Linxian County in Henan Province, Northern China is known as the region with the highest incidence and mortality rate of esophageal cancer worldwide. Since 1959, the Henan medical team has conducted field work on esophageal cancer prevention and treatment in Linxian. Through three generations of effort exerted by oncologists over 65 years of research on esophageal cancer prevention and treatment in Linxian, the incidence rate of esophageal squamous cell carcinoma in this area has dropped by nearly 50%, and the 5-year survival rate has increased to 40%, reaching the international leading level. This article aims to summarize the history, present opportunities and new challenges, and explore the experience of esophageal cancer prevention and treatment in Linxian (referred to as the “Linxian experience”), providing reference and guidance to cancer prevention and treatment research in China.

AIM: To investigate the mechanism of Hexue Mingmu Tablets(HXMMT)in improving diabetic retinopathy(DR)based on transcriptomics.METHODS: Zebrafish DR models were established by 3-day glucose induction(130 mmol/L)starting at 3 days post-fertilization(dpf). Larvae were randomized into four groups: control group(CG; aquaculture water), model group(MG; 130 mmol/L glucose), low-dose HXMMT treatment group(L-HX; 130 mmol/L glucose +7.5 mg/L HXMMT), and high-dose HXMMT treatment group(H-HX; 130 mmol/L glucose +75 mg/L HXMMT), with a 3-day intervention period until 6 dpf. The area and length of eyes, and body length of zebrafish were observed by stereomicroscopy, retinal morphology was observed by hematoxylin-eosin staining(HE), and retinal vessel diameter was observed under fluorescence microscope. Differentially expressed genes(DEGs)were identified by RNA-sequencing(RNA-seq)technology to further elucidate the molecular mechanism of HXMMT in improving DR in zebrafish, and the sequencing accuracy was validated through quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: HE staining demonstrated that the intervention with HXMMT significantly improved the disordered cell arrangement, widened gaps, and thickened inner nuclear layer(INL)in ganglion cell layer GCL); retinal vascular diameter quantification revealed that the retinal vessel diameter of the MG significantly increased compared with the CG, and it was significantly changed after the intervention of HXMMT, with significant efficacy in the H-HX(P<0.05); transcriptomics profiling identified 1 470 reversed DEGs, predominantly enriched in the AMPK signaling pathway, FoxO signaling pathway, retinal developmental processes, and tight junction regulation. Technical validation confirmed strong correlation between qRT-PCR and RNA-seq data(R2=0.8571, P<0.05).CONCLUSION: HXMMT may improve retinal vascular microcirculation disorders in DR by regulating core targets including vsx1, pde6c, arr3a, plk1, fbp1b, foxo1a, pcna, and cdk1, as well as synergistically modulating processes such as retinal development in camera-type eyes, visual perception, microtubule cytoskeletal organization, tight junctions, and the AMPK signaling pathway, Foxo signaling pathway.

ObjectiveTo decipher the mechanism of Wenxiao powder in alleviating corticosterone-induced depression-like behaviors in mice. MethodMale ICR mice were randomized into normal， model， paroxetine （20 mg·kg^-1）， and low- and high-dose （3.27， 6.54 g·kg^-1， respectively） Wenxiao powder groups. The mice in normal and model groups received equal volume of saline. Other groups except the normal group were injected with corticosterone subcutaneously 0.5 h after gavage to induce depression. Mice were tested for depression-like behaviors after drug administration. Enzyme-linked immunosorbent assay （ELISA） was performed to measure the corticosterone content in the serum. Nissl staining was performed to observe the damage of hippocampal neurons. Immunofluorescence staining was employed to observe the expression of double cortin （DCX） in the dentate gyrus （DG） of the hippocampus. Western blot was employed to determine the expression of proteins in the brain-derived neurotrophic factor （BDNF）/tyrosine kinase receptor B （TrkB）/extracellular signal-regulated kinase （ERK）/cAMP-response element-binding protein （CREB） pathway in the hippocampus. ResultCompared with the normal group， the model group showed decreased sucrose preference rate， increased immobility time in the tail suspension test （P<0.01）， and reduced residence time in the central area of the open field and the total movement distance （P<0.05， P<0.01）. In addition， the modeling elevated the corticosterone level in the serum （P<0.01）， decreased the volume and intensified the nuclear staining of hippocampal neurons in the DG area， reduced the expression of DCX in the DG area， and down-regulated the protein levels of BDNF， phosphorylated （p）-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. Compared with the model group， low-dose Wenxiao powder improved the mouse behavivors in the sucrose preference， open field， and tail suspension tests （P<0.05， P<0.01）， and high-dose Wenxiao powder improved the behaviors in the sucrose preference and open field tests （P<0.05， P<0.01）. In addition， Wenxiao powder lowered the serum corticosterone level （P<0.01） and recovered the structure and morphology of neurons with obvious nuclei and presence of Nissl bodies in the DG area of the hippocampus. Moreover， Wenxiao powder at both doses promoted the expression of DCX in the DG area， and high-dose Wenxiao powder up-regulated the protein levels of BDNF， p-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. ConclusionWenxiao powder can alleviate corticosterone-induced depression-like behaviors and promote neurogenesis in mice possibly by activating the BDNF/TrkB/ERK/CREB signaling pathway.

Objective:To analyze the improvement effect of monk fruit on diabetic nephropathy(DN)by network pharmacology,and to elucidate its possible related mechanism.Methods:The Traditional Chinese Medicine Systems Pharmacology(TCMSP)Database was used to detect the active ingredients and their targets of monk fruit;the DN target genes were screened out by DisGeNET Database and Genecards Database;the key targets of monk fruit against DN were obtained by comparing the monk fruit with DN targets;protein-protein interaction(PPI)network diagram was constructed by STRING Database and Cytoscape software;Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis were performed by Cytoscape software.Molecular docking technology was used to predict the binding abilities of the core targets and the main active ingredients of monk fruit.Results:The TCMSP Database combined with the selection criteria was used to screen out a total of five active ingredients of monk fruit(ZINC03860434,Perlolyrine,beta-sitosterol,Kaempferol,and Flazin)as well as 85 targets represented by serine/threonine protein kinase 1(AKT1),transcription factor RELA,c-Jun N-terminal kinase(JUN),and tumor necrosis factor(TNF).Among them,Kaempferol contained the most targets.Among the 85 targets,34 were associated with DN.The GO functional enrichment analysis mainly included biological process(BP)such as oxidative stress,regulation of inflammation and apoptosis,and cell signaling transduction.The KEGG enrichment analysis included advanced glycosylation end product(AGE)-receptor of AGE(AGE-RAGE)signaling pathway,TNF signaling pathway,and C-type lectin receptor signaling pathway.The results molecular docking technology of the main active ingredients of monk fruit and DN target proteins showed that 5 kinds of molecular docking engergy were-8.00--5.00 kJ·mol-1.Conclusion:Kaempferol is the most effective active ingredient in the monk fruit for the treatment of DN,and its mechanism is mainly related to anti-inflammatory.

Mitochondrial quality control plays an important role in maintaining homeostasis of mitochondrial network and normal function of mitochondria. ATPase family AAA domain-containing protein 3A (ATAD3A) is one of the mitochondrial membrane proteins involved in the regulation of mitochondrial structure and function, mitochondrial dynamics, mitophagy and other important biological processes. Recent studies show that ATAD3A not only interacts with Mic60/Mitofilin and mitochondrial transcription factor A (TFAM) to maintain mitochondrial cristae morphology and oxidative phosphorylation, but also interacts with dynamin-related protein 1 (Drp1) to positively/negatively regulate mitochondrial fission. In addition, ATAD3A serves as a bridging factor between the translocase of the outer mitochondrial membrane (TOM) complex and translocase of the inner mitochondrial membrane (TIM) complex to facilitate the import of PTEN-induced putative kinase protein 1 (PINK1) into mitochondria and its processing displays a pro-autophagic or anti-autophagic activity. This article reviews the role and mechanism of ATAD3A in regulating mitochondrial quality control. Firstly, as an inner mitochondrial membrane protein, ATAD3A is involved in maintaining the stability of mitochondrial crista structure, and its gene deletion or mutation will cause the loss and breakage of crista. Secondly, ATAD3A is also involved in maintaining mitochondrial respiratory function and mitochondrial nucleoid homeostasis, and its gene deletion or mutation can reduce the activity of mitochondrial respiratory chain complex and enhance the size and movement of nucleoid. Thirdly, ATAD3A participates in the negative regulation of mitochondrial fusion, but its role in mitochondrial fission may dependent on specific cell types, as it can promote and/or inhibit the mitochondrial fission by increasing and/or decreasing phosphorylation or oligomerization of Drp1. Finally, ATAD3A can interact with mitophagy-related proteins (e.g. PINK1, autophagy/beclin-1 regulator 1 (AMBRA1), acylglycerol kinase (AGK)) to enhance/reduce PINK1-Parkin-dependent mitophagy.

Glioma is the most common malignancy of the central nervous system, originating mainly from glial cells. Because of its highly aggressive nature, glioma has one of the highest rates of death among all types of cancer. Therefore, it is very important to develop new therapeutic approaches and drugs for glioma treatment. Instead of activate the telomerase, approximately 30% of glioma use alternative lenthening of telomere (ALT) to maintain telomere length. The mechanism of ALT development is poorly understood, however, some genetic mutations have been reported to induce the development of ALT glioma, such as ATRX, IDH1, p53, etc. The lack of ALT glioma cell lines and preclinical ALT glioma models has limited the mechanistic studies of ALT glioma. Therefore, this review listed ALT glioma cell lines that derived from primary culture or gene editing in the last decade, as well as the xenografted animal models established by ALT glioma cell lines, and discussed the role and significance these cell and animal models play in preclinical studies.

Objective To explore the risk factors of apathy and correlations with cognitive function in patients with hypertension combined with cerebral small vessel disease(CSVD).Methods Totally 141 patients with hypertension combined with CSVD were prospectively enrolled and were divided into apathy group(n=43)and non-apathy group(n= 98)according to neuropsychiatric inventory-apathy scale(NPI-Apathy)scores.The general data,imaging marker scores and total imaging burden scores were compared between groups.In hypertension combined with CSVD patients,multivariate logistic regression analysis was performed to screen the independent risk factors of apathy,and Spearman correlation analysis was also performed to observe the correlation of apathy and cognitive function.Results The patients'age,high density lipoprotein cholesterol(HDL-C),Fazekas scores of lateral periventricular white matter hyper-intensity(WMH),cerebral microbleed of depth/infratentorial and total imaging burden scores of apathy group were all higher,while mini-mental state examination(MMSE)and Montreal cognitive assessment(MoCA)scores were both lower than those of non-apathy group(all P＜0.05).HDL-C and Fazekas scores of lateral periventricular WMH were both independent risk factors for apathy(both P＜0.05),while NPI-Apathy scores were moderately negatively correlated with cognitive function in patients with hypertension combined with CSVD(r=-0.543,-0.484,both P＜0.001).Conclusion HDL-C and Fazekas scores of lateral periventricular WMH were both independent risk factors for apathy in patients with hypertension combined with CSVD.The more severe the apathy,the lower the cognitive function.

Objective To investigate the role of Smad signaling pathway in rat model of cerebral in-farction and explore the expression of insulin-like growth factor binding protein 3(IGFBP-3)in brain tissue and its relationship with neural function.Methods Sixty healthy adult male SD rats were randomly and equally divided into model group,sham-operation group,and normal control group.The model of cerebral infarction was established by using intraluminal thread occlusion,and the rats of the sham-operation group were only given exposure of the internal carotid artery and direct suture of the incision.In 1 week after successful modeling,Modified Neurological Seve-rity Score(mNSS)was used to evaluate the neurological function.HE staining was employed to observe the histopathological changes in the brain tissues.Western blotting and RT-PCR were adopted to detect the brain expression of IGFBP-3,Smad2 and Smad4 at protein and mRNA le-vels.Spearman correlation analysis was conducted to analyze the correlation among the expression levels of IGFBP-3,Smad2,Smad4 and P21.Results HE staining displayed that obvious brain ede-ma,characterized by disordered arrangement of brain cells,increased microglia,and blurred nucleo-lus of brain cells were observed in the rats of the model group,with the area of cerebral infarct of 20.55％.The mNSS score and the protein and mRNA levels of IGFBP-3,Smad2 and Smad4 were significantly higher,but the P21 protein and mRNA levels were obviously reduced in the model group than the sham-operation group and normal control group(P＜0.05,P＜0.01).Spearman correlation analysis showed that the mRNA level of IGFBP-3 in cerebral infarction rats was posi-tively correlated with the mNSS score and mRNA expression levels of Smad2 and Smad4(r=0.568,r=0.623,r=0.597;P＜0.01),and negatively with P21 mRNA level in the brain tissue(r=-0.573;P＜0.01).Conclusion The level of IGFBP-3 is significantly increased in brain tissue of rats with cerebral infarction,and it is closely associated with neural function of these rats,which may be related to Smad signaling pathway.

ObjectiveTo explore new targets and herbal medicines of total ginsenosides in ameliorating alcoholic hepatitis （AH） by data mining and experimental validation and to provide new directions for the clinical treatment of AH. MethodGSE28619 was selected as the test set from the GEO database and GSE83148 and GSE103580 were selected as the validation sets. The limma package and weighted gene co-expression network analysis （WGCNA） were employed to identify the AH-related differentially expressed genes and modular genes， and Venny was used to extract the common genes. The protein-protein interaction （PPI） network was constructed and the enrichment analysis was carried out. The hub genes were further screened and evaluated for their diagnostic value. After validation with the datasets， new potential targets of AH and traditional Chinese medicine were predicted. Molecular docking between the targets and active ingredients of traditional Chinese medicine was performed， and the results were validated by experiments. Eight out of 48 SD rats were randomly selected into a blank group and received an equal amount of normal saline. The rest rats were subjected to modeling with ethanol by gavage and then randomized into low- （10 mg·kg^-1）， medium- （20 mg·kg^-1）， and high-dose （40 mg·kg^-1） total ginsenosides， model， and positive control （metadoxine， 117 mg·kg^-1） groups. After 3 weeks of gavage， serum samples were collected for the measurement of aspartate aminotransferase （AST） and alanine aminotransferase （ALT） levels， and liver samples were collected for hematoxylin-eosin （HE） staining. Western blot and Real-time PCR were employed to determine the protein and mRNA levels， respectively， of potential targets in the liver tissue. ResultData mining predicted the potential genes： Proto-oncogene FOS and collagen type Ⅰ alpha 2 （COL1A2）. Experimental validation showed that the liver injury was alleviated after drug administration compared with that after modeling. The serum AST and ALT levels were reduced after drug administration. The protein and mRNA levels of FOS were significantly up-regulated， while those of COL1A2 were down-regulated after drug administration. ConclusionTotal ginsenosides ameliorate HA via FOS and COL1A2.

Background Excessive radon exposure is considered the second risk factor for lung cancer. Since the opening of the subway in a city of Zhejiang Province, the exposure level of radioactive gas radon in subway stations and its impact on occupational health have become one of the important issues of public concern. Objective To monitor the radon concentration of subways in a city in Zhejiang Province and explore the effect of radon exposure on chromosome aberration and micronuclei in the working population. Methods A total of 55 vehicle control rooms of 55 stations affiliated to two different subway lines in a city were measured for one year; the 110 ticket offices and 55 security checkpoints from the same 55 stations were measured from 16 March to 14 June. The radon concentrations were compared by job types, subway lines, and seasons referring to Measurement methods for determination of radon in environmental air (HJ 1212-2021). Peripheral blood lymphocyte chromosome aberration and micronucleus analyses were conducted in 165 subway workers from monitoring sites for three different job types, then the influencing factors were analyzed. The detection methods were adopted from the standards of Test and assessment of chromosomal aberrations on occupational health examinations for radiation workers (GBZ/T 248-2014) and Standard for the method of micronucleus detection in lymphocytes on occupational health examination for radiation workers and exposure dose estimation (GBZ/T 328-2023). Results The radon concentration range of the target subways in Zhejiang Province was 10-320 Bq·m⁻³, all lower than the national limit (≤400 Bq·m⁻³). The differences in radon radioactivity levels among different lines, job types, and time segments were statistically significant (P<0.05). The rates of chromosomal aberration and micronucleus formation among the 165 subjects were 0.224% and 0.024%, respectively. There were significant differences in the rates of chromosome aberration and micronuclei among different jobs (vehicle control room, ticket office, security checkpoint) (P<0.05), but the abnormal rates were lower than the limits of the corresponding national standard. No significant correlation was found between jobs and chromosomal aberrations or micronuclei (P>0.05). Chromosome aberration and micronuclei varied by age, subway station seniority, and smoking (P<0.05). No effect of the above factors on chromosome aberration and micronuclei was observed by logistic regression (P>0.05). Conclusion The radon concentration in the target subway system is at a normal level. The rates of chromosomal aberration and micronucleus formation vary by jobs, but both are lower than the corresponding national limits. Therefore, radon exposure has not yet caused outstanding health impact on the subway workers.