Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
Ferroptosis/drug effects* ; Humans ; Iron/metabolism* ; Glioblastoma/metabolism* ; Tumor Suppressor Protein p53/metabolism* ; Homeostasis/physiology* ; Ferritins/metabolism* ; Brain Neoplasms/genetics* ; Mutation ; Astrocytes/drug effects* ; Cell Line, Tumor ; Piperazines/pharmacology* ; Quaternary Ammonium Compounds/pharmacology* ; Ferric Compounds

OBJECTIVE: To investigate the impact of autophagy on cardiac tissue injury following common bile duct ligation (CBDL) in rats. METHODS: Twenty-four SPF grade healthy adult male Sprague-Dawley (SD) rats were randomly divided into four groups, with 6 rats in each group. The sham-operated (Sham) group underwent only dissection of the common bile duct without ligation. The CBDL group underwent CBDL to simulate jaundice-induced myocardial injury. The autophagy inhibitor 3-methyladenine (3-MA)+CBDL group was intraperitoneally injected with 15 mg/kg 3-MA 2 hours before modeling, and then injected once every other day. The CBDL+autophagy enhancer rapamycin (Rapa) group was intraperitoneally injected with Rapa 1 mg/kg 0.5 hour after modeling, and then injected once every other day. The rats in each group were sacrificed 2 weeks after surgery, and blood was taken from the inferior vena cava. Serum total bilirubin (TBil), alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), and MB isoenzyme of creatine kinase (CK-MB) were detected by using a fully automated animal biochemical analyzer. Serum oxidative stress marker superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were detected by colorimetric assay. The heart tissues of rats were taken and pathological changes were observed under a light microscope after hematoxylin-eosin (HE) staining. Transmission electron microscope was used to observe autophagosomes after double staining with uranyl acetate and lead citrate. The expressions of autophagy-related proteins were detected using Western blotting. RESULTS: Compared with the Sham group, the serum SOD activity of rats in the CBDL group was significantly decreased, while the serum MDA, TBil, ALT, AST, LDH, and CK-MB were significantly increased; the expressions of autophagy-related proteins Beclin-1 and microtubule-associated protein 1 light chain 3-II/I (LC3-II/I) were significantly increased, and p62 protein expression was significantly decreased. Autophagosomes were seen under electron microscopy in the CBDL group, and cardiac histopathological morphology showed focal necrosis in the myocardium as well as infiltration of inflammatory cells, dilatation of small interstitial blood vessels, and myocardial fiber degeneration. Compared with the CBDL group, cardiac tissue injury in rats was attenuated by pretreatment with the autophagy inhibitor 3-MA, with a decrease in inflammatory cell infiltration in myocardial tissue, a reduction in interstitial vasodilatation, and a decrease in the area of myocardial fibrosis; a decrease in the number of autophagosomes by electron microscopy; and a further rise in the viability of serum TBil, ALT, and AST [TBil (μmol/L): 184.40±6.74 vs. 120.70±16.93, ALT (U/L): 501.10±62.18 vs. 178.80±22.30, AST (U/L): 806.50±76.92 vs. 275.50±55.81, all P < 0.01], as well as a decrease in the levels of serum SOD, MDA, LDH, and CK-MB [SOD (kU/L): 85.00±5.29 vs. 107.50±7.86, MDA (μmol/L): 10.72±0.93 vs. 15.06±1.88, LDH (U/L): 387.40±119.50 vs. 831.30±84.35, CK-MB (U/L): 320.10±14.04 vs. 814.70±75.66, all P < 0.05]. The expressions of the autophagy-related proteins Beclin-1 and LC3-II/I in cardiac tissues were significantly decreased [Beclin-1 protein (Beclin-1/GAPDH): 0.67±0.04 vs. 0.89±0.01, LC3-II/I ratio: 0.93±0.03 vs. 1.09±0.01, both P < 0.01], and p62 protein expression was significantly increased (p62/GAPDH: 0.99±0.01 vs. 0.60±0.01, P < 0.01). In contrast, compared with the CBDL group, after administration of the autophagy enhancer Rapa, the rats showed increased cardiac tissue injury, increased inflammatory cell infiltration in myocardial tissues, increased interstitial vasodilatation, and increased area of myocardial fibrosis; an increase in autophagosomes was seen by electron microscopy; the change tendency of serum biochemical indicators and proteins in myocardial tissues were opposite with autophagy inhibition group with a decrease in serum TBil, ALT, and AST [TBil (μmol/L): 22.00±3.21 vs. 120.70±16.93, ALT (U/L): 72.13±5.97 vs. 178.80±22.30, AST (U/L): 135.20±12.95 vs. 275.50±55.81, all P < 0.05], as well as a increase in the levels of serum SOD, MDA, LDH, and CK-MB [SOD (kU/L): 208.00±2.65 vs. 107.50±7.86, MDA (μmol/L): 20.38±0.40 vs. 15.06±1.88, LDH (U/L): 1 268.00±210.90 vs. 831.30±84.35, CK-MB (U/L): 1 150.00±158.70 vs. 814.70±75.66, all P < 0.05]. The protein expressions of Beclin-1 and LC3-II/I in cardiac tissues were significantly increased [Beclin-1 protein (Beclin-1/GAPDH): 0.96±0.01 vs. 0.89±0.01, LC3-II/I ratio: 1.19±0.01 vs. 1.09±0.01, both P < 0.05], and p62 protein expression was significantly decreased (p62/GAPDH: 0.19±0.02 vs. 0.60±0.01, P < 0.01). CONCLUSIONS Activation of autophagy in CBDL rats led to myocardial tissue injury and reduced cardiac function. Inhibition of autophagy improved cardiac tissue injury in CBDL rats, while increasing autophagy exacerbated myocardial tissue injury.
Animals ; Autophagy ; Rats, Sprague-Dawley ; Male ; Ligation ; Rats ; Common Bile Duct/surgery* ; Myocardium/pathology* ; Adenine/pharmacology*

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Lysosomal dysfunction plays an important role in neurodegenerative diseases, including Parkinson’s disease (PD) and possibly Parkinson-plus syndromes such as progressive supranuclear palsy (PSP). This role is exemplified by the involvement of variants in the GBA1 gene, which results in a deficiency of the lysosomal enzyme glucocerebrosidase and is the most frequently identified genetic factor underlying PD worldwide. Pathogenic variants in the SMPD1 gene are a recessive cause of Niemann–Pick disease types A and B. Here, we provide the first report on an association between a loss-of-function variant in the SMPD1 gene present in a heterozygous state (p.Pro332Arg/p.P332R, which is known to result in reduced lysosomal acid sphingomyelinase activity), with PSP-Richardson syndrome in three unrelated patients of Chinese ancestry.

Background Ultrasound-guided continuous thoracic paravertebral block can provide pain-relieving and opioid-sparing effects in patients receiving open hepatectomy. We hypothesize that these effects may improve the quality of recovery (QoR) after open hepatectomy. Methods Seventy-six patients undergoing open hepatectomy were randomized to receive a continuous thoracic paravertebral block with ropivacaine (CTPVB group) or normal saline (control group). All patients received patient-controlled intravenous analgesia with morphine postoperatively for 48 hours. The primary outcome was the global Chinese 15-item Quality of Recovery score on postoperative day 7, which was statistically analyzed using Student's t-test. Results Thirty-six patients in the CTPVB group and 37 in the control group completed the study. Compared to the control group, the CTPVB group had significantly increased global Chinese 15-item Quality of Recovery scores (133.14 ± 12.97 vs. 122.62 ± 14.89, P = 0.002) on postoperative day 7. Postoperative pain scores and cumulative morphine consumption were significantly lower for up to 8 and 48 hours (P < 0.05; P = 0.002), respectively, in the CTPVB group. Conclusion Perioperative CTPVB markably promotes patient's QoR after open hepatectomy with a profound analgesic effect in the early postoperative period.
Anesthetics, Local/therapeutic use* ; Double-Blind Method ; Hepatectomy/adverse effects* ; Humans ; Morphine/therapeutic use* ; Pain Measurement ; Pain, Postoperative/etiology* ; Ultrasonography, Interventional

Vascular endothelial cells and oxidation reduction system play an important role in the pathogenesis of atherosclerosis (AS). If these conditions are disordered, it will inevitably lead to plaque formation and even rupture. Astragaloside IV (AsIV) and salvianolic acid B (Sal B) are the main active ingredients of Astragalus membranaceus and Salvia miltiorrhiza, respectively, and found to ameliorate vascular endothelial dysfunction and protect against oxidative stress in recent studies. However, it is still unknown if the combination of AsIV and Sal B (AsIV + Sal B) can inhibit the development of plaque through amplifying the protective effect of vascular endothelial cells and anti-oxidative stress effect. To clarify the role of AsIV + Sal B in AS, we observed the efficacy of each group (Control, Model, AsIV, Sal B, and AsIV + Sal B) by biomolecular assays, such as observing the pathological morphology of the aorta by oil red O staining, evaluating the level of oxidative stress and endothelial cells in the serum by the Elisa test, and analyzing the changes of all small molecule metabolites in liver tissue by UPLC-QTOF-MS. Results showed that AsIV, Sal B and AsIV + Sal B decreased the deposition of lipid in the arterial wall, so as to exert the effect of anti-oxidant stress and vascular endothelial protection, where the inhibitory effect of AsIV + Sal B was the most obvious. Metabonomics analysis showed that Sal B regulated the metabolic pathways of arginine and proline. AsIV regulated glycerol metabolism and saturated fatty acid biosynthesis metabolism. AsIV + Sal B is mainly related to the regulation of the citrate cycle (TCA cycle), alanine, aspartic acid, and glutamate metabolism, cysteine, and methionine metabolism. Succinic acid and methionine are synergistic metabolites that exert an enhancing effect when AsIV and Sal B were used in combination. In conclusion, we demonstrated that AsIV acompanied with Sal B can be successfully used for anti-oxidative stress and vascular endothelial protection of AS, and succinic acid and methionine are the synergistic metabolites.
Antioxidants ; Atherosclerosis ; Benzofurans ; Endothelial Cells ; Humans ; Methionine ; Saponins ; Succinic Acid ; Triterpenes

Objective: To evaluate the short-and mid-term efficacy of pediatric kidney transplantation and the risk factors for kidney graft and recipient. Methods: The baseline data and postoperative complications of pediatric donors and recipients of 284 kidney transplants were retrospectively analyzed in the Department of Kidney Transplantation in the First Affiliated Hospital of Zhengzhou University from August 2010 to May 2021 and all subjects were followed up until December 31, 2021. According to the survival status of donors and recipients, they were divided into the graft-loss group and the graft-survival group, and the recipient death group and survival group, respectively. Univariate comparison between groups was performed by Log-rank test, and Cox proportional risk model was used to explore the independent risk factors for the graft and recipient survival. Results: Among the 284 children recipients, 184 cases (64.8%) were male and 100 cases(35.2%) were female, and 19 cases (6.7%) were living relative donor renal transplantation, 19 cases (6.7%) were preemptive transplantation, and 8 cases were secondary transplantation. The age of 284 recipients at the time of transplantation was 13.0 (9.0, 15.0) years, among whom 29 cases aged 0-6 years, 96 cases aged 7-11 years old, and 159 cases aged 12-18 years. The 1, 3, and 5 year survival rates were 92.3%, 88.9% and 84.8% for the kidney grafts, and were 97.1%, 95.6% and 94.4% for the recipients, respectively. Multivariate analysis showed postoperative acute rejection (HR=3.14, 95%CI 1.38-7.15, P=0.006) and perioperative vascular complications (HR=4.73, 95%CI 2.03-11.06, P<0.001) were independent risk factors for the survival of kidney graft. Postoperative infection (HR=14.23, 95%CI 3.45-58.72, P<0.001) was an independent risk factor for the postoperative mortality of recipients. Conclusions: Pediatric kidney transplantation shows a good short-and mid-term prognosis. Postoperative acute rejection and perioperative vascular complications are the risk factors for the survival of kidney graft, and postoperative infection is the risk factor affecting the survival of recipient.
Child ; Female ; Graft Rejection ; Graft Survival ; Humans ; Kidney Transplantation/adverse effects* ; Living Donors ; Male ; Postoperative Complications ; Prognosis ; Retrospective Studies ; Risk Factors

Objective: To investigate the daily variation of LPR and the significance of 48-hour oropharyngeal pH monitoring in the diagnosis of LPRD. Methods: 72 subjects with suspected LPRD who were treated in our department from June 2018 to June 2021 were included. All patients were hospitalized to complete continuous 48-hour oropharyngeal Dx-pH monitoring. The consistency of Ryan index and W index and the correlation of various reflux parameters between the first and second 24-hour were compared. SPSS 24.0 was used for statistical analysis. Results: All 72 subjects successfully completed 48-hour oropharyngeal Dx-pH monitoring. Ryan index was positive in 11 cases (15.2%) in the first 24-hour, in 17 cases (23.6%) in the second 24-hour, in 5 cases (6.9%) both first and second, and in 23 cases (31.9%) in either 24-hour, Kappa=0.211 (P=0.064), 18 cases (25%) had inconsistent results of the first 24-hour and the second 24-hour, and there was no significant difference in the positive rate between the first and second (P=0.234). The number of positive cases in 48-hour monitoring increased by 109.1% compared with 24-hour monitoring.For W index, 49 cases (68.1%) were positive in the first 24-hourf 53 cases (73.6%) were positive in the second 24-hour, 42 cases (58.3%) were positive both first and second, and 58 cases (80.6%) were positive in either 24-hour, Kappa=0.477 (P<0.001), 16 cases (22.2%) had inconsistent results of the first and second, and there was no significant difference in the positive rate between the first and second (P=0.804). The number of positive cases in 48-hour monitoring increased by 18.4% compared with 24-hour monitoring. There was no significant difference in all the reflux parameters of first and second (P>0.05). The correlation comparison showed that the correlation of various reflux parameters in the upright position was lower than that in the supine position. Conclusion: Laryngeal reflux has daily variability. Extending the monitoring time of Dx-pH to 48-hour can help reduce the missed diagnosis caused by daily variability; the use of W index can reduce the influence of daily variability on the diagnostic results of LPRD.
Humans ; Laryngopharyngeal Reflux/diagnosis* ; Hydrogen-Ion Concentration ; Hypopharynx ; Larynx

Aim To investigate the hub genes associated with response to valproate treatment in patients with epilepsy by using weighted gene co-expression network analysis.Methods We downloaded data from the GEO database and constructed the gene co-expression network.Pearson correlation test was used to calculate the correlation between module genes and clinical traits, to screen gene modules significantly associated with response to valproate treatment, and to screen hub genes according to the connectivity within modules.GO functional enrichment analysis and KEGG pathway analysis were used to annotate the functions of the modules.Results A total of 12 gene co-expression modules were constructed from the correlations of gene expression, in which the yellow module was significantly correlated with the drug treatment(r=0.57, P<0.000 1)and the blue module was significantly correlated with the response to valproate(r=-0.53, P<0.000 1).We found that S1PR5, SARM1 and MAGED1, FBXO31 were in the hub of the co-expression network.The biological annotation function revealed that the genes in both modules were mainly enriched in immune response and MPAK pathways.Conclusions Our work delivers preliminary data that valproate treatment causes the changes of immune and metabolic pathways in patients, and the response to epilepsy may be related to the expression of MAGED1, FBXO31.