Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, functional impairment, and neuropsychiatric symptoms. It represents the most prevalent form of dementia among the elderly population. Accumulating evidence indicates that oxidative stress plays a pivotal role in the pathogenesis of AD. Notably, elevated levels of oxidative stress have been observed in the brains of AD patients, where excessive reactive oxygen species (ROS) can cause extensive damage to lipids, proteins, and DNA, ultimately compromising neuronal structure and function. Amyloid β‑protein (Aβ) has been shown to induce mitochondrial dysfunction and calcium overload, thereby promoting the generation of ROS. This, in turn, exacerbates Aβ aggregation and enhances tau phosphorylation, leading to the formation of two pathological features of AD: extracellular Aβ plaque deposition and intracellular neurofibrillary tangles (NFTs). These events ultimately culminate in neuronal death, forming a vicious cycle. The interplay between oxidative stress and these pathological processes constitutes a core link in the pathogenesis of AD. The signaling pathways mediating oxidative stress in AD include Nrf2, RCAN1, PP2A, CREB, Notch1, NF‑κB, ApoE, and ferroptosis. Nrf2 signaling pathway serves as a key regulator of cellular redox homeostasis, exerts important antioxidant capacity and protective effects in AD. RCAN1 signaling pathway, as a calcineurin inhibitor, and modulates AD progression through multiple mechanisms. PP2A signaling pathway is involved in regulating tau phosphorylation and neuroinflammation processes. CREB signaling pathway contributes to neuroplasticity and memory formation; activation of CREB improves cognitive function and reduce oxidative stress. Notch1 signaling pathway regulates neuronal development and memory, participates in modulation of Aβ production, and interacts with Nrf2 toco-regulate antioxidant activity. NF‑κB signaling pathway governs immune and inflammatory responses; sustained activation of this pathway forms “inflammatory memory”, thereby exacerbating AD pathology. ApoE signaling pathway is associated with lipid metabolism; among its isoforms, ApoE-ε4 significantly increases the risk of AD, leading to elevated oxidative stress, abnormal lipid metabolism, and neuroinflammation. The ferroptosis signaling pathway is driven by iron-dependent lipid peroxidation, and the subsequent release of lipid peroxidation products and ROS exacerbate oxidative stress and neuronal damage. These interconnected pathways form a complex regulatory network that regulates the progression of AD through oxidative stress and related pathological cascades. In terms of therapeutic strategies targeting oxidative stress, among the drugs currently used in clinical practice for AD treatment, memantine and donepezil demonstrate significant therapeutic efficacy and can improve the level of oxidative stress in AD patients. Some compounds with antioxidant effects (such asα-lipoic acid and melatonin) have shown certain potential in AD treatment research and can be used as dietary supplements to ameliorate AD symptoms. In addition, non-drug interventions such as calorie restriction and exercise have been proven to exerted neuroprotective effects and have a positive effect on the treatment of AD. By comprehensively utilizing the therapeutic characteristics of different signaling pathways, it is expected that more comprehensive multi-target combination therapy regimens and combined nanomolecular delivery systems will be developed in the future to bypass the blood-brain barrier, providing more effective therapeutic strategies for AD.

Cells not only contain membrane-bound organelles (MBOs), but also membraneless organelles (MLOs) formed by condensation of many biomacromolecules. Examples include RNA-protein granules such as nucleoli and PML nuclear bodies (PML-NBs) in the nucleus, as well as stress granules and P-bodies in the cytoplasm. Phase separation is the basic organizing principle of the form of the condensates or membraneless organelles (MLOs) of biomacromolecules including proteins and nucleic acids. In particular, liquid-liquid phase separation (LLPS) compartmentalises and concentrates biological macromolecules into liquid condensates. It has been found that phase separation of biomacromolecules requires some typical intrinsic characteristics, such as intrinsically disordered regions, modular domains and multivalent interactions. The phase separation of biomacromolecules plays a key role in many important cell activities. In recent years, the phase separation of biomacromolecules phase has become a focus of research in gene transcriptional regulation. Transcriptional regulatory elements such as RNA polymerases, transcription factors (TFs), and super enhancers (SEs) all play important roles through phase separation. Our group has previously reported for the first time that long-term inactivation or absence of assembly factors leads to the formation of condensates of RNA polymerase II (RNAPII) subunits in the cytoplasm, and this process is reversible, suggesting a novel regulatory model of eukaryotic transcription machinery. The phase separation of biomacromolecules provides a biophysical understanding for the rapid transmission of transcriptional signals by a large number of TFs. Moreover, phase separation during transcriptional regulation is closely related to the occurrence of cancer. For example, the activation of oncogenes is usually associated with the formation of phase separation condensates at the SEs. In this review, the intrinsic characteristics of the formation of biomacromolecules phase separation and the important role of phase separation in transcriptional regulation are reviewed, which will provide reference for understanding basic cell activities and gene regulation in cancer.

Objective To explore the application effect and safety of general anesthesia with different doses of remimazolam during vascular intervention anesthesia of intracranial aneurysms.Methods Patients with intracranial aneurysms were divided into high,middle and low dose groups according to the random number table method.The venous access was opened after the patients entered the room,and the vital signs were closely monitored.The low,middle and high dose groups were intravenously injected with 0.25,0.30 and 0.35 mg·kg-1remazolam,respectively.After the loss of consciousness,alfentanil and mivacurium chloride were given for anesthesia induction.The anesthetic effect,recovery quality,hemodynamic indexes,cerebral hemodynamic indexes and neurological function indexes before anesthesia induction(T0),at the time of laryngeal mask insertion(T1),embolization(T2),5 min after operation(T3)and 30 min after operation(T4)were compared among the three groups.The incidence of postoperative cerebral vasospasm(CVS),delayed ischemic neurological dysfunction(DIND)and the incidence of adverse drug reactions related to anesthesia were counted.Results The onset times of anesthesia in the high,middle,and low dose groups were(5.03±1.28),(5.17±1.09),and(7.21±1.15)min,respectively;the number of anesthesia rescue interventions were(0.12±0.02),(0.21±0.06),and(1.51±0.23)times,respectively.There was statistically significant difference in the number of rescue interventions between the high and middle dose groups compared to the low dose group(all P＜0.05).The therapeutic efficacy rates of flumazenil in the high,middle,and low dose groups were 18.18％,11.11％and 2.86％,respectively.the mean arterial pressure(MAP)at T2 were(87.06±6.02),(86.85±5.61)and(81.09±5.37)mmHg;the MAP at T4 were(92.05±5.13),(87.57±6.29)and(84.42±5.16)mmHg,respectively.There was statistically significant difference in MAP between the high and low dose groups(all P＜0.05).There were no statistically significant differences in heart rate(HR),oxygen saturation(SpO2),left peak systolic velocity of middle cerebral artery(Vp-MCA),left mean systolic velocity of middle cerebral artery(Vm-MC)and pulsatility index(PI),S100β protein,and neuron-specific enolase(NSE)levels among the three groups at different time points(all P＞0.05).There were no statistically significant differences in the incidence rates of cardiovascular system complications,delayed postoperative cognitive dysfunction,or anesthesia-related adverse reactions between the three groups(all P＞0.05).Conclusion The safety of different doses of remimazolam general anesthesia in the vascular interventional therapy of intracranial aneurysms is high,and the effects on cerebral hemodynamics and neurological function are similar.However,high-dose remimazolam have shorter general anesthesia induction time and less intraoperative anesthesia remedy frequency while the high-dose remimazolam has higher postoperative flumazenil antagonist therapy.

Objective To investigate the clinical efficacy of Bushen Yijing Decoction for the treatment of xerophthalmia of kidney yang deficiency type and to observe its effect on serum Th1/Th17 cytokines.Methods From January 2021 to January 2023,a total of 96 patients with xerophthalmia of kidney yang deficiency type were selected as the study objects.According to the treatment methods,the patients were divided into observation group and control group,with 48 cases in each group.The control group was treated with Sodium Hyaluronate Eye Drops externally,and the observation group was given oral use of Bushen Yijing Decoction together with Sodium Hyaluronate Eye Drops externally.The course of treatment for the two groups covered 21 days.The changes of tear film break-up time(BUT),corneal fluorescein staining(FL)score,SchirmerⅠtest(SIT)value,serum Th1/Th17 cytokines,Ocular Surface Disease Index(OSDI)questionnaire scores,and 25-Item National Eye Institute Visual Function Questionnaire(NEI-VFQ-25)score in the two groups were observed before and after treatment.Moreover,the clinical efficacy and incidence of adverse reactions were compared between the two groups.Results(1)After 21 days of treatment,the total effective rate of the observation group was 95.83%(46/48),and that of the control group was 70.83%(34/48).The intergroup comparison(tested by chi-square test)showed that the clinical efficacy of the observation group was significantly superior to that of the control group(P＜0.01).(2)After treatment,the ocular surface function indicators of BUT and SIT values in the two groups were higher and the FL values were lower than those before treatment(P＜0.05).The increase of BUT and SIT values and the decrease of FL values in the observation group were significantly superior to those in the control group(P＜0.01).(3)After treatment,the levels of serum cytokines of interleukin 17(IL-17),tumor necrosis factor alpha(TNF-α)and interferon gamma(IFN-γ)in the two groups were lower than those before treatment(P＜0.05),and the decrease of serum IL-17,TNF-α and IFN-γ levels in the observation group was significantly superior to that in the control group(P＜0.01).(4)After treatment,the questionnaire scores of OSDI in the two groups were lower and the NEI-VFQ-25 scores were higher than those before treatment(P＜0.05).The decrease of OSDI scores and the increase of NEI-VFQ-25 scores in the observation group were significantly superior to those in the control group(P＜0.01).(5)The incidence of adverse reactions in the observation group was 4.17%(2/48),and that in the control group was 8.33%(4/48).There was no significant difference between the two groups(P＞0.05).Conclusion Bushen Yijing Decoction can enhance the clinical efficacy of xerophthalmia of kidney yang deficiency type,and the decoction is effective on alleviating the eye discomforts,improving the ocular surface function of patients,regulating the levels of Th1/Th17 cytokines,and relieving the inflammatory response without inducing severe adverse reactions while with high safety.

Objective To analyze and verify the role of senescent genes in the treatment,prognosis,and tumor microenvironment(TME)characteristics of osteoblastic osteosarcoma,bioinformatic methods were employed.Methods Senescent genes were obtained from the China National Genome Science database(https://ngdc.cncb.ac.cn/aging/index).The gene expression profile and clinical information of osteosarcoma patients were sourced from the TARGET database(https://ocg.cancer.gov/programs/target),while single-cell RNA-sequencing(scRNA-seq)data was collected from GSE162454 on the Gene Expression Omnibus(GEO)for downstream analysis.Osteosarcoma cells were classified based on scRNA-seq,and differential expression analysis between osteoblasts/chondroblasts and other cell types was conducted to identify differently expressed genes(DEGs).After matching with the senescent genes,prognostic senescent DEGs were identified through univariable and multivariable Cox regression analysis.Subsequently,the osteosarcoma senescent-related model(OSRM)was constructed,and the risk score was calculated.The role of OSRM in treatment,prognosis,and TME of osteosarcoma was further investigated.Results The analysis revealed that GSE162454 contained 6 osteosarcoma samples,with 19933 cells identified after filtering,quality control,and normalization.Seventeen cellular subtypes were identified using uniform manifold approximation and projection(UMAP)methods.A total of 4821 DEGs were found between osteoblasts/chondroblasts and other subtypes,with 132 senescent DEGs obtained after matching with the senescent gene set.In the TARGET database,4 prognostic senescent DEGs[ADH5(alcohol dehydrogenase 5),ARHGAP1(Rho GTPase activating protein 1),APOE(apolipoprotein E),and ATF4(activating transcription factor 4)]were identified through univariable and multivariable Cox analyses to construct OSRM.Based on risk score,patients were stratified into high-and low-risk groups,with the latter showing better prognosis(HR=0.13,95%CI 0.06-0.28,P<0.001)and higher sensitivity to immune checkpoint inhibitors.qRT-PCR and Western blotting confirmed the high expression of senescent genes ADH5(P<0.01),APOE(P<0.01),and ATF4(P<0.05)in the K7M2 osteosarcoma cell line,suggesting the potential for predicting the response to anti-PD-1 immunotherapy for osteosarcoma.Conclusions scRNA-seq facilitated the division of osteosarcoma into 17 cell subtypes.ADH5,ARHGAP1,APOE,and ATF4 emerged as potential cancer-promoting or suppressing senescent genes in osteosarcoma.OSRM was found to be associated with treatment response,prognosis,and TME characteristics,thereby promoting the molecular pathological diagnosis of osteoblastic osteosarcoma and prediction for anti-PD-1 immunotherapy.

Objective To construct and validate a nomogram prediction model for the high-risk human papilloma-virus(HPV)infection and its natural clearance in professional women.Methods Women with regular professions,who underwent professional medical examination and were confirmed with high-risk HPV infection without cervical cancer and cervical epithelial neoplasia in a hospital from March 2020 to March 2021 were studied.Patients were di-vided into the model group and the validation group in a 7:3 ratio.The model group were subdivided into the natural clearance group and the persistent infection group based on follow-up results.The general information,reproduc-tive-related treatment,sexual partner-related information,and examination results of the two groups of patients were compared.Potential factors for natural clearance of high-risk HPV infection in professional women were screened out by LASSO regression.Independent influencing factors were screened out with multivariate logistic re-gression.Based on multivariate logistic regression results,a nomogram prediction model was constructed and valida-ted using R programming language.Results A total of 329 cases were included,230 in the model group and 99 in the validation group.There was no statistically significant difference in general information between the two groups of patients(all P＞0.05).Among the 230 high-risk HPV infection patients in the model group,165 turned negative at the end of follow-up,with a natural clearance rate of 71.74％.Based on LASSO regression analysis,multivariate logistic regression analysis showed that age,contraceptive method,number of sexual partners,excessive foreskin of sexual partners,initial viral load,HPV infection type,and reproductive tract inflammation were independent influ-encing factors for the natural clearance of high-risk HPV infection in professional women(all P＜0.05).The re-ceiver operating characteristic(ROC)curve analysis showed that the areas under the curve(AUC)of natural clea-rance of high-risk HPV infection in professional women in the model group and validation group were 0.834(95％CI:0.776-0.893)and 0.817(95％CI:0.755-0.879),respectively.H-L goodness-of-fit test result showed that the difference between the nomogram model and the ideal model was not statistically significant(P＞0.05).The cali-bration curve results showed that the predicted curves of the model group and validation group were basically fit with the standard curve,indicating a high predictive accuracy of the model.The decision curve analysis results of the model group showed that when the probability threshold of natural clearance of high-risk HPV infection in profes-sional women predicted by the nomogram model was 0.15-0.95,the net benefit rate of patients was＞0.Conclusion The natural clearance rate of high-risk HPV infection in professional women is high,mainly influenced by factors such as age,contraceptive method,and number of sexual partners.The nomogram model constructed in this study has high accuracy and discrimination in predicting the natural clearance rate of high-risk HPV infection in profes-sional women.

Aim To investigate the effects of bone-forming protein BMP9 on aerobic glycolysis,migration and invasion ability in triple-negative breast cancer MDA-MB-231 cells and the underlying mechanisms.Methods The experimental group infected MDA-MB-231 cells with human BMP9 recombinant adenovirus(AdBMP9),while the control group infected cells with empty GFP adenovirus.Lactate,glucose and ATP as-say kits were used to detect glucose uptake,lactate and ATP production.The correlation between BMP9 and key glycolytic enzyme genes in pancarcinoma was ana-lyzed using GEPIA2 database.The mRNA expression levels of GLUT1,HK2,PKM2 and LDHA in MDA-MB-231 cells after overexpression of BMP9 were detec-ted by qRT-PCR.Potential targets of BMP9 inhibiting MDA-MB-231 aerobic glycolysis were analyzed in STRING database.The expression levels of HIF-1αand downstream protein were detected by Western blot.The changes of cell migration and invasion ability after different treatments were evaluated by the scratch heal-ing assay and Transwell assay.Results Compared with the control group,BMP9 down-regulated glucose uptake,lactate production,ATP level(P＜0.01),and inhibited HIF-1α and its downstream protein ex-pression in MDA-MB-231 cells.Overexpression of HIF-1α in rescue experiment reversed the inhibitory effect of BMP9 on aerobic glycolysis,migration and in-vasion of MDA-MB-231 breast cancer cells.Conclu-sion BMP9 down-regulates HIF-1α to inhibit the aer-obic glycolysis and migration and invasion ability of MDA-MB-231 breast cancer cells.

Aim To investigate the effects of autophagy regula-ted by LncRNA SNHG3 on the proliferation,migration,invasion and EMT of human breast cancer cell line MCF-7.Methods The expression of SNHG3 in breast cancer and breast cancer cell line MCF-7 was analyzed by bioinformatics and real-time fluores-cent quantitative PCR(RT-qPCR);RNAi technology was used to construct MCF-7 recombinant cell lines with knockdown SNHG3(siSNHG3)and control(siNC),and Western blot and cellular immunofluorescence were applied to detect autophagy markers;autophagosome lysosomal fusion inhibitor BafA1 or ear-ly autophagosome formation inhibitor 3-MA was employed to treat MCF-7 cells with or without SNHG3 knockdown,Western blot was used to detect the expression of LC3-Ⅱ or p62,and the effect on autophagic vesicle formation or autophagic degradation was observed;clone formation experiment,CCK8 experiment,wound healing experiment,and Transwell experiment were used to detect the effects of siSNHG3 combined or not combined with BafA1 or 3-MA on the proliferation,lateral migration,longitudi-nal migration,and invasion of MCF-7 cells.Western blot was used to detect its effect on the EMT of MCF-7 cells.Results Bioinformatics analysis and RT-qPCR confirmed that SNHG3 was highly expressed in breast cancer and breast cancer cell line MCF-7;Western blot and cellular immunofluorescence confirmed that knockdown of SNHG3 could activate autophagy in breast cancer;the clone formation,CCK-8,wound healing,and Tran-swell experiment confirmed that downregulation of SNHG3 ex-pression could inhibit tumor proliferation,migration,and inva-sion by activating autophagy;Western blot confirmed that SNHG3 promoted EMT process of breast cancer through negative regulation of autophagy.Conclusions SNHG3 is abnormally overexpressed in breast cancer and negatively regulates autoph-agy,and can enhance the proliferation,migration,invasion and EMT process of breast cancer cells through negatively regulating autophagy,suggesting that SNHG3 is a potential target for diag-nosis and treatment of breast cancer.

OBJECTIVE: This study was aimed at investigating the carrier rate of, and molecular variation in, α- and β-globin gene mutations in Hunan Province. METHODS: We recruited 25,946 individuals attending premarital screening from 42 districts and counties in all 14 cities of Hunan Province. Hematological screening was performed, and molecular parameters were assessed. RESULTS: The overall carrier rate of thalassemia was 7.1%, including 4.83% for α-thalassemia, 2.15% for β-thalassemia, and 0.12% for both α- and β-thalassemia. The highest carrier rate of thalassemia was in Yongzhou (14.57%). The most abundant genotype of α-thalassemia and β-thalassemia was -α ^3.7/αα (50.23%) and β ^IVS-II-654/β ^N (28.23%), respectively. Four α-globin mutations [CD108 (ACC>AAC), CAP +29 (G>C), Hb Agrinio and Hb Cervantes] and six β-globin mutations [CAP +8 (C>T), IVS-II-848 (C>T), -56 (G>C), beta nt-77 (G>C), codon 20/21 (-TGGA) and Hb Knossos] had not previously been identified in China. Furthermore, this study provides the first report of the carrier rates of abnormal hemoglobin variants and α-globin triplication in Hunan Province, which were 0.49% and 1.99%, respectively. CONCLUSION Our study demonstrates the high complexity and diversity of thalassemia gene mutations in the Hunan population. The results should facilitate genetic counselling and the prevention of severe thalassemia in this region.
Humans ; beta-Thalassemia/genetics* ; alpha-Thalassemia/genetics* ; Hemoglobinopathies/genetics* ; China/epidemiology* ; High-Throughput Nucleotide Sequencing

Circadian rhythm is an internal regulatory mechanism formed in organisms in response to the circadian periodicity in the environment, which modulates the pathophysiological events, occurrence and development of diseases, and the response to treatment in mammals. It significantly influences the susceptibility, injury, and recovery of ischemic stroke, and the response to therapy. Accumulating evidence indicates that circadian rhythms not only regulate the important physiological factors of ischemic stroke events, such as blood pressure and coagulation-fibrinolysis system, but also participate in the immuno-inflammatory reaction mediated by glial cells and peripheral immune cells after ischemic injury and the regulation of neurovascular unit(NVU). This article aims to link molecular, cellular, and physiological pathways in circadian biology to the clinical consequences of ischemic stroke and to illustrate the impact of circadian rhythms on ischemic stroke pathogenesis, the regulation of NVU, and the immuno-inflammatory responses. The regulation of circadian rhythm by traditional Chinese medicine is reviewed, and the research progress of traditional Chinese medicine intervention in circadian rhythm is summarized to provide a reasonable and valuable reference for the follow-up traditional Chinese medicine research and molecular mechanism research of circadian rhythm.
Animals ; Ischemic Stroke ; Medicine, Chinese Traditional ; Circadian Rhythm ; Blood Coagulation ; Blood Pressure ; Mammals