Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine, particularly in peripheral nerve regeneration. Adipose-de-rived stem cells are easily harvested, although they may show the effects of aging, hence their potential in nerve repair may be limited by cellular senescence or donor age. Cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events (e.g., DNA damage) or environmental cues (e.g., stressful stimuli or diseases), which determine a permanent growth arrest. Several mechanisms are implicated in stem cell senescence, although no one is exclusive of the others. In this review we report some of the most important factors modulating the senescence process, which can inlfuence adipose-derived stem cell morphology and function, and compromise their clinical application for peripheral nerve regenerative cell therapy.

电离辐射诱导人外周血淋巴细胞gadd45基因表达的变化

电离辐射诱导的一些特殊基因表达的改变,有可能作为新的分子生物标记物用于估算细胞的受照剂量.其中生长抑制和DNA损伤诱导基因gadd45(growth arrest and DNA damage 45)[1]尤其引人关注.当DNA受到辐射损伤后,作为p53基因下游基因,gadd45表达增强,诱导受损细胞停滞于G1期,抑制细胞进入S期进行DNA复制及细胞增殖,同时激活细胞的核酸切除修复(Nucleotide excision repair,NER)功能[2].

彗星荧光原位杂交技术在检测特定基因损伤与修复中的应用

彗星荧光原位杂交技术(fluorescence in situ hybridization in combination with the Comet assay,Comet-FISH)是彗星试验(Comet assay,又称单细胞凝胶电泳)和荧光原位杂交(fluorescence in situ hybridization,FISH)技术的结合,是一种在单细胞水平上检测特定基因损伤和修复的有效方法[1].

发育及DNA损伤反应调节基因1的研究进展

REDD1,发育及DNA损伤反应调节基因1(regulated in development and DNA damage responses1)又称为RTP801、DDIT4、Dig2,是一个新发现的低氧诱导因子-1(hypoxia inducible factor -1,HIF -1)的靶基因,在人体正常组织广泛低表达,对多种细胞刺激均能产生应激反应,受多种细胞信号通路的调控,在细胞凋亡过程中发挥着重要的调节作用,和很多疾病的发生有关.深入研究REDD1的功能和作用机制可为临床某些疾病的防治提供新的思路.

Gadd45在恶性肿瘤中的研究进展

Gadd45与DNA损伤修复密切相关,全称为生长阻滞与DNA损伤诱生蛋白45(growth arrest and dNA damage inducible protein 45,Gadd45),其基因家族属于p53和BRCA1的下游靶基因,在细胞生存及细胞凋亡中发挥重要作用.Gadd45家族由Gadd45α、Gadd45β和Gadd45γ三个成员组成,它们的基因排列序列非常相似,通常会在环境损伤因子作用下,随DNA修复过程的启动而诱导产生.

Genetic toxicology is a multidisciplinary field of research involved in detecting DNA damaging and protective compounds, understanding the biological consequences of DNA damage and their molecular modes of action that lead to alterations and repair of the genetic material.

Emerging evidence has indicated that BRCC 36-mediated K63-linked ubiquitination modification was involved in diverse cellular functions , including endocytosis , apoptosis and DNA damage repair .We previously showed that activation of cGMP/PKG pathway con-tributed to the binding of BRCC36 and the pro-fibrotic factor Smad3.The current study tested the hypothesis that BRCC 36 functions as a negative regulator of transforming growth factor-beta ( TGF-β)/Smad3 pathway and participates in cardiac remodeling .In isolated adult mouse cardiac fibroblasts , we have demonstrated that TGF-β1 treatment significantly increased the expression of BRCC 36.Over-expression BRCC36 suppressed TGF-β1-induced Smad3 phosphorylation, nuclear translocation, extracellular matrix molecular expres-sion and cell proliferation .On the contrary, silencing BRCC36 by transfection of adenovirus-carrying BRCC36 shRNA potentiated to
enhance the pro-fibrotic effect of TGF-β.In vivo, under chronic pressure overload condition-induced by transverse aortic constriction , myocardial pro-survival protein Bcl-2 and Mcl-1 expression were significantly decreased and the pro-apoptosis protein Puma was in-creased.However, the cardiac-specific over-expression of BRCC36 significantly increased myocardial Bcl-2 and Mcl-1 and inhibited Puma expression .Interestingly , we also found that sustained pressure overload resulted in a significant myocardial DNA injury in wild type mice, which was characterized by the increase of γH2AX level.However, cardiac-specific BRCC36 over-expression significantly decreased the level of γH2AX in the pressure overloaded heart in the transgenic mice , while effectively enhanced myocardial RAD 51 expression, a marker of DNA damage repair.Furthermore, BRCC36 over-expression effectively attenuated TAC-induced cardiac fibro-sis and remodeling in the transgenic mice , compared with the wild type mice .Collectively , the results have suggested that BRCC 36 ef-fectively protected heart against chronic pressure overload-induced cardiac remodeling though antagonizing TGF-β/Smad3 pathway and enhancing myocardial DNA injury repair response .

AIM:To analyze the proteins included in exosomes derived from blood of patients with hypertension and seek the main pathologi -cal changes in hypertension .METHODS:Forty-seven patients and healthy subjects were recruited and divided into two comparisons :healthy subjects vs atherosclerosis ( HS vs AS) , and atherosclerosis vs hypertension plus atherosclerosis ( AS vs HT+AS) .We extrac-ted exosomes from blood and utilized LC-MS/MS to identify the protein expression .We used GO analysis to established the hierarchy programs of biological process and molecular function .PPI was used to find the proteins related to the terms .RESULTS:It was found that three final child terms repeatedly shown in BP of the two categories ( HS vs AS and AS vs HT+AS):“signal transduction in re-sponse to DNA damage”,“response to zinc ion”, and“platelet aggregation”.It was found that two final child terms in MF of the two categories:“interleukin 2 receptor binding” and“ploy(A) RNA binding”.The proteins, PSMA6, PSMA7 and CA2, were related to the terms in the two categories .CONCLUSION: We discovered that the exosome proteins may indicate the pathological changes in hypertension through the biological processes related with the specific proteins .These specific proteins, such as VCL, PSMA6, DP, AKAP, ATP5B and CA2, can be the new indicators for severity of hypertension and new therapeutic targets .

Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cel cycle progression by targeting substrates including damage-specific DNA-binding protein 2 (DDB2), xeroderma pigmentosum complementation group C (XPC), chromatin licensing and DNA replication factor 1 (Cdt1), and p21. Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas. On a cel ular level, Cul4a-deficient cel s have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21, respectively. This suggests that CUL4A promotes tumorigenesis (as well as accumulation of skin damage and subsequent premature aging) by limiting DNA repair activity and expediting S phase entry. In addition, CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers, hepatocellular carcinomas, squamous cell carcinomas, adrenocortical carcinomas, childhood medulloblastomas, and malignant pleural mesotheliomas. Because of its oncogenic activity in skin cancer and up-regulation in other malignancies, CUL4A has arisen as a potential candidate for targeted therapeutic approaches. In this review, we outline the established functions of CUL4A and discuss the E3 ligase’s emergence as a potential driver of tumorigenesis.

Background: In clinical studies, the findings on sulfur mustard (SM) toxicity for CD3+CD4+ and CD3+CD8+ T lymphocyte subsets are contradictory. In animal experiments, the effect of SM on the T cell number and proliferation is incompatible and is even the opposite of the results in human studies. In this study, we observed the dynamic changes of T lymphocytes in the first week in a high-dose SM-induced model. Methods: Mice were exposed to SM by subcutaneous injection (20 mg/kg) and were sacrificed 4 h, 24 h, 72 h and 168 h later. Spleen T lymphocyte proliferation was evaluated by3H-TdR. Flow cytometric analysis was used to observe the percentage of CD3+CD4+ and CD3+CD8+ T lymphocyte subsets. The IL-1β, IL-6, IL-10 and TNF-α levels in plasma were assayed using the Luminex method. DNA damage in bone marrow cells was observed with the single cell gel electrophoresis technique (SCGE). Results: SM continuously inhibited the proliferation of lymphocytes for 7 days, and there was a significant rebound of Con A-induced T lymphocyte proliferation only at 24 h. The percentage of CD3+CD4+ and CD3+CD8+ lymphocytes was upregulated, which was accompanied by increased IL-1β and TNF-α and decreased IL-10. The IL-6 level was gradually decreased in the PG group at 4 h. The peak of lymphocytic apoptosis and DNA damage occurred at 24 h and 72 h, respectively. Conclusion: Our results show that SM significantly inhibited T lymphocyte proliferation as well as induced CD3+CD4+ and CD3+CD8+ upregulation. SM intoxication also significantly increased the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and inhibited the level of anti-inflammatory cytokine IL-10. Our results may partly be due to the significant SM induced significant apoptosis and necrosis of lymphocytes as well as DNA damage of bone marrow cells. The results provided a favorable evaluation of SM immune toxicity in an animal model.