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In the aftermath of the pandemic,the government is accelerating the development of top-tier medical resources to broaden the supply and deliver superior healthcare services.However,during this transitional phase,hospitals are experiencing operational challenges due to concurrent construction activities.Notably,a shortage of parking facilities and increased traffic con-gestion continue to impactmedial consultation experience of patients.This paper tries to explore strategies and methods for dynam-ic parking management during hospital campus expansions,offering insights for other medical institutions into grappling with pa-tient parking issues.
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Pharmacological perturbation studies based on protein-level signatures are fundamental for drug dis-covery.In the present study,we used a mass spectrometry(MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds.The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells.Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol,as well as the noncanonical targets of clinically approved tamoxifen,lovastatin,and their derivatives.Furthermore,the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints.This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.
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Acute kidney disease (AKD) is a critical transitional period between acute kidney injury and chronic kidney disease. The incidence of AKD following acute kidney injury is approximately 33.6%, and it can occur without identifiable preceding acute kidney injury. The development of AKD is associated with increased risks of chronic kidney disease, dialysis, and mortality. Biomarkers and subphenotypes are promising tools to predict prognosis in AKD. The complex clinical situations in patients with AKD necessitate a comprehensive and structured approach, termed “KAMPS” (kidney function check, advocacy, medications, pressure, sick day protocols). We introduce “MAND-MASS,” an acronym devised to summarize the reconciliation of medications during episodes of acute illness, as a critical component of the sick day protocols at AKD. A multidisciplinary team care, consisting of nephrologists, pharmacists, dietitians, health educators, and nurses, is an optimal model to achieve the care bundle in KAMPS. Although the evidence for patients with AKD is still lacking, several potential pharmacological agents may improve outcomes, including but not limited to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists. In conclusion, accurate prognosis prediction and effective treatment for AKD are critical yet unmet clinical needs. Future studies are urgently needed to improve patient care in this complex and rapidly evolving field.
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Objective:To survey the status quo and influencing factors of contracted family doctor pay services in urban communities of Suzhou city.Methods:This study was a cross-sectional study. A questionnaire survey on the status quo and influencing factors of contracted family doctor pay services was conducted from July to October 2022 among 750 residents from 40 communities of 4 subdistricts in Suzhou Gusu District, selected by stratified random sampling method. A self-designed questionnaire was used for the survey, which included demographic information, status quo of pay services among residents and factors influencing the service contracting. Chi-square test and binary logistic regression were used to analyze the influencing factors of contracted family doctor pay services.Results:A total of 750 questionnaires were distributed, with 720 valid ones returned at a recovery rate of 96.0%. Among the 720 residents, 370 (51.4%) were female, and 300 (41.7%) were between the age of 35 and 60 years old. There were 71 residents who had contracted pay services with a contracting rate of 9.9% (71/720), and the renewal rate was 80.3% (57/71). The top 3 reasons for signing the contract were health guidance (67.6%, 48/71), medical counselling (63.4%, 45/71) and 3 free consultations (57.7%, 41/71). The top 3 reasons for not signing a contract were not needing services (49.9%, 324/649), not knowing about contracted services (41.9%, 272/649) and rarely visiting the community health service center (25.6%, 166/649). Age ( χ2=21.072), marital status ( χ2=10.969), knowing the family doctor team ( χ2=145.954), knowing the family doctor contract system ( χ2=133.981), knowing the content and the rights of the contracted services ( χ2=132.905), using primary medical institutions as first choice for common and chronic diseases ( χ2=13.532), multiple comorbid chronic diseases ( χ2=30.024), being agreed by family members ( χ2=46.258), signing contract in family members ( χ2=108.833) or relatives and friends ( χ2=47.492), and experience in community health service centers ( χ2=26.116) were significantly associated with the contract signing (all P<0.05). Logistic regression analysis showed that knowing family doctor team well ( OR=23.13,95% CI:5.05-105.97) or very well( OR=95.28,95% CI: 10.71-847.68); having ≥3 chronic diseases compared to no chronic diseases ( OR=5.60, 95% CI: 1.88-16.75, P<0.05); contracting agreed by family members compared to not agreed ( OR=2.66, 95% CI: 1.03-6.84, P<0.05); signing contract in family members compared to not signing ( OR=4.42, 95% CI:2.05-9.55, P<0.05) were independent influencing factors of signing contract of family doctor pay services. Conclusions:The rate of contracted of family doctor pay services in Gusu District of Suzhou City is relatively low. Knowing the family doctor team, having multiple comorbid chronic diseases, agreement among family members, and signing contract in family members are influencing factors of contracted family doctor pay services.
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Kawasaki disease is an acute febrile illness that predominantly affects children under 5 years of age.The pathology is distinguished by small and medium-sized vasculitis.The most severe outcome of this disease is the development of coronary artery lesions, which can result in dilation, stenosis, aneurysm, and potentially long-term progression.MiRNAs, a type of short non-coding RNAs, could directly bind to mRNAs to regulate gene expression at the post-transcriptional level.Numerous studies have demonstrated that miRNAs may play an important role in genetic susceptibility, immunity, inflammatory response, and vascular wall structural abnormalities and dysregulation pertaining to Kawasaki disease.Consequently, comprehensive investigations into targets and pathways influenced by dysregulated miRNAs can facilitate the identification of the molecular mechanism underlying coronary artery lesions, thereby provide insights into early diagnosis, risk prediction, and targeted therapeutic intervention.This review succinctly outlines the involvement of miRNAs in the pathogenesis of coronary artery lesions associated with Kawasaki disease.
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Objective To explore the molecular mechanism of pituitary growth hormone adenoma cell proliferation.Methods Functional growth hormone-secreting pituitary adenoma(fGH-PA)tissue samples were collected from 12 patients with acromegaly.The exchange protein 1 directly activated by cAMP(Epac1)mRNA expression levels in fGH-PA tissues and rat RGC-5,MMQ and GH3 cells were determined by qPCR.The expression levels of Epac1 in fGH-PA tissues were determined by immunohistochemistry.Western blot was used to determine the expression levels of Epac1 in MMQ and GH3 cells.Overexpression or knockdown of Epac1,or knockdown of cAMP response element-binding protein(CREB)in GH3 cells,cell cycle changes were determined by flow cytometry,cell proliferation ability was determined by CCK-8 assay,and the expression levels of p-CREB,CREB,Cyclin D1,CDK2 and p21 in cells were determined by Western blot.Results qPCR and immunohistochemistry results showed that the expression levels of Epac1 mRNA and protein in fGH-PA tissues were significantly higher than those in adjacent normal tissues(P<0.05).qPCR and Western blot results showed that compared with RGC-5 cells,the expression levels of Epac1 mRNA and protein in MMQ and GH3 cells were significantly increased(P<0.05).After overexpres-sion of Epac1 in GH3 cells,compared with the Control group,the proportion of cells in G0/G1 phase and S phase in the Epac1-OE group were significantly reduced(P<0.05),and the proportion of cells in G2/M phase were significantly increased(P<0.05);the cell prolifera-tion ability were significantly enhanced(P<0.05);the expression levels of p-CREB and Cyclin D1 in cells were significantly increased(P<0.05),the expression levels of CDK2 and p21 were significantly decreased(P<0.05),while there was no significant change in the expression level of CREB between the two groups(P>0.05).After knockdown of Epac1 or knockdown of CREB in GH3 cells,all of the above results were reversed(P<0.05).Conclusion The overexpression of Epac1 in pituitary growth hormone adenoma cells can up-regulate the levels of p-CREB in cells,and promote adenoma cells to pass through G1/S phase checkpoint,resulting in cell cycle checkpoint disorder and massive proliferation,but it does not affect the expression levels of CREB.
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Objective:To survey the post competency of general practitioners who completed residency training in Suzhou Municipal Hospital.Methods:A questionnaire survey on post competency of general practitioners was conducted from January to March 2022. General practitioners who completed standardized residential training in Suzhou Municipal Hospital from 2009 to 2021 were randomly selected for the survey. The self-designed questionnaire included the basic information and post competency in terms of clinical, public health, research and teaching abilities as well as medical ethics and humanism. A self-evaluation was also performed and the abilities were graded (A 86-100, B 70-85, C 55-69, D 0-54), and grade A was classified as excellent.Results:A total of 163 questionnaires were distributed and 157 valid ones were collected with a recovery rate of 96.3%. Among 157 respondents 62 (39.5%) were males. The participants mainly worked in urban community health service institutions (78 (49.7%)), and most of them worked as general practice (119 (75.8%)). For the self-assessment of clinical skills, the proportion of respondents with excellent abilities in history taking, basic drug use, diagnosis and treatment of common diseases, and chronic disease management was 58.8% (70/119), 57.1% (68/119), 54.6% (65/119) and 54.6% (65/119), respectively. The proportion of respondents with excellent abilities in evidence-based clinical decision making, physical examination, tests interpretation, referral services, family medical services, rehabilitation services, first aid, and psychological counseling and treatment was 43.7% (70/119), 42.9% (52/119), 38.7% (46/119), 37.8% (45/119), 33.6% (40/119), 22.7% (27/119), 21.0% (25/119), and 16.8% (20/119), respectively. For the self-assessment of basic public health service ability, the proportion of respondents with excellent abilities in health education, disease prevention and control, health management, health care for key and special groups, handling public health emergencies, management of infectious diseases, epidemiology-based community diagnosis and community health leadership was 38.7% (46/119), 33.6% (40/119), 33.6% (40/119), 26.1% (31/119), 25.2% (30/119), 2.7% (27/119), 22.7% (27/119), and 21.0% (25/119), respectively. For humanistic literacy, the proportion of respondents with excellent abilities in privacy protection, sense of responsibility for patients, understanding patients′ needs, effective communication and cooperation with patients was 82.4% (98/119), 73.9% (88/119), 61.3% (73/119), 55.5% (66/119) and 2.1% (62/119), respectively. For research and teaching, the proportion of respondents with excellence abilities in continuous learning and innovation, training and teaching and literature retrieval was 47.9% (57/119), 10.9% (13/119), 10.1% (12/119), respectively. In addition 56.3% (67/119) of respondents were interested in scientific research, 23.5% (28/119) had published articles as the first author or correspondence author, and only 6.7% (8/119) had scientific research projects in the last 5 years.Conclusion:The post competency of general practitioners who received standardized residency training in our hospital varies in different aspects, their abilities in basic public health service, scientific research and teaching are relatively low, which need to be strengthened.
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Forty two general practice residents who participated in the standardized training in Suzhou Municipal Hospital from April to December 2022 were randomly divided into two groups with 21 in each group. The control group received the traditional teaching method, and the study group received additional training with a special management model for chronic obstructive pulmonary disease. After 3 months of training, the teaching effects were evaluated with the improved Mini Clinical Evaluation Exercise (Mini CEX) in two groups and the teaching satisfaction was also assessed. Compared with the control group, the study group showed significant better performance in outpatient service, including the treatment and rehabilitation planning ( t=3.82, P<0.001), humanistic care ( t=4.83, P<0.001), health education ( t=9.56, P<0.001), communication skills ( t=3.34, P=0.002), and overall performance ( t=3.13, P=0.003). The satisfaction of teaching in study group was also higher than that in the control group ( Z=-2.02, P=0.044). The study shows that incorporating the "specialized management of chronic obstructive pulmonary disease" model into the general practice standardized residency training can significantly improve the teaching effects.
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Objective:To survey on the training needs of general practitioners (GPs) in the context of public health emergency.Methods:A questionnaire was developed through literature review and interviews with health department leaders, administrators and GPs in grassroots health institutions as well as experts in the field. The contents of questionnaire included the basic information, perception of epidemic impact, knowledge and skills to learn, and the preferred training contents related to public health emergency. The questionnaire survey was conducted among 430 GPs from 44 grass-roots institutions of 6 cities/districts in Suzhou selected by multi-stage convenient sampling method from April to May 2022. Kano model was used to analyze the needs and preferences of general practitioners for training contents related to the prevention and control of COVID-19 epidemic.Results:A total of 391 valid questionnaires were collected, with an effective response rate of 90.93%. More than half of respondents hoped to learn about the general diagnosis and treatment, first aid, and emergency management of common cardiovascular and cerebrovascular diseases, as well as common community emergencies through training. In the training contents domains, special training for COVID-19 prevention and control was necessary; knowledge and practical skills were expected as the basic training needs; research and teaching ability and self-regulation ability were training needs of charm attributes; and professional quality, doctor-patient communication, and management ability were all training needs of no difference attributes.Conclusion:In the context of public health emergency, the specialized training of epidemic prevention and control is prioritized for GPs, the training of knowledge and practical skills, research and teaching abilities and self-regulation abilities are also needed.
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A flavoring agent and a suspension agent were prepared for extemporaneous compounding. The stability of the two agents before and after drug loading was investigated, and the taste of the suspension after extemporaneous compounding was evaluated by electronic tongue technology. The two agents remained stable under the conditions of influence factor test, accelerated test and long-term test. The appearance properties of the two agents did not change. The relative density of the flavoring agent was maintained at 1.053-1.075, and the pH was stable at 4.2-4.5. The relative density of the suspension agent was maintained at 0.999-1.022, and the pH was stable at 4.0-4.5. Seven kinds of drugs, including warfarin sodium tablets and spironolactone tablets, were mixed with these two oral solvents, and the content uniformity and stability were detected respectively. The results showed that the preparations could be evenly dispersed and the physical and chemical properties were stable. The results of taste evaluation showed that in captopril group and chloral hydrate group, the flavoring agent had the best effect on taste correction. In warfarin sodium group, rifampicin group, spironolactone group, vitamin B1 group and vitamin B2 group, the blending agents had the best effect on taste correction.
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Azithromycin dry suspension is one of the most commonly used drugs in pediatric clinic, but its taste masking has been difficult to achieve. 5 representative products of azithromycin dry suspension were chose to compare their tastes both using electronic tongue and human sensory evaluation methods, and there existed the differences of bitterness, later bitterness, graininess, and adhesion among these products. Raman micro-imaging was used to determine the difference in taste mainly due to different prescription ingredients and manufacturing techniques. Through mixing the dry suspensions with alkaline mixing solvent, the bad taste of each product was masked after evenly dispersing in the solvent, and their tastes were all close to the taste of the solvent. In the future, it is planned to investigate the stability and bioavailability of the solvent preparations, and then to give the medication suggestion of solvent preparation after ensuring their efficacy.
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It has been noted for decades that cancer is essentially a genomic disease. Benefiting from the latest development of high-throughput sequencing and bioinformatics technologies, a variety of genetic alterations have been identified for their roles in cancer occurrence and development, giving rise to new opportunities for anti-cancer drug discovery. In particular, the rapid advancement of cancer genomics has paved the way for the precision medicine that has gained compelling achievement in the past years and significantly benefited cancer patients. In this review, we summarize the main types of genomic abnormalities in cancer, the application of functional genomics research in cancer research, and in particular the translational application of cancer genomics in clinical diagnosis, drug discovery and cancer precision medicine. With this review, we hope to better understand cancer genomics research and provide future perspectives for its application in precision medicine.
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The most toxic DNA damage is DNA double strand breaks (DSBs), which are mainly repaired by non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA-PK) belongs to phosphatidylinositol-3-kinase-related protein kinase family (PIKK) and plays a key role in NHEJ. DNA-PK is overexpressed in a variety of cancer cells and is related to the occurrence, development and drug resistance of malignant tumors. In this article, the representative DNA-PK inhibitors with anticancer effects are reviewed, in order to provide a reference to discovery novel DNA-PK inhibitors.
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【Objective】 To analyze the hepatitis B virus (HBV) infection data of blood donors from 18 domestic blood stations, so as to investigate the HBV infection situation of blood donors. 【Methods】 The positive rate of HBV and its distribution characteristics of regions, the percentage of HBsAg+ ELISA in first-time vs repeated blood donors, and the percentage of HBsAg-/HBV DNA+ blood donors of 18 domestic blood stations during 2017 to 2020 were collected from the Working Platform for Practice Comparison of Blood Centers, and the HBV infection among blood donors were statistically analyzed. 【Results】 From 2017 to 2020, the positive rate of HBV in blood donors among 18 domestic blood stations was 13.48/10 000-144.02/10 000, with the average HBV positive rate in eastern, central and western region at 26.14/10 000, 51.98/10 000 and 41.00/10 000, respectively. The HBsAg+ rate by ELISA among first-time and repeated blood donors was 14.55/10 000-305.39/10 000 vs 1.04/10 000-87.43/10 000 The HBsAg-/HBV DNA+ yield was 1.80/10 000-35.31/10 000. 【Conclusion】 The distribution of HBV infection in blood donors has regional characteristics, and HBV prevalence was low in repeated blood donors. HBsAg ELISA combined with HBV DNA detection can better ensure blood safety.
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Abstract@#Allergic diseases can occur in all systems of the body, covering the whole life cycle, from children to adults and to old age, can be lifelong onset and even fatal in severe cases. Children account for the largest proportion of the victims of allergic disease, Children s allergies start from scratch, ranging from mild to severe, from less to more, from single to multiple systems and systemic performance, so the prevention and treatment of allergic diseases in children is of great importance, which can not only prevent high risk allergic conditions from developing into allergic diseases, but also further block the process of allergy. At present, there is no consensus on the management system of allergic children in kindergartens and primary schools. The "Consensus on Allergy Management and Prevention in Kindergartens and Primary Schools", which includes the organizational structure, system construction and management of allergic children, provides evidence informed recommendations for the long term comprehensive management of allergic children in kindergartens and primary schools, and provides a basis for the establishment of the prevention system for allergic children.
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@#Tumor-associated macrophage promotes the progression of glioblastoma (GBM) by infiltrating into tumor tissue, yet its mechanism has not been fully elucidated.This paper aimed to investigate the mechanism of M2 macrophages in affecting the migratory capacity of GBM via secreting exosomes.Ultracentrifugation was used to extract exosomes; RNA sequencing was carried out to screen differentially expressed miRNAs; target prediction database was used to predict the possible target proteins of miRNA; Dual-luciferase reporter assay was performed to verify the interaction between miRNA and target genes; and the proliferation ability of tumor cells was detected by subcutaneous xenograft model in nude mice.Results showed that tumor-related macrophages were mainly M2 macrophages, and that exosomes secreted by M2 macrophages could promote the migration of glioma cells.Meanwhile, exosomes secreted by M2 macrophages transported miR-1260b and affected the migration of glioma cells through directly targeted AJAP1, suggesting that exosomes secreted by macrophages could affect the migration ability of GBM through transporting miR-1260b.
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Epilepsy is a chronic nervous system disease, which affects more than 70 million people all over the world. Although more than 30 kinds of antiepileptic drugs (AEDs) have been on the market, about one third of the patients with epilepsy fail to respond to medical treatment, who become drug-resistant epilepsy patients. Identifying the mechanism and developing effective treatment methods for drug-resistant epilepsy have become a hot area in the field of epilepsy research. This review discussed resent advance on the pathogenesis of drug-resistant epilepsy from the transporter hypothesis, neural network hypothesis and target hypothesis, and we also summarized the existing potential treatment methods and research progress of drug-resistant epilepsy, such as surgical resection, deep brain stimulation, ketogenic diet, precise treatment, and traditional Chinese medicine treatment. Our review may provide useful clues for the mechanisms research and clinical treatments of drug-resistant epilepsy.
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Objective@#To understand the public health emergency response capacity in primary and secondary schools, and to explore the problems and challenges in the prevention and control of public health emergency in primary and secondary schools for specific strategies.@*Methods@#By using the stratified group sampling method, a questionnaire survey on general situation, knowledge, attitude and training, as well as public health emergencies response capacity among 2 988 teachers or leaders responsible for school emergency response in primary and secondary schools from Beijing, Chongqing and Yunnan.@*Results@#Participants varied on their positions, titles, educational background and knowledge accuracy. Higher knowledge accuracy was associated with higher educational background ( χ 2=50.73-203.36, P < 0.05 ). The implementation of regular public health emergency related programs was poorly conducted in high schools (50.0%). Urban schools (42.0%) had higher proportion of qualified health care professionals than rural schools (18.2%), and private schools (48.5%) was higher than public schools (24.7%). The primary challenges included the shortage of guidance from professionals and the lack of related testing equipment (84.91%, 74.03%).@*Conclusion@#Although the ability of emergency handling of public health emergencies in schools in the three regions is advancing with the times, there are still many deficiencies, some omissions in the mastery of knowledge. It is suggested to inerease pre service and special training of school health work CDC should strengthen technical guidance and work supervision of infectious disease management in schools.
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Aim To investigate the absorption of thalidomide in inflammatory bowel disease(IBD)SD rats compared with healthy rats to provide a basis for the safety and efficacy of thalidomide in clinical practice. Method The IBD rat model was induced by the 2, 4, 6-trinitrobenzene sulfonic acid, by which the rats were continuously intervened for six days. The general state and disease activity index of the rats were recorded every day. The rats in IBD group after modeling and control group were administered with thalidomide at a dose of 10 mg·kg-1. The blood sample of the rats was collected at different time points. After a comprehensive evaluation of morphological and histopathological results, the samples of rats with IBD were determined by proven high performance liquid chromatography-mass spectrometry,and the pharmacokinetic parameters were calculated and compared with the healthy rats. Results The body weight of rats in IBD group was obviously lower than that in control group and the disease activity index, score of colonic macroscopic morphous and histopathology were obviously higher than those in control group. The success rate of modeling was 62.5%. The pharmacokinetic results showed that the Cmax(P<0.05)and AUC(P<0.01)of the IBD group both increased by 2 to 3 times, but there was no significant difference in t1/2,Tmax,MRT and other parameters. Conclusions The rate and extent of oral thalidomide absorption of rats in the model of inflammatory bowel disease significantly increase compared to those of healthy rats, which may provide new considerations for clinical practice of thalidomide in the treatment of IBD.
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Background Paraquat (PQ) is one of the environmental factors that can cause sporadic Parkinson's disease (PD). Microglia-mediated neuroinflammation plays an important role in the occurrence and development of PD. Our previous studies have found that low doses of PQ can activate BV-2 microglia to the M1 phenotype and exert pro-inflammatory effects, but the associated mechanism is not clear yet. Objective To explore the role of c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) signaling pathway in PQ-induced activation of the NOD-like receptor thermal protein domain associated protoin 3 (NLRP3) inflammasome in microglia. Methods An in vitro microglia model was established. The cells were treated with 0, 0.03, 0.06,and 0.12 μmol·L−1 PQ for 24 h, the whole cell protein was extracted. The relative expression levels of JNK, AP-1 constituent proteins (c-Jun, c-Fos), NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspasse-1 precursor (pro caspase-1), interleukin-18 (IL-18), and interleukin-1β (IL-1β) were evaluated by Western blotting, to observe the effects of PQ exposure on JNK/AP-1 signaling pathway and NLRP3 inflammasome. After the treatment of 20 μmol·L−1 JNK inhibitor SP600125, the above proteins were detected again, to explore the driving effect of JNK/AP-1 signaling pathway on NLRP3 inflammasome activation. Results After PQ exposure, the relative expression levels of key proteins of JNK, c-Jun, and c-Fos, NLRP3, ASC, and pro caspase-1 in the 0.06 μmol·L−1 PQ group and the 0.12 μmol·L−1 PQ group were higher than those in the 0 μmol·L−1 PQ group (P<0.05), and the relative expression levels of IL-18 and IL-1β increased with higher exposure (P<0.05). After the treatment of JNK inhibitor SP600125, the relative expression levels of key proteins of JNK/AP-1 signaling pathway (JNK, c-Jun, and c-Fos), NLRP3 inflammasome (NLRP3, ASC, and Pro caspase-1), and inflammatory factors (IL-18 and IL-1β) in the control group, the 20 μmol·L−1 SP600125 group, and the 20 μmol·L−1 SP600125+0.06 μmol·L−1 PQ group were lower than those in the 0.06 μmol·L−1 PQ group (P<0.05). Conclusion PQ exposure can activate the JNK/AP-1 signaling pathway and subsequently drive the activation of NLRP3 inflammasome in BV-2 microglia to mediate neuroinflammatory responses..