Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver condition globally, lacks adequate and effective therapeutic remedies in clinical practice. Recent studies have increasingly highlighted the close connection between the ubiquitin-proteasome system (UPS) and the progression of MASLD. This relationship is crucial for understanding the disease's underlying mechanism. As a sophisticated process, the UPS govern protein stability and function, maintaining protein homeostasis, thus influencing a multitude of elements and biological events of eukaryotic cells. It comprises four enzyme families, namely, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin-protein ligases (E3), and deubiquitinating enzymes (DUBs). This review aims to delve into the array of pathways and therapeutic targets implicated in the ubiquitination within the pathogenesis of MASLD. Therefore, this review unveils the role of ubiquitination in MASLD while spotlighting potential therapeutic targets within the context of this disease.

OBJECTIVE To explore the clinical efficacy of Fuxin Mixture in the treatment of patients with heart failure of yang deficiency and water inundation type after myocardial infarction and its effect on serum myocardial injury and ventricular remodeling re-lated indicators.METHODS A total of 92 patients with heart failure of yang deficiency and water inundation type after myocardial infarction were randomly divided into an observation group and a control group(n=46).The control group was given basic western medicine treatment,and the observation group was given Fuxin Mixture on the basis of the control group's treatment.The TCM syn-drome scores,ultrasound cardiogram indices[left ventricular ejection fraction(LVEF),left ventricular Tei index,and stroke volume(SV)],serum myocardial injury indices[serum N-terminal pro-B-type natriuretic peptide(NT-ProBNP)level,serum high-sensitiv-ity cardiac troponin I(hs-cTnI)level,and creatine kinase isoenzyme(CK-MB)level],serum ventricular remodeling indices[hypoxi-a-inducible factor 1α(HIF-1α),soluble growth-stimulated gene expressed 2 protein(sST2),and angiotensin Ⅱ(AngⅡ)],and changes in the Minnesota Living with Heart Failure Questionnaire(MLHFQ)were evaluated before and after treatment.The two groups were followed up for 1 year after treatment to observe the occurrence of major adverse cardiovascular events.RESULTS After treat-ment,the TCM syndrome scores of both groups were significantly reduced(P＜0.01),the observation group was better than the control group(P＜0.05,P＜0.01),and the total effective rate of TCM in the observation group was better than that of the control group(P＜0.05);the serum ultrasound cardiogram indexes,myocardial injury,ventricular remodeling indexes and MLHFQ scores of the two groups were significantly reduced(P＜0.01),and the observation group was better than the control group(P＜0.01).During the fol-low-up period,the all-cause mortality,malignant arrhythmia rate and acute heart failure rate of the observation group after treatment were significantly lower than those of the control group(P＜0.05,P＜0.01).CONCLUSION Fuxin Mixture has significant clinical efficacy in the treatment of patients with heart failure of yang deficiency and water inundation type after myocardial infarction,and the efficacy mechanism may be related to its reduction of myocardial injury and inhibition of ventricular remodeling.

Objective:To evaluate the relationship between intracerebroventricular glial cell line-derived neurotrophic factor (GDNF)-induced improvement in long-term postoperative cognitive function and expression of PKMζ and Kalirin in the hippocampus of neonatal rats.Methods:Sixty 7-day old Sprague-Dawley rats, male or female, were divided into 4 groups ( n=15 each) using a random number table method: control group (group C), GDNF group (group G), surgery group (group S) and surgery plus GDNF group (group S+ G). Group C did not receive anesthesia, surgery or drug treatment. Group G received intracerebroventricular injection of 0.3 μg recombinant rat GDNF. Group S and group S+ G underwent right carotid artery exposure surgery under 3% sevoflurane anesthesia, and in addition group S+ G received intracerebroventricular injection of GDNF. The Barnes maze test and the fear conditioning test were performed starting from postnatal day 33. The animals were then sacrificed under sevoflurane anesthesia after behavioral testing, the brains were obtained and divided into 2 halves sagittally along the midline. The left half of the brain was used for Golgi staining to observe dendritic morphology and measure dendritic spine density. The hippocampal protein was extracted from the right half of the brain to detect the expression of PKMζ and Kalirin by Western blot. Results:Compared with group C, the time to identify the target box in the Barnes maze test was significantly prolonged, the context-related freezing time in the fear conditioning test was shortened, the total dendritic length, the number of branches, the number of intersections in sholl analysis and spinal density in the hippocampus were reduced, and the expression of PKMζ and Kalirin was down-regulated in group S ( P<0.05), and no significant change was found in the aforementioned parameters in group G ( P>0.05). Compared with group S, the time to identify the target box in the Barnes maze test was significantly shortened, the context-related freezing time in the fear conditioning test was prolonged, the total dendritic length, the number of branches, the number of intersections in sholl analysis and spinal density in the hippocampus were increased, and the expression of PKMζ and Kalirin was up-regulated in group S+ G ( P<0.05). Conclusions:The mechanism by which intracerebroventricular GDNF improves long-term postoperative cognitive function may be related to up-regulating the expression of PKMζ and Kalirin and promoting the development of dendrites and dendritic spines in the hippocampus of neonatal rats.

Objective:To evaluate the relationship between the mechanism of preoperative sleep deprivation aggravating postoperative cognitive dysfunction and theta oscillations in the hippocampal CA1 region in aged mice.Methods:Twenty-four SPF male C57BL/6J mice, aged 18 months, weighing 20-30 g, were divided into 3 groups ( n=8 each) by a random number table method: normal control group (group C), operation group (group S) and preoperative sleep deprivation + operation group (group SD+ S). The sleep deprivation model was established using the sleep deprivation rod method, and the sleep deprivation time was 24 h before operation. The sleep deprivation rod was set to rotate continuously at 6 rpm/min, and the direction was randomly reversed to force the mice to exercise to achieve the purpose of sleep deprivation. Group C received no treatment. Group S underwent exploratory laparotomy under isoflurane anesthesia. After sleep deprivation for 24 h, SD+ S group underwent exploratory laparotomy under isoflurane anesthesia. Y-maze and Morris water maze tests were used to evaluate postoperative cognitive function. The theta oscillations in the hippocampal CA1 region were observed and recorded by EEG electrodes in vivo. The animals were then sacrificed and brain tissues were obtained for determination of the density of dendritic spines in the hippocampal CA1 region. Results:Compared with group C, the number of crossing the original platform was significantly decreased, and the time of staying at the original platform quadrant and time of exploring the novel arm were shortened, and the number of entries into the novel arm was reduced, the density of dendritic spines in the hippocampal CA1 region was reduced, and the percentage of theta oscillation power was decreased during the Y maze test in group S ( P<0.05). Compared with S group, the number of crossing the original platform was significantly decreased, and the time of staying at the original platform quadrant and time of exploring the novel arm were shortened, and the number of entries into the novel arm was reduced, the density of dendritic spines in the hippocampal CA1 region was reduced, and the percentage of theta oscillation power was decreased during the Y maze test in SD+ S group ( P<0.01). Conclusions:The mechanisms by which preoperative sleep deprivation exacerbates postoperative cognitive dysfunction may be related to reduction in theta oscillations in the hippocampal CA1 region of aged mice.

Objective:To evaluate the role of sphingosine-1-phospho-1 receptor 1 (S1PR1) in remifentanil-induced hyperalgesia in rats with incisional pain and the relationship with KCNQ2/3 potassium channels in the dorsal root ganglia (DRG).Methods:Forty-eight male Sprague-Dawley rats with successful caudal vein catheterization, aged 2-3 months, weighing 260-280 g, were divided into 6 groups ( n=8 each) using a random number table method: control group (group C), S1PR1 inhibitor group (FTY720) group (group F), remifentanil group (group R), remifentanil + S1PR1 inhibitor (FTY720) group (group RF), remifentanil + incision pain group (group RI) and remifentanil + incision pain + S1PR1 inhibitor (FTY720) group (group RIF). In group C, normal saline 0.1 ml· kg -1·min -1 was intravenously infused for 60 min. In group F, FTY720 3 nmol was intrathecally injected at 10 min before normal saline injection, and 0.1 ml · kg -1·min -1 normal saline was infused into the caudal vein for 60 min. Remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein in group R. In RF group, FTY720 (3 nmol) was intrathecally injected, and 10 min later remifentanil 1.0 μg· kg -1·min -1 was infused via the caudal vein for 60 min. The incisional pain model was established, and remifentanil 1.0 μg· kg -1·min -1 was infused via the caudal vein for 60 min in RI group. In RIF group, FTY720 3 nmol was intrathecally injected at 10 min before remifentanil infusion, then the incisional pain model was developed, and remifentanil 1.0 μg· kg -1·min -1 was infused via the caudal vein at the same time for 60 min. The mechanical paw withdraw threshold (MWT) and thermal paw withdraw latency (TWL) were measured at 24 h before remifentanil or normal saline infusion (T 0) and 2, 6, 24 and 48 h after remifentanil or normal saline infusion (T 1-4). The rats were sacrificed after the last measurement of pain threshold, and the L 4-6 segments of the DRG were taken for determination of the expression of S1PR1, KCNQ2 and KCNQ3 protein and mRNA in the DRG by Western blot and real-time polymerase chain reaction. Results:Compared with group C, the MWT was significantly decreased, and the TWL was shortened at T 1-4, the expression of S1PR1 protein and mRNA in the DRG was up-regulated, the expression of KCNQ2 and KCNQ3 protein and mRNA in the DRG was down-regulated ( P<0.05), and no significant change was found in each parameter in R and RI groups ( P>0.05). Compared with group R, the MWT was significantly decreased, and the TWL was shortened at T 1-4, the expression of S1PR1 protein and mRNA in the DRG was up-regulated, and the expression of KCNQ2 and KCNQ3 protein and mRNA in the DRG was down-regulated in group RI, and the MWT was significantly increased, and the TWL was prolonged at T 1-4, the expression of S1PR1 protein and mRNA in the DRG was down-regulated, and the expression of KCNQ2 and KCNQ3 protein and mRNA in the DRG was up-regulated in group RF ( P<0.05). Compared with group RI, the MWT was significantly increased, and the TWL was prolonged at T 1-4, the expression of S1PR1 protein and mRNA in the DRG was down-regulated, and the expression of KCNQ2 and KCNQ3 protein and mRNA in the DRG was up-regulated in group RIF ( P<0.05). Conclusions:S1PR1 is involved in the process of remifentanil-induced hyperalgesia in rats with incisional pain, which is related to the inhibition of KCNQ2/3 potassium channel expression in the DRG.

Objective:To establish a risk prediction model dominated by diaphragm thickening fraction (DTF) and intra-abdominal pressure (IAP) monitoring, and to explore the predictive value of the model for weaning failure in patients with severe acute pancreatitis (SAP).Methods:A prospective research was conducted. Sixty-three patients undergoing invasive mechanical ventilation treatment who diagnosed with SAP admitted to intensive care unit of the First Affiliated Hospital of Jinzhou Medical University from August 2020 to October 2021 were enrolled. The spontaneous breathing trial (SBT) was carried out when the clinical weaning criteria was met. The stable cardiovascular status, good pulmonary function, no chest and abdominal contradictory movement, and adequate oxygenation were defined as successful weaning. Otherwise, it was defined as failure weaning. The clinical indicators such as SBT 30-minure DTF, IAP, tidal volume (VT), respiratory rate (RR), body mass index (BMI), and blood lactic acid (Lac) were compared between the weaning success group and the weaning failure group. The indicators with statistically significant differences in the single-factor analysis were included in the secondary multivariable Logistic regression analysis to establish a risk prediction model. The correlation between the DTF and IAP at 30 minutes of SBT was analyzed. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of the risk prediction model for SAP patient withdrawal failure at 30 minutes of SBT.Results:Finally, 63 patients with SAP were enrolled. Among the 63 patients, 42 were successfully weaned and 21 failed. There were no significant differences in age, gender, and oxygenation index (PaO 2/FiO 2), sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score at admission between the two groups, indicating that the data in the two groups were comparable. Compared with the weaning success group, IAP, RR, BMI and Lac at 30 minutes of SBT in the weaning failure group were significantly increased [IAP (mmHg, 1 mmHg≈0.133 kPa): 14.05±3.79 vs. 12.12±3.36, RR (times/min): 25.43±8.10 vs. 22.02±5.05, BMI (kg/m 2): 23.71±2.80 vs. 21.74±3.79, Lac (mmol/L): 5.27±1.69 vs. 4.55±1.09, all P < 0.05], while DTF and VT were significantly decreased [DTF: (29.76±3.45)% vs. (31.86±3.67)%, VT (mL): 379.00±98.74 vs. 413.60±33.68, both P < 0.05]. Secondary multivariable Logistic regression analysis showed that DTF [odds ratio ( OR) = 0.758, 95% confidence interval (95% CI) was 0.584-0.983, P = 0.037], IAP ( OR = 1.276, 95% CI was 1.025-1.582, P = 0.029), and RR ( OR = 1.145, 95% CI was 1.014-1.294, P = 0.029) were independent risk factors for SBT withdrawal failure in 30 minutes in SAP patients. The above risk factors were used to establish the risk prediction model of aircraft withdrawal failure at 30 minutes of SBT: Logit P = -0.237-0.277×DTF+0.242×IAP+0.136×RR. Pearson correlation analysis showed that SBT 30-minute DTF was significantly correlated with IAP in SAP patients, and showed a significant positive correlation ( r = 0.313, P = 0.012). The ROC curve analysis results showed that area under the ROC curve (AUC) of the risk prediction model for SAP patient withdrawal failure at 30 minutes of SBT was 0.716, 95% CI was 0.559-0.873, P = 0.003, with the sensitivity of 85.7% and the specificity of 78.6%. Conclusions:DTF, IAP and RR were independent risk factors for SBT withdrawal failure in 30 minutes in SAP patients. The DTF and IAP monitoring-oriented risk prediction model based on the above three variables has a good predictive value for weaning failure in patients with SAP.

Objective:To evaluate the role of sphingosine-1-phospho-1 receptor(S1PR1)in the dorsal root ganglion in remifentanil-induced hyperalgesia in rats with incisional pain.Methods:Forty-eight male Sprague-Dawley rats with successful intrathecal and caudal vein catheterization, weighing 260-280 g, aged 2-3 months, were divided into 6 groups ( n= 8 each) using a random number table method: control group (group C), S1PR1 antagonist (FTY720) group (group F), remifentanil group (group R), remifentanil + S1PR1 antagonist (FTY720) group (group R+ F), remifentanil + incisional pain group (group R+ I), and remifentanil + incisional pain + S1PR1 antagonist (FTY720) group (group R+ I+ F). In C group, normal saline 0.1 μg·kg -1·min -1 was intravenously infused for 60 min. In R group, remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In F group, FTY720 3 nmol was intrathecally injected, and 10 min later normal saline 1.0 μg· kg -1·min -1 was infused for 60 min via the caudal vein. In R+ F group, FTY720 3 nmol was intrathecally injected, and 10 min later remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In R+ I group, remifentanil 1.0 μg·kg -1·min -1 was infused for 60 min through the caudal vein while the model of incisional pain was developed. In R+ I+ F group, FTY720 3 nmol was intrathecally injected, 10 min later the incisional pain model was prepared, and remifentanil 1.0 μg·kg -1·min -1 was injected for 60 min through the caudal vein at the same time. The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 24 h before remifentanil or normal saline infusion (T 0) and 2, 6, 24 and 48 h after stopping remifentanil or normal saline infusion (T 1-4). Rats were sacrificed after the last measurement of pain threshold, and the L 4-6 segments of dorsal root ganglion were taken for determination of the expression of S1PR1, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), interleukin-1β (IL-1β) and glutamate transporter-1 (GLT-1) protein and mRNA (by Western blot and quantitative polymerase chain reaction). Results:Compared with C group, the MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and the expression of GLT-1 protein and mRNA in dorsal root ganglion was down-regulated in R group ( P<0.05), and no significant change was found in the parameters mentioned above in group F ( P>0.05). Compared with R group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and GLT-1 protein and mRNA expression in dorsal root ganglion was down-regulated in R+ I group, and MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and GLT-1 protein and mRNA expression in the dorsal root ganglion was up-regulated in R+ F group ( P<0.05). Compared with R+ I group, MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and the expression of GLT-1 protein and mRNA in the dorsal root ganglion was up-regulated in R+ I+ F group( P<0.05). Conclusions:The mechanism by which remifentanil induces hyperalgesia is associated with up-regulation of S1PR1 expression, activation of inflammatory factors, and down-regulation of GLT-1 expression in the rats with incisional pain.

Objective:To evaluate the effect of sleep fragmentation on postoperative cognitive dysfunction (POCD) and hippocampal glutaminergic metabolism in aged mice anesthetized with isoflurane.Methods:Forty healthy SPF-grade male C57BL/6J mice, aged 18 months, weighing 20-30 g, were divided into 4 groups ( n= 10 each) by the random number table method: normal control group (group C), sleep fragmentation group (group SF), isoflurane anesthesia/surgery group (group I/S), and sleep fragmentation plus isoflurane anesthesia/surgery group (group SF+ I/S). Group C did not received any treatment. Group SF received sleep fragmentation for 24 h. The right carotid artery exposure was performed under isoflurane anesthesia in group I/S. Group SF+ I/S received isoflurane anesthesia/right carotid artery exposure at 24 h after sleep fragmentation. The metabolic levels of glutamate (Glu), glutamine (Gln), Glu/Gln complex (Glx), and N-acetylaspartate (NAA) and their ratio to creatine (Cr) were measured by in vivo 9.4T hydrogen proton magnetic resonance spectroscopy at 2 h after anaesthesia. Y maze and Morris water maze tests were used to evaluate the cognitive function at 1-7 days after surgery. The mice were sacrificed after the behavioral testing, brain tissues were immediately obtained, and the number of Nissl bodies and density of dendritic spines in the hippocampal CA1 region were measured by Nissl staining and Golgi staining, respectively. Results:Compared with group C, the percentage of exploration time and shuttle times at the novel arm were significantly decreased, the number of crossing the original platform was decreased, the time of stay at the target quadrant was shortened, the ratios of Glu/Cr, Gln/Cr and Glx/Cr in the hippocampal CA1 region were increased, and the ratio of NAA/Cr was decreased, and the number of Nissl bodies and density of dendritic spines were decreased in SF, I/S and SF+ I/S groups ( P<0.05). Compared with group SF and group I/S, the percentage of exploration time and shuttle times at the novel arm were significantly decreased, the number of crossing the original platform was decreased, the time of stay at the target quadrant was shortened, the ratios of Glu/Cr and Glx/Cr in hippocampal CA1 region was increased, the ratio of NAA/Cr was decreased, and the number of Nissl bodies and density of dendritic spines were decreased in group SF+ I/S ( P<0.05). Conclusions:Sleep fragmentation exacerbates POCD in aged mice anesthetized with isoflurane, and the mechanism is related to nerve injury induced by abnormality in hippocampal glutaminergic metabolism excitability.

Objective:To evaluate the effect of gender on anesthetic potency of ciprofol for gastroscopy when combined with fentanyl.Methods:American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ patients, aged 18-50 yr, with body mass index of 18-25 kg/m 2, undergoing elective gastroscopy with intravenous anesthesia, were divided into 2 groups according to gender: male group (M group) and female group (F group). After fentanyl 1.5 μg/kg was intravenously injected, ciprofol was given by the Dixon′s up-and-down method, with the initial dose of 0.4 mg/kg followed by dose increment/decrement of 0.04 mg/kg. The ED 50 and 95% confidence interval of ciprofol for gastroscopy anesthesia were calculated by the probit regression analysis. Results:The ED 50 (95% confidence interval) of ciprofol for gastroscopy was 0.33 (0.32-0.34) mg/kg in F group and 0.27 (0.26-0.28) mg/kg in M patients when combined with fentanyl 1.5 μg/kg. There was no significant difference between the two groups ( P>0.05). Conclusions:There is no significant gender difference in the anesthetic potency of ciprofol for gastroscopy (ED 50: female 0.33 mg/kg, male 0.27 mg/kg) when combined with fentanyl (1.5 μg/kg).

Objective To explore the relevant risk factors of thyroid malignant tumor and provide basis for distinguishing the nature of thyroid nodules.Methods A total of 337 patients who underwent surgical treatment for thyroid nodules at the Second Hospital of Lanzhou University from June 2018 to January 2020 were selected,according to the pathological results,the patients were divided into benign nodule group and malignant nodule group.Clinical data of the two groups of patients were analyzed to explore the relevant risk factors for thyroid malignant tumors.Results ①The average age,longitudinal and transverse diameters of malignant nodule group were smaller than those of benign nodule group(P<0.001);②The proportion of patients with elevated serum thyrotropin(TSH),thyroglobulin antibody(TgAb),and thyroid peroxidase antibody(TPOAb)in malignant nodule group were higher than those in benign nodule group;The proportion of thyroglobulin(TG)elevation was lower than in benign nodule group(P<0.01);③The incidence of neck lymph node enlargement,low echogenicity within the nodule,nodule aspect ratio>1,irregular or irregular morphology,and unclear boundaries in malignant nodule group were higher than those in benign nodule group(P<0.05);④Binary Logistic regression analysis suggests that low echogenicity,calcification,irregular or irregular morphology,aspect ratio>1,and unclear or unclear boundaries were risk factors for malignant nodules;For every year of age increase,the incidence of malignant nodules decreases by 5.4%(P<0.05).Conclusion Ultrasound prompts low echo,calcification,irregular or irregular morphology,aspect ratio>1,and unclear or unclear boundaries are risk factors for thyroid cancer;Age is negatively correlated with the risk of thyroid cancer.