Identification and validation of lipid metabolism-related key genes as novel biomarkers in acute myocardial infarction and pan-cancer analysis.

BACKGROUND: Acute myocardial infarction (AMI) is associated with high morbidity and mortality, and is associated with abnormal lipid metabolism. We identified lipid metabolism related genes as biomarkers of AMI, and explored their mechanisms of action. METHODS: Microarray datasets were downloaded from the GEO database and lipid metabolism related genes were obtained from Molecular Signatures Database. WGCNA was performed to identify key genes. We evaluated differential expression and performed ROC and ELISA analyses. We also explored the mechanism of AMI mediated by key genes using gene enrichment analysis. Finally, immune infiltration and pan-cancer analyses were performed for the identified key genes. RESULTS: TRL2, S100A9, and HCK were identified as key genes related to lipid metabolism in AMI. Internal and external validation (including ELISA) showed that these were good biomarkers of AMI. In addition, the results of gene enrichment analysis showed that the key genes were enriched in inflammatory response, immune system process, and tumor-related pathways. Finally, the results of immune infiltration showed that key genes were concentrated in neutrophils and macrophages, and pan-cancer analysis showed that the key genes were highly expressed in most tumors and were associated with poor prognosis. CONCLUSIONS: TLR2, S100A9, and HCK were identified as lipid metabolism related novel diagnostic biomarkers of AMI. In addition, AMI and tumors may be related through the inflammatory immune response.

Analysis of the fatigue status of medical security personnel during the closed-loop period using multiple machine learning methods: a case study of the Beijing 2022 Olympic Winter Games.

Using machine learning methods to analyze the fatigue status of medical security personnel and the factors influencing fatigue (such as BMI, gender, and wearing protective clothing working hours), with the goal of identifying the key factors contributing to fatigue. By validating the predicted outcomes, actionable and practical recommendations can be offered to enhance fatigue status, such as reducing wearing protective clothing working hours. A questionnaire was designed to assess the fatigue status of medical security personnel during the closed-loop period, aiming to capture information on fatigue experienced during work and disease recovery. The collected data was then preprocessed and used to determine the structural parameters for each machine learning algorithm. To evaluate the prediction performance of different models, the mean relative error (MRE) and goodness of fit (R2) between the true and predicted values were calculated. Furthermore, the importance rankings of various parameters in relation to fatigue status were determined using the RF feature importance analysis method. The fatigue status of medical security personnel during the closed-loop period was analyzed using multiple machine learning methods. The prediction performance of these methods was ranked from highest to lowest as follows: Gradient Boosting Regression (GBM) > Random Forest (RF) > Adaptive Boosting (AdaBoost) > K-Nearest Neighbors (KNN) > Support Vector Regression (SVR). Among these algorithms, four out of the five achieved good prediction results, with the GBM method performing the best. The five most critical parameters influencing fatigue status were identified as working hours in protective clothing, a customized symptom and disease score (CSDS), physical exercise, body mass index (BMI), and age, all of which had importance scores exceeding 0.06. Notably, working hours in protective clothing obtained the highest importance score of 0.54, making it the most critical factor impacting fatigue status. Fatigue is a prevalent and pressing issue among medical security personnel operating in closed-loop environments. In our investigation, we observed that the GBM method exhibited superior predictive performance in determining the fatigue status of medical security personnel during the closed-loop period, surpassing other machine learning techniques. Notably, our analysis identified several critical factors influencing the fatigue status of medical security personnel, including the duration of working hours in protective clothing, CSDS, and engagement in physical exercise. These findings shed light on the multifaceted nature of fatigue among healthcare workers and emphasize the importance of considering various contributing factors. To effectively alleviate fatigue, prudent management of working hours for security personnel, along with minimizing the duration of wearing protective clothing, proves to be promising strategies. Furthermore, promoting regular physical exercise among medical security personnel can significantly impact fatigue reduction. Additionally, the exploration of medication interventions and the adoption of innovative protective clothing options present potential avenues for mitigating fatigue. The insights derived from this study offer valuable guidance to management personnel involved in organizing large-scale events, enabling them to make informed decisions and implement targeted interventions to address fatigue among medical security personnel. In our upcoming research, we will further expand the fatigue dataset while considering higher precisionprediction algorithms, such as XGBoost model, ensemble model, etc., and explore their potential contributions to our research.

The crosstalk between mitochondrial quality control and metal-dependent cell death.

Mitochondria are the centers of energy and material metabolism, and they also serve as the storage and dispatch hubs of metal ions. Damage to mitochondrial structure and function can cause abnormal levels and distribution of metal ions, leading to cell dysfunction and even death. For a long time, mitochondrial quality control pathways such as mitochondrial dynamics and mitophagy have been considered to inhibit metal-induced cell death. However, with the discovery of new metal-dependent cell death including ferroptosis and cuproptosis, increasing evidence shows that there is a complex relationship between mitochondrial quality control and metal-dependent cell death. This article reviews the latest research results and mechanisms of crosstalk between mitochondrial quality control and metal-dependent cell death in recent years, as well as their involvement in neurodegenerative diseases, tumors and other diseases, in order to provide new ideas for the research and treatment of related diseases.

[Mechanism of intestinal injury induced by acute diquat poisoning in rats].

OBJECTIVE: To investigate the effects of diquat (DQ) on the expression of intestinal pyroptosis-related proteins and tight junction proteins in rats,and to analyze the role of pyroptosis in the intestinal injury of rats with acute DQ poisoning. METHODS: A total of 36 Wistar male rats were randomly divided into control group, and 3 hours, 12 hours, 36 hours and 3 days exposure groups, with 6 rats in each group. Each exposure group was given 1/2 median lethal dose (LD50) of 115.5 mg/kg DQ by one-time gavage. The control group was given the same amount of normal saline by gavage. The control group was anesthetized at 3 hours after DQ gavage to take jejunal tissues; each exposure group was anesthetized at 3 hours, 12 hours, 36 hours, and 3 days after DQ gavage to take jejunal tissues, respectively. The general conditions of the rats were recorded. The pathological changes of jejunum tissue were observed by hematoxylin-eosin (HE) staining. The expression of intestinal pyroptosis-related proteins [NOD-like receptor protein 3 (NLRP3), cysteine aspartate-specific protease 1 (caspase-1), Gasdemin D (GSDMD)] in the intestinal tissues was observed by immunohistochemical staining. Western blotting was used to detect the expression of intestinal pyroptosis-related proteins and intestinal tight junction proteins (Occludin and Claudin-1). RESULTS: Light microscopy showed that pathological changes occurred in jejunum tissue at the early stage of exposure (3 hours), and the injury was the most serious in the 12 hours exposure group, with a large number of inflammatory cells infiltrating in the tissue, and the damage was significantly reduced after 3 days exposure. Immunohistochemical results showed that NLRP3, caspase-1 and GSDMD were expressed in the jejunal mucosa of the control group and the exposure groups, and the positive cells in the control group were less expressed with light staining. The expression of the above proteins in the exposed group was increased significantly and the staining was deep. Western blotting results showed that compared with the control group, the expression of NLRP3 protein in jejunum tissues of all groups was increased, with the most significant increase in the 36 hours group (NLRP3/ß-actin: 1.47±0.06 vs. 0.43±0.14, P < 0.01). Compared with the control group, the expression of GSDMD protein in the 3 hours, 12 hours and 36 hours exposure groups increased, and the expression of GSDMD protein in the 3 hours and 12 hours exposure groups increased significantly (GSDMD/ß-actin: 1.04±0.40, 1.25±0.15 vs. 0.65±0.25, both P < 0.05). The expression of caspase-1 protein was increased in 36 hours exposure group compared with the control group (caspase-1/ß-actin: 1.44±0.34 vs. 0.98±0.19, P > 0.05). Compared with the control group, the expression of Occludin and Claudin-1 proteins in each exposure group decreased, and the expression of Occludin proteins was significantly decreased in the 3 hours, 12 hours, and 36 hours exposure groups decreased significantly (Occludin/ß-actin: 0.74±0.17, 0.91±0.20, 0.79±0.23 vs. 1.41±0.08, all P < 0.05). Although the protein expression of Claudin-1 decreased in each exposure group, the difference was not statistically significant. CONCLUSIONS: The intestinal injury caused by acute DQ poisoning may be related to the activation of pyroptosis pathway of small intestinal cells and the reduction of the density of intercellular junctions.

A national survey on current state and development needs of clinical and academic emergency medicine in China.

BACKGROUND: To characterize the current state of emergency medicine (EM) and the requirements for advancing EM clinical practice, education and research in China. METHODS: An anonymous electronic survey was conducted by Chinese Society of Emergency Medicine during September to October 2021. The survey contained 30 questions divided into 2 sections: the current state of EM development and the requirements for EM growth. RESULTS: 722 hospitals were included, of 487 were Level III and 235 were Level II hospitals. We found that after 40 years of development, EM had established a mature disciplinary system and refined sub-specialties including critical care, cardiopulmonary resuscitation, toxicology, disaster and emergency rescue. In Level III hospitals, 70.8% of EDs were standardized training centers for EM residents, but master's degree program, Doctor Degree program and post-doctoral degree program was approved in only 37.8%, 8.4% and 2.9% of EDs respectively and postgraduate curriculum was available in 1/4 of EDs. Only 8% have national or provincial key laboratories. In addition to advance clinical practice, there was also a high demand to improve teaching and research capacities, mainly focusing on literature review, research design and delivery, paper writing, residency training. CONCLUSIONS: EM has built a mature discipline system and refined sub-specialties in China. Teaching and research developed parallel with clinical practice. However, there was still a lack of EM master's and doctoral programs and research capacities need to be improved. More outstanding clinical and academic training should be provided to promote the rapid growth of EM in China.

Ferritinophagy: A novel insight into the double-edged sword in ferritinophagy-ferroptosis axis and human diseases.

Nuclear receptor coactive 4 (NCOA4), which functions as a selective cargo receptor, is a critical regulator of the particularly autophagic degradation of ferritin, a process known as ferritinophagy. Mechanistically, NCOA4-mediated ferritinophagy performs an increasingly vital role in the maintenance of intracellular iron homeostasis by promoting ferritin transport and iron release as needed. Ferritinophagy is not only involved in iron-dependent responses but also in the pathogenesis and progression of various human diseases, including metabolism-related, neurodegenerative, cardiovascular and infectious diseases. Therefore, ferritinophagy is of great importance in maintaining cell viability and function and represents a potential therapeutic target. Recent studies indicated that ferritinophagy regulates the signalling pathway associated with ferroptosis, a newly discovered type of cell death characterised by iron-dependent lipid peroxidation. Although accumulating evidence clearly demonstrates the importance of the interplay between dysfunction in iron metabolism and ferroptosis, a deeper understanding of the double-edged sword effect of ferritinophagy in ferroptosis has remained elusive. Details of the mechanisms underlying the ferritinophagy-ferroptosis axis in regulating relevant human diseases remain to be elucidated. In this review, we discuss the latest research findings regarding the mechanisms that regulate the biological function of NCOA4-mediated ferritinophagy and its contribution to the pathophysiology of ferroptosis. The important role of the ferritinophagy-ferroptosis axis in human diseases will be discussed in detail, highlighting the great potential of targeting ferritinophagy in the treatment of diseases.

Food-Borne Poisoning Accident from Amanitin Toxin in Wild Mushrooms - Xingtai City, Hebei Province, China, 2023.

What is already known about this topic?: Fatal poisonings caused by wild mushrooms containing amanita toxins pose a significant threat in the southern regions of China. These toxins primarily induce gastrointestinal symptoms initially, which are then followed by potentially life-threatening acute liver damage. What is added by this report?: This report contributes to the existing knowledge on these cases of poisoning by documenting the second occurrences in Hebei Province and the first occurrences in Xingtai City. Five individuals reported consuming wild mushrooms from the same origin, and laboratory tests confirmed the presence of α-amanitin in their blood samples. What are the implications for public health practice?: This underscores the risk associated with the collection and consumption of amanita toxin-containing mushrooms in Hebei. It is important to note that the identification of toxic and non-toxic mushrooms should not solely rely on personal experience or appearance.

Anisodamine hydrobromide in the treatment of critically ill patients with septic shock: a multicenter randomized controlled trial.

BACKGROUND: Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. METHODS: This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. RESULTS: Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. CONCLUSION: Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

Multicenter, randomized controlled, open label evaluation of the efficacy and safety of arbidol hydrochloride tablets in the treatment of influenza-like cases.

OBJECTIVE: To study the efficacy and safety of arbidol hydrochloride tablets as a treatment for influenza-like diseases. METHODS: In this multicenter, randomized, controlled, open label study, a total of 412 influenza-like cases were collected from 14 hospitals in seven regions of Hebei Province from September 2021 to March 2022. Patients were randomly divided into two groups. The control group (n = 207) were administered oseltamivir phosphate capsules for five days and the experimental group (n = 205) were administered arbidol hydrochloride tablets for five days. The primary endpoint was the time to normal body temperature, and the secondary endpoints included the time to remission of influenza symptoms, incidence of influenza-like complications, and incidence of adverse reactions. RESULTS: Before treatment, there was no significant difference between the two groups in general conditions, blood routine, body temperature, or symptom severity. After treatment, there was no significant difference between the groups in the mean time to fever remission (59.24 h ± 25.21 vs. 61.05 h ± 29.47) or the mean time to remission of influenza symptoms (57.31 h ± 30.19 vs. 62.02 h ± 32.08). Survival analyses using Log-rank and Wilcoxon bilateral tests showed that there was no significant difference in fever relief time or influenza symptom relief time between the two groups. Regarding the incidence of complications and adverse events, there was only one case of tracheitis, one case of nausea, one case of vomiting, and one case of dizziness in the control group. In the experimental group, there was one case of nausea, one case of vomiting, and one case of drowsiness. In addition, one patient in the control group was hospitalized for urinary calculi. CONCLUSION: There was no significant difference between the patients with influenza-like cases treated with arbidol hydrochloride tablets and those treated with oseltamivir phosphate capsules. Further, the patients treated with arbidol hydrochloride tablets had fewer adverse reactions, and thus, the tablets were safe to use.

[Experimental study on the toxicokinetics and gastrointestinal damage in rats poisoned with acute diquat poisoning at different exposure doses].

OBJECTIVE: To observe the toxicokinetic parameters, absorption characteristics and pathomorphological damage in different parts of the gastrointestinal tract of rats poisoned with different doses of diquat (DQ). METHODS: Ninety-six healthy male Wistar rats were randomly divided into a control group (six rats) and low (115.5 mg/kg), medium (231.0 mg/kg) and high (346.5 mg/kg) dose DQ poisoning groups (thirty rats in each dose group), and then the poisoning groups were randomly divided into 5 subgroups according to the time after exposure (15 minutes and 1, 3, 12, 36 hours; six rats in each subgroup). All rats in the exposure groups were given a single dose of DQ by gavage. Rats in the control group was given the same amount of saline by gavage. The general condition of the rats was recorded. Blood was collected from the inner canthus of the eye at 3 time points in each subgroup, and rats were sacrificed after the third blood collection to obtain gastrointestinal specimens. DQ concentrations in plasma and tissues were determined by ultra-high performance liquid chromatography and mass spectrometry (UPHLC-MS), and the toxic concentration-time curves were plotted to calculate the toxicokinetic parameters; the morphological structure of the intestine was observed under light microscopy, and the villi height and crypt depth were determined and the ratio (V/C) was calculated. RESULTS: DQ was detected in the plasma of the rats in the low, medium and high dose groups 5 minutes after exposure. The time to maximum plasma concentration (Tmax) was (0.85±0.22), (0.75±0.25) and (0.25±0.00) hours, respectively. The trend of plasma DQ concentration over time was similar in the three dose groups, but the plasma DQ concentration increased again at 36 hours in the high dose group. In terms of DQ concentration in gastrointestinal tissues, the highest concentrations of DQ were found in the stomach and small intestine from 15 minutes to 1 hour and in the colon at 3 hours. By 36 hours after poisoning, the concentrations of DQ in all parts of the stomach and intestine in the low and medium dose groups had decreased to lower levels. Gastrointestinal tissue (except jejunum) DQ concentrations in the high dose group tended to increase from 12 hours. Higher doses of DQ were still detectable [gastric, duodenal, ileal and colonic DQ concentrations of 6 400.0 (1 232.5), 4 889.0 (6 070.5), 10 300.0 (3 565.0) and 1 835.0 (202.5) mg/kg respectively]. Light microscopic observation of morphological and histopathological changes in the intestine shows that acute damage to the stomach, duodenum and jejunum of rats was observed 15 minutes after each dose of DQ, pathological lesions were observed in the ileum and colon 1 hour after exposure, the most severe gastrointestinal injury occurred at 12 hours, significant reduction in villi height, significant increase in crypt depth and lowest V/C ratio in all segments of the small intestine, damage begins to diminish by 36-hour post-intoxication. At the same time, morphological and histopathological damage to the intestine of rats at all time points increased significantly with increasing doses of the toxin. CONCLUSIONS: The absorption of DQ in the digestive tract is rapid, and all segments of the gastrointestinal tract may absorb DQ. The toxicokinetics of DQ-tainted rats at different times and doses have different characteristics. In terms of timing, gastrointestinal damage was seen at 15 minutes after DQ, and began to diminish at 36 hours. In terms of dose, Tmax was advanced with the increase of dose and the peak time was shorter. The damage to the digestive system of DQ is closely related to the dose and retention time of the poison exposure.

A simple and sensitive LC-MS/MS method for therapeutic drug monitoring of digoxin in children.

This short communication introduced a simple and sensitive LC-MS/MS method for therapeutic drug monitoring of digoxin in children with the lower limit of quantitation of 0.2 ng/mL based on 30 µL of plasma. The plasma sample was pretreated by one-step protein precipitation. Then the chromatographic separation was performed on a short C-18 column with a total run time of 2.4 min. The detection was achieved through multiple reaction monitoring using positive ionization mode on a triple quadrupole mass spectrometer. The linear range of digoxin in human plasma was among 0.2-6.4 ng/mL. The intra-day and inter-day accuracies of digoxin ranged from -6.0 % to 10.1 % and imprecisions were less than 8.8 %. The extraction recovery rate of digoxin in plasma samples was above 90 %. Matrix factor normalized by internal standard was within acceptance criteria. This method was fully verified and applied to determine the plasma digoxin concentrations of 43 pediatric patients. It is approved appropriate and practical for the therapeutic drug monitoring of digoxin in routine clinical laboratory practice, especially for children.

Publication trends of research on sepsis and programmed cell death during 2002-2022: A 20-year bibliometric analysis.

Background: Sepsis is considered an intractable dysfunction that results from the disordered host immune response to uncontrolled infection. Even though the precise mechanism of sepsis remains unclear, scientific advances have highlighted the key role of various programmed cell death processes in the pathophysiology of sepsis. The current study aims to explore the worldwide research trend on programmed cell death in the setting of sepsis and assesses the achievements of publications from various countries, institutions, journals, and authors globally. Material and methods: Associated publications during 2002-2022 with the topical subject of sepsis and programmed cell death were extracted from the Web of Science. VOSviewer was utilized to evaluate and map the published trend in the relevant fields. Results: All 2,037 relevant manuscripts with a total citation of 71,575 times were screened out by the end of 1 January 2022. China accounted for the largest number of publications (45.07%) and was accompanied by corporate citations (11,037) and H-index (48), which ranked second globally. The United States has been ranked first place with the highest citations (30,775) and H-index (88), despite a low publication number (29.95%), which was subsequent to China. The journal Shock accounted for the largest number of publications in this area. R. S. Hotchkiss, affiliated with Washington University, was considered to have published the most papers in the relevant fields (57) and achieved the highest citation frequencies (9,523). The primary keywords on the topic of programmed cell death in sepsis remarkably focused on "inflammation" "immunosuppression", and "oxidative stress", which were recognized as the core mechanisms of sepsis, eventually attributing to programmed cell death. The involved research on programmed cell death induced by immune dysregulation of sepsis was undoubtedly the hotspot in the pertinent areas. Conclusions: The United States has been academically outstanding in sepsis-related research. There appears to be an incompatible performance between publications and quantity with China. Frontier advances may be consulted in the journal Shock. The leading-edge research on the scope of programmed cell death in sepsis should preferably focus on immune dissonance-related studies in the future.

[Clinical features of 86 cases of acute diquat poisoning].

OBJECTIVE: To explore the clinical features of acute diquat (DQ) poisoning, and further improve the awareness of acute DQ poisoning. METHODS: A retrospective analysis was performed on the clinical data of patients with acute DQ poisoning diagnosed in the emergency department of the Second Hospital of Hebei Medical University from January 1, 2019 to December 31, 2021. The clinical data included age, gender, exposure routes, presence of pesticides (drugs) mixture poisoning, dosage of poison, the time from taking poisoning to admitting in the emergency department, clinical manifestations, laboratory data, treatment, hospital days, prognosis and survival days. RESULTS: The number of cases who firstly complained of acute DQ poisoning in the past three years were 19 cases in 2019, 28 cases in 2020, and 51 cases in 2021. A total of 12 patients were excluded due to being diagnosed paraquat (PQ) poisoning by toxicology detection. Finally, 86 cases of acute DQ poisoning were included, including 80 cases of oral DQ poisoning, 1 case of intramuscular injection, 1 case of binocular contact and 4 cases of dermal exposure. In 80 cases of oral DQ poisoning, there were 70 cases of diquat poisoning alone (42 cases survived, 28 cases died) and 10 cases of pesticide mixture poisoning (6 cases survived, 4 cases died). The time from oral poisoning to admitting in the emergency department was 0.5-96.0 hours, with an average of (8.6±5.8) hours. The time of intramuscular injection poisoning to admitting in the emergency department was 3 hours. The time of dermal exposure to admitting in the emergency department was relatively long, with an average of 66.1 hours. The time from oral simple DQ poisoning to death was 12.0-108.0 hours, and the time from oral mixed DQ poisoning to death was 24.0-576.0 hours. A total of 70 patients with oral diquat poisoning alone presented various degrees of multiple organ injuries. All patients presented gastrointestinal symptoms such as nausea and vomiting. Renal injury and central nervous system injury were the most significant and closely related to the prognosis. CONCLUSIONS: Acute oral DQ poisoning can cause to multiple organ injuries, and the clinical manifestations are related to the dose of the poison. In severe cases, acute renal failure and refractory circulatory failure occur within 24 hours after poisoning, and severe central nervous system injury with disturbance of consciousness as the primary manifestation occurs within 36 hours, followed by multiple organ failure until death.

miR-199b-5p-AKAP1-DRP1 Pathway Plays a Key Role in ox-LDL-induced Mitochondrial Fission and Endothelial Apoptosis.

BACKGROUND: Atherosclerosis (AS) remains prevalent despite hyperlipidemia-lowering therapies. Although multiple functions of miR-199b-5p have been implicated in cancers, its role in endothelial apoptosis and AS remains unclear. This study aimed to examine the role of miR-199b-5p in mitochondrial dynamics and endothelial apoptosis. METHODS: Human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL) were subjected to other treatments, followed by a series analysis. We found that ox-LDL-treated HUVECs were associated with miR-199b-5p downregulation, increased reactive oxygen species level, reduced adenosine triphosphate (ATP) production, mitochondrial fission, and apoptosis, whereas enhanced miR-199b-5p expression or applied mitochondrial division inhibitor 1 (Mdivi-1) markedly reversed these changes. RESULTS: Mechanistically, A-kinase anchoring protein 1 (AKAP1) was confirmed as a downstream target of miR-199b-5p by dual-luciferase activity reporter assay. AKAP1 overexpression reversed the anti-apoptotic effects of miR-199b-5p through the enhanced interaction of AKAP1 and dynamin protein 1 (DRP1) in ox-LDL-treated HUVECs. Moreover, miR-199b-5p downregulation, AKAP1 upregulation, and excessive mitochondrial fission were verified in human coronary AS endothelial tissues. CONCLUSION: The miR-199b-5p-dependent regulation of AKAP1/DRP1 is required to inhibit hyperlipidemia- induced mitochondrial fission and endothelial injury and may be a promising therapeutic target for AS.

[Early predictive value of high density lipoprotein cholesterol for secondary acute kidney injury in sepsis patients].

Objective: To investigate the changes of high density lipoprotein cholesterol (HDL-C) in sepsis patients and its early predictive value for secondary acute kidney injury (AKI) in such patients. Methods: A retrospective case series study was conducted. From June 2019 to June 2021, 232 sepsis patients who met the inclusion criteria were admitted to the Second Hospital of Hebei Medical University, including 126 males and 106 females, aged 24 to 71 years. According to whether complicating secondary AKI, the patients were divided into non-AKI group (n=158) and AKI group (n=74). Data of patients between the two groups were compared and statistically analyzed with independent sample t test or chi-square test, including the sex, age, body mass index (BMI), body temperature, heart rate, primary infection site, combined underlying diseases, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score and sepsis-related organ failure assessment (SOFA) score at admission, and the serum levels of C-reactive protein (CRP), procalcitonin, creatinine, cystatin C, and HDL-C measured at diagnosis of sepsis. The multivariate logistic regression analysis was performed on the indicators with statistically significant differences between the two groups to screen the independent risk factors for developing secondary AKI in 232 sepsis patients, and the joint prediction model was established based on the independent risk factors. The receiver operating characteristic (ROC) curve of the independent risk factors and the joint prediction model predicting secondary AKI in 232 sepsis patients were drawn, and the area under the curve (AUC), the optimal threshold, and the sensitivity and specificity under the optimal threshold were calculated. The quality of the above-mentioned AUC was compared by Delong test, and the sensitivity and specificity under the optimal threshold were compared using chi-square test. Results: The sex, age, BMI, body temperature, heart rate, primary infection site, combined underlying diseases, and CRP level of patients between the two groups were similar (P>0.05). The procalcitonin, creatinine, cystatin C, and scores of APACHE Ⅱ and SOFA of patients in AKI group were all significantly higher than those in non-AKI group (with t values of -3.21, -16.14, -12.75, -11.13, and -12.88 respectively, P<0.01), while the HDL-C level of patients in AKI group was significantly lower than that in non-AKI group (t=6.33, P<0.01). Multivariate logistic regression analysis showed that creatinine, cystatin C, and HDL-C were the independent risk factors for secondary AKI in 232 sepsis patients (with odds ratios of 2.45, 1.68, and 2.12, respectively, 95% confidence intervals of 1.38-15.35, 1.06-3.86, and 0.86-2.56, respectively, P<0.01). The AUCs of ROC curves of creatinine, cystatin C, HDL-C, and the joint prediction model for predicting secondary AKI in 232 sepsis patients were 0.69, 0.79, 0.89, and 0.93, respectively (with 95% confidence intervals of 0.61-0.76, 0.72-0.85, 0.84-0.92, and 0.89-0.96, respectively, P values all below 0.01); the optimal threshold were 389.53 µmol/L, 1.56 mg/L, 0.63 mmol/L, and 0.48, respectively; the sensitivity under the optimal threshold were 76.6%, 81.4%, 89.7%, and 95.5%, respectively; the specificity under the optimal threshold values were 78.6%, 86.7%, 88.6%, and 96.6%, respectively. The AUC quality of cystatin C was significantly better than that of creatinine (z=2.34, P<0.05), the AUC quality and sensitivity and specificity under the optimal threshold of HDL-C were all significantly better than those of cystatin C (z=3.33, with χ2 values of 6.43 and 7.87, respectively, P<0.01) and creatinine (z=5.34, with χ2 values of 6.32 and 6.41, respectively, P<0.01); the AUC quality and sensitivity and specificity under the optimal threshold of the joint prediction model were all significantly better than those of creatinine, cystatin C, and HDL-C (with z values of 6.18, 4.50, and 2.06, respectively, χ2 values of 5.31, 7.23, 3.99, 6.56, 7.34, and 4.00, respectively, P<0.05 or P<0.01). Conclusions: HDL-C level in sepsis patients with secondary AKI is significantly lower than that in patients without secondary AKI. This is an independent risk factor for secondary AKI in sepsis patients with a diagnostic value being superior to that of creatinine and cystatin C. The combination of the aforementioned three indicators would have higher predicative valuable for secondary AKI in sepsis patients.

5­Aminosalicylic acid attenuates paraquat­induced lung fibroblast activation and pulmonary fibrosis of rats.

Pulmonary fibrosis is one of the most important pathological processes associated with paraquat (PQ) poisoning. 5­Aminosalicylic acid (5­ASA) has been shown to be a promising agent against fibrotic diseases. In the present study, the alleviating role of 5­ASA was evaluated in a rat model of pulmonary fibrosis induced by PQ intragastric poisoning (80 mg/kg). Wistar rats were divided into control, PQ, 5­ASA (30 mg/kg daily, 14 days) and PQ + 5­ASA groups. Histological examination revealed congestion, edema and inflammatory cell infiltration in the bronchial and alveolar walls at 3 days after PQ exposure. Alveolar septum thickening with alveolar lumen narrowing was observed at 14 days, while fibroblast proliferation, increase in collagen fiber number and fibrous thickening of the alveolar walls were observed at 28 day. All the aforementioned pulmonary injury changes in the PQ group were attenuated in the PQ + 5­ASA group. Hydroxyproline (HYP) content increased in the lung tissues of the rats at 14 days after PQ treatment and reached a peak at 28 days. Compared with the PQ group, HYP contents of lung tissue decreased at 14 and 28 days after PQ + 5­ASA treatment. Masson's trichrome staining revealed that the increase in the amount of collagen fibers in the lung tissues of rats in the PQ group was inhibited by 5­ASA treatment, further confirming the alleviating effect of 5­ASA on fibrosis. In addition, the results showed that 5­ASA attenuated the upregulation of transforming growth factor­ß1 and phosphorylated­SMAD3, and the reduction of peroxisome proliferator activated receptor γ induced by PQ in lung tissue of rats and human lung fibroblast WI­38 VA13 cells. In conclusion, the results suggested that 5­ASA had an alleviating effect on PQ­induced pulmonary fibrosis, partly by suppressing the activation of the TGF­ß1 signaling pathway.

A Novel Insight Into the Fate of Cardiomyocytes in Ischemia-Reperfusion Injury: From Iron Metabolism to Ferroptosis.

Ischemia-reperfusion injury (IRI), critically involved in the pathology of reperfusion therapy for myocardial infarction, is closely related to oxidative stress the inflammatory response, and disturbances in energy metabolism. Emerging evidence shows that metabolic imbalances of iron participate in the pathophysiological process of cardiomyocyte IRI [also termed as myocardial ischemia-reperfusion injury (MIRI)]. Iron is an essential mineral required for vital physiological functions, including cellular respiration, lipid and oxygen metabolism, and protein synthesis. Nevertheless, cardiomyocyte homeostasis and viability are inclined to be jeopardized by iron-induced toxicity under pathological conditions, which is defined as ferroptosis. Upon the occurrence of IRI, excessive iron is transported into cells that drive cardiomyocytes more vulnerable to ferroptosis by the accumulation of reactive oxygen species (ROS) through Fenton reaction and Haber-Weiss reaction. The increased ROS production in ferroptosis correspondingly leads cardiomyocytes to become more sensitive to oxidative stress under the exposure of excess iron. Therefore, ferroptosis might play an important role in the pathogenic progression of MIRI, and precisely targeting ferroptosis mechanisms may be a promising therapeutic option to revert myocardial remodeling. Notably, targeting inhibitors are expected to prevent MIRI deterioration by suppressing cardiomyocyte ferroptosis. Here, we review the pathophysiological alterations from iron homeostasis to ferroptosis together with potential pathways regarding ferroptosis secondary to cardiovascular IRI. We also provide a comprehensive analysis of ferroptosis inhibitors and initiators, as well as regulatory genes involved in the setting of MIRI.