Activating transcription factor 5 (ATF5) is a member of the activating transcription factor/cyclic adenosine monophosphate response element binding protein (ATF/CREB) family. As a stress-induced transcription factor, ATF5 plays a crucial role in cellular inflammatory stress responses. Under cellular inflammatory stress conditions, ATF5 maintains cell homeostasis and survival by regulating key genes in the mitochondrial unfolded protein response (UPR^mt) and endoplasmic reticulum stress (ERS). As a key regulator in UPR^mt, ATF5 senses mitochondrial stress and translocate to the nucleus to activate the transcription of UPR^mt-related genes, thereby promoting mitochondrial function recovery. Meanwhile, in ERS, ATF5 maintains endoplasmic reticulum homeostasis by regulating the expression of genes related to protein folding, degradation, and apoptosis, determining cell survival or death. ATF5 plays a vital role in various cellular inflammatory stress responses. In infectious inflammation, ATF5 plays an important role in alleviating neuroinflammation and maintaining intestinal barrier function by regulating UPR^mt. In inflammation related to degenerative diseases, ATF5 improves intervertebral disc degeneration and delays the progression of osteoarthritis by regulating UPR^mt. In metabolic inflammation such as diabetes and obesity, ATF5 regulates UPR^mt and ERS to maintain the function of pancreatic β-cells, controlling their survival or inducing apoptosis, thus influencing the progression of diabetes. ATF5 protects mitochondria in the kidneys, adipose tissue, and pancreas, slows the progression of diabetic nephropathy, and improves insulin sensitivity. Furthermore, in immune-related inflammation, ATF5 alleviates glomerulonephritis and promotes tissue repair by enhancing immune tolerance in dendritic cells. In summary, ATF5, as a key regulator in cellular inflammatory stress responses, maintains cell homeostasis through regulating UPR^mt and ERS and determines cell fate. Its critical regulatory role in cellular inflammatory stress responses makes ATF5 a potential clinical therapeutic target. This article summarizes the structural features and translational regulatory mechanisms of ATF5, focusing on its role in cellular inflammatory stress responses, particularly its regulatory mechanisms in UPR^mt and ERS, aiming to provide a theoretical basis for understanding ATF5's role in cell and organ protection and to offer new insights into the treatment of related inflammatory diseases.
Humans ; Endoplasmic Reticulum Stress ; Inflammation/metabolism* ; Activating Transcription Factors/metabolism* ; Unfolded Protein Response ; Mitochondria/metabolism* ; Apoptosis ; Animals

The real-time Delphi method represents a refinement of the classical Delphi technique, designed to overcome limitations such as prolonged study duration and delayed feedback during consensus development. This article, building upon the classical Delphi foundation, systematically elaborates on the application process, advantages, and limitations of the real-time Delphi method. It further presents currently available websites or software capable of facilitating real-time Delphi exercises and offers considerations and recommendations for its application in guideline development, aiming to serve as a reference for relevant researchers.

Objective:To evaluate the role of ryanodine receptor 2 (RyR2) in postoperative cognitive dysfunction (POCD) in aged rats.Methods:Sixty SPF healthy male Sprague-Dawley rats, aged 20 months, weighing 600-650 g, were divided into 3 groups ( n=20 each) using a random number table method: control group (group C), POCD group (group P) and dantrolene group (group D). A rat POCD model was prepared by closed reduction and internal fixation of left tibial fractures with sevoflurane anesthesia in P and D groups. RyR inhibitor dantrolene 2 mg/kg was injected via a tail vein at 30 min before surgery in group D. Morris water maze tests were conducted on day 1 before surgery and day 7 after surgery to evaluate the cognitive function. An open field test was conducted to detect the spontaneous motor function starting from day 7 after surgery. The rats were sacrificed after the end of Morris water maze tests and hippocampal tissues were taken for determination of the expression of RyR2 and cleaved caspase-3 (by Western blot), apoptosis rate and cytoplasmic calcium ion concentrations (by flow cytometry) and for microscopic examination of the pathological changes in hippocampal CA1 area (using HE staining). Results:There was no significant difference in the speed, distance and duration of stay in the center in the open field test among the three groups ( P>0.05). Compared with group C, the escape latency was significantly prolonged after surgery, the number of crossing the original platform was reduced, the expression of RyR2 and cleaved caspase-3 was up-regulated, and the neuronal apoptosis rate and cytoplasmic calcium ion concentration were increased ( P<0.05), and the pathological changes were found in the hippocampal CA1 area in group P. Compared with group P, the escape latency was significantly shortened after surgery, the number of crossing the original platform was increased, the expression of RyR2 and cleaved caspase-3 was down-regulated, and the neuronal apoptosis rate and cytoplasmic calcium ion concentration were decreased ( P<0.05), and the pathological changes were significantly reduced in the hippocampal CA1 area in group D. Conclusions:RyR2 activation is involved in the process of POCD in aged rats, which may be associated with increased calcium overload-induced hippocampal neuronal apoptosis.

Objective To understand the molecular epidemiological characteristics of Norovirus outbreaks and the genome evolution of Norovirus epidemic strains in Hainan Province from 2020 to 2022.Methods The information and samples have been collected from the norovirus outbreaks from 2020 to 2022.Norovirus was detected by using the real-time PCR in these samples,then the detected sequences were amplified the analyzed.The Norovirus se-quences of 8 strains had been amplified and analyzed.Results From 2020 to 2022,39 gastroenteritis outbreaks were reported,and 25 outbreaks caused by Norovirus which mainly occurred in childcare institutions and schools(20/25,80％).The Norovirus outbreaks were mainly concentrated in counties around Haikou(northeast),which including Ding'an(5 cases),Wenchang(4 cases),Chengmai(4 cases),and Lingao(3 cases);following by western regions which included Baisha(2 cases),Ledong(2 cases),and Dongfang(3 cases).1 case was in Wanning in the southeast.Among individuals aged 2-17,the positive proportion of Norovirus in males was higher than that in females.Among individuals aged over 55,the proportion of Norovirus positive in females was higher than that in males.The gender of positive samples among individuals aged 18-40 was related to their profession.According to RT-PCR typing and sequencing,GⅡ group Norovirus were classified in13 outbreaks.There were 4 genotypes detected.GⅡ.2[P1 6]was the main epidemic strain with 60％(9/13),and the other three genotypes were GⅡ.4 Sydney[P31](15.4％,2/13)GⅡ.4 Sydney[P16](7.7％,1/13)and GⅡ.3[P12](7.7％,1/13).Further genic analysis of 8 Norovirus strains showed that all of them were still in the same branch as the previ-ous strain,and all exhibited a certain amount of amino acid variation.Conclusion Norovirus is the main pathogen of gastroenteritis outbreaks in Hainan province,and the main epidemic strain is GⅡ.2[P16].It is necessary to continue to strengthen the monitoring that provides scientific evidence for the prevention and control of norovirus out-breaks in Hainan region.

Heart failure(HF)has complex pathophysiological mechanisms and is associated with high mortality and readmission rates.As the terminal manifestation of cardiovascular disease and the main cause of death,HF remains a critical focus in the medical community.Despite advances in standardized treatment through western medicine,many patients remain at high risk for cardiovascular events.Shenfu Qiangxin pill,a traditional Chinese patent medicine,has shown promising results in recent years regarding its mechanisms and clinical applications for HF treatment.This article elaborates on the latest research trends of Shenfu Qiangxin pill in the treatment of HF,examining its composition,efficacy,and mechanisms from both traditional Chinese and western medical perspectives.It also explores its clinical applications and safety,highlighting its potential and prospects in HF treatment and providing a theoretical basis for clinical practice.

Objective:To describe the characteristics, etiology and patterns of outpatients and inpatients patients with moderate or severe valvular heart disease (VHD).Methods:This is a cross-sectional study. Outpatients and inpatients with moderate or severe VHD who underwent transthoracic echocardiography for first examination from 1 st January 2001 to 1 st January 2020 in Southwest Hospital, Army Medical University were enrolled. Data were collected from medical records and big data platform of Southwest Hospital. Characteristics of age and gender, etiology and types of VHD were descriptively analysed. Results:A total of 68 354 patients with moderate or severe VHD were enrolled. The age was 63 (50, 72) years. And 35 706 (52.24%) patients were female. (1) Age characteristics: There was similar age trend between male and female patients with moderate or severe VHD. The number of patients increased firstly and then decreased and reached its peak in the age group of 65-69 years old. The peak age of mitral stenosis patients was 45-49 years, which was earlier than that of whole patients with moderate or severe VHD. The median age of patients with bicuspid aortic valve was 42 years. (2) Gender characteristics: The proportion of tricuspid regurgitation, pulmonary regurgitation, mitral regurgitation, mitral stenosis and valve surgery in female patients with moderate or severe VHD were higher than those in male patients. The proportion of aortic regurgitation, aortic stenosis and bicuspid aortic valve in male patients with moderate or severe VHD were significantly higher than those in female patients (all P<0.05). (3) Etiology: The proportion of rheumatic VHD was 13.07% (8 934/68 354), which was higher than that of degenerative VHD (0.67% (458/68 354)). (4) Types of VHD: Tricuspid regurgitation made contribution to the largest proportion with 60.72% (41 503/68 354), followed by mitral regurgitation, aortic regurgitation, mitral stenosis, pulmonary regurgitation and aortic stenosis. Conclusions:There are certain regional characteristics in the prevalence of moderate or severe VHD in southwest China, suggesting different attention should be paid on the whole process of refined management of moderate or severe VHD.

Objective:To evaluate the effect of intermittent fasting on postoperative cognitive function in aged rats and the role of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in it.Methods:Eighty SPF healthy male Sprague-Dawley rats, aged 20 months, weighing 600-650 g, were divided into 4 groups ( n=20 each) using a random number table method: control group (group C), postoperative cognitive dysfuction (POCD) group (group P), intermittent fasting + POCD group (group IF+ P), and intermittent fasting+ JAK2/STAT3 signaling pathway agonist C-A1+ POCD group (group IF+ A+ P). IF+ P group and IF+ A+ P group underwent a 4-week intermittent fasting procedure: fasting for 24 h followed by free eating for 24 h, without limiting water intake throughout the entire process, in addition C-A1 100 μg/kg was intraperitoneally injected daily during intermittent fasting in IF+ A+ P group. Rats underwent exploratory laparotomy under sevoflurane anesthesia to prepare POCD models in P group, IF+ P group and IF+ A+ P group. Three days after surgery, open field tests were conducted to evaluate the autonomous motor function of rats, and Morris water maze tests were conducted to evaluate the cognitive function of rats on 3-7 days after surgery. After the Morris water maze tests, the rats were sacrificed and the hippocampal CA1 area was removed for determination of the expression of JAK2, phosphorylated JAK2 (p-JAK2), STAT3, and phosphorylated STAT3 (p-STAT3) (by Western blot) and contents of interleukin-6 (IL-6), IL-1β and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay) and for microscopic examination of pathological changes of hippocampal CA1 region (using HE staining). Results:There was no statistically significant difference in the speed, distance and duration of stay at the center of the open field test among the four groups ( P>0.05). Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, and the p-JAK2/JAK2 ratio, p-STAT3/STAT3 ratio and contents of IL-6, IL-1β and TNF-α in the hippocampal CA1 region were increased ( P<0.05), and the pathological damage occurred in the hippocampal CA1 region in group P. Compared with P group, the escape latency was significantly shortened, the number of crossing the original platform was increased, and the p-JAK2/JAK2 ratio, p-STAT3/STAT3 ratio and contents of IL-6, IL-1β and TNF-α in the hippocampal CA1 region were decreased ( P<0.05), and the pathological damage in the hippocampal CA1 area was significantly alleviated in IF+ P group. Compared with IF+ P group, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, and the p-JAK2/JAK2 ratio, p-STAT3/STAT3 ratio and contents of IL-6, IL-1β and TNF-α in the hippocampal CA1 region were increased ( P<0.05), and the pathological damage in the hippocampal CA1 area was aggravated in group IF+ A+ P. Conclusions:Intermittent fasting can improve postoperative cognitive function in aged rats, and the mechanism may be related to inhibiting the JAK2/STAT3 signaling pathway and reducing the neuroinflammatory responses in the hippocampal CA1 region.

Objective:To evaluate the role of Homer1a/metabotropic glutamate receptor 5 (mGluR5) signaling pathway in sleep deprivation-induced cognitive dysfunction in aged rats.Methods:One hundred and four SPF healthy male Sprague-Dawley rats, aged 22-24 months, weighing 320-360 g, were divided into 4 groups ( n=26 each) using a random number table method: normal control group (group Control), sleep deprivation+ vehicle group (group SD+ Vehicle), sleep deprivation+ mGluR5 forward allosteric agent CDPPB group (group SD+ CDPPB), and sleep deprivation+ mGluR5 antagonist MPEP group (group SD+ MPEP). A 48-h sleep deprivation model was developed by sleep-deprived rod method. At the beginning of developing the model and 24 h after developing the model, CDPPB 10 mg/kg, MPEP 10 mg/kg and the equal volume of 1% Tween 80 were intraperitoneally injected in group SD+ CDPPB, group SD+ MPEP and group SD+ Vehicle, respectively.Morris water maze and novel object recognition tests were conducted to evaluate cognitive function after development of the model. The expression of Homer1a and mGluR5 in the hippocampus was detected by Western blot, the dendritic spine density in the hippocampal CA1 region was detected by Golgi staining, and the field excitatory postsynaptic potential (fEPSP) slope in the hippocampal CA1 region was detected by isolated electrophysiology. Results:Compared with Control group, the number of crossing the original platform, time of staying at the target quadrant, and novel object recognition index at 1 and 24 h after training were significantly decreased, the expression of Homer1a in the hippocampus was up-regulated, the expression of mGluR5 in the hippocampus was down-regulated, and the density of dendritic spine and fEPSP slope in the hippocampal CA1 region were decreased in group SD+ Vehicle ( P<0.05). Compared with group SD+ Vehicle, the number of crossing the original platform, time of staying at target quadrant, and novel object recognition index at 1 and 24 h after training were significantly increased, the expression of mGluR5 in hippocampus was up-regulated, and the density of dendritic spines and fEPSP slope in the hippocampal CA1 region were increased in group SD+ MPEP( P<0.05), and no statistically significant change was found in the parameters mentioned above in group SD+ CDPPB ( P>0.05). Conclusions:Sleep deprivation impairs the synaptic plasticity of hippocampal neurons by regulating Homer1a/mGluR5 signaling pathway, and thus mediating the process of cognitive dysfunction in aged rats.

Objective:To investigate the relationship between the mechanism of exogenous hydrogen sulfide (H 2S)-induced reduction of apoptosis in neurons during focal cerebral ischemia-reperfusion (I/R) and PINK1/Parkin pathway-mediated mitochondrial autophagy in rats. Methods:Two hundred and sixteen healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 250-270 g, were divided into 4 groups ( n=54 each) using a random number table method: control group (group C), I/R group, H 2S group and H 2S plus 3-methyladenine (3-MA) group (H 2S+ 3-MA group). Focal cerebral ischemia was induced by middle cerebral artery occlusion in anesthetized rats.In group H 2S+ 3-MA, 3-MA 10 mg/kg was intraperitoneally injected at 15 min before the onset of reperfusion, while the equal volume of normal saline was given instead in the other groups.In H 2S and H 2S+ 3-MA groups, 0.25% NaSH (a donor of exogenous H 2S) 10 mg/kg was intraperitoneally injected at the onset of reperfusion, while the equal volume of normal saline was given instead in the other groups.At 1, 3 and 7 days of reperfusion, neural function was scored, and corner test (the percentage of left turn was calculated) was performed.Brains were removed and brain tissues were obtained for determination of the cerebral infarct size, Bax, Bcl-2 and caspase-3 positive cells, cell apoptosis, and expression of mitophagy-related protein microtubule-associated protein 1 light chain 3 (LC3), PINK1 and Parkin (by Western blot). The percentage of cerebral infarct size, rate of Bax, Bcl-2 and caspase-3 positive cells and apoptosis rate were calculated.The ratio of LC3-Ⅱexpression to LC3-Ⅰexpression (LC3-Ⅱ/LC3-Ⅰ) was also calculated. Results:Compared with group C, the neural function score was significantly decreased, the percentage of left turn, percentage of cerebral infarct size, rate of Bax, Bcl-2 and caspase-3 positive cells, apoptosis rate of neurons, and LC3-Ⅱ/LC3-Ⅰ were increased, and the expression of PINK1 and Parkin was up-regulated at each time point of reperfusion in group I/R ( P<0.05). Compared with group I/R, the neural function score and rate of Bcl-2 positive cells were significantly increased, the percentage of left turn, percentage of cerebral infarct size, rate of Bax and caspase-3 positive cells, and apoptosis rate of neurons were decreased, the expression of PINK1 and Parkin was up-regulated, and LC3-Ⅱ/LC3-Ⅰ were increased at each time point of reperfusion in group H 2S ( P<0.05), and no significant change was found in the parameters mentioned above in group H 2S+ 3-MA ( P>0.05). Compared with group H 2S, the neural function score and rate of Bcl-2 positive cells were significantly decreased, the percentage of left turn, percentage of cerebral infarct size, rate of Bax and caspase-3 positive cells, and apoptosis rate of neurons were increased, the expression of PINK1 and Parkin was down-regulated, and LC3-Ⅱ/LC3-Ⅰ was decreased at each time point of reperfusion in H 2S+ 3-MA group ( P<0.05). Conclusion:The mechanism by which exogenous H 2S inhibits apoptosis in neurons during focal cerebral I/R is related to enhancing mitochondrial autophagy mediated by the PINK1/Parkin pathway in rats.

Objective:To determine the median effective dose (ED 50) and the 95% effective dose (ED 95) of remifentanil inhibiting responses to endotracheal intubation without neuromuscular relaxant when combined with dexmedetomidine in patients undergoing thyroid surgery. Methods:American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients of either sex, aged 18-64 yr, with body mass index of 18-28 kg/m 2, scheduled for elective thyroid surgery under intraoperative neuromonitoring, were enrolled in this study.Dexmedetomidine was intravenously injected in a loading dose of 0.8 μg/kg at 10 min before anesthesia induction.Anesthesia was induced by intravenously injecting midazolam 0.1 mg/kg, etomidate 0.4 mg/kg and the preset dose of remifentanil.The dose of remifentanil was determined using up-and-down sequential method.The initial dose was set at 3.7 μg/kg.The dose of remifentanil in the next case was determined according to whether responses to endotracheal intubation occurred, and the ratio between the two successive doses was 1.1.The ED 50, ED 95 and 95% confidence interval (CI) were calculated by Probit analysis. Results:when combined with dexmedetomidine for anesthesia induction, the ED 50 (95% CI) of remifentanil inhibiting responses to endotracheal intubation without neuromuscular relaxant was 3.39 (3.29-3.50) μg/kg, and the ED 95 (95% CI) was 3.52 (3.48-3.64) μg/kg. Conclusion:when combined with dexmedetomidine, the ED 50 of remifentanil inhibiting responses to endotracheal intubation without neuromuscular relaxant is 3.39 μg/kg, and the ED 95 is 3.52 μg/kg.