Cbf?1 gene encodes an osteoblast specific transcription factor that regulates osteoblast differentiation and bone formation. The Cbf?1 gene contains 9 exons, however, the alternative splicing of its exons leads to genesis of multiple Cbf?1 isoforms with differences in transactivation potentials. Several signal transduction pathways, such as Ras MAPK pathway, cAMP pathway, or Smads DPC4 pathway, are involved in regulating Cbf?1 activity or its expression. These studies open new doors in pharmacological control of bone formation and gene or cell therapy of slowing the progression of osteoporosis.

OBJECTIVE To investigate the effect of tacrolimus on cell proliferation and osteoblastic differentiation of primary human bone marrow-derived mesenchymal stem cells (hBMSCs). METHODS hBMSCs were cultured with tacrolimus 0.001-5 μmol·L-1. BrdU incorporation was used to assess the cell proliferation while cellular alkaline phosphatase (ALP) activity and calcium deposition were measured to evaluate the osteoblastic differentiation of hBMSCs cultures. The calcineurin (CaN) activity was also examined using commercial CaN assay kit, and core binding factor 1 alpha subunit (Cbfα1) protein level was determined by Western blotting. RESULTSTacrolimus 0.001-0.1 μmol·L-1 promoted BrdU incorporation but had no effect on ALP activity and calcium deposition, whereas tacrolimus 0.5-5 μmol·L-1 resulted in significant decrease in both cell proliferation and osteoblastic maturation, by reducing BrdU incorporation, ALP activity, and calcium deposition of hBMSCs cultures in a concentration-dependent manner. In addition, tacrolimus 0.5-5 μmol·L-1 led to concentration-dependent decrement in CaN activity, which was consistent with down-regulated Cbfα1 protein in the tacrolimus treated cells. CONCLUSION High concentration of tacrolimus might inhibit the cell proliferation and osteoblastic differentiation of hBMSCs cultures through a CaN/Cbfα1 pathway.

Aim To investigate the role of p38 mitogen-activated protein kinases(MAPKs) in genistein-induced osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cells(BMSCs).Methods Mouse BMSCs cultured in phenol red-free ?-MEM containing 10% V/V FBS,were added ?-glycerophosphate and ascorbic acid for inducing osteoblastic differentiation,and treated with 0.01~1 ?mol?L~(-1) genistein and/or SB203580 and PD98059.The temporal sequence of osteoblastic differentiation in BMSCs cultures was assayed by measuring alkaline phosphatase activity(ALP) and calcium deposition.The MAPK phosphorylation level was detected by Western-blot.Results Genistein(0.01~1 ?mol?L~(-1)) showed a dose-dependent effect on osteoblastic differentiation as evidenced by increased alkaline phosphatase(ALP) activity and calcium deposition in mouse BMSCs cultures.Genistein(1 ?mol?L~(-1))-induced osteoblastic differentiation of BMSCs was diminished by p38 MAPK inhibitor but not the p44/42 MAPK inhibitor.The effects of Genistein were associated with rapid and sustained activation of p38 MAPK in the BMSCs cultures,which was blocked by SB203580(1 ?mol?L~(-1)).In contrast,Genistein treatment resulted in inactivation of p42/44MAPK,which was further attenuated by PD98059(25 ?mol?L~(-1)).Conclusion p38 MAPK plays an important role in genistein-induced osteoblastic differentiation of mouse BMSCs cultures.

The induced pluripotent stem cells (iPSCs), derived by ectopic expression of reprogramming factors in somatic cells, can potentially provide unlimited autologous cells for regenerative medicine. In theory, the autologous cells derived from patient iPSCs should be immune tolerant by the host without any immune rejections. However, our recent studies have found that even syngeneic iPSC-derived cells can be immunogenic in syngeneic hosts by using a teratoma transplantation model (Nature 474:212-215, 2011). Recently two research groups differentiated the iPSCs into different germ layers or cells, transplanted those cells to the syngeneic hosts, and evaluated the immunogenicity of those cells. Both of the two studies support our conclusions that some certain but not all tissues derived from iPSCs can be immunogenic, although they claimed either "negligible" or "lack of" immunogenicity in iPSC derivatives (Nature 494:100-104, 2013; Cell Stem Cell 12:407-412, 2013). To test the immunogenicity of clinically valuable cells differentiated from human iPSCs are emergently required for translation of iPSC technology to clinics.
Animals ; Cell Cycle Proteins ; metabolism ; Cell Transplantation ; methods ; Graft Rejection ; immunology ; Induced Pluripotent Stem Cells ; immunology ; transplantation ; Membrane Proteins ; metabolism ; Mice, Knockout ; Teratoma ; immunology ; metabolism

Obesity is a great risk factor for type 2 diabetes and certain types of cancer, which become a major burden for public health worldwide. As a classic complex disease, obesity is regarded as the interaction of genetic and environmental factors. However, it is controversial which of these two factors have greater effect on obesity. Several genetic loci have recently been reported to contribute to the development of obesity reported in genome-wide association study (GWAS) these years. GWAS play an important role in complex disease research and explore the potential effect of genetic variance. To further understand the genetic influence on obesity risk, we reviewed and collected articles on Pubmed for genes that reported in recent GWAS. We summarized the publications in GWAS and found 49 candidate genes, which were strongly suggested to relate to obesity risk in human. Despite the findings of this and other similar, contemporary research projects, much of the single nucleotide polymorphism details and underlying mechanism in this field of study remains, to a great extent, unknown. As a result, future studies are needed for obesity risk in human beings.
Aldose-Ketose Isomerases ; genetics ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Brain-Derived Neurotrophic Factor ; genetics ; Genome-Wide Association Study ; trends ; Humans ; Obesity ; genetics ; physiopathology ; Polymorphism, Single Nucleotide ; Proteins ; genetics

Objective:To analyze the compliance with enhanced recovery after surgery (ERAS) protocol in geriatric patients with fresh fracture.Methods:A retrospective study was conducted on the data of the patients with fresh extremity fracture which had been included in the ERAS perioperative protocol database during May 2019 and January 2022 at Department of Orthopaedic Trauma, Beijing Jishuitan Hospital. The patients ≥65 years were selected as a study group which was matched by a control group of the patients < 65 years in sex, fracture type and date frame of hospitalization at a ratio of 1∶1. The 2 groups were compared in the compliance with the 14 ERAS core perioperative elements.Results:The study group and the control group each included 66 patients who were matched in sex and fracture type. 62.1% (41/66) of the patients in the study group had combined diseases, significantly more than that [16.7% (11/66)] in the control group( P<0.001). Altogether, the compliance with the 14 ERAS core perioperative elements was 78.6 (71.4, 85.7) % in both groups, showing no significant difference between them ( P>0.05). Respectively, the compliance with the postoperative oral intake in the study group (80.3%, 53/66) was significantly lower than that in the control group (92.4%, 61/66) ( P<0.05); the compliance with the other 13 elements showed no statistically significant difference between the 2 groups ( P>0.05). Conclusion:The ERAS perioperative protocol can be carried out smoothly in geriatric patients with fresh fracture whose compliance may be comparable to that of the none-elderly patients.

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10^-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10^-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.