葛根素对儿茶酚胺诱导大鼠心肌损伤时凋亡相关蛋白的影响

目的 :探讨在儿茶酚胺诱导的心肌损伤过程中 ,心肌细胞的凋亡相关基因 Fas和 Bcl 2的蛋白表达改变及葛根素干预的影响。方法 :5 0只健康雄性 SD大鼠随机分成 3组 :心肌损伤组 (2 0只 )、葛根素干预组 (2 0只 )和对照组 (10只 )。动物模型仿用异丙肾上腺素 (ISO)皮下注射致心肌损伤方法。心肌组织切片分别行 HE及 Fas和 Bcl 2蛋白表达的免疫组织化学染色检测。结果 :心肌损伤组 :Fas蛋白和 Bcl 2蛋白的表达等级均上调 (P均 <0 .0 0 1) ,Fas蛋白的表达水平更高 (P<0 .0 0 1)。葛根素干预组 :心肌组织的 HE病理损害等级明显减轻 (P<0 .0 5 ) ;Fas蛋白表达等级下调 (P<0 .0 5 )。结论 :在儿茶酚胺诱导的心肌损伤过程中 ,Fas和 Bcl 2的蛋白表达水平表现出高水平的差异 ,葛根素能抑制损伤过程中 Fas蛋白的表达。     

Formaldehyde induces neurotoxicity to PC12 cells involving inhibition of paraoxonase-1 expression and activity

1. Formaldehyde (FA) has been found to cause toxicity to neurons. However, its neurotoxic mechanisms have not yet been clarified. Increasing evidence has shown that oxidative damage is one of the most critical effects of formaldehyde exposure. Paraoxonase-1 (PON-1) is a pivotal endogenous anti-oxidant. Thus, we hypothesized that FA-mediated downregulation of PON1 is associated with its neurotoxicity. 2. In the present work, we used PC12 cells to study the neurotoxicity of FA and explore whether PON-1 is implicated in FA-induced neurotoxicity. 3. We found that FA has potent cytotoxic and apoptotic effects on PC12 cells. FA induces an accumulation of intracellular reactive oxygen species along with downregulation of Bcl-2 expression, as well as increased cytochrome c release. FA significantly suppressed the expression and activity of PON-1 in PC12 cells. Furthermore, H(2)S, an endogenous anti-oxidant gas, antagonizes FA-induced cytotoxicity as well as 2-hydroxyquinoline, a specific inhibitor of PON-1, which also induces cytotoxicity to PC12 cells. 4. The results of the present study provide, for the first time, evidence that the inhibitory effect on PON-1 expression and activity is involved in the neurotoxicity of FA, and suggest a promising role of PON-1 as a novel therapeutic strategy for FA-mediated toxicity.     

Medulloblastomas: a correlative study of MIB-1 proliferation index along with expression of c-Myc,ERBB2, and anti-apoptotic proteins along with histological typing and clinical outcome

Background  Medulloblastoma (MB) is the most common pediatric brain tumor. It is however rare in adults. The genetic and protein expression profile of medulloblastoma is complex, which is worthwhile in terms of prognostication and development or selection of targeted therapy. Aims and objectives  The aims and objectives to correlate the MIB-1 proliferation index and protein expression profiles of c-Myc, ERBB2, and anti-apoptotic proteins (Bcl2 and Bcl-xL) in tumor cells with histological subtypes and clinical outcome. Methods and material  In 50 cases, histopathological subtyping was done, and protein expression profiling by immunohistochemical technique was performed by stains for MIB-1, Bcl2, Bcl-xL, c-Myc, and ERBB2 in 30 cases. The findings were correlated with histological types and patient’s average follow-up data. Results  Histological subtypes were similar to that described in literatures. The average expression of Bcl2, Bcl-xL, MIB-1, c-Myc, and ERBB2 were as follows: 50.38%, 38.18%, 59.03%, 46.16%, and 59.62%, respectively. Bcl2 expression showed statistically significant correlation with progress-free survival (PFS) [p = 0.046], while ERBB2 and MIB-1 showed a trend of higher expression in progressive disease. The protein expression pattern did not correlate with histological subtypes. Conclusion  Though Bcl-2, ERBB2, and MIB-1 LI came out to be potential markers of aggressive behavior, c-Myc did not correlate with PFS in MB.     

Involvement of the intrinsic and extrinsic cell‐death pathways in the induction of apoptosis of mature lymphocytes by the Escherichia coli heat‐labile enterotoxin

Escherichia coli heat‐labile enterotoxin (LT) exhibits a broad range of immunomodulatory activities, including the induction of lymphocyte‐programmed cell death. In previous studies, we have demonstrated that in vivo LT promotes apoptosis of immature T and B cells through the stimulation of endogenous glucocorticoids. In the present study, we show that the extrinsic cell‐death pathway as well as the apoptosis‐inducing factor do not participate in the LT‐induced elimination of thymocytes. In contrast to developing lymphocytes, LT promotes the death of mature lymphocytes by both glucocorticoid‐ and Fas death receptor/Fas ligand‐dependent mechanisms. However, the dependency of these mechanisms in the LT‐induced cell‐death activity seems to be different among CD4⁺ and CD8⁺ T cells. Altogether, our study shows that the same bacterial toxin can induce apoptosis of lymphoid cells through several mechanisms depending on the status of differentiation of these cells.     

Association of early phase of colorectal carcinogenesis with STAT3 activation and its relevance in apoptosis regulation

Expression of STAT3/pSTAT3 in colorectal cancer (CRC) patients of Indian origin was studied to assess its significance in early detection and apoptosis regulation. Colorectal tissues with malignant lesions were STAT3/pSTAT3 positive in 66% of the cases and among these positive cases, well differentiated, moderately differentiated and poorly differentiated cancers were 86%, 60% and 0% respectively. All CRC specimens studied were immunoreactive with anti-carcinoembryonic antigen antibody. Cells purified from CRC tissues exhibited greater STAT3/pSTAT3 reactivity than peripheral blood mononuclear cells (PBMC) from healthy individuals, which served as control. apoptotic index (AI) was comparatively low in tissue specimens with STAT3/pSTAT3 expression. CRC cells with a comparatively less number of apoptotic cells, expressed a minimum number of Caspase-3 positive cells (4.73%), in comparison to healthy-PBMC (12.63%). CRC cells with high STAT3/pSTAT3 staining had cells with greater percentage of Bcl2 reactivity (23.05%), but less positivity with Caspase3 antibody (2.05%). Overall data suggests that CRC population was STAT3/pSTAT3 immunoreactive in a stage specific manner and STAT3 protects cancerous colorectal epithelial cells from apoptosis. Bcl-2, Cyclin D1 and Caspase-3 control the activity of apoptosis regulator, STAT3.     

Autophagy in cancer: having your cake and eating it

Autophagy, one of two major intracellular degradation pathways, plays a critical role in energy homeostasis and the quality control of macromolecules and intracellular organelles. Previous work has demonstrated the importance of autophagy in maintaining cellular fitness, both in healthy and stressful conditions, revealing the complex interplay between autophagy and other stress-responsive phenotypes. The complex outcomes of stress-responsive autophagy confer on it both pro- and anti-tumourigenic roles, depending on the cellular and environmental context. Furthermore, recent findings that functionally link autophagy to the tumour suppressor mechanism, cellular senescence, have revealed a new role of autophagy in cancer biology. In this review we summarise the current evidence on the relationship between autophagy and cancer, with a focus on its role in senescence.     

Pinocembrin triggers Bax-dependent mitochondrial apoptosis in colon cancer cells

Bioflavanoids are the major pigments in plants with multitude of biological activities including inhibition of proliferation or induction of apoptosis in tumor cells. Even though the safety records of most flavanoids are exceptional, its therapeutic use is still in its infancy. We have isolated pinocembrin (5,7-dihydroxyflavanone) from Alpinia galanga that showed cytotoxicity against a variety of cancer cells including normal lung fibroblasts with relative nontoxicity to human umbilical cord endothelial cells. The compound induced loss of mitochondrial membrane potential with subsequent release of cytochrome c and processing of caspase-9 and -3 in colon cancer cell line HCT 116. Processing of caspase-8 was minimal. The initial trigger for mitochondrial apoptosis appears to be by the translocation of cytosolic Bax protein to mitochondria. Overexpression of proapoptotic Bax protein sensitized the colon cancer cells to pinocembrin-induced apoptosis and Bax knockout cells were resistant to pinocembrin-induced apoptosis. Antiapoptotic protein Bcl-X(L) only partially prevented apoptosis induced by this compound. The Bax-dependent cell death involving classical cytochrome c release and processing of caspase-9 and -3 suggests that pinocembrin is a classical mitochondrial apoptosis inducer. But the failure of Bcl-X(L) overexpression to completely prevent apoptosis induced by this compound suggests that pinocembrin is capable of triggering mitochondrial-independent cell death that needs to be clarified. The existence of cell death upon Bcl-X(L) overexpression is a promising feature of this compound that can be exploited against drug resistant forms of cancer cells either alone or in combination with other drugs.     

放射复合伤口愈合中外周血淋巴细胞凋亡及其与愈合延迟的关系

为研究放射复合伤口愈合中外周血淋巴细胞凋亡规律并探讨其与愈合延迟的关系，将120只大鼠随机分为单纯创伤组与创伤复合照射组，用原位末端标记（TUNEL）方法检测细胞凋亡，碱磷酶免疫组织化学方法检测Bax,Bcl-2蛋白表达，结果发现，创伤复合照射组动物白细胞数出现下降，伤后3天降至最低，伤后5天仍显著低于单纯创伤组；伤后两组动物中血淋巴细胞凋亡率均升高，但创伤照射组凋亡率始终高于单纯创伤组；伤后不同时间淋巴细胞Bax蛋白出现升高，创伤照射组明显高于单纯创伤组，而Bcl-2呈现相反的变化趋势，该结果提示，照射后外周血白细胞数的降低和淋巴细胞凋亡的增加是辐射延迟伤口愈合的重要原因，Bax和Bcl-2蛋白参与了淋巴细胞凋亡的调控。