Neddylation is a crucial posttranslational modification that involves the attachment of neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to a lysine residue in the substrate via the sequential actions of the E1 NEDD8-activating enzyme (NAE) (E1), E2 NEDD8-conjugating enzyme (E2), and E3 NEDD8-ligase (E3). The most extensively studied substrates of neddylation are members of the cullin family, which act as scaffold components for cullin ring E3 ubiquitin ligases (CRLs). Since cullin neddylation activates CRLs, which are frequently overactive in tumors, inhibiting neddylation has emerged as a promising strategy for developing novel antitumor therapies. This review explores the antitumor effects of inhibiting neddylation that leads to the inactivation of CRLs and provides a summary of known inhibitors that target protein-protein interactions (PPIs) within the neddylation enzymatic cascade.

Peri-implantitis is a pathologic condition associated with dental plaque that occurs in the implant tissue and is characterized by inflammation of the mucous membrane surrounding the implant, followed by the progressive loss of supporting bone. In this study, a case of guided bone regeneration therapy based on plaque control of peri-implant inflammation was reported. Four years after surgery for the left second premolar implant, the patient presented with "left lower posterior tooth swelling and discomfort for more than 2 years". The X-ray periapical film showed a decrease in distal bone mineral density of implant, and the clinical diagnosis was peri-implantitis of the left second premolar. Implants underwent guided bone regeneration and regular periodontal maintenance treatment. Re-examination at 3.5 months, 11 months, 18 months, and 7 years showed that the alveolar bone height and bone mineral density were stable, and the periodontal depth became shallow. However, the gingival recession was mild. In the present case, follow-up at 7 years demonstrated that the clinical periodontal indexes could be remarkably improved after complete periodontal treatment for peri-implantitis, and the alveolar bone could be well restored and regenerated.
Humans ; Peri-Implantitis/etiology* ; Follow-Up Studies ; Bone Regeneration ; Guided Tissue Regeneration, Periodontal/methods* ; Dental Plaque/prevention & control* ; Male ; Female ; Dental Implants/adverse effects*

ObjectiveThe bioinformatics method was used to screen ferroptosis differential genes （FRGs） closely related to ulcerative colitis （UC）， and animal experiments were conducted to verify whether the mechanism of Xiezhuo Jiedu recipe in treating UC is related to the regulation of ferroptosis. MethodThe differentially expressed genes （DEGs） of colonic mucosa tissue of UC patients were obtained from the GEO database， and the intersection of the genes with ferroptosis genes was used to obtain FRGs. The core FRGs were obtained by cluster analysis， minimum absolute contraction and selection operator （LASSO） regression， and receiver operating characteristic curve （ROC） curve analysis. In animal experiments， the UC mouse model was prepared by making the mouse freely drink 2.5% dextran sodium sulfate （DSS）. Xiezhuo Jiedu recipe and mesalazine were given by gavage for seven days， and the inflammatory infiltration of colonic mucosa was observed by hematoxylin-eosin （HE） staining. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression levels of E3 ubiquitin ligase （FBXW7）， zinc finger protein （ZFP36）， solute carrier family 7 member 11 （SLC7A11）， and Toll-like receptor 4 （TLR4） in colon tissue. The protein expression levels of FBXW7， ZFP36， SLC7A11， and TLR4 in colon tissue were detected by Western blot. ResultDataset GSE87466 was screened from the GEO database， and its intersections with the ferroptosis gene were analyzed to obtain 21 FRGs. After cluster analysis， LASSO regression， and ROC analysis， core FRGs （FBXW7， ZFP36， SLC7A11， and TLR4） were obtained. Immunoinfiltration analysis showed significant differences in the expression of initial B cells， M1 macrophages， plasma cells， and M2 macrophages in the colonic mucosa tissue of UC mice， and there was a significant correlation between core FRGs and these immune cells. Further animal experiments showed that the colonic mucosa tissue of mice in the model group was disorganized and infiltrated by a large number of inflammatory cells. The inflammation of the colonic mucosa tissue of mice in each group was relieved to varying degrees after treatment with Xiezhuo Jiedu recipe and mesalazine， while the colonic mucosa tissue of mice in the high-dose group of Xiezhuo Jiedu recipe showed almost no inflammatory changes. Compared with the normal group， the protein and mRNA expressions of FBXW7， ZFP36， SLC7A11， and TLR4 in the model group were significantly increased， and the expression of core FRGs in colonic mucosa tissue of mice in all groups was significantly down-regulated after treatment with Xiezhuo Jiedu recipe and mesalazine. ConclusionFBXW7， ZFP36， SLC7A11， and TLR4 are ferroptosis genes closely related to the pathogenesis of UC， and Xiezhuo Jiedu recipe can significantly alleviate colonic mucosa inflammation in mice by down-regulating core ferroptosis genes.

ObjectiveThe differential expression of microRNAs （miRNAs） between the active stage and the remission stage of ulcerative colitis （UC） was analyzed by bioinformatics method， and the regulatory relationship was constructed by screening the differentially expressed genes （DEGs）. The mechanism of Xizhuo Jiedu recipe in the treatment of UC was speculated and verified by animal experiments. MethodThe miRNAs data set of colonic mucosa tissue of UC patients was obtained from the gene expression database （GEO）， and the most differentially expressed miRNAs were screened by GEO2R， Excel， and other tools as research objects. TargetScan， miRTarbase， miRDB， STRING， TRRUST， and Matescape databases were used to screen key DEGs， predict downstream transcription factors （TFs）， gene ontology （GO）， and conduct Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis. The key signaling pathways were selected for animal experiments. In animal experiments， the UC mouse model was prepared by making the mouse freely drink 2.5% dextran sodium sulfate （DSS）. Xiezhu Jiedu recipe and mesalazine were given by gavage for seven days， and the inflammatory infiltration of colonic mucosa was observed by hematoxylin-eosin （HE） staining. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of miR-155-5p in colon tissue. Immunohistochemistry and Western blot were used to detect the protein expression levels of cytokine signal transduction inhibitor （SOCS1）， phosphorylated transcriptional signal transductor and activator 3 （p-STAT3）， phosphorylated Janus kinase 2 （p-JAK2）， and retinoic acid-associated orphan receptor-γt （ROR-γt）. The expression levels of transforming growth factor-β （TGF-β）， interleukin-17 （IL-17）， interleukin-6 （IL-6）， and interleukin-10 （IL-10） in serum were detected by enzyme linked immunosorbent assay （ELISA）. ResultThe GSE48957 dataset was screened from the GEO database， and miR-155-5p was selected as the research object from the samples in the active and remission stages. 131 DEGs were screened. The GO/KEGG enrichment analysis was closely related to biological processes such as positive regulation of miRNA transcription and protein phosphorylation， as well as signaling pathways such as stem cell signaling pathway， IL-17 signaling pathway， and helper T cell 17 （Th17） cell differentiation. The Matescape database was used to screen out 10 key DEGs， among which SOCS1 was one of the key DEGs of miR-155-5p. Further screening of the TFS of key DEGs revealed that STAT3 was one of the main TFs of SOCS1. The results of animal experiments showed that Xiezhu Jiedu Recipe could effectively down-regulate the mRNA expression of miR-155-5p and protein expression of p-STAT3， p-JAK2， and ROR-γt in colon tissue of UC mice and the expression of IL-17 and IL-6 in serum of UC mice， up-regulate the protein expression of SOCS1 and the expression of TGF-β and IL-10， increase the level of anti-inflammatory factors， and reduce inflammatory cell infiltration. ConclusionIt is speculated that Xizhuo Jiedu recipe may interfere with SOCS1 by regulating the expression of miR-155-5p in UC mice， inhibit the phosphorylation of STAT3， inhibit the differentiation of CD4⁺ T cells into Th17 cells， reduce the levels of pro-inflammatory factors （IL-17 and IL-6）， and increase the levels of anti-inflammatory factors （TGF-β and IL-10）. As a result， the inflammation of colon mucosa in UC mice was alleviated.

To perform a comprehensive analysis of the pathogenic causes of a food poisoning case in a district of Wuhan Cit-y,we investigated the molecular epidemiological relationships among pathogenic bacteria,to aid in traceability analysis of food-borne disease outbreaks,as well as clinical diagnosis and treatment.The pathogenic bacteria in this food poisoning case were i-solated and identified according to GB789.4-2016.The isolated strains were subjected to genotyping with pulsed field gel elec-trophoresis(PFGE).Drug resistance gene analysis,multi-locus sequence typing(MLST),and genome-wide single-nucleotide polymorphism analysis(wgSNP)were conducted via whole genome sequencing(WGS).The evolutionary tree for cluster analy-sis was constructed in fasttree software.Drug susceptibility testing was conducted with the broth microdilution method.A total of 12 strains of Salmonella were detected in seven anal swab samples and two fecal samples from the case,as well as three anal swab samples from unaffected individuals.The serotype of the strains was Salmonella typhimurium.The strain exhibited severe multiple drug resistance,including resistance to amikacin,ampi-cillin,cefazolin,gentamicin,piperacillin,and tetracycline,but susceptibility to other antibiotics.The coincidence rate between drug resistance genes and drug resistance phenotypes was high.PFGE revealed that nine strains from this food poisoning case were highly homologous.WGS revealed that the MLST type was ST19,and varying numbers of SNPs(1-6)were present a-mong strains.The phylogenetic tree revealed nine isolated strains forming a distinct cluster,differing from other Salmonella strains in the database and belonging to a novel clonal branch.The single nucleotide site in the strains was highly homologous to that of GCF in Jiangxi_020221795.1.The food poisoning case was caused by Salmonella typhimurium ST19,and all nine iso-lated strains originated from the same source.The chef is closely connected to this food poisoning case.This strain of Salmo-nella typhimurium belongs to a new clonal branch and exhibits multiple drug resistance.

AIM To optimize the processing technology of red Notoginseng Radix et Rhizoma and evaluate its blood tonifying activity.METHODS On the basis of a single factor experiment,with steaming temperature,steaming time,drying temperature,and drying time as influencing factors,the total contents of notoginsenoside R1,ginsenoside Rg1,Rb1,Rk3,Rh4,and 20(R)-ginsenoside Rg3 as evaluation indicators,Box-Behnken response surface method ology was used to optimize the processing technology.Upon the anemic mouse models jointly induced by 1-acetyl-2-phenylhydrazine(APH)and cyclophosphamide(CTX),the investigation of the blood tonifying activity of red Notoginseng Radix et Rhizoma was carried out in contrast to that of the steamed Notoginseng Radix et Rhizoma.RESULTS The optimal conditions,contributing saponin content of 8.326%and RSD of 0.087%,were determined as follows:steaming temperature of 130℃,steaming time of 4 hours,drying temperature of 60℃,and drying time of 48 h.The pharmacological activity revealed that the different processing techniques were responsible for the different blood enriching activity of notoginseng,with red Notoginseng Radix et Rhizoma displaying a better efficacy than that of steamed Notoginseng Radix et Rhizoma.CONCLUSION This stable and feasible method can be used to control the production of red Notoginseng Radix et Rhizoma.

Objective:To investigate the effect of drug therapy on heart failure caused by supraventricular tachycardia(SVT) in infants.Methods:Fifty-five infants with heart failure caused by SVT, including 24 boys and 31 girls, were treated at Beijing Children′s Hospital of Capital Medical University from January 2014 to December 2021.The drug treatment effects of heart failure caused by SVT were analyzed.Results:The average age of 55 infants at the first diagnosis was 5.8 months(1-11 months). All of them had heart failure, including three cases of atrial flutter, 23 cases of atrial tachycardia(13 cases of disordered atrial tachycardia and ten cases of monomorphic atrial tachycardia), and 29 cases of paroxysmal supraventricular tachycardia.Ultrasonic cardiogram showed that the left ventricular diameter increased and/or left ventricular systolic function decreased.Anti-heart failure therapy was effective in 55 cases(100.0%). Anti-arrhythmic drug therapy: atrial flutter and atrial tachycardia were mainly treated by controlling ventricular rate, digitalis combined with metoprolol was effective in 21 cases(80.8%, 21/26), digitalis alone was effective in four cases(15.4%, 4/26), and sotalol was effective in one case(3.8%, 1/26); paroxysmal supraventricular tachycardia was mainly treated with sinus rhythm conversion.The success rates of conversion were: ATP 20.7%(6/29), ATP combined with digitalis 26.1%(6/23), propafenone combined with digitalis 42.9%(3/7), amiodarone combined with digitalis 60.0%(3/5), and sotalol 92.9%(12/13). During follow-up period for 1 to 12 months, heart failure symptoms of all 55 cases(100.0%) improved, and ultrasonic cardiogram of 53 cases(96.3%)returned to normal.Conclusion:Anti-heart failure and anti-arrhythmic drugs for infants with heart failure caused by SVT need to be selected individually.Atrial tachycardia, especially disordered atrial tachycardia, is sensitive to digitalis.Sotalol can be used to treat refractory SVT.

Objective:To investigate the effect of radiofrequency ablation on infants with incessant ventricular tachycardia(IIVT) and heart failure.Methods:Twenty-eight infants with IIVT combined with heart failure admitted to Beijing Children′s Hospital of Capital Medical University from January 2006 to December 2021 were selected, including 16 boys and 12 girls; 26 cases were treated with radiofrequency ablation.The characteristics of IIVT and heart failure and the results of radiofrequency ablation were analyzed.Results:The average age of the first diagnosis of 28 infants was 13.9 months old, and all of them had heart failure.Eleven infants had cardiogenic shock, three infants had cardiogenic syncope, two infants had respiratory failure for respiratory support, and one infant died.Color Doppler echocardiography showed that the left ventricular diameter increased and/or left ventricular systolic function decreased.Anti-heart failure treatment was effective in 27 cases(96.4%), electrical cardioversion in five cases, effective in three cases, and anti-arrhythmic drugs were effective in 17 cases(60.7%). Twenty-six cases(92.9%, 26/28) were treated with radiofrequency ablation, with immediate success in 23 cases(88.5%, 23/26) and effective in three cases(11.5%, 3/26). During the follow-up period for 3 to 36 months, cardiac function returned to normal in 25 cases(96.2%, 25/26) and recurred in three cases(11.5%, 3/26 cases), which were cured after radiofrequency ablation again.Temporary complications of atrioventricular block occurred in one case(3.8%, 1/26). In 26 cases of surgical children, 15 cases were measured by X-ray two-dimensional mapping and 11 cases were measured by three-dimensional mapping.The cumulative X-ray exposure was 87.0(51.5, 151.5) mGy and 1.2(0, 15.9) mGy, respectively, and the dose area product was 39.8(19.2, 427.8) μGy/m 2 and 2.8(0, 44.3) μGy/m 2.The cumulative X ray exposure and the dose area product were significantly reduced under the three-dimensional mapping method( P<0.001). Conclusion:The infants with IIVT combined with heart failure are prone to serious complications, and the effects of cardioversion and anti-arrhythmic drugs are limited.Radiofrequency ablation should be performed as soon as possible after heart failure is controlled.The application of three-dimensional mapping technology in surgery can significantly reduce ionizing radiation.

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*

Objective:To explore the risk factors related to death in patients with tuberculosis complicated with sepsis in an intensive care unit, in order to provide reference for the clinical treatment of patients with tuberculosis complicated with sepsis.Methods:A retrospective case-control study was conducted to collect the general clinical data of 384 patients with tuberculosis complicated with sepsis in intensive care unit of Public Health Clinical Center of Chengdu from March 2020 to November 2022. Multivariate logistic regression model was used to analyze independent risk factors for death in patients with tuberculosis complicated with sepsis.Results:Among 384 patients with tuberculosis complicated with sepsis, the 28-day mortality rate was 43.2%(166/384). Multivariate logistic regression analysis showed that age ≥60 years old (odds ratio ( OR)=1.924, 95% confidence interval ( CI) 1.033 to 3.585, P=0.039), body mass index (BMI) <18.5 kg/m 2 ( OR=4.496, 95% CI 2.242 to 9.016, P<0.001), acute physiology and chronic health evaluation (APACHE) Ⅱ ≥20 points ( OR=2.133, 95% CI 1.093 to 4.162, P=0.026), blood urea nitrogen-to-albumin ratio>5.945 mg/g ( OR=20.886, 95% CI 10.883 to 40.084, P<0.001) and septic shock ( OR=6.137, 95% CI 2.852 to 13.209, P<0.001) were independent risk factors for death in patients with tuberculosis complicated with sepsis in intensive care unit. Conclusions:Age≥60 years old, BMI<18.5 kg/m 2, APACHE Ⅱ≥20 points, blood urea nitrogen-to-albumin ratio>5.945 mg/g and septic shock are independent risk factors for the death in patients with tuberculosis complicated with sepsis. Early attention should be paid to these patients and cluster therapy should be started as soon as possible in order to shorten the disease process, and to improve the prognosis and reduce mortality.