Taurine supplementation protects lens against glutathione depletion.

OBJECTIVE: Cataract which is defined as opacification of eye lens forms approximately 40% of total blindness causes all through the world. Age is the biggest risk factor for cataracts and oxidative stress is known to be one of the most important factors causing cataract formation. Age-related nuclear cataract (ARN) is associated with a loss of glutathione in the center of the lens. Taurine is an important antioxidant in lens tissue. Although, there is a high amount of taurine in lenses in early life, its concentration declines with age. In this study, we aimed to investigate the effects of supplemental taurine in lens tissues in an in vivo oxidative stress model which is induced by glutathione depletion to mimic ARN. MATERIALS AND METHODS: Glutathione depletion was induced in rabbits subcutaneously with l-Buthionine -(S,R)-sulfoximine (BSO)- a glutathione inhibitor and the rabbits were treated with taurine. Total GSH, reduced GSH, GSH/GSSG ratio and MDA levels were measured. RESULTS: BSO lowered the reduced GSH and total GSH levels and GSH/GSSG ratio. Taurine reversed these effects. On the other hand, BSO enhanced MDA level which is normalized by taurine. CONCLUSIONS: These findings suggest that glutathione depletion with BSO may be a useful model to mimic ARN and dietary intake of taurine, may have an important role in decelerating the process of cataract formation.

In vivo prevention of bladder urotoxicity: purified hydroxytyrosol ameliorates urotoxic effects of cyclophosphamide and buthionine sulfoximine in mice.

Urotoxicity is a troublesome complication associated with cyclophosphamide (CP) and L-buthionine-SR-sulfoximine (BSO) treatment in chemotherapy. With this concern in mind, the present study investigated the potential effects of a hydroxytyrosol extract from olive mill waste (OMW) on urotoxicity induced by acute CP and BSO doses using a Swiss albino mouse model. Toxicity modulation was evaluated by measuring lipid peroxidation (LPO) and antioxidants in urinary bladder. The findings revealed that the hydroxytyrosol extract exerted a protective effect not only on LPO but also on enzymatic antioxidants. When compared to the controls, the CP-treated animals underwent significant decreases in the glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GP), and catalase (CAT) activities. The level of glutathione (GSH) was also reduced with increased doses of LPO in the CP-treated animals. L-Buthionine-SR-sulfoximine treatment exerted an additive toxic effect on the CP-treated animals. Interestingly, pretreatment with the hydroxytyrosol extract restored the activities of all enzymes back to normal levels and exhibited an overall protective effect on the CP- and BSO-induced toxicities in urinary bladder. The restoration of GSH through the treatment with the hydroxytyrosol extract can play an important role in reversing CP-induced apoptosis and free radical-mediated LPO. 

A carbazole derivative protects cells against endoplasmic reticulum (ER) stress and glutathione depletion.

Enhanced levels of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress are implicated in various neuropathological conditions including brain ischemia and neurodegeneration. During a search for compounds that regulate ER stress and ER stress-induced cell death, we identified a carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole] that protected against both ER stress and glutathione depletion. 16-14 suppressed tunicamycin (Tm)-induced cell death in both F9 Herp KO cells and PC12 cells, and its regulation of ER stress was associated with reduced levels of unfolded protein response (UPR) signaling. ER stress caused by overexpression of a fluorescent ER-resident protein, GFP-KDEL, was also attenuated by 16-14 without altering the expression levels of GFP-KDEL. 16-14 also prevented glutathione depletion-induced cell death caused by buthionine sulfoximine (BSO), but not likely via its anti-oxidative activity. Further analysis revealed that 16-14 suppressed increases in intracellular Ca(2+) in response to thapsigargin (Tg). These results suggest that 16-14 may protect cells against different stresses via the maintenance of intracellular Ca(2+) homeostasis. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08136FP].

Oxidative stress-induced renal angiotensin AT1 receptor upregulation causes increased stimulation of sodium transporters and hypertension.

Reactive oxygen species have emerged as important molecules in cardiovascular dysfunction such as diabetes and hypertension. Recent work has shown that oxidative stress and angiotensin II signaling mutually regulate each other by multiple mechanisms and contribute to the development of hypertension. Most of the known biological actions of angiotensin II can be attributed to AT1 receptors. The present study was carried out to investigate the role of renal AT1 receptor signaling in oxidative stress-mediated hypertension. Male Sprague-Dawley rats received tap water (control) or 30 mM L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mM tempol (an antioxidant) for 2 wk. Compared with control rats, BSO-treated rats exhibited increased oxidative stress and reduced antioxidant levels and developed hypertension. BSO treatment also caused increased renal proximal tubular AT1 receptor protein abundance, message levels, and ligand binding. In these rats, angiotensin II caused significantly higher accumulation of inositol trisphosphate (IP3) and phospholipase C (PLC) activation which was sensitive to blockade by AT1 but not to AT2 antagonist. Also, angiotensin II-mediated, AT1-dependent MAP kinase, Na-K-ATPase, and Na/H exchanger 3 activation was higher in BSO-treated rats than in control rats. Tempol supplementation of BSO-treated rats restored redox status, normalized AT1 receptor expression, and decreased blood pressure. Tempol also normalized the angiotensin II-mediated, AT1-dependent IP3 accumulation and PLC, MAP kinase, Na-K-ATPase, and Na/H exchanger 3 stimulation. These data suggest that oxidative stress leads to AT1 receptor upregulation, which in turn causes overstimulation of sodium transporters and subsequently contributes to sodium retention and hypertension. Tempol, while reducing oxidative stress, normalizes AT1 receptor signaling and decreases blood pressure.

Aqueous extract of Trigonella foenum-graecum L. ameliorates additive urotoxicity of buthionine sulfoximine and cyclophosphamide in mice.

Cyclophosphamide (CP) is a commonly used anti-cancer drug which causes toxicity by its reactive metabolites such as acrolein and phosphoramide mustard. In the present study modulation of toxicity caused by concomitant exposure to CP and l-buthionine-SR-sulfoximine (BSO) by fenugreek (Trigonella foenum-graecum L.) extract was evaluated by measuring lipid peroxidation (LPO) and anti-oxidants in urinary bladder in mice. Fenugreek, a common dietary and medicinal herb, showed protective effect not only on LPO but also on the enzymatic anti-oxidants. CP-treated animals exhibited a significant decrease in the activities of glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GP) and catalase (CAT) when compared to the controls. Level of reduced glutathione (GSH) was also reduced with an increase in LPO in CP-treated animals. BSO treatment depicted an additive toxic effect in CP-treated animals. Pre-treatment of herbal extract restored activities of all the enzymes and thus showed an overall protective effect on additive effect of CP and BSO. Restoration of GSH by extract treatment may play an important role in reversing CP-induced apoptosis and free radical-mediated LPO in urinary bladder. Fenugreek, known for its hypoglycemic, anti-inflammatory and immunomodulatory activity, may be a promising protective medicinal herb for consideration in complementary therapy in cancer patients under chemotherapeutic interventions.