Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Cellular drug screening represents a key approach in the preclinical discovery of AD therapeutics. Moreover, selecting an appropriate cellular model is essential for exploring the mechanisms underlying AD pathogenesis. Objective: This study aimed to establish a progressive strategy integrating cell model construction, monomer evaluation, and effective component group-based drug discovery for the development of novel therapeutics targeting AD. Methods: A novel AD12 cell line stably expressing the double-transgenic genes amyloid precursor protein (APP)695/presenilin 1(PS1)-ΔE9 was first constructed and subjected to lipopolysaccharide (LPS) stimulation. The resulting LPS-induced neuroinflammatory response was characterized using metabolomic analysis. Subsequently, 16 alkaloids derived from traditional Chinese medicine(TCM) were screened with the LPS-AD12 cell model. Molecular docking was then performed to assess the binding affinity of benzoylaconitine (BAC) with APP and PS1 proteins. A targeted metabolomics approach focusing on amino acids and the tricarboxylic acid (TCA) cycle was applied to BAC-treated LPS-AD12 cells. Finally, aconite extract was administered to five-familial-AD-mutations(5xFAD) transgenic mice, and therapeutic efficacy was evaluated through phenotypic and metabolomic analyses. Results: LPS stimulation induced neuroinflammation in AD12 cells, characterized by elevated levels of interleukin-6, amyloid-β (Aβ ), and PS1. The primary metabolic pathways affected in AD12 cells included alanine, aspartate, and glutamate metabolism, as well as arginine biosynthesis. Notably, BAC significantly reduced the levels of Aβ and interleukin-6 in LPS-AD12 cells. Furthermore, molecular docking analyses revealed a strong binding affinity of BAC with APP and PS1 proteins. Targeted metabolomics analysis indicated that the pharmacological activity of BAC was primarily associated with its anti-inflammatory effects, modulation of the cholinergic signaling pathway, and regulation of energy metabolism. Behavioral experiments in 5xFAD mice, together with immunofluorescence assessments of brain tissues (amyloid-β, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1), demonstrated that aconite extract treatment significantly alleviated AD-related symptoms. In addition, metabolomics-based mechanistic analyses revealed that serine, acetylcholine, ornithine, and gamma-aminobutyric acid exhibited consistent trends in both brain tissue and serum samples from treated mice. Conclusion: This study established a novel AD12 cell model and an effective, reliable LPS-induced cell-based screening system. Additionally, we proposed a new drug discovery strategy integrating cell model construction, monomer evaluation, and effective component group-based drug discovery. This screening system has the potential to accelerate the identification of anti-AD agents and provides a feasible framework for subsequent in-depth investigations into new drug development from TCM, thereby contributing to the modernization of TCM-derived therapeutics.

Objective To investigate the factors influencing the natural outcome of low-grade squamous intraepithelial lesions(LSIL)of the cervix.Methods A total of 154 patients who underwent colposcopic cervical biopsy in the Third Affiliated Hospital of Zhengzhou University from January 2022 to January 2023 were selected and divided into negative conversion group(55 cases),continuous group(70 cases)and upgraded group(29 cases)according to the follow-up results.Logistic regression was used to analyze the influence of related factors on the outcome of LSIL.Results There were statistically significant differences in the number of vaginal births,the results of thin-prep cytology test,human papilloma virus(HPV)typing,whether vaginal LSIL was combined,whether there were symptoms,and vaginal microecology among three groups(P＜0.05).Multivariate Logistic analysis showed that combined vaginal LSIL,vaginal microecological abnormalities,atypical squamous cell-cannot exclude high-grade squamous intraepithelial lesion(ASC-H)/high-grade squamous intraepithelial lesion(HSIL),HPV 16/18 positive or mixed positive were independent risk factors for persistent infection(P＜0.05),combined vaginal LSIL,symptomatic,vaginal microecological abnormalities,ASC-H/HSIL,HPV 16/18 positive or mixed positive were all independent risk factors for escalation of lesions(P＜0.05).Conclusion Patients with vaginal LSIL,vaginal microecological abnormalities,ASC-H/HSIL,HPV 16/18 positive or mixed positive should be followed up and early intervention to reduce the risk of disease escalation.

Purpose This study aimed to investigate the expression and clinical significance of TLDC2 in colorec-tal adenocarcinoma.Methods Data from the human protein atlas(HPA)and the cancer genome atlas(TCGA)indi-cated that TLDC2 was highly expressed in colorectal adenocarcinoma.We further analyzed the expression of TLDC2 in 400 colorectal adenocarcinomas and 447 other solid tumors using tissue microarrays and immunohistochemical(IHC)staining.Result The positive expression rate of TLDC2 was significantly higher than that of SATB2 in colorectal ade-nocarcinomas(96.5％vs 87.0％,P＜0.000 1).TLDC2 positivity exceeded that of SATB2 in both low-or high-grade colorectal adenocarcinoma(99.4％vs 88.7％,P＜0.000 1;83.3％vs 79.2％,P=0.669 9).In addition,the expression of TLDC2 and SATB2 was evaluated in 447 cases of other types of solid tumors.TLDC2 was expressed in neuroendocrine tumors as well as in gastric and appendiceal adenocarcinomas,whereas SATB2 was detected in a small number of melanomas,ovarian cancers,breast cancers and gallbladder cancers.The positive and specificity of TLDC2 for colorectal adenocarcinoma were 97％(95％CI=0.94-0.98)and 85％(95％CI=0.81-0.88),respectively.Combined detection of TLDC2 and SATB2 yielded a sensitivity of 96％(95％CI=0.93-0.97)and a specificity of 93％(95％CI=0.90-0.95).Conclusion Analysis of large-scale datasets and IHC staining demonstrated that TLDC2 is a highly sensitive and specific biomarker for colorectal adenocarcinoma.

Purpose This study aimed to investigate the expression and clinical significance of TLDC2 in colorec-tal adenocarcinoma.Methods Data from the human protein atlas(HPA)and the cancer genome atlas(TCGA)indi-cated that TLDC2 was highly expressed in colorectal adenocarcinoma.We further analyzed the expression of TLDC2 in 400 colorectal adenocarcinomas and 447 other solid tumors using tissue microarrays and immunohistochemical(IHC)staining.Result The positive expression rate of TLDC2 was significantly higher than that of SATB2 in colorectal ade-nocarcinomas(96.5％vs 87.0％,P＜0.000 1).TLDC2 positivity exceeded that of SATB2 in both low-or high-grade colorectal adenocarcinoma(99.4％vs 88.7％,P＜0.000 1;83.3％vs 79.2％,P=0.669 9).In addition,the expression of TLDC2 and SATB2 was evaluated in 447 cases of other types of solid tumors.TLDC2 was expressed in neuroendocrine tumors as well as in gastric and appendiceal adenocarcinomas,whereas SATB2 was detected in a small number of melanomas,ovarian cancers,breast cancers and gallbladder cancers.The positive and specificity of TLDC2 for colorectal adenocarcinoma were 97％(95％CI=0.94-0.98)and 85％(95％CI=0.81-0.88),respectively.Combined detection of TLDC2 and SATB2 yielded a sensitivity of 96％(95％CI=0.93-0.97)and a specificity of 93％(95％CI=0.90-0.95).Conclusion Analysis of large-scale datasets and IHC staining demonstrated that TLDC2 is a highly sensitive and specific biomarker for colorectal adenocarcinoma.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of Lewy bodies, leading to motor and nonmotor symptoms. While both genetic and environmental factors contribute to PD, recent studies highlight the crucial role of lipid metabolism disturbances in disease progression. Altered lipid homeostasis promotes protein aggregation and oxidative stress, with significant changes in lipid classes such as sphingolipids and glycerolipids observed in patients with PD. These disturbances are involved in key pathological processes, such as α-synuclein aggregation, organelle dysfunction, lipid-mediated neuroinflammation, and impaired lipid homeostasis. This review examines the relationship between lipid species and PD progression, focusing on the physiological roles of lipids in the central nervous system. It explores the mechanistic links between lipid metabolism and PD pathology, along with lipid-related genetic risk factors. Furthermore, this review discusses lipid-targeting therapeutic strategies to mitigate PD progression, emphasizing the potential of lipid modulation for effective treatment development.
Humans ; Parkinson Disease/metabolism* ; Lipid Metabolism/physiology* ; Animals ; Oxidative Stress/physiology* ; alpha-Synuclein/metabolism*

Objective To investigate the factors influencing the natural outcome of low-grade squamous intraepithelial lesions(LSIL)of the cervix.Methods A total of 154 patients who underwent colposcopic cervical biopsy in the Third Affiliated Hospital of Zhengzhou University from January 2022 to January 2023 were selected and divided into negative conversion group(55 cases),continuous group(70 cases)and upgraded group(29 cases)according to the follow-up results.Logistic regression was used to analyze the influence of related factors on the outcome of LSIL.Results There were statistically significant differences in the number of vaginal births,the results of thin-prep cytology test,human papilloma virus(HPV)typing,whether vaginal LSIL was combined,whether there were symptoms,and vaginal microecology among three groups(P＜0.05).Multivariate Logistic analysis showed that combined vaginal LSIL,vaginal microecological abnormalities,atypical squamous cell-cannot exclude high-grade squamous intraepithelial lesion(ASC-H)/high-grade squamous intraepithelial lesion(HSIL),HPV 16/18 positive or mixed positive were independent risk factors for persistent infection(P＜0.05),combined vaginal LSIL,symptomatic,vaginal microecological abnormalities,ASC-H/HSIL,HPV 16/18 positive or mixed positive were all independent risk factors for escalation of lesions(P＜0.05).Conclusion Patients with vaginal LSIL,vaginal microecological abnormalities,ASC-H/HSIL,HPV 16/18 positive or mixed positive should be followed up and early intervention to reduce the risk of disease escalation.

Aortic aneurysm and dissection are critical cardiovascular diseases that threaten human life and health seriously. No pharmacological treatment can effectively prevent disease progression. The imbalance of aortic wall cells and non-cellular components leads to structural or functional degeneration of the aorta, which is a prerequisite for disease occurrence. As the important non-cellular component, extracellular matrix (ECM) is crucial to maintain the aortic structure, function, and homeostasis. Abnormal production of elastin and collagen, destruction of cross-linking between elastic fibers and collagen fibers, and the imbalance of metalloproteinase and inhibitors leads to excessive degradation of ECM proteins, all of which have destroyed the structure and function of aorta. It will provide more ideas for disease prevention and treatment by learning ECM proteins and their metabolic mechanism. Here, we focus on the ECM proteins that have been reported to be involved in aortic aneurysm and dissection, and discuss the regulatory mechanism of metalloproteinase and inhibitors.

Objective To investigate the effect of the glutathione peroxidase 4(GPx4)on mouse so-matic cell reprogramming.Methods To compare the expressions of GPx4 in OG2 mouse embryonic fibroblast(OG2-MEF)cells(MEFs group)and mouse embryonic stem cells(mESC,mESCs group),the expression lev-el of intracellular GPx4 was determined by transcriptome sequencing technique and Western blot.To verify the effect of GPx4 on the efficiency of the somatic cells reprogramming,the complete open reading frame se-quence of GPx4 gene and its selenocysteine insertion sequence(SECIS)were connected to the retroviral vector pMXs for constructing the overexpressed plasmid pMXs-GPx4.Gpx4-targeting short hairpin RNA(shRNA)was synthesized and connected to pSUPER vector,GPx4 shRNA1 and GPx4 shRNA2 were constructed to knockdown GPx4 expression.The above plasmids were co-transfected with pMXs-Sox2,pMXs-Klf4 and pMXs-Oct4 into MEF cells for reprogramming induction to obtain the pMXs no-load control group(pMXs NC),pMXs GPx4 group,pSUPER no-load control group(pSUPER NC),GPx4 shRNA1 group and GPx4 shRNA2 group.The expressions of GPx4 gene and multifunctional marker genes Rex1,Sox2,Dappa3,Sall4,Oct4 and Nanog were detected by real-time fluorescence quantitative PCR.The induced pluripotent stem cells(iPSC)were detected by immunofluorescence staining;the number of iPSC clones generation was detected by alkaline phosphatase staining of pluripotent stem cells;the GPx4 protein expression was detected by Western blot.Results The mRNA and protein expression of GPx4 in the mESCs group was higher than that in the MEFs group;compared with the pMXs NC group,the expression level of GPx4 mRNA in the pMXs GPx4 group was significantly increased;compared with the pSUPER NC group,the GPx4 mRNA and protein levels in the GPx4 shRNA1 group and GPx4 shRNA2 group were decreased(P＜0.05);the iPSC clone number in the pMXs GPx4 group was higher than that in the pMXs NC group,but the difference was not statistically significant(P＞0.05).The number of iPSC clones in the GPx4 shRNA1 group and GPx4 shRNA2 group was significantly lower than that in the pSUPER NC group,and the difference was statistically significant(P＜0.05).After completing the reprogramming,compared with the original MEF cells,the expression levels of various pluripotent marker genes Rex1,Sox2,Dappa3,Sall4,Oct4 and Nanog in the generated iPSC of each group were increased.Conclusion GPx4 knockdown could inhibit the efficiency of somatic cell reprogram-ming,its generated induced pluripotent stem cells have the normal pluripotent gene expression ability.

At present,the commonly used clinical protocols of oral comestic restoration are mostly based on the aes-thetic indicators proposed by Western developed countries(referred to as Western aesthetics).Mechanically copying the Western aesthetic scheme,ignoring the difference between it and the Chinese oral aesthetic indicators(referred to as Chinese aesthetics),is unable to effectively support personalized cosmetic restoration diagnosis and treatment.In addition,new technologies and new solutions for cosmetic restoration,which are developing rapidly in recent years,are emerging one after another,but many popular concepts are confusing and lack of proper hierarchical diagnosis and treatment norms,and there is indeed an urgent need for discussion and clarity.From the perspective of serving clinical application,this paper discusses the deficiencies of the Chinese translation of the word"aesthetics",the diffe-rence and connection between aesthetics and cosmetolo-gy,and the relationship between cosmetic restoration and fixed restoration.It also discusses the difference be-tween anterior teeth,esthetic zone and exposed zone,the diagnostic and therapeutic value of oral aesthetic analysis,as well as the application methods of desensitization,suggestion,and other therapies in difficult oral cosmetic restoration cases.We further introduce the decision tree and the clinical pathway for restoration and reconstruction of teeth in ex-posed zone guided by aesthetic analysis,and introduce the clinical process of aesthetic analysis and evaluation,the clinical triclassification of oral cosmetic restoration,and the corresponding clinical classification diagnosis and treat-ment points.

At present,the commonly used clinical protocols of oral cosmetic restoration are mostly based on the oral aesthetic indexes proposed by Western developed countries(referred to as Western aesthetics),which are different from the oral aesthetic indexes unique to Chinese people(referred to as Chinese aesthetics).In the design of restoration schemes and the evaluation of restoration effects,these differences have a large or small effect on the doctor-patient-tech-nology triad.Improper handling could directly weaken the cooperation efficiency of the three parties,reduce patient satis-faction,and even lead to medical disputes in serious cases.From doing a good job of oral cosmetic restoration in China,the connotative characteristics of Chinese oral aesthetics are introduced in this paper,and the value of oral aesthetic anal-ysis in diagnosis and treatment is discussed.The process and method of aesthetic analysis and assessment through the modified Chinese psychosocial impact of dental aesthetics questionnaire and the evaluation ruler of the expected value of oral cosmetic restoration are further introduced in detail.