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 explore the optimal morning discharge time and pipeline disinfection frequency of the fi-nal rinse water from the endoscopy center according to the microbial culture results.Methods Different morning discharge timing and number of bacterial colonies in the pipeline for the final rinse water from the endoscopy center of a hospital in Jiangsu Province were monitored.Microbial detection was conducted on water samples collected from the two final rinse water sampling sites in the endoscopy room after 0,1,3,5,and 7 minutes of discharge,respec-tively(100 mL each,continuously monitored for 35 days,with 70 samples at each time point)to explore the optimal discharge timing.The optimal disinfection frequency of pipelines for purified water was explored according to the determined optimal morning discharge timing.Two samples were taken daily from 2 sampling sites after pipeline disinfection and continued for 5 weeks,resulting in 70 samples in total.Results Sampling and monitoring of the fi-nal rinse water at different morning discharge time points showed that the median numbers of bacterial colonies at 0,1,3,5,and 7 minutes were 745.00(373.00,1 452.50),150.00(96.75,235.75),44.00(38.00,48.00),12.00(5.00,18.00),and 6.00(4.00,9.00)CFU/100 mL,respectively.Except the difference between the 5 minute group and the 7 minute group(P＞0.05),differences among all the other groups were statistically significant(all P＜0.05).The median of the 0,1,3,and 5 minute groups was＞10 CFU/100 mL,while the median of the 7 mi-nute group was＜10 CFU/100 mL,within the qualified range.The discharge time was therefore determined to be 7 minutes.The average numbers of bacterial colonies from the final rinse water samples taken at different time points after pipeline disinfection(1,2,3,4,and 5 weeks after disinfection)were(4.21±0.86),(4.43±0.71),(6.00±0.56),(6.43±0.45),and(13.57±1.03)CFU/100 mL,respectively.The qualification rates of pipeline in terms of bacterial colony were 100％,100％,100％,100％,and 28.57％,respectively.The differences of average num-bers of bacterial colonies from the final rinse water samples taken at different time points after pipeline disinfection were statistically significant(P＜0.001).The average number of bacterial colonies 5 weeks after pipeline disinfec-tion was different from those after 1,2,3,and 4 weeks,with statistically significant differences(all P＜0.05),while no statistically significant differences among the other groups were observed(all P＞0.05).The optimal disin-fection frequency for the purified water pipeline was once every 4 weeks.Conclusion The final rinse water remai-ning in the terminal of pipeline is contaminated to a certain degree.It is recommended to discharge water in the morning for 7 minutes before using it,and disinfect the purified water pipeline every 4 weeks.

AIM:To investigate whether crocin alleviates right ventricular injury induced by monocrotaline(MCT)in rats with pulmonary arterial hypertension(PAH),and to explore the underlying mechanisms.METHODS:Forty male SD rats were randomly divided into 4 groups:normal group,PAH group,crocin group and sildenafil group,with 10 rats in each group.The rats in PAH,crocin and sildenafil groups received subcutaneous injection of MCT(50 mg/kg)to establish the PAH model.Starting from the day of MCT injection,the rats in crocin group received crocin(200 mg/kg),the rats in sildenafil group received sildenafil(30 mg/kg),and those in PAH and normal groups were orally gavaged with an equal volume of saline once daily.After 4 weeks,measurements of right ventricular systolic pressure(RVSP),mean pulmonary artery pressure(mPAP),right ventricular hypertrophy index(RVHI)and right ventricular mass index(RVMI)were taken for the rats in each group.Tissue staining was conducted to observe pathological changes in the right ventricle,and the expression levels of inflammatory factors(IL-1β,IL-6 and TNF-α),the p38 MAPK/NF-κB inflammato-ry pathway,CCL2,CCR2,and the macrophage marker CD68 were assessed.RESULTS:Compared with PAH group,the rats in crocin and sildenafil groups exhibited significant reductions in RVSP,mPAP,RVHI and RVMI(P＜0.05).Right ventricular tissue displayed no evident infiltration of inflammatory cells or proliferation of collagen fibers.The down-regulation of the p38 MAPK/NF-κB pathway and inflammatory factors(IL-1β,IL-6 and TNF-α)was significant(P＜0.05).Additionally,the CCL2/CCR2 pathway and the infiltration of CD68+ macrophages were markedly decreased(P＜0.05).CONCLUSION:Crocin effectively mitigates right ventricular damage in MCT-induced PAH rats,with its effica-cy comparable to that of sildenafil at the dosage utilized in this experiment.Some protective mechanisms of crocin may be attributed to its regulatory effects on inflammation.

Jinqi Jiangtang Capsule (JQJTC) is clinically used for the prevention and treatment of type 2 diabetes, but the contents of its main chemical components are not yet clear. In this study, an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established for the determination of 15 components in JQJTC, including new chlorogenic acid, chlorogenic acid, cryptochlorogenic acid, formononetin, ononin, calycosin, calycosin-7-glucoside, astragaloside IV, berberine, epiberberine, berberrubine, coptisine, jatrorrhizine, palmatine and magnoflorine. The method was used to determine the contents of 15 components in the capsule and then to investigate the influence of excipients on the contents of the components in JQJTC. The separation was performed on a ACQUITY UPLC BEH C₁₈ column (100 mm × 2.1 mm, 1.7 μm) with a mobile phase consisting of 0.1% acetic acid and 5 mmol·L^-1 ammonium acetate (A) and acetonitrile (B) with gradient elution at a flow rate of 0.3 mL·min^-1 and a column temperature at 40 ℃. Electron spray ionization was used for mass spectrometry in positive ion mode. The established method meets the requirements of methodology of content determination in Chinese pharmacopoeia. The contents of 15 components in JQJTC varied from high to low. The top 5 contents were berberine, chlorogenic acid, magnoflorine, coptisine, and cryptochlorogenic acid, accounting for 87.31% of the total content. The contents of 10 components, including the alkaloids of coptidis rhizoma (berberine, epiberberine, berberrubine, coptisine, jatrorrhizine, palmatine and magnoflorine) and the organic acids of honeysuckle (new chlorogenic acid, chlorogenic acid, and cryptochlorogenic acid) in the whole formula extract without excipients was significantly lower than that in the capsule. These components accounted for 99.20% of the determined component contents. In this experiment, an accurate, sensitive and efficient UHPLC-MS/MS method for the determination of multi-components in JQJTC was established, which stably and reliably detected the contents of 15 components in the capsule and could provide the basis for more comprehensive quality analysis. It was also found that excipients had an increasing effect on the contents of detected alkaloid and organic acid components, which may be beneficial to the effectiveness of the capsules.

Objective To summarize the epidemiological and clinical features of infectious diseases of the central nervous system(CNS)by a single-center analysis.Methods A retrospective analysis was conducted on the data of 1247 cases of CNS infectious diseases diagnosed and treated in the First Medical Center of PLA General Hospital from 2001 to 2020.Results The data for this group of CNS infectious diseases by disease type in descending order of number of cases were viruses 743(59.6％),Mycobacterium tuberculosis 249(20.0％),other bacteria 150(12.0％),fungi 68(5.5％),parasites 18(1.4％),Treponema pallidum 18(1.4％)and rickettsia 1(0.1％).The number of cases increased by 177 cases(33.1％)in the latter 10 years compared to the previous 10 years(P<0.05).No significant difference in seasonal distribution pattern of data between disease types(P>0.05).Male to female ratio is 1.87︰1,mostly under 60 years of age.Viruses are more likely to infect students,most often at university/college level and above,farmers are overrepresented among bacteria and Mycobacterium tuberculosis,and more infections of Treponema pallidum in workers.CNS infectious diseases are characterized by fever,headache and signs of meningeal irritation,with the adductor nerve being the more commonly involved cranial nerve.Matagenomic next-generation sequencing improves clinical diagnostic capabilities.The median hospital days for CNS infectious diseases are 18.00(11.00,27.00)and median hospital costs are ￥29,500(￥16,000,￥59,200).The mortality rate from CNS infectious diseases is 1.6％.Conclusions The incidence of CNS infectious diseases is increasing last ten years,with complex clinical presentation,severe symptoms and poor prognosis.Early and accurate diagnosis and standardized clinical treatment can significantly reduce the morbidity and mortality rate and ease the burden of disease.

Objective:This study aimed to share preliminary experiences of single-incision plus two ports laparoscopic proximal gastrectomy with right-sided overlap and single-flap valvuloplasty (ROSF).Methods:Following the 6th edition of the Japanese Gastric Cancer Treatment Guidelines, proximal gastrectomy with lymphadenectomy was performed. Using a single-port approach, the esophagus was transected at least 2 cm above the tumor's upper margin with linear staplers. The stomach was then extracted through a periumbilical incision, and the proximal stomach was subsequently transected extracorporeally, while ensuring appropriate resection margins on both the greater and lesser curvatures. A single flap was created before returning the remnant stomach to the abdominal cavity and re-establishing pneumoperitoneum. The No.2 clip was used to grasp and elevate the esophageal stump. An incision was made at the right lower edge of the esophageal stump to guarantee that the esophageal lumen was open. The linear stapler was then inserted into the openings of the stomach and esophagus to perform a side overlap anastomosis with a length of 3 cm. Another barbed suture was used to close the common opening of the esophagus and the stomach, and the same barbed suture were used to suture the gastric wall to the lower edge of the muscle flap. The first barbed suture was then used to sequentially suture the proximal brim of the flap to the esophagus and the right brim of the flap to the right brim of the mucosal window. After completion of anastomosis, a drainage tube was inserted through the right upper port. This procedure was employed from November 2023 to March 2024 on five patients diagnosed with adenocarcinoma of the esophagogastric junction and upper stomach. The cohort consisted of three males and two females, with an age range of 62 to 75 years and a body mass index (BMI) of 13.7 to 24.2 kg/m2. All cases were preoperatively staged as T1-2N0M0, confirmed by endoscopic biopsy and enhanced CT scans of the chest, abdomen, and pelvis.Results:All five patients successfully underwent the surgery. The median surgery time was 180-325 minutes, with the intraoperative blood loss of 30-50 ml. The number of lymph nodes harvested ranged from 18 to 27. The time to first flatus, and restore liquid diet and was 2.0-5.0 and 1.0-3.0 days, respectively. The postoperative length of stay was 9.0-11.0 days. The pain scores on the Numeric Rating Scale (NRS). On the first day, the pain scores were 3.0 in two cases, 2.0 in two cases, and 1.0 in one case. On the second day, the pain scores were 2.0 in two cases and 1.0 in three cases. On the third day, the pain scores were 1.0 in four cases and 2.0 in one case. No short-term postoperative complications were observed, and there were no perioperative deaths.Conclusion:Single-incision plus two ports laparoscopic proximal gastrectomy with ROSF is safe and feasible.

Microplastics(MPs)are emerging contaminants in aquatic environments characterized by their polar structure,small particle size(Typically less than 5 mm),large surface area,good stability,and resistance to biodegradation.They pose adverse effects on the normal physiological activities of aquatic organisms and can accumulate in biota,including humans.Therefore,there is an urgent need for rapid and accurate quantitative analysis of MPs in water environments.In this study,Raman spectroscopy combined with partial least squares(PLS)was employed for rapid and accurate quantitative analysis of polyethylene(PE)and polystyrene(PS)MPs in real water samples.Initially,33 simulated water samples containing different concentrations of MPs were prepared,and their Raman spectra were collected.Six spectral preprocessing methods(Normalization,multiplicative scatter correction,standard normal variate transformation,first derivative,second derivative,and wavelet transform)were investigated for their impact on the predictive performance of PLS calibration models.Subsequently,three variable selection methods including synergy interval partial least squares(SiPLS),variable importance in projection(VIP)and mutual information(MI)were employed to optimize the input variables of the PLS calibration model.The predictive capability of the PLS calibration model was evaluated and validated using leave-one-out cross-validation.Under the optimal conditions of spectral preprocessing,variable selection,input variables and latent variables,the wavelet transform-partial least squares(WT-PLS)calibration model based on distilled water was established,and the contents of PE and PS in real water samples were predicted with prediction correlation coefficients(R2p)of 0.9540 and 0.8472 for PE and PS,respectively,and prediction errors(Errorp)of 0.0690 and 0.1126,respectively.Furthermore,a mixed sample MI-PLS calibration model was developed,demonstrating the best predictive performance in real water samples(With R2p values of 0.9776 and 0.9755 for PE and PS,respectively,and Errorp values of 0.0360 and 0.0392,respectively).This method provided a novel approach and new methodology for quantitative analysis of MPs and other organic pollutants in real water samples.

Objective:This study aimed to share preliminary experiences of single-incision plus two ports laparoscopic proximal gastrectomy with right-sided overlap and single-flap valvuloplasty (ROSF).Methods:Following the 6th edition of the Japanese Gastric Cancer Treatment Guidelines, proximal gastrectomy with lymphadenectomy was performed. Using a single-port approach, the esophagus was transected at least 2 cm above the tumor's upper margin with linear staplers. The stomach was then extracted through a periumbilical incision, and the proximal stomach was subsequently transected extracorporeally, while ensuring appropriate resection margins on both the greater and lesser curvatures. A single flap was created before returning the remnant stomach to the abdominal cavity and re-establishing pneumoperitoneum. The No.2 clip was used to grasp and elevate the esophageal stump. An incision was made at the right lower edge of the esophageal stump to guarantee that the esophageal lumen was open. The linear stapler was then inserted into the openings of the stomach and esophagus to perform a side overlap anastomosis with a length of 3 cm. Another barbed suture was used to close the common opening of the esophagus and the stomach, and the same barbed suture were used to suture the gastric wall to the lower edge of the muscle flap. The first barbed suture was then used to sequentially suture the proximal brim of the flap to the esophagus and the right brim of the flap to the right brim of the mucosal window. After completion of anastomosis, a drainage tube was inserted through the right upper port. This procedure was employed from November 2023 to March 2024 on five patients diagnosed with adenocarcinoma of the esophagogastric junction and upper stomach. The cohort consisted of three males and two females, with an age range of 62 to 75 years and a body mass index (BMI) of 13.7 to 24.2 kg/m2. All cases were preoperatively staged as T1-2N0M0, confirmed by endoscopic biopsy and enhanced CT scans of the chest, abdomen, and pelvis.Results:All five patients successfully underwent the surgery. The median surgery time was 180-325 minutes, with the intraoperative blood loss of 30-50 ml. The number of lymph nodes harvested ranged from 18 to 27. The time to first flatus, and restore liquid diet and was 2.0-5.0 and 1.0-3.0 days, respectively. The postoperative length of stay was 9.0-11.0 days. The pain scores on the Numeric Rating Scale (NRS). On the first day, the pain scores were 3.0 in two cases, 2.0 in two cases, and 1.0 in one case. On the second day, the pain scores were 2.0 in two cases and 1.0 in three cases. On the third day, the pain scores were 1.0 in four cases and 2.0 in one case. No short-term postoperative complications were observed, and there were no perioperative deaths.Conclusion:Single-incision plus two ports laparoscopic proximal gastrectomy with ROSF is safe and feasible.

The clinical data of maintenance hemodialysis (MHD) patients from twenty hemodialysis centers in Guizhou province from June to September 2020 were collected by cross-sectional study. The patients were divided into AFD group and non-AFD group according to whether AFD had occurred. LTI was measured by body composition monitor. The results showed that the incidence of AFD in 2 781 MHD patients was 30.0% (835/2 781). Median LTI level was 15.2 (13.2, 17.5) kg/m². The LTI level in the AFD group was higher than that in the non-AFD group (P < 0.05). According to the tertiles of LTI, low LTI group (LTI ≤ 13.9 kg/m²) had the highest incidence of AFD (35.5%, 334/940), and the high LTI group had the lowest incidence of AFD (26.3%, 241/916), and the difference among the three groups was statistically significant (χ²=20.182,P < 0.001). Multivariate logistic regression analysis showed that low LTI group as the reference, the risk of AFD in moderate LTI group (13.9 kg/m² < LTI ≤ 16.6 kg/m²) and high LTI group were associated with the 20.0% (OR=0.800, 95% CI 0.650-0.986, P=0.036) and 22.8% (OR=0.772, 95% CI 0.616-0.966, P=0.024) decrease, respectively. These results suggest that low LTI level is independently associated with an increased risk of AFD in MHD patients.
Humans ; Cross-Sectional Studies ; Renal Dialysis/adverse effects* ; Body Composition

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.
Mice ; Animals ; Alzheimer Disease/pathology* ; Receptor, Nerve Growth Factor ; Amyloid beta-Peptides ; Autoantibodies ; Mice, Transgenic