Objective:To investigate the neuroprotective effect of hesperidin combined with enriched environment on ferroptosis in collagenase-induced intracerebral hemorrhage(ICH) mouse model as well as the ferroptosis mechanism.Methods:ICH model was established by injecting collagenase Ⅶ into caudate putamen nucleus. Ninty C57BL/6J mice were randomly divided into 6 groups according to a random number table: sham group, intracerebral hemorrhage group, enriched environment group, hesperidin group, enriched environment and hesperidin group (combination group), and combination group + Nrf2 specific inhibitor ML385 (inhibitor group), with 15 mice in each group. The mice in inhibitor group, intracerebral hemorrhage group, enriched environment group, hesperidin group and combination group were injected with 0.5 μL collagenase type Ⅶ solution (0.075 U/μL, dissolved with 0.9% NaCl solutin) for ICH modeling, and the mice in sham group were injected with 0.9% normal saline. The hesperidin group, combination group, and inhibitor group were given hesperidin solution (dissolved in 0.5% carboxymethyl cellulose sodium) by gavage within 6 hours after the modeling surgery. The sham group, intracerebral hemorrhage group, and enriched environment group were given equal volumes of 0.5% carboxymethyl cellulose sodium solution by gavage. The inhibitor group was intraperitoneally injected with Nrf2 specific inhibitor ML385 (30 mg/kg, dissolved in 5% DMSO), while the other groups were intraperitoneally injected with an equal volume of 5% DMSO. Both gastric perfusion and intraperitoneal injection were completed within 6 hours after the end of modeling operation, once a day for 14 days. After the postoperative recovery of the mice, the enriched environment group, combination group, and inhibitor group were placed in enriched environment cages, while the sham group, intracerebral hemorrhage group, and hesperidin group were placed in regular cages. After all intervention were completed, all mice were evaluated using the modified neurological severity score (mNSS). Then the mice were subjected to brain water content detection, Prussian blue staining, ELISA detection of changes in malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), glutathione peroxidase 4 (Gpx4), PCR and Western blot detection of nuclear factor E2 related factor 2 (Nrf2) and Gpx4 at the mRNA level and protein level. The GraphPad Prism 9 software was used for statistical analysis. ANOVA was used for multi-group comparison, and Tukey test was used for multiple comparisons.Results:(1) There was a statistically significant difference in mNSS scores among the 6 groups ( F=66.35, P<0.001). The mNSS score of the intracerebral hemorrhage group(8.00±1.46) was higher than that of the sham group(0.86±0.83)( P<0.05). The mNSS scores of the enriched environment group (6.47±1.13) and hesperidin group (6.13±1.25) were lower than that of the intracerebral hemorrhage group, but higher than that of the combination group (4.53±1.30)(all P<0.05). (2) There was a statistically significant difference in the percentage of brain water content among the 6 groups ( F=33.29, P<0.001). The percentage of brain water content in the intracerebral hemorrhage group was higher than that in the sham group.The percentage of brain water content in the enriched environment group and hesperidin group were lower than that in the intracerebral hemorrhage group, but higher than that in the combination group (all P<0.05). (3) The result of Prussian blue staining showed that iron deposition in the intracerebral hemorrhage group was higher than that in the sham group, while the iron depositions in the enriched environment group and hesperidin groups were lower than that in the intracerebral hemorrhage group, but higher than that in the combination group(all P<0.05). (4) There were statistically significant differences in the expression levels of Nrf2 and Gpx4 mRNA and protein among the 6 groups ( F=27.73, 31.24, 26.79, 13.79, all P<0.001). The mRNA and protein levels of Nrf2 and Gpx4 in the combination group were higher than those in the enriched environment group, hesperidin group, but higher than those in the inhibitor group(all P<0.05). (5) The results of ELISA showed that the levels of MDA, Gpx4, ROS, and SOD in the brain tissues of 6 groups were statistically significant ( F=111.20, 21.53, 29.45, 22.75, all P<0.001). Among them, the MDA and ROS in the combination group ((14.05±0.57) nmol/mL, (75.46±3.40) ng/mL) were lower than those in the enriched environment group ((18.17±2.51) nmol/mL, (97.23±3.43) ng/mL), hesperidin group ((17.24±0.68) nmol/mL, (90.02±9.46) ng/mL) and the inhibitor group ((17.08±0.64) nmol/mL, (101.07±3.38) ng/mL), while Gpx4 and SOD ((340.40±31.21) pg/mL, (62.55±2.81) ng/mL) were higher than those in the enriched environment group ((267.81±27.17) pg/mL, (50.47±8.38) ng/mL), hesperidin group ((271.55±34.36) pg/mL, (50.55±8.19) ng/mL) and the inhibitor group ((235.65±72.54)pg/mL, (52.67±3.56)ng/mL)(all P<0.05). Conclusion:Enriched environment and hesperidin can inhibit ferroptosis after ICH by activating the Nrf2/GPX4 pathway, exerting neuroprotective effects on ICH mouse models, and the combined treatment of the enriched environment and hesperidin has a more significant effect.

Objective To investigate the neuroprotective effect and potential mechanism of rehabilitation training combined with citicoline on cerebral hemorrhage model in mice based on Keap1/Nrf2/ARE signaling pathway.Methods The C57BL/6 male mice were randomly divided into sham operation group(sham operation treatment),model group(right caudate putamen hemorrhage model induced by type Ⅶcollagenase),choline group(model+choline 64 mg·kg-1),rehabilitation training group(rehabilitation training)and combined group(model+rehabilitation training+choline 64 mg·kg-1).The study observed the modified neurological severity score(mNSS)in mice with cerebral hemorrhage;colorimetric assays were used to detect the expression of malondialdehyde(MDA),superoxide dismutase(SOD)and catalase(CAT)in brain tissues;protein imprinting and reverse transcription-quantitative polymerase chain reaction were employed to assess the expression of Kelch-like ECH-associated protein 1(Keap1),nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE),heme oxygenase-1(HO-1),quinone oxidoreductase 1(NQ01)proteins and mRNA in brain tissues.Results The mNSS scores of sham operation group,model group,citicoline group,rehabilitation training group and combined group were 0,1.56±0.73,1.00±0.00,0.78±0.44 and 0.67±0.50;the MDA contents were(6.93±0.92),(22.97±0.77),(19.26±1.73),(13.21±0.78)and(7.25±0.97)nmol·mgprot-1;the relative expression of Keap1 protein were 0.79±0.03,1.02±0.04,0.95±0.10,0.90±0.09 and 0.86±0.05;the relative expression levels of Nrf2 protein were 0.94±0.12,0.71±0.08,0.90±0.07,0.98±0.12 and 1.33±0.25.There were significant differences in the above indexes between the model group and the sham operation group(P＜0.05,P＜0.01);there were significant differences between the citicoline group and the rehabilitation training group,the model group(P＜0.05,P＜0.01);there were significant differences between the combined group and the citicoline group,the rehabilitation training group except for protein expression of Keap1(all P＜0.01).Conclusion Rehabilitation training and citicoline can reduce the symptoms of neurological deficits in mice with cerebral hemorrhage.The mechanism way be that they can activate the Keap1/Nrf2/ARE signaling pathway to exert anti-oxidative stress,and the combined effect is the best.

Objective To explore the relationship of menarche age,menopause age,and reproductive period with cognitive function in the female patients with hypertension.Methods Hypertension screening was carried out in Wuyuan county of Jiangxi province from July to August in 2018.Data were collected through a face-to-face questionnaire survey,physical measurement,and biochemical tests.The cognitive function was scored according to the mini-mental state examination(MMSE)scale.Multiple linear regression and Logistic regression were employed to analyze the effects of menarche age,menopause age,and reproductive period on cognitive function,and the penalized spline regression to fit the curves.Results A total of 4595 postmenopausal women with hypertension were included in the analysis,with the mean age of(65.1±8.4)years,mean menarche age of(16.6±2.2)years,mean menopause age of(48.2±5.0)years,mean reproductive period of(31.7±5.5)years,mean MMSE score of(19.0±6.3)points,and total cognitive impairment detection rate of 40.4%(1859/4595).The detection rates of cognitive impairment were 28.4%,39.1%,and 45.8% in the females with the menarche ages of <15,15-16,and ≥17 years,47.9%,39.7%,and 38.3% in the females with the menopausal ages of <45,45-49,and ≥50 years,and 56.0%,44.4%,40.6%,and 32.6% in the females with the reproductive periods of <25,25-29,30-34,and ≥35 years,respectively.Moreover,the detection rates of cognitive impairment among different age groups were statistically significant(all P<0.05).Compared with the group with the menarche age <15 years,the groups with the menarche ages of 15-16 years and ≥17 years showed increased detection rates of cognitive impairment(OR=1.45,95%CI=1.19-1.75,P<0.001;OR=1.65,95%CI=1.37-1.98,P<0.001).Compared with the group with the menopausal age <45 years,the groups with the menopausal ages of 45-49 years and ≥50 years showed decreased detection rates of cognitive impairment(OR=0.80,95%CI=0.66-0.95,P=0.013;OR=0.78,95%CI=0.65-0.93,P<0.001).Compared with the group with the reproductive period <25 years,the groups with the reproductive periods of 25-29,30-34,and ≥35 years showed decreased detection rates of cognitive impairment(OR=0.66,95%CI=0.52-0.84,P<0.001;OR=0.62,95%CI=0.50-0.76,P<0.001;OR=0.51,95%CI=0.41-0.63,P<0.001).Conclusion The detection rate of cognitive impairment had a positive correlation with menarche age and negative correlations with menopause age and reproductive period in the female patients with hypertension.
Humans ; Female ; Middle Aged ; Aged ; Adolescent ; Menopause ; Menarche ; Reproduction ; Hypertension ; Cognition ; Age Factors ; Risk Factors

Transparency Ecosystem for Research and Journals in Medicine (TERM) working group summarized the essential recommendations that should be considered to review and publish a high-quality guideline. These recommendations from editors and reviewers included 10 components of essential requirements: systematic review of existing relevant guidelines, guideline registration, guideline protocol, stakeholders, conflicts of interest, clinical questions, systematic reviews, recommendation consensus, guideline reporting and external review. TERM working group abbreviates them as PAGE (essential requirements for Publishing clinical prActice GuidelinEs), and recommends guideline authors, editors, and peer reviewers to use them for high-quality guidelines.
Humans ; Practice Guidelines as Topic

Tumor-associated macrophages (TAMs), one of the dominating constituents of tumor microenvironment, are important contributors to cancer progression and treatment resistance. Therefore, regulation of TAMs polarization from M2 phenotype towards M1 phenotype has emerged as a new strategy for tumor immunotherapy. Herein, we successfully initiated antitumor immunotherapy by inhibiting TAMs M2 polarization via autophagy intervention with polyethylene glycol-conjugated gold nanoparticles (PEG-AuNPs). PEG-AuNPs suppressed TAMs M2 polarization in both in vitro and in vivo models, elicited antitumor immunotherapy and inhibited subcutaneous tumor growth in mice. As demonstrated by the mRFP-GFP-LC3 assay and analyzing the autophagy-related proteins (LC3, beclin1 and P62), PEG-AuNPs induced autophagic flux inhibition in TAMs, which is attributed to the PEG-AuNPs induced lysosome alkalization and membrane permeabilization. Besides, TAMs were prone to polarize towards M2 phenotype following autophagy activation, whereas inhibition of autophagic flux could reduce the M2 polarization of TAMs. Our results revealed a mechanism underlying PEG-AuNPs induced antitumor immunotherapy, where PEG-AuNPs reduce TAMs M2 polarization via induction of lysosome dysfunction and autophagic flux inhibition. This study elucidated the biological effects of nanomaterials on TAMs polarization and provided insight into harnessing the intrinsic immunomodulation capacity of nanomaterials for effective cancer treatment.

Objective:To characterize the histopathological subtypes and their clinicopathological parameters of gender and onset age by common, rare and sparse primary esophageal malignant tumors (PEMT).Methods:A total of 272 437 patients with PEMT were enrolled in this study, and all of the patients were received radical surgery. The clinicopathological information of the patients was obtained from the database established by the State Key Laboratory of Esophageal Cancer Prevention & Treatment from September 1973 to December 2020, which included the clinical treatment, pathological diagnosis and follow-up information of esophagus and gastric cardia cancers. All patients were diagnosed and classified by the criteria of esophageal tumor histopathological diagnosis and classification (2019) of the World Health Organization (WHO). The esophageal tumors, which were not included in the WHO classification, were analyzed separately according to the postoperative pathological diagnosis. The χ 2 test was performed by the SPSS 25.0 software on count data, and the test standard α=0.05. Results:A total of 32 histopathological types were identified in the enrolled PEMT patients, of which 10 subtypes were not included in the WHO classification. According to the frequency, PEMT were divided into common (esophageal squamous cell carcinoma, ESCC, accounting for 97.1%), rare (esophageal adenocarcinoma, EAC, accounting for 2.3%) and sparse (mainly esophageal small cell carcinoma, malignant melanoma, etc., accounting for 0.6%). All the common, rare, and sparse types occurred predominantly in male patients, and the gender difference of rare type was most significant (EAC, male∶ female, 2.67∶1), followed with common type (ESCC, male∶ female, 1.78∶1) and sparse type (male∶ female, 1.71∶1). The common type (ESCC) mainly occurred in the middle thoracic segment (65.2%), while the rare type (EAC) mainly occurred in the lower thoracic segment (56.8%). Among the sparse type, malignant melanoma and malignant fibrous histiocytoma were both predominantly located in the lower thoracic segment (51.7%, 66.7%), and the others were mainly in the middle thoracic segment.Conclusion:ESCC is the most common type among the 32 histopathological types of PEMT, followed by EAC as the rare type, and esophageal small cell carcinoma and malignant melanoma as the major sparse type, and all of which are mainly occur in male patients. The common type of ESCC mainly occur in the middle thoracic segment, while the rare type of EAC mainly in the lower thoracic segment. The mainly sparse type of malignant melanoma and malignant fibrous histiocytoma predominately occur in the lower thoracic segment, and the remaining sparse types mainly occur in the middle thoracic segment.

Adulterants and counterfeits were found in some of the commercial traditional Chinese medicine (TCM) decoctions in Hongjin Xiaojie Jiaonang, Hongjin Xiaojie Pian, and Chaihuang Keli during the national drug sampling inspection. However, it was difficult to determine the species of the adulterants and counterfeits by conventional testing methods. Therefore, a total of 184 samples of the TCM decoctions and raw materials belong to the prescriptions of above mentioned traditional Chinese patent medicines, including Bupleuri Radix, Bajiaolian, Heimayi, and Shufuchong, were collected and authenticated by DNA barcoding technology. 111 ITS2 sequences were obtained from 115 commercial TCM decoctions and raw materials of Bupleuri Radix, among which 71 were Bupleurum chinense, three were B. scorzonerifolium, and 31 were closely related species in the same genus. In addition, counterfeits derived from different genera, such as Ailanthus altissima (one sample), Saposhnikovia divaricate (two samples), and Solidago decurrens (three samples), were also detected. 21 ITS2 sequences were obtained from 22 commercial TCM raw materials of Bajiaolian, among which 15 were Diphylleia sinensis and six were Dysosma versipellis and other species in genus Dysosma. For 22 Heimayi samples, PCR amplification of COI sequence was failed due to genomic DNA degradation. Among 38 Shufuchong samples, 24 COI sequences were obtained and only nine of them were the genuine species (Armadillidium vulgare) recorded in the Chinese Pharmacopoeia, 11 were Porcellio laevis, two were Mongoloniscus sinensis, and two samples could not be identified due to the limitation of database. This study demonstrates that DNA barcoding technology is suitable for the species authentication of the decoctions of traditional Chinese patent medicine prescription. It is a conductive way for the establishment of traceability system for the whole TCM industrial chain.

Objective: To confirm the impact of obstructive sleep apnea hypopnea syndrome (OSAHS) on perioperative and long-term outcome in patients with Stanford type A aortic dissection. Methods: From June 2010 to July 2017, the clinical data of 91 patients with Stanford type A aortic dissection were analyzed. Among them, 51 patients with OSAHS were included in the study group and 40 patients without OSAHS were included in the control group. After 36 months follow-up, all-cause death was regarded as the end event. The clinical baseline data, perioperative period and 36 months survival rate of the two groups were compared. Kanplan-Meier method was used to describe the 36 month survival curve of the two groups. Cox proportional risk model was used to evaluate the risk ratio (HR) and 95%CI of 36 month survival rate. Results: The mortality rate during hospitalization was 5.9% (3 cases) in the study group and 5.0% (2 cases) in the control group, and the difference was not statistically significant (χ~2=0.03, P>0.05). The actual follow-up was (36.2±1.5) months, 88 cases were followed up and 3 cases were lost. The all cause mortality rate of 36 months was 27.5% (14/51)in the study group and 10.0%(4/40) in the control group, the difference was statistically significant (χ~2=4.30, P<0.05).By Cox proportional risk model analysis, 36 months after operation, the study group was compared with the control group after adjusting for age, male, bicuspid of aortic valve, chronic obstructive pulmonary disease, anemia, preoperative pericardial tamponade, postoperative organ dysfunction, preoperative LVEF, emergency operation, Sun's operation, coronary artery bypass grafting, hypertension, cardiac arrhythmia, and advanced avulsion of distal aortic dissection The survival rate was lower, the difference was statistically significant (P<0.05).In addition to OSAHS, coronary artery bypass grafting and preoperative pericardial tamponade were also risk factors for the increase of 36 month mortality rate (HR=11.28,95%CI: 1.98-46.25, P=0.009; HR=9.08, 95%CI: 2.22-41.3, P=0.032). Conclusions: There was no significant difference in mortality during hospitalization in patients with Stanford A aortic dissection combined with OSAHS. The survival rate of 36 months after operation was lower than that of the control group.
Aneurysm, Dissecting/surgery* ; Humans ; Hypertension ; Male ; Postoperative Period ; Risk Factors ; Sleep Apnea, Obstructive

Asian Continental Ancestry Group/genetics* ; Charcot-Marie-Tooth Disease/genetics* ; China ; Genetic Profile ; Humans ; Pedigree

Objective:To analyze the mutation types and frequency of deafness genes in Ningbo newborns. Methods:From January to September, 2019, 1781 newborns in Ningbo Women and Children's Hospital accepted deafness gene screening, including 22 mutations of four common deafness genes. Results:There were 104 newborns who were found deafness gene mutation (5.84%), 59 boys and 45 girls. Mutation rate was 3. 31% (59/1781) for GJB2, 0.56% (10/1781) for GJB3, 0.39% (7/1781) for mtDNA, and 1.57% (28/1781) for SLC26A4. Conclusion:The mutation rate of deafness gene in newborns in Ningbo is higher than the China average level, especially the rate of GJB2. It is necessary to screen newborn deafness gene earlier.