SIRT1 inhibitors mitigate radiation-induced GI syndrome by enhancing intestinal-stem-cell survival.

High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.

Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy.

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.

Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy.

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of disulfide high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.

Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease.

Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD.

Antiinflammatory and Antimicrobial Effects of Thiocyanate in a Cystic Fibrosis Mouse Model.

Thiocyanate (SCN) is used by the innate immune system, but less is known about its impact on inflammation and oxidative stress. Granulocytes oxidize SCN to evolve the bactericidal hypothiocyanous acid, which we previously demonstrated is metabolized by mammalian, but not bacterial, thioredoxin reductase (TrxR). There is also evidence that SCN is dysregulated in cystic fibrosis (CF), a disease marked by chronic infection and airway inflammation. To investigate antiinflammatory effects of SCN, we administered nebulized SCN or saline to ß epithelial sodium channel (ßENaC) mice, a phenotypic CF model. SCN significantly decreased airway neutrophil infiltrate and restored the redox ratio of glutathione in lung tissue and airway epithelial lining fluid to levels comparable to wild type. Furthermore, in Pseudomonas aeruginosa-infected ßENaC and wild-type mice, SCN decreased inflammation, proinflammatory cytokines, and bacterial load. SCN also decreased airway neutrophil chemokine keratinocyte chemoattractant (also known as C-X-C motif chemokine ligand 1) and glutathione sulfonamide, a biomarker of granulocyte oxidative activity, in uninfected ßENaC mice. Lung tissue TrxR activity and expression increased in inflamed lung tissue, providing in vivo evidence for the link between hypothiocyanous acid metabolism by TrxR and the promotion of selective biocide of pathogens. SCN treatment both suppressed inflammation and improved host defense, suggesting that nebulized SCN may have important therapeutic utility in diseases of both chronic airway inflammation and persistent bacterial infection, such as CF.

[Analysis of iodine nutrition and thyroid function of adults in urban areas of Wuwei city Gansu province].

OBJECTIVE: To find out the iodine nutrition and thyroid function of adults in urban areas of Wuwei city Gansu province and to provide a basis for scientific iodine supplementation. METHODS: A cross-sectional survey was performed in 104 adults in Wuwei city form the April 2009 to January 2010. The morning blood samples and one urine samples selected randomly of different people were collected and three free triiodothyronine (FT3), free thyroid hormone (FT4), total triiodothyronine (TT3), total thyroxine (TT4), the thyroid-stimulating hormone (TSH), thyroglobulin antibodies (TGAb), thyroid microsomal antibodies (TMAb) in blood samples and iodine in urine samples were detected. RESULTS: The medians of urinary iodine were respectively 139.3 microg/L and 212.6 microg/L for male and female, female was significantly higher than male, there were statisticant differences (P < 0.05). TT3, TT4, FT4, FT3 and TSH's mean values were in the normal range, the abnormal ratio of TT3, TT4, FT3, FT4, TSH were respectively 1.9%, 1.0%, 3.8%, 1.9%, 16.3%. The positive rate of TGAb and TMAb in female were all higher than male, there were statisticant differences (P < 0.05). Subclinical hypothyroidism in all thyroid function disorders was most and accounted for 14.4% and female were all higher than male (P < 0.05). The survey were divided into iodine deficiency group, adequate iodine group, over adequate iodine group and iodine excess group for urinary iodine level. The abnormal ratio of TT3, TT4, FT3, FT4, TSH in four groups had no statistically differences, but the positive rate of TGAb and TMAb raised with increased urinary iodine level. Thyroid function disorders occurred in the other three groups except iodine deficiency group, and there were statisticant differences. CONCLUSION: Iodine nutrition level is appropriate for adults in urban areas, but the female was higher than male. Subclinical hypothyroidism in all thyroid function disorders was most, the positive rate of TGAb and TMAb raised with increased urinary iodine level, the risk of female suffered from thyroid disease was higher than male.

Temporal and spatial increase of reactive nitrogen species in the kainate model of temporal lobe epilepsy.

Steady-state levels of reactive oxygen species (ROS) and oxidative damage to cellular macromolecules are increased in the rodent hippocampus during epileptogenesis. However, the role of reactive nitrogen species (RNS) in epileptogenesis remains to be explored. The goal of this study was to determine the spatial and temporal occurrence of RNS i.e. nitric oxide levels in a rat model of temporal lobe epilepsy (TLE). Rats were injected with a single high dose of kainate and monitored by video for behavioral seizures for 6weeks to determine the onset and severity of chronic seizures. RNS and tissue/mitochondrial redox status (glutathione redox couple and coenzyme A:glutathione redox couple) were measured in the hippocampus at 8h, 24h, 48h, 1wk, 3wk and 6wk following kainate to assess the level of reactive species in subcellular compartments. We observed a biphasic increase in RNS levels with a return to control values at the 48h time point. However, both tissue and mitochondrial redox status showed permanent and significant decreases during the entire time course of epilepsy development. 3 nitrotyrosine (3NT) protein adducts were found to gradually increase throughout epileptogenesis, conceivably as a result of the local environment under oxidative and nitrosative stress. Colocalization of 3NT immunostaining with neuron- or astrocyte-specific markers revealed neuron-specific localization of 3NT in hippocampal principal neurons. Persistent and concurrent glutathione oxidation and nitrosative stress occur during epileptogenesis suggesting a favorable environment for posttranslational modifications.

[Analysis on iodine nutritional status and thyroid function in pregnant women].

OBJECTIVE: To investigate the iodine nutritional status and thyroid function of pregnant women during different periods of pregnancy, to provide evidence for guiding iodine supplementation for them. METHODS: A cross-sectional survey was performed in 90 pregnant women in Wuwei City from April 2009 to January 2010. The morning blood samples and random urine samples were collected, and the thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroid hormone (FT4), thyroglobulin antibodies (TGAb), thyroid microsomal antibodies (TMAb) in blood samples and iodine in urine samples were detected. RESULTS: The medians of urinary iodine were 231.49, 158.25 and 328.35 microg/L for women in early, middle and late period of pregnancy, The ratio of urinary iodine below 150 microg/L were 39.29%, 45.16% and 25.81%, respectively. The FT3, FT4 levels in the first trimester were higher than those in the third trimester (P < 0.05) and TSH level was increased, but no significant difference (P > 0.05). The positive rate of TGAb and TMAb antibody of pregnant women in different period of time were not significantly different (P > 0.05). The incidence of thyroid function disorder was significantly different in different gestation periods. CONCLUSION: Generally, the iodine nutritional status of these pregnant women was appropriate, but there was a tendency towards hypothyroid in some women. Monitoring urinary iodine and thyroid function in pregnant women should be carried out regularly.