Taurine Treatment Research Articles

MP94-16 OXIDATIVE STRESS-RELATED ALTERATIONS IN THE BLADDER OF A SHORT-PERIOD DIABETES TYPE-2 RAT MODEL

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology II1 Apr 2017MP94-16 OXIDATIVE STRESS-RELATED ALTERATIONS IN THE BLADDER OF A SHORT-PERIOD DIABETES TYPE-2 RAT MODEL Panagiota Tsounapi, Masashi Honda, Fotios Dimitriadis, Yusuke Kimura, Shogo Shimizu, Bunya Kawamoto, Katsuya Hikita, Motoaki Saito, Nikolaos Sofikitis, and Atsushi Takenaka Panagiota TsounapiPanagiota Tsounapi More articles by this author , Masashi HondaMasashi Honda More articles by this author , Fotios DimitriadisFotios Dimitriadis More articles by this author , Yusuke KimuraYusuke Kimura More articles by this author , Shogo ShimizuShogo Shimizu More articles by this author , Bunya KawamotoBunya Kawamoto More articles by this author , Katsuya HikitaKatsuya Hikita More articles by this author , Motoaki SaitoMotoaki Saito More articles by this author , Nikolaos SofikitisNikolaos Sofikitis More articles by this author , and Atsushi TakenakaAtsushi Takenaka More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2919AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Diabetes type-2 accounts for almost 90% of diabetes cases worldwide. Diabetes among other complications induces bladder dysfunction. In the current study we aimed to create a short-period diabetes type-2 model in order to investigate oxidative stress-related alterations in the bladder in the initiation of the disease. Additionally antioxidant treatment with resveratrol or taurine was provided in order to examine whether it is possible to prevent these alterations in the very beginning of the disease. METHODS Diabetes was induced in 8-week-old male Wistar rats with a single dose of streptozotocin (40mg/kg) intraperitoneally (i.p.). The next day they were randomly separated into 3 groups and 14 days feeding with a high fat diet followed. One group received no treatment (DM group), another group received orally resveratrol (10mg/Kg; Resv group) and the third one received taurine i.p. (1g/Kg; Tau group). Age matched control animals were used and were fed with normal diet (Control group). Two weeks later animals were sacrificed and bladder were processed for histological evaluation, measurements of malondialdehyde (MDA) and immunohistochemistry (IHC) for oxidative stress markers. RESULTS At the end of 2 weeks all diabetic groups had significantly lower body weight compared to the Control group. DM group demonstrated significantly higher ratio of bladder weight to body weight compared to the Control (Figure 1). Histological evaluation demonstrated mild damage of the bladder tissue in the DM group such as abruption of the mucosa from the muscularis as well as edema in the transitional epithelium. All these alterations were not observed in the treatment groups. MDA levels in the bladder were significantly larger in the DM group compared with Control, Resv or Tau group (Figure 1). Fourteen days of diabetes without treatment in the DM group induced moderate to strong intensity and positivity for oxidative stress marker MDA, 4-Hydroxynonenal and DNA oxidative stress marker 8-deoxyguanosine compared with the other three groups. CONCLUSIONS The prompt diagnosis of diabetes can be crucial for the progression of the disease. Specifically in the bladder, it appears that both mild damage in structural level as well as oxidative damage in molecular level can be prevented by resveratrol or taurine treatment. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1252 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Panagiota Tsounapi More articles by this author Masashi Honda More articles by this author Fotios Dimitriadis More articles by this author Yusuke Kimura More articles by this author Shogo Shimizu More articles by this author Bunya Kawamoto More articles by this author Katsuya Hikita More articles by this author Motoaki Saito More articles by this author Nikolaos Sofikitis More articles by this author Atsushi Takenaka More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Taurine Protects Mouse Spermatocytes from Ionizing Radiation-Induced Damage Through Activation of Nrf2/HO-1 Signaling

Background/Aims: The increasing prevalence of ionizing radiation exposure has inevitably raised public concern over the potential detrimental effects of ionizing radiation on male reproductive system function. The detection of drug candidates to prevent reproductive system from damage caused by ionizing radiation is urgent. We aimed to investigate the protective role of taurine on the injury of mouse spermatocyte-derived cells (GC-2) subjected to ionizing radiation. Methods: mouse spermatocytes (GC-2 cells) were exposed to ionizing radiation with or without treatment of Taurine. The effect of ionizing radiation and Taurine treatment on GC-2 cells were evaluated by cell viability assay (CCK8), cell cycle and apoptosis. The relative protein abundance change was determined by Western blotting. The siRNA was used to explore whether Nrf2 signaling was involved in the cytoprotection of Taurine. Results: Taurine significantly inhibited the decrease of cell viability, percentage of apoptotic cells and cell cycle arrest induced by ionizing radiation. Western blot analysis showed that taurine significantly limited the ionizing radiation-induced down-regulation of CyclinB1 and CDK1, and suppressed activation of Fas/FasL system pathway. In addition, taurine treatment significantly increased the expression of Nrf2 and HO-1 in GC-2 cells exposed to ionizing radiation, two components in antioxidant pathway. The above cytoprotection of Taurine was blocked by siNrf2. Conclusion: Our results demonstrate that taurine has the potential to effectively protect GC-2 cells from ionizing radiation- triggered damage via upregulation of Nrf2/HO-1 signaling.

A Novel Cysteine Sulfinic Acid Decarboxylase Knock-Out Mouse: Taurine Distribution in Various Tissues With and Without Taurine Supplementation.

Taurine, a sulfur containing amino acid, has various physiological functions including development of the eye and brain, immune function, reproduction, osmo-regulatory function as well as anti-oxidant and anti-inflammatory activities. In order to understand the physiological role, we developed taurine deficient mice deleting a rate-liming enzyme, cysteine sulfinic acid decarboxylase (CSAD) for biosynthesis of taurine. Taurine was measured in various tissues including the liver, brain, lung, spleen, thymus, pancreas, heart, muscle and kidney as well as plasma from CSAD knock-out mice (CSAD KO) with and without treatment of taurine in the drinking water at the age of 2 months (2 M). Taurine was determined using HPLC as a phenylisothiocyanate derivative of taurine at 254 nm. Taurine concentrations in the liver and kidney from homozygotes of CSAD KO (HO), in which CSAD level is high, were 90% and 70% lower than WT, respectively. Taurine concentrations in the brain, spleen and lung, where CSAD level is low, were 21%, 20% and 28% lower than WT, respectively. At 2 M, 1% taurine treatment of HO restored taurine concentrations in all tissues compared to that of WT. To select an appropriate taurine treatment, HO were treated with various concentrations (0.05, 0.2, 1%) of taurine for 4 months (4 M). Restoration of taurine in all tissues except the liver, kidney and lung requires 0.05% taurine to be restored to that of WT. The liver and kidney restore taurine back to WT with 0.2% taurine. To examine which enzymes influence taurine concentrations in various tissues from WT and HO at 2 M, expression of five taurine-related enzymes, two antioxidant enzymes as well as lactoferrin (Lft) and prolactin receptor (Prlr) was determined using RT2 qPCR. The expression of taurine transporter in the liver, brain, muscle and kidney from HO was increased except in the lung. Our data showed expression of glutamate decarboxylase-like 1(Gadl-1) was increased in the brain and muscle in HO, compared to WT, indicating taurine in the brain and muscle from HO was replenished through taurine transporter and increased biosynthesis of taurine by up-regulated Gadl-1. The expression of glutathione peroxidase 3 was increased in the brain and peroxireductase 2 was increased in the liver and lung, suggesting taurine has anti-oxidant activity. In contrast to newborn and 1 month CSAD KO, Ltf and Prlr in the liver from CSAD KO at 2 M were increased more than two times and 52%, respectively, indicating these two proteins may be required for pregnancy of CSAD KO. Ltf in HOT1.0 was restored to WT, while Prlr in HOT1.0 was increased more than HO, explaining improvement of neonatal survival with taurine supplementation.These data are essential for investigating the role of taurine in development of the brain and eye, immune function, reproduction and glucose tolerance.

Taurine Improves Sexual Function in Streptozotocin-Induced Diabetic Rats.

Previous studies have identified that diabetic erectile dysfunction is associated with androgen and nitric oxide deficiency resulting from hyperglycemia. It has been demonstrated that taurine can stimulate testosterone secretion, increase nitric oxide synthase (NOS) activity and nitric oxide (NO) production, and reduce blood glucose levels in the diabetic animals. Furthermore, recent studies have found that taurine relaxes both the corpus cavernosum and the vasculature. Accordingly, we hypothesized that taurine might exert beneficial effects on erectile function of the diabetic rats. Here, we assessed the effects of taurine on sexual function in streptozotocin (STZ) -induced diabetic male rats. We observed that taurine treatment could markedly increase sexual response and mating ability of STZ-diabetic rats. The serum concentration of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) were also significantly increased by taurine administration. Importantly, taurine supplementation notably increased mRNA levels and activity of endothelial NOS (eNOS) and neuronal NOS (nNOS), as well as NO and cGMP content, in the corpus cavernosum of the diabetic rats. In conclusion, the present data indicate that taurine can increase sexual function of STZ-induced diabetic male rats mainly by correcting the diabetes, increasing sexual desire, which is implicated in ameliorating the hypothalamic-pituitary-testicular axis function, and by improving penile erection, which requires increased signaling from the penile endothelial- and neuronal-dependent NO-cGMP pathway.

Effects of Taurine on Alterations of Neurobehavior and Neurodevelopment Key Proteins Expression in Infant Rats by Exposure to Hexabromocyclododecane.

Hexabromocyclododecanes (HBCDs) is a widely used flame retardant. Studies have found that HBCDs has toxic effects on endocrine and neural development, leading to adverse effects on behavior, learning and memory. This study aimed to investigate the protective effects of taurine on cognitive function, neurotrophic factors expression of infant rats exposured to HBCDs. Sprague-Dawley rats of 10-days old were oral gavaged of different doses (0.3, 3 and 30mg/kg) of HBCDs and 30mg/kg HBCDs with 300mg/kg taurine for 60 consecutive days. Rat cognitive function was detected by the method of Morris water maze test. The protein expressions of brain derived neurotrophic factor (BDNF), nerve growth factor (NGF) and fibroblast growth factor (FGF) were assayed by Western-blotting. Results showed that rats exposed to HBCDs significantly declined rats spatial learning and memory ability by increasing the latency time of seeking the platform (P<0.05), decreasing the numbers that each rat had crossed the non-exits and the time spent in the target quadrant as compared with those in control rats (P<0.05). Taurine treatment significantly reversed the effects of HBCDs. Western-blotting results showed that expression of BDNF, NGF and FGF proteins in the low dose group were obviously increased compared with those in control rats (P<0.01), and middle-dose and high dose groups significantly decreased. Taurine treatment increased BDNF and NGF expression as compared with high dose groups while Taurine seemed to have no effects on FGF. These result suggested that higher doses of HBCDs early exposure in the developing rats could decrease neurotrophic factors including BDNF, NGF, FGF, which have an impact on neural development, damage on learning and memory.

Analysis of Neuroprotection by Taurine and Taurine Combinations in Primary Neuronal Cultures and in Neuronal Cell Lines Exposed to Glutamate Excitotoxicity and to Hypoxia/Re-oxygenation.

Ischemic stroke is one of the greatest contributors to death and long term disability in developed countries. Ischemia induced brain injury arises due to excessive release of glutamate and involves cell death due to apoptosis and endoplasmic reticulum (ER) stress responses. Despite major research efforts there are currently no effective treatments for stroke. Taurine, a free amino acid found in high concentrations in many invertebrate and vertebrate systems can provide protection against a range of neurological disorders. Here we demonstrate that taurine can combat ER stress responses induced by glutamate or by hypoxia/re-oxygenation in neuronal cell lines and primary neuronal cultures. Taurine decreased expression of ER stress markers GRP78, CHOP, Bim and caspase 12 in primary neuronal cultures exposed to hypoxia/re-oxygenation. In analyzing individual ER stress pathways we demonstrated that taurine treatment can result in reduced levels of cleaved ATF6 and decreased p-IRE1 levels. We hypothesized that because of the complex nature of stroke a combination therapy approach may be optimal. For this reason we proceeded to test combination therapies using taurine plus low dose administration of an additional drug: either granulocyte colony stimulating factor (G-CSF) or sulindac a non-steroidal anti-inflammatory drug with potent protective functions through signaling via ischemic preconditioning pathways. When primary neurons were pretreated with 25mM taurine and 25ng/mL G-CSF for I hour and then exposed to high levels of glutamate, the taurine/G-CSF combination increased the protective effect against glutamate toxicity to 88% cell survival compared to 75% cell survival from an individual treatment with taurine or G-CSF alone. Pre-exposure of PC12 cells to 5mM taurine or 25μM sulindac did not protect the cells from hypoxia/re-oxygenation stress whereas at these concentrations the combination of taurine plus sulindac provided significant protection. In summary we have demonstrated the protective effect of taurine in primary neuronal cultures against hypoxia with re-oxygenation through inhibition of ATF6 or p-IRE-1 pathway but not the PERK pathway of ER stress. Furthermore the combinations of taurine plus an additional drug (either G-CSF or sulindac) can show enhanced potency for protecting PC 12 cells from glutamate toxicity or hypoxia/re-oxygenation through inhibition of ER stress responses.

Neuroprotective Functions Through Inhibition of ER Stress by Taurine or Taurine Combination Treatments in a Rat Stroke Model.

Taurine, as a free amino acid, is found at high levels in many tissues including brain, heart and skeletal muscle and is known to demonstrate neuroprotective effects in a range of disease conditions including stroke and neurodegenerative disease. Using in vitro culture systems we have demonstrated that taurine can elicit protection against endoplasmic reticulum stress (ER stress) from glutamate excitotoxicity or from excessive reactive oxygen species in PC12 cells or rat neuronal cultures. In our current investigation we hypothesized that taurine treatment after stroke in the rat middle cerebral artery occlusion (MCAO) model would render protection against ER stress processes as reflected in decreased levels of expression of ER stress pathway components. We demonstrated that taurine elicited high level protection and inhibited both ATF-6 and IRE-1 ER stress pathway components. As ischemic stroke has a complex pathology it is likely that certain combination treatment approaches targeting multiple disease mechanisms may have excellent potential for efficacy. We have previously employed the partial NMDA antagonist DETC-MeSO to render protection against in vivo ischemic stroke using a rat cerebral ischemia model. Here we tested administration of subcutaneous administration of 0.56mg/kg DETC-MeSO or 40mg/kg of taurine separately or as combined treatment after a 120 min cerebral ischemia in the rat MCAO model. Neither drug alone demonstrated protection at the low doses employed. Remarkably however the combination of low dose DETC-MeSO plus low dose taurine conferred a diminished infarct size and an enhanced Neuroscore (reflecting decreased neurological deficit). Analysis of ER stress markers pPERK, peIF-2-alpha and cleaved ATF-6 all showed decreased expression demonstrating that all 3 ER stress pathways were inhibited concurrent with a synergistic protective effect by the post-stroke administration of this DETC-MeSO-taurine combination treatment.

Taurine Recovers Testicular Steroidogenesis and Spermatogenesis in Streptozotocin-Induced Diabetic Rats.

A great deal of investigations have verified that diabetic male reproductive impairment is associated with the dysfunction of testicular steroidogenesis and spermatogenesis resulted from insulin deficiency and hyperglycaemia-induced oxidative stress. It has been identified taurine is profitable for diabetes mellitus and diabetic implications through its insulin-like and islet cells protective activity. Furthermore, our previous studies found that taurine could increase testicular antioxidative ability, stimulate the endocrine activity of hypothalamic-pituitary-testicular axis, elevate testosterone level, raise sperm quality, suppress the deterioration of testicular function. Accordingly, we hypothesized that taurine may have beneficial effects on testicular dysfunction under diabetic mellitus status. Here, we investigated the effects of taurine on testicular steroidogenesis and spermatogenesis in streptozotocin (STZ)-induced type I diabetic rats. We observed that taurine treatment can markedly increase the body and testis weights, testicular SDH and G6PDH activities, decrease the serum fasting glucose concentration of diabetic rats. Serum contents of GnRH, LH, FSH, T, and testicular StAR, 3β-HSD, 17β-HSD mRNA expression levels were also obviously raised by taurine administration, indicating that taurine can improve testicular steroidogenesis in diabetic animals. Finally, we found taurine supplementation effectively elevated the sperm count and motility, reduced sperm abnormality, suggesting that taurine can increase the testicular spermatogenesis function of diabetic rat. In summary, the present data indicated that taurine can rescue the function of testicular steroidogenesis and spermatogenesis in STZ-induced type I diabetic rats possibly by increasing the endocrine activity of hypothalamic-pituitary-testicular axis.

Behavioral Changes and Survival in Drosophila melanogaster: Effects of Ascorbic Acid, Taurine, and Caffeine.

In this study, we used Drosophila as a model species to examine the effects of vitamin or energy-drink and theses ingredients on behavioral activity, life-span, and survivorship. Behavioral assays were performed to analyze total activity during the subjective daytime and nighttime and the lifespan assay was performed to investigate the influence of the drink ingredients. Quantitative RT-PCR and enzyme activity analyses were applied to analyze the mutual relationship of neural pathways and anti-oxidant activities. Caffeine and taurine treatments resulted in significant differences between the control and ascorbic acid groups with respect to subjective daytime and nighttime activity (p<0.05). Additionally, the lifespan and survival on individual flies significantly decreased with 1.6% taurine, and 0.025 and 0.05% caffeine treatment compared to the normal group (p<0.05). These results are related to the transcript levels of neuromodulator (p<0.05). In addition, ascorbic acid treatments significantly increased the activity of antioxidant-related enzymes (p<0.05). We successfully demonstrated that 0.5 and 1.0% ascorbic acid increases the lifespan of fruit flies to a greater extent than 1.6% taurine, and 0.025 and 0.05% caffeine, and that this effect is driven by changes in gene expression and the activity of oxidative stress-related enzyme. In summary, these findings support the use of ascorbic acid as a drink ingredient to enhance body function. Use of the fruit fly in combination with behavior activities and biological processes is recommended for validating the effects of functional substances used by the drink and food industry.

Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia.

Ammonia-induced mitochondrial dysfunction and energy crisis is known as a critical consequence of hepatic encephalopathy (HE). Hence, mitochondria are potential targets of therapy in HE. The current investigation was designed to evaluate the role of taurine treatment on the brain and liver mitochondrial function in a rat model of hepatic encephalopathy and hyperammonemia. The animals received thioacetamide (400mg/kg, i.p, for three consecutive days at 24-h intervals) as a model of acute liver failure and hyperammonemia. Several biochemical parameters were investigated in the serum, while the animals' cognitive function and locomotor activity were monitored. Mitochondria was isolated from the rats' brain and liver and several indices were assessed in isolated mitochondria. Liver failure led to cognitive dysfunction and impairment in locomotor activity in the rats. Plasma and brain ammonia was high and serum markers of liver injury were drastically elevated in the thioacetamide-treated group. An assessment of brain and liver mitochondrial function in the thioacetamide-treated animals revealed an inhibition of succinate dehydrogenase activity (SDA), collapsed mitochondrial membrane potential, mitochondrial swelling, and increased reactive oxygen species (ROS). Furthermore, a significant decrease in mitochondrial ATP was detected in the brain and liver mitochondria isolated from thioacetamide-treated animals. Taurine treatment (250, 500, and 1000mg/kg) decreased mitochondrial swelling, ROS, and LPO. Moreover, the administration of this amino acid restored brain and liver mitochondrial ATP. These data suggest taurine to be a potential protective agent with therapeutic capability against hepatic encephalopathy and hyperammonemia-induced mitochondrial dysfunction and energy crisis.

Effects of taurine and housing density on renal function in laying hens.

This study investigated the putative protective effects of supplemental 2-aminoethane sulfonic acid (taurine) and reduced housing density on renal function in laying hens. We randomly assigned fifteen thousand green-shell laying hens into three groups: a free range group, a low-density caged group, and a high-density caged group. Each group was further divided equally into a control group (C) and a taurine treatment group (T). After 15 d, we analyzed histological changes in kidney cells, inflammatory mediator levels, oxidation and anti-oxidation levels. Experimental data revealed taurine supplementation, and rearing free range or in low-density housing can lessen morphological renal damage, inflammatory mediator levels, and oxidation levels and increase anti-oxidation levels. Our data demonstrate that taurine supplementation and a reduction in housing density can ameliorate renal impairment, increase productivity, enhance health, and promote welfare in laying hens.

Taurine Treatment Modulates Circadian Rhythms in Mice Fed A High Fat Diet.

Close ties have been made among certain nutrients, obesity, type 2 diabetes and circadian clocks. Among nutrients, taurine has been documented as being effective against obesity and type 2 diabetes. However, the impact of taurine on circadian clocks has not been elucidated. We investigated whether taurine can modulate or correct disturbances in daily rhythms caused by a high-fat diet in mice. Male C57BL/6 mice were divided in four groups: control (C), control + taurine (C+T), high-fat diet (HFD) and HFD + taurine (HFD+T). They were administered 2% taurine in their drinking water for 10 weeks. Mice were euthanized at 6:00, 12:00, 18:00, and 24:00. HFD mice increased body weight, visceral fat and food intake, as well as higher levels of glucose, insulin and leptin, throughout the 24 h. Taurine prevented increments in food intake, body weight and visceral fat, improved glucose tolerance and insulin sensitivity and reduced disturbances in the 24 h patterns of plasma insulin and leptin. HFD downregulated the expression of clock genes Rev-erbα, Bmal1, and Per1 in pancreatic islets. Taurine normalized the gene and protein expression of PER1 in beta-cells, which suggests that it could be beneficial for the correction of daily rhythms and the amelioration of obesity and diabetes.

OS 12-04 TAURINE SUPPLEMENTATION LOWERS BLOOD PRESSURE AND REDUCES CAROTID INTIMA-MEDIA THICKNESS IN PREHYPERTENSION

Objective: Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to improve metabolic status in animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human, especially in prehypertensive participants. Design and Method: In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on metabolic parameters, such as blood pressure (BP) levels, carotid intima-media thickness (IMT), ankle brachial index (ABI)/toe brachial index (TBI), BMI and biochemical parameters in prehypertensive participants. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Then we further validated the results in spontaneously hypertensive rats (SHR), which were were intervented with 2% taurine water for 12 weeks. Results: Totally 97 participants completed the trial and no significant difference observed between the taurine and placebo groups. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. In addition, taurine supplementation significantly improved endothelium-dependent and -independent vasodilation and reduced IMTs of these prehypertensive participants. Meanwhile taurine intervention increased plasma H2S and taurine concentrations. Other parameters did not change significantly upon taurine treatment compared with pre-treatment or placebo group. To further elucidate the mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment exerts hypotensive effects by upregulating the expressions of H2S-synthesizing enzymes and reducing agonist-induced vascular reactivity through the inhibition of TRPC3-mediated calcium influx in human and mouse mesenteric arteries. Also, taurine reduced ROS levels and improved mitochondrial respiratory fucntions in VSMCs from SHR compared with control group, thus inhibiting vascular remodeling pathways. Conclusions: Taurine supplementation improved vascular function of prehypertensive participants and SHRs by lowering BP levels and reducing IMT values. Taurine may become a new dietary factor improving the metabolic status in prehypertension.

The change of metabotropic glutamate receptor 5 expression level in rats with late-stage traumatic brain injury and the therapeutic effect of taurine

Objective To investigate the change of metabotropic glutamate receptor 5 (mGluR5) expression level in rats with late-stage (the 7th day) traumatic brain injury (TBI) and the role of taurine. Methods The left cerebral TBI rat models were made by using lateral fluid percussion method. A total of 30 specific pathogen free (SPF) male Sprague-Dawley (SD) rats were randomly divided into 3 groups: sham operation group (control group), TBI model group (TBI group) and taurine treatment group (taurine group). Wet and dry weight method was used to measure the brain water content. Real-time fluorescent quantitative polymerase chain reaction (PCR) and Western blotting were used to detect the change of mRNA and protein expression of aquaporin 4 (AQP4) and mGluR5 in each group. Results Compared with control group, the brain water content ( t = 4.893, P = 0.002), AQP4 mRNA ( t = 6.523, P = 0.000) and protein ( t = 4.366, P = 0.008) expression were upregulated, while mGluR5 mRNA ( t = 5.776, P = 0.001) and protein ( t = 3.945, P = 0.014) expression were downregulated in TBI group. After taurine treatment, the brain water content ( t = 2.151, P = 0.140), AQP4 mRNA ( t = 1.144， P = 0.432) and protein ( t = 0.367, P = 0.804) decreased to normal, while mGluR5 mRNA ( t = 1.824, P = 0.216) and protein ( t = 1.185, P = 0.414) increased to normal. Correlation analysis showed brain water content was negatively correlated with mGluR5 mRNA ( r = -0.617, P = 0.014) and mGluR5 protein ( r = -0.665, P = 0.007), while it was positively correlated with AQP4 protein ( r = 0.658, P = 0.008). Conclusions Taurine can significantly increase the mGluR5 expression level of brain issue in the late-stage (the 7th day) of TBI and decline brain edema and brain water content. It may be a potential protective agent as an inhibitory neurotransmitter. DOI: 10.3969/j.issn.1672-6731.2016.08.008

Modulatory Effect of Taurine on 7,12-Dimethylbenz(a)Anthracene-Induced Alterations in Detoxification Enzyme System, Membrane Bound Enzymes, Glycoprotein Profile and Proliferative Cell Nuclear Antigen in Rat Breast Tissue.

The modulatory effect of taurine on 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer in rats was studied. DMBA (25mg/kg body weight) was administered to induce breast cancer in rats. Protein carbonyl levels, activities of membrane bound enzymes (Na(+) /K(+) ATPase, Ca(2+) ATPase, and Mg(2+) ATPase), phase I drug metabolizing enzymes (cytochrome P450, cytochrome b5, NADPH cytochrome c reductase), phase II drug metabolizing enzymes (glutathione-S-transferase and UDP-glucuronyl transferase), glycoprotein levels, and proliferative cell nuclear antigen (PCNA) were studied. DMBA-induced breast tumor bearing rats showed abnormal alterations in the levels of protein carbonyls, activities of membrane bound enzymes, drug metabolizing enzymes, glycoprotein levels, and PCNA protein expression levels. Taurine treatment (100mg/kg body weight) appreciably counteracted all the above changes induced by DMBA. Histological examination of breast tissue further supported our biochemical findings. The results of the present study clearly demonstrated the chemotherapeutic effect of taurine in DMBA-induced breast cancer.

Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia.

Hyper-beta-alaninemia is a rare metabolic condition that results in elevated plasma and urinary β-alanine levels and is characterized by neurotoxicity, hypotonia, and respiratory distress. It has been proposed that at least some of the symptoms are caused by oxidative stress; however, only limited information is available on the mechanism of reactive oxygen species generation. The present study examines the hypothesis that β-alanine reduces cellular levels of taurine, which are required for normal respiratory chain function; cellular taurine depletion is known to reduce respiratory function and elevate mitochondrial superoxide generation. To test the taurine hypothesis, isolated neonatal rat cardiomyocytes and mouse embryonic fibroblasts were incubated with medium lacking or containing β-alanine. β-alanine treatment led to mitochondrial superoxide accumulation in conjunction with a decrease in oxygen consumption. The defect in β-alanine-mediated respiratory function was detected in permeabilized cells exposed to glutamate/malate but not in cells utilizing succinate, suggesting that β-alanine leads to impaired complex I activity. Taurine treatment limited mitochondrial superoxide generation, supporting a role for taurine in maintaining complex I activity. Also affected by taurine is mitochondrial morphology, as β-alanine-treated fibroblasts undergo fragmentation, a sign of unhealthy mitochondria that is reversed by taurine treatment. If left unaltered, β-alanine-treated fibroblasts also undergo mitochondrial apoptosis, as evidenced by activation of caspases 3 and 9 and the initiation of the mitochondrial permeability transition. Together, these data show that β-alanine mediates changes that reduce ATP generation and enhance oxidative stress, factors that contribute to heart failure.

Effect of Taurine on the expression of glucose regulated protein 78 and growth arrest and DNA damage-inducible protein 34 in zebrafish larvae brain after hypoxia/reoxygenation brain injury

Objective To investigate the expression of endoplasmic reticulum stress-related factors, glucose-regulated protein 78 (GRP78)and growth arrest and DNA damage-inducible protein 34 (GADD34)and neuronal apoptosis in the brain of zebrafish larvae after hypoxia/reoxygenation brain injury, and the neuroprotective role of Taurine. Methods The 5 day post-fertilization zebrafish larvae were randomly assigned to 3 groups: control group, hypoxia/reoxygenation model group (model group) and Taurine treatment group(Taurine group). According to the different time points for observation, each group was subdivided into 5 subgroups (1 h, 3 h, 6 h, 24 h, 48 h)with 100 zebrafish larvae each.The pathological changes in the brain tissues and cell apoptosis were detected by fluorescence terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling(TUNEL). The expression of GRP78 and GADD34 mRNA in the brain of zebrafish larvae were detected by real-time quantitative reverse transcription PCR(qRT-PCR). The changes in GRP78 and GADD34 protein were detected by Western blot. Results (1)TUNEL: apoptosis index(AI)was increased after hypoxia/reoxygenation, and reached the peak at 3 h in model group, the AI in Taurine group was decreased compared with that in the model group at the same time point (1 h: 22.83±1.80 vs 30.18±1.81, 3 h: 23.22±2.46 vs 42.97±4.01, 6 h: 16.80±1.69 vs 22.97±1.91, all P<0.05). (2) qRT-PCR: the expression of GRP78 and GADD34 mRNA was increased at 1 h after hypoxia/reoxygenation, and reached the peak at 3 h in the model group, the expression in Taurine group was decreased compared with that in the model group at the same time point (GRP78 mRNA: 1 h: 2.35±0.13 vs 5.36±0.35, 3 h: 3.08±0.33 vs 4.27±0.52, 6 h: 1.57±0.12 vs 3.00±0.13, all P<0.05; GADD34 mRNA: 1 h: 5.14±0.55 vs 7.45±0.67, 3 h: 2.79±0.58 vs 5.83±0.51, 6 h: 1.79±0.22 vs 3.67±0.30, all P<0.05). (3) Western blot: the expression of GRP78 and GADD34 protein was increased at 1 h, reached the peak at 6 h, but it was decreased in Taurine group (GRP78 protein: 1 h: 1.12±0.11 vs 1.37±0.13, 3 h: 0.79±0.11 vs 1.25±0.10, 6 h: 0.55±0.10 vs 1.52±0.14, all P<0.05; GADD34 protein: 1 h: 0.92±0.11 vs 1.11±0.13, 3 h: 0.96±0.11 vs 1.52±0.09, 6 h: 0.76±0.05 vs 1.89±0.06, all P<0.05). (4) The expression of GRP78 and GADD34 protein was positively correlated with AI in the model group(r=0.53, 0.56 respectively, all P<0.05). Conclusion One of neuroprotective mechanisms of Taurine against hypoxia/reoxygenation brain injury may down-regulate GRP78 and GADD34 expression. Key words: Endoplasmic reticulum stress; Hypoxic-ischemic brain damage; Glucose-regulated protein 78; Growth arrest and DNA damage-inducible protein 34; Apoptosis

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study.

Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to lower blood pressure (BP) in hypertensive animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human hypertension or prehypertension, a key stage in the development of hypertension. In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on BP and vascular function in prehypertension. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mm Hg, and diastolic BP was 4.7/1.3 mm Hg. Mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mm Hg, and diastolic BP was 3.5/0.6 mm Hg. In addition, taurine supplementation significantly improved endothelium-dependent and endothelium-independent vasodilation and increased plasma H2S and taurine concentrations. Furthermore, changes in BP were negatively correlated with both the plasma H2S and taurine levels in taurine-treated prehypertensive individuals. To further elucidate the hypotensive mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment upregulated the expression of hydrogen sulfide-synthesizing enzymes and reduced agonist-induced vascular reactivity through the inhibition of transient receptor potential channel subtype 3-mediated calcium influx in human and mouse mesenteric arteries. In conclusion, the antihypertensive effect of chronic taurine supplementation shows promise in the treatment of prehypertension through improvement of vascular function.

Increased expression of long noncoding RNA TUG1 predicts a poor prognosis of gastric cancer and regulates cell proliferation by epigenetically silencing of p57.

Recent evidence highlights long noncoding RNAs (lncRNAs) as crucial regulators of cancer biology that contribute to tumorigenesis. LncRNA TUG1 was initially detected in a genomic screen for genes upregulated in response to taurine treatment in developing mouse retinal cells. Our previous study showed that TUG1 could affect cell proliferation through epigenetically regulating HOXB7 in human non-small cell lung cancer. However, the clinical significance and potential role of TUG1 in GC remains unclear. In this study, we found that TUG1 is significantly increased and is correlated with outcomes in gastric cancer (GC). Further experiments revealed that knockdown of TUG1 repressed GC proliferation both in vitro and in vivo. Mechanistic investigations showed that TUG1 has a key role in G0/G1 arrest. We further demonstrated that TUG1 was associated with PRC2 and that this association was required for epigenetic repression of cyclin-dependent protein kinase inhibitors, including p15, p16, p21, p27 and p57, thus contributing to the regulation of GC cell cycle and proliferation. Together, our results suggest that TUG1, as a regulator of proliferation, may serve as a candidate prognostic biomarker and target for new therapies in human GC.

Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation, oxidative stress and myofibre necrosis. Cysteine precursor antioxidants such as N-acetyl cysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) reduce dystropathology in the mdx mouse model for DMD, and we propose this is via increased synthesis of the amino acid taurine. We compared the capacity of OTC and taurine treatment to increase taurine content of mdx muscle, as well as effects on in vivo and ex vivo muscle function, inflammation and oxidative stress. Both treatments increased taurine in muscles, and improved many aspects of muscle function and reduced inflammation. Taurine treatment also reduced protein thiol oxidation and was overall more effective, as OTC treatment reduced body and muscle weight, suggesting some adverse effects of this drug. These data suggest that increasing dietary taurine is a better candidate for a therapeutic intervention for DMD. Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease for which there is no widely available cure. Whilst the mechanism of loss of muscle function in DMD and the mdx mouse model are not fully understood, disruptions in intracellular calcium homeostasis, inflammation and oxidative stress are implicated. We have shown that protein thiol oxidation is increased in mdx muscle, and that the indirect thiol antioxidant l-2-oxothiazolidine-4-carboxylate (OTC), which increases cysteine availability, decreases pathology and increases in vivo strength. We propose that the protective effects of OTC are a consequence of conversion of cysteine to taurine, which has itself been shown to be beneficial to mdx pathology. This study compares the efficacy of taurine with OTC in decreasing dystropathology in mdx mice by measuring in vivo and ex vivo contractile function and measurements of inflammation and protein thiol oxidation. Increasing the taurine content of mdx muscle improved both in vivo and ex vivo muscle strength and function, potentially via anti-inflammatory and antioxidant effects of taurine. OTC treatment increased taurine synthesis in the liver and taurine content of mdx muscle, improved muscle function and decreased inflammation. However, OTC was less effective than taurine treatment, with OTC also decreasing body and EDL muscle weights, suggesting that OTC had some detrimental effects. These data support continued research into the use of taurine as a therapeutic intervention for DMD, and suggest that increasing dietary taurine is the better strategy for increasing taurine content and decreasing severity of dystropathology.