Objective:To evaluate the role of the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling pathway in the reduction of cerebral ischemia-reperfusion injury (CIRI) by trilobatin pretreatment in rats.Methods:Eighty clean-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 250-300 g, were divided into 4 groups ( n=20 each) using a random number table method: sham operation group (group S), group CIRI, trilobatin+ CIRI group (group TC) and trilobatin+ CIRI+ AAV-TLR4 group (group TCA). The model of CIRI was established by middle cerebral artery occlusion in anesthetized animals in CIRI, TC and TCA groups. In group TCA, the adeno associated virus was injected into the cortical region to up-regulate the expression of TLR4 at 21 days before developing the model. Trilobatin 15 mg/kg was administered by gavage twice daily for 3 days prior to ischemia in TC and TCA groups. The cognitive function was assessed using the modified Longa score at 24 h of reperfusion. Then the rats were sacrificed and the whole brain tissues were isolated for determination of the cerebral infarct size (by TTC staining), expression of TLR4, MyD88 and TRAF6 (by Western blot), and contents of interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay) and for microscopic examination of the neuronal ultrastructure in ischemic cerebral cortex tissues (with a transmission electron microscope). Results:Compared with group S, the Longa score and percentage of cerebral infarct size were significantly increased, the expression of TLR4, MyD88 and TRAF6 in cerebral cortex tissues of ischemic regions was up-regulated, the contents of IL-1β, IL-6 and TNF-α were increased ( P<0.05), and the pathological damage to cortical neurons was aggravated in CIRI group. Compared with group CIRI, the Longa score and percentage of cerebral infarct size were significantly decreased, the expression of TLR4, MyD88 and TRAF6 was down-regulated, the contents of IL-1β, IL-6 and TNF-α were decreased in cerebral cortex tissues of ischemic regions ( P<0.05), and the pathological damage to cortical neurons was significantly attenuated in group TC. Compared with group TC, the Longa score and percentage of cerebral infarct size were significantly increased, the expression of TLR4, MyD88 and TRAF6 was up-regulated, the contents of IL-1β, IL-6 and TNF-α were increased in cerebral cortex tissues of ischemic regions ( P<0.05), and the pathological damage to cortical neurons was aggravated in group TCA. Conclusions:The TLR4-MyD88-TRAF6 signaling pathway is involved in the reduction of cerebral I/R injury by trilobatin pretreatment in rats.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

The drugs used to improve brain metabolism mainly include ergotamine derivatives,GABA derivatives,vitamin B6 derivatives,neuropeptides,morpholines,hormones and other.However,these drugs may have adverse reactions during clinical application.This article focuses on the adverse effects of commonly used drugs for brain metabolism,and reviews the studies on the new state of pharmaceutical substances,such as drug combination,chiral resolution of isomers,crystal form of dominant drugs,co-crystal drugs and nanodrugs,with the aim of reducing adverse reactions.By summarizing the research on modifying the solid state of drugs to mitigate adverse reactions,this article provides new research insights for obtaining new drug with less adverse reaction and greater clinical value.

Objective:To evaluate the role of the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling pathway in the reduction of cerebral ischemia-reperfusion injury (CIRI) by trilobatin pretreatment in rats.Methods:Eighty clean-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 250-300 g, were divided into 4 groups ( n=20 each) using a random number table method: sham operation group (group S), group CIRI, trilobatin+ CIRI group (group TC) and trilobatin+ CIRI+ AAV-TLR4 group (group TCA). The model of CIRI was established by middle cerebral artery occlusion in anesthetized animals in CIRI, TC and TCA groups. In group TCA, the adeno associated virus was injected into the cortical region to up-regulate the expression of TLR4 at 21 days before developing the model. Trilobatin 15 mg/kg was administered by gavage twice daily for 3 days prior to ischemia in TC and TCA groups. The cognitive function was assessed using the modified Longa score at 24 h of reperfusion. Then the rats were sacrificed and the whole brain tissues were isolated for determination of the cerebral infarct size (by TTC staining), expression of TLR4, MyD88 and TRAF6 (by Western blot), and contents of interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay) and for microscopic examination of the neuronal ultrastructure in ischemic cerebral cortex tissues (with a transmission electron microscope). Results:Compared with group S, the Longa score and percentage of cerebral infarct size were significantly increased, the expression of TLR4, MyD88 and TRAF6 in cerebral cortex tissues of ischemic regions was up-regulated, the contents of IL-1β, IL-6 and TNF-α were increased ( P<0.05), and the pathological damage to cortical neurons was aggravated in CIRI group. Compared with group CIRI, the Longa score and percentage of cerebral infarct size were significantly decreased, the expression of TLR4, MyD88 and TRAF6 was down-regulated, the contents of IL-1β, IL-6 and TNF-α were decreased in cerebral cortex tissues of ischemic regions ( P<0.05), and the pathological damage to cortical neurons was significantly attenuated in group TC. Compared with group TC, the Longa score and percentage of cerebral infarct size were significantly increased, the expression of TLR4, MyD88 and TRAF6 was up-regulated, the contents of IL-1β, IL-6 and TNF-α were increased in cerebral cortex tissues of ischemic regions ( P<0.05), and the pathological damage to cortical neurons was aggravated in group TCA. Conclusions:The TLR4-MyD88-TRAF6 signaling pathway is involved in the reduction of cerebral I/R injury by trilobatin pretreatment in rats.

The drugs used to improve brain metabolism mainly include ergotamine derivatives,GABA derivatives,vitamin B6 derivatives,neuropeptides,morpholines,hormones and other.However,these drugs may have adverse reactions during clinical application.This article focuses on the adverse effects of commonly used drugs for brain metabolism,and reviews the studies on the new state of pharmaceutical substances,such as drug combination,chiral resolution of isomers,crystal form of dominant drugs,co-crystal drugs and nanodrugs,with the aim of reducing adverse reactions.By summarizing the research on modifying the solid state of drugs to mitigate adverse reactions,this article provides new research insights for obtaining new drug with less adverse reaction and greater clinical value.

Objective To discuss the application of gelatin sponge-hemocoagulase plugging agent in patients with pulmonary puncture bleeding.Methods The clinical data of 43 patients with hemorrhage caused by DSA-guided lung puncture biopsy,who received gelatin sponge-hemocoagulase plugging agent treatment at the Jining Municipal First People's Hospital of China between September 2021 and May 2023,were collected,and the hemostatic effect of gelatin sponge-hemocoagulase plugging agent was analyzed.Results Successful lung puncture needle biopsy was achieved in all the 43 patients.The puncture needle channel occlusion was accomplished by using gelatin sponge-hemocoagulase plugging agent.Five minutes after occlusion treatment,in one patient,whose moderate hemoptysis with moderate bleeding shadow before puncture needle biopsy changed to bloody sputum,the intrapulmonary bleeding shadow displayed on image became slightly enlarged when compared the size five minutes ago,while in all the remaining patients successful hemostasis was achieved,the hemoptysis disappeared and the pulmonary hemorrhage shadow was similar to that five minutes ago.No occlusion-related complications occurred in all patients.Conclusion For the treatment of pulmonary hemorrhage caused by DSA-guided lung puncture biopsy,gelatin sponge-hemocoagulase plugging agent is clinically safe and effective.

Objective:To explore the application effect of chain pain management model in perioperative nursing of children with traumatic fractures.Methods:Using the convenient sampling method, a total of 174 children with traumatic fractures and 174 caregivers who were treated in Henan Children's Hospital from May 2020 to May 2021 and underwent surgical treatment were selected as the research subjects. Among them, 85 children and 85 caregivers from May to November 2020 were used as the control group, and they were given the conventional pain management model for intervention. A total of 89 children and 89 caregivers from December 2020 to May 2021 were selected as the experimental group, and they were given chain pain management model for intervention. The perioperative pain, psychological stress status and nursing satisfaction of caregivers were compared between the two groups.Results:At 24 hours after admission and 24 hours after operation, score of FLACC Pain Assessment Scale of the experimental group was lower than that of the control group, and the difference was statistically significant ( P<0.05) . At discharge, the Short-term Response Scale of Stress Disorder in the experimental group was lower than that in the control group, and the satisfaction score of caregivers in the experimental group was higher than that in the control group, and the differences were statistically significant ( P<0.05) . Conclusions:The application of chain pain management model in perioperative nursing of children with traumatic fractures can reduce perioperative pain, improve the psychological stress state of children and improve satisfaction of caregivers with nursing work, which has certain clinical application value.

Objective:To investigate the protective role and mechanism of hypoxia inducible factor(HIF)-1α in myocardial ischemia postconditioning.Methods:Forty healthy adult SD rats were randomly divided into four groups with 10 rats in each group.The control group(group A)was sham operation group, and the rats underwent the same surgical procedures except that the suture passed under the left anterior descending branch(LAD)of the coronary artery was not tightened for 225 minutes.In the ischemia-reperfusion group(group B), the LAD was blocked for 45 minutes, and then reperfusion for 3 hours.In the ischemic postconditioning group(group C), 45 minutes after blocking the LAD, reperfusion was performed for 10 seconds-ischemia for 10 seconds at the beginning of reperfusion, a total of 3 cycles of intervention, and reperfusion for 3 hours.Ischemic postconditioning + HIF-1α inhibitor group(group D): 45 minutes after blocking the LAD, HIF-1α inhibitor AG490 (3 μg/g) was injected intraperitoneally, and reperfusion was performed for 10 seconds-ischemia 10 seconds at the moment of reperfusion.A total of 3 cycles of intervention, reperfusion for 3 hours.Blood samples were harvested from femoral vein at three time points(before ligation of the LAD, 45 minutes after ischemia, 3 hours after reperfusion)to analyze the serum levels of creatine kinase and cardiac troponin respectively.After 3 hours of reperfusion, myocardial tissue was used to measure the infarction size through 2, 3, 5-triphenyltetrazolium chloride staining method; and Western blot method was used to detect the expression of HIF-1α in each group.Results:(1) There were no significant differences in the serum levels of creatine kinase and cardiac troponin among four groups before ligation( P>0.05); 45 minutes after ischemia, there were significant differences between group B, group C, and group D compared with group A ( P<0.01). After 3 hours of reperfusion, there were significant differences between group B, group C, and group D compared with group A (all P<0.01), and group B, group D were significantly higher than that in group C ( P<0.05). (2)Compared with group A[(2.46±1.13)%], the area of myocardial infarction in group B was (45.81±5.96)%, in group C was (37.17±4.99)%, and group D was (45.00±3.29) %, and the differences were statistically significant ( P<0.01). (3)The HIF-1α protein in myocardial tissue in group A was slightly expressed; the expression of HIF-1α protein in group B was higher than that in group A( P<0.05); and group C was significantly higher than that in group B ( P<0.05); HIF-1α protein was almost not expressed in group D. Conclusion:After ischemic postconditioning, HIF-1α increased in myocardium; the increased expression of HIF-1α may be involved in the protective process of myocardial ischemic postconditioning in rats.