ObjectiveTo investigate whether Huanglian Jiedutang can inhibit neutrophil infiltration in the brains of middle cerebral artery occlusion （MCAO） mice by regulating the expression of neutrophil-related chemokines in exosomes， thereby achieving therapeutic effects. MethodsA total of 130 male specific pathogen-free （SPF） C57BL/6J mice were randomly divided into four groups： Sham-operated group， MCAO model group， Huanglian Jiedutang group （6 g·kg^-1）， and Ginaton group （21.6 mg·kg^-1）， with 10 mice in the Ginaton group and 40 mice in each of the remaining three groups. Mice in the Huanglian Jiedutang group and the Ginaton group were administered the corresponding drugs by oral gavage once daily at a volume of 0.15 mL·（10 g）^-1 for 7 consecutive days， while the sham-operated and model groups received an equal volume of saline via the same route. After 7 days， MCAO surgery was performed. The distal and proximal ends of the right common carotid artery （CCA） were ligated， a small incision was made between the two ligatures， and a silicone rubber-coated monofilament with a rounded tip was inserted into the lumen to occlude the CCA. The filament was left in place for 1 h to establish a focal cerebral ischemia model. At 24 h after modeling， mice were evaluated. Neurological function was assessed using the Longa score. Cerebral infarct volume was measured by 2，3，5-triphenyltetrazolium chloride （TTC） staining. Cerebral blood flow was observed by laser speckle imaging. Hematoxylin and eosin （HE） staining and Nissl staining were used to observe pathological changes in brain tissues. Exosomes were isolated from mouse plasma and brain tissues by ultracentrifugation and molecular size exclusion and identified by electron microscopy， particle size analysis， and protein blotting. Long-chain RNA libraries of exosomes were constructed and sequenced. Real-time quantitative reverse transcription polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of inflammatory factors and neutrophil-related chemokines in exosomes from plasma and brain tissues of each group. Enzyme-linked immunosorbent assay （ELISA） was used to detect the protein expression of inflammatory factors and neutrophil-related chemokines in exosomes from brain tissues of each group. Immunohistochemistry was used to detect the expression of the neutrophil-specific protein myeloperoxidase （MPO） in the brains of mice in each group. ResultsCompared with the sham-operated group， the model group showed decreased neurological function scores （P<0.01）， obvious cerebral infarction （P<0.01）， reduced cerebral blood flow （P<0.01）， neuronal necrosis in the brain， and decreased numbers of Nissl bodies （P<0.01）. The mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were significantly increased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were increased （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were elevated （P<0.01）. Compared with the model group， the Huanglian Jiedutang group and the Ginaton group showed increased neurological function scores （P<0.05）， reduced cerebral infarct volume （P<0.01）， restored cerebral blood flow （P<0.01）， reduced necrotic cells in the brain， and increased numbers of Nissl bodies （P<0.01）. In the Huanglian Jiedutang group， the mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were decreased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were reduced （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were decreased （P<0.01）. ConclusionHuanglian Jiedutang can effectively regulate the expression of neutrophil-related chemokines in exosomes from plasma and brain tissues of MCAO mice， thereby reducing neutrophil infiltration in the brain and achieving therapeutic effects.

ObjectiveTo investigate whether Huanglian Jiedutang can inhibit neutrophil infiltration in the brains of middle cerebral artery occlusion （MCAO） mice by regulating the expression of neutrophil-related chemokines in exosomes， thereby achieving therapeutic effects. MethodsA total of 130 male specific pathogen-free （SPF） C57BL/6J mice were randomly divided into four groups： Sham-operated group， MCAO model group， Huanglian Jiedutang group （6 g·kg^-1）， and Ginaton group （21.6 mg·kg^-1）， with 10 mice in the Ginaton group and 40 mice in each of the remaining three groups. Mice in the Huanglian Jiedutang group and the Ginaton group were administered the corresponding drugs by oral gavage once daily at a volume of 0.15 mL·（10 g）^-1 for 7 consecutive days， while the sham-operated and model groups received an equal volume of saline via the same route. After 7 days， MCAO surgery was performed. The distal and proximal ends of the right common carotid artery （CCA） were ligated， a small incision was made between the two ligatures， and a silicone rubber-coated monofilament with a rounded tip was inserted into the lumen to occlude the CCA. The filament was left in place for 1 h to establish a focal cerebral ischemia model. At 24 h after modeling， mice were evaluated. Neurological function was assessed using the Longa score. Cerebral infarct volume was measured by 2，3，5-triphenyltetrazolium chloride （TTC） staining. Cerebral blood flow was observed by laser speckle imaging. Hematoxylin and eosin （HE） staining and Nissl staining were used to observe pathological changes in brain tissues. Exosomes were isolated from mouse plasma and brain tissues by ultracentrifugation and molecular size exclusion and identified by electron microscopy， particle size analysis， and protein blotting. Long-chain RNA libraries of exosomes were constructed and sequenced. Real-time quantitative reverse transcription polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of inflammatory factors and neutrophil-related chemokines in exosomes from plasma and brain tissues of each group. Enzyme-linked immunosorbent assay （ELISA） was used to detect the protein expression of inflammatory factors and neutrophil-related chemokines in exosomes from brain tissues of each group. Immunohistochemistry was used to detect the expression of the neutrophil-specific protein myeloperoxidase （MPO） in the brains of mice in each group. ResultsCompared with the sham-operated group， the model group showed decreased neurological function scores （P<0.01）， obvious cerebral infarction （P<0.01）， reduced cerebral blood flow （P<0.01）， neuronal necrosis in the brain， and decreased numbers of Nissl bodies （P<0.01）. The mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were significantly increased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were increased （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were elevated （P<0.01）. Compared with the model group， the Huanglian Jiedutang group and the Ginaton group showed increased neurological function scores （P<0.05）， reduced cerebral infarct volume （P<0.01）， restored cerebral blood flow （P<0.01）， reduced necrotic cells in the brain， and increased numbers of Nissl bodies （P<0.01）. In the Huanglian Jiedutang group， the mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were decreased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were reduced （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were decreased （P<0.01）. ConclusionHuanglian Jiedutang can effectively regulate the expression of neutrophil-related chemokines in exosomes from plasma and brain tissues of MCAO mice， thereby reducing neutrophil infiltration in the brain and achieving therapeutic effects.

BACKGROUND:Finite element modeling,as an important engineering analysis technique,has been widely used in various fields of bioengineering research.However,there is little literature on what material properties should be selected for each anatomical structure of the knee joint finite element modeling at different ages for different research purposes.OBJECTIVE:To summarize the material properties of knee joint finite element models at different ages based on previous knee joint finite element studies.METHODS:The search terms were"knee,finite element,material selection,ligament injury,osteoarthritis,elderly,children,young people"in Chinese and English.Articles were searched on CNKI and PubMed,with a timeframe of 1950 to 2024.According to inclusion and exclusion criteria,108 articles were finally included for summary.RESULTS AND CONCLUSION:Children's knee bone density will increase with age,reaching peaks in adulthood.From middle-aged to the age,the elastic modulus of knee joint femur,tibia,fibula,and patella will decrease with age,and then return to the elastic modulus of childhood.The elastic modulus of children and adult cartilage is basically the same,and the elastic modulus of the elderly increases.With the increase of age,the elastic modulus of the knee ligament will decrease to a certain extent,but there is no significant difference in the elastic modulus of the knee ligament of young people and the elderly.With the increase of age,the loss of mechanical integrity of the knee meniscus will damage the biomechanical function of the tissue and disturb the various anisotropic biomechanical responses that are effectively carried and transmitted by the tissue.Knee joint finite element modeling can be used to deeply understand the biomechanical characteristics of the knee joints,develop new implanted materials,predict knee joint diseases,improve surgical technology,and guide patients to rehabilitate exercise.

Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
Humans ; Neoplasms/metabolism* ; Cyclin-Dependent Kinases/antagonists & inhibitors* ; Cyclins/metabolism* ; Proteolysis ; Antineoplastic Agents/pharmacology* ; Molecular Targeted Therapy ; Proteasome Endopeptidase Complex/metabolism* ; Animals

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

Objective This study analyzes the optical coherence tomography(OCT)characteristics of patients with symptomatic carotid artery stenosis(CAS)prior to carotid stenting and the influencing factors associated with symptomatic CAS.Methods This study retrospectively included consecutive CAS patients who underwent carotid OCT examination prior to carotid stenting at Department of Nerolgical Intervention and Nerological Intensive Care,Central Hospital of Dalian University of Technology(Dalian Municipal Central Hospital)from November 2022 to November 2024.Patients were categorized into symptomatic and asymptomatic CAS groups.General clinical data and laboratory test results were collected and compared between the two groups,including age,sex,body mass index,systolic and diastolic blood pressure(measured on the morning of procedure without antihypertensive medication intervention with patient at resting state for over 30 minutes),medical history(including hypertension,diabetes,atrial fibrillation,coronary heart disease,stroke,and transient ischemic attack),smoking history,alcohol consumption history,and fasting laboratory results obtained on the morning before procedure laboratory results(including,white blood cell count,red blood cell count,monocyte percentage,neutrophil percentage,lymphocyte percentage,platelet count,blood creatinine,blood glucose,international normalized ratio,D-dimer,total cholesterol,triglycerides,homocysteine,low-density lipoprotein cholesterol,and high-density lipoprotein cholesterol).Additionally,OCT image parameters were collected and compared between the two groups,including the minimum lumen diameter and minimum lumen area of the target lesion segment,the distal lumen diameter and area of the reference vessel(internal carotid artery),the percentage of lumen area stenosis([reference vessel lumen cross-sectional area-minimum lumen cross-sectional area]/reference vessel lumen cross-sectional area×100%),the lesion length,fibrous cap thickness,lipid arc,and the presence of fibrous plaques,calcified plaques,lipid plaques,white thrombus,cholesterol crystals,macrophage infiltration,microchannels,and plaque rupture.Variables with P＜0.05 from univariate analysis were included in the multivariate Logistic regression analysis to assess the influencing factors of symptomatic CAS.Results A total of 68 patients with CAS were enrolled,comprising 57males and 11females,aged 53 to 84 years with a mean age of(68±7)years.Among them,32 patients were categorized into the symptomatic CAS group and 36 into the asymptomatic CAS group.(1)Compared to the asymptomatic CAS group,patients in the symptomatic CAS group exhibited higher systolic blood pressure([150±23]mmHg vs.[138±21])mmHg,P=0.025).There were no statistically significant differences in general,clinical data,and laboratory test results between the two groups(all P＞0.05).The preoperative OCT imaging parameters comparison between the two groups of CAS patients revealed that the reference vessel distal lumen area was significantly smaller in the symptomatic CAS group([18.67±5.44]mm2 vs.[21.95±5.57]mm2,P=0.017),and the proportion of patients with white thrombus(40.62%[13/32]vs.13.89%[5/36],P=0.013)and microchannels(21.88%[7/32]vs.2.78%[1/36],P=0.014)were higher.(2)A multivariate Logistic regression analysis was conducted using systolic blood pressure,white thrombus,microchannels,and the reference vessel(internal carotid artery)distal lumen area as independent variables.The results indicated that high systolic blood pressure(OR,1.030,95%CI 1.002-1.060,P=0.038),and the presence of white thrombus(OR,3.956,95%CI 1.072-14.600,P=0.039)and microchannels(OR,13.850,95%CI 1.277-150.203,P=0.031)were independent risk factors for symptomatic CAS.Conclusions Compared to patients with asymptomatic CAS,those with symptomatic CAS exhibited higher preoperative(pre-carotid stenting)systolic blood pressure and a smaller distal lumen area of the reference vessel(internal carotid artery),as observed through OCT.Furthermore,a higher proportion of symptomatic CAS patients presented with white thrombus and microchannels.Preoperative systolic blood pressure,along with the presence of white thrombus and microchannels on OCT,are identified as independent risk factors for symptomatic CAS.The conclusions drawn from this study necessitate further validation through large-scale,multicenter,prospective research.

Objective:To explore the aperiodic components(1/f slopes)and their associations with cognitive impairment in patients with schizophrenia.Methods:Nineteen patients with schizophrenia according to the Interna-tional Statistical Classification of Diseases and Related Health Problem,Tenth Revision(ICD-10)and 21 normal controls were administrated the total Brief Assessment of Cognition in Schizophrenia(BACS)to measure the cogni-tive performance.The 5-minute eyes-closed and eyes-open resting EEG signals were collected and parameterized in-to aperiodic components(1/f slope).Finally,Pearson correlation was used to examine the relationships between the 1/f slope and cognition assessment scores.Results:The patients with schizophrenia had higher 1/f slope compared to HC on central location of scalp(P＜0.05).The vocal memory scores showed a significantly positive relation with 1/f slopes in patients with schizophrenia(anterior location:r=-0.68,P＜0.05;central location:r=-0.44,P＜0.05),but a significantly negative relation in normal controls(anterior location:r=0.57,P＜0.05;posterior lo-cation:r=0.54,P＜0.05).Conclusion:The 1/f slopes of EEG in schizophrenia were steeper than normal control,suggesting its strong cognitive functional significance and complex mechanisms in schizophrenia.

Objective This study analyzes the optical coherence tomography(OCT)characteristics of patients with symptomatic carotid artery stenosis(CAS)prior to carotid stenting and the influencing factors associated with symptomatic CAS.Methods This study retrospectively included consecutive CAS patients who underwent carotid OCT examination prior to carotid stenting at Department of Nerolgical Intervention and Nerological Intensive Care,Central Hospital of Dalian University of Technology(Dalian Municipal Central Hospital)from November 2022 to November 2024.Patients were categorized into symptomatic and asymptomatic CAS groups.General clinical data and laboratory test results were collected and compared between the two groups,including age,sex,body mass index,systolic and diastolic blood pressure(measured on the morning of procedure without antihypertensive medication intervention with patient at resting state for over 30 minutes),medical history(including hypertension,diabetes,atrial fibrillation,coronary heart disease,stroke,and transient ischemic attack),smoking history,alcohol consumption history,and fasting laboratory results obtained on the morning before procedure laboratory results(including,white blood cell count,red blood cell count,monocyte percentage,neutrophil percentage,lymphocyte percentage,platelet count,blood creatinine,blood glucose,international normalized ratio,D-dimer,total cholesterol,triglycerides,homocysteine,low-density lipoprotein cholesterol,and high-density lipoprotein cholesterol).Additionally,OCT image parameters were collected and compared between the two groups,including the minimum lumen diameter and minimum lumen area of the target lesion segment,the distal lumen diameter and area of the reference vessel(internal carotid artery),the percentage of lumen area stenosis([reference vessel lumen cross-sectional area-minimum lumen cross-sectional area]/reference vessel lumen cross-sectional area×100%),the lesion length,fibrous cap thickness,lipid arc,and the presence of fibrous plaques,calcified plaques,lipid plaques,white thrombus,cholesterol crystals,macrophage infiltration,microchannels,and plaque rupture.Variables with P＜0.05 from univariate analysis were included in the multivariate Logistic regression analysis to assess the influencing factors of symptomatic CAS.Results A total of 68 patients with CAS were enrolled,comprising 57males and 11females,aged 53 to 84 years with a mean age of(68±7)years.Among them,32 patients were categorized into the symptomatic CAS group and 36 into the asymptomatic CAS group.(1)Compared to the asymptomatic CAS group,patients in the symptomatic CAS group exhibited higher systolic blood pressure([150±23]mmHg vs.[138±21])mmHg,P=0.025).There were no statistically significant differences in general,clinical data,and laboratory test results between the two groups(all P＞0.05).The preoperative OCT imaging parameters comparison between the two groups of CAS patients revealed that the reference vessel distal lumen area was significantly smaller in the symptomatic CAS group([18.67±5.44]mm2 vs.[21.95±5.57]mm2,P=0.017),and the proportion of patients with white thrombus(40.62%[13/32]vs.13.89%[5/36],P=0.013)and microchannels(21.88%[7/32]vs.2.78%[1/36],P=0.014)were higher.(2)A multivariate Logistic regression analysis was conducted using systolic blood pressure,white thrombus,microchannels,and the reference vessel(internal carotid artery)distal lumen area as independent variables.The results indicated that high systolic blood pressure(OR,1.030,95%CI 1.002-1.060,P=0.038),and the presence of white thrombus(OR,3.956,95%CI 1.072-14.600,P=0.039)and microchannels(OR,13.850,95%CI 1.277-150.203,P=0.031)were independent risk factors for symptomatic CAS.Conclusions Compared to patients with asymptomatic CAS,those with symptomatic CAS exhibited higher preoperative(pre-carotid stenting)systolic blood pressure and a smaller distal lumen area of the reference vessel(internal carotid artery),as observed through OCT.Furthermore,a higher proportion of symptomatic CAS patients presented with white thrombus and microchannels.Preoperative systolic blood pressure,along with the presence of white thrombus and microchannels on OCT,are identified as independent risk factors for symptomatic CAS.The conclusions drawn from this study necessitate further validation through large-scale,multicenter,prospective research.

To investigate the association between neutrophil to lymphocyte ratio (NLR) andestimated glomerular filtration rate (eGFR) in patients with diabetes using large-scale data.

ObjectiveTo investigate the effect and molecular mechanism of exosomes derived from bone marrow mesenchymal stem cells（BMSC-exos） modified with Bushen Yisui capsule（BSYS）-containing serum on promoting the differentiation and maturation of OLN-93 oligodendrocytes by regulating miR-15b/Wnt signaling pathway. MethodsOLN-93 cells were divided into 5 groups， including the normal（NC） group， BMSC-exos group， BSYS-BMSC-exos group， BSYS-BMSC+LV-miR-15b-5p inhibitor-exos group， and BSYS-BMSC+LV-miR-15b-5p NC-exos group. DiR staining was used to observe the uptake of Exos by OLN-93 cells. The effective dosage of BSYS-BMSC-exos on OLN-93 cells was assessed by cell proliferation and activity assay（CCK-8）. Stable BMSCs lentiviral transfection strains were established to inhibit miR-15b-5p expression in both BMSCs and their exos， and transfection efficiency was verified by real-time fluorescent quantitative polymerase chain reaction（Real-time PCR） detection of miR-15b-5p. The expressions of 2′，3′-cyclic nucleotide 3′-phosphodiesterase（CNPase） and myelin proteolipid protein（PLP） in OLN-93 cells were detected by immunocytochemistry（ICC） and Western blot. The mRNA expressions of miR-15b-5p and Wnt3a in OLN-93 cells were detected by Real-time PCR， and the protein expression of Wnt3a was measured by Western blot. The expression levels of key molecules in the Wnt/β-catenin signaling pathway of OLN-93 cells， including glycogen synthase kinase（GSK）-3β， β-catenin， and T-cell specific transcription factor 4/transcription factor 7-like 2（TCF4/TCF7L2）， were measured by Real-time PCR and Western blot. ResultsDiR-labeled Exos were efficiently taken up by OLN-93 cells. The CCK-8 assay results indicated that 20 mg·L^-1 of BSYS-BMSC-exos exhibited the most significant effect in enhancing OLN-93 cell viability（P<0.01） and this dosage was selected for subsequent experiments. Following lentiviral transfection of BMSCs， Real-time PCR results revealed that miR-15b-5p was significantly suppressed in BMSCs（P<0.01）， and miR-15b-5p was also notably inhibited in BSYS-BMSC-exos（P<0.01）. ICC analysis further revealed an increase in the number of differentiated， mature CNPase and PLP-positive cells following BSYS-BMSC-exos treatment（P<0.01）. Western blot results demonstrated that the protein expression of CNPase and PLP was significantly enhanced with BSYS-BMSC-exos treatment（P<0.01）. Additionally， BSYS-BMSC-exos also increased the expression levels of miR-15b-5p and p-β-catenin proteins in OLN-93 cells， while decreased the mRNA and protein expressions of Wnt3a， as well as the mRNA expressions of β-catenin and TCF4/TCF7L2， and the protein expression level of p-GSK-3β（Ser9） was significantly reduced（P<0.05， P<0.01）. After the transfection of miR-15b-5p inhibitor into BSYS-BMSC-exos， the above effects were significantly diminished（P<0.05， P<0.01）. ConclusionBSYS-BMSC-exos facilitate the differentiation and maturation of OLN-93 cells， and its mechanism is related to the upregulation of miR-15b-5p in OLN-93 cells， which inhibits the expression of Wnt3a and thereby suppresses the Wnt signaling pathway.