BACKGROUND:Osteoarthritis is a complex disease closely related to metabolic abnormalities.However,previous studies only involved limited blood lipid indicators and did not conduct more comprehensive blood lipid profile analysis.An in-depth exploration of the causal relationship between the seven items of blood lipids and osteoarthritis will not only help understand the pathogenesis of osteoarthritis,but also provide new research directions and clinical basis for its prevention and treatment.OBJECTIVE:To explore the causal relationship between blood lipids and osteoarthritis.METHODS:The genome-wide association analysis statistical data of 7 items of blood lipids and osteoarthritis from the IEU OPEN GWAS database were used to summarize,and significant single nucleotide polymorphisms were used as instrumental variables.The causal relationship between seven items(serum total cholesterol,triacylglycerol,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,apolipoprotein B,apolipoprotein AI and apolipoprotein A1)of blood lipids and osteoarthritis(osteoarthritis,knee or hip osteoarthritis,knee osteoarthritis and hip osteoarthritis)was determined through two-sample Mendelian randomization analysis.The inverse variance weighting was the main effect,and the MR-Egger regression method and the weighted median method were the supplementary effects.Bonferroni correction and reverse Mendelian randomization analysis could ensure validity.Multivariable Mendelian randomization analysis was used to further eliminate confounding factors.A significant causal relationship between seven items of blood lipids and osteoarthritis was obtained to ensure the robustness of the analysis.Co-localization analysis was used to once again ensure the robustness of the causal relationship and identify significantly influencing gene loci,making the evidence of causality more complete.RESULTS AND CONCLUSION:(1)In the two sample Mendelian randomization analysis,the results from inverse variance weighting indicated negative correlations between osteoarthritis and the following serum lipids:total cholesterol(OR=0.937 2,95%CI=0.885 6-0.991 9,P=0.025),low-density lipoprotein cholesterol(OR=0.959 4,95%CI=0.923 6-0.996 6,P=0.033),high-density lipoprotein cholesterol(OR=0.911 2,95%CI=0.833 5-0.996 2,P=0.04),apolipoprotein B(OR=0.926 7,95%CI=0.887 7-0.967 4,P=0.000 5),and apolipoprotein AI(OR=0.951 2,95%CI=0.911 0-0.993 1,P=0.023).Additionally,total cholesterol(OR=0.892 3,95%CI=0.843 1-0.944 3,P=0.000 08),triglycerides(OR=0.938 5,95%CI=0.884 7-0.995 6,P=0.035),and apolipoprotein B(OR=0.911 6,95%CI=0.865 9-0.959 7,P=0.000 4)were negatively associated with knee or hip osteoarthritis.For knee osteoarthritis specifically,total cholesterol(OR=0.898 3,95%CI=0.841 2-0.959 3,P=0.001),high-density lipoprotein cholesterol(OR=0.881 2,95%CI=0.794 7-0.977 0,P=0.016),and apolipoprotein B(OR=0.919 0,95%CI=0.869 8-0.971 0,P=0.002)also showed negative correlations.Lastly,with respect to hip osteoarthritis,total cholesterol(OR=0.864 5,95%CI=0.797 5-0.937 3,P=0.000 4),low-density lipoprotein cholesterol(OR=0.925 6,95%CI=0.879 5-0.974 1,P=0.003),and apolipoprotein B(OR=0.888 8,95%CI=0.817 6-0.966 3,P=0.005)exhibited negative correlations.No statistically significant differences were found in the reverse Mendelian randomization analysis.(2)In the multivariable Mendelian randomization analysis,the results from inverse variance weighting indicated a negative correlation between high-density lipoprotein cholesterol and osteoarthritis(OR=0.942 7,95%CI=0.896 1-0.991 8,P=0.022).Additionally,total cholesterol(OR=0.799 8,95%CI=0.647 8-0.987 6,P=0.037)and high-density lipoprotein cholesterol(OR=0.865 1,95%CI=0.7781-0.961 9,P=0.007)were also negatively associated with knee osteoarthritis.(3)Colocalization analysis revealed that total cholesterol and low-density lipoprotein were significantly associated with osteoarthritis at single nucleotide polymorphisms rs13107325(H4 posterior probability=99.9%).(4)These findings,using international databases and non-Asian populations,provide valuable insights for early clinical diagnosis,understanding the pathogenesis,and researching prevention and treatment of osteoarthritis in Chinese biomedicine and the Chinese population.

BACKGROUND:Osteoarthritis is a complex disease closely related to metabolic abnormalities.However,previous studies only involved limited blood lipid indicators and did not conduct more comprehensive blood lipid profile analysis.An in-depth exploration of the causal relationship between the seven items of blood lipids and osteoarthritis will not only help understand the pathogenesis of osteoarthritis,but also provide new research directions and clinical basis for its prevention and treatment.OBJECTIVE:To explore the causal relationship between blood lipids and osteoarthritis.METHODS:The genome-wide association analysis statistical data of 7 items of blood lipids and osteoarthritis from the IEU OPEN GWAS database were used to summarize,and significant single nucleotide polymorphisms were used as instrumental variables.The causal relationship between seven items(serum total cholesterol,triacylglycerol,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,apolipoprotein B,apolipoprotein AI and apolipoprotein A1)of blood lipids and osteoarthritis(osteoarthritis,knee or hip osteoarthritis,knee osteoarthritis and hip osteoarthritis)was determined through two-sample Mendelian randomization analysis.The inverse variance weighting was the main effect,and the MR-Egger regression method and the weighted median method were the supplementary effects.Bonferroni correction and reverse Mendelian randomization analysis could ensure validity.Multivariable Mendelian randomization analysis was used to further eliminate confounding factors.A significant causal relationship between seven items of blood lipids and osteoarthritis was obtained to ensure the robustness of the analysis.Co-localization analysis was used to once again ensure the robustness of the causal relationship and identify significantly influencing gene loci,making the evidence of causality more complete.RESULTS AND CONCLUSION:(1)In the two sample Mendelian randomization analysis,the results from inverse variance weighting indicated negative correlations between osteoarthritis and the following serum lipids:total cholesterol(OR=0.937 2,95%CI=0.885 6-0.991 9,P=0.025),low-density lipoprotein cholesterol(OR=0.959 4,95%CI=0.923 6-0.996 6,P=0.033),high-density lipoprotein cholesterol(OR=0.911 2,95%CI=0.833 5-0.996 2,P=0.04),apolipoprotein B(OR=0.926 7,95%CI=0.887 7-0.967 4,P=0.000 5),and apolipoprotein AI(OR=0.951 2,95%CI=0.911 0-0.993 1,P=0.023).Additionally,total cholesterol(OR=0.892 3,95%CI=0.843 1-0.944 3,P=0.000 08),triglycerides(OR=0.938 5,95%CI=0.884 7-0.995 6,P=0.035),and apolipoprotein B(OR=0.911 6,95%CI=0.865 9-0.959 7,P=0.000 4)were negatively associated with knee or hip osteoarthritis.For knee osteoarthritis specifically,total cholesterol(OR=0.898 3,95%CI=0.841 2-0.959 3,P=0.001),high-density lipoprotein cholesterol(OR=0.881 2,95%CI=0.794 7-0.977 0,P=0.016),and apolipoprotein B(OR=0.919 0,95%CI=0.869 8-0.971 0,P=0.002)also showed negative correlations.Lastly,with respect to hip osteoarthritis,total cholesterol(OR=0.864 5,95%CI=0.797 5-0.937 3,P=0.000 4),low-density lipoprotein cholesterol(OR=0.925 6,95%CI=0.879 5-0.974 1,P=0.003),and apolipoprotein B(OR=0.888 8,95%CI=0.817 6-0.966 3,P=0.005)exhibited negative correlations.No statistically significant differences were found in the reverse Mendelian randomization analysis.(2)In the multivariable Mendelian randomization analysis,the results from inverse variance weighting indicated a negative correlation between high-density lipoprotein cholesterol and osteoarthritis(OR=0.942 7,95%CI=0.896 1-0.991 8,P=0.022).Additionally,total cholesterol(OR=0.799 8,95%CI=0.647 8-0.987 6,P=0.037)and high-density lipoprotein cholesterol(OR=0.865 1,95%CI=0.7781-0.961 9,P=0.007)were also negatively associated with knee osteoarthritis.(3)Colocalization analysis revealed that total cholesterol and low-density lipoprotein were significantly associated with osteoarthritis at single nucleotide polymorphisms rs13107325(H4 posterior probability=99.9%).(4)These findings,using international databases and non-Asian populations,provide valuable insights for early clinical diagnosis,understanding the pathogenesis,and researching prevention and treatment of osteoarthritis in Chinese biomedicine and the Chinese population.

Tumor microenvironment (TME) plays a key role in the development and progression of tumors, such as pro?moting local drug resistance, immune escape, and distal metastasis. According to the TME of different individuals, accurate evaluation and selection of clinical medication can effectively control the malignant transformation of carcinoma in situ and metastatic cancer. At present, the main method to treat cancer is chemotherapy, TME can regulate the reaction of the tumor cells to the standard chemotherapy and target drug therapy, so the combination of the targeted TME therapy and chemothera?py will achieve better clinical efficacy. In this review, we summarized the mechanisms of TME in breast cancer, including ex?tracellular matrix, carcinoma-associated fibroblasts, carcinoma-associated macrophages, regulatory T cells and bone marrow mesenchymal stem cells, which providing a theoretical basis for the development of TME targeted therapy.

Objective To evaluate the sealing properties of three resin-based sealers,EndoREZ,RealSEAL and RealSEAL SE.Methods Forthy-eight extracted human anterior teeth with single root and canal were prepared using ProTaper files with crown-down technique to F3.The teeth were filled with three sealer respectively with hot gutta-percha vertical condensation technique simulating the clinical situation.Leakage quantity was detected using computerized fluid filtration meter with 10 samples in each group.The cross section morphology of apical parts of roots of 5 mm was observed with scanning electron microscope and transmission electron microscope in 3 samples of each group,respectively.Results The leakage quantity of EndoREZ,RealSEAL and RealSEAL SE were (2.61 ± 0.60),(1.43± 0.11) and (1.76 ± 0.18) μl/min,respectively.The gaps between the the sealer and the canal wall were increased in in order of RealSEAL,RealSEAL SE and EndoREZ.No obvious demineralized dentin under EndoREZ and the smear layer was not completed removed.The partly demineralized dentin was observed under RealSEAL and the smear layer was totally removed.The partly demineralized dentin was seen under RealSEAL SE and the majority of smear layer was removed.Conclusions Among the three resin-based sealers,RealSEAL has the best sealing properties,followed by RealSEAL SE and EndoREZ.

10.3969/j.issn.1007-3969.2013.05.009

Protein phosphorylation is one of the most common post-translational modification processes that play an essential role in regulating protein functionality.The Helicoverpa armigera single nucleopolyhedrovirus (HearNPv) orf2-encoded nucleocapsid protein HA2 participates in orchestration of virus-induced actin polymerization through its WCA domain,in which phosphorylation status are supposed to be critical in respect to actin polymerization.In the present study,two putative phosphorylation sites (232Thr and 250Ser) and a highly conserved Serine (245Ser) on the WCA domain of HA2 were mutated,and their phenotypes were characterized by reintroducing the mutated HA2 into the HearNPV genome.Viral infectivity assays demonstrated that only the recombinant HearNPV bearing HA2 mutation at 245Ser can produce infectious virions,both 232Tbr and 250Ser mutations were lethal to the virus.However,actin polymerization assay demonstrated that all the three viruses bearing HA2 mutations were still capable of initiating actin polymerization in the host nucleus,which indicated the putative phosphorylation sites on HA2 may contribute to HearNPV replication through another unidentified pathway.

Objective: To study the effect of wortmannin (WM), a PI3K/Akt inhibitor, on the proliferation and apoptosis of leukemia cells and the possible mechanism. Methods: Human leukemia cell line K562 was treated with different concentrations of WM. The proliferation of K562 cells was examined by MTT assay. DNA damage in K562 cells was examined by single cell gel electrophoresis assay, and apoptosis of K562 cells was detected by Annexin V-FITC/PI double-staining. The expressions of total Akt, phosphorate-Akt (p-Akt), and NF-κB p65 mRNA and protein were detected by RT-PCR and Western blotting, respectively. Results: WM inhibited the proliferation of K562 cells in a dose- and time-dependent manner, with the IC((50) value of 24 h being 25 nmol/L. WM also induced apoptosis of K562 cells in a dose-dependent manner. DNA damage in K562 cells was demonstrated by appearance of comet tail after treatment with WM, with the rate of DNA tail and the tail length being significantly higher than those in the control group (P<0.01). WM dose-dependently inhibited P-Akt and NF-κB p65, but not the total Akt, mRNA and protein expressions. Conclusion: WM can inhibit proliferation and induce apoptosis of K562 cells in a dose- and time-dependent manner, probably through down-regulation of phosphorate PI3K/Akt signal pathway and NF-κB expression.