Background Breast cancer is one of the most common malignant tumors among women worldwide. The occurrence of breast cancer is related to multiple factors, including genetics, hormone levels, environmental pollution, and lifestyle. In recent years, more and more studies have begun to focus on the impact of environmental pollutants on breast cancer, but relevant research in China is still relatively limited. Objective To evaluate the association between phthalate exposure and the risk of breast cancer in adult women. Methods Data were extracted from the National Health and Nutrition Examination Survey (NHANES) 2015–2023. Participants were categorized into breast cancer cases and non-cancer controls based on Medical Conditions Questionnaire. Urine samples from included participants were analyzed using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) to measure twelve phthalate metabolites: mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), monoisobutyl phthalate (MiBP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), etc. Logistic regression was used to investigate the association between phthalate exposure and breast cancer. Multiple comparisons were adjusted using the Bonferroni correction. Weighted quantile sum (WQS) regression was applied to assess the effects of mixed phthalate exposure. Sensitivity analyses were conducted including Bootstrap resampling, extreme value exclusion, and propensity score matching (PSM). Restricted cubic spline models were constructed to characterize potential dose-response relationships. Results A total of 1486 adult female participants were included, comprising 89 breast cancer cases. Levels of MECPP, MEHHP, MiBP, and MEOHP metabolites were significantly higher in the breast cancer cases compared to the controls (P<0.05). The logistic regression results showed that MECPP (OR=1.011, 95%CI: 1.002, 1.020) and MiBP (OR=1.020, 95%CI: 1.009, 1.030) were independent risk factors for breast cancer. After Bonferroni correction, the association between MiBP and breast cancer remained statistically significant (P<0.001). The WQS regression model adjusted for selected covariates showed that the combined phthalate exposure was associated with an increased breast cancer risk (OR=1.421, 95%CI: 1.183, 1.714, P<0.001). The mixed exposure analysis revealed that MiBP (weight=0.38), MECPP (weight=0.22), and MEOHP (weight=0.15) contributed 75% of the cumulative weight, highlighting their dominant influence on the association between phthalate mixtures and disease risk. The MiBP-breast cancer association remained robust across sensitivity analyses. Dose-response modeling indicated linear trends for both MECPP and MiBP (P_nonlinearity>0.05), with no evidence of non-linear associations. Conclusion High-level phthalate exposure is significantly associated with an increased risk of breast cancer in adult women. Among the metabolites studied, MiBP is identified as the most robust risk factor and MECPP also demonstrates a notable association. Furthermore, our findings suggest that phthalate mixtures may exert synergistic effects, collectively elevating breast cancer risk.

Objective Zinc finger protein 335 (Zfp335) plays a crucial role in the early development of thymic T cells and the differentiation of peripheral T cell subpopulations. The objective of this study is to investigate the role and underlying mechanisms of Zfp335 in the regulation of regulatory T cell (Treg) within tumor immunity. Methods The Zfp335 gene was specifically knocked out in Treg using tamoxifen (Zfp335^fl/fl FOXP3^creERT2), and the MC38 tumor model was established. On the 7th day after tumor inoculation, tumor size was observed and measured. Tumor size was monitored and recorded daily starting from day 7 post-inoculation. On day 12, tumors were harvested, and the proportions of CD4⁺ T cells, CD8⁺ T cells, and Treg were analyzed by flow cytometry. Additionally, the mitochondrial function of effector regulatory T cell (eTreg) was assessed. Results From day 10 post-tumor inoculation, tumor volume in the Zfp335^CKO group was significantly reduced compared to that of the wild-type (WT) group. Furthermore, the infiltration of CD4⁺ and CD8⁺ T cells, along with their respective effector cells, was significantly higher in the Zfp335^CKO group than in the WT group. The proportions of CD4⁺ and CD8⁺ T cells producing interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were also significantly increased in the Zfp335^CKO group compared to that of the WT group. In addition, the percentage of CD8⁺ T cells secreting granzyme B (GzmB) was significantly higher in the Zfp335^CKO group than that in the WT group. In contrast, the proportion of Treg and inducible T cell co-stimulator (ICOS)⁺ Treg in the Zfp335^CKO group was significantly lower than that in the WT group. Finally, the expression level of Mitotracker Deep Red in eTreg from the Zfp335^CKO group was significantly reduced compared to that in the WT group. Conclusion During tumorigenesis, the specific deletion of Zfp335 impairs Treg activation, which is related to decreased mitochondrial function in eTreg. In Zfp335^CKO mice. Tumors exhibit increased infiltration of effector T cells, accompanied by elevated levels of cytotoxic cytokines, ultimately enhancing resistance to tumor progression.
Animals ; T-Lymphocytes, Regulatory/metabolism* ; Mice ; CD8-Positive T-Lymphocytes/immunology* ; Neoplasms/genetics* ; Cell Line, Tumor ; Mice, Inbred C57BL ; Mice, Knockout ; DNA-Binding Proteins/genetics* ; Female

Objective:To investigate the difference in brain activity intensity between methamphetamine (MA) dependent patients (MA group) and healthy controls (control group) using fractional amplitude of low-frequency fluctuation (fALFF), and to establish a classification model between these two groups using support vector machine (SVM).Methods:From February 2014 to October 2019, a total of 46 male MA-dependent patients and 46 male healthy controls were recruited from the Affiliated Kangning Hospital of Ningbo University. The study collected resting-state functional magnetic resonance imaging (rs-fMRI) data and analyzed the differences in brain functional activity between the two groups. This analysis was conducted using both static and dynamic fractional amplitude of low-frequency fluctuations (d-fALFF). Additionally, the study examined the correlation between fALFF/d-fALFF values in specific brain regions and the total scores, as well as each factor score, of the Brief Psychiatric Rating Scale (BPRS). Furthermore, the relationship between fALFF/d-fALFF values and the age of first use and total dose of MA in the MA group was investigated. Finally, the fALFF map and d-fALFF map of brain regions with significant differences between groups were used as features for constructing classification.Results:Compared to the healthy control group, those dependent on MA showed significantly increased fALFF mainly in the nucleus accumbens, caudate nucleus, thalamus, and amygdala nucleus( t=-5.21--2.72, all P<0.05). The MA group exhibited decreased fALFF in the superior frontal gyrus, middle frontal gyrus, orbital gyrus, and cingulate gyrus( t=3.59-5.00, all P<0.05). Most of the brain regions with decreased d-fALFF overlapped with those exhibiting decreased fALFF( t=3.33-4.87, all P<0.05). The results of the correlation analysis showed that the fALFF value of the right nucleus accumbens was positively correlated with the age of first use of MA ( r=0.537, P<0.001). There is no significant relationship between the abnormal fALFF and d-fALFF values in the MA group and the total scores and each factor scores of BPRS, as well as the total dose of MA taken (after removing outliers). Based on fALFF and d-fALFF values, the SVM classifier achieved accuracies of 90.33%±6.89% and 71.56%±7.80%, respectively. Conclusions:There are significant abnormalities in the low-frequency fluctuation of the resting brain in patients dependent on MA. These abnormalities reflect the rigidity of prefrontal cortex activity, functional impairment, and dysfunction of the anti-reward system. These factors may be one of the causes for MA dependent behavior and repeated episodes. In addition, the fALFF values may be helpful for distinguishing MA dependent individuals from the control group.

BACKGROUND:Marine traditional Chinese medicine offers a potentially effective and less adverse treatment for osteoporosis.OBJECTIVE:To explore the pharmacological regulations and procedures of traditional Chinese medicine in treating osteoporosis through data mining and network pharmacology techniques.METHODS:Data mining and network pharmacology methods were used to study the medication pattern and mechanism of marine Chinese medicine patented prescriptions approved by China National Intellectual Property Administration for the treatment of osteoporosis,and special attention was paid to the core Chinese medicine constituents of these prescriptions.The core constituents of the compound drug group composed of oyster-Dipsacus asper-epimedium were comprehensively identified and analyzed by using ultra-high-performance liquid chromatography tandem mass spectrometry.RESULTS AND CONCLUSION:(1)We collected 381 authorized compound patents for the treatment of osteoporosis from the database inception to April 1,2024.Among these,48 patent groups utilized marine traditional Chinese medicine.These prescriptions contained 183 Chinese herbal medicines,of which 13 marine traditional Chinese medicines were used 574 times in total,and the number of flavors used in a single patented formula ranged from 2 to 41.(2)Oyster was the most frequently used marine ingredient,while Dipsacus asper,epimedium,Rehmannia glutinosa,Eucommia ulmoides Oliv.were the most frequent non-marine components.Association rule analysis identified oyster,Dipsacus asper,and epimedium as the core drug group.Network pharmacology analysis revealed that the core targets of this group for the treatment of osteoporosis included ALB,AKT1,TP53,PPARG,and SRC.Sitosterol,liquiritigenin,japonine,luteolin,and kaempferol were identified as the core components within the marine traditional Chinese medicine prescriptions.(3)The GO and KEGFG enrichment analyses suggested a potential association between the mechanism of the core drug group and the rap1/mapk signaling pathway in the treatment of osteoporosis.(4)The molecular docking verified the beneficial interactions between core components and core targets.(5)The ultra-high-performance liquid chromatography tandem mass spectrometry analysis of the compound medicine confirmed the presence of luteolin,sitosterol,kaempferol,and other components,aligning with the drug components identified by network pharmacology.Quantitative analysis indicated that flavonoids,terpenes,and alkaloids constituted a significant proportion of the compound medicine's components.

OBJECTIVE To observe the effect of acupuncture combined with a modified Zhengan Xifeng Decoction on the early clinical symptoms and oxidative stress status of patients with hypertensive intracerebral hemorrhage(HICH)of liver-kidney yin defi-ciency syndrome.METHODS A total of 60 patients with hypertensive intracerebral hemorrhage(liver-kidney yin deficiency syn-drome)who successfully received 24-hour acute-phase treatment at the Department of Neurosurgery,Acupuncture and Rehabilitation Department,and wards of Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine(Kunshan Traditional Chinese Medi-cine Hospital)from July 2021 to January 2023 were recruited.A randomization table generated by SPSS 22.0 software was used to di-vide the patients into a control group and an observation group,with 30 patients in each group.The control group received symptomatic treatment,conventional rehabilitation training,and modified Zhengan Xifeng Decoction,while the observation group received additional acupuncture treatment on the basis of the control group.The treatment course was 1 month for both groups.Clinical effective rate,TCM syndrome scores,motor and neurological function scores[Activity of Daily Living(ADL)scale,National Institutes of Health Stroke Scale(NIHSS),Modified Ashworth Scale(MAS),Simplified Fugl-Meyer Assessment(FMA)scale],improvement in hematoma lesions,Fraction anisotropy(FA)ratio(rFA),and serum levels of antioxidant stress response factors Kelch-like ECH-associated protein 1(Keap1)and nuclear factor-E2-related factor 2(Nrf2)were observed before and after treatment in both groups.RESULTS After treat-ment,the clinical effective rate in the observation group was significantly higher than that in the control group(P<0.05);the TCM syn-drome scores in both groups decreased significantly(P<0.05),with the observation group showing better results than the control group(P<0.05);the ADL and FMA scores in both groups reduced significantly(P<0.05,P<0.01),while the NIHSS and Ashworth Scale scores increased significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);serum Keap1 levels decreased significantly in both groups(P<0.01),while Nrf2 levels enhanced significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);imaging studies showed that after treat-ment,the residual hematoma volume decreased significantly in both groups(P<0.05,P<0.01),and the rFA value increased signifi-cantly(P<0.05,P<0.01),with the observation group showing better results than the control group(P<0.01).CONCLUSION On the basis of standard treatment for the acute phase,acupuncture combined with Zhengan Xifeng Decoction can significantly improve the early clinical symptoms of HICH patients with liver-kidney yin deficiency,reduce oxidative stress levels,and promote the recovery of nerve and motor functions.

Pyroptosis is a novel,inflammatory programmed cell death mediated by gasdermins(GSDMs),which characterized by the formation of membrane pores and the release of pro-inflammatory cytokines.Rheumatoid arthritis(RA)is a chronic,inflamma-tory autoimmune disease characterized by persistent synovitis in multiple joints,progressive destruction of bone and cartilage,and eventually leading to joint deformity and disability.Recently,it has been shown that pyroptosis plays an important role in development of RA.This review summarizes the molecular mechanism of pyroptosis,its pathogenic role and therapeutic strategies in RA,aiming of providing new insights for the mechanism research and new drug development of RA.

OBJECTIVE To observe the effect of acupuncture combined with a modified Zhengan Xifeng Decoction on the early clinical symptoms and oxidative stress status of patients with hypertensive intracerebral hemorrhage(HICH)of liver-kidney yin defi-ciency syndrome.METHODS A total of 60 patients with hypertensive intracerebral hemorrhage(liver-kidney yin deficiency syn-drome)who successfully received 24-hour acute-phase treatment at the Department of Neurosurgery,Acupuncture and Rehabilitation Department,and wards of Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine(Kunshan Traditional Chinese Medi-cine Hospital)from July 2021 to January 2023 were recruited.A randomization table generated by SPSS 22.0 software was used to di-vide the patients into a control group and an observation group,with 30 patients in each group.The control group received symptomatic treatment,conventional rehabilitation training,and modified Zhengan Xifeng Decoction,while the observation group received additional acupuncture treatment on the basis of the control group.The treatment course was 1 month for both groups.Clinical effective rate,TCM syndrome scores,motor and neurological function scores[Activity of Daily Living(ADL)scale,National Institutes of Health Stroke Scale(NIHSS),Modified Ashworth Scale(MAS),Simplified Fugl-Meyer Assessment(FMA)scale],improvement in hematoma lesions,Fraction anisotropy(FA)ratio(rFA),and serum levels of antioxidant stress response factors Kelch-like ECH-associated protein 1(Keap1)and nuclear factor-E2-related factor 2(Nrf2)were observed before and after treatment in both groups.RESULTS After treat-ment,the clinical effective rate in the observation group was significantly higher than that in the control group(P<0.05);the TCM syn-drome scores in both groups decreased significantly(P<0.05),with the observation group showing better results than the control group(P<0.05);the ADL and FMA scores in both groups reduced significantly(P<0.05,P<0.01),while the NIHSS and Ashworth Scale scores increased significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);serum Keap1 levels decreased significantly in both groups(P<0.01),while Nrf2 levels enhanced significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);imaging studies showed that after treat-ment,the residual hematoma volume decreased significantly in both groups(P<0.05,P<0.01),and the rFA value increased signifi-cantly(P<0.05,P<0.01),with the observation group showing better results than the control group(P<0.01).CONCLUSION On the basis of standard treatment for the acute phase,acupuncture combined with Zhengan Xifeng Decoction can significantly improve the early clinical symptoms of HICH patients with liver-kidney yin deficiency,reduce oxidative stress levels,and promote the recovery of nerve and motor functions.

BACKGROUND:Marine traditional Chinese medicine offers a potentially effective and less adverse treatment for osteoporosis.OBJECTIVE:To explore the pharmacological regulations and procedures of traditional Chinese medicine in treating osteoporosis through data mining and network pharmacology techniques.METHODS:Data mining and network pharmacology methods were used to study the medication pattern and mechanism of marine Chinese medicine patented prescriptions approved by China National Intellectual Property Administration for the treatment of osteoporosis,and special attention was paid to the core Chinese medicine constituents of these prescriptions.The core constituents of the compound drug group composed of oyster-Dipsacus asper-epimedium were comprehensively identified and analyzed by using ultra-high-performance liquid chromatography tandem mass spectrometry.RESULTS AND CONCLUSION:(1)We collected 381 authorized compound patents for the treatment of osteoporosis from the database inception to April 1,2024.Among these,48 patent groups utilized marine traditional Chinese medicine.These prescriptions contained 183 Chinese herbal medicines,of which 13 marine traditional Chinese medicines were used 574 times in total,and the number of flavors used in a single patented formula ranged from 2 to 41.(2)Oyster was the most frequently used marine ingredient,while Dipsacus asper,epimedium,Rehmannia glutinosa,Eucommia ulmoides Oliv.were the most frequent non-marine components.Association rule analysis identified oyster,Dipsacus asper,and epimedium as the core drug group.Network pharmacology analysis revealed that the core targets of this group for the treatment of osteoporosis included ALB,AKT1,TP53,PPARG,and SRC.Sitosterol,liquiritigenin,japonine,luteolin,and kaempferol were identified as the core components within the marine traditional Chinese medicine prescriptions.(3)The GO and KEGFG enrichment analyses suggested a potential association between the mechanism of the core drug group and the rap1/mapk signaling pathway in the treatment of osteoporosis.(4)The molecular docking verified the beneficial interactions between core components and core targets.(5)The ultra-high-performance liquid chromatography tandem mass spectrometry analysis of the compound medicine confirmed the presence of luteolin,sitosterol,kaempferol,and other components,aligning with the drug components identified by network pharmacology.Quantitative analysis indicated that flavonoids,terpenes,and alkaloids constituted a significant proportion of the compound medicine's components.

Pyroptosis is a novel,inflammatory programmed cell death mediated by gasdermins(GSDMs),which characterized by the formation of membrane pores and the release of pro-inflammatory cytokines.Rheumatoid arthritis(RA)is a chronic,inflamma-tory autoimmune disease characterized by persistent synovitis in multiple joints,progressive destruction of bone and cartilage,and eventually leading to joint deformity and disability.Recently,it has been shown that pyroptosis plays an important role in development of RA.This review summarizes the molecular mechanism of pyroptosis,its pathogenic role and therapeutic strategies in RA,aiming of providing new insights for the mechanism research and new drug development of RA.

Objective:To investigate the difference in brain activity intensity between methamphetamine (MA) dependent patients (MA group) and healthy controls (control group) using fractional amplitude of low-frequency fluctuation (fALFF), and to establish a classification model between these two groups using support vector machine (SVM).Methods:From February 2014 to October 2019, a total of 46 male MA-dependent patients and 46 male healthy controls were recruited from the Affiliated Kangning Hospital of Ningbo University. The study collected resting-state functional magnetic resonance imaging (rs-fMRI) data and analyzed the differences in brain functional activity between the two groups. This analysis was conducted using both static and dynamic fractional amplitude of low-frequency fluctuations (d-fALFF). Additionally, the study examined the correlation between fALFF/d-fALFF values in specific brain regions and the total scores, as well as each factor score, of the Brief Psychiatric Rating Scale (BPRS). Furthermore, the relationship between fALFF/d-fALFF values and the age of first use and total dose of MA in the MA group was investigated. Finally, the fALFF map and d-fALFF map of brain regions with significant differences between groups were used as features for constructing classification.Results:Compared to the healthy control group, those dependent on MA showed significantly increased fALFF mainly in the nucleus accumbens, caudate nucleus, thalamus, and amygdala nucleus( t=-5.21--2.72, all P<0.05). The MA group exhibited decreased fALFF in the superior frontal gyrus, middle frontal gyrus, orbital gyrus, and cingulate gyrus( t=3.59-5.00, all P<0.05). Most of the brain regions with decreased d-fALFF overlapped with those exhibiting decreased fALFF( t=3.33-4.87, all P<0.05). The results of the correlation analysis showed that the fALFF value of the right nucleus accumbens was positively correlated with the age of first use of MA ( r=0.537, P<0.001). There is no significant relationship between the abnormal fALFF and d-fALFF values in the MA group and the total scores and each factor scores of BPRS, as well as the total dose of MA taken (after removing outliers). Based on fALFF and d-fALFF values, the SVM classifier achieved accuracies of 90.33%±6.89% and 71.56%±7.80%, respectively. Conclusions:There are significant abnormalities in the low-frequency fluctuation of the resting brain in patients dependent on MA. These abnormalities reflect the rigidity of prefrontal cortex activity, functional impairment, and dysfunction of the anti-reward system. These factors may be one of the causes for MA dependent behavior and repeated episodes. In addition, the fALFF values may be helpful for distinguishing MA dependent individuals from the control group.