Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites

1.?Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC).

2.?Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC₅₀ values for daphnetin (0.51～0.53?μM) and 8-O-methyldaphnetin (22.5～24.3?μM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (K_i) between daphnetin (competitive, 0.37?μM) and 8-O-methyldaphnetin (noncompetitive, 25.7?μM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro–in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin.

3.?With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.     

Alterations of Collagen Matrix in Weight-Bearing Bones during Skeletal Unloading

Skeletal unloading induces loss of bone mineral density in weight-bearing bones. The objectives of this study were to characterize the post-translational modifications of collagen of weight-bearing bones subjected to hindlimb unloading for 8 weeks. In unloaded bones, tibiae and femurs, while the overall amino acid composition was essentially identical in the unloaded and control tibiae and femurs, the collagen cross-link profile showed significant differences. Two major reducible cross-links (analyzed as dihydroxylysinonorleucine and hydroxylysinonorleucine) were increased in the unloaded bones. In addition, the ratios of the former to the latter as well as pyridinoline to deoxypyridinoline were significantly decreased in the unloaded bones indicating a difference in the extent of lysine hydroxylation at the cross-linking sites between these two groups. These results indicate that upon skeletal unloading the relative pool of newly synthesized collagen is increased and it is post-translationally altered. The alteration could be associated with impaired osteoblastic differentiation induced by skeletal unloading that results in a mineralization defect.     

Protective effect of polypeptides from larva of housefly (Musca domestica) on hydrogen peroxide-induced oxidative damage in HepG2 cells

Housefly (Musca domestica) is an important medical insect and its larva is an ideal high protein food source. We isolated from housefly larvae the polypeptides hydrolyzed by neutral protease (PHNP), and investigated the protective effect of PHNP on hydrogen peroxide (H₂O₂)-induced oxidative damage in HepG2 cells. Cells exposed to H₂O₂ showed a marked decrease in proliferation and intracellular superoxide dismutase (SOD) activity, and a significant increase in reactive oxygen species (ROS) level and malondialdehyde (MDA) content. H₂O₂ also caused apoptosis and mitochondrial dysfunction including mitochondrial fragmentation and the loss of mitochondrial membrane potential. Pretreatment with PHNP at concentrations of 2.5, 5, 10 μg/mL blocked these H₂O₂-induced cellular events in a dose-dependent manner. The effect of PHNP at 10 μg/mL is equal to that of ascorbic acid at 10 μM. In summary, PHNP has a protective effect against H₂O₂-induced oxidative injury in cells due to its ability to decrease intracellular ROS and elevate antioxidant enzyme activities.     

组蛋白修饰在酒精成瘾中的作用及机制

酒精是全世界最常用且已被公认的成瘾物质,随着我国经济的快速发展,与饮酒相关的健康问题和社会问题亦急剧增加。酒精成瘾是一种精神疾病,会对人体带来多方面的影响。本文从表观遗传学的角度介绍酒精成瘾对组蛋白修饰的作用及其机制,有助于读者了解酒精成瘾的发生机制以及与之相关的长期神经适应。     

不同剂量的前列地尔对心绞痛患者氧化应激及血液流变学的影响

目的探析不同剂量前列地尔对心绞痛患者氧化应激及血液流变学的影响。方法以我院2011年6月到2015年6月共收治心绞痛门诊患者87例进行研究,分为A组(n=44)与B组(n=43),两组均首先给予常规抗心绞痛治疗,在此基础上应用前列地尔注射液,A组剂量为20μg、B组剂量为10μg,比较两组治疗前后氧化应激(评估指标包括CRP、TNF-α、IL-6)、治疗前后血液流变学(评估指标高切黏度、低切黏度、血浆黏度、血小板聚集率)及心电图总有效率。结果两组治疗前CRP、TNF-α、IL-6的差异均无统计学意义,治疗后A组CRP、TNF-α、IL-6均分别低于该组治疗前及B组治疗后,差异有统计学意义(P0.05)。两组治疗前各项血液流变学指标的差异均无统计学意义,治疗后A组高切黏度、低切黏度、血浆黏度、血小板聚集率均分别低于该组治疗前及B组治疗后,差异有统计学意义(P0.05)。A组治疗总有效率为95.4%(42/44),高于B组86.0%(37/43),但差异无统计学意义(χ~2=2.305,P=0.1290.05)。结论常规剂量(20μg/d)前列地尔治疗心绞痛患者可更有效改善氧化应激及流变,为理想治疗方案。     

Are antioxidant enzymes essential markers in the diagnosis and monitoring of cancer patients – A review

Reactive oxygen species (ROS) play a significant role in human cells. Excessive ROS production damages important macromolecules such as nucleic acids and can initiate and develop the carcinogenesis process. Antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), and xanthine oxidoreductase (XOR) are responsible for maintaining the balance between the functions of free radical formation and eliminating their excessive amounts.Based on the analyzed literature, the following conclusions can be made:1. Antioxidant enzymes activity are important for diagnosing neoplastic diseases such as non-small-cell lung cancer, bladder cancer, ovarian cancer, and colon cancer.2. Non-small-cell lung cancer is usually characterized by decreased SOD and CAT activity and increased glutathione GST activity. Lowered SOD, CAT, and GPx activity is characteristic of bladder cancer. XOR, CAT, SOD and GPx expression is decreased in patients with ovarian cancer. Colorectal cancer is characterized by increased MnSOD expression (in vitro studies) and SOD expression while CAT, GPx, and GR are decreased (in vivo study).3. SOD, CAT, and XOR are promising prognostic markers in cancer of the lung, bladder, ovarian, and colon.     

Comparative effect of ochratoxin A on inflammation and oxidative stress parameters in gut and kidney of piglets

Ochratoxin A (OTA) is a secondary metabolite produced by fungi of Aspergillus and Penicillium genra. OTA is mainly nephrotoxic but can also cause hepatotoxicity, mutagenicity, teratogenicity, neurotoxicity and immunotoxicity. As recent studies have highlighted the close relationship between gastrointestinal tract and kidney, as principal organs involved in absorption and respective excretion of xenobiotics, the aim of the present study was to analyze the effect of a subchronic exposure (30 days) to 0.05 mg/kg OTA on immune response and oxidative stress parameters at the level of intestine and kidney of young swine. The experiment was realised on twelve crossbred weaned piglets randomly allotted to both control group or toxin group fed 0.050 mg OTA/kg feed. Our results have shown that a subchronic intoxication with a low dose of OTA for 30 days affected the immune response and the anti-oxidant self-defense at gut and kidney level. The gene expression of both markers of signaling pathways involved in inflammation and inflammatory cytokines were affected in a much higher extent in the gut than in the kidney Of OTA intoxicated piglets.     

Kolaviron protects the brain in cuprizone-induced model of experimental multiple sclerosis via enhancement of intrinsic antioxidant mechanisms: Possible therapeutic applications?

Multiple sclerosis is a demyelinating condition of the central nervous system which commonly affects young adults. Kolaviron, a biflavonoid isolate of Garcinia kola, has been used in experimental studies which explored its anti-oxidative, anti-inflammatory and anti-genotoxic properties. This work was aimed at unraveling the possible ameliorative effect of kolaviron on cuprizone-induced demyelination in the prefrontal cortices of Wistar rats. A total of 28 adult male Wistar rats were divided into four groups A–D. Group A received corn oil (Control), group B received 0.2% Cuprizone, group C received kolaviron (200?mg/kg?bw), while group D rats were treated concomitantly with both kolaviron and cuprizone. All groups were treated for 42 days, after which behavioral, histological, immunohistochemical and biochemical analyses were carried out on the prefrontal cortices. Cuprizone significantly down-regulated the level of superoxide dismutase, exacerbated lipid peroxidation and, reduced spatial memory. Cuprizone also induced peripheral and central chromatolysis alongside with atrophied astrocytes in the prefrontal cortex. These alterations were significantly prevented in kolaviron-treated rats, as kolaviron sustained the integrity of neuronal and non-neuronal cells. The activity of kolaviron observed in this study was due to its intrinsic antioxidant properties, which enabled it to combat oxidative damage induced by cuprizone, thereby making kolaviron a potential tool in neurodegeneration therapy of demyelination origin.     

The different roles of selective autophagic protein degradation in mammalian cells

Autophagy is an intracellular pathway for bulk protein degradation and the removal of damaged organelles by lysosomes. Autophagy was previously thought to be unselective; however, studies have increasingly confirmed that autophagy-mediated protein degradation is highly regulated. Abnormal autophagic protein degradation has been associated with multiple human diseases such as cancer, neurological disability and cardiovascular disease; therefore, further elucidation of protein degradation by autophagy may be beneficial for protein-based clinical therapies. Macroautophagy and chaperone-mediated autophagy (CMA) can both participate in selective protein degradation in mammalian cells, but the process is quite different in each case. Here, we summarize the various types of macroautophagy and CMA involved in determining protein degradation. For this summary, we divide the autophagic protein degradation pathways into four categories: the post-translational modification dependent and independent CMA pathways and the ubiquitin dependent and independent macroautophagy pathways, and describe how some non-canonical pathways and modifications such as phosphorylation, acetylation and arginylation can influence protein degradation by the autophagy lysosome system (ALS). Finally, we comment on why autophagy can serve as either diagnostics or therapeutic targets in different human diseases.