Oncostatic-Cytoprotective Effect of Melatonin and Other Bioactive Molecules: A Common Target in Mitochondrial Respiration

For several years, oncostatic and antiproliferative properties, as well as thoses of cell death induction through 5-methoxy-N-acetiltryptamine or melatonin treatment, have been known. Paradoxically, its remarkable scavenger, cytoprotective and anti-apoptotic characteristics in neurodegeneration models, such as Alzheimer’s disease and Parkinson’s disease are known too. Analogous results have been confirmed by a large literature to be associated to the use of many other bioactive molecules such as resveratrol, tocopherol derivatives or vitamin E and others. It is interesting to note that the two opposite situations, namely the neoplastic pathology and the neurodegeneration, are characterized by deep alterations of the metabolome, of mitochondrial function and of oxygen consumption, so that the oncostatic and cytoprotective action can find a potential rationalization because of the different metabolic and mitochondrial situations, and in the effect that these molecules exercise on the mitochondrial function. In this review we discuss historical and general aspects of melatonin, relations between cancers and the metabolome and between neurodegeneration and the metabolome, and the possible effects of melatonin and of other bioactive molecules on metabolic and mitochondrial dynamics. Finally, we suggest a common general mechanism as responsible for the oncostatic/cytoprotective effect of melatonin and of other molecules examined.     

PARP-1在苯代谢物氢醌诱导细胞凋亡中的作用

苯（benzene）是一种常见的职业性毒物和环境污染物,主要由其代谢产物氢醌（Hydroquinone,HQ）发挥毒性作用。聚腺苷二磷酸核糖聚合酶[Poly（ADP-ribose）polymerase,PARP]是一类存在于多数真核细胞内的多功能蛋白质翻译后修饰酶,其中PARP-l是研究最早、最为深入的一种。PARP-1在氢醌诱导细胞凋亡中发挥了重要作用。本文从HQ的概述、PARP-1的结构与功能以及PARP-1在HQ诱导细胞凋亡中的作用等方面做一综述,以期对苯暴露引起的各类疾病的防治提供理论指导。     

Lycium barbarum polysaccharide inhibits the proliferation of HeLa cells by inducing apoptosis

BACKGROUND: Lycium barbarum polysaccharide (LBP), isolated with boiling water from the famous Chinese medicinal herb Lycium barbarum fruits, is one of the most important functional constituents in Lycium barbarum. In this study the effects of LBP on cell proliferation, cell cycle and apoptosis in human cervical carcinoma cells (HeLa cells) were investigated. RESULTS: LBP could inhibit the proliferation of HeLa cells by changing cell cycle distribution and inducing apoptosis. In addition, the loss of mitochondrial transmembrane potential (Δψ_m) was observed by flow cytometry and the increase of intracellular Ca²⁺ concentration was detected by laser scanning confocal microscope in apoptotic cells. At the same time, the nitric oxide content, nitric oxide synthase and inducible nitric oxide synthase activities were also increased. CONCLUSION: The inhibitory effect of LBP on the proliferation of HeLa cells was caused by inducing apoptosis through the mitochondrial pathway. The results showed that LBP can be developed as a potential chemotherapeutic agent candidate against human cervical cancer. Copyright © 2012 Society of Chemical Industry     

Synthesis and Evaluation of Water‐Soluble Prodrugs of Ursodeoxycholic Acid (UDCA), an Anti‐apoptotic Bile Acid

Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti‐apoptotic activity in both in vitro and in vivo models. However, its utility is hampered by limited aqueous solubility. As such, water‐soluble prodrugs of UDCA could have an advantage over the parent bile acid in indications where intravenous administration might be preferable, such as decreasing damage from stroke or acute kidney injury. Five phosphate prodrugs were synthesized, including one incorporating a novel phosphoryloxymethyl carboxylate (POMC) moiety. These prodrugs were highly water‐soluble, but showed significant differences in chemical stability, with oxymethylphosphate prodrugs being the most unstable. In a series of NMR experiments, the POMC prodrug was bioactivated to UDCA by alkaline phosphatase (AP) faster than a prodrug containing a phosphate directly attached to the alcohol at the 3‐position of UDCA. Both of these prodrugs showed significant anti‐apoptotic activity in a series of in vitro assays, although the POMC prodrug required the addition of AP for activity, while the other compound was active without exogenous AP.     

Ultraviolet B (UVB) Irradiation-Induced Apoptosis in Various Cell Lineages in Vitro

Ultraviolet B (UVB) radiation acts as a strong apoptotic trigger in many cell types, in tumor and normal cells. Several studies have demonstrated that UVB-induced cell death occurs through the generation of reactive oxygen species. The consequent oxidative stress includes the impairment of cellular antioxidants, the induction of DNA damage and the occurrence of apoptosis. In this review, we investigated UVB apoptotic action in various cell models by using ultrastructural, molecular and cytofluorimetric techniques. Myeloid leukemia HL-60, T-lymphoblastoid Molt-4 and myelomonocytic U937 human cells, generally affected by apoptotic stimuli, were studied. Human chondrocytes and C2C12 skeletal muscle cells, known to be more resistant to damage, were also considered. All of them, when exposed to UVB radiation, revealed a number of characteristic apoptotic markers. Membrane blebbing, cytoplasm shrinkage and chromatin condensation were detected by means of electron microscopy. DNA cleavage, investigated by using agarose gel electrophoresis and TUNEL reaction, was observed in suspended cells. Differently, in chondrocytes and in skeletal muscle cells, oligonucleosomic DNA fragmentation did not appear, even if a certain TUNEL positivity was detected. These findings demonstrate that UVB radiation appears to be an ideal tool to study the apoptotic behavior.     

异嗪皮啶对人乳腺癌干细胞凋亡相关基因Bcl-2与Caspase家族表达的影响

目的: 研究草珊瑚中异嗪皮啶成分对乳腺癌干细胞中凋亡相关基因通路Bcl-2、Caspase-3、Caspase-8基因表达影响，进而明确其抑制增殖、迁移和促凋亡的机制。方法: 无血清培养法诱导MDA-MB-231细胞株富集乳腺癌干细胞，流式细胞仪分选CD44⁺ /CD24 ^-/low干细胞群。各组分别给予0、17、50、150、450 μmol/L异嗪皮啶，CCK-8法观察给药后24、48、72 h的细胞活力；细胞划痕实验法检测给药后细胞痕道宽度变化值并判断其对细胞迁移能力的影响；Annexin V-FITC/PI染色法检测给药后细胞总凋亡率变化；实时荧光定量PCR测定各组Bcl-2、Caspase-3、Caspase-8基因的mRNA水平；Western blot检测上述基因的蛋白水平。结果: 与对照组比较，50、150和450 μmol/L异嗪皮啶组24、48、72 h的细胞活力降低，细胞迁移能力下降。与对照组比较，50、150和450 μmol/L异嗪皮啶组细胞总凋亡率高于对照组，Bcl-2基因mRNA和蛋白表达水平降低，Caspase-3和Caspase-8基因mRNA和蛋白表达水平升高。以上结果均呈明显剂量效应关系。结论: 异嗪皮啶能通过下调Bcl-2基因表达与激活Caspase基因家族诱导乳腺癌干细胞的凋亡，同时能抑制其增殖与迁移。