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.

This study aimed to evaluate the cost-effectiveness of Chaiyin Granules compared with Oseltamivir Phosphate Capsules in the treatment of influenza(exogenous wind-heat syndrome). Based on a randomized, double-blind, positive drug parallel control clinical trial, this study evaluated the pharmacoeconomics of Chaiyin Granules with cost-effectiveness analysis method. A total of 116 patients with influenza from eight hospitals(grade Ⅱ level A above) in 6 cities were selected in this study, including 78 cases in the experimental group with Chaiyin Granules and Oseltamivir Phosphate Capsules placebo, and 38 cases in the control group with Oseltamivir Phosphate Capsules and Chaiyin Granules placebo. The total cost of this study included direct medical cost, direct non-medical cost, and indirect cost. The remission time of clinical symptoms, cure time/cure rate, antipyretic onset time/complete antipyretic time, viral nucleic acid negative rate, and traditional Chinese medicine(TCM) syndrome curative effect were selected as the effect indicators for cost-effectiveness analysis. Four-quadrant diagram was used to estimate the incremental cost-effectiveness ratio. The results showed that Chaiyin Granules were not inferior to Oseltamivir Phosphate Capsules in the remission time of clinical symptoms of influenza(3.1 d vs 2.9 d, P=0.360, non-inferiority margin was 0.5 d). Compared with Oseltamivir Phosphate Capsules, Chaiyin Granules would delay the remission time of clinic symptoms of influenza for 1 d, but could save 213.9 yuan. 1 d delay in cure time could save 149.3 yuan; 1% reduction in the cure rate could save 8.2 yuan; 1 d delay in antipyretic onset time could save 295.4 yuan; 1 d delay in complete antipyretic time could save 114.3 yuan; 1% reduction in the 5-day cure rate of TCM syndrome could save 19.2 yuan. Different from other indicators, there was no statistically significant difference between two groups in the effect of negative conversion rate of viral nucleic acid, but the cost was lower and the effect was superior, and the pharmacoeconomics was not different from that of Oseltamivir Phosphate Capsules in the field of influenza treatment.
Humans ; Antipyretics/therapeutic use* ; Antiviral Agents/therapeutic use* ; Cost-Effectiveness Analysis ; Influenza, Human/drug therapy* ; Nucleic Acids/therapeutic use* ; Oseltamivir/therapeutic use* ; Phosphates/therapeutic use* ; Treatment Outcome ; Double-Blind Method

Peripheral bacterial infections without impaired blood-brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease (PD). Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation. However, how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown. In this study, we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS. GSDMD in peripheral myeloid cells promoted microglial immune training, thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner. Furthermore, pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models. Collectively, these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD. Based on these findings, GSDMD may serve as a therapeutic target for patients with PD.

Objective: To investigate the prognostic factors of children with congenital heart disease (CHD) who had undergone cardiopulmonary resuscitation (CPR) in pediatric intensive care unit (PICU) in China. Methods: From November 2017 to October 2018, this retrospective multi-center study was conducted in 11 hospitals in China. It contained data from 281 cases who had undergone CPR and all of the subjects were divided into CHD group and non-CHD group. The general condition, duration of CPR, epinephrine doses during resuscitation, recovery of spontaneous circulation (ROSC), discharge survival rate and pediatric cerebral performance category in viable children at discharge were compared. According to whether malignant arrhythmia is the direct cause of cardiopulmonary arrest or not, children in CHD and non-CHD groups were divided into 2 subgroups: arrhythmia and non-arrhythmia, and the ROSC and survival rate to discharge were compared. Data in both groups were analyzed by t-test, chi-square analysis or ANOVA, and logistic regression were used to analyze the prognostic factors for ROSC and survival to discharge after cardiac arrest (CA). Results: The incidence of CA in PICU was 3.2% (372/11 588), and the implementation rate of CPR was 75.5% (281/372). There were 144 males and 137 females with median age of 32.8 (5.6, 42.7) months in all 281 CPA cases who received CPR. CHD group had 56 cases while non-CHD had 225 cases, with the percentage of 19.9% (56/281) and 80.1% (225/281) respectively. The proportion of female in CHD group was 60.7% (34/56) which was higher than that in non-CHD group (45.8%, 103/225) (χ²=4.00, P=0.045). There were no differences in ROSC and rate of survival to discharge between the two groups (P>0.05). The ROSC rate of children with arthythmid in CHD group was 70.0% (28/40), higher than 6/16 for non-arrhythmic children (χ²=5.06, P=0.024). At discharge, the pediatric cerebral performance category scores (1-3 scores) of CHD and non-CHD child were 50.9% (26/51) and 44.9% (92/205) respectively. Logistic regression analysis indicated that the independent prognostic factors of ROSC and survival to discharge in children with CHD were CPR duration (odds ratio (OR)=0.95, 0.97; 95%CI: 0.92~0.97, 0.95~0.99; both P<0.05) and epinephrine dosage (OR=0.87 and 0.79, 95%CI: 0.76-1.00 and 0.69-0.89, respectively; both P<0.05). Conclusions: There is no difference between CHD and non-CHD children in ROSC and survival rate of survival to discharge was low. The epinephrine dosage and the duration of CPR are related to the ROSC and survival to discharge of children with CHD.
Cardiopulmonary Resuscitation ; Child ; Child, Preschool ; Female ; Heart Arrest/therapy* ; Heart Defects, Congenital/therapy* ; Humans ; Intensive Care Units, Pediatric ; Male ; Retrospective Studies

Objective: To analyze HIV/AIDS surveillance data in men who have sex with men (MSM) aged from 15 to 24 years in Fuzhou and understand the HIV infection status in MSM and related factors. Methods: From 2016 to 2021, MSM aged 15-24 years who had oral or anal sex with men in the past 6 months were recruited through internet, and their demographic and behavioral characteristics, HIV antibody positive rate and risk factors were analyzed. Results: From 2016 to 2021, a total of 4 234 MSM aged 15-24 years were surveyed. The proportion of MSM from other provinces increased from 13.00% (85/654) to 23.42% (163/696) (trend χ²=60.23, P<0.001); and the proportion of MSM seeking male partners through internet increased from 93.27% (610/654) to 99.71% (694/696) (trend χ²=65.20, P<0.001); In the last anal sex in the past 6 months, the proportion of MSM using condom decreased from 88.16% (484/549) to 74.11% (415/560) (trend χ²=32.32, P<0.001); and in the past 6 months, the proportion of MSM using condom at each anal sex decreased from 65.76% (361/549) to 55.54% (311/560) (trend χ² =6.82, P<0.001); The proportion of MSM with HIV antibody testing increased from 5.66% (37/654) to 25.29% (176/696) (trend χ²=98.51, P<0.001). The cumulative HIV antibody positive rate in the MSM was 3.64% (154/4 234), and there was no significant difference in annual HIV antibody positive rate in the MSM (trend χ²=0.50, P=0.453). The HIV antibody positive rate in the MSM with education level of junior high school or below and the MSM living in Fuzhou for 1-2 years showed an upward trend (P<0.05). The results of multivariate logistic regression analysis showed that the risk for HIV infection in the MSM with education level of high school or technical secondary school was 0.54 times higher than that in those with education level of junior high school or below (95%CI: 0.30-0.99), and the risk for HIV infection in the MSM with education level of junior college or below was 0.29 times higher than that in those with education level of junior high school or below (95%CI: 0.17-0.51). The risk for HIV infection in the MSM who lived in Fuzhou for 1-2 years was 0.35 times higher than that in those who lived in Fuzhou for less than 1 year (95%CI: 0.16-0.74), the risk for HIV infection in the MSM who lived in Fuzhou for more than two years was 0.58 times higher than that in those who lived in Fuzhou for less than 1 year (95%CI: 0.37-0.91). The number of MSM using condoms at each anal sex was 0.18 times higher than that in the those never using condoms (95%CI: 0.08-0.42), and the number of the MSM who didn't suffered from sexually transmitted diseases was 0.25 times higher than that in those who suffered from sexually transmitted diseases (95%CI: 0.13-0.50). Conclusions: The MSM aged 15-24 years in Fuzhou have higher risk for HIV infection, and internet based intervention should be strengthened in adolescent MSM without permanent residence and with low education level.
Adolescent ; Male ; Humans ; Acquired Immunodeficiency Syndrome/epidemiology* ; HIV Infections/epidemiology* ; Homosexuality, Male ; Sexual and Gender Minorities ; Internet

Objective Coronavirus disease 2019 (COVID-19) and tuberculosis (TB) are major public health and social issues worldwide. The long-term follow-up of COVID-19 with pulmonary TB (PTB) survivors after discharge is unclear. This study aimed to comprehensively describe clinical outcomes, including sequela and recurrence at 3, 12, and 24 months after discharge, among COVID-19 with PTB survivors. Methods From January 22, 2020 to May 6, 2022, with a follow-up by August 26, 2022, a prospective, multicenter follow-up study was conducted on COVID-19 with PTB survivors after discharge in 13hospitals from four provinces in China. Clinical outcomes, including sequela, recurrence of COVID-19, and PTB survivors, were collected via telephone and face-to-face interviews at 3, 12, and 24 months after discharge. Results Thirty-two COVID-19 with PTB survivors were included. The median age was 52 (45, 59) years, and 23 (71.9％) were men. Among them, nearly two-thirds (62.5％) of the survivors were moderate, three (9.4％) were severe, and more than half (59.4％) had at least one comorbidity (PTB excluded). The proportion of COVID-19 survivors with at least one sequela symptom decreased from 40.6％ at 3 months to 15.8％ at 24 months, with anxiety having a higher proportion over a follow-up. Cough and amnesia recovered at the 12-month follow-up, while anxiety, fatigue, and trouble sleeping remained after 24 months. Additionally, one (3.1％) case presented two recurrences of PTB and no re-positive COVID-19 during the follow-up period. Conclusion The proportion of long symptoms in COVID-19 with PTB survivors decreased over time, while nearly one in six still experience persistent symptoms with a higher proportion of anxiety. The recurrence of PTB and the psychological support of COVID-19 with PTB after discharge require more attention.

Traditional Chinese medicine （TCM） and western medicine have their respective advantages and limitations in the diagnosis and treatment of common otorhinolaryngology head and neck diseases. Although the integrated TCM and western medicine exhibits definite curative effects， there is no consensus on the otorhinolaryngology head and neck diseases responding specifically to TCM or integrated TCM and western medicine， as well as the diagnosis and treatment schemes. The China Association of Chinese Medicine （CACM） thus organized the otorhinolaryngology head and neck specialists of both TCM and western medicine to discuss the etiology， pathogenesis， and clinical diagnosis and treatment methods of common otorhinolaryngology head and neck diseases with the results of multiple clinical trials taken into account. The acute pharyngitis， chronic pharyngolaryngitis， paraesthesia pharyngis， hysterical aphasia， allergic rhinitis， subjective tinnitus， and otogenic vertigo were confirmed to respond specifically to TCM or integrated TCM and western medicine. Then a mutually agreed diagnosis and treatment scheme and recommendation with integrated TCM and western medicine was formulated as a reference for clinical practice， thus benefiting more patients.

Objective: To investigate the expression pattern of tropomyosin 2(TPM2) in aorta of patients with aortic dissection and explore its clinical implication. Methods: Thirteen cases with acute type A aortic dissection(TAAD) diagnosed by transabdominal aortic angiography from 2015 in Tongji Hospital were included. During the operation, the aortic wall tissues of these patients were collected. Ten patients with heart transplantation were selected as control group, and normal aortic wall tissues were taken. The hematoxylin-eosin (HE) and Verhoeff's Van Gieson (EVG) staining were performed to observe the morphological changes of aorta. The mRNA expression level of TPM2 was measured by real-time fluorescent quantitative-PCR, and the protein levels of TPM2 were detected by Western blot and immunohistochemical staining. Image The J software was used to collect the optical density values of each point on the image, obtain the integrated optical density(IOD) value, and calculate the average density(%, IOD/area of the target distribution area). Results: HE and EVG staining revealed medial degeneration and broken elastic fiber in aorta of TAAD patients. The mRNA expression levels of TPM2 were significantly upregulated in aorta of TAAD patients as compared to the control group (P<0.05), so as the TPM2 protein expression levels ((9.73±1.20)% vs. (0.11±0.04)%, P<0.05). And TPM2 was mainly expressed in cytoplasm. Conclusion: The increased expression of TPM2 in TAAD patients hints that TPM2 might be involved in the pathogenesis of aortic dissection.
Aneurysm, Dissecting/genetics* ; Aorta ; Aortic Aneurysm, Thoracic/genetics* ; Gene Expression ; Humans ; RNA, Messenger ; Tropomyosin/metabolism*

Objective Mild hypothermia (MHT) can effectively protect the brain in traumatic brain injury (TBI). This study was to investigate the effects of MHT on the calmodulin (CAM) expression and brain edema in the rat model of TBI. Methods Ninety adult SD rats were randomly divided into a sham operation, a normal temperature and an MHT group of equal number. Immediately after TBI, the rats of the MHT group maintained at a rectal temperature of (32 ± 0.5) °C for 6 hours. Modified neurological severity scores (mNSS) were obtained from 6 rats in each group at 1, 3, 5 and 7 days after modeling, and the rest of the animals subjected to brain MRI at 6, 12, 24 and 48 hours and then killed for determination of the CAM gene transcription and protein expression in the brain tissue by real-time PCR, immunohistochemistry and Western blot. Results The mNSSs were significantly higher in the MHT and normal temperature groups than in the sham operation control (P < 0.05) at all time points, neurological severity markedly decreased in the MHT group compared with the normal temperature group (P < 0.05). At 6, 12, 24 and 48 hours, the expression of CAM mRNA was remarkably down-regulated in the MHT group (1.83 ± 0.19, 1.72 ± 0.12, 1.59 ± 0.06 and 1.60 ± 0.07) in comparison with the normal temperature group (2.76 ± 0.25, 2.49 ± 0.18, 2.04 ± 0.14 and 1.65 ± 0.09) (P < 0.05), even lower in the MHT than in the normal temperature group (P < 0.05), but higher in both of the two groups than in the sham operation group (P < 0.05). At 6, 12, 24 and 48 hours, the volume of brain edema was significantly reduced in the MHT group ([32.14 ± 4.52], [36.52 ± 4.10], [42.10 ± 4.38] and [46.25 ± 5.02] mm³) as compared with the normal temperature group ([48.56 ± 5.35], [53.13 ± 6.31], [59.23 ± 6.82] and [62.35 ± 7.25] mm³) (P < 0.05). Conclusion Mild hypothermia can improve the neurological function and reduce the CAM expression and brain edema in the brain tissue of rats with traumatic brain injury, which may be related to the neuroprotective effect of mild hypothermia.

Animals ; Chromosomal Proteins, Non-Histone ; chemistry ; genetics ; metabolism ; Humans ; Models, Molecular ; Mutation ; Transcription Factors ; chemistry ; genetics ; metabolism