Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

The glucagon receptor (GCGR) is a critical target for the treatment of metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity. Activation of GCGR enhances systemic insulin sensitivity through paracrine stimulation of insulin secretion, presenting a promising avenue for treatment. However, the discovery of effective GCGR agonists remains a challenging and resource-intensive process, often requiring time-consuming wet-lab experiments to synthesize and screen potential compounds. Recent advances in artificial intelligence technologies have demonstrated great potential in accelerating drug discovery by streamlining screening and efficiently predicting bioactivity. In the present work, we propose DeepGCGR, a two-layer deep learning model that leverages graph convolutional networks (GCN) integrated with a multiple attention mechanism to expedite the identification of GCGR agonists. In the first layer, the model predicts the bioactivity of various compounds against GCGR, efficiently filtering large chemical libraries to identify promising candidates. In the second layer, DeepGCGR classifies high bioactive compounds based on their functional effects on GCGR signaling, identifying those with potential agonistic or antagonistic effects. Moreover, DeepGCGR was specifically applied to identify novel GCGR-regulating compounds for the treatment of T2DM from natural products derived from traditional Chinese medicine (TCM). The proposed method will not only offer an effective strategy for discovering GCGR-targeting compounds with functional activation properties but also provide new insights into the development of T2DM therapeutics.
Deep Learning ; Drug Discovery/methods* ; Humans ; Diabetes Mellitus, Type 2/metabolism* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology*

This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
Animals ; Male ; Mice ; Aquatic Organisms/chemistry* ; Biological Availability ; Cytochrome P-450 Enzyme System/metabolism* ; Glucuronosyltransferase/metabolism* ; Microsomes, Liver/metabolism* ; Molecular Structure ; Biological Products/pharmacokinetics* ; Pyridines/pharmacokinetics*

BACKGROUND:Inflammation is one of the important factors that induce cerebral ischemia-reperfusion injury.Studies have shown that electroacupuncture can effectively reduce inflammation after ischemic stroke and improve the symptoms of neurological deficits,but the mechanism is not clear. OBJECTIVE:To observe the effect of electroacupuncture on Toll-like receptor 4/nuclear factor-κB in rats with cerebral ischemia-reperfusion injury. METHODS:Forty-eight male Sprague-Dawley rats were randomly divided into sham operation group,model group and electroacupuncture group,with 16 rats in each group.The rat model of cerebral ischemia-reperfusion injury was prepared by middle cerebral artery occlusion.At 24 hours after modeling,the rats in the electroacupuncture group were treated with electroacupuncture,once a day,20 minutes each time,for a total of 5 days.The sham operation group and the model group did not do any intervention.After 5 days of intervention,Longa method was used to evaluate the degree of neurological injury in rats.Triphenyl tetrazolium chloride staining and hematoxylin-eosin staining were used to measure the volume of cerebral infarction and the pathological changes of brain tissue in rats.Serum interleukin-6,interleukin-18 and tumor necrosis factor-α were detected by ELISA.Expressions of Toll-like receptor 4 and nuclear factor-κB in the cerebral cortex at mRNA and protein levels were detected by fluorescence quantitative PCR and western blot,respectively. RESULTS AND CONCLUSION:Compared with the sham operation group,the neurological function scores,serum interleukin-6,interleukin-18,and tumor necrosis factor-α levels,Toll-like receptor 4 and nuclear factor-κB mRNA and protein expression levels were significantly higher in the model group(P＜0.01).Compared with the model group,electroacupuncture significantly reduced the neurological function scores,serum interleukin-6,interleukin-18,and tumor necrosis factor-α levels,Toll-like receptor 4 and nuclear factor-κB mRNA and protein expression levels(P＜0.05,P＜0.01).Compared with the sham operation group,the volume of cerebral infarction in the model group increased significantly(P＜0.01).Compared with the model group,the volume of cerebral infarction in the electroacupuncture group decreased(P＜0.05).In the model group,the arrangement of neurons was disordered,some nerve cells disappeared,nuclei presented with pyknosis and incomplete structure.After electroacupuncture intervention,the degree of neuronal degeneration and neuronal loss in the cerebral cortex of rats were reduced compared with those in the model group.To conclude,electroacupuncture can significantly improve the neurobehavior of rats with cerebral ischemia-reperfusion injury,reduce brain tissue injury,and effectively reduce the level of serum inflammatory factors.The mechanism may be related to the inhibition of Toll-like receptor 4/nuclear factor-κB signaling pathway.

Background Occupational stress is an important public health problem in the military. At present, there are few studies about occupational stress of officers and soldiers of the armed forces in China, especially the effects of plateau related environmental factors on occupational stress. Objective To understand current status and identify influencing factors of occupational stress among officers and soldiers stationed in plateaus, and provide a scientific basis for managing occupational stress. Methods In April 2023, stratified cluster sampling was used to recruit troops by deployed altitudes ranging from 500 to 3000 m into two strata of low altitude (＜2500 m) and high altitude (≥2500 m) based on the medical definition of plateau. Two regimental units were randomly selected from each stratum respectively, and one battalion unit was randomly selected from each regimental unit with all the officers and soldiers. Four selected battalion units were surveyed with a total of 2284 officers and soldiers. We designed a general questionnaire to collect their basic information, and distributed effort-reward imbalance questionnaires to evaluate occupational stress. We used logistic regression to identify potential influencing factors of occupational stress. Results Positive occupational stress was reported in 508 plateau-stationed officers and soldiers, with a prevalence rate of 22.2%. The total effort-reward imbalance score and the dimensional scores of effort, reward, and overcommitment in M (P₂₅, P₇₅) were 0.9 (0.7, 1.0), 16.0 (13.0, 19.0), 36.0 (33.0, 39.0), and 18.0 (15.0, 19.0), respectively. There were significant differences in the positive rate of occupational stress by gender, age, military service length, marital status, only child or not, physical fitness condition, reporting underlying diseases or not, exercise frequency before conscription, psychological changes after entering the plateaus, and having altitude sickness or not (P <0.05). The results of logistic regression showed that being female (OR=1.532, 95%CI: 1.061, 2.213), only child (OR=1.281, 95%CI: 1.038, 1.581), and with underlying diseases (OR=1.950, 95%CI: 1.340, 2.839) were associated with a higher risk of occupational stress. While setting 0 to <3 years of military service as the control group, the risk of occupational stress was higher in subgroups of 3 to 9 years (OR=1.380, 95%CI: 1.113, 1.710) and ≥9 years (OR=2.141, 95%CI: 1.461, 3.137). The participants reporting nervousness or fear (OR=1.728, 95%CI: 1.133, 2.635) and agitation or euphoria (OR=1.380, 95%CI: 1.113, 1.710) had a higher risk of reporting occupational stress than those with no psychological changes after entering the plateaus. Meanwhile, those who had regular exercise (OR=0.670, 95%CI: 0.492, 0.913) before enlistment, good physical fitness condition (OR=0.572, 95%CI: 0.426, 0.767) and excellent physical fitness condition (OR=0.502, 95%CI: 0.366, 0.688) had a lower risk of occupational stress. Conclusion Officers and soldiers in plateaus generally report a high rate of occupational stress. Female, military service length ≥3 years, being only child, with underlying diseases, nervousness/ fear or agitation/ euphoria after entering plateaus are risk factors for elevated occupational stress in this group; while good or excellent physical fitness condition and frequent exercise before enlistment are protective factors for occupational stress. Therefore, it is necessary to pay attention to the occupational stress problems in officers and soldiers stationed in plateaus and provide targeted intervention measures.

Nowadays,the prevalence of nonalcoholic fatty liver disease(NAFLD)is constantly rising in China and globally,and its incidence rate is increasing year by year,which has seriously affected human life and health.Lipophagy is molecular chaperone-mediated autophagy and has the functions of promoting lipolysis,maintaining the lipid homeostasis of hepatocytes,and alleviating hepatocyte fatty degeneration.Lipophagy has three main processes of lipid droplet catabolism,lipid droplet autophagy,and fatty acid β-oxidation,which are regulated by key genes,receptors,and enzymes.Currently,important advances have been achieved for the intervention methods of traditional Chinese medicine,Western medicine,diet,and exercise in the research on lipophagy,which provides new perspectives for the prevention and treatment strategies for NAFLD.

Gynecological cancer significantly affect the health of women.This review aimed to describe the global patterns and trends in the survival of patients with gynecological cancers.We searched PubMed,Embase,Web of Science,SinoMed,and SEER for survival analyses of cancer registration data of cervical,endometrial,and ovarian cancers published between 1980 and 2022.Globally,the highest 5-year observed survival rate for cervical cancer was 76.5%in Anshan,Liaoning,China(2008-2017).The 5-year observed survival rates of endometrial and ovarian cancers were higher in Finland(1995-1999,82.5%)and Singapore(1988-1992,62.0%).The 5-year relative survival rate of cervical cancer patients was higher in Haining,Zhejiang,China(2011-2014,85.8%).Korea ranked first at 89.0%and 64.5%for endometrial and ovarian cancers,respectively.Survival rates have improved for cervical,endometrial,and ovarian cancers.Patients aged≥75 years and those with advanced-stage disease had the worst 5-year survival rates.Survival rates were better for squamous cell carcinoma in cervical cancer,for endometrial carcinoma and mucinous adenocarcinoma in endometrial cancer,and for germ cell and sex-cord stromal tumors in ovarian cancer.Over the past four decades,the survival rates of gynecological cancers have increased globally,with notable increases in cervical and endometrial cancers.Survival rates are higher in developed countries,with a slow-growing trend.Future studies should focus on improving survival,especially in ovarian cancer patients.