OBJECTIVE To investigate the improvement effects and mechanism of Achyranthes bidentata total saponins （ABS） extract on vascular endothelial dysfunction in spontaneously hypertensive rat （SHR） based on cytochrome P450 4A （CYP4A）/20-hydroxyeicosatetetraenoic acid （20-HETE）/G protein-coupled receptor 75 （GPR75） axis. METHODS Ten Wistar- Kyoto rats were taken as the normal control group. Forty SHR were first stratified by systolic blood pressure and then， within each stratum， randomly assigned using a random-number table to the model group （MOD group）， captopril positive control group （CAP group， 10 mg/kg）， ABS low- and high-dose extract groups （ABS-L group， ABS-H group， 60 and 120 mg/kg）， with 10 rats in each group. Animals in each group were given the corresponding drug or equal volume of pure water by gavage， once a day， for 28 consecutive days. After the last administration， systolic blood pressure of rats was measured. The levels of vasoactive substances， inflammatory factors and oxidative stress indicators in serum were measured. The pathological changes of rat thoracic aorta were observed. The level of reactive oxygen species （ROS） in aortic tissue was analyzed. The expressions of endothelial nitric oxide synthase （eNOS）， CYP4A， GPR75， nuclear factor-κB p65 （NF-κB p65）， phosphorylated NF-κB p65， p22phox， and reduced nicotinamide adenine dinucleotide phosphate oxidase 4（NOX4） in thoracic aorta tissue were detected. RESULTS After 28 d of treatment， compared with MOD group， the systolic blood pressure of rats in the ABS-L and ABS-H groups decreased significantly. The levels of 20-HETE， angiotensin Ⅱ， interleukin-1β， interleukin-6， tumor necrosis factor-α， intercellular cell adhesion molecule-1 and malondialdehyde in serum were significantly reduced （P＜0.05 or P＜0.01）， while the levels of nitric oxide， superoxide dismutase， glutathione peroxidase and catalase were significantly increased （P＜0.05 or P＜0.01）. Intimal damage of thoracic aorta was reduced， and endothelial cell morphology was improved. The expressions of ROS， CYP4A， GPR75， p22phox， NOX4 and the phosphorylation level of NF-κB p65 protein in thoracic aorta were down-regulated or reduced （P＜0.05 or P＜0.01）， while the expression of eNOS was up-regulated （P＜0.05 or P＜0.01）. CONCLUSIONS ABS extract may alleviate the inflammatory response and oxidative stress in SHR effectively by down-regulating the expression of CYP4A， reducing the production of 20-HETE， inhibiting the activation of GPR75， and subsequently suppressing the activation of downstream NF-κB and NOX4， thereby improving hypertension-related vascular endothelial dysfunction.

OBJECTIVE To study the mechanism of action of Rehmannia glutinosa-medicated serum （RG） in regulating lipopolysaccharide （LPS）-induced polarization of BV2 microglia to interfere with neuroinflammation. METHODS An in vitro neuroinflammation model of BV2 cells induced by LPS was established. Cells were divided into control group， LPS group， 10%RG group， 20%RG group， BAY 11-7082 [nuclear factor kappa B （NF-κB） inhibitor] group， and 20%RG+BAY 11-7082 group. Except for the control group， cells in all other groups were pretreated with corresponding drugs for 12 h and then stimulated with LPS for 24 h. The morphology of cells in each group was observed， and the fluorescence intensity of ionized calcium binding adaptor molecule 1 （Iba-1）， inducible nitric oxide synthase （iNOS）， CD206， the mRNA expression of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， IL-1β， iNOS， IL-4， IL-10， transforming growth factor-β （TGF-β）， arginase-1 （Arg-1）， and the Toll-like receptor 4 （TLR4）/NF-κB/NOD-like receptor thermal protein domain associated protein 3 （NLRP3） signaling pathway-related protein expression were detected. RESULTS Compared with the control group， the LPS group showed significant changes in cell morphology， exhibiting a typical M1 activated morphology. The fluorescence intensity of Iba-1 and iNOS， the relative expression levels of TNF-α， IL-6， IL-1β， iNOS mRNA， the relative expression levels of TLR4， NLRP3， caspase-1 p20， IL-1β p17 protein， and the phosphorylation levels of NF-κB p65 and inhibitor of nuclear factor kappa B α were significantly increased （P＜0.05）. The fluorescence intensity of CD206 and the relative expression levels of IL-4， IL-10， TGF-β， and Arg-1 mRNA were significantly reduced （P＜0.05）. Compared with the LPS group， the changes in the above indicators in the cells of the 10%RG group， 20%RG group， BAY 11-7082 group， and 20%RG+BAY 11-7082 group were significantly reversed （P＜0.05）， and there was no statistically significant difference in the comparison of the last three groups （P＞0.05）. CONCLUSIONS RG can effectively inhibit the overall activation of microglia and correct their M1/M2 polarization imbalance， and its mechanism may be closely related to the inhibition of excessive activation of the TLR4/NF-κB/NLRP3 signaling pathway.

Objective:To study the correlation between osteoporosis and the joint of small articular process of lumbar vertebra,and the correlation between bone mineral density(BMD)and various parameters of small joint based on quantitative computed tomography(QCT),so as to provide scientific basis for formulating clinically treatment strategies.Methods:This study included 63 patients who admitted to orthopedics of The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine from December 2023 to March 2024 due to waist discomfort and lower limb pain.According to BMD standard of CT examination for lumbar vertebra,these patients were divided into normal BMD group(31 cases),osteopenia group(21 cases)and osteoporosis group(11 cases).All patients underwent CT scan on lumbar vertebra.The mode with body membrane were adopted to measure BMD,the area of left and right articular process,CT value,height after the scan was completed.Whether existed osteophytes,endplate inflammation and intervertebral disc herniation in each group were checked.Univariate Analysis of Variance(ANOVA)was employed to assess the differences among different BMD groups in age,gender,area of articular process,CT value and height.The Pathria grading system was adopted to assess the degeneration degree of intervertebral joint,and the Fisher's exact test was used to analyze the differences in degeneration scores of articular process among three groups.At the same time,the pairwise comparison between groups also was conducted.Spearman's rank correlation analysis was conducted to explore the correlation between BMD and the degeneration degree of intervertebral joint.Results:The BMD value of normal BMD group was(165.14±30.11)mg/cm3,and that of osteopenia group was(98.98±10.14)mg/cm3,and that of osteoporosis group was(58.62±18.73)mg/cm3.There was a statistically significant difference in BMD value among three groups(F=103.121,P＜0.001),and there was a statistically significant difference in BMD value between normal BMD group and osteopenia group as the result of pairwise comparison between groups(t=10.018,P＜0.001).There was statistically significant difference in BMD value between normal BMD group and osteoporosis group(t=12.989,P＜0.001),and there was statistically significant difference in BMD value between osteopenia group and osteoporosis group(t=4.641,P＜0.001).The areas of left and right upper articular process of normal BMD group were less than that of other two groups,and the differences of CT value and height of left and right upper articular process among three groups were significant(F=27.350,24.458,P＜0.05),respectively.The CT value of normal BMD group was higher than that of other two groups,and CT values of right upper articular process of osteopenia group was significantly lower than that of osteoporosis group,and the difference was statistical significance(t=2.191,P＜0.05).The heights of left and right upper articular processes of normal BMD group were lower than those of osteoporosis group,and the height of right upper articular process was lower than that of osteopenia group(t=2.331,-2.798,-2.618,P＜0.05).There was a negative correlation between osteoporosis degree and the degeneration of articular process joints(r=-0.745,P＜0.001).With the decreasing of BMD value,the degeneration of articular process joint gradually aggravated,and the ratios of osteophytes,endplate inflammation and intervertebral discs increased.Conclusion:There is a certain correlation between the osteoporosis and the degeneration of articular process joints of lumbar intervertebral disc.The ratios of osteophytes,endplate inflammation and intervertebral disc herniation increase,and both the area and height of the left and right articular process increase when the reduction of bone mass reaches to a serious degree.

OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

Insulin-like growth factor 2 (IGF2) is a critical endocrine mediator implicated in male reproductive physiology. To investigate the correlation between IGF2 protein levels and various aspects of male infertility, specifically focusing on sperm quality, inflammation, and DNA damage, a cohort of 320 male participants was recruited from the Women's Hospital, Zhejiang University School of Medicine (Hangzhou, China) between 1 st January 2024 and 1 st March 2024. The relationship between IGF2 protein concentrations and sperm parameters was assessed, and Spearman correlation and linear regression analysis were employed to evaluate the independent associations between IGF2 protein levels and risk factors for infertility. Enzyme-linked immunosorbent assay (ELISA) was used to measure IGF2 protein levels in seminal plasma, alongside markers of inflammation (tumor necrosis factor-alpha [TNF-α] and interleukin-1β [IL-1β]). The relationship between seminal plasma IGF2 protein levels and DNA damage marker phosphorylated histone H2AX (γ-H2AX) was also explored. Our findings reveal that IGF2 protein expression decreased notably in patients with asthenospermia and teratospermia. Correlation analysis revealed nuanced associations between IGF2 protein levels and specific sperm parameters, and low IGF2 protein concentrations correlated with increased inflammation and DNA damage in sperm. The observed correlations between IGF2 protein levels and specific sperm parameters, along with its connection to inflammation and DNA damage, underscore the importance of IGF2 in the broader context of male reproductive health. These findings lay the groundwork for future research and potential therapeutic interventions targeting IGF2-related pathways to enhance male fertility.
Humans ; Male ; Insulin-Like Growth Factor II/metabolism* ; Infertility, Male/genetics* ; DNA Damage ; Adult ; Inflammation/metabolism* ; Spermatozoa/metabolism* ; Semen Analysis ; Semen/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Histones/metabolism* ; Interleukin-1beta/metabolism*

OBJECTIVE To explore the clinical distribution and drug resistance of common species of pathogens iso-lated from a three-A hospital of Guangzhou from Jan.2017 to 2023 Dec.so as to provide bases for clinical diagno-sis and reasonable use of antibiotics.METHODS A total of 10,086 strains of aerobic bacteria were clinically isola-ted from the patients who were hospitalized in a three-A hospital of Guangzhou from 2017 to 2023.The constituent ratios of the common species of pathogens,specimen sources,distribution of departments and drug resistance rates to commonly used antibiotics were retrospectively analyzed.RESULTS Totally 10,086 strains of pathogens were isolated from the specimens of the hospitalized patients from 2017 to 2023.Klebsiella pneumoniae,Pseudo-monas aeruginosa,Escherichia coli,Acinetobacter baumannii and Staphylococcus aureus ranked the top 5 species of pathogens.The sputum,midstream urine and whole blood were the major specimen sources.The hospital-asso-ciated infection was highly prevalent in critical care medicine department,neurology department,geriatrics depart-ment,neurosurgery department and urology department.The result of drug resistance showed that the drug re-sistance rates of the K.pneumoniae and P.aeruginosa strains to various types of antibiotics showed upward trends(P＜0.05);the drug resistance rate of the A.baumannii strains to imipenem was decreased,while the drug resist-ance rates to most of the antibiotics were more than 45％.No gram-positive cocci strains that were resistant to vancomycin,teicoplanin or linezolid were found.CONCLUSIONS The common clinical isolates of pathogens are generally resistant to antibiotics.It is necessary for clinicians to attach great importance to the culture of pathogens and drug susceptibility testing and reasonably use antibiotics based on the result of drug susceptibility testing so as to reduce the occurrence and spread of drug-resistant strains.The hospital should strengthen the surveillance of drug resistance of bacteria so as to boost the clinical curative effect,standardize the management and use of antibi-otics and take effective measures to control of the hospital-associated infection.

Objective To explore the characteristics and influencing factors of drug-induced liver injury(DILI)associated with the postoperative use of propacetamol,and to provide guidance for rational clinical medication.Methods A retrospective analysis was conducted on hospitalized patients who underwent surgical treatment and were administered propacetamol from January 2022 to June 2024.Cases were screened based on established inclusion and exclusion criteria.Statistical analyses were performed on patients'demographic data,medication information,liver function indicators before and after medication,comorbid conditions,and concomitant medications to assess the incidence and influencing factors of propacetamol-related DILI.A multivariate Logistic regression analysis was conducted to identify related risk factors.Results A total of 7,579 patients were sampled,of which 2,114 met the inclusion criteria.Among them,531 patients(25.1%)experienced DILI,primarily presenting with abnormal liver function indicators.This included elevated alanine aminotransferase in 379 cases(71.4%),elevated aspartate aminotransferase in 197 cases(37.1%),elevated alkaline phosphatase in 209 cases(39.4%),and elevated total bilirubin in 92 cases(17.3%).Univariate analysis revealed that there were significant differences in gender,height,age,weight,body mass index(BMI),duration of propacetamol use,total medication dosage,concomitant use of hepatic-metabolized antibiotics,and history of liver disease between the DILI group and non-DILI group(P<0.05).Multivariate Logistic regression analysis showed that patient gender,BMI,total propacetamol dosage,liver-related diseases,and concomitant use of hepatic-metabolized antibiotics as independent risk factors for DILI(P<0.05).Conclusion The use of propacetamol for postoperative analgesia presents a risk for liver injury,and the risk is particularly pronounced in males,obesity,high-dose dosing,patients with underlying hepatic disease,and comorbid hepatic metabolism of antimicrobial drug use.It is recommended to strengthen the monitoring of liver function in clinical application,strictly control the dosage and duration of treatment,and avoid co-administration with hepatotoxic drugs to ensure the safety of drug use.

Neutrophils are important effector cells of innate immunity and play a key role in immune defense.When pathogens invade, neutrophils can kill microorganisms by phagocytosis and degradation through synthesis of reactive oxygen species, degranulation or release of antimicrobial peptides.In recent years, studies have discovered a new neutrophil defense mechanism that captures microorganisms by forming neutrophil extracellular traps (NETs). NETs are DNA networks that are released outside the cell after depolymerization and diffusion of chromatin in the nucleus of neutrophils.Different stimuli can activate different patterns of NETs formation, the essence of which is whether the release of neutrophil contents affects its own phagocytic function.NETs were initially thought to be a kind of mediator with bactericidal effect, which can wrap and remove bacteria and fungi in keratitis, preventing bacteria from ascending into the brain, but it will lead to irreversible damage to the cornea.At the same time, studies have found that NETs also have pro-inflammatory effects and play a role in the development of a variety of inflammatory eye diseases, including dry eye, diabetic retinopathy, glaucoma, and age-related macular degeneration, etc.Currently, more and more studies are focusing on the role of NETs in autoimmune eye diseases, that is, NETs can generate new antigens that are beneficial to autoimmune eye diseases, but also increase tissue damage.This review summarizes the related studies on NETs, focuses on describing the formation and role of NETs in ocular diseases, and provides new ideas for targeted treatment of ocular diseases.