Triple-negative breast cancer (TNBC) remains a refractory subtype of breast cancer due to its resistance to various therapeutic strategies. In this study, we introduce a "brake-release and accelerator-pressing" approach to engineer a microneedle patch embedded with copper-doped Prussian blue nanoparticles (Cu-PB) and the ferroptosis inducer sorafenib (SRF) for raised chemodynamic (CDT)/photothermal (PTT) combination therapy against TNBC. Upon transdermal insertion, the dissolving microneedles swiftly disintegrate and facilitate the release of SRF. Under gentle external light exposure, copper ions (Cu²⁺) and iron ions (Fe³⁺) were liberated from Cu-PB. The direct chelation of Cu²⁺ and the indirect suppression by SRF, collectively attenuate glutathione peroxidase 4 (GPX4) enzymatic function, destabilizing the cellular redox equilibrium (referred to as the "brake-release" strategy). The release of Cu²⁺ and Fe³⁺ ions instigates a Fenton/Fenton-like reaction within tumor cells, further yielding hydroxyl radicals and elevating reactive oxygen species (ROS) concentrations (referred to as the "accelerator-pressing" strategy). This overwhelming ROS accumulation, coupled with the impaired clearance of resultant lipid peroxides (LPO), ultimately triggers a robust ferroptosis cell death response. In summary, this study presents an innovative combinatorial therapeutic strategy based on dual-ferroptosis induction for TNBC, implying a promising therapeutic platform for developing ferroptosis-centered treatments for this aggressive breast cancer subtype.

OBJECTIVES: To explore the mechanism of Circ-MYOCD back-splicing and its regulatory role in myocardial hypertrophy. METHODS: Sanger sequencing and RNase R assays were performed to verify the circularity and stability of Circ-MYOCD, whose subcellular distribution was determined by nuclear-cytoplasmic fractionation. Bioinformatics analysis and mass spectrometry from pull-down assays were conducted to predict the RNA-binding proteins (RBPs) interacting with Circ-MYOCD. In rat cardiomyocytes H9C2 cells, the effects of HNRNPH1 and HNRNPL knockdown and overexpression on Circ-MYOCD back-splicing were evaluated. In a H9C2 cell model of angiotensin II (Ang II)-induced myocardial hypertrophy, the expression of HNRNPH1 was detected, the effects of HNRNPH1 knockdown and overexpression on progression of myocardial hypertrophy were assessed, and the regulatory effect of HNRNPH1 on Circ-MYOCD back-splicing was analyzed. RESULTS: Sanger sequencing confirmed that the junction primers could amplify the correct Circ-MYOCD sequence. RNase R and nuclear-cytoplasmic fractionation assays showed that Circ-MYOCD was stable and predominantly localized in the cytoplasm. Bioinformatics analysis and mass spectrometry from the Circ-MYOCD pull-down assay identified HNRNPH1 and HNRNPL as the RBPs interacting with Circ-MYOCD. In H9C2 cells, HNRNPH1 knockdown significantly enhanced while its overexpression inhibited Circ-MYOCD back-splicing; HNRNPH1 overexpression obviously increased the expressions of myocardial hypertrophy markers ANP and BNP, while its knockdown produced the opposite effect. In Ang II-induced H9C2 cells, which exhibited a significant increase of HNRNPH1 expression and increased expressions of ANP and BNP, HNRNPH1 knockdown obviously increased Circ-MYOCD expression, decreased MYOCD expression and lowered both ANP and BNP expressions. CONCLUSIONS HNRNPH1 regulates Circ-MYOCD back-splicing to influence the progression of myocardial hypertrophy.
Animals ; Rats ; RNA, Circular/genetics* ; Cardiomegaly/metabolism* ; Myocytes, Cardiac/metabolism* ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism* ; Cell Line ; RNA Splicing ; Angiotensin II ; RNA-Binding Proteins

Objective To investigate the effect of miR-495-3p targeting budding uninhibited by benzimidazoles(BUB1)on signal transducer and activator of transcription 3(STAT3)signaling pathway on biological behavior of esophageal cancer(EC)cells.Methods The differentially expressed genes in EC tissues and normal tissues were screened by the cDNA microarray technique.The differentially expressed genes were analyzed by bioinformatics methods.The target genes of miRNAs were predicted by the TargetScan database and verified by a dual luciferase gene reporter assay.KYSE150 cells were divided into blank control group,NC mimics group and miR-495-3p mim-ics group.The activity of KYSE150 cells were detected by the CCK-8 method.Cell cycle and apoptosis were meas-ured by flow cytometry.The expression of BUB1 mRNA was measured by real-time fluorescence quantitative reverse transcription polymerase chain reaction(RT-qPCR).The levels of BUB1,STAT3,phosphor(p)-STAT3,cyclin dependent kinase 1(CCNB1),cyclin dependent kinase 1(CDK1),B-cell lymphoma-2(Bcl-2),cysteinyl aspar-tate-specific proteinase-3(Caspase-3)and cysteinyl aspartate-specific proteinase-3(Caspase-9)were measured by Western blot.The migration and invasion abilities of the cells were measured by wound-healing and Transwell inva-sion assays.Results Differentially expressed genes were involved in biological processes,signaling pathways and network construction,which were mainly related to cell cycle.BUB1 is the key(Hub)gene,and BUB1 is the tar-get gene of miR-495-3p.In vitro experiments showed that overexpression of miR-495-3p could significantly inhibit the migration and invasion of EC cells and induce apoptosis and G2/M phase arrest.After treatment with overex-pression of miR-495-3p,the expression of Caspase-3 and Caspase-9 in EC cells increased significantly(P＜0.01),while the expression of Bcl-2,BUB 1,CCNB1,CDK1 and p-STAT3 decreased significantly(P＜0.01).Moreover,the STAT3 signaling pathway might play an important role in this process.Conclusion miR-495-3p may influence the biological behavior of esophageal cancer cells by down-regulating BUB 1-mediated STAT3 signaling pathway.

This study presents a case of a girl of three year and 4 month old with ataxia and severe sen-sorineural hearing loss for 2 years.In order to improve hearing,she was hospitalized in the PUMC Hospital.Ge-netic testing performed found compound heterozygous variants of c.1186C＞T(p.P396S)and c.1357C＞T(p.R453W)in TWNK gene.After a multidisciplinary discussion of the case,the team suspected mitochondrial DNA depletion syndrome type 7(hepatocerebral type).The patient has shown nervous system impairment in-volvement but no evidence of liver dysfunction.The efficacy of cochlear implantation is uncertain and general anesthesia if applied will accelerate the progress of encephalopathy and might lead to multiple organ failure.Unsure of the perioperative safety,the parents of the girl did not chose the option of hearing intervention tempo-rarily,but chose oral symptomatic supportive treatment with coenzyme Q10,folate,levocarnitine,and complex vitamins as recommended.

Objective:To investigate the prevalence and mortality of dementia and assess the impact of geriatric syndromes (GS) on the risk for dementia and death in elderly population in Beijing.Methods:A cross-sectional survey was conducted in the elderly population aged ≥65 years and selected by a multi-stage sampling in Beijing during 2013-2015. Cognitive function was screened using the Chinese Revised Version of the Mini-Mental State Examination (MMSE). Then, neurological examination and psychiatric assessment were performed for those with the MMSE score lower than the cut-off value. The information about GS prevalence was also collected. The study also collected death records for all individuals from baseline until December 31, 2019. Based on the age and gender distribution from Beijing data of the 2010 Six th National Population Census, the dementia prevalence in the study population was directly standardized. Logistic regression analysis was used to evaluate the association of different forms of dementia with GS, and Cox proportional hazards regression model was used to estimate the hazard ratio ( HR) and 95% CI of death. Results:During 2013-2015, a total of 2 935 individuals completed dementia assessments, of which 167 were diagnosed with dementia. The standardized prevalence of dementia was 5.9% (95% CI: 5.0%-17.4%). The individuals with Alzheimer's disease (AD) and vascular dementia (VaD) accounted for 58.7% and 28.1% of total individuals with dementia, respectively. Aging, lower education level, urinary incontinence, and fall were risk factors for AD, while disability of activity of daily life dependence, hypertension, and stroke were found to be risk factors for VaD. After a median follow-up of 5.44 person-years, 399 deaths were recorded. The 5-year mortality risk was 2.87 (95% CI: 1.92-4.17) times and 4.93 (95% CI: 3.23-7.53) times higher for the elderly individuals with AD and VaD, respectively, compared to non-demented individuals. After adjusting for demographic, GS, and cardiovascular risk factors, the mortality risk in the elderly individuals with AD showed no significant difference compared with non-demented individuals ( HR=1.32, 95% CI: 0.89-1.97), while the mortality risk in those with VaD was 2.46 (95% CI: 1.49-4.05) times higher than that in non-demented individuals. Conclusions:The prevalence of dementia in Beijing increased significantly in the context of population aging, especially the prevalence of AD. The presence of GS increased the risks for AD and VaD, as well as the risk for death. Close attention needs to be paid to GS management in dementia prevention in elderly population.

OBJECTIVE To design and synthesize novel α-naphthylthiol amino acid ester lysine specific demethylase 1(LSD1) inhibitors, evaluate their inhibitory activity with selectivity against LSD1, and explore their binding mechanism through molecular docking and dynamics simulation. METHODS Based on the binding mode of hit compound 3a with LSD1, the α- naphthyl mercapto amino acid ethyl ester small molecule compound were designed by fixing the planar hydrophobic naphthyl ring in the structure, while introducing hydrophilic amino fragment, and they were prepared through a multi-component one-pot cascade reaction. All the compounds were evaluated for their inhibitory activity against LSD1 at concentrations of 5.0 and 1.0 μmol·L–1 using the LSD1 screening platform of research group. The most potent compound was tested for its IC50 value and enzyme selectivity over MAO-A and MAO-B, and its binding mode was investigated through molecular docking and dynamics simulation. RESULTS A total of 13 compounds were obtained, all of which exhibited significant inhibitory effects on LSD1. Among them, nine compounds showed an inhibitory rate of over 50.0% against LSD1 at a concentration of 1.0 μmol·L–1, while compound 3l displaying the best activity with an IC50 value of 0.17 μmol·L–1, 174 times higher than the positive control. It also showed excellent selectivity towards MAO-A and MAO-B. Molecular docking and dynamics simulations indicated that compound 3l inhibited the activity of LSD1 through multiple interactions. CONCLUSION The structures of α-naphthylthiol amino acid ester can serve as lead compounds or active fragments, laying a solid foundation for the subsequent design of LSD1 inhibitors based on structure-oriented drug design.

[Objective] To explore the application of pelvic floor ultrasonography in the treatment of mixed urinary incontinence (MUI) by transvaginal retropubic midurethral synthetic sling (RMUS), in order to understand the relationship between the morphological changes of pelvic floor structures and the efficacy of RMUS. [Methods] Clinical data of 44 female MUI patients undergoing RMUS during Jan.2018 and Dec.2020 were retrospectively analyzed.Urodynamics detected detrusor overactivity (DO) in 9 cases (20.5%). During RMUS procedure, the tension of the sling was adjusted based on the anatomical landmarks. The changes of ultrasonic parameters before and after operation, the relationship between the ultrasonic results, surgical efficacy and urodynamic results were analyzed. [Results] The patients averaged (58.59±9.08) years, with the body mass index being 24.71±2.77.The subjective cure rate was 91.3% (21/23) 3 months after surgery, and 85.0% (34/40) 2 years after surgery.Pelvic floor ultrasonography showed significant differences in posterior urethravesical angel at rest and during Valsalva, bladder neck descent distance and the rate of urethral funneling during Valsalva (P<0.05). According to the group analysis of the preoperative ultrasonic results, there was no statistical significance in the subjective cure rate between the funneling group and the non-funneling group during Valsalva, and the bladder neck non downward group/mild downward group/moderate downward group/severe downward group during Valsalva 3 months and 2 years after surgery (P>0.05). At 3-month follow-up, all pre-RMUS urethral funneling during Valsalva disappeared in patients without preoperative DO.Comparatively, 50.0% (3/6) urethral funneling still presented in DO patients, who had a lower cure rate (55.6%, 5/9) at the 2-year follow-up. [Conclusion] RMUS can reduce the posterior urethravesical angel at rest and during Valsalva, reduce bladder neck descent distance and the rate of urethral funneling during Valsalva in MUI patients, which can enhance urinary continence.There seems to be a correlation between DO and urethral funneling during Valsalva, while RMUS may potentially reverse the two markers.

Objective To analyze the disease burden and change trend of breast cancer mortality among Chinese women from 2013 to 2021.Methods The indicators of breast cancer-related mortality (MR),age-standardized mortality rate (ASMR),deaths,and urban-rural deaths in the Chinese Cause of Death Surveil-lance Dataset from 2013 to 2021 were collected and collated,and the trend changes of MR,ASMR,and years lost in life of premature death (YLL) were analyzed,annual percentage change (APC) was used for trend a-nalysis,and Fisher substitution test was used to compare APC in different regions.Results From 2013 to 2021,a total of 88112 cases of breast cancer died,with an average annual MR of 7.56/100000 and an ASMR of 6.34/100000.From 2013 to 2021,the MR rate of breast cancer (APC=2.12%,t=5.414,P<0.001),MR in rural areas (APC=2.84%,t=7.581,P<0.001),and YLL in rural areas (APC=1.61%,t=3.588,P=0.009) showed an upward trend in China.MR at 40-<45 years old showed a downward trend (APC=-2.76%,t=-4.689,P=0.002),and at 70-<75 years old (APC=1.41%,t=2.494,P=0.041),75-<80 years old (APC=3.05%,t=3.690,P=0.008),and 80-<85 years old (APC=1.82%,t=2.909,P=0.023).There was a statistically significant difference in APC between MR and ASMR in urban and rural areas (P<0.001).There was no significant difference in the trend of other indicators (P>0.05).Conclusion From 2013 to 2021,the disease burden of breast cancer mortality in Chinese women showed an upward trend,and the comprehensive prevention and treatment of breast cancer should be strengthened to reduce the risk of breast cancer death.

Objective To explore the neuroprotective effect of curcumin(Cur)on Parkinson's disease model and its mechanism.Methods Sprague-Dawley rats were randomly divided into the control(CON)group,the model(PD)group,and the low-,medium-,and highdose curcumin(Cur)groups,with ten rats in each group.Lipopolysaccharide was injected into the substantia nigra to establish a Parkinson's disease model.Rats in the Cur groups were administered Cur intraperitoneally at doses of 20 mg/kg,40 mg/kg,and 60 mg/kg daily for 21 days.α-synuclein(α-syn),nuclear transcription factor κB proteins(NF-κB,IKBα,p-NF-κB,p-IKBα)and the activation levels of astrocytes were detected in rat brain tissues by immunohistochemistry(IHC).mRNA levels of pro-inflammatory cytokines(TNF-α,IL-β,IFN-γ,IL-6),inducible nitric oxide synthase(iNOS),cyclooxygenase-2(COX-2),NADPH oxidase complex(gp47phox,gp91phox,gp67phox),and apoptosis-related factors(Bax,Bcl-2,Caspase-3,and Caspase-9)were measured by quantitative reverse transcription polymerase chain reaction(qRT-PCR).The rotarod and pole climbing tests were used to evaluate the motor coordination of the rats.Results Compared to the CON group,PD rats showed significantly increased levels of α-syn,p-NF-κB,p-IKBα proteins,activation of astrocytes,TNF-α,IL-β,IFN-γ,IL-6,iNOS,COX-2,Bax,Caspase-3,Caspase-9,gp47phox,gp91phox and gp67phox mRNA levels(P<0.05);while the Bcl-2 level was significantly decreased(P<0.05).Compared with the PD group,the medium-and high-dose Cur treatment groups inhibited the aggregation of α-syn protein,reduced the activation of the NF-κB pathway,and the expression of inflammatory and apoptosis-related factors(P<0.05).Moreover,medium and high doses of Cur significantly improved the motor coordination in rats,and compared with the PD group,the performance of rotarod and pole climbing tests was significantly improved(P<0.05).Conclusion cur may inhibit the aggregation of α-syn by suppressing neuroinflammation and oxidative stress responses,thereby improving motor coordination in Parkinson's disease rats and exerting neuroprotective effects.

Precancerous lesions of gastric cancer is a key stage in the development of gastric cancer.The reprogramming of glucose metabolism is a prominent feature of precancerous lesions of gastric cancer.Hypoxic microenvironment and hypoxia-inducible factors are important factors influencing the occurrence of glucose metabolic reprogramming.This article summarized the relationship between hypoxic microenvironment and the reprogramming of glucose metabolism in precancerous lesions of gastric cancer,and concluded the relevant research on TCM compounds and effective components to improve hypoxic microenvironment and further regulate glycolysis for the treatment of this disease.It was concluded that the mechanism may be the inhibition of angiogenesis,regulation of signaling pathways and key proteins of glycolysis,expression of multiple enzymes,reduction of lactate secretion,inhibition of cell malignant proliferation and invasion.It explored the mechanism of Chinese materia medica in improving hypoxic microenvironment and regulating glycolysis,so as to provide reference for the prevention and treatment of precancerous lesions of gastric cancer.