BACKGROUND:Polyurethane materials,with their outstanding physicochemical properties,present extensive opportunities in the realm of biomedical engineering.Biomimetic design and functional modification of polyurethane nerve conduits are expected to further address the challenges of nerve regeneration and repair.OBJECTIVE:To review the current status and advancements in the application of polyurethane-based nerve conduits in the field of peripheral nerve repair.METHODS:The Chinese and English search terms consisted of"polyurethane,PU,polyurethane material,polyurethane biomaterials,nerve regeneration,peripheral nerve injury,nerve repair,nerve scaffold,nerve guidance conduit,nerve conduits."The search was conducted in databases such as PubMed,Web of Science,CNKI(China National Knowledge Infrastructure),and WanFang for articles published from 2014 to 2024.Finally,61 articles were included in the review.RESULTS AND CONCLUSION:Biomimetic composition is an effective strategy for enhancing the biological activity of polyurethane nerve conduits.Through structural biomimicry,polyurethane nerve conduits can be optimized to provide biological guidance cues for neural tissue regeneration.The biomechanically biomimetic polyurethane nerve conduits are likely to play a significant role in immune modulation and the promotion of axonal growth.By optimizing the conductive microenvironment of polyurethane materials,the reconstruction of neural electrical signal pathways can be facilitated.Polyurethane nerve conduits can serve as drug carriers,exerting anti-inflammatory and neuroprotective effects.Although the combined application of multiple design strategies can improve various aspects of damaged nerve function,the complex structure and dynamically changing pathophysiological microenvironment of nerves mean that nerve conduit design strategies still require refinement.Future advancements and innovations in nerve biomimetic design strategies hold promise for providing new insights and opportunities in the field of neural tissue engineering.

Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Background: Psoralea corylifolia L. (Buguzhi, BGZ), known for its efficacy in supporting pregnancy and preventing miscarriage, has been used in China for over 1000 years. Recently, BGZ has been identified as a potential cause of drug-induced liver injury. However, its safety during pregnancy remains unclear, which significantly hinders its routine clinical application. Objective: To investigate the effects of BGZ administration during pregnancy on the liver of mouse mothers and their weaned 21-day-old offspring. Methods: Mice were orally administered BGZ at doses of 2.5 and 10 g/kg during pregnancy, with BGZ withdrawal during the lactation period. Liver histopathology (hematoxylin-eosin staining), biochemical analysis, and evaluation of liver bile acid metabolism were performed after the lactation period. Results: BGZ administration at doses of 2.5 and 10 g/kg during pregnancy, followed by withdrawal during the lactation period, caused mild liver damage in both mothers and their 21-day-old offspring. Serum total bile acid (TBA) levels were elevated compared with those in the control group. Additionally, changes were observed in the levels and proportions of various bile acids (BAs) in the liver, suggesting mild effects on BA metabolism. Conclusion: BGZ administration during pregnancy caused mild liver damage and increased serum TBA levels in both mouse mothers and their 21-day-old offspring. This phenomenon may be associated with imbalanced BA metabolism in the liver. Based on the present study and the limited toxicological research on BGZ, pregnant women should avoid prolonged use of BGZ. If BGZ is administered during pregnancy, serum TBA levels should be monitored, and if elevated, BGZ should be discontinued.

Background: Aristolochic acid II (AAII), a major nephrotoxic and carcinogenic component of aristolochic acids (AAs), has been less studied compared with its well-characterized analog, aristolochic acid I (AAI). Although AAs are known to induce carcinogenesis via DNA adduct formation, the toxicity mechanisms, environmental prevalence, and long-term health impacts of AAII remain poorly understood. Objective: This study aimed to systematically evaluate AAII’s acute and chronic toxicity, carcinogenic mechanisms, and environmental exposure patterns using integrated murine models and phytochemical analyses to clarify its toxicological profile and associated health risks. Methods: C57BL/6J mice were used in the following experiments: (1) determination of AAII content in 3 commonly used Aristolochia medicinal materials via liquid chromatography-mass spectrometry/mass spectrometry; (2) acute toxicity testing with single doses of 10, 20, or 40 mg/kg; and (3) chronic exposure with 1 or 10 mg/kg administered every other day for 24 weeks, followed by 21 to 40 weeks of postexposure monitoring. Histopathological examination, whole-exome sequencing, biochemical assays, and micronucleus tests were performed to assess multi-organ damage, tumorigenesis, genomic mutation signatures, and direct clastogenicity. Phytochemical analyses were used to evaluate environmental distribution. Results: (1) A single 40 mg/kg dose of AAII induced dose-dependent renal tubular degeneration without hepatotoxicity; (2) the 10 mg/kg group showed significant mortality (20%), tumor incidence (33.3%, primarily forestomach and bladder transitional cell carcinomas), persistent renal interstitial fibrosis, and subclinical hepatic injury. Chronic exposure to 1 mg/kg still induced 13.3% mortality and 15.5% tumor incidence over a 64-week period; (3) whole-exome sequencing revealed a predominance of C>T mutations and pathway enrichment in chemical carcinogenesis and cytochrome P450-mediated metabolism, indicating reactive metabolite-driven mechanisms distinct from classical AA-DNA adducts; and (4) no histopathological changes were observed in nontarget organs (brain, heart, and testes), and micronucleus assays confirmed the absence of direct clastogenicity. Conclusion: This study highlights the delayed carcinogenic risks of low-dose chronic AAII exposure and emphasizes the need to update regulatory frameworks to ensure the safe use of aristolochiaceae-containing herbal products.

AIM:To investigate the role of SET and MYND domain-containing protein 3(SMYD3)-mediated histone H3 lysine 4 trimethylation(H3K4me3)dysregulation in pulmonary vascular remodeling in a rat model of pulmo-nary arterial hypertension associated with atrial septal defect(PAH-ASD).METHODS:The PAH-ASD rat model was created using transseptal puncture and radiofrequency ablation techniques.The rats were randomly assigned to 5 groups:normal,sham,PAH-ASD,PAH-ASD+vehicle(Veh),and PAH-ASD+BCI-121(SMYD3 inhibitor).Four weeks after modeling,lung tissues and pulmonary vessels were harvested for subsequent analysis.Western blot analysis was conducted to evaluate the protein levels of SMYD3,H3K4me3,transforming growth faction-β1(TGF-β1),and collagen type Ⅲ(Col Ⅲ).The mRNA expression of TGF-β1 was quantified using RT-qPCR.Histological assessment of pulmonary vascu-lar fibrosis,vascular wall thickness and smooth muscle proliferation was executed through Masson's trichrome and HE staining.Co-immunoprecipitation(Co-IP)assay was performed to investigate the interactions among SMYD3,H3K4me3,and TGF-β1.Hemodynamic parameters,including mean pulmonary artery pressure(mPAP),were quantified using a computerized physiological signal acquisition system.RESULTS:The Western blot analysis indicated a significant in-crease in the protein levels of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 in the PAH-ASD group compared with the sham group(P<0.05).RT-qPCR corroborated the elevation of TGF-β1 mRNA expression in the PAH-ASD group(P<0.05).Furthermore,Masson's trichrome and HE staining techniques revealed more pronounced pulmonary vascular fibrosis,an augmented vascular wall area,and an elevated vascular area index within the PAH-ASD group(P<0.05).Additionally,the right ventricular hypertrophy index(RVHI)and mPAP were significantly elevated in the PAH-ASD group(P<0.05).The administration of BCI-121 resulted in a significant reduction of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 levels(P<0.05),while also mitigating pulmonary vascular fibrosis,RVHI,mPAP,pulmonary vascular area,and area index(P<0.05).Co-IP confirmed direct interactions among SMYD3,H3K4me3,and TGF-β1.CONCLUSION:Histone methyl-transferase SMYD3-mediated histone H3K4me3 modification plays a role in the pulmonary vascular remodeling of PAH-ASD model rats.The underlying mechanism may involve the regulation of pulmonary vascular proliferation and fibrosis me-diated by the overexpression of TGF-β1 and Col Ⅲ.

OBJECTIVE To explore the changes of serum inflammatory factors and immune function indexes in the children with asthma induced by Mycoplasma pneumoniae infection so as to make a new breakthrough in diagnosis and treatment of the children with M.pneumoniae infection-induced asthma.METHODS A total of 118 children with M.pneumoniae infection who were treated in pediatrics department of The Affiliated Hospital of Binzhou Medical College from Jan.2020 to May 2023 were enrolled in the study and were divided into the asthma group with 26 cases and the no asthma group with 92 cases according to the status of induction of asthma.The levels of peripheral blood interleukin(IL)-1β,IL-18,tumor necrosis factor-α(TNF-α)and immune function indexes(CD3+,CD4+,CD8+and CD4+/CD8+)were observed and compared between the two groups.The values of the above indexes in diagnosis of the M.pneumoniae infection-induced asthma were analyzed by means of receiver op-erating characteristic(ROC)curves.RESULTS There were significant differences in the levels of inflammatory factors and immune function indexes between the asthma group and the no asthma group(P＜0.05).The levels of TNF-α,IL-1β,IL-18 and CD8+of the asthma group were(46.33±5.30)pg/ml,(50.60±6.33)pg/ml,(40.26±4.89)pg/ml and(40.11±6.85)％,respectively,higher than those of the no asthma group;the levels of CD3+,CD4+and CD4+/CD8+of the asthma group were(43.33±5.89)％,(15.62±3.61)％and(0.35±0.12),re-spectively,lower than those of the no asthma group.In the asthma group,the levels of TNF-α,IL-1β,IL-18 and CD8+of the MP-Immunoglobulin M(IgM)-positive children were higher than those of the MP-IgM-negative chil-dren(P＜0.05),while the levels of CD3+,CD4+and CD4+/CD8+of the MP-IgM-positive children were lower than those of the MP-IgM-negative children(P＜0.05).The areas under the ROC curves(AUCs)of the serum TNF-α,IL-1β,IL-18,CD3+,CD4+,CD8+and CD4+/CD8+were 0.812,0.805,0.795,0.814,0.768,0.805 and 0.841,respectively,in diagnosis of the M.pneumoniae infection-induced asthma.CONCLUSION The serum TNF-α,IL-1β,IL-18,CD3+,CD4+,CD8+and CD4+/CD8+of the children with M.pneumoniae infection can be used for prediction of the asthma.

BACKGROUND:Polyurethane materials,with their outstanding physicochemical properties,present extensive opportunities in the realm of biomedical engineering.Biomimetic design and functional modification of polyurethane nerve conduits are expected to further address the challenges of nerve regeneration and repair.OBJECTIVE:To review the current status and advancements in the application of polyurethane-based nerve conduits in the field of peripheral nerve repair.METHODS:The Chinese and English search terms consisted of"polyurethane,PU,polyurethane material,polyurethane biomaterials,nerve regeneration,peripheral nerve injury,nerve repair,nerve scaffold,nerve guidance conduit,nerve conduits."The search was conducted in databases such as PubMed,Web of Science,CNKI(China National Knowledge Infrastructure),and WanFang for articles published from 2014 to 2024.Finally,61 articles were included in the review.RESULTS AND CONCLUSION:Biomimetic composition is an effective strategy for enhancing the biological activity of polyurethane nerve conduits.Through structural biomimicry,polyurethane nerve conduits can be optimized to provide biological guidance cues for neural tissue regeneration.The biomechanically biomimetic polyurethane nerve conduits are likely to play a significant role in immune modulation and the promotion of axonal growth.By optimizing the conductive microenvironment of polyurethane materials,the reconstruction of neural electrical signal pathways can be facilitated.Polyurethane nerve conduits can serve as drug carriers,exerting anti-inflammatory and neuroprotective effects.Although the combined application of multiple design strategies can improve various aspects of damaged nerve function,the complex structure and dynamically changing pathophysiological microenvironment of nerves mean that nerve conduit design strategies still require refinement.Future advancements and innovations in nerve biomimetic design strategies hold promise for providing new insights and opportunities in the field of neural tissue engineering.

OBJECTIVE To explore the changes of serum inflammatory factors and immune function indexes in the children with asthma induced by Mycoplasma pneumoniae infection so as to make a new breakthrough in diagnosis and treatment of the children with M.pneumoniae infection-induced asthma.METHODS A total of 118 children with M.pneumoniae infection who were treated in pediatrics department of The Affiliated Hospital of Binzhou Medical College from Jan.2020 to May 2023 were enrolled in the study and were divided into the asthma group with 26 cases and the no asthma group with 92 cases according to the status of induction of asthma.The levels of peripheral blood interleukin(IL)-1β,IL-18,tumor necrosis factor-α(TNF-α)and immune function indexes(CD3+,CD4+,CD8+and CD4+/CD8+)were observed and compared between the two groups.The values of the above indexes in diagnosis of the M.pneumoniae infection-induced asthma were analyzed by means of receiver op-erating characteristic(ROC)curves.RESULTS There were significant differences in the levels of inflammatory factors and immune function indexes between the asthma group and the no asthma group(P＜0.05).The levels of TNF-α,IL-1β,IL-18 and CD8+of the asthma group were(46.33±5.30)pg/ml,(50.60±6.33)pg/ml,(40.26±4.89)pg/ml and(40.11±6.85)％,respectively,higher than those of the no asthma group;the levels of CD3+,CD4+and CD4+/CD8+of the asthma group were(43.33±5.89)％,(15.62±3.61)％and(0.35±0.12),re-spectively,lower than those of the no asthma group.In the asthma group,the levels of TNF-α,IL-1β,IL-18 and CD8+of the MP-Immunoglobulin M(IgM)-positive children were higher than those of the MP-IgM-negative chil-dren(P＜0.05),while the levels of CD3+,CD4+and CD4+/CD8+of the MP-IgM-positive children were lower than those of the MP-IgM-negative children(P＜0.05).The areas under the ROC curves(AUCs)of the serum TNF-α,IL-1β,IL-18,CD3+,CD4+,CD8+and CD4+/CD8+were 0.812,0.805,0.795,0.814,0.768,0.805 and 0.841,respectively,in diagnosis of the M.pneumoniae infection-induced asthma.CONCLUSION The serum TNF-α,IL-1β,IL-18,CD3+,CD4+,CD8+and CD4+/CD8+of the children with M.pneumoniae infection can be used for prediction of the asthma.

AIM:To investigate the role of SET and MYND domain-containing protein 3(SMYD3)-mediated histone H3 lysine 4 trimethylation(H3K4me3)dysregulation in pulmonary vascular remodeling in a rat model of pulmo-nary arterial hypertension associated with atrial septal defect(PAH-ASD).METHODS:The PAH-ASD rat model was created using transseptal puncture and radiofrequency ablation techniques.The rats were randomly assigned to 5 groups:normal,sham,PAH-ASD,PAH-ASD+vehicle(Veh),and PAH-ASD+BCI-121(SMYD3 inhibitor).Four weeks after modeling,lung tissues and pulmonary vessels were harvested for subsequent analysis.Western blot analysis was conducted to evaluate the protein levels of SMYD3,H3K4me3,transforming growth faction-β1(TGF-β1),and collagen type Ⅲ(Col Ⅲ).The mRNA expression of TGF-β1 was quantified using RT-qPCR.Histological assessment of pulmonary vascu-lar fibrosis,vascular wall thickness and smooth muscle proliferation was executed through Masson's trichrome and HE staining.Co-immunoprecipitation(Co-IP)assay was performed to investigate the interactions among SMYD3,H3K4me3,and TGF-β1.Hemodynamic parameters,including mean pulmonary artery pressure(mPAP),were quantified using a computerized physiological signal acquisition system.RESULTS:The Western blot analysis indicated a significant in-crease in the protein levels of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 in the PAH-ASD group compared with the sham group(P<0.05).RT-qPCR corroborated the elevation of TGF-β1 mRNA expression in the PAH-ASD group(P<0.05).Furthermore,Masson's trichrome and HE staining techniques revealed more pronounced pulmonary vascular fibrosis,an augmented vascular wall area,and an elevated vascular area index within the PAH-ASD group(P<0.05).Additionally,the right ventricular hypertrophy index(RVHI)and mPAP were significantly elevated in the PAH-ASD group(P<0.05).The administration of BCI-121 resulted in a significant reduction of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 levels(P<0.05),while also mitigating pulmonary vascular fibrosis,RVHI,mPAP,pulmonary vascular area,and area index(P<0.05).Co-IP confirmed direct interactions among SMYD3,H3K4me3,and TGF-β1.CONCLUSION:Histone methyl-transferase SMYD3-mediated histone H3K4me3 modification plays a role in the pulmonary vascular remodeling of PAH-ASD model rats.The underlying mechanism may involve the regulation of pulmonary vascular proliferation and fibrosis me-diated by the overexpression of TGF-β1 and Col Ⅲ.

ObjectiveBased on ultra performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS^E） technique， we identified qualitatively the metabolites of aristolochic acid（AAs） in rat in order to analyze the metabolic differences between water extract of Aristolochiae fructus（AFE） and Aristolochic acid Ⅰ（AAⅠ）. MethodSD rats were selected and administered AFE（110 g·kg^-1·d^-1） or AAⅠ（5 mg·kg^-1·d^-1） by oral for 5 days， respectively. Serum， urine and feces were collected after administration. Through sample pretreatment， ACQUITY UPLC BEH C₁₈ column（2.1 mm×100 mm， 1.7 μm） was used with the mobile phase of 0.01% formic acid methanol（A）-0.01% formic acid water（B， containing 5 mmol·L^-1 ammonium acetate） for gradient elution（0-1 min， 10%B； 1-7 min， 10%-75%B； 7-7.2 min， 75%-95%B； 7.2-10.2 min， 95%B； 10.2-10.3 min， 95%-10%B； 10.3-12 min， 10%B） at a flow rate of 0.3 mL·min^-1. Positive ion mode of electrospray ionization（ESI⁺） was performed in the scanning range of m/z 100-1 200. In combination with UNIFI 1.9.4.053 system， the Pathway-MS^E was used to qualitatively analyze and identify the AAs prototype and related metabolites in biological samples（serum， urine and feces）， and to compare the similarities and differences of metabolites in rats in the subacute toxicity test between AFE group and AAⅠ group. ResultCompared with AAⅠ group， 6， 10， 13 common metabolites and 14， 20， 30 unique metabolites were identified in biological samples（serum， urine and feces） of AFE group， respectively. Moreover， the main AAs components always followed the metabolic processes of demethylation， nitrate reduction and conjugation. Compared with common metabolites in AAⅠ group， prototype components of AAⅠ in serum and most metabolic derivatives of AAⅠ［AAⅠa， aristolochic lactam Ⅰ（ALⅠ）a， 7-OHALⅠ and its conjugated derivatives］ in biological samples were significantly increased in AFE group（P<0.05， P<0.01）， except that the metabolic amount of ALⅠ in feces of AFE group was remarkably lowed than that of AAⅠ group（P<0.01）. In addition， a variety of special ALⅠ efflux derivatives were also identified in the urine and feces of the AFE group. ConclusionAlthough major AAs components in AFE all show similar metabolic rules as AAⅠ components in vivo， the coexistence of multiple AAs components in Aristolochiae Fructus may affect the metabolism of AAⅠ， and achieve the attenuating effect by increasing the metabolic effection of AAⅠ and ALⅠ.