Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

BACKGROUND:Overactive osteoclasts disrupt bone homeostasis and play a bad role in the pathological mechanisms of related skeletal diseases,such as osteoporosis,fragility fractures,and osteoarthritis.Studies have confirmed that ellagic acid and ellagtannin have the potential to inhibit osteoclast differentiation.As their natural metabolites,urolithin A has antioxidant,anti-inflammatory,anti-proliferative and anti-cancer effects,but its effect on osteoclast differentiation and its underlying molecular mechanisms remain unclear. OBJECTIVE:To explore the effect of urolithin A on osteoclast differentiation induced by receptor activator for nuclear factor-κB ligand and its mechanism. METHODS:Mouse mononuclear macrophage leukemia cells(RAW264.7)that grew stably were cultured in vitro.Toxicity of urolithin A(0,0.1,0.5,1.5,2.5 μmol/L)to RAW264.7 cells were detected by cytotoxic MTS assay to screen out the safe concentration.Different concentrations of urolithin A were used again to intervene with receptor activator for nuclear factor-κB ligand-induced differentiation of RAW264.7 cells in vitro.Then,tartrate-resistant acid phosphatase staining and F-actin ring and nucleus staining were performed to observe its effect on the formation and function of osteoclasts.Finally,the expressions of urolithin A on upstream and downstream genes and proteins in the MAPK signaling pathway were observed by western blot and RT-qPCR assays. RESULTS AND CONCLUSION:Urolithin A inhibited osteoclast differentiation and F-actin ring formation in a concentration-dependent manner and 2.5 μmol/L had the strongest inhibitory effect.Urolithin A inhibited the mRNA expression of Nfatc1,Ctsk,Mmp9 and Atp6v0d2 and the protein synthesis of Nfatc1 and Ctsk,related to osteoclast formation and bone resorption.Urolithin A inhibited the activity of osteoclasts by downregulating the phosphorylation of p38 protein to inhibit the mitogen-activated protein kinase signaling pathway.

Objective:To investigate the pregnancy outcomes of different treatment methods for triplet pregnancies with different chorionicities.Methods:A retrospective study was conducted on 97 triplet pregnancies who visited and delivered at the Department of Obstetrics, the Third Affiliated Hospital of Zhengzhou University, from January 1, 2017, to November 30, 2023. The pregnancies were categorized based on chorionicity into monochorionic triamniotic (MCTA) ( n=24), dichorionic triamniotic (DCTA) ( n=33), and trichorionic triamniotic (TCTA) ( n=40). They were further divided into expectant management group ( n=46), reduction to twins group ( n=40), and reduction to singleton group ( n=11) based on the treatment method. Pregnancy outcomes were compared among the groups. Statistical analysis were performed using t-test, corrected t-test, one-way analysis of variance and LSD test, Kruskal-Wallis test and Mann-Whitney U test, Chi-square test, continuity correction Chi-square test, Fisher's exact test, and Bonferroni correction. Results:(1) Comparison of pregnancy outcomes with different treatment methods for the same chorionicity: In MCTA, there were no statistically significant differences in gestational age at delivery, live birth rate before 37 weeks, live birth rate before 32 weeks, neonatal birth weight, and incidence of severe neonatal complications between the expectant management group and the reduction to monochorionic diamniotic (MCDA) group (all P>0.05). In DCTA, compared to the reduction to singleton group, the expectant management group had lower gestational age at delivery [(31.8±2.7) vs. (37.9±1.3) weeks, U=－3.66] and neonatal birth weight [(1 604.3±422.6) vs. (2 997.1±598.9) g, U=－3.84] (both P<0.05), but higher live birth rate before 37 weeks (9/10 vs.1/8, Bonferroni correction, P<0.017). The expectant management group showed a trend towards higher rates of pregnancy complications (5/10 vs. 2/15 and 0/8) and severe neonatal complications [37.0% (10/27) vs. 10.7% (3/28) and 0/7] compared to the groups reduced to dichorionic diamniotic (DCDA) twins and singletons. However, the differences between the groups were not statistically significant (all P>0.017). In TCTA, compared to the expectant management group, the reduction to DCDA group had a higher gestational age at delivery [(37.1±0.9) vs. (34.1±2.7) weeks, t'=－4.36], and increased neonatal birth weight [(2 647.5±377.8) vs. (1 902.5±459.9) g, t'=－6.98] (both P<0.05). The incidence of maternal pregnancy complications [3/15 vs. 54.2% (13/24)] and live birth rate before 37 weeks [3/15 vs. 66.7% (16/24)] were lower (Fisher's exact test, both P<0.05). (2) Comparison of pregnancy outcomes with different chorionicities for the same treatment method: In the expectant management group, the DCTA group had the lower neonatal birth weight compared to the MCTA and TCTA groups [(1 604.3±422.6) vs. (1 948.3±573.4) and (1 902.5±459.9) g, LSD test, both P<0.05]. In the fetal reduction group, the TCTA group had higher neonatal birth weight compared to the MCTA and DCTA groups [(2 657.6±373.3) vs. (2 000.8±443.3) and (2 078.8±799.9) g, U=－2.91 and U=－3.12] (both P<0.05). Conclusions:The appropriate treatment method for triplet pregnancies should be selected based on chorionicity. Expectant management is recommended for MCTA, fetal reduction is suggested for DCTA to improve pregnancy outcomes. For TCTA, the pregnant woman should be informed of the risks of preterm birth associated with expectant management, who should then decide whether to undergo fetal reduction.

Objective·To examine the expression level of protein arginine methyltransferase 6(PRMT6)in breast carcinoma tissues and to assess its impact on the proliferative and migratory behaviors of breast cancer cells.Methods·The PRMT6 transcriptome sequencing data between 33 tumor tissues and normal tissues from The Cancer Genome Atlas(TCGA)database was analyzed through the R language.The gene expression profile interactive analysis(GEPIA2)online database was used to analyze the difference of PRMT6 expression in normal breast tissues and breast cancer tissues.By using the immunohistochemistry(IHC)data of human normal breast tissues and breast cancer tissues from Human Protein Atlas(HPA)database to analyze the protein expression of PRMT6.IHC was used to detect the expression of PRMT6 in breast cancer tissues and paired para-tumor tissues from 27 clinical samples.After PRMT6 was knocked down with small interfering RNA(siRNA)in MDA-MB-231 and MCF-7 cells,the expression of PRMT6 was detected by qRT-PCR and Western blotting.The proliferation ability of breast cancer cells was measured with cell counting kit-8(CCK-8)assay and colony formation assay.The effect of PRMT6 on the migration ability of breast cancer cells was detected by wound healing assay and Transwell assay.By using the RNA-sequence data from GSE210948 of Gene Expression Omnibus(GEO)database,differentially expressed genes were analyzed in control and low expression groups of PRMT6.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis was performed to reveal the signaling pathways associated with PRMT6.Cell cycle analysis was detected by flow cytometry.The expressions of cyclin D1 and EMT-related proteins(E-cadherin,N-cadherin and Vimentin)were detected by Western blotting after knocking down PRMT6.Results·Bioinformatics analysis and IHC results showed that PRMT6 was highly expressed in breast cancer tissues compared with normal tissues(P=0.000)and para-tumor tissues(P=0.001).qRT-PCR and Western blotting results verified that the siRNA significantly reduced the expression level of PRMT6 in MDA-MB-231 and MCF-7 cell lines compared with the control group(mRNA:P=0.006,P=0.004;P=0.001,P=0.043.Protein:P=0.035,P=0.001;P=0.003,P=0.002).After knocking down PRMT6,the proliferation(P=0.014,P=0.000;P=0.003,P=0.003)and migration(P=0.000,P=0.000;P=0.000,P=0.002)ability of breast cancer cells were inhibited significantly.The KEGG pathway enrichment analysis showed that the expression of PRMT6 affected the cell cycle pathway.After knocking down PRMT6,the expression of cyclin D1 decreased in protein level(P=0.021,P=0.000;P=0.034,P=0.014)and transcription level(P=0.036,P=0.001;P=0.044,P=0.000).Knock down of PRMT6 increased the number of cells in G0/G1 phase(P=0.000;P=0.003)and decreased the number of cells in G2/M phase of the cell cycle.The expression level of E-cadherin increased(P=0.002,P=0.012;P=0.043,P=0.003),while the expression levels of N-cadherin(P=0.004,P=0.041;P=0.032,P=0.034)and Vimentin(P=0.028,P=0.005;P=0.024,P=0.001)decreased in PRMT6 knockdown cells.Conclusion·PRMT6 is highly expressed in breast cancer,which can promote the proliferation and migration of breast cancer cells.

Objective·To identify key genes that may be regulated by fatty acid alteration in pancreatic cancer through tumor transcriptome screening,and to explore the expression of zinc finger protein 143(ZNF143)in pancreatic cancer and its effect on the migration and invasion of pancreatic cancer cells.Methods·The R language was utilized to integrate transcriptome data,including the GSE164760 dataset from the Gene Expression Omnibus(GEO)database,179 pancreatic cancer tissue samples and 4 adjacent non-cancerous tissue samples from The Cancer Genome Atlas(TCGA)database,as well as 167 normal pancreatic tissue samples from the Genotype-Tissue Expression(GTEx)database.We conducted screening and analysis of potential differential genes that may be induced by dysregulation of fatty acid metabolism in pancreatic cancer.After treating pancreatic cancer cells with palmitic acid(PA)and oleic acid(OA)for 24 hours,the mRNA levels of candidate genes were detected by qRT-PCR.According to the median expression level of the screened gene,pancreatic cancer patients in the TCGA database were divided into two groups with high and low expression of ZNF143.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway and Gene Ontology(GO)enrichment analyses were performed for the differential genes of the two groups.siRNA was used to knock down the expression of ZNF143 in pancreatic cancer cells,and the effects on cell migration and invasion were examined by wound healing assay and invasion assay.Western blotting was used to explore the impact of ZNF143 on epithelial mesenchymal transition(EMT)-related proteins and the Wnt/β-catenin pathway.Results·The bioinformatics database was processed to analyze key genes associated with the up-regulation of genes in lipid metabolism disorders in pancreatic cancer and liver cancer.Among them,ZNF143 was a potential gene associated with fatty acid accumulation in pancreatic cancer.In vitro experiments confirmed that the mRNA level of ZNF143 was significantly up-regulated after treating pancreatic cancer cells with palmitic acid or oleic acid.Both KEGG and GO enrichment analyses demonstrated that the differentially expressed genes associated with ZNF143 were predominantly enriched in adhesion pathways.In functional experiments,the migration and invasion abilities of pancreatic cancer cells transfected with ZNF143 siRNA were reduced,and the expression of EMT-related proteins was also decreased,potentially related to the activation of the Wnt/β-catenin pathway.Conclusion·Fatty acid accumulation up-regulates the mRNA expression of ZNF143 in pancreatic cancer cells,and ZNF143 may enhance the migration and invasion of these cells by facilitating EMT through activation of the Wnt/β-catenin pathway.

Objectives: . The annual prevalence of chronic rhinosinusitis (CRS) is increasing, and the lack of effective treatments imposes a substantial burden on both patients and society. The formation of nasal polyps in patients with CRS is closely related to tissue remodeling, which is largely driven by the epithelial-mesenchymal transition (EMT). MicroRNA (miRNA) plays a pivotal role in the pathogenesis of numerous diseases through the miRNA-mRNA regulatory network; however, the specific mechanism of the miRNAs involved in the formation of nasal polyps remains unclear. Methods: . The expression of EMT markers and Smad3 were detected using western blots, quantitative real-time polymerase chain reaction, and immunohistochemical and immunofluorescence staining. Differentially expressed genes in nasal polyps and normal tissues were screened through the Gene Expression Omnibus database. To predict the target genes of miR-145-5p, three different miRNA target prediction databases were used. The migratory ability of cells was evaluated using cell migration assay and wound healing assays. Results: . miR-145-5p was associated with the EMT process and was significantly downregulated in nasal polyp tissues. In vitro experiments revealed that the downregulation of miR-145-5p promoted EMT. Conversely, increasing miR-145-5p levels reversed the EMT induced by transforming growth factor-β1. Bioinformatics analysis suggested that miR-145-5p targets Smad3. Subsequent experiments confirmed that miR-145-5p inhibits Smad3 expression. Conclusion . Overall, miR-145-5p is a promising target to inhibit nasal polyp formation, and the findings of this study provide a theoretical basis for nanoparticle-mediated miR-145-5p delivery for the treatment of nasal polyps.

Bacterial resistance is a serious problem in use of antibiotics and an urgent global public health challenge. The drug-resistant bacteria and drug-resistant genes carried by migratory birds are not only related to clinical antibiotics, but also the use of pesticides and veterinary drugs as well as the pollution of the surrounding environment of drug factories. However, studies on drug-resistant genes carried in migratory birds have been gradually reported around the world. Migratory birds have the characteristics of large range of movement and long flight distance, which leads to the complexity of bacterial resistance. Under the influence of environment and human activities, drug-resistant genes carried in bacteria are transmitted among species,human beings, domestic animals, environment and wild birds through mobile elements. This study summarizes the current situation of antibiotic resistance bacteria carried by migratory birds,the status of drug-resistant genes in migratory birds and the relationship between the resistance of migratory birds and the environment and human activities. The aim is to better understand the important role of migratory birds as hosts and vectors in the global spread of antibiotic resistance.

Bacterial resistance is a serious problem in use of antibiotics and an urgent global public health challenge. The drug-resistant bacteria and drug-resistant genes carried by migratory birds are not only related to clinical antibiotics, but also the use of pesticides and veterinary drugs as well as the pollution of the surrounding environment of drug factories. However, studies on drug-resistant genes carried in migratory birds have been gradually reported around the world. Migratory birds have the characteristics of large range of movement and long flight distance, which leads to the complexity of bacterial resistance. Under the influence of environment and human activities, drug-resistant genes carried in bacteria are transmitted among species,human beings, domestic animals, environment and wild birds through mobile elements. This study summarizes the current situation of antibiotic resistance bacteria carried by migratory birds,the status of drug-resistant genes in migratory birds and the relationship between the resistance of migratory birds and the environment and human activities. The aim is to better understand the important role of migratory birds as hosts and vectors in the global spread of antibiotic resistance.

Objective: To evaluate the association between the frequency of bowel movement (BMF) and the risk of Parkinson’s disease (PD). Methods: In this study, 510 134 participants from the China Kadoorie Biobank (CKB) were included after excluding those who reported to had been diagnosed with cancer at baseline survey. The baseline survey was conducted from 2004 to 2008. The study used the data from the baseline survey and follow-up until December 31, 2016. Cox proportional hazards regression models were used to estimate the HRs and the 95%CIs of risk of PD diagnosis with BMF. Results: During an average follow-up period of (9.9±1.9) years, 808 participants were diagnosed with PD. Compared with participants who had bowel movements every day, the multivariable-adjusted HR (95%CI) for those who had bowel movements<3 times/week, once every 2-3 days, and>1 time/day were 3.62 (2.88-4.54), 2.13 (1.74-2.60), and 0.81 (0.63-1.05), respectively. The linear trend test results of the association between BMF and risk of PD diagnosis was significant (P<0.001). Compared with the participants who had bowel movements ≥1 time/day, the multivariable-adjusted HR (95%CI) for those who had bowel movements<1 time/day was 3.13 (2.32-4.23) within the 5 years of follow- up and was 2.48 (2.05-3.01) beyond the 5 years of follow-up. The gender specific results were similar. The association of BMF<1 time/day with risk of PD diagnosis was stronger in older participants. Conclusions The participants with low BMF at baseline survey would have higher risk for PD diagnosis in the subsequent 10 years on average. Since abnormal decrease of BMF is easy to be found, programs could be set up for the early screening of PD in older people, along with other early symptoms of PD.

Objective To evaluate the intervention effect of iodine deficiency disorders (IDD) health education on primary students.Methods Using random cluster sampling,five towns were selected from five directions and a primary school was selected in every town in 2017.Health education was carried out to 1 505 students from grade 4 to grade 6.After 5 months intervention,the IDD awareness rate and the change in attitude were compared before and after the intervention.Results After the health education,IDD awareness rate and correct answer rate among students were all improved from 60.29％ (9 032/14 980),60.83％ (4 556/7 490) to 84.64％ (12 653/14 950),83.05％ (6 208/7 475),with statistically significant differences (x2 =2 221.33,915.01,P ＜ 0.01).Conclusion Health education and intervention is an effective measure to improve the knowledge level of the IDD prevention control among primary students in Cixi City.