Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Zinc finger protein 36 (ZFP36) was found to be downregulated in osteosarcoma (OS) tumor tissues. We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development. Two Gene Expression Omnibus (GEO) datasets showed that ZFP36 was a differentially expressed gene (DEG) in OS. Western blot and immunohistochemistry results showed that ZFP36 was downregulated in OS tumors and cell lines. ZFP36 overexpression plasmids and small interfering RNAs (siRNAs) were respectively transfected into OS cells. ZFP36 overexpression restrained proliferation, migration, and invasion in MG63 and U2OS cells, while ZFP36 knockdown displayed the opposite results. Moreover, ZFP36 overexpression increased the levels of intracellular Fe²⁺, reactive oxygen species (ROS), and malondialdehyde (MDA), and decreased the levels of glutathione (GSH), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). ZFP36 overexpression disturbed mitochondrial membrane potential (MMP) and mitochondrial morphology in OS cells. However, ZFP36 knockdown had the opposite results. Mechanistic studies indicated that ZFP36 promoted E2F transcription factor 1 (E2F1) messenger RNA (mRNA) degradation by binding to the AU-rich elements (AREs) within E2F1 3' untranslated region (3'UTR) in OS cells. E2F1 overexpression abrogated the effects of ZFP36 overexpression on malignant progression, ferroptosis, and mitochondrial dysfunction in OS cells. Furthermore, E2F1 promoted the transcription activation of activating transcription factor 4 (ATF4) by binding to ATF4 promoter. E2F1 knockdown inhibited malignant progression, and promoted ferroptosis and mitochondrial dysfunction in OS cells, which was abrogated by ATF4 overexpression. Additionally, MG63 cells transfected with lentivirus ZFP36 overexpression vector (Lv-ZFP36) were injected into nude mice and tumor growth was monitored. ZFP36 overexpression significantly suppressed OS tumor growth under in vivo settings. In conclusion, ZFP36 overexpression promoted ferroptosis and mitochondrial dysfunction and inhibited malignant progression in OS by regulating the E2F1/ATF4 axis. We may provide the promising ZFP36 target for OS treatment.

Objective To evaluate the effect of driving pressure(DP)-guided individualized positive end-expiratory pressure(PEEP)combined with regular lung recruitment maneuvers(RMs)on atelectasis in elderly patients undergoing laparoscopic surgery in the Trendelenburg position using lung ultrasound.Methods A total of 62 patients aged 65-85 years old and classified by ASA status Ⅰ-Ⅲ undergoing laparoscopic radical resection of colorectal cancer were included and randomly divided into the experimental group(n=31)and the control group(n=31).Both groups received one RM after the beginning of pneumoperitoneum,followed immediately by titration of individualized PEEP with the lowest DP,and both groups received another RM after the end of pneumoperitoneum.The experimental group received additional RM every 30 min from the beginning of pneumoperitoneum,while the control group received no intervention.Recording time points for observation were:before induction of anesthesia(T0),30 min after pneumoperitoneum(T1),90 min after pneumoperitoneum(T2),at the end of surgery(T3)and 45 min after entering the postanesthesia care unit(PACU,T4).Lung ultrasound score(LUS)was recorded at T0,T3 and T4.Dynamic lung compliance(Cdyn)was recorded at T1-T3.Oxygenation index(OI),mean arterial pressure(MAP)and heart rate(HR)were recorded at T0-T4.Hypotension during RM,hypoxic saturation events in PACU and the incidence of pulmonary complications(POPC)within the first 7 days after surgery were recorded.Results Compared with the control group,LUSs at T3 and T4 were significantly decreased in the experimental group(P<0.05),and OI and Cdyn at T2 and T3 were significantly increased(P<0.05).In addition,the incidence of hypoxia saturation events in PACU was lower in the experimental group than that in the control group(P<0.05).There were no significant differences in the incidence of hypotension during lung recruitment and the incidence of POPC within 7 days after surgery between the two groups.Conclusion The individualized PEEP combined with regular RMs can effectively reduce the atelectasis observed by lung ultrasound immediately after laparoscopic radical resection of colorectal cancer and in PACU in elderly patients.

Objective:To investigate the characteristics of attention bias to aggressive information under self-threat priming in college students with different types of high self-esteem.Methods:A total of 650 college students were selected,and high self-esteem participants were selected through the Self Esteem Scale(SES).Then,43 partic-ipants were selected from different types of high self-esteem(fragile and safe)groups through the Implicit Associa-tion Test(IAT).Each group participated in Raven's Standard Progressive Matrices(SPM)with different difficulty levels to complete self-threat priming,and then completed the spatial cue experiment.When the cue was invalid,the attention bias was obtained according to the variation of the reaction time difference(RTI)between the subjects're-sponses to aggressive words and neutral words.Results:The RTI values of the fragile high self-esteem group were higher under high self-threat priming than that of the secure high self-esteem group(P＜0.01).Under low self-threat priming,there was no significant difference in RTI values among different types of high self-esteem groups(P＞0.05).Conclusion:Fragile high self-esteem group are more likely to develop attention bias towards aggressive words under high self-threat priming than that of secure high self-esteem group.

Objective To study the role of ubiquitin-conjugating enzyme 9(UBC9)in the pyroptosis of homocysteine-induced macrophages mediated by small ubiquitin-like modifier(SUMO)modification.Methods First,the effects of homocysteine at different concentrations(0 μmol/L,50 μ.mol/L,100 μmol/L,150 μmol/L and 200 μmol/L)on the viability and pyrodeath of mouse macrophages(RAW264.7)were detected by CCK-8 and Western blot.Western blot was used to detect the expression levels of UBC9,SUMO-1,and the inflammatory cytokine IL-1β in different groups of cells.qRT-PCR was used to detect the mRNA expression of UBC9 before and after RNA interference and the expression of UBC9,pyrogen-related protein,and SUMO-1 after RNA interference.Results After stimulation with 100 μmol/L homocysteine,the effect of macrophage activity was minimal,and NLRP3 and Caspase-1 were the proteins with the most obvious increase in expression(P＜0.05).Compared with the Control group,the Hcy group's expression of IL-1β and SUMO-1 was increased(P＜0.01).Compared with the Control group,the Hcy group's UBC9 protein and mRNA levels were increased(P＜0.05).The expression of NLRP3,Caspase-1,IL-1β,UBC9,and SUMO-1 was decreased in the si-UBC9+Hcy group compared with the si-NC+Hcy group(P＜0.01).Conclusions Homocysteine induces pyroptosis in macrophages,and its mechanism of action is related to the up-regulation of UBC9 to induce SUMO modification.

AIM:To investigate the role of specific long noncoding RNA SLC25a6(lncSLC25a6)in homocys-teine(Hcy)-induced cuproptosis in cardiomyocytes.METHODS:Rat cardiomyocytes were cultured in vitro and divided into control group and Hcy group.After 48 h of intervention,the expression levels of cuproptosis-related proteins,ferre-doxin 1(FDX1)and heat shock protein 70(HSP70),were detected by Western blot and immunofluorescence staining.The oxidative stress state of cardiomyocytes was assessed using fluorescence staining,and the intracellular Cu2+levels were measured using a copper ion assay kit.Furthermore,the impact of Hcy on the expression of cuproptosis-related proteins in cardiomyocytes was analyzed following overexpression of lncSLC25a6.RESULTS:Compared with the control group,80 μmol/L Hcy significantly accelerated cardiomyocyte damage,with a notable underexpression of lncSLC25a6(P<0.05).Western blot results indicated that,compared with the control group,the expression level of FDX1 in the Hcy intervention group was significantly reduced(P<0.05),while the expression level of HSP70 was significantly elevated(P<0.05),and the expression level of copper ions in cardiomyocytes of the Hcy group was increased(P<0.05).Immunofluorescence staining showed a significant reduction in FDX1 fluorescence intensity and a significant increase in HSP70 fluorescence in-tensity in the Hcy group.Further overexpression of lncSLC25a6 significantly mitigated Hcy-induced cuproptosis in cardio-myocytes,resulting in elevated expression of FDX1 and reduced expression of HSP70(P<0.05).Pearson correlation analysis demonstrated that the expression level of lncSLC25a6 was negatively correlated with FDX1 protein expression(r=-0.676,P=0.046)and positively correlated with HSP70 expression(r=0.680,P=0.044).CONCLUSION:lnc-SLC25a6 significantly mitigates Hcy-induced cuproptosis in cardiomyocytes,positioning it as a potential therapeutic target for managing Hcy-induced cardiac injury.

BACKGROUND:Ischemic postconditioning is one of the effective ways to reduce ischemia-reperfusion injury and has been more and more widely used in clinical practice in recent years,but its specific molecular mechanism has yet to be studied. OBJECTIVE:To investigate the role and mechanism of piRNA-005854 in the aging cardiomyocytes caused by hypoxic postconditioning. METHODS:In vitro,cardiomyocytes were administered 8 mg/mL D-galactose for 9 days to induce their aging.β-Galactosidase staining was used to observe the aging of cardiomyocytes.Senescent cells were treated with hypoxia/reoxygenation and hypoxic postconditioning.ELISA was utilized to detect changes in myocardial injury markers creatine kinase isoenzyme MB and lactate dehydrogenase levels.Western blot assay was applied to detect the expression changes of autophagy-related proteins LC3II,p62,ULK1 and phosphorylated ULK1 in aging cardiomyocytes.qRT-PCR was employed to determine the expression level of piRNA-005854.piRNA-005854 inhibitor and piRNA-005854 mimics were transferred into aging cardiomyocytes and followed with hypoxic postconditioning.Western blot assay was used to examine the expression of LC3II,p62,ULK1 and phosphorylated ULK1. RESULTS AND CONCLUSION:(1)D-galactose induced obvious senescence of cardiomyocytes 9 days later.(2)Compared with the normoxia group,creatine kinase isoenzyme MB and lactate dehydrogenase levels increased in the hypoxia/reoxygenation group(P<0.01);LC3 II/I expression was increased;p62 expression was decreased;ULK1 phosphorylation level was increased,and piRNA-005854 expression was increased(P<0.01).(3)Compared with the hypoxia/reoxygenation group,creatine kinase isoenzyme MB and lactate dehydrogenase levels significantly reduced in the hypoxic postconditioning group(P<0.01);LC3 II/I expression significantly decreased(P<0.05);p62 expression increased(P<0.01);ULK1 phosphorylation level decreased(P<0.05),and piRNA-005854 expression decreased(P<0.01).(4)After transfection of piRNA-005854 inhibitor,LC3II/I expression was decreased(P<0.01);the expression of p62 was increased significantly(P<0.05);the phosphorylation level of ULK1 was decreased significantly(P<0.01).After transfection of piRNA-005854 mimics,LC3II/I expression was increased significantly;the expression of p62 was decreased,and the phosphorylation level of ULK1 was increased significantly(P<0.01).(5)The results show that piRNA-005854-mediated reduction of ULK1-dependent autophagy level is a possible mechanism that hypoxic postconditioning exerts its protective effect on aging cardiomyocytes.

BACKGROUND:Hyperhomocysteinemia is closely related to the function of islet β cells,but its specific molecular mechanism is not fully understood. OBJECTIVE:To investigate the role of N6 methyltransferase-like 3(METTL3)in homocysteine(Hcy)-induced autophagy of mouse islet β cells. METHODS:The 3rd and 4th generation mouse islet β cells were taken for the experiment.(1)Cell modeling and grouping:cells in control group were not treated with Hcy,while those in homocysteine group were treated with 100 μmol/L Hcy for 48 hours.(2)The mouse islet β-cells were transfected with the plasmids overexpressing Ad-METTL3 and si-METTL3 according to the instructions of LipofectamineTM 2000.Three different interfering fragments were designed,and the one with the best interfering efficiency was verified and screened by PCR.(3)After transfection,the cells were divided into control group,Hcy group,Ad-NC(negative control)+Hcy group,Ad-METTL3+Hcy group,si-NC(negative control)+Hcy group and si-METTL3+Hcy group.(4)qRT-PCR and western blot were used to detect the expression levels of METTL3 and autophagy-related proteins LC3Ⅱ/Ⅰ and p62 in cells.Insulin level was determined by ELISA to evaluate insulin secretion capacity of islet cells.Autophagy-related proteins and insulin level were detected after overexpression and interference with METTL3. RESULTS AND CONCLUSION:Compared with the control group,the expression level of LC3Ⅱ/Ⅰ was increased(P＜0.05),the expression of p62 was significantly reduced(P＜0.05),and the insulin secretion capacity was significantly decreased(P＜0.05)in the Hcy group.Compared with the control group,the protein and mRNA levels of METTL3 were reduced in the Hcy group(P＜0.05).After METTL3 silencing in islet β cells,Hcy further upregulated the expression of LC3Ⅱ/Ⅰ(P＜0.05),significantly dowregulated the expression of p62(P＜0.05),and increased the insulin level(P＜0.05).After overexpression of METTL3,Hcy significantly decreased the LC3Ⅱ/Ⅰ expression and increased the p62 expression in islet β cells(P＜0.05).To conclude,METTL3 is involved in the Hcy-induced autophagy regulation of islet β cells and plays a role in the regulation of insulin secretion.

OBJECTIVE: To investigate the correlation between postoperative driving pressure (DP) and the prognosis of lung transplantation, and to further evaluate the value of early DP monitoring in lung transplantation. METHODS: A observational study was conducted. The patients after lung transplantation who admitted to the intensive care unit (ICU) of Wuxi People's Hospital from February 1, 2022 to February 1, 2023 were collected. They were divided into low DP group (DP≤15 cmH₂O, 1 cmH₂O ≈ 0.098 kPa) and high DP group (DP > 15 cmH₂O) according to DP within 2 hours after operation. The clinical data including general information, primary disease, chronic diseases, cardiopulmonary function, laboratory indicators, intraoperative condition, postoperative lactic acid (Lac) and ventilator parameters were collected. Primary outcomes included 28-day and 90-day survival, and secondary outcomes included occurrence of primary graft dysfunction (PGD), duration of extracorporeal membrane oxygenation (ECMO), duration of mechanical ventilation, weaning of mechanical ventilation, and length of ICU stay. The general data and observations between the two groups were compared. Kaplan-Meier curve analysis was conducted to analyze the situation of mechanical ventilation and 90-day survival. Receiver operator characteristic curve (ROC curve) was used to evaluate the predictive ability of DP for failed weaning of mechanical ventilation and 90-day death. The dose-response relationship between DP and 90-day death risk was determined by restricted cubic spline model. Univariate analysis was performed using Cox proportional hazards model. RESULTS: A total of 101 patients were enrolled, with 68 patients (67.3%) in the low DP group and 33 patients (32.7%) in the high DP group. No statistically significant difference in general information, chronic diseases, primary diseases, cardiopulmonary function, laboratory indicators, intraoperative conditions, and postoperative Lac between the two groups was found. Compared with the low DP group, the patients in the high DP group had higher inspiratory pressure (Pinsp) and incidence of PGD with grade 3 at 24 hours after operation [Pinsp (cmH₂O): 21.0±0.6 vs. 20.0±0.7, PGD with grade 3 at 24 hours: 60.6% (20/33) vs. 39.7% (27/68), both P < 0.05], longer duration of ECMO, duration of mechanical ventilation, and the length of ICU stay [duration of ECMO (hours): 37 (21, 109) vs. 22 (14, 43), duration of mechanical ventilation (days): 3.1 (1.8, 10.7) vs. 1.9 (1.1, 3.2), length of ICU stay (days): 6 (3, 13) vs. 4 (3, 5), all P < 0.05], and lower successful weaning rate of mechanical ventilation [81.8% (27/33) vs. 95.6% (65/68), P < 0.05). The 28-day and 90-day survival rates in the high DP group were significantly higher than those in the low DP group [28-day: 69.7% (23/33) vs. 86.8% (59/68), 90-day: 63.6% (21/33) vs. 83.8% (57/68), both P < 0.05]. Kaplan-Meier curve showed that the patients in the low DP group were weaned and extubated earlier than high DP group, and the cumulative situation of weaning was better (Log-Rank test: χ ² = 14.054, P < 0.001), and the 90-day cumulative survival rate in the low DP group was significantly higher than that in the high DP group (Log-Rank test: χ ² = 4.791, P = 0.029). ROC curve analysis showed that the area under ROC curve (AUC) of DP for predicting 90-day death was 0.664 [95% confidence internal (95%CI) was 0.540-0.787, P = 0.017], and the AUC for predicting failed weaning of mechanical ventilation was 0.794 (95%CI was 0.667-0.921, P = 0.004). Results of restricted cubic spline model analysis showed that the 90-day death risk continued to increase with the DP < 18 cmH₂O; when DP≥18 cmH₂O, elevated DP did not continue to increase the 90-day death risk, showing a plateau effect. Univariate analysis showed that DP was independent risk factors of 90-day death, and the death risk increased by 9.3% for every 1 cmH₂O increase in DP [hazard ratio (HR) = 1.093, 95%CI was 1.007-1.186, P = 0.033]. CONCLUSIONS DP is an independent risk factor of death after lung transplantation, and early postoperative DP may be used as a predictor of failed weaning of mechanical ventilation and 90-day death after lung transplantation.
Humans ; Lung Transplantation ; Prognosis ; Respiration, Artificial ; Intensive Care Units ; Postoperative Period ; Pressure ; Primary Graft Dysfunction/epidemiology* ; Transplant Recipients ; Female ; Extracorporeal Membrane Oxygenation ; Male ; ROC Curve ; Middle Aged

Objective : To investigate the effect of paederosidic acid methyl ester (PAME) on postoperative learning and memory impairment in mice and its mechanism. Methods : C57BL/6J male mice were randomly divided into Sham group , operation group , operation + PAME group ( PAME group) , operation + NADPH oxidase 4(Nox4) adeno⁃associated virus overexpression group (Nox4 overexpression group) , operation + Nox4 adeno⁃associated virus no⁃laden group ( AAV no⁃load group) , and operation + PAME + Nox4 overexpression group ( PN group) . Exploratory laparotomy was performed. PAME(20 mg/kg) was administered by continuous gavage for 7 days after operation , and adeno⁃associated virus was injected into the hippocampus 28 days before operation. Morris water maze test and conditioned fear test were used to detect the learning and memory ability of mice. The expression of Nox4 protein was observed by immunofluorescence. The protein expressions of Nox4 , long chain acyl CoA synthetase 4 (ACSL4) and glutathione peroxidase 4 (GPX4) were detected by Western blot. Reactive oxygen species (ROS) and iron content were determined by spectrophotometry. Results : Compared with the Sham group , the learning and memory ability of the operation group , the Nox4 overexpression group and the AAV no⁃load group decreased , the protein expression of Nox4 and ACSL4 increased , the protein expression of GPX4 decreased , and the ROS and iron content increased. After PAME treatment , the postoperative learning and memory ability of mice was improved , and Nox4 and ferroptosis in hippocampal neurons were alleviated. Conclusion Conclusion PAME treatment can improve the learning and memory ability of postoperative mice , which may be related to the inhibition of hippocampal Nox4⁃mediated ferroptosis.