1.Effects of Yangxin Tongmai Formula (养心通脉方) on Methylation Key Genes and the PERK/ATF4/CHOP Signaling Pathway in Myocardial Tissue of Coronary Heart Disease Model Rats with Blood Stasis Syndrome
Chun ZHANG ; Shumeng ZHANG ; Yan MAO ; Xing CHEN ; Huifang KUANG ; Yi YANG ; Lingli CHEN ; Jie LI
Journal of Traditional Chinese Medicine 2026;67(7):784-791
ObjectiveTo investigate the mechanism of Yangxin Tongmai Formula (养心通脉方, YTF) in trea-ting coronary heart disease with blood stasis syndrome based on DNA methylation. MethodsSeventy-two SD rats were randomly divided into a control group (n=12) and a modeling group (n=60). The modeling group was subjected to a high-fat diet, intragastric administration of vitamin D3, and subcutaneous injection of isoprenaline to establish the rat model of coronary heart disease with blood stasis syndrome. Forty-one successfully modeled rats were then randomly allocated into model group, YTF low-, medium-, and high-dose groups, and the atorvastatin calcium group, with 8 rats in each group and 1 rat reserved. The YTF low-, medium-, and high-dose groups received YTF at 6, 12, and 18 g/(kg·d) by gavage, respectively. The atorvastatin calcium group received atorvastatin calcium tablets at 1.8 mg/(kg·d) by gavage. The control group and the model group received 0.9% sodium chloride injection at 4 ml/(kg·d) by gavage. All administrations were performed once daily for 3 weeks. Twenty-four hours after the last administration, serum lipid levels including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), myocardial enzymes including cardiac troponin T (cTnT), creatine kinase MB (CK-MB), and lactate dehydrogenase (LDH), and inflammatory factors including interleukin-1β (IL-1β) and interleukin-10 (IL-10) were detected by ELISA. Pathological changes in myocardial tissue were observed via HE staining. Whole blood DNA methylation sequencing was used to analyze differential methylation gene expression among the control group, model group, and YTF high-dose group. Western Blotting was used to verify the protein levels of the key genes and downstream signaling pathways. ResultsCompared to the control group, the model group showed increased levels of TC, TG, LDL-C, cTnT, CK-MB, LDH, and IL-1β, along with decreased levels of HDL-C and IL-10 (P<0.05 or P<0.01). Compared to the model group, all treatment groups exhibited decreased levels of TC, LDL-C, CK-MB, and LDH, along with increased IL-10 levels. Among these, the high-dose YTF group demonstrated superior efficacy in reducing cTnT levels compared to the other TCM groups (P<0.05 or P<0.01). HE staining indicated that the YTF high-dose group ameliorated myocardial cell swelling, disordered arrangement, pyknosis, and disappearance of nuclei, thereby reducing myocardial cell damage. Whole blood DNA methylation sequencing identified 240 differentially methylated genes shared by the control group, model group, and YTF high-dose group, including 109 hypermethylated and 131 hypomethylated genes; eif2ak3 was identified as a key differentially methylated gene. Compared to the control group, the model group exhibited increased protein levels of eukaryotic translation initiation factor 2 alpha kinase 3 (eIf2ak3), phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and Bax, along with a decreased level of B-cell lymphoma-2 (Bcl-2) protein (P<0.05 or P<0.01). Compared to the model group, the YTF high-dose group showed decreased protein levels of eIf2ak3, p-PERK, ATF4, CHOP, and Bax, and an increased level of Bcl-2 protein (P<0.05 or P<0.01). ConclusionYTF may regulate key differentially methylated genes such as eIf2ak3 and the PERK/ATF4/CHOP signaling pathway, thereby inhibiting endoplasmic reticulum stress, reducing myocardial cell apoptosis, and exerting therapeutic effects in coronary heart disease blood stasis syndrome.
2.Risk factors for decompensated liver cirrhosis and the construction of a nomogram prediction model
Yuanyuan LIANG ; Huifang QU ; Xiyue WANG ; Yan WANG ; Hezhao ZHANG ; Jun XU
Journal of Clinical Hepatology 2026;42(6):1327-1334
ObjectiveTo investigate the independent risk factors for decompensation in patients with liver cirrhosis, to construct a nomogram-based risk assessment model, and to assess its risk assessment performance and clinical value by comparing it with Model for End-Stage Liver Disease (MELD), MELD combined with serum sodium concentration (MELD-Na), and MELD 3.0 scoring system. MethodsA retrospective analysis was performed for 514 patients with liver cirrhosis who attended The First Hospital of Shanxi Medical University from January 2020 to May 2025, and related data were collected, including demographic data and laboratory markers. According to the presence or absence of decompensation, the patients were divided into compensation group with 275 patients and decompensation group with 239 patients. The Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The least absolute shrinkage and selection operator regression analysis was used for screening of variables, and the multivariate logistic regression analysis was used to identify independent risk factors for decompensated liver cirrhosis and construct a nomogram model. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis were used to assess the discriminatory ability, calibration, and net clinical benefit of the model. ResultsThe multivariate logistic regression analysis showed that low hemoglobin (odds ratio [OR]=0.984, 95% confidence interval [CI]: 0.969 — 0.999, P<0.05), low lymphocytes (OR=0.564, 95%CI: 0.383 — 0.830, P<0.05), high international normalized ratio (OR=3.131, 95%CI: 1.242 — 7.891, P<0.05), and low serum sodium (OR=0.922, 95%CI: 0.872 — 0.975, P<0.05) were independent risk factors for decompensation events in patients with liver cirrhosis. Construct the prediction model equation: Logit(P)=intercept value-0.016×hemoglobin-0.573×lymphocytes+1.141×INR-0.081×serum sodium. The nomogram constructed based on these factors had a good discriminatory ability, with an area under the ROC curve (AUC) of 0.787, a specificity of 77.8%, and a sensitivity of 67.4%, and it had significantly better predictive performance than MELD score (AUC=0.718), MELD-Na score (AUC=0.719), and MELD 3.0 score (AUC=0.725). The calibration curve showed good consistency between the probability of risk assessed by the model and the observed probability. The decision curve analysis showed that compared with the MELD-based scores, this model provided higher net clinical benefit across a wide range of risk thresholds. ConclusionThis study successfully constructed and validated a nomogram risk assessment model incorporating hemoglobin, international normalized ratio, lymphocytes, and serum sodium. This model has good clinical practicability and can help to achieve early identification of high-risk patients with decompensated liver cirrhosis and optimize intervention strategies in clinical practice.
3.Clinical diagnostic value of MRI combined with serum CYR61 and CXCL1 for acute stroke
Juan TIAN ; Huifang WANG ; Weijing ZHANG
Chinese Journal of Radiological Health 2026;35(3):394-400
Objective To evaluate the clinical utility of combining magnetic resonance imaging (MRI) findings with serum levels of cysteine-rich protein 61 (CYR61) and C-X-C motif chemokine ligand 1 (CXCL1) for early identification of acute stroke. Methods The study was conducted 205 patients with suspected acute stroke admitted to the neurology department of our hospital between April 2021 and April 2024. Based on brain CT imaging and clinical diagnosis, 119 patients were acute stroke group and 86 to non-acute stroke group. All patients underwent MRI examination. Serum levels of CYR61 and CXCL1 were measured. Receiver operating characteristic (ROC) curves were generated to assess diagnostic value, and Kappa tests were used to performed to evaluate the consistency. Results Serum level of CYR61 and CXCL1were significantly higher in the acute stroke group than in the non-acute stroke group (P<0.05). The area under the ROC curve (AUC) for serum CYR61 in diagnosing acute stroke was 0.867 (95%CI: 0.819-0.915), with diagnostic threshold of 6.02 μg/L; for CXCL1, the AUC was 0.818 (95%CI: 0.762-0.875), with a threshold of 1.28 ng/mL. The Kappa values for agreement between MRI, serum CYR61, and CXCL1 clinical diagnosis results were 0.766, 0.586, and 0.528, respectively, the Kappa value for the consistency between the combination of the three with clinical diagnosis results was 0.920 (P<0.05). The sensitivity, negative predictive value, and accuracy of the combination of MRI, serum CYR61, and CXCL1 were obviously higher than that of the individual diagnosis, and the specificity and positive predictive value were obviously higher than that of the individual diagnosis of serum CYR61 and CXCL1 (P<0.05). Conclusion The clinical diagnostic accuracy of MRI combined with serum CYR61 and CXCL1 in the diagnosis of acute stroke is high, the combined diagnosis is obviously better than the individual diagnosis of each indicator.
4.Effects of the Bushen Zhuyun Formula(补肾助孕方)on JAK2/STAT3 Signaling Pathway and Macrophage Polarization in Uterine Tissues of Mice with Embryo Implantation Failure
Yunan LIU ; Huifang ZHOU ; Chen WANG ; Mengwen ZHANG ; Ping CHEN
Journal of Traditional Chinese Medicine 2026;67(16):1767-1774
ObjectiveTo explore the effect of Bushen Zhuyun Formula(补肾助孕方, BZF) on macrophage pola-rization in mouse uterine tissue with embryo implantation failure based on the janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) signaling pathway. MethodsFifty female and 25 male C57BL/6 mice were randomly divided into five groups including blank group, model group, low- and high-dose BZF groups, and dydrogesterone group, with 10 female and 5 male mice in each group. Except for the blank group, female mice in the estrous phase were subjected to superovulation induction. At 18:00 on the same day, female mice were co-housed with male mice at a ratio of 2∶1. The presence of sperm in vaginal exfoliated cells was examined on the following day, which was designated as gestational day 1 (GD1). On GD4, an oil-based mifepristone solution was subcutaneously injected into the neck region of female mice to establish an embryo implantation dysfunction model. Beginning on GD1, mice in the low- and high-dose BZF groups were given 11.18 and 22.36 g/kg of the BZF solution by gavage, respectively. The dydrogesterone group was given 2.6 mg/kg of dydrogesterone solution by gavage. The blank group and the model group were given 10 g/kg of normal saline by gavage once daily. Interventions were administered once a day until GD4. On GD5, uterine tissues were collected, and HE staining was performed to evaluate endometrial morphology, endometrial thickness, and glandular number in female mice. The proportions of M1 and M2 macrophages in uterine tissues were detected by flow cytometry, and the levels of transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) in uterine tissue were measured by ELISA. The protein expression levels of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3) in uterine tissue were detected by western blotting, and the mRNA expressions of JAK2, STAT3, IL-10, and TGF-β1 in uterine tissue was detected by real-time quantitative PCR. ResultsCompared to the blank group, the model group exhibited smaller and straighter endometrial glands, denser stroma, and fewer blood vessels, with reduced endometrial thickness and decreased glandular numbers. The proportion of M1 macrophages in uterine tissue increased, while the proportion of M2 macrophages and the levels of IL-10 and TGF-β1 decreased. The protein expression levels of JAK2, p-JAK2, STAT3, and p-STAT3, as well as the p-JAK2/JAK2 and p-STAT3/STAT3 ratios, were reduced. The mRNA expressions of JAK2, STAT3, IL-10, and TGF-β1 also decreased (P<0.05). Compared to the model group, the above indicators were improved in the low- and high-dose BZF groups, while some indicators were improved in the dydrogesterone group (P<0.05). Compared to the dydrogesterone group and the low-dose BZF group, the high-dose BZF group showed superior effects in improving endometrial morphology, endometrial thickness, glandular number, the proportion of M1 macrophages in uterine tissues, TGF-β1 levels, JAK2, p-JAK2, and p-STAT3 protein expression levels, the p-STAT3/STAT3 and p-JAK2/JAK2 ratios, as well as JAK2, IL-10, and TGF-β1 mRNA expressions (P<0.05). ConclusionBZF can improve the morphology of the endometrium during implantation in mice with embryo implantation failure, which may be related to specific regulation of the JAK2/STAT3 signaling pathway, modulation of macrophage polarization, and promotion of anti-inflammatory cytokine expression.
5.Clinical analysis of treatment free remission outcomes after discontinuation of tyrosine kinase inhibitors in childhood chronic myeloid leukemia
Huifang ZHAO ; Lixin LIANG ; Yingling ZU ; Chunlei ZHANG ; Juan WANG ; Xianwei WANG ; Yongping SONG ; Xudong WEI ; Yanli ZHANG
Chinese Journal of Pediatrics 2025;63(3):272-277
Objective:To analyze the treatment-free remission (TFR) outcomes after discontinuation of tyrosine kinase inhibitor (TKI) in children with chronic myeloid leukemia (CML).Methods:In this retrospective cohort study, clinical data of 14 chronic phase CML children aged <18 years who had achieved stable deep molecular response (DMR) for ≥ 2 years after standardized treatment with TKI and had a strong desire to discontinue TKI at Henan Cancer Hospital from September 30, 2016 to January 30, 2022 were collected retrospectively. According to the different TFR outcomes after discontinuation of TKI, patients were divided into loss of major molecular response (MMR) group and without loss of MMR group, differences in clinical characteristics between the two groups of children were analyzed using Mann-Whitney U test and Fisher exact test. Results:Out of 14 children with TKI discontinuation, 7 were male and 7 were female. The age at diagnosis was 14.0 (4.8, 17.0) years, and the age at TKI discontinuation was 22.0 (12.5, 27.0) years. Among them, 8 children were treated with imatinib prior to TKI discontinuation and 6 children were treated with second-line substitution of the second-generation TKI nilotinib or dasatinib prior to TKI discontinuation. The follow-up time was 37.0 (27.8, 47.5) months, and 7 cases lost MMR at the time of discontinuation of 3.0 (2.0, 11.0) months. Eight children gained TFR at 6 months, 7 children gained TFR at 12 and 24 months. Amongst the 6 children who received second-generation TKI prior to TKI discontinuation, 2 children lost MMR at 3 and 11 months and 4 children gained TFR, among the 8 children who discontinued imatinib, 5 children lost MMR at the time 3.0 (2.0, 9.0) months and 3 children gained TFR. The age at diagnosis and TKI discontinuation, the time from TKI treatment to the acquisition of DMR, the duration of TKI treatment before TKI discontinuation, the duration of DMR before TKI discontinuation, and the number of children treated with second-generation TKI were not statistically different between the 7 children in the group that did not lose the MMR and the 7 children in the group that lost the MMR (all P>0.05) . All the 7 children with confirmed loss of MMR immediately restarted TKI therapy, and all regained DMR after 2.0 (2.0, 11.0) months of therapy. None of the children had disease progression. After TKI discontinued, only 1 child had mild bone pain, which could be relieved by oral antipyretic analgesic drugs. Conclusions:Children with CML who have achieved a durable stable DMR for≥2 years on TKI therapy can discontinue the TKI and obtain TFR. Both the longer duration of TKI therapy, the longer duration of DMR and the use of second-generation TKI therapy before TKI discontinuation, may allow more children with CML who are expecting TKI discontinuation to have access to TFR.
6.Expert consensus on clinical treatment of acute radiation syndrome from external irradiation
Li LIANG ; Long YUAN ; Changlin YU ; Qingjie LIU ; Yulong LIU ; Wenfeng YANG ; Jin WANG ; Weixu HUANG ; Ying LIU ; Cuiping LEI ; Huifang CHEN ; Ximing FU ; Baoshan CAO ; Mopei WANG ; Zhaohui ZHANG ; Yu XIAO ; Yamei CHEN ; Quanfu SUN
Chinese Journal of Radiological Medicine and Protection 2025;45(9):827-839
China emerges as a major country in nuclear energy development and the application of nuclear and radiologic technology. The diagnosis and treatment of acute radiation syndrom (ARS) caused by external irradiation represent a core function in the country′s medical rescue of nuclear and radiological emergencies. Clinically, ARS manifests hematopoietic, gastrointestinal, cutaneous, and central nervous system syndromes, with specific clinical manifestations, signs, severity, and prognosis strongly correlated with radiation dose. China has established a number of national and provincial centers for treating radiation-induced damage. Nevertheless, most medical staff have limited experience in ARS treatment. This consensus presents a summary of recent experience in treating ARS of China. In combination with recommendations from international organizations such as the World Health Organization (WHO), this consensus proposes key evidence of critical clinical issues of ARS, covering all links in the rescue of external irradiation-induced ARS. Initially, clinical diagnosis, syndromes, and severe degrees should be determined based on clinical symptoms and dose estimates. It is necessary to normalize clinical treatment measures for hematopoietic recovery, gastrointestinal injury treatment, infection control, symptomatic treatment, and multi-organ function preservation. To this end, this consensus offers cautions. This consensus provides principles of treatment with traditional Chinese medicine, psychological intervention, and follow-up. Additionally, it highlights multidisciplinary collaboration. It is recommended that this consensus be applied in relevant treatment centers.
7.Epidemiological Characteristics of Female Breast Cancer in Henan Province in 2020 and Its Temporal Trends from 2010 to 2020
Shucun MAO ; Qiong CHEN ; Shuzheng LIU ; Hongwei LIU ; Yin LIU ; Huifang XU ; Xiaoli GUO ; Hong WANG ; Xiaoyang WANG ; Chenxi FENG ; Ning ZHANG ; Shaokai ZHANG
China Cancer 2025;34(7):507-512
[Purpose]To analyze the incidence and mortality rates of female breast cancer in Henan Province in 2020 and the trends from 2010 to 2020.[Methods]Breast cancer incidence and mor-tality data stratified by urban and rural areas and age groups were collected from Henan Provincial tumor registry,and the province's household population statistics were used.The crude incidence/mortality rate,age-standardized incidence/mortality rate by Chinese standard population(ASIRC/ASMRC)and world standard population(ASIRW/ASMRW),cumulative rate(0~74 year old)were calculated.The annual percentage change(APC),average annual percentage change(AAPC)and 95%confidence interval(CI)were calculated using Joinpoint software to analyze the trends of the incidence and mortality from 2010 to 2020.[Results]In 2020,24 744 new cases and 4 989 deaths of female breast cancer were documented in Henan Province,with a crude incidence rate of 46.96/105,ASIRC of 38.43/105 and ASIRW of 35.71/105;a crude mortality rate of 9.47/105,ASMRC of 6.80/105 and ASMRW of 6.72/105,respectively.The above indicators in urban areas were signifi-cantly higher than those in rural areas.The highest incidence was observed in the age group of 50~54 years old,while the highest mortality reached in the age group of 85 years old and above.From 2010 to 2020,the overall incidence of female breast cancer showed a slow upward trend(AAPC=2.09%,95%CI:0.62%~3.58%,P=0.010),while the mortality rate exhibited a signif-icant downward trend(AAPC=-3.49%,95%CI:-5.62%~-1.30%,P=0.005).[Conclusion]The incidence and mortality rates of female breast cancer in Henan Province are still at a high level,and corresponding preventive measures and control strategies are needed to effectively reduce the health hazards of breast cancer to women.
8.Impact of GA/ALB on the prognosis of heart failure in patients with coronary heart disease
Chenchen LIU ; Haoran WANG ; Huifang XING ; Hongli LI ; Zhihong GUO ; Lele ZHANG ; Dong YANG ; Hongping LIANG
International Journal of Laboratory Medicine 2025;46(19):2311-2318
Objective To explore the potential clinical value of the ratio of glycated albumin to albumin(GA/ALB)in the occurrence of heart failure(HF)among patients with coronary atherosclerotic heart disease(CHD).Methods A total of 337 CHD patients admitted to the Department of Cardiology in Shanxi Provincial People's Hospital from July 2023 to June 2024 were selected in this study.CHD patients were divided into HF group and non-HF group based on whether they progressed to HF.The clinical data and laboratory parame-ters of the two groups were compared.Restricted cubic spline curve was used to analyze the relationship be-tween GA/ALB levels and the risk of HF in CHD patients.Receiver operating characteristic curve was applied to evaluate the diagnostic efficacy of GA/ALB,GA,platelet to lymphocyte ratio(PLR),and monocyte to lym-phocyte ratio(MLR)in CHD patients with the occurrence of HF.Logistic regression was used to explore the relationship between serum GA/ALB levels and the risk of CHD patients occurrence of HF,and to analyze the degree of influence and stability of subgroup variables on results.Results There were statistically significant differences in GA/ALB,GA,PLR,MLR,and other indicators between the HF group and the non-HF group in CHD patients(P<0.05).A non-linear relationship was observed between GA/ALB levels and the risk of HF in CHD patients.When the value of GA/ALB multiplied by 10 was less than 5.751,the risk of HF in CHD pa-tients increased with the increase of GA/ALB levels(P<0.001).GA/ALB was an effective predictor for HF occurrence in CHD patients.Multivariable Logistic regression model showed that GA/ALB was an independ-ent risk factor for CHD patients with occurrence of HF.Subgroup analysis also confirmed the stability of GA/ALB in predicting the occurrence of HF in CHD patients.Conclusion GA/ALB is an independent risk factor for the occurrence of HF in CHD patients,and monitoring GA/ALB levels provides predictive value for the oc-currence of HF in these patients.
9.Clinical features of benign paroxysmal positional vertigo in children.
Jing ZHANG ; Ying GUO ; Jiao ZHANG ; Juan SU ; Mingxin WANG ; Geng ZHANG ; Huifang ZHOU ; Qiuju WANG
Journal of Clinical Otorhinolaryngology Head and Neck Surgery 2025;39(3):243-249
Objective:To explore relevant factors to accurately diagnose BPPV in vertigo children. Methods:A retrospective study was conducted on the proportion of BPPV in children(<18 years) with vertigo who visited the Hearing and Vertigo Diagnosis and Treatment Center of Tianjin Medical University General Hospital from September 2017 to August 2023. The clinical characteristics of BPPV children, including general demographics, medical history, first visit department, comorbidities, canal involvement, response to treatment, and incidence of recurrence, were analyzed. Data analysis was conducted using SPSS 25.0 software. Results:BPPV was diagnosed in 22.8% of patients seen for vertigo during the study period. There are differences in the proportion of BPPV diagnosis among children with dizziness in different age groups(P<0.05), and the diagnosis of BPPV in the 7-12-year-old group has a longer disease course than in the 13-17-year-old group(P<0.05). 72.3%(47/65) of patients or their families were able to provide a typical history of positional vertigo. 49.2%(32/65) of BPPV patients had comorbidities, and there were differences in the proportion of comorbidities among different age groups of BPPV patients(P<0.05). With the progress of study, the proportion of BPPV in children with vertigo has shown an upward trend, and the proportion of children with otolaryngology as the first diagnosis department has also increased(P<0.05). The proportion of horizontal semicircular canals in children with BPPV has increased. All BPPV patients underwent canalith repositioning maneuvers, with good treatment outcomes and a recurrence rate of 12.3%(8/65). The recurrence rate in the group of BPPV patients with comorbidities was 21.9%, which was higher than that in the group without comorbidities(P<0.05). Conclusion:Childhood BPPV has clinical characteristics such as unclear medical history, high proportion of comorbidities, easy recurrence in BPPV children with comorbidities and high proportion of horizontal semicircular canal involvement. For children diagnosed with other vertigo diseases, do not ignore the BPPV diagnostic test. It is recommended to perform routine position tests on children with vertigo if conditions permit to reduce missed diagnosis of BPPV in children.
Humans
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Benign Paroxysmal Positional Vertigo/diagnosis*
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Child
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Retrospective Studies
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Adolescent
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Female
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Male
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Recurrence
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Vertigo/diagnosis*
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Comorbidity
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Child, Preschool
10.Modulating active targeting nanoparticle design according to tumor progressions.
Huifang NIE ; Rong HUANG ; Guangwei JIANG ; Wenshuai LI ; Lan YANG ; Meng ZHANG ; Min QIAN ; Wei GUO ; Tao YE ; Rongqin HUANG
Acta Pharmaceutica Sinica B 2025;15(2):1143-1158
Targeting drug delivery systems mediated by nanoparticles has shown great potential in the diagnosis and treatment of cancer. However, influences of different tumor progressions on the accumulation of nanoparticles, especially the ligand-modified active targeting nanoparticles are seldom exploited. In this work, the accumulation and penetration of RGD-modified gold nanoparticles (active AuNPs) with different sizes were investigated in orthotopic breast cancer with different tumor progressions. The results showed that the smallest active AuNPs had better accumulation and permeation effects in early tumor tissues with the relatively looser extracellular matrix, larger gaps, lower interstitial fluid pressure, and less receptor expression, which was due to size effects. However, the larger active AuNPs had better accumulation and penetration effects in late tumor tissues with highly expressed target receptors integrin α v β 3 because of the multivalent interactions between larger active nanoparticles and integrin α v β 3. In the midterm, tumor accumulation of active AuNPs was equally influenced by size effects and multivalent interactions. Therefore, RGD-modified nanoparticles with sizes of 7 and 90 nm accumulated more in tumors. This study will guide a rational design of active targeting nanoparticles for enhancing the diagnosis and treatment of tumors based on their progressions.

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