OBJECTIVE To investigate the ameliorative effect and potential mechanism of imperatorin （IMP） on doxorubicin （DOX） resistance in breast cancer. METHODS The effects of maximum non-toxic concentration （100 μg/mL） of IMP combined with different concentrations of DOX （12.5， 25， 50， 75， 100 μg/mL） on the proliferation of MCF-7/DOX cells were determined by MTT method. MCF-7/DOX cells were divided into blank control group （1‰ dimethyl sulfoxide）， DOX group （50 μg/mL）， IMP+DOX group （100 μg/mL IMP+50 μg/mL DOX） and IMP group （100 μg/mL）. mRNA and protein expressions of multidrug resistance protein 1 （MDR1） and multidrug resistance-associated protein 1 in each group were measured. The relevant pathways and targets involved in the improvement of DOX resistance in breast cancer cells by IMP were screened and validated by using transcriptome sequencing technology， along with gene ontology （GO） enrichment analyses and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analyses. RESULTS Compared with DOX alone， the combination of IMP and DOX reduced the half inhibitory concentration of DOX on MCF-7/DOX cells from 81.965 μg/mL to 43.170 μg/mL， the reverse fold was 1.90， and the mRNA expression of MDR1 was significantly down-regulated （P＜0.05）. The results of GO enrichment analyses and KEGG pathway enrichment analyses indicated that the reversal of DOX resistance in breast cancer by IMP was mainly associated with the regulation of biological processes such as detoxification， multiple biological processes， and cell killing. The main pathway involved was the p53 signaling pathway， and the key targets mainly included constitutively photomorphogenic protein 1 （COP1）， cyclin E1 （CCNE1）， growth arrest and DNA damage-inducible protein 45A E-mail：tangxilan1983@163.com （GADD45A） and GADD45B. The results of the verification experiments showed that compared with DOX group， there was a trend of up-regulation of COP1 mRNA， and significant down- regulation of CCNE1， GADD45A， and GADD45B mRNA expression in IMP+DOX group （P＜0.05）. CONCLUSIONS The effect of IMP in ameliorating DOX resistance in breast cancer is related to its regulation of COP1， CCNE1， GADD45A and GADD45B targets in the p53 signaling pathway.

Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

PANoptosis is a newly defined type of programmed cell death (PCD), which is triggered by a variety of stimuli and covers three known forms of PCD: apoptosis, pyroptosis and necroptosis. In physiological state, cell death plays an important protective role against pathogen invasion, but its over-activation may aggravate inflammatory response and cause tissue damage. Studies have shown that the occurrence and progression of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), asthma, chronic obstructive pulmonary disease (COPD) and other lung diseases are closely related to PANoptosis. The purpose of this review is to deeply explore the molecular mechanism of PANoptosis and its regulatory factors in lung diseases, in order to discover potential therapeutic targets and provide new targets and innovative ideas for clinical treatment for lung diseases.
Humans ; Lung Diseases ; Apoptosis ; Pyroptosis ; Pulmonary Disease, Chronic Obstructive ; Necroptosis ; Acute Lung Injury

Background::Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD.Methods::This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied.Results::At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs. placebo, 95% CI 31%–69%) and 45% (low vs. placebo, 95% CI 26%–64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator’s Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. Conclusion::CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.Trial Registration::ClinicalTrials.gov, NCT04805411.

Objective:To investigate the incidence and risk factors of deep vein thrombosis(DVT)in patients with rheumatoid arthritis(RA).Methods:The clinical data of RA patients who were hospi-talized in the Department of Rheumatology and Immunology of Aerospace Center Hospital from May 2015 to September 2021 was retrospectively analyzed,including demographic characteristics,concomitant diseases,laboratory examinations(blood routine,biochemistry,coagulation,inflammatory markers,rheumatoid factor,antiphospholipid antibodies and lupus anticoagulant,etc.)and treatment regimens.The patients were compared according to the presence or absence of DVT,and the t test,Mann-Whitney U test or Chi-square test were applied to screen for relevant factors for DVT,followed by Logistic regres-sion analysis to determine risk factors for DVT in patients with RA.Results:The incidence of DVT in the RA patients was 9.6％(31/322);the median age of RA in DVT group was significantly older than that in non-DVT group[64(54,71)years vs.50(25,75)years,P＜0.001];the level of disease activity score using 28 joints(DAS28)-erythrocyte sedimentation rate(ESR)in DVT group was higher than that in non-DVT group[5.2(4.5,6.7)vs.4.5(4.5,5.0),P＜0.001];the incidence of hypertension,chronic kidney disease,fracture or surgery history within 3 months,and varicose veins of the lower ex-tremities in DVT group was higher than that in non-DVT group(P＜0.001).The levels of hemoglobin and albumin in DVT group were significantly lower than that in non-DVT group(P=0.009,P=0.004),while the D-dimer level and rheumatoid factor positive rate in DVT group were significantly higher than that in non-DVT group(P＜0.001).The use rate of glucocorticoid in DVT group was higher than that in non-DVT group(P=0.009).Logistic regression analysis showed that the age(OR=1.093,P＜0.001),chronic kidney disease(OR=7.955,P=0.005),fracture or surgery history with-in 3 months(OR=34.658,P=0.002),DAS28-ESR(OR=1.475,P=0.009),and the use of glu-cocorticoid(OR=5.916,P=0.003)were independent risk factors for DVT in RA patients.Conclu-sion:The incidence of DVT in hospitalized RA patients was significantly increased,in addition to tradi-tional factors,such as age and chronic kidney disease,increased DAS28-ESR level and the use of glu-cocorticoid were also independent risk factors for DVT.

Objective:To evaluate the relationship between the mechanism of curcumin attenuating lidocaine-induced neurotoxicity and autophagy.Methods:In vitro human neuroblastoma SH-SY5Y cells at the logarithmic phase were divided into 3 groups ( n=12 each) using the random number table method: blank control group (C group), lidocaine group (Lid group), and curcumin + lidocaine group (Cur + Lid group). The cells were incubated with complete medium containing 1.0 μmol/L curcumin for 24 h, and the other groups were incubated with fresh medium for 24 h under the same conditions in Cur+ Lid group. Then the medium was incubated with the complete medium containing 4.0 mmol/L lidocaine for 24 h in Lid and Cur+ Lid groups, and the medium was replaced with the fresh medium and the cells were incubated for 24 h under the same conditions in group C. At the end of incubation or culture, the cell viability was detected by CCK-8 method, the level of autophagosomes was detected by the MDC method, and the expression of P62, microtubule-associated protein light chain 3-Ⅱ (LC3-Ⅱ) and LC3-Ⅰ was detected by Western blot, and the LC3-Ⅱ/LC3-Ⅰ ratio was calculated. Results:Compared with group C, the cell viability was significantly decreased, the level of autophagosomes was increased, the expression of LC3-Ⅱ was up-regulated, the expression of LC3-Ⅰ was down-regulated, the LC3-Ⅱ/LC3-Ⅰ ratio was increased, and the expression of P62 was down-regulated in Lid and Cur+ Lid groups ( P<0.05). Compared with Lid group, the cell viability and level of autophagosome were significantly increased, the expression of LC3-Ⅱ was up-regulated, the expression of LC3-Ⅰ was down-regulated, the LC3-Ⅱ/LC3-Ⅰ ratio was increased, and the expression of P62 was down-regulated in Cur+ Lid group ( P<0.05). Conclusions:The mechanism by which curcumin reduces the neurotoxicity induced by lidocaine may be related to the activation of autophagy.

Burnout is a complex syndrome, which is characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment. Existing researches had demonstrated that burnout impairs cognitive functions, including executive function, memory and attention, with most studies focusing on behavioral aspects. This paper systematically reviewed previous burnout-related researches, including the changes in neural electrical activity, as well as alterations in brain structure and function which affected cognitive performance. The paper highlighted the negative impact of burnout on cognitive abilities and explored its underlying neural mechanisms. Additionally, it identified that cognitive behavioral therapy, cognitive training, and aerobic exercise were effective interventions for managing burnout. Therefore, future research can be conducted by investigating intervention studies that focus on the impairment of cognitive ability and brain function, as well as burnout at varying degrees of severity. Furtherly, the interventions designed to prevent burnout and the development of proactive burnout prevention questionnaires for different groups are highly warranted.

Objective To establish a bone knife deformation prediction model for periacetabular osteotomy and quickly and accurately predict bone knife deformation.Methods A finite element numerical model of a pelvic bone knife containing both cortical and cancellous bones was established,and the correlation between nodal strain and deformation was analyzed.The strains of 5 nodes with the strongest integrated correlation were selected as the inputs,and the displacement increments of the nodes on the blade part were established as the outputs.After training the model with the dataset,a deep learning neural network regression model based on the finite element dataset was used to establish a prediction model for the strain deformation of the bone knife.After the model prediction was completed,a binocular visual localization system was used to determine the spatially accurate position of the bone knife during the osteotomy procedure as a means of intraoperative tracking of the bone knife.Results The R2 value of the prediction model was 0.987 81 and the average deformation error after discretizing the bone knife into nodes was 0.07 mm.The prediction model quickly and accurately acquired bone knife deformation and showed great potential for reducing PAO surgical accidents.Conclusions The bone knife deformation prediction model developed in this study rapidly predicted bone knife deformation from strain information.Thus,it can avoid injuring tissues,such as nerves and blood vessels around the tissue,reduce the difficulty and risk of periacetabular osteotomy,and provide theoretical support for clinical application.

This study aimed to observe the protective effect of momordicine I, a triterpenoid compound extracted from momordica charantia L., on isoproterenol (ISO)-induced hypertrophy in rat H9c2 cardiomyocytes and investigate its potential mechanism. Treatment with 10 μM ISO induced cardiomyocyte hypertrophy as evidenced by increased cell surface area and protein content as well as pronounced upregulation of fetal genes including atrial natriuretic peptide, β-myosin heavy chain, and α-skeletal actin; however, those responses were markedly attenuated by treatment with 12.5 μg/ml momordicine I. Transcriptome experiment results showed that there were 381 and 447 differentially expressed genes expressed in comparisons of model/control and momordicine I intervention/model, respectively. GO enrichment analysis suggested that the anti-cardiomyocyte hypertrophic effect of momordicine I may be mainly associated with the regulation of metabolic processes. Based on our transcriptome experiment results as well as literature reports, we selected glycerophospholipid metabolizing enzymes group VI phospholipase A 2 (PLA2G6) and diacylglycerol kinase ζ (DGK-ζ) as targets to further explore the potential mechanism through which momordicine I inhibited ISO-induced cardiomyocyte hypertrophy.Our results demonstrated that momordicine I inhibited ISO-induced upregulations of mRNA levels and protein expressions of PLA2G6 and DGK-ζ. Collectively, momordicine I alleviated ISO-induced cardiomyocyte hypertrophy, which may be related to its inhibition of the expression of glycerophospholipid metabolizing enzymes PLA2G6 and DGK-ζ.

Objective:To systematically review and evaluate the effect of small-dose naloxone on the development of nausea and vomiting during postoperative analgesia with opioid drugs in patients.Methods:Electronic Databases including Pubmed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure, Wanfang Data, China Biomedical Literature Database, and China Science and Technology Journal Database databases were searched from inception to May 2023 for randomized controlled trials involving the effect of small-dose naloxone on the development of adverse effects during postoperative analgesia with opioids. All randomized controlled trials enrolled included naloxone group and control group, the primary outcome was the incidence of postoperative nausea and vomiting, and the secondary outcome was postoperative VAS. Meta-analysis was performed using Stata 16.0 software.Results:Seven randomized controlled trials involving 542 patients were finally included in this meta-analysis. Compared with control group, the incidence of nausea and vomiting during postoperative analgesia was significantly decreased in naloxone group ( P<0.05), and no significant change was found in postoperative VAS scores ( P>0.05). Conclusions:Small-dose naloxone can reduce the development of nausea and vomiting during postoperative analgesia with opioid drugs.