Local anesthetics (LAs), such as articaine (AT), exhibit limited efficacy in inflammatory environments, which constitutes a significant limitation in their clinical application within oral medicine. In our prior research, we developed AT-17, which demonstrated effective properties in chronic inflammatory conditions and appears to function as a novel oral LA that could address this challenge. In the present study, we further elucidated the beneficial effects of AT-17 in acute inflammation, particularly in oral acute inflammation, where mitochondrial-related apoptosis played a crucial role. Our findings indicated that AT-17 effectively inhibited lipopolysaccharide (LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro. This process involved the inhibition of mitochondrial reactive oxygen species (mtROS) production and the subsequent activation of the NRF2 pathway. Most notably, improvements in mitochondria-related apoptosis were key contributors to AT-17's inhibition of voltage-gated sodium channels. Additionally, AT-17 was shown to reduce mtROS production in nerve cells through the Na⁺/NCLX/ETC signaling axis. In conclusion, we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis. This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.

Objective:To evaluate the relationship between glutathione S-transferase μ1 (GSTM1) and the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling pathway during therapeutic hypothermia-induced reduction of cerebral ischemia-reperfusion injury (CIRI) in rats.Methods:One hundred clean-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 260-280 g, were divided into 5 groups ( n=20 each) using a random number table method: sham operation group (S group), cerebral ischemia-reperfusion group (I/R group), therapeutic hypothermia group (H group), GSTM1 inhibitor+ therapeutic hypothermia group (IH group), and GSTM1 inhibitor + ASK1 inhibitor + therapeutic hypothermia group (IAH group). CIRI model was developed by occlusion of the left middle cerebral artery for 2 h, followed by restoration of the blood flow. A nylon thread was inserted into the internal carotid artery and advanced cephalad until resistance was met. The brain temperature was maintained at 36-37 ℃ during surgery. In H group, the head and neck were wiped with 75% alcohol immediately after reperfusion, and the brain temperature was maintained at 32-33℃ for 3 h, and the rest procedures were the same as those previously described in I/R group. In IH group, GSTM1 inhibitor itaconic acid 8.6 mg/kg was intraperitoneally injected at 24 and 1 h before developing the model, and the rest procedures were the same as those previously described in H group. In IAH group, ASK1 inhibitor selonsertib 10 mg/kg was given orally once a day for 4 consecutive days starting from 4 days before developing the model, and the rest procedures were the same as those previously described in IH group. Modified Neurological Severity Score (mNSS) was assessed at 24 h of reperfusion, then the rats were sacrificed and brains were harvested for microscopic examination of brain infarction, neuronal morphology (using HE staining) and for determination of the expression of GSTM1, ASK1, phosphorylated ASK1 (p-ASK1), JNK, phosphorylated JNK (p-JNK), p-38 MAPK and phosphorylated p-38 MAPK (p-p38 MAPK) (by Western blot) and neuronal apoptosis (by TUNEL assay). The percentage of the infarct size was calculated using TTC staining. The apoptosis rate was calculated. Results:Compared with S group, the mNSS, apoptosis rate of neurons, percentage of the cerebral infarct size, p-ASK1/ASK1 ratio, p-JNK/JNK ratio and p-p38 MAPK/p38 MAPK ratio were significantly increased, and the expression of GSTM1 was down-regulated in I/R group ( P<0.05). Compared with I/R group and IH group, the mNSS, apoptosis rate of neurons, percentage of the cerebral infarct size, p-ASK1/ASK1 ratio, p-JNK/JNK ratio and p-p38 MAPK/p38 MAPK ratio were significantly decreased, the expression of GSTM1 was up-regulated ( P<0.05), and the neuronal injury was significantly attenuated in H group. Compared with IH group, the mNSS, apoptosis rate of neurons, percentage of the cerebral infarct size, p-ASK1/ASK1 ratio, p-JNK/JNK ratio and p-p38 MAPK/p38 MAPK ratio were significantly decreased ( P<0.05), no significant change was found in GSTM1 expression ( P>0.05), and the neuronal damage was significantly attenuated in IAH group. Conclusions:The mechanism by which therapeutic hypothermia alleviates CIRI is related to up-regulating the expression of GSTM1 and inhibiting the activation of the ASK1-JNK-p38 MAPK signaling pathway in rats.

Objective:To investigate the related risk factors of surgical appendectomy after endoscopic retrograde appendicitis therapy (ERAT) in children.Methods:From September 2019 to November 2023 at the Children's Hospital Affiliated to Shandong University,the data from all related children with appendectomy after ERAT were analyzed. The general situation and main clinical manifestations of the children were collected. According to the effect of ERAT,the patients were divided into transfer to surgical group and appendicitis recurrence group by the reasons and time of transfer to surgical treatment. The indexes such as ERAT and reoperation process and pathological types of appendix after operation were collected,and the clinical experience was summarized.Results:Among the 242 children who underwent ERAT,32 cases underwent appendectomy again,including 19 males and 13 females,with an average age of（9.16±2.77）years,and the reoperation rate was 13.2%. The clinical manifestation was abdominal pain (32 cases,100.0%),mainly right lower abdominal pain (28 cases,87.5%),and the main duration was less than 3 months (30 cases,93.8%). Abdominal ultrasound or CT before ERAT mainly indicated appendicitis (11 cases,34.4%) and appendicitis complicated with appendiceal calculus (11 cases,34.4%). There were 9 children in transferred to surgical group,of which 5 cases were transferred to surgery because of ERAT intubation failure,and 4 cases were transferred to surgery because of appendix perforation or abscess. Postoperative pathology showed acute suppurative appendicitis in 5 cases and acute gangrenous appendicitis in 4 cases. There were 23 children in appendicitis recurrence group,whose abdominal pain was relieved after ERAT,but their symptoms were repeated after discharge. After clinical evaluation,they were diagnosed as recurrent appendicitis and underwent surgical appendectomy. Most of them were reoperated within 6 months after ERAT (21 cases,91.3%).Postoperative pathology was mainly chronic appendicitis (10 cases,43.5%).Conclusion:Acute suppurative appendicitis and acute gangrenous appendicitis are prone to catheterization or endoscopic failure during ERAT,and there is a high risk of surgical transfer. ERAT may relieve the symptoms of chronic appendicitis in children. If the symptoms are repeated,surgery is still needed to remove the appendix.

Surgery-based multidisciplinary comprehensive treatment is the preferred treatment strategy for local advanced esophageal cancer. Neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy have been recommended by the Chinese Society of Clinical Oncology (CSCO) guideline. With the advent of immunotherapy, neoadjuvant immunotherapy combined with chemotherapy has received much attention, and the first phase Ⅲ study has also confirmed that neoadjuvant immunotherapy combined chemotherapy is a promising treatment option. This article will review the recent advances and hot spots of neoadjuvant immunotherapy combined with chemotherapy.

OBJECTIVE: To investigate the expression and physiological significance of the ferroptosis marker 4-hydroxynonenal (4-HNE) in myofibroblasts induced by transforming growth factor-β1 (TGF-β1), providing theoretical evidence for its potential role in the diagnosis and treatment of fibrosis in systemic sclerosis (SSc). METHODS: Mouse embryonic fibroblasts (NIH3t3) were cultured and divided into two groups after 12 h of starvation: the control group (cultured in 1% serum-containing medium) and the TGF-β1 group (cultured in 10 μg/L TGF-β1 with 1% serum-containing medium). Cell morphology changes in both groups were observed under a microscope. To confirm successful establishment of the SSc cell model, fibrosis markers were analyzed using reverse transcription quantitative real-time PCR (RT-qPCR) and Western blot. Next, flow cytometry was employed to assess the intracellular levels of reactive oxygen species (ROS) in both groups. Finally, Western blot and immunofluorescence staining were used to measure the expression of 4-HNE in the TGF-β1-treated cells. RESULTS: Microscopic observations revealed that TGF-β1 treatment caused the NIH3t3 cells to transition from a typical spindle shape to a flat, polygonal shape with multiple protrusions, indicating fibroblast activation. The RT-qPCR and Western blot analyses showed that the expression of the fibrosis marker Vimentin was significantly upregulated in the TGF-β1 group compared with the control group (P < 0.01), confirming that TGF-β1 effectively promoted fibrosis-related gene and protein expression. Flow cytometry results indicated that TGF-β1 significantly elevated intracellular ROS levels, suggesting the induction of oxidative stress. Furthermore, both Western blot and immuno-fluorescence staining demonstrated a significant increase in 4-HNE expression in the TGF-β1-treated cells (immunofluorescence intensity P < 0.05). CONCLUSION TGF-β1 promotes fibroblast activation and fibrosis while inducing ROS production, leading to a marked increase in 4-HNE expression. Given the role of 4-HNE as a marker of lipid peroxidation and its elevated levels in the SSc cell model, this study suggests that 4-HNE could serve as a potential biomarker for fibrosis in SSc. The findings highlight the importance of investigating the mechanisms of 4-HNE in fibrosis and suggest that targeting this pathway could offer new therapeutic opportunities for treating SSc.
Animals ; Mice ; Scleroderma, Systemic/pathology* ; Aldehydes/pharmacology* ; Transforming Growth Factor beta1/metabolism* ; NIH 3T3 Cells ; Ferroptosis ; Reactive Oxygen Species/metabolism* ; Fibrosis ; Fibroblasts/metabolism* ; Biomarkers/metabolism* ; Myofibroblasts/metabolism*

Objective To explore the construction of modular intervention for patients dependent on mechanical ventilation in ICU,and to conduct the clinical empirical study.Methods A total of 100 mechanical ventilation-dependent patients in ICU were enrolled and divided into two groups according to the admission order,with 50 patients in each group.Control group received routine intervention,while observation group was treated with modular intervention in addition to the treatment given to control group.The weaning success rate,weaning time,complications,rehabilitation index,blood gas analysis index,psychological state,and nutritional status were compared between two groups.Results Compared with control group,observation group had higher weaning success rate,shorter weaning time,ICU stay and general ward admission,and lower incidence of complications(P<0.05).After intervention,observation group had lower PaCO2,and higher PaO2 and PaO2/FiO2 than control group(P<0.05);the scores of SAS,SDS and APACHEⅡwere lower in observation group than in control group(P<0.05);and the serum levels of ALB,PA,TRF and TP in observation group were higher than those in control group(P<0.05).Conclusion Modular intervention for mechanical ventilation-dependent patients in ICU can increase weaning success rate,improve blood gas analysis index and nutritional status,alleviate negative emotions,reduce complications and speed recovery.

Objective     To explore the causes of conversion to thoracotomy in patients with minimally invasive esophagectomy (MIE) in a surgical team, and to obtain a deeper understanding of the timing of conversion in MIE. Methods     The clinical data of patients who underwent MIE between September 9, 2011 and February 12, 2022 by a single surgical team in the Department of Thoracic Surgery of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. The main influencing factors and perioperative mortality of patients who converted to thoracotomy in this group were analyzed. Results     In the cohort of 791 consecutive patients with MIE, there were 520 males and 271 females, including 29 patients of multiple esophageal cancer, 156 patients of upper thoracic cancer, 524 patients of middle thoracic cancer, and 82 patients of lower thoracic cancer. And 46 patients were converted to thoracotomy for different causes. The main causes for thoracotomy were advanced stage tumor (26 patients), anesthesia-related factors (5 patients), extensive thoracic adhesions (6 patients), and accidental injury of important structures (8 patients). There was a statistical difference in the distribution of tumor locations between patients who converted to thoracotomy and the MIE patients (P<0.05). The proportion of multiple and upper thoracic cancer in patients who converted to thoracotomy was higher than that in the MIE patients, while the proportion of lower thoracic cancer was lower than that in the MIE patients. The perioperative mortality of the thoracotomy patients was not significantly different from that of the MIE patients (P=1.000). Conclusion     In MIE, advanced-stage tumor, anesthesia-related factors,extensive thoracic adhesions, and accidental injury of important structures are the main causes of conversion to thoracotomy. The rate varies at different tumor locations. Intraoperative conversion to thoracotomy does not affect the perioperative mortality of MIE.

Objective:To assess the effectiveness and characteristics of intratumoral radioactive seed implantation in pancreatic cancer pain management.Methods:Clinical data of 160 patients with pancreatic cancer receiving radioactive seed implantation were retrospectively analyzed. Both pre- and postoperative pain intensities were evaluated using the visual analog scale (VAS) .Results:About 71.88% (115) of 160 patients experienced abdominal or low back pain. Postoperative pain in 104 patients was relieved at various degrees after radioactive seed implantation with an analgesic efficacy of 90.43% (the efficacy for abdominal and low back pain relief was 86.52% and 96.34%, respectively). The between-group difference was statistically significant. Pain relief was observed 1-7 days postoperatively, and the maximal degree of pain relief was achieved 2-14 days after treatment initiation.Conclusion:Intratumoral implantation of radioactive seeds was microinvasive, quick-acting, and effective in pancreatic cancer pain management.

The aim of this study was to investigate the role of selenoprotein M (SelM) in endoplasmic reticulum stress and apoptosis in nickel-exposed mouse hearts and to explore the detoxifying effects of melatonin. At 21 d after intraperitoneal injection of nickel chloride (NiCl₂) and/or melatonin into male wild-type (WT) and SelM knockout (KO) C57BL/6J mice, NiCl₂ was found to induce changes in the microstructure and ultrastructure of the hearts of both WT and SelM KO mice, which were caused by oxidative stress, endoplasmic reticulum stress, and apoptosis, as evidenced by decreases in malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) activity. Changes in the messenger RNA (mRNA) and protein expression of genes related to endoplasmic reticulum stress (activating transcription factor 4 (ATF4), inositol-requiring protein 1 (IRE1), c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP)) and apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Caspase-9, and Caspase-12) were also observed. Notably, the observed damage was worse in SelM KO mice. Furthermore, melatonin alleviated the heart injury caused by NiCl₂ in WT mice but could not exert a good protective effect in the heart of SelM KO mice. Overall, the findings suggested that the antioxidant capacity of SelM, as well as its modulation of endoplasmic reticulum stress and apoptosis, plays important roles in nickel-induced heart injury.
Animals ; Male ; Mice ; Antioxidants/pharmacology* ; Apoptosis ; Endoplasmic Reticulum Stress ; Melatonin/pharmacology* ; Mice, Inbred C57BL ; Nickel/adverse effects* ; Selenoproteins/genetics* ; Heart/drug effects*

Objective: To compare the prognostic evaluation value of preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) in rectal cancer patients. Nomogram survival prediction model based on inflammatory markers was constructed. Methods: The clinical and survival data of 585 patients with rectal cancer who underwent radical resection in the First Affiliated Hospital of Xi'an Jiao tong University from January 2013 to December 2016 were retrospectively analyzed. The optimal cut-off values of NLR, PLR, LMR, and SII were determined by the receiver operating characteristic (ROC) curve. The relationship between different NLR, PLR, LMR and SII levels and the clinic pathological characteristics of the rectal cancer patients were compared. Cox proportional risk model was used for univariate and multivariate regression analysis. Nomogram prediction models of overall survival (OS) and disease-free survival (DFS) of patients with rectal cancer were established by the R Language software. The internal validation and accuracy of the nomograms were determined by the calculation of concordance index (C-index). Calibration curve was used to evaluate nomograms' efficiency. Results: The optimal cut-off values of preoperative NLR, PLR, LMR and SII of OS for rectal cancer patients were 2.44, 134.88, 4.70 and 354.18, respectively. There was statistically significant difference in tumor differentiation degree between the low NLR group and the high NLR group (P<0.05), and there were statistically significant differences in T stage, N stage, TNM stage, tumor differentiation degree and preoperative carcinoembryonic antigen (CEA) level between the low PLR group and the high PLR group (P<0.05). There was statistically significant difference in tumor differentiation degree between the low LMR group and the high LMR group (P<0.05), and there were statistically significant differences in T stage, N stage, TNM stage, tumor differentiation degree and preoperative CEA level between the low SII group and the high SII group (P<0.05). The multivariate Cox regression analysis showed that the age (HR=2.221, 95%CI: 1.526-3.231), TNM stage (Ⅲ grade: HR=4.425, 95%CI: 1.848-10.596), grade of differentiation (HR=1.630, 95%CI: 1.074-2.474), SII level (HR=2.949, 95%CI: 1.799-4.835), and postoperative chemoradiotherapy (HR=2.123, 95%CI: 1.506-2.992) were independent risk factors for the OS of patients with rectal cancer. The age (HR=2.107, 95%CI: 1.535-2.893), TNM stage (Ⅲ grade, HR=2.850, 95%CI: 1.430-5.680), grade of differentiation (HR=1.681, 95%CI: 1.150-2.457), SII level (HR=2.309, 95%CI: 1.546-3.447), and postoperative chemoradiotherapy (HR=1.837, 95%CI: 1.369-2.464) were independent risk factors of the DFS of patients with rectal cancer. According to the OS and DFS nomograms predict models of rectal cancer patients established by multivariate COX regression analysis, the C-index were 0.786 and 0.746, respectively. The calibration curve of the nomograms showed high consistence of predict and actual curves. Conclusions: Preoperative NLR, PLR, LMR and SII levels are all correlated with the prognosis of rectal cancer patients, and the SII level is an independent prognostic risk factor for patients with rectal cancer. Preoperative SII level can complement with the age, TNM stage, differentiation degree and postoperative adjuvant chemoradiotherapy to accurately predict the prognosis of rectal cancer patients, which can provide reference and help for clinical decision.
Biomarkers, Tumor ; Carcinoembryonic Antigen ; Humans ; Inflammation/classification* ; Lymphocytes ; Neutrophils ; Nomograms ; Preoperative Period ; Prognosis ; Rectal Neoplasms/surgery* ; Retrospective Studies