Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

Gabapentin for complex regional pain syndrome in Machado-Joseph disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chronic pain is a common problem for patients with Machado-Joseph disease. Most of the chronic pain in Machado-Joseph disease has been reported to be of musculoskeletal origin, but now there seems to be different chronic pain in patients with Machado-Joseph disease.</p> <p>Case presentation</p> <p>A 29-year-old man (Han Chinese, Hoklo) with Machado-Joseph disease experienced severe chronic pain in both feet, cutaneous thermal change, thermal hypersensitivity, focal edema, and sweating and had a history of bone fracture. These symptoms were compatible with a diagnosis of complex regional pain syndrome. After common analgesics failed to relieve his pain, gabapentin was added and titrated to 2000 mg/day (500 mg every six hours) in less than two weeks. This relieved 40% of his pain and led to significant clinical improvement.</p> <p>Conclusions</p> <p>The pathophysiology of complex regional pain syndrome includes peripheral and central sensitizations, the latter of which might be associated with the neurodegeneration in Machado-Joseph disease. In this report, we suggest that gabapentin could inhibit central sensitization as an adjunct for complex regional pain syndrome in patients with Machado-Joseph disease.</p

Targeted gene therapy of nasopharyngeal cancer in vitro and in vivo by enhanced thymidine kinase expression driven by human TERT promoter and CMV enhancer

<p>Abstract</p> <p>Background/Aim</p> <p>To explore the therapeutic effects of thymidine kinase (TK) expressed by enhanced vector pGL3-basic- hTERTp-TK-EGFP-CMV driven by human telomerase reverse transcriptase promoter (hTERTp) as well as cytomegalovirus immediate early promoter enhancer (CMV).</p> <p>Materials/Methods</p> <p>Enhanced TK-EGFP expression was confirmed by fluorescent microscopy, real time PCR and telomerase activity. Its effects were examined by survival of tumor cells NPC 5-8F and MCF-7, index of xenograft implanted in nude mice and histology.</p> <p>Results</p> <p>Compared with non-enhanced vector pGL3-basic-TK-hTERTp-EGFP, TK expressed by the enhanced vector significantly decreased NPC 5-8F and MCF-7 cell survival rates after ganciclovir (GCV) treatment (p < 0.001) and tumor progress in nude mice with NPC xenograft and treated with GCV, without obvious toxicity to mouse liver and kidney.</p> <p>Conclusion</p> <p>The enhanced TK expression vector driven by hTERTp with CMV enhancer has brighter clinical potentials in nasopharyngeal carcinoma therapy than the non-enhanced vector.</p

Genetic polymorphisms of DNA double strand break gene Ku70 and gastric cancer in Taiwan

<p>Abstract</p> <p>Background and aim</p> <p>The DNA repair gene <it>Ku70</it>, an important member of non-homologous end-joining repair system, is thought to play an important role in the repairing of DNA double strand breaks. It is known that defects in double strand break repair capacity can lead to irreversible genomic instability. However, the polymorphic variants of <it>Ku70</it>, have never been reported about their association with gastric cancer susceptibility.</p> <p>Methods</p> <p>In this hospital-based case-control study, the associations of <it>Ku70 </it>promoter T-991C (rs5751129), promoter G-57C (rs2267437), promoter A-31G (rs132770), and intron 3 (rs132774) polymorphisms with gastric cancer risk in a Taiwanese population were investigated. In total, 136 patients with gastric cancer and 560 age- and gender-matched healthy controls recruited from the China Medical Hospital in Taiwan were genotyped.</p> <p>Results</p> <p>As for <it>Ku70 </it>promoter T-991C, the ORs after adjusted by age and gender of the people carrying TC and CC genotypes were 2.41 (95% CI = 1.53-3.88) and 3.21 (95% CI = 0.96-9.41) respectively, compared to those carrying TT wild-type genotype. The <it>P </it>for trend was significant (<it>P </it>< 0.0001). In the dominant model (TC plus CC versus TT), the association between <it>Ku70 </it>promoter T-991C polymorphism and the risk for gastric cancer was also significant (adjusted OR = 2.48, 95% CI = 1.74-3.92). When stratified by age and gender, the association was restricted to those at the age of 55 or elder of age (TC vs TT: adjusted OR = 2.52, 95% CI = 1.37-4.68, <it>P </it>= 0.0139) and male (TC vs TT: adjusted OR = 2.58, 95% CI = 1.33-4.47, <it>P </it>= 0.0085). As for the other three polymorphisms, there was no difference between both groups in the distributions of their genotype frequencies.</p> <p>Conclusion</p> <p>In conclusion, the <it>Ku70 </it>promoter T-991C (rs5751129), but not the <it>Ku70 </it>promoter C-57G (rs2267437), promoter A-31G (rs132770) or intron 3 (rs132774), is associated with gastric cancer susceptibility. This polymorphism may be a novel useful marker for gastric carcinogenesis.</p

Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay

The decay channel $\psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p})$ is studied using a sample of $1.06\times 10^8$ $\psi^\prime$ events collected by the BESIII experiment at BEPCII. A strong enhancement at threshold is observed in the $p\bar{p}$ invariant mass spectrum. The enhancement can be fit with an $S$-wave Breit-Wigner resonance function with a resulting peak mass of $M=1861^{+6}_{-13} {\rm (stat)}^{+7}_{-26} {\rm (syst)} {\rm MeV/}c^2$ and a narrow width that is $\Gamma<38 {\rm MeV/}c^2$ at the 90% confidence level. These results are consistent with published BESII results. These mass and width values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics

NK Cells Are Not Required for Spontaneous Autoimmune Diabetes in NOD Mice

NK cells have been shown to either promote or protect from autoimmune diseases. Several studies have examined the role of receptors preferentially expressed by NK cells in the spontaneous disease of NOD mice or the direct role of NK cells in acute induced disease models of diabetes. Yet, the role of NK cells in spontaneous diabetes has not been directly addressed. Here, we used the NOD.NK1.1 congenic mouse model to examine the role of NK cells in spontaneous diabetes. Significant numbers of NK cells were only seen in the pancreas of mice with disease. Pancreatic NK cells displayed an activated surface phenotype and proliferated more than NK cells from other tissues in the diseased mice. Nonetheless, depletion of NK cells had no effect on dendritic cell maturation or T cell proliferation. In spontaneous disease, the deletion of NK cells had no significant impact on disease onset. NK cells were also not required to promote disease induced by adoptively transferred pathogenic CD4+ T cells. Thus, NK cells are not required for spontaneous autoimmune diabetes in NOD mice

Anti-tumor effect of Liqi, a traditional Chinese medicine prescription, in tumor bearing mice

<p>Abstract</p> <p>Background</p> <p><it>Liqi</it>, an herbal preparation used in traditional Chinese medicine, has been used to treat cancer in China for centuries. We investigated the anti-tumor effects of liqi and their mechanisms in mice that had been xenografted with tumors.</p> <p>Methods</p> <p>Sarcoma 180 tumor, Lewis lung carcinoma, and SGC-7901 cells were implanted in BALB/c mice, C57BL/6 mice, and BALB/c nude mice, respectively. Liqi was administered to subgroups of these mice. The tumor weight and size were measured. Cell cycle analysis and T lymphocyte subsets were determined by flow cytometry. The activity of NK cells and TNF was tested using cytotoxicity assay on YAC-1 cells and L929 cells, respectively, and the activity of IL-2 was tested with an IL-2-dependent CTLL-2 cell proliferation assay. Platelet aggregation was monitored by measuring electric impedance, and the levels of thromboxane A2 (TXA₂) and prostacyclin (PGI₂) in blood were measured by ¹²⁵I-TXB₂and ¹²⁵I-Keto-PGF_1αradioimmunoassay.</p> <p>Results</p> <p>The results showed that liqi inhibited tumor growth in tumor-implanted mice and arrested the cell proliferation in the G0/G1 phase and reduced the portion of cells in S and G2/M phase for SGC-7901 cells. Liqi increased the activity of NK cells and TNF-α, stimulated IL-2 production and activity, and regulated T lymphocyte subpopulations. Liqi inhibited the Lewis lung carcinoma metastasis by inhibiting platelet aggregation and normalizing the balance between TXA₂and PGI₂.</p> <p>Conclusion</p> <p>All these findings demonstrated that liqi has an anti-tumor effect in vivo. The mechanism may be related to immune regulation and anticoagulation effects.</p

Delayed Treatment of Diagnosed Pulmonary Tuberculosis in Taiwan

<p>Abstract</p> <p>Background</p> <p>Mycobacterium tuberculosis infection is an ongoing public health problem in Taiwan. The National Tuberculosis Registry Campaign, a case management system, was implemented in 1997. This study examined this monitoring system to identify and characterize delayed treatment of TB patients.</p> <p>Methods</p> <p>Records of all tuberculosis cases treated in Taiwan from 2002 through 2005 were obtained from the National Tuberculosis Registry Campaign. Initiation of treatment more than 7 days after diagnosis was considered a long treatment delay.</p> <p>Results</p> <p>The study included 31,937 patients. The mean day of delayed treatment was 3.6 days. Most patients were treated immediately after diagnosis. The relationship between number of TB patients and days of delayed treatment after diagnosis exhibited a Power-law distribution. The long tail of the power-law distribution indicated that an extreme number occur cannot be neglected. Tuberculosis patients treated after an unusually long delay require close observation and follow up.</p> <p>Conclusion</p> <p>This study found that TB control is generally acceptabl in Taiwan; however, delayed treatment increases the risk of transmission. Improving the protocol for managing confirmed TB cases can minimize disease transmission.</p