The molecular mechanism underlying male reproductive toxicity associated with Perfluorooctanoic acid (PFOA), a persistent environmental endocrine disruptor (EDC), has not yet been fully elucidated. Six-week-old male C57BL/6 mice were treated with PFOA by oral gavage at 0, 1.25, 5, 10, and 20 mg/kg/day for 35 days to explore its toxic effects on the male reproductive system and the underlying mechanisms. Analyses of semen quality, testicular histopathology, and blood-testis barrier (BTB) integrity revealed that PFOA caused dose-dependent structural and functional damage to the BTB, leading to markedly reduced semen quality. Based on transcriptomic sequencing and differential gene enrichment analysis, the glycolytic pathway was identified as a key regulatory target for PFOA-induced damage to the reproductive system. Further validation revealed that PFOA exposure inhibited glycolysis-related enzymes (Hexokinase 1 (HK1), Glucose Transporter 1 (GLUT1), and Lactate Dehydrogenase A (LDHA)), reduced lactate production and ATP synthesis, lowered Pan-Kla and H3K18la levels, and diminished H3K18la enrichment at the Hk1, Glut1, and Ldha promoters, whereas exogenous sodium lactate reversed these changes. This study is the first to identify the "glycolysis-lactate-H3K18la" chain as a key regulator in PFOA-induced BTB damage and spermatogenesis impairment, offering a new theoretical foundation for understanding EDC-induced male reproductive toxicity.

Despite the known association between calcium and magnesium in drinking water and stone risk, the difference in stone prevention of purified water remineralized with varying calcium-to-magnesium ratios (Ca:Mg) remains unclear. Objectives: This study investigates the impact of different Ca:Mg in the remineralization of purified water on calcium oxalate crystallization and renal injury. Methods: Sixty male Sprague-Dawley rats were induced calcium oxalate crystals by a sodium oxalate diet and divided into six groups, where they drank purified water with or without remineralized varying Ca:Mg (0.5, 3.4, 10, 20, 100). Serum and urine biomarkers of renal function, renal injury, mineral metabolism, bone metabolism, and urine calcium oxalate crystals were detected. Kidneys were isolated for pathological examination. Results: Findings showed that remineralization by 0.5 and 3.4 Ca:Mg significantly reduced urinary calcium oxalate crystallization, renal injury, and improved renal function, while extreme ratios (Ca:Mg over 10) showed no benefits. Conclusions: These results elucidate the pathophysiological effects of Ca:Mg in drinking water on renal health, particularly emphasizing the protective role of the 0.5 and 3.4 in inhibiting calcium oxalate crystallization and mitigating renal injury. It provides a quantifiable reference for purified water remineralization aimed at stone prevention.

Limited immune cell infiltration is the main reason for poor immunotherapeutic efficacy in colorectal cancer patients. Here we design a peptide-based nanorobot that recognizes PD-L1 and breaks cancer cell membranes by in situ forming fibrils through a pH-responsive module. The nanorobot shows long retention in targeted tumours (>120 h) through interaction with PD-L1 and blocks PD-1/PD-L1 to activate the T cell killing effect. At the same time, in the tumour microenvironment (pH 6.5), it forms fibrils that break the cancer cell membrane, inducing immunogenic cell death with the release of damage-associated molecular patterns and the subsequent infiltration of T cells. The nanorobot shows higher therapeutic efficacy than the regimen of αPD-L1+oxaliplatin in a variety of colorectal-cancer-tumour-bearing mouse models and has good biocompatibility due to the targeted breakage of cancer cells, exhibiting great potential for colorectal cancer immunotherapy in clinic.

Lead (Pb) is one of the most common environmental pollutants that negatively impacts male reproductive health. Thus far, the underlying molecular mechanisms of Pb-induced reproductive toxicity are still not well understood. In this study, 64 male ICR mice were given drinking water with Pb (0, 100, 200, and 300 mg/L) for 90 days. We found that exposure to 300 mg/L Pb resulted in reduced sperm quality and elevated autophagy-related protein levels in the mouse testes. Our findings indicate that the Pb hindered the autophagic clearance by impairing the lysosomes’ function and then obstructing the fusion of lysosomes and autophagosomes. The autophagy cycle obstruction prevented the lipid droplets from breakdown and led to their accumulation in the Sertoli cells. In turn, the ccytotoxic effects that resulted from the interruption of the autophagy maturation stage, instead of the elongation phase, could be alleviated by either Chloroquine or Bafilomycin A1. Furthermore, exposure to 400 μM Pb initiated the TFE3 nuclear translocation and caused the increased expression of its target genes. Then, the knockdown of TFE3 reduced the formation of the autophagosome. In addition, the use of the antioxidant NAC notably enhanced the autophagic activity and reduced the occurrence of lipid droplets in the Sertoli cells. This study demonstrated that Pb disrupted the autophagic flow, which caused lipid droplet accumulation in the TM4 cells. Consequently, focusing on the maturation stage of autophagy might offer a potential therapeutic approach to alleviate male reproductive toxicity caused by Pb exposure.

Di (2-ethylhexyl) phthalate (DEHP) is an acknowledged endocrine disruptor with male reproductive toxicity; nevertheless, the transgenerational impacts on male offspring resulting from paternal exposure, along with the mechanisms involved, are not well understood. To develop a transgenerational model of DEHP paternal exposure, male C57BL/6J mice (4-week) exposed to DEHP (5, 250, and 500 mg/kg/d) for 35 days were then bred with unexposed female mice at a ratio of 1:2 to produce offspring. Findings indicate that the sperm quality and relative sex hormones were adversely affected in males of F1 and F2 generations, and pathological damage in the testes and the apoptosis of testicular cells were also observed. Interestingly, an increase in the expression levels of H3K27me3 was observed in the testicular tissues of male descendants. It was further confirmed by in vitro approach that H3K27me3 may down-regulate the expression of Bcl-2 and plays a role in regulating the initiation of apoptosis in Leydig cells triggered by MEHP (the primary metabolite of DEHP). Additionally, the down-regulation of Bcl-2 can be reversed by treatment with the H3K27me3 inhibitor GSK126. To conclude, DEHP leads to transgenerational harm to male offspring reproductive systems, with the epigenetic mechanism of H3K27me3 playing a key role in mediating these effects.

Microcystin-LR (MC-LR), a prevalent cyanotoxin present in hazardous cyanobacterial blooms, is recognized as a neurotoxic environmental pollutant that induces brain damage and neurobehavioral deficits. However, the mechanisms underlying MC-LR-induced neurotoxicity remain unclear. This study aims to elucidate the role of mitophagy in MC-LR-induced neurotoxicity both in vitro and in vivo. We found that administration of 10 mu g/kg body weight (intraperitoneally) MC-LR impaired learning and memory abilities and induced neuronal damage and apoptosis in the CA1 region of the hippocampus in rats. Exposure to MC-LR (1 mu M-10 mu M) resulted in cellular damage and apoptosis in PC-12 and HT22 cells. MC-LR induced mitophagy through the PINK1/Parkin pathway but hindered mitophagy progression by repressing Scd2 transcription in neurons. These inhibitory effects were reversed by Scd2 overexpression. Furthermore, MC-LR was found to repress Scd2 transcription by directly binding to type 1 insulin-like growth factor receptor (IGF-1R) and competitively inhibiting its activation by Insulin-like growth factor 1 (IGF-1). Overexpression of IGF-1R and administration of exogenous IGF-1 mitigated the MC-LR-induced inhibition of Scd2 and the associated mitophagy defects. These findings indicate that IGF-1R is the direct target of MC-LR in neurons. MC-LR initiates mitophagy defects and apoptosis by inhibiting Scd2 transcription through binding to IGF-1R.

This study looked at how desalinated seawater, which has low minerals and high boron, could affect bone health. Prior research suggests that low mineral water may harm bone health and boron could be beneficial, but the overall impact on bone health is still unclear. Eighty-nine-week-old male Balb/C mice were allocated into eight groups and administered either tap water or purified water with varying boron concentrations (0, 5, 40, and 200 mg/L). They were kept in an environment mimicking tropical conditions (35–40 °C, 70–80% humidity) and underwent daily treadmill exercise for 13 weeks. At the 14th week, serum, femora, and lumbar vertebrae were collected for mineral metabolism, bone biomarker, microstructure, and biomechanics evaluation. Boron exposure improved bone formation, microstructure, and biomechanics initially but the benefits weakened with higher levels of exposure (p < 0.05). Co-exposure to purified water elevated serum boron but weakened the promotion of boron on bone minerals and the bone benefits of boron compared to tap water (p < 0.05). Thus, when studying the health effects of boron in desalinated seawater, it is crucial to look at various health effects beyond bone health. Furthermore, it is important to consider the mineral composition of drinking water when using boron for bone health benefits.

Microcystin-leucine arginine (MC-LR) is a common cyantotoxin produced by hazardous cyanobacterial blooms, and eutrophication is increasing the contamination level of MC-LR in drinking water supplies and aquatic foods. MC-LR has been linked to colorectal cancer (CRC) progression associated with tumor microenvironment, however, the underlying mechanism is not clearly understood. In present study, by using GEO, KEGG, GESA and ImmPort database, MC-LR related differentially expressed genes (DEGs) and pathway- and gene set-enrichment analysis were performed. Of the three identified DEGs (CXCL1, GUCA2A and GDF15), CXCL1 was shown a positive association with tumor infiltration, and was validated to have a dominantly higher upregulation in MC-LR-treated tumor-associated macrophages (TAMs) rather than in MC-LR-treated CRC cells. Both CRC cell/macrophage co-culture and xenograft mouse models indicated that MC-LR stimulated TAMs to secrete CXCL1 resulting in promoted proliferation, migration, and invasion capability of CRC cells. Furtherly, IP-MS assay found that interaction between TAMs-derived CXCL1 and CRC cell-derived IGHG1 may enhance CRC cell proliferation and migration after MC-LR treatment, and this effect can be attenuated by silencing IGHG1 in CRC cell. In addition, molecular docking analysis, co-immunoprecipitation and immunofluorescence further proved the interactions between CXCL1 and IGHG1. In conclusion, CXCL1 secreted by TAMs can trigger IGHG1 expression in CRC cells, which provides a new clue in elucidating the mechanism of MC-LR-mediated CRC progression.

《军队环境卫生学》是军事预防医学专业必修课.当前这门课主要通过举例的方式进行课堂思政,形式单一,学生接受度不强,且课堂思政例子与教学要点结合不够紧密,不能够与专业知识传授相辅相成.通过在教学案例中发掘思政要素,将课程思政融入案例教学.这种思政模式可以在帮助学生理解、整理和归纳知识,提升实践能力的同时,完成课堂思政,做到课堂教学和课堂思政两不误.

As a typical environmental endocrine disrupting chemical (EDC), di-(2-ethylhexyl) phthalate (DEHP) is thought to be related to reproductive disorders, especially in males. Growing evidence suggests that various EDCs may result in an impaired telomere structure and function, which is associated with male infertility. However, the adverse effect of DEHP on telomeres in male reproductive cells has rarely been studied, and the related mechanisms remain unclear. In this study, we tested the effects of mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, on telomere dysfunction in mouse spermatogonia-derived cells (GC-1) and the potential role of TERT and c-Myc in MEHP-induced spermatogenic cell damage. Results showed that MEHP induced cell viability inhibition, G0/G1 phase cell cycle arrest, and apoptosis in GC-1 cells in a dose-dependent manner. Shortened telomeres, reduced telomerase activity, and decreased expression of TERT, c-Myc, and upstream transcription factors of c-Myc were also observed in the MEHP-treated cells. In conclusion, it can be concluded that TERT-mediated telomere dysfunction may contribute to MEHP-induced G0/G1 phase cell cycle arrest and apoptosis in GC-1 cells through the impairment of c-Myc and its upstream transcription factors.

微课作为军事医学新型的信息化教学方式之一,为教育创新模式增添了新色彩.军队环境卫生学是军医大学预防医学专业本科学员的专业课程之一,在军队内外卫生防疫部门、环境卫生以及环境医学部门都广为应用.文章结合前期开展的微视频建设,从教学目标和要求出发,关注于教学重难点,结合传统教学设计和课程模式,对军队环境卫生学微课的建设进行探索,并探讨微课建设面对的问题,为下一步提升教学方法、提高教学质量提供支持.

Gastric cancer (GC) is the fourth leading cause of cancer-related death. Its poor prognosis is attributed to unclear pathogenesis. Currently, the most widely accepted model for elucidating the mechanism of GC is the Correa cascade, which covers several histological lesions of the gastric mucosa. GC stem cells (CSCs) are crucial for oncogenesis in the Correa cascade and GC progression. As Helicobacter pylori (H. pylori) is the etiological factor in the Correa cascade, growing evidence suggests that enhancement of gastric stem cell-like properties and increase in CSCs correlate with H. pylori infection. In this paper, we review recent studies that present pathogenic mechanisms by which H. pylori induces gastric stem cell-like properties and CSCs, which may supplement the existing Correa model of GC. First, the dysfunction of developmental signaling pathways associated with H. pylori infection leads to the enhancement of gastric stemness. Second, H. pylori infection promotes alteration of the gastric mucosal microenvironment. In addition, epithelial-mesenchymal transition (EMT) may contribute to H. pylori -induced gastric stemness. Taken together, understanding these pathogeneses will provide potential therapeutic targets for the treatment of CSCs and malignant GC in H. pylori induced-Correa cascade of GC.

Considered as the most popular pathogen worldwide, Helicobacter pylori is intensively associated with diverse gastric diseases, including gastric ulcers, chronic progressive gastritis, and gastric cancer. Aside from its pathogenic effect on gastric diseases, growing evidences reveal that H. pylori may be related to numerous extragastric diseases. In this article, we reviewed recent studies and systematically elucidated that H. pylori may interfere with many biological processes outside the stomach and influence the occurrence of various extragastric diseases. Many epidemiological studies have indicated that H. pylori plays a pathogenic role in COVID-19, atherosclerosis, hyperemesis gravidarum and several other extragastric diseases, while the effect of H. pylori is currently under investigation in gastroesophageal reflux disease, asthma, and inflammatory bowel disease. Moreover, we also summarized the possible pathogenic mechanisms of H. pylori that may be related to chronic systemic inflammation and molecular mimicker. Taken together, this review provides a new perspective on the role of H. pylori in extragastric diseases and explores the possible mechanisms, which may help guide clinical treatment.

Microcystin-LR (MC-LR) exists widely in polluted food and water in humid and warm areas, and facilitates the progression of colorectal cancer (CRC). However, the molecular mechanism associated with the MC-LR-induced CRC progression remains elusive. The purpose of this study is to explore the role of the hub genes associated with MC-LR-induced CRC development at the molecular, cellular and clinical levels through bioinformatics and traditional experiments. By utilizing R, we screened and investigated the differentially expressed genes (DEGs) between the MC-LR and the control groups with the GEO, in which, HOXB4 highly expressed in MC-LR-treated group was identified and further explored as a hub gene. With the aid of TCGA, GEPIA, HPA, UALCAN, Cistrome, and TIMER, the increased mRNA and protein levels of HOXB4 in CRC tissue were found to be positively associated with high tumor stage and poor prognosis, and were linked to immune infiltration, especially tumor-associated macrophages and cancer-associated fibroblasts. Cox regression analysis and nomogram prediction model indicated that high HOXB4 expression was correlated to poor survival probability. To elucidate the mechanism of high HOXB4 expression induced by MC-LR, we overlapped the genes involved in the MC-LR-mediated CRC pathways and the HOXB4-correlated transcription genes. Importantly, C-myc instead of PPARG and RUNX1 promoted the high expression of HOXB4 through experiment validation, and was identified as a key target gene. Interestingly, C-myc was up-regulated by HOXB4 and maintained cell cycle progression. In addition, MC-LR was proved to up-regulate HOXB4 expression, thus promoting proliferation and migration of Caco2 cells and driving the cell cycle progression. In conclusion, MC-LR might accelerate CRC progression. In the process, MC-LR induced C-myc augmentation elevates the high expression of HOXB4 through increasing the S phase cell proportion to enhance Caco2 cell proliferation. Therefore, HOXB4 might be considered as a potential prognostic biomarker for CRC.

Objective To determine whether metformin(Met) inhibits the proliferation of colorectal cancer cells by inducing cell senescence, and to preliminarily explore the underlying mechanism. Methods LOVO and SW480 colorectal cancer cells were treated with different concentrations of Met(0, 2.5, 5.0, 10.0, 20.0 and 40.0 mmol/L). The cell viability was detected by CCK-8 assay, and apoptosis and cell cycle were detected by flow cytometry. According to the results of apoptosis, differences between control group (0 mmol/L) and 5.0 mmol/L Met group(n=3) were compared in following experiments. Cell proliferation was detected by CCK-8 assay, EdU assay, and clone formation assay, senescence metabolism was detected by senescence-associated β-galactosidase(SA-β-gal)staining, protein phosphatase 2A(PP2A) enzyme activity was measured with ELASA, and protein expression was detected with Western blotting. PP2A inhibitor LB-100 was used to treat the cells alone or combined with Met, and then the cells were divided into control group, Met group, Met+LB-100 group, and LB-100 group(n=3). Above experiments were performed again. Results Met treatment significantly inhibited LOVO and SW480 cells proliferation in a concentration- and time-dependent manner(P < 0.05). Under the treatment of low concentration(≤5.0 mmol/L) of Met, the cells presented no obvious apoptosis, but were obviously inhibited for proliferation and arrested at G0/G1 phase. The cells displayed a typical senescence-like morphology of large, flat and vacuolated, and the number of SA-β-gal positive cells was increased significantly. For PP2A, total protein expression showed no change, but phosphorylation level decreased obviously and PP2A activity increased statistically(P < 0.05), in the meantime, the phosphorylation level of downstream AKT protein decreased and senescence-related proteins p53 and P21 increased significantly. Treatment by PP2A inhibitor LB-100 combined with Met significantly reversed the inhibition of Met on cell proliferation and delayed Met-induced cell senescence. Conclusion Low concentration of Met can induce cell senescence through PP2A/AKT pathway and then inhibit the proliferation of colorectal cancer cells.

Objective To determine the effects of ethanol on the cell proliferation, migration and invasion in human colorenctal cancer HT29 and SW480 cells and investigate the underlying mechanisms. Methods The effect of ethanol on the proliferation of HT29 and SW480 cells was detected by CCK-8 assay. After the IC50 value was obtained by the relevant analysis, and low concentration ethanol exposure models (1/10 IC50 value) were established. The cell cycle distribution was measured by flow cytometry, cell migration and invasion were detected by cell scratch test and Transwell chamber assay respectively, and the cell ROS production were detected using flow cytometry. The protein levels of epithelial-mesenchymal transition (EMT) related proteins, such as E-cadherin, N-cadherin and vimentin were detected by Western blotting. The production of acetaldehyde in the cells after ethanol treatment was detected with acetaldehyde detection kit. Results The IC50 values of ethanol to HT29 and SW480 cells were 436 and 424 mmol/L, respectively. With the increase of ethanol concentration, the proportion of cells at G1 stage was increased. Compared with the control group, the cell scratch test showed that the percentages of wound closure of HT29 and SW480 cells were increased significantly after ethanol treatment in each concentration group (P < 0.05). Transwell chamber test indicated that ethanol treatment significantly increased the number of HT29 and SW480 cells permeating without and with matrigel (P < 0.05). Further experiments showed that ethanol significantly enhanced the intracellular ROS level of HT29 and SW480 cells (P < 0.05). Western blotting displayed that ethanol decreased the expression level of E-cadherin, while increased those of N-cadherin and vimentin (P < 0.05). And as the concentration of ethanol increasing, the acetaldehyde content was elevated in the cells. Conclusion Ethanol may enhance the invasion and migration of colorectal cancer cells through ROS-mediated EMT pathway.

Objective To investigate the association of single nucleotide polymorphisms (SNPs) of homologous recombination repair (HRR) pathway genes with the genetic susceptibility of colorectal cancer (CRC) in Chinese population. Methods Bioinformatics database analysis combined with literature screening was used to identify the key genes involved in the HRR pathway. Following a pathway-based case-control study design, 413 patients with CRC and 1 671 cancer-free controls were recruited from 3 affiliated hospitals of the Army Military Medical University. TagSNPs of the selected genes and 50 kb of their upstream and downstream regions were genotyped using ILLUMINA human genome chip. Conditional logistic regression analysis was used to evaluate the association between the SNPs and the risk of CRC. Results Seventeen key genes in the HRR pathway were selected based on literature screening and bioinformatics database analysis. Sixteen of the total of 2207 genotyped SNPs were found significantly associated with the risk of CRC, among them the allele A at rs11226 of RAD52 3'-UTR was associated with an 1.4-fold higher risk of CRC than the allele G (OR=1.42, 95% CI: 1.22~1.66, P=6.67×10-6), and the allele G at rs75893366 of CRTC3-AS1 gene was associated with a 0.43-fold lower risk of CRC than allele A (OR=0.43, 95% CI: 0.25~0.74, P=1.81×10-3). But after Bonferroni correction, only the SNP of rs11226 showed significant differences in both male and female patients in stratified analysis. Conclusion The 17 SNPs of the key genes in the HHR pathway are significantly associated with the risk of CRC, suggesting that the variations in HHR pathway genes contribute to the genetic susceptibility of CRC.

目的 通过对PC4基因启动子区潜在功能性SNP位点与结直肠癌的发病风险的关联分析,探索PC4基因遗传变异作为结直肠癌遗传易感性分子标记的可能性.方法 ①经生物信息学方法筛选PC4基因启动子区SNP位点;②采用探针法和测序法对选定SNP位点进行基因分型后于病例对照研究中作多因素Logistic回归分析.结果 ①筛选出PC4启动子区7个潜在功能性SNP位点;②位点rs116123859 CC+ CT基因型(OR=4.89,95％ CI=1.29 ～ 18.51,P=0.020;ORadj=3.31,95％ CI =0.84～13.06,Padj=0.087)和位点rs6891588 AG+GG基因型(ORadj=1.28,95％ CI =1.00 ～1.64,Padj=0.048)与结直肠癌的发病风险有关联,但效应微弱;③随个体携带的“风险”倾向基因型的数量增多,结直肠癌风险也有随之增加的趋势(Ptrend=0.004);④单倍型T_C_C_G_G_A_A、T_G_A_G_G_G_A患结直肠癌的风险是其他单倍型的2倍(OR分别为2.67、2.98,95％ CI分别为1.78 ～4.02、1.46 ～6.04,P值分别为＜0.001、0.003).结论 PC4基因启动区单核苷酸多态性与结直肠癌的风险之间具有显著关联性,提示PC4基因启动子区多态性具有作为结直肠癌遗传易感性分子标记的潜能.

[Objectivo] To investigate the pulmonary injury induced by novel nano materials,nitrogen-doped nano titanium dioxide (N-nTiO2).[Methods] Forty-two specific-pathogen-free SD rats were divided into one blank control group and five N-nTiO2 groups (13.64,27.27,40.91,54.55,and 68.18 mg/kg,respectively,in terms of body weight thereafter),with seven rats in each group.The rats were exposed to N-nTiO2 by intratracheal instillation every three days and for 28 days.Lung function changes were monitored with lung function measurement instrument,the quantity of total protein and activities of lactate dehydrogenase and alkaline phosphatase in bronchoalveolar lavage fluid were measured with multi-mode enzyme-labelled meter,and the lung histopathological damage was observed using HE staining.[Results] The body weight gain was less in each N-nTiO2 group compared with the blank control group (P＜0.05).The minute ventilation volume significantly increased in the 54.55 and 68.18 mg/kg N-nTiO2 groups compared with the blank control group (P＜ 0.05),the peak expiratory flow significantly increased in the 40.91 mg/kg and above N-nTiO2 groups (P＜0.05),and the tidal volume and peak expiratory flow significantly increased in the 68.18 mg/kg N-nTiO2 group (P ＜ 0.05).Compared with the blank control group,the quantity of total protein significantly increased only in the 40.91 mg/kg N-nTiO2 group (P＜0.05),the enzyme activity of lactate dehydrogenase increased in the 27.27 mg/kg and above N-nTiO2 groups,and the enzyme activity of alkaline phosphatase increased in the 54.55 mg/kg and above N-nTiO2 groups (P ＜ 0.05).The results of lung histopathological examination results demonstrated that lung tissue injury was aggravated in the groups treated with higher levels of N-nTiO2,such as cell proliferation,hypermia,and inflammatory cell infiltration,as well as lung obstruction,atelectasis,and consolidation.[Conclusion] Intratracheal instillation of N-nTiO2 may induce not only organic lesion but also lung function impairment in rats.