3):257-265
		                        		
		                        			
		                        			Objective:To explore the early coagulation function changes of penetrating intestinal firearm injury of pig in high-altitude environments.Methods:Twenty healthy long white piglets were selected and divided into the plain group and the high-altitude group using the random number table method, with 10 pigs in each group. Pigs in the plain group were placed in a plain environment at an altitude of 800 meters, while pigs in the high-altitude group were placed in an experimental chamber simulating an altitude of 6 000 meters for 48 hours. Both groups received pistol gunshot to have firearm penetrating wounds to the abdominal intestinal tract and then returned to the plain observation room. At 0, 2, 4, 8, 12 and 24 hours after injury, coagulation in the peripheral blood and fibrinolytic indexes [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fbg), D-dimer (D-D), and fibrinogen degradation product (FDP)], thromboelastogram (TEG) [reaction time (R), clotting time (K), clot formation rate (α), maximum amplitude (MA) and coagulation composite index (CI) ], platelet parameters [platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and platelet-large cell ratio (P-LCR)] in the two groups were detected separately.Results:The PT values at 0 and 2 hours after injury in the high-altitude group were significantly lower than those in the plain group, while they were significantly higher at 8, 12 and 24 hours than those in the plain group ( P<0.01); there was no significant difference at 4 hours between the two groups ( P>0.05). The APTT values at 0, 2 and 4 hours after injury in the high-altitude group were significantly lower than those in the plain group, while they were significantly higher at 8, 12 and 24 hours after injury than those in the plain group ( P<0.01). The TT values at 0, 2 and 4 hours after the injury in the high-altitude group were significantly lower than those in the plain group, while they were significantly higher at 12 and 24 hours after injury than those in the plain group ( P<0.01); there was no significant difference at 8 hours after injury between the two groups ( P>0.05). The Fbg, D-D and FDP values at 0, 2, 4, 8, 12 and 24 hours after injury were higher in the high-altitude group than those in the plain group ( P<0.01). The R values at 0, 2 and 4 hours after injury in the high-altitude group were significantly lower than those in the plain group, while they were significantly higher at 8, 12 and 24 hours after injury than those in the plain group ( P<0.01). The K values at 0, 2, 4 and 8 hours after injury in the high-altitude group were significantly lower than those in the plain group, while they were significantly higher at 12 and 24 hours after injury than those in the plain group ( P<0.05 or 0.01). The α angles at 0, 2 and 4 hours after injury in the high-altitude group were significantly higher than those in the plain group, while they were significantly lower at 8, 12 and 24 hours after injury than those in the plain group ( P<0.01). The MA values at 0, 2 and 4 hours after the injury in the high-altitude group were significantly higher than those in the plain group, while they were significantly lower at 8, 12 and 24 hours after injury than those in the plain group ( P<0.01). The CI values at 0, 2 and 4 hours after injury in the high-altitude group were significantly higher than those in the plain group, while they were significantly lower at 8, 12 and 24 hours after injury than those in the plain group ( P<0.01). The PLT values at 0, 2, 4 and 8 hours after injury in the high-altitude group were significantly higher than those in the plain group, while they were significantly lower at 12 and 24 hours after injury than those in the plain group ( P<0.05 or 0.01). The MPV values at 0, 2, 4, 8, 12 and 24 hours after injury in the high-altitude group were significantly higher than those in the plain group ( P<0.01). The PDW values at 2, 4, 8, 12 and 24 hours after injury in the high-altitude group were significantly higher than those in the plain group ( P<0.05 or 0.01), while there was no significant difference in PDW at 0 hour after injury between the two groups ( P>0.05). The P-LCR values at 0, 2, 4, 8, 12 and 24 hours after injury in the high-altitude group were all significantly higher than those in the plain group ( P<0.01). Conclusion:Compared with the plain environments, pig intestinal firearm penetrating injury in the high-altitude environments is more prone to early hypercoagulable state accompanied by mild hyperfibrinolysis, and faster to reach a hypocoagulable state accompanied by obvious hyperfibrinolysis.
		                        		
		                        		
		                        		
		                        	
2.Role of BDNF-TrkB signaling pathway in early-life cadmium exposure induced cognitive dysfunction in mice
Yan SHI ; Siqi YANG ; Yougang WANG ; Qiumei WU ; Jinquan LI
Journal of Environmental and Occupational Medicine 2024;41(11):1283-1289
		                        		
		                        			
		                        			Background With the rapid industrialization, cadmium has become a primary heavy metal pollutant in cultivated land soil in China, which seriously affects human health. Previous studies have found that cadmium exposure associates with cognitive dysfunction in individuals, but there is a lack of research on the mechanism of cadmium exposure associated cognitive impairment in offspring in early life which is more vulnerable to various toxins and crucial for development of the neuro. Objective To explore the potential mechanism of brain-derived neurotrophic factor/tyrosine kinase receptor B (BDNF-TrkB) signaling pathway in cognitive dysfunction in mice after cadmium exposure in early-life. Methods Twelve 8-week-old C57BL/6 pregnant mice were randomly divided into 2 groups, namely control group and cadmium exposure group, with 6 mice in each group. The exposure period was from pregnancy day 4.5 to lactation day 21 (E4.5-P21), during which distilled water or cadmium chloride solution (2.5 mg·kg−1·d−1) was given. After lactation, the offspring of the control group and the cadmium exposure group were given distilled water until 8 weeks of age. Then the toxicity effects of cadmium exposure on mice were evaluated by body weight and selected biochemical indicators. The cadmium content in brain was detected and the learning and memory ability was tested by Y maze and Morris water maze to evaluate cognitive function of offspring mice. Histopathological changes of the hippocampus were observed after Nissl staining and Golgi staining. The mRNA and protein expression levels of the BDNF-TrkB pathway and synapse were detected by real-time quantitative PCR (qPCR) and Western blot. Results Compared with the control group, no significant change was found in body weight, liver or kidney function in the cadmium exposure group (P> 0.05). However, compared with the control group, the cadmium content in brain was increased in the cadmium exposure group (P<0.001). The behavioral changes associated with cognitive dysfunction were positive in the cadmium exposure group (all P<0.05). The histopathological observation after Nissl staining showed abnormal tissue structure, decreased number of neurons and increased karyopyknosis in the cadmium exposure group (P<0.01).The spine density of Golgi staining was decreased in the cadmium exposure group (P<0.001). The BDNF-TrkB pathway-related mRNA and the synapse-related mRNA in the hippocampus were reduced in the cadmium exposure group (all P<0.05). The expression levels of BDNF-TrkB pathway-related proteins and synapse-related proteins in the hippocampus were also reduced in the cadmium exposure group (P<0.05). Conclusion Early-life cadmium exposure may induce synaptic dysplasia and lead to cognitive dysfunction by down-regulating the BDNF-TrkB signaling pathway in mice.
		                        		
		                        		
		                        		
		                        	
3.Effects of Electroacupuncture on Motor Function and the Expressions of Irisin,Decorin and Myostatin in SAMP8 Mice
Chenguang WEN ; Weiguo DONG ; Wanqing GUO ; Junyan HUANG ; Jinquan LI ; Shaomin YANG ; Lan LIN ; Feng WANG
Chinese Journal of Information on Traditional Chinese Medicine 2024;31(11):110-115
		                        		
		                        			
		                        			Objective To observe the effects of electroacupuncture on the motor function and expressions of Irisin,Decorin and Myostatin in skeletal muscle of SAMP8 mice;To explore the mechanism of electroacupuncture in the treatment of the motor dysfunction of Alzheimer disease(AD).Methods Totally 247-month-old male SAMP8 mice were randomly divided into model group and electroacupuncture group,with 12 mice in each group,and the 12 male SAMR1 mice with the same age were set as the control group."Baihui","Dazhui"and"Shenshu"were selected in the electroacupuncture group,once a day,8 days as one course of treatment,with an interval of 2 days,for a total of 3 courses.The control group and the model group were not intervened.The motor function of mice was tested by grip strength test,pole climbing test and open field test,the mRNA expressions of Irisin,Decorin and Myostatin in quadriceps muscle were detected by RT-qPCR,and the protein expressions of Irisin,Decorin and Myostatin in quadriceps muscle were detected by immunohistochemistry and Western blot.Results Compared with the control group,the grip peak and duration of the mice in the model group decreased,head turning time and pole climbing time were prolonged(P<0.01),the mRNA and protein expressions of Irisin and Decorin decreased(P<0.05,P<0.01),and the expressions of Myostatin mRNA and protein increased(P<0.05).Compared with the model group,the grip peak and duration of the mice in the electroacupuncture group increased,head turning time and pole climbing time were decreased(P<0.05),the mRNA and protein expressions of Irisin and Decorin increased(P<0.05),and the expressions of Myostatin mRNA and protein decreased(P<0.05).Conclusion Electroacupuncture can improve the motor dysfunction of SAMP8 mice,and its mechanism may be related to regulating the expressions of Irisin,Decorin and Myostatin in skeletal muscle.
		                        		
		                        		
		                        		
		                        	
4.Study on changes to intestinal permeability secondary to firearm-related penetrating wound of pig abdominal intestine in cold environment at high altitudes
Jinquan QU ; Jiajia LI ; Hongnan LU ; Xinyue YANG ; Jiu SUN ; Feixing LIANG ; Yan WANG ; Jiangwei LIU
Chinese Journal of Comparative Medicine 2024;34(9):34-42
		                        		
		                        			
		                        			Objective To observe the changes to,and possible mechanism of,intestinal permeability in pigs without direct injury after an abdominal-and intestinal-penetrating injury from firearms in cold environment at high altitudes.Methods Fifty-five experimental pigs were divided into two groups:high-altitude cold group(HC)and low-altitude normal temperature group(LN).According to the observation time,each group was divided into five experimental subgroups:0h,2h,4 h,8h,and 24 h.There were six pigs in each HC subgroup and five pigs in each LN subgroup.After euthanasia,intestinal tissues were taken,and the levels of the inflammatory factors TNF-α,and IL-6 in intestinal homogenate and the concentrations of intestinal permeability-related proteins DAO and D-lactate acid in blood were detected by ELISA method.The intestinal tissues of experimental pigs were taken at 0 h and 8 h for LN and 8 h for HC,and intestinal pathological changes were observed and scored after HE staining.The concentrations of Occludin,ZO-1,Claudin-3,TLR4,NF-κB,and MLCK(proteins related to intestinal permeability)were detected by Western blot to explore the effect of a cold environment at high altitude on secondary intestinal permeability changes after injury and the possible mechanisms.Results Both the HC group and LN group experienced typical abdominal intestinal penetrating injuries,and there were no significant differences in their abdominal infection scores or intestinal adhesion(P>0.05).The levels of DAO and D-LA in the serum of experimental pigs in the HC and LN groups gradually increased over time.The levels of DAO and D-LA in the HC group were significantly higher than those in the LN group at all time points(P<0.01 or P<0.001).The fastest increase in DAO and D-LA in the HC group was 4 h to 8 h,while in the LN group,it was 8 h to 24 h.The pathological score of intestinal tissue in the HC group was significantly higher than that in the LN group of experimental pigs(P<0.01).The inflammatory factors TNF-α and IL-6 both increased over time in the intestinal tissue of LN and HC groups.The most significant time point for a increase of inflammatory factors in the HC group was 4 h to 8 h,while in the LN group,it was 8 h to 24 h.The intestinal tissue IL-6 and TNF-α levels of experimental pigs in the HC group were higher than those in the LN group the entire time(P<0.05,P<0.01,or P<0.001).The levels of occludin and ZO-1 in the HC group at 8 h decreased significantly compared to those of the LN group at the 8 h time point(P<0.05),while claudin-3 showed a significant decrease in LN(P<0.001).In the HC group,TLR4,NF-κB,and MLCK were both higher than those in the LN group at 8 h,and the difference was statistically significant(P<0.05).Conclusions A high-altitude cold environment can lead to a secondary increase in intestinal permeability after abdominal-penetrating firearm injury,and its mechanism may be related to the TLR4/NF-κB/MLCK pathway.
		                        		
		                        		
		                        		
		                        	
5.Screening for asymptomatic atrial fibrillation in elder community populations in Dalian: a single center study.
Yi Heng YANG ; Rong Qian XU ; Rong Feng ZHANG ; Yu Shan WEI ; Li HONG ; Jie SUN ; Tao CONG ; Yun Long XIA
Chinese Journal of Cardiology 2023;51(10):1056-1062
		                        		
		                        			
		                        			Objective: We aimed to determine the epidemiological characteristics of asymptomatic AF in elder community population (≥65 years old) to analyze the detection rate of different screening methods. Methods: The study was a prospective cohort study. The elder (≥65 years old) residents who voluntarily participated in free physical examination in Dalian community were selected. The participants were randomly divided into screening group (including intensive screening group and single screening group) and control group. The control group received interrogation, medical history collection and routine 12-lead electrocardiogram (ECG) examination. Screening group received an additional single-lead ambulatory ECG equipment worn for 5-7 days. Intensive screening group received two equal-length wearings in 2020 and 2021 respectively, while one screening group only wore once in 2020. Results: Finally 3 340 residents ((70.7±5.0) years old) which consisted of 1 488 males (44.55%) were enrolled. There were 1 945 residents in screening group, including 859 in intensive screening group and 1 086 in one-time screening group. The control group included 1 395 people. Detection rate of asymptomatic AF was significantly higher in screening group than control group (79(4.06%) vs. 24(1.72%), P<0.001). Higher detection rate was found in screening group than control group in AF risk factors (1 or 2-3) subgroups and CHA2DS2-VASc score (2-3 or≥4) subgroups (P<0.05). Additionally, no difference was found between intensive screening group and single screening group (42(4.89%) vs. 37(3.41%), P=0.100). Intensive screening increased detection rate (7(6.93%) vs. 1(0.58%), P=0.009) only in residents those with low thrombosis risk (CHA2DS2-VaSc<2). Conclusions: Screening in elderly (≥65 years old) can significantly improve the detection rate of asymptomatic AF by wearing single lead dynamic ECG device. The rate increased significantly with the increase of risk factors associated with AF by single screening. In addition, repeat screening of the same method may only improve detection rates in the group with low risk thrombotic scores and non-combination of AF risk factors.Screening methods that are appropriate for different populations may require further exploration.
		                        		
		                        		
		                        		
		                        			Male
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Aged
		                        			;
		                        		
		                        			Atrial Fibrillation/epidemiology*
		                        			;
		                        		
		                        			Prospective Studies
		                        			;
		                        		
		                        			Electrocardiography
		                        			;
		                        		
		                        			Risk Factors
		                        			;
		                        		
		                        			Stroke
		                        			;
		                        		
		                        			Risk Assessment
		                        			;
		                        		
		                        			Mass Screening/methods*
		                        			
		                        		
		                        	
6.Screening for asymptomatic atrial fibrillation in elder community populations in Dalian: a single center study.
Yi Heng YANG ; Rong Qian XU ; Rong Feng ZHANG ; Yu Shan WEI ; Li HONG ; Jie SUN ; Tao CONG ; Yun Long XIA
Chinese Journal of Cardiology 2023;51(10):1056-1062
		                        		
		                        			
		                        			Objective: We aimed to determine the epidemiological characteristics of asymptomatic AF in elder community population (≥65 years old) to analyze the detection rate of different screening methods. Methods: The study was a prospective cohort study. The elder (≥65 years old) residents who voluntarily participated in free physical examination in Dalian community were selected. The participants were randomly divided into screening group (including intensive screening group and single screening group) and control group. The control group received interrogation, medical history collection and routine 12-lead electrocardiogram (ECG) examination. Screening group received an additional single-lead ambulatory ECG equipment worn for 5-7 days. Intensive screening group received two equal-length wearings in 2020 and 2021 respectively, while one screening group only wore once in 2020. Results: Finally 3 340 residents ((70.7±5.0) years old) which consisted of 1 488 males (44.55%) were enrolled. There were 1 945 residents in screening group, including 859 in intensive screening group and 1 086 in one-time screening group. The control group included 1 395 people. Detection rate of asymptomatic AF was significantly higher in screening group than control group (79(4.06%) vs. 24(1.72%), P<0.001). Higher detection rate was found in screening group than control group in AF risk factors (1 or 2-3) subgroups and CHA2DS2-VASc score (2-3 or≥4) subgroups (P<0.05). Additionally, no difference was found between intensive screening group and single screening group (42(4.89%) vs. 37(3.41%), P=0.100). Intensive screening increased detection rate (7(6.93%) vs. 1(0.58%), P=0.009) only in residents those with low thrombosis risk (CHA2DS2-VaSc<2). Conclusions: Screening in elderly (≥65 years old) can significantly improve the detection rate of asymptomatic AF by wearing single lead dynamic ECG device. The rate increased significantly with the increase of risk factors associated with AF by single screening. In addition, repeat screening of the same method may only improve detection rates in the group with low risk thrombotic scores and non-combination of AF risk factors.Screening methods that are appropriate for different populations may require further exploration.
		                        		
		                        		
		                        		
		                        			Male
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Aged
		                        			;
		                        		
		                        			Atrial Fibrillation/epidemiology*
		                        			;
		                        		
		                        			Prospective Studies
		                        			;
		                        		
		                        			Electrocardiography
		                        			;
		                        		
		                        			Risk Factors
		                        			;
		                        		
		                        			Stroke
		                        			;
		                        		
		                        			Risk Assessment
		                        			;
		                        		
		                        			Mass Screening/methods*
		                        			
		                        		
		                        	
7.The Wuhan model of visual health management for students: a referential framework for the public-school health system
Chinese Journal of School Health 2021;42(1):142-145
		                        		
		                        			Abstract
		                        			According to the Healthy China Action Plan, Wuhan gives full play to the role of preventing and controlling student myopia by promoting student health. The primary focus is placed on education in schools, and Wuhan has integrated educational resources to develop a multi-level myopia prevention and control system and service network for school students. The network contains educational adminstrative, schools, families, and professional technical service organizations. By integrating multiple disciplines, Wuhan has built a comprehensive vision health management service system for all students. The Internet and cloud intelligent monitoring facilitated the establishment of a smart vision health management platform for students, which thoroughly and efficiently implemented myopia prevention and control to safeguard students visual health by engaging in education, monitoring, and supervision. The prevention and control of student myopia is a breakthrough for comprehensive healthy development of students. A comparison of the standard myopia rate in Wuhan in 2019 and 2018 revealed that the standard myopia rate at different learning stages of primary school, junior high school, and high school dropped by 3.31, 2.50, and 2.26 percentage points, respectively, and the rate of myopia in primary school was significantly lower than the national level. Post-epidemic surveys showed that the compliance rate and the awareness rate of the visual environment and visual behaviors of primary and secondary school students in Wuhan reached more than 80%, and prevalence of newly onset myopia or decreased vision was 30%, which was lower than the national average. The "Wuhan Model" provides an important referential framework for public health services for school students.
		                        		
		                        		
		                        		
		                        	
8.Effect of melatonin on prefrontal cortex ischemia-induced cognitive impairment in rats and the receptor mechanism
Ying YUAN ; Hong CHANG ; Hongqiong YUAN ; Congwen YANG ; Kaizhi LU ; Jinquan WANG
Chinese Journal of Anesthesiology 2021;41(12):1514-1517
		                        		
		                        			
		                        			Objective:To evaluate the effect of melatonin on prefrontal cortex ischemia-induced cognitive impairment in rats and to investigate the receptor mechanism.Methods:Clean-grade adult male Sprague-Dawley rats, weighing 300 g, were selected, and a catheter was implanted into the prefrontal cortex.The experiment was performed in two parts.Experiment Ⅰ Twenty-four rats, in which catheters were successfully inserted into the prefrontal cortex, were assigned into 3 groups ( n=8 each) using a random number table method: control group (group C), model group (group M) and melatonin group (group ME). Normal saline 0.5 μl was injected into the prefrontal cortex in group C, 1 μmol/L endothelin 0.5 μl was microinjected into the prefrontal cortex in group M, and 1 μmol/L endothelin and 1 μmol/L melatonin 0.5 μl were injected into the prefrontal cortex in group ME.Experiment Ⅱ Forty-four rats, in which catheters were successfully inserted into the prefrontal cortex, were assigned into 4 groups ( n=11 each) using a random number table method: model group (group M), melatonin group (group ME), MT 1/2R antagonist luzindole + melatonin group (group L + ME) and MT 2R antagonist 4p-pdot + melatonin group (group P + ME). In group M, 1 μmol/l endothelin 0.5 μl was microinjected into the prefrontal cortex.In group ME, 1 μmol/L endothelin + 1 μmol/L melatonin 0.5 μl was injected into the prefrontal cortex.In group L + ME, 1 μmol/L endothelin + 1 μmol/L MT 1/2R antagonist + 1 μmol/L melatonin 0.5 μl was injected into the prefrontal cortex.In group P + ME, 1 μmol/L endothelin + 1 μmol/L MT 2R antagonist + 1 μmol/L melatonin 0.5 μl was injected into the prefrontal cortex.T-maze and the open field tests were performed at 1 week after administration. Results:Experiment Ⅰ There was no significant difference in the locomotor speed in open field test among C, M and ME groups ( P>0.05). The rate of correct selection in T-maze test was significantly lower in M and ME groups than in group C and higher in group ME than in group M( P<0.05). Experiment Ⅱ There was no significant difference in the locomotor speed in open field test among the four groups( P>0.05). Compared with group M, the rate of correct selection in open field test was significantly increased in ME and P+ ME groups ( P<0.05), and no significant change was found in group L+ ME ( P>0.05). Compared with group ME, the rate of correct selection in open field test was significantly decreased in group L+ ME ( P<0.05), and no significant change was found in group P+ ME( P>0.05). Conclusion:Melatonin can attenuate prefrontal cortex ischemia-induced cognitive impairment in the rats, and the mechanism is related to activation of MT 1R.
		                        		
		                        		
		                        		
		                        	
9.Relationship between lateral hypothalamus and melatonin-induced reduction of wakefulness in rats and the receptor mechanism
Bo CAO ; Ming ZHANG ; Yang CHEN ; Bin YI ; Kaizhi LU ; Jinquan WANG
Chinese Journal of Anesthesiology 2021;41(3):311-314
		                        		
		                        			
		                        			Objective:To investigate the relationship between lateral hypothalamus and melatonin-induced reduction of wakefulness in rats and the receptor mechanism.Methods:Forty clean-grade adult male Sprague-Dawley rats, weighing 250-300 g, were divided into 4 groups ( n=10 each) using a random number table method: control group (group C), melatonin group (group M), melatonin type-1/2 receptor (MT 1R) antagonist luzindole plus melatonin group (group L+ M), and melatonin type-2 receptor (MT 2R) antagonist 4P-PDOT plus melatonin group (P+ M group). In group C, 0.5 μl of 0.9% NaCl solution was microinjected into the lateral hypothalamus.In group M, 1 μmol/L melatonin 0.5 μl was microinjected into the lateral hypothalamus.In group L+ M, 1 μmol/L MT 1/2R and 1 μmol/L melatonin (0.5 μl in total) was microinjected into the lateral hypothalamus.The microinjection time was from 19: 30 to 20: 00.The changes in sleep-wake duration and the oscillating energy in different frequency bands of electroencephalogram were detected by using electroencephalogram and electromyogram recording technology. Results:Compared with group C, the percentage of wakefulness time was significantly decreased, the percentage of non-rapid eye movement sleep and rapid eye movement sleep time was increased, the energy for delta oscillation was increased, the energy for theta oscillation was decreased, and no significant change was found in the energy for alpha oscillation in M and P+ M groups ( P<0.01), and no significant change was found in the parameters mentioned above in group L+ M ( P>0.05). Compared with group M, the percentage of wakefulness time was significantly increased, the percentage of non-rapid eye movement sleep and rapid eye movement sleep time was decreased, the energy for delta oscillation was decreased, and the energy for theta oscillation was increased in group L+ M ( P<0.01), and no significant change was found in the parameters mentioned above in group P+ M ( P>0.05). Conclusion:The lateral hypothalamus may be involved in melatonin-induced reduction of wakefulness in rats, and the mechanism may be related to activating MT 1R in the lateral hypothalamus.
		                        		
		                        		
		                        		
		                        	
10.Mutant IDH1 Enhances Temozolomide Sensitivity via Regulation of the ATM/CHK2 Pathway in Glioma
Lin LIN ; Jinquan CAI ; Zixiao TAN ; Xiangqi MENG ; Ruiyan LI ; Yang LI ; Chuanlu JIANG
Cancer Research and Treatment 2021;53(2):367-377
		                        		
		                        			Purpose:
		                        			Isocitrate dehydrogenase 1 (IDH1) mutations are the most common genetic abnormalities in low-grade gliomas and secondary glioblastomas. Glioma patients with these mutations had better clinical outcomes. However, the effect of IDH1 mutation on drug sensitivity is still under debate. 
		                        		
		                        			Materials and Methods:
		                        			IDH1-R132H mutant cells were established by lentivirus. IDH1-R132H protein expression was confirmed by western blot. The expression of ataxia telangiectasia mutated (ATM) signaling pathway and apoptosis-related proteins were detected by immunofluorescence and western blot. Temozolomide (TMZ) induced cell apoptosis was detected by flow cytometry. Tumor cell proliferation was detected by Cell Counting Kit-8. In vivo nude mice were used to confirm the in vitro roles of IDH1 mutation. 
		                        		
		                        			Results:
		                        			We established glioma cell lines that expressed IDH1-R132H mutation stably. We found that TMZ inhibited glioma cells proliferation more significantly in IDH1 mutant cells compared to wild type. The IC50 of TMZ in IDH1-R132H mutant group was less than half that of wild-type group (p < 0.01). TMZ significantly induced more DNA damage (quantification of γH2AX expression in IDH1 mutation vs. wild type, p < 0.05) and apoptosis (quantification of AnnexinV+propidium iodide–cells in IDH1 mutation versus wild type, p < 0.01) in IDH1 mutant gliomas compared to wild-type gliomas. The ATM-associated DNA repair signal was impaired in IDH1 mutant cells. Inhibiting the ATM/checkpoint kinase 2DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy. We found that IDH1 mutation significantly inhibited tumor growth in vivo (the tumor size was analyzed statistically, p < 0.05). Moreover, we confirmed that gliomas with IDH1 mutation were more sensitive to TMZ in vivo compared to wild type significantly and the results were consistent with the in vitro experiment. 
		                        		
		                        			Conclusion
		                        			These results provide evidence that combination of TMZ and ATM inhibitor enhances the antitumor effect in IDH1 mutant gliomas.
		                        		
		                        		
		                        		
		                        	
            

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