Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Objective To investigate the protective effect of placental mesenchymal stem cells(P-MSCs)on pancreatic trauma(PT)in rats.Methods Sixty healthy adult male SD rats were randomly divided into control group,pancreatic trauma group(inject 1 ml of PBS solution locally in the pancreatic injury area and around the trauma area),and P-MSCs group[inject 1 ml of P-MSCs(1×106/ml)locally in the pancreatic injury area and around the trauma area],with 20 rats in each group.The pancreatic trauma rat model was established using a traumatic pressure of 400 kPa.Five rats were sacrificed at 1,3,5,and 7 d after modeling in each group,and serum and pancreatic tissue were collected.HE staining was used to observe the pathological changes of pancreatic tissue and pathological scores were performed.The ELISA method was used to measure the concentrations of serum amylase(AMS),lipase(LPS),tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),IL-10,and transforming growth factor-β1(TGF-β1),as well as the activities of myeloperoxidase(MPO)and superoxide dismutase(SOD)in pancreatic tissue.The TUNEL method was used to observe the level of apoptosis in pancreatic tissue was observed by the TUNEL method.Results Compared with control group,pancreatic trauma group and P-MSCs group showed significant differences after pancreatic trauma,including the generation of peritoneal fluid increased(P<0.05),the ratio of pancreas to body weight and the total score of pancreatic tissue pathological damage increased(P<0.05),and serum levels of AMS,LPS,TNF-α,IL-6,and MPO activity increased early and showed a decreasing trend over time(P<0.05),while anti-inflammatory factors IL-10 and SOD activity showed an increasing trend over time(P<0.01),level of TGF-β1 in the early decline showed an upward trend over time(P<0.01),and the apoptosis index(AI)significantly increased(P<0.001).Compared with pancreatic trauma group,P-MSCs group showed an improvement in the overall morphology of pancreatic tissue,the generation of peritoneal fluid decreased(P<0.001),the pancreas to body weight ratio and the total score of pancreatic tissue pathological damage decreased(P<0.05),and serum levels of AMS,LPS,IL-6,TNF-α and MPO activity returned to normal levels faster(P<0.05);and the rate of anti-inflammatory factors IL-10,TGF-β1 and SOD activity elevation increased(P<0.05),the AI increased(P<0.001).Conclusion P-MSCs can achieve therapeutic effects on pancreatic trauma in rats by promoting pancreatic tissue repair,reducing local and systemic inflammation,improving tissue oxidative stress,and enhancing pancreatic acinar cell apoptosis.

Objective: To evaluate the efficacy and safety of intravenous iron supplementation in patients with recurrent iron deficiency anemia (IDA) . Methods: This retrospective analysis of 90 patients with recurrent IDA from May 2012 to December 2021 was conducted, comparing the efficacy and safety of the intravenous iron therapy group and the oral iron therapy group. Results: Among the 90 patients with recurrent IDA, 20 were males and 70 were females, with a median age of 40 (range: 14-85) years. A total of 60 patients received intravenous iron supplementation and 30 received oral iron supplementation. The hematologic response rates in the intravenous iron group were significantly higher than those in the oral iron group at 4 and 8 weeks after treatment [80.0% (48/60) vs 3.3% (1/30) and 96.7% (58/60) vs 46.7% (14/30), all P<0.001, respectively]. The median increase in hemoglobin levels was also significantly higher in the intravenous iron group than in the oral iron group [38 (4, 66) g/L vs 7 (1, 22) g/L at week 4 and 44.5 (18, 80) g/L vs 19 (3, 53) g/L at week 8, all P<0.001]. The intravenous iron group had a significantly higher proportion of patients who achieved normal hemoglobin levels than the oral iron group (55.0% vs 0 and 90% vs 43.3%, all P<0.001, respectively). Iron metabolism indicators were tested before and after 8 weeks of treatment in 26 and 7 patients in the intravenous and oral iron groups, respectively. The median increase in serum ferritin (SF) levels in the intravenous iron group 8 weeks after treatment was 113.7 (49.7, 413.5) μg/L, and 54% (14/26) of these patients had SF levels of ≥100 μg/L, which was significantly higher than the median increase in SF levels in the oral iron group [14.0 (5.8, 84.2) μg/L, t=4.760, P<0.001] and the proportion of patients with SF levels of ≥100 μg/L (P=0.013). The incidence of adverse reactions was 3.3% (2/60) in the intravenous iron group, which was significantly lower than that in the oral iron group [20.0% (6/30), P=0.015]. Conclusion: Intravenous iron supplementation is more effective for hematologic response, faster hemoglobin increase, and higher iron storage replenishment rates compared with oral iron supplementation in patients with recurrent IDA, and it is well tolerated by patients.
Male ; Female ; Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Anemia, Iron-Deficiency/epidemiology* ; Sucrose/therapeutic use* ; Ferric Compounds/therapeutic use* ; Retrospective Studies ; Iron/therapeutic use* ; Hemoglobins/therapeutic use*

OBJECTIVE: This study assesses the impact of smoke-free legislation on the incidence rate for acute myocardial infarction (AMI) and stroke in Shenzhen. METHODS: Data on ischemic ( n = 72,945) and hemorrhagic ( n = 18,659) stroke and AMI ( n = 17,431) incidence covering about 12 million people in Shenzhen from 2012 to 2016 were used. Immediate and gradual changes in incidence rates were analyzed using segmented Poisson regression. RESULTS: Following the smoke-free legislation, a 9% (95% CI: 3%-15%) immediate reduction was observed in AMI incidence, especially in men (8%, 95% CI: 1%-14%) and in those aged 65 years and older (17%, 95% CI: 9%-25%). The gradual annual benefits were observed only in hemorrhagic and ischemic stroke incidence, with a 7% (95% CI: 2%-11%) and 6% (95% CI: 4%-8%) decrease per year, respectively. This health effect extended gradually to the 50-64 age group. In addition, neither the immediate nor gradual decrease in stroke and AMI incidence rates did not show statistical significance among the 35-49 age group ( P > 0.05). CONCLUSION Smoke-free legislation was enforced well in Shenzhen, which would generate good experiences for other cities to enact and enforce smoke-free laws. This study also provided more evidence of the health benefits of smoke-free laws on stroke and AMI.
Male ; Humans ; Middle Aged ; Adult ; Incidence ; Interrupted Time Series Analysis ; Stroke/etiology* ; Myocardial Infarction/etiology* ; China/epidemiology* ; Tobacco Smoke Pollution

This study aimed to investigate the prognostic significance of tumor mutation burden (TMB) among patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Tumor tissue specimens after surgical resection were collected for DNA extraction. Somatic mutation detection and TMB analysis were conducted using next-generation sequencing (NGS). Recurrence status of the patients was assessed in the hospital during the adjuvant chemotherapy period, and long-term survival data of patients were obtained by telephone follow-up. Univariate analysis between TMB status and prognosis was carried out by survival analysis. A retrospective review of 78 patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy showed a median disease-free survival of 3.6 years and median overall survival (OS) of 5.3 years. NGS analysis exhibited that the most common mutated somatic genes among the 78 patients were tumor suppressor protein p53 (TP53), epidermal growth factor receptor, low-density lipoprotein receptor related protein 1B, DNA methyltransferase 3 alpha and FAT atypical cadherin 3, and their prevalence was 56.4%, 48.7%, 37.2%, 30.7%, and 25.6%, respectively. TMB status was divided into TMB-L (≤ 4.5/Mb) and TMB-H (> 4.5/Mb) based on the median TMB threshold. Relevance of TMB to prognosis suggested that the median OS of patients with TMB-L was significantly longer than that of patients with TMB-H (NR vs. 4.6, P = 0.014). Higher TMB status conferred a worse implication on OS among patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy.

Chronic and infectious wound healing has always been an issue of concern in clinical and scientific research, in which bacterial infection and oxidative damage are the key factors hindering wound healing. Carbon dots, as a new material, has attracted much attention because of its unique physical and chemical properties and good biological safety. In recent years, the researches on the antibacterial property, antioxidant, and photoluminescence properties of carbon dots are more and more extensive and carbon dots have great potential in the treatment of chronic and infectious wounds. This paper reviews the research progress of carbon dots in three aspects: antibacterial, anti-oxidation and monitoring of wound infection are reviewed, and further discusses its specific mechanism, potential research direction, and application prospect.
Anti-Bacterial Agents/therapeutic use* ; Bacterial Infections/drug therapy* ; Carbon/therapeutic use* ; Humans ; Wound Healing ; Wound Infection/drug therapy*

OBJECTIVES: To reconstruct the cases of acceleration craniocerebral injury caused by blunt in forensic cases by finite element method (FEM), and to study the biomechanical mechanism and quantitative evaluation method of blunt craniocerebral injury. METHODS: Based on the established and validated finite element head model of Chinese people, the finite element model of common injury tool was established with reference to practical cases in the forensic identification, and the blunt craniocerebral injury cases were reconstructed by simulation software. The cases were evaluated quantitatively by analyzing the biomechanical parameters such as intracranial pressure, von Mises stress and the maximum principal strain of brain tissue. RESULTS: In case 1, when the left temporal parietal was hit with a round wooden stick for the first time, the maximum intracranial pressure was 359 kPa; the maximum von Mises stress of brain tissue was 3.03 kPa at the left temporal parietal; the maximum principal strain of brain tissue was 0.016 at the left temporal parietal. When the right temporal was hit with a square wooden stick for the second time, the maximum intracranial pressure was 890 kPa; the maximum von Mises stress of brain tissue was 14.79 kPa at the bottom of right temporal lobe; the maximum principal strain of brain tissue was 0.103 at the bottom of the right temporal lobe. The linear fractures occurred at the right temporal parietal skull and the right middle cranial fossa. In case 2, when the forehead and left temporal parietal were hit with a round wooden stick, the maximum intracranial pressure was 370 kPa and 1 241 kPa respectively, the maximum von Mises stress of brain tissue was 3.66 kPa and 26.73 kPa respectively at the frontal lobe and left temporal parietal lobe, and the maximum principal strain of brain tissue was 0.021 and 0.116 respectively at the frontal lobe and left temporal parietal lobe. The linear fracture occurred at the left posterior skull of the coronary suture. The damage evaluation indicators of the simulation results of the two cases exceeded their damage threshold, and the predicted craniocerebral injury sites and fractures were basically consistent with the results of the autopsy. CONCLUSIONS The FEM can quantitatively evaluate the degree of blunt craniocerebral injury. The FEM combined with traditional method will become a powerful tool in forensic craniocerebral injury identification and will also become an effective means to realize the visualization of forensic evidence in court.
Humans ; Finite Element Analysis ; Biomechanical Phenomena ; Wounds, Nonpenetrating ; Head ; Craniocerebral Trauma

Endoscopy/methods* ; Humans ; Neurosurgical Procedures ; Nose ; Skull Base/surgery* ; Technology

Objective To investigate the expression and clinicopathological significance of Bcl-2 and Bax genes in colorectal cancer (CRC) patients complicated with schistosomiasis. Methods The CRC patients receiving surgical treatment in the First Affiliated Hospital of Dali University from June 2016 to June 2020 were recruited as the study subjects, and 30 subjects were randomly sampled from the CRC patients complicated with schistosomiasis (CRC-S group) and 30 subjects were randomly sampled from the CRC patients without schistosomiasis (CRC group) using a random number table method. The cancer specimens were sampled from subjects in the CRC-S and CRC groups, and the peri-cancer specimens were sampled from subjects in the CRC group. The Bcl-2 and Bax expression was quantified in cancer and peri-cancer specimens using a real-time fluorescent quantitative PCR (qPCR) assay and immunohistochemistry at transcriptional and translational levels, and the cell apoptosis was detected in cancer specimens using HE staining. Results A total of 60 subjects were enrolled, including 30 cases in the CRC group and 30 cases in the CRC-S group. There were no significant differences between the two groups in terms of gender distribution (χ² = 0.271, P > 0.05), mean age (t = -0.596, P > 0.05), tumor growth pattern (χ² = 0.275, P > 0.05), tumor location (χ² = 4.008, P > 0.05), tumor invasion depth (χ² = 0.608, P > 0.05), degree of tumor differentiation (χ² = 0.364, P > 0.05), or presence of vascular metastasis (χ² = 1.111, P > 0.05), while significant differences were seen between the two groups in terms of histological type, presence of lymph node metastasis and TMN staging (χ² = 5.963, 8.297 and 5.711, all P values < 0.05). qPCR assay and immunohistochemistry quantified significantly higher Bcl-2 and Bax expression in cancer specimens from the CRC and CRC-S groups than in the peri-cancer specimens from the CRC group at both translational and transcriptional levels (all P values < 0.05), and higher Bcl-2 and lower Bax expression were seen in the cancer specimens from the CSC-S group than that from the CRC group (all P values < 0.05). In addition, the cell apoptotic rate was significantly greater in the cancer specimens in the CRC group than in the CRC-S group (42.00% vs. 23.35%; χ² = 41.500, P = 0.000). Conclusion Schistosomiasis may be involved in the development and progression of CRC through affecting Bcl-2 and Bax gene expression in the apoptosis signaling pathway.

OBJECTIVE: To analyze gene expression profile of T cell lymphoma Jurkat cell line treated with paclitaxel by computational biology based on next generation sequencing and to explore the possible molecular mechanism of paclitaxel resistance to T cell lymphoma at gene level. METHODS: IC50 of paclitaxel on Jurkat cell line was determined by CCK-8 assay. Gene expression profile of Jurkat cells treated with paclitaxel was acquired by next generation sequencing technology. Gene microarray data related to human T cell lymphoma were screened from Gene Expression Omnibus (GEO) database (including 720 cases of T cell lymphoma and 153 cases of normal tissues). Combined with the sequencing data, differential expression genes (DEGs) were intersected and screened. DAVID database was used for enrichment analysis of GO function and KEGG pathway to determine and visualize functional entries of DEGs, and protein-protein interactions network of DEGs was drawn. The levels of gene expression were detected and verified by RT-qPCR. RESULTS: CCK-8 results showed that the proliferation of Jurkat cells was inhibited by paclitaxel depended on the concentration apparently. Treated by paclitaxel for 48 h, P<0.05 and |log2(FC)|≥1 were used as filter criteria on the results of RNA Sequencing (RNA-Seq) and GeoChip, 351 DEGs were found from Jurkat cells, including 323 up-regulated genes and 28 down-regulated genes. The GO functional annotation and KEGG pathway enrichment analysis showed that the role of paclitaxel was mainly concentrated in protein heterodimerization activity, nucleosome assembly and transcriptional dysregulation in cancer, etc. The results of RT-qPCR were consistent with those of the sequencing analysis, which verified the reliability of this sequencing. CONCLUSION Paclitaxel can affect the proliferation and apoptosis of T-cell lymphoma by up-regulating JUN gene, orphan nuclear receptor NR4A family genes and histone family genes.
Computational Biology ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; High-Throughput Nucleotide Sequencing ; Humans ; Lymphoma, T-Cell ; Paclitaxel ; Reproducibility of Results