UXT at the crossroads of cell death, immunity and neurodegenerative diseases

The ubiquitous expressed transcript (UXT), a member of the prefoldin-like protein family, modulates regulated cell death (RCD) such as apoptosis and autophagy-mediated cell death through nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), P53, P62, and methylation, and is involved in the regulation of cell metabolism, thereby affecting tumor progression. UXT also maintains immune homeostasis and reduces proteotoxicity in neuro-degenerative diseases through selective autophagy and molecular chaperones. Herein, we review and further elucidate the mechanisms by which UXT affects the regulation of cell death, maintenance of immune homeostasis, and neurodegenerative diseases and discuss the possible UXT involvement in the regulation of ferroptosis and immunogenic cell death, and targeting it to improve cancer treatment outcomes by regulating cell death and immune surveillance

Antidiabetic Activity of a Flavonoid-Rich Extract From Sophora davidii (Franch.) Skeels in KK-Ay Mice via Activation of AMP-Activated Protein Kinase

The present study was undertaken to investigate the hypoglycemic activity and potential mechanisms of action of a flavonoid-rich extract from Sophora davidii (Franch.) Skeels (SD-FRE) through in vitro and in vivo studies. Four main flavonoids of SD-FRE namely apigenin, maackiain, leachianone A and leachianone B were purified and identified. In vitro, SD-FRE significantly promoted the translocation and expression of glucose transporter 4 (GLUT4) in L6 cells, which was significantly inhibited by Compound C (AMPK inhibitor), but not by Wortmannin (PI3K inhibitor) or Gö6983 (PKC inhibitor). These results indicated that SD-FRE enhanced GLUT4 expression and translocation to the plasma membrane via the AMPK pathway and finally resulted in an increase of glucose uptake. In vivo, using a spontaneously type 2 diabetic model, KK-Ay mice received intragastric administration of SD-FRE for 4 weeks. As a consequence, SD-FRE significantly alleviated the hyperglycemia, glucose intolerance, insulin resistance and hyperlipidemia in these mice. Hepatic steatosis, islet hypertrophy and larger adipocyte size were observed in KK-Ay mice. However, these pathological changes were effectively relieved by SD-FRE treatment. SD-FRE promoted GLUT4 expression and activated AMPK phosphorylation in insulin target tissues (muscle, adipose tissue and liver) of KK-Ay mice, thus facilitating glucose utilization to ameliorate insulin resistance. Regulation of ACC phosphorylation and PPARγ were also involved in the antidiabetic effects of SD-FRE. Taken together, these findings indicated that SD-FRE has the potential to alleviate type 2 diabetes

Retrospective analysis of COX-2 inhibitors on SIRS in acute pancreatitis

Objective To investigate the effect of cyclooxygenase-2 (COX-2) inhibitor parecoxib on systemic inflammatory response syndrome (SIRS) in patients with acute pancreatitis (AP). Methods A retrospective analysis was performed on 206 AP patients who were treated in Shanxi Norman Bethune Hospital from April 2021 to April 2022. The patients treated with COX-2 inhibitors were assigned to group A (n=100), and the patients treated with other analgesics were assigned to group B (n=106). The patients with SIRS at admission in group A and B were divided into A1 group (n=48) and B1 group (n=49), and those without SIRS were divided into A2 group (n=52) and B2 group (n=57). The incidence of SIRS in each group was compared, including SIRS duration and rating. The organ failure score (Sequential Organ Failure Assessment, SOFA) and serum CRP level on the 4th day of hospitalization, as well as the length of hospitalization, cost, and incidence of complications between group A and group B were compared. Multivariate logistic regression analysis of risk factors for SIRS in patients who did not experience SIRS at admission. Results Compared with those in group B1, the proportion of patients with SIRS durationP＜0.05＝. On the 4th day, SIRS score in group A1 was statistically lower than that in group B1 (P＜0.01＝, and there was no statistical difference in it between two groups on the 8th day (P＞0.05). The incidence of SIRS in group A2 was significantly lower than that in group B2 (32.65% vs 52.63%, χ=5.328, P=0.021). In group A, the organ failure assessment score and the serum CRP were statistically lower than those in group B on the 4th day (P＜0.05）, and the hospital stay and the hospitalization costs were significantly lower than those in group B (P＜0.05＝. Multivariable logistic regression of patients without SIRS at admission showed that COX-2 inhibitor was a protective factor associated with the occurrence of SIRS (P＜0.05). Conclusion For patients with AP, COX-2 inhibitor pareoxib can reduce the incidence of SIRS, which is closely related to the improvement of SIRS and organ failure, but has no significant difference with the analgesic effect of opioids. It can reduce serum CRP and has good cost-effectiveness. COX-2 inhibitor parecoxib is an independent protective factor for the occurrence of SIRS

Sensitivity analysis of the causal association between physical activity/sedentary behavior and the risk of AP/CP.

Sensitivity analysis of the causal association between physical activity/sedentary behavior and the risk of AP/CP.</p

S1 Fig -

BackgroundAlthough observational studies have shown that physical activity is a protective factor for acute pancreatitis, the causal associations between PA/ sedentary behavior and acute pancreatitis (AP) and chronic pancreatitis (CP) remain unclear.MethodsWe used Mendelian randomization as a strategy to assess the causalities between exposures and outcomes by simulating randomized experiments with genetic variation. The collected genetic variants data of physical activity were from UK Biobank, the data on sedentary behavior were also from UK Biobank, and both of them could be found in the GWAS catalog, and the data on AP and CP were from FinnGen. There were three physical activity related activity patterns (moderate to vigorous physical activity [MVPA], accelerometer-based physical activity with average acceleration, [AccAve] and accelerometer-based physical activity with accelerations >425 milli-gravities, [Acc425]) and three sedentary behavior-related lifestyle patterns (Leisure screen time [LST], Sedentary commuting, Sedentary behavior at work). We used inverse variance weighted (IVW), weighted median and MR-Egger for the analysis of Mendelian randomization, followed by sensitivity tests with the Cochran Q test, MR-Egger intercepts analysis and MR-PRESSO.ResultsA causal relationship was found between LST and acute pancreatitis based on IVW analysis (odds ratios [OR] = 1.38, corresponding 95% confidence intervals [CI] = 1.16–1.64, p = 0.0002) and there were no causal relationships between physical activity/sedentary behavior and chronic pancreatitis. Sensitivity analysis showed no pleiotropy and heterogeneity of the results.ConclusionsResults show that reducing LST contributes to the prevention of acute pancreatitis, thereby reducing the health burden associated with it.</div

Causal effects of physical activity/sedentary behavior on acute pancreatitis by IVW.

MVPA: moderate to vigorous physical activity; AccAve: accelerometer-based physical activity (average acceleration); Acc425: accelerometer-based physical activity (fraction of time with accelerations >425 milli-gravities); LST: leisure screen time; IVW: inverse variance weighted.</p

S1-S7 Tables are included in file.

BackgroundAlthough observational studies have shown that physical activity is a protective factor for acute pancreatitis, the causal associations between PA/ sedentary behavior and acute pancreatitis (AP) and chronic pancreatitis (CP) remain unclear.MethodsWe used Mendelian randomization as a strategy to assess the causalities between exposures and outcomes by simulating randomized experiments with genetic variation. The collected genetic variants data of physical activity were from UK Biobank, the data on sedentary behavior were also from UK Biobank, and both of them could be found in the GWAS catalog, and the data on AP and CP were from FinnGen. There were three physical activity related activity patterns (moderate to vigorous physical activity [MVPA], accelerometer-based physical activity with average acceleration, [AccAve] and accelerometer-based physical activity with accelerations >425 milli-gravities, [Acc425]) and three sedentary behavior-related lifestyle patterns (Leisure screen time [LST], Sedentary commuting, Sedentary behavior at work). We used inverse variance weighted (IVW), weighted median and MR-Egger for the analysis of Mendelian randomization, followed by sensitivity tests with the Cochran Q test, MR-Egger intercepts analysis and MR-PRESSO.ResultsA causal relationship was found between LST and acute pancreatitis based on IVW analysis (odds ratios [OR] = 1.38, corresponding 95% confidence intervals [CI] = 1.16–1.64, p = 0.0002) and there were no causal relationships between physical activity/sedentary behavior and chronic pancreatitis. Sensitivity analysis showed no pleiotropy and heterogeneity of the results.ConclusionsResults show that reducing LST contributes to the prevention of acute pancreatitis, thereby reducing the health burden associated with it.</div

The process of instrumental variable selection and study design.

IVs: Instrumental variables; MVPA: moderate to vigorous physical activity; AccAve: accelerometer-based physical activity (average acceleration); Acc425: accelerometer-based physical activity (fraction of time with accelerations >425 milli-gravities); LST: leisure screen time; AP: acute pancreatitis; CP: chronic pancreatitis.</p

Instrumental variables fit the assumptions of MR.

BackgroundAlthough observational studies have shown that physical activity is a protective factor for acute pancreatitis, the causal associations between PA/ sedentary behavior and acute pancreatitis (AP) and chronic pancreatitis (CP) remain unclear.MethodsWe used Mendelian randomization as a strategy to assess the causalities between exposures and outcomes by simulating randomized experiments with genetic variation. The collected genetic variants data of physical activity were from UK Biobank, the data on sedentary behavior were also from UK Biobank, and both of them could be found in the GWAS catalog, and the data on AP and CP were from FinnGen. There were three physical activity related activity patterns (moderate to vigorous physical activity [MVPA], accelerometer-based physical activity with average acceleration, [AccAve] and accelerometer-based physical activity with accelerations >425 milli-gravities, [Acc425]) and three sedentary behavior-related lifestyle patterns (Leisure screen time [LST], Sedentary commuting, Sedentary behavior at work). We used inverse variance weighted (IVW), weighted median and MR-Egger for the analysis of Mendelian randomization, followed by sensitivity tests with the Cochran Q test, MR-Egger intercepts analysis and MR-PRESSO.ResultsA causal relationship was found between LST and acute pancreatitis based on IVW analysis (odds ratios [OR] = 1.38, corresponding 95% confidence intervals [CI] = 1.16–1.64, p = 0.0002) and there were no causal relationships between physical activity/sedentary behavior and chronic pancreatitis. Sensitivity analysis showed no pleiotropy and heterogeneity of the results.ConclusionsResults show that reducing LST contributes to the prevention of acute pancreatitis, thereby reducing the health burden associated with it.</div

Causal effects of physical activity /sedentary behavior on acute pancreatitis by IVW.

MVPA: moderate to vigorous physical activity; AccAve: accelerometer-based physical activity (average acceleration); Acc425: accelerometer-based physical activity (fraction of time with accelerations >425 milli-gravities); LST: leisure screen time; IVW: inverse variance weighted.</p