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1.
Adv Exp Med Biol ; 1370: 243-256, 2022.
Article in English | MEDLINE | ID: mdl-35882800

ABSTRACT

Hyperglycemia-induced oxidative stress is an intrinsic feature of diabetes mellitus and a recognized causative factor of complications associated with the disease. As a result, compounds possessing antioxidant properties are commonly investigated as possible ways of minimizing and even preventing diabetes-related oxidative stress. On these premises, the present study was carried out to investigate the antioxidant properties of metformin (MET), a common oral hypoglycemic agent, of taurine (TAU), a sulfonic acid compound with known antioxidant benefits in diabetes, and of insulin (INS), a standard antidiabetic serving as a reference compound, by using in vitro and in vivo tests. A battery of seven in vitro tests was used to assess antioxidant/antiradical activity. The addition of a treatment compound led to a mean percentage decrease of values for free radical/lipid peroxidation (LPO) that ranged from very high (82%) with INS to moderate (43%) with MET) and to low (31%) with TAU. Combining MET with TAU leads to an improvement of the effect seen with MET alone (46%). By contrast, under the same conditions, N-acetylcysteine, a known antioxidant, was more potent (92%) than any of the test compounds. In vivo studies were conducted using rats made diabetic with streptozotocin and treated with daily doses of INS, MET, TAU, and MET-TAU for 6 weeks. Among the test compounds, the greatest hypoglycemic effect was attained with INS (>90% decrease), followed by MET (~70% decrease), with TAU providing only a modest effect (-30% decrease). Unexpectedly, however, all three compounds reduced the diabetic values for brain LPO, nitric oxide, antioxidant enzymes, glutathione, and glutathione-related enzymes to values that varied in extent within a narrow range (<12% from one another). On the other hand, pairing MET with TAU led to a small enhancement (<10%) of the effects seen with MET alone. In short, while in vitro tests for antioxidant/antiradical activity suggest marked differences in potency for INS, MET, and TAU as a result of different structures, changes in the values of indices of oxidative stress affected by these compounds in the brain of diabetic rats varied within a rather narrow range. Also, the present results suggest that although hyperglycemia is an important determinant of the oxidative stress of diabetes, other factors may be involved since a weak hypoglycemic like TAU demonstrated in vivo antioxidant actions that were comparable to those of more potent hypoglycemic agents like INS and MET.


Subject(s)
Diabetes Mellitus, Experimental , Hyperglycemia , Metformin , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Blood Glucose , Brain , Diabetes Mellitus, Experimental/complications , Glutathione/pharmacology , Hyperglycemia/complications , Hyperglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , In Vitro Techniques , Insulin/therapeutic use , Metformin/pharmacology , Metformin/therapeutic use , Oxidative Stress , Rats , Rats, Sprague-Dawley , Taurine/pharmacology , Taurine/therapeutic use
2.
Adv Exp Med Biol ; 1155: 71-85, 2019.
Article in English | MEDLINE | ID: mdl-31468387

ABSTRACT

This study has evaluated the effects of a supplementation with taurine (TAU) on the actions of fish oil (FO) against the hypoglycemia, hypoproteinemia, and hepatic accumulation of lipids and liver damage caused by D-galactosamine (GAL) in the rat. To this end, male Sprague-Dawley rats (200-225 g), in groups of 6, were orally treated with physiological saline (2.5 mL, control group), FO (60 mg/kg), TAU (2.4 mmol/kg) or FO-TAU for three consecutive days and before a single oral dose of GAL (400 mg/kg) given on day 3. In parallel, rats receiving only GAL on day 3 or N-acetylcysteine (NAC, 2.4 mmol/kg) for 3 days before GAL served as controls. On day 4 blood samples were collected by cardiac puncture and used to either measure glucose (GLC) or to obtain plasma fractions. Immediately thereafter, the livers were excised, made into a homogenate in phosphate buffered saline pH 7.4, and centrifuged to obtain clear supernatant. Plasma samples were assayed for their total protein (TP), triglycerides (TG), cholesterol (CHOL), phospholipids (PLP), free fatty acids (FFA) and total bilirubin (TB) and direct bilirubin (DB) contents, and for the activities of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP). The liver homogenates were used to measure TG, CHOL, PLP and total lipids (TL) contents. Without exceptions, GAL was found to markedly affect (p < 0.001) all of the experimental parameters examined, with increases occurring in all instances except for the values of the plasma GLC, TP and PLP which were decreased. A pretreatment with either FO or TAU led to significant attenuation of the effects of GAL and which, in most cases, were of similar magnitude. On the other hand, a combined pretreatment with FO plus TAU usually resulted in a greater protection than with either agent alone (p ≤ 0.05). NAC, serving as a reference treatment, was, in most instances, equipotent with FO alone and. in addition, was the only agent that significantly attenuated the increases in both liver weight and liver weight to body weight ratio caused by GAL.


Subject(s)
Fish Oils/pharmacology , Galactosamine/adverse effects , Lipid Metabolism , Liver/drug effects , Taurine/pharmacology , Animals , Liver/metabolism , Male , Rats , Rats, Sprague-Dawley
3.
Adv Exp Med Biol ; 1155: 87-99, 2019.
Article in English | MEDLINE | ID: mdl-31468388

ABSTRACT

The present study has investigated the effect of adding taurine (TAU) to a treatment of diabetes with metformin (MET), a hypoglycemic, and lovastatin (LOV), an antihyperlipidemic. To this end, male Sprague-Dawley rats, agent, 250-275 g in weight, were made diabetic with a single 60 mg/kg intraperitoneal (i.p.) dose of streptozocin (STZ) in 10 mM citrate buffer pH 4.5, and, after 14 days, treated daily with oral doses of MET (2.4 mM/kg), LOV (0.075 mM/kg) or TAU (2.4 mM/kg), and with binary and ternary combinations of these agents. Rats receiving only 10 mM citrate buffer pH 4.5 or only STZ served as negative and positive controls, respectively. In addition, rats receiving insulin (INS, 4 units/kg) by the subcutaneous route served as a reference treatment. All the rats were sacrificed on day 57 and their bloods collected into heparinized tubes. The corresponding plasma samples were analyzed for their glucose (GLC), insulin (INS), glycated hemoglobin (HbA1c), cholesterol (CHOL) and triglycerides (TG) contents. In comparison to normal rats, diabetic ones showed marked increases in GLC (+313%), HbA1c (+207%), CHOL (+66%) and TG (+188) and a profound decrease of INS levels (-76%) (p < 0.001 vs. control values). Among the various treatments, one with INS produced the greatest lowering effect on the plasm a GLC (+23%, p < 0.05), INS (+23%, p < 0.05) and TG (+3%), with the remaining changes being similar to those seen with MET. A treatment with MET reduced all the diabetic changes by at least threefold; and one with LOV had a significant (p < 0.001) lowering effect on the plasma CHOL and TG but was without an effect on the plasma GLC, INS and HbA1c. In common with LOV, TAU reduced the diabetic levels of both CHOL and TG and, in addition, reduced the diabetic plasma GLC and raised the corresponding INS level. Among binary combinations, one with LOV-MET provided a greater effect than MET alone only in terms of the plasma CHOL and TG; and one with LOV-TAU was only significantly better than TAU alone in lowering the TG levels. However, a treatment with LOV-MET-TAU led to reductions in all the plasma parameters examined that were much greater than those achieved with any of the individual agents or with their binary combinations (at p ≤ 0.05).


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Lovastatin/pharmacology , Metformin/pharmacology , Taurine/pharmacology , Animals , Blood Glucose , Carbohydrates/blood , Hypolipidemic Agents/pharmacology , Insulin , Lipids/blood , Male , Rats , Rats, Sprague-Dawley , Streptozocin
4.
Adv Exp Med Biol ; 1155: 369-380, 2019.
Article in English | MEDLINE | ID: mdl-31468415

ABSTRACT

The present study was carried out in diabetic rats to examine the effects of ethanol (EtOH) and taurine (TAU), singly and in combination, in reducing the changes of laboratory test values indicating renal dysfunction. For this purpose, male Sprague-Dawley rats, 250-280 g in weight and in groups of 6, were made diabetic with a single, 60 mg/kg intraperitoneal dose of streptozotocin in 10 mM citrate buffer pH 4.5. On day 15 and for the remaining 14 days of the study, the diabetic rats (a) started to drink 5% EtOH in place of water, (b) received a single daily 2.4 mM/kg oral dose of TAU or (c) were allowed to drink 5% EtOH after receiving a dose of TAU. Starting from day 28 and ending on day 29, a 24 h urine sample was collected, its volume was measured, and then used to measure glucose (GLC), total protein (TP) and electrolytes (Na+, K+, Ca++, Mg++). Blood samples collected immediately thereafter via cardiac puncture were processed for the plasma fractions which were analyzed for their creatinine (CRT) and urea nitrogen (UN) contents. In comparison to normal (control) rats, diabetic ones showed a higher output of urine (+5.6-fold), a massive increase in plasma GLC (+473%), passed more GLC (+73.8-fold) and TP (+8.2-fold) in the urine, showed higher plasma CRT (+241%) and UN (+74%) levels, a lower plasma UN/CRT ratio (-47%) and a greater output of electrolytes in the urine (by at least twofold). By themselves both EtOH and TAU were found to markedly lower the effects of diabetes, with EtOH generally appearing more effective than TAU. However, the concurrent availability of EtOH and TAU was found to be more protective than either treatment alone.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Ethanol/pharmacology , Kidney Diseases/drug therapy , Taurine/pharmacology , Animals , Blood Glucose , Diabetes Mellitus, Experimental/complications , Kidney Diseases/etiology , Male , Rats , Rats, Sprague-Dawley , Urinalysis
5.
Adv Exp Med Biol ; 975 Pt 1: 371-400, 2017.
Article in English | MEDLINE | ID: mdl-28849470

ABSTRACT

This study has examined the role of supplementing a treatment of diabetic rats with captopril (CAP), metformin (MET) or CAP-MET with the antioxidant amino acid taurine (TAU) on biochemical indices of diabetes-induced metabolic changes, oxidative stress and nephropathy. To this end, groups of 6 male Sprague-Dawley rats (250-375 g) were made diabetic with a single, 60 mg/kg, intraperitoneal dose of streptozotocin (STZ) in 10 mM citrate buffer pH 4.5 and, after 14 days, treated daily for up to 42 days with either a single oral dose of CAP (0.15 mM/kg), MET (2.4 mM/kg) or TAU (2.4 mM/kg), or with a binary or tertiary combination of these agents. Rats receiving only 10 mM citrate buffer pH 4.5 or only STZ served as negative and positive controls, respectively. All rats were sacrificed by decapitation on day 57 and their blood and kidneys collected. In addition, a 24 h urine sample was collected starting on day 56. Compared to normal rats, untreated diabetic ones exhibited frank hyperglycemia (+313%), hypoinsulinemia (-76%) and elevation of the glycated hemoglobin value (HbA1c, +207%). Also they showed increased plasma levels of Na+ (+35%), K+ (+56%), creatinine (+232%), urea nitrogen (+158%), total protein (-53%) and transforming growth factor-ß1 (TGF-ß1, 12.4-fold) values. These changes were accompanied by increases in the renal levels of malondialdehyde (MDA, +42%), by decreases in the renal glutathione redox state (-71%), and activities of catalase (-70%), glutathione peroxidase (-71%) and superoxide dismutase (-85%), and by moderate decreases of the urine Na+ (-33%) and K+ (-39%) values. Following monotherapy, MET generally showed a greater attenuating effect than CAP or TAU on the changes in circulating glucose, insulin and HbA1c levels, urine total protein, and renal SOD activity; and CAP appeared more potent than TAU and MET, in that order, in antagonizing the changes in plasma creatinine and urea nitrogen levels. On the other hand, TAU generally provided a greater protection against changes in glutathione redox state and in CAT and GPx activities, with other actions falling in potency between those of CAP and MET. Adding TAU to a treatment with CAP, but not to one with MET, led to an increase in protective action relative to a treatment with drug alone. On the other hand, the actions of CAP-MET, which were about equipotent with those of MET, became enhanced in the presence of TAU, particularly against the changes of the glutathione redox state and activities of antioxidant enzymes. In short, the present results suggest that the addition of TAU to a treatment of diabetes with CAP or CAP-MET, and sometimes to one with MET, will lead to a gain in protective potency against changes in indices of glucose metabolism and of renal functional impairment and oxidative stress.


Subject(s)
Antihypertensive Agents/pharmacology , Diabetic Nephropathies , Hypoglycemic Agents/pharmacology , Kidney/drug effects , Taurine/pharmacology , Animals , Blood Glucose/drug effects , Captopril/pharmacology , Diabetes Mellitus, Experimental , Male , Metformin/pharmacology , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley
6.
Adv Exp Med Biol ; 975 Pt 1: 353-369, 2017.
Article in English | MEDLINE | ID: mdl-28849469

ABSTRACT

This study has compared the effects of metformin (MET) and taurine (TAU), singly and in combination, on the oxidative stress caused by diabetes in the rat brain. For this purpose, male Sprague-Dawley rats, 200-225 g in weight, assigned to groups of 6, were intraperitoneally (i.p.) treated with the diabetogen streptozotocin (STZ, 60 mg/kg, in citrate buffer pH 4.5) on day 1 and, after 14 days, orally (p.o.) with either MET, TAU or MET-TAU (each at 2.4 mM/kg, in water). Control rats received only citrate buffer pH 4.5 (2 mL) or only STZ on day 1 by the i.p. route. All the animals were sacrificed by decapitation on day 57 and their brains collected by the freeze clamp technique. Blood samples were placed in heparinized tubes and used for the assay of the plasma glucose (GLC) and blood insulin (INS) levels. Immediately thereafter, the brains were surgically removed and a portion was used to prepare a homogenate in 0.1 M PBS pH 7.4, which was used for the assay of indices of oxidative stress. Diabetes raised the plasma GLC level (+313%) but lowered that of the blood INS (-76%) compared to corresponding values from nondiabetic rats. In addition it raised the brain malondialdehyde level (+59%) but lowered the reduced/disulfide glutathione ratio (-46%), and activities of catalase (-43%), glutathione peroxidase (-48%), superoxide dismutase (-65%), glutathione reductase (-50%) and glutathione S-transferase (-51%) significantly (all at p < 0.001). Except for the greater decrease in GLC (+90% vs. +22%) and increase in INS (-26% vs. -52%) levels seen in rats receiving MET than in rats receiving TAU, these compounds protected the brain against oxidative stress to significant (p ≤ 0.05%) and rather similar extents. Furthermore, the concurrent administration of MET and TAU to the diabetic rats led to brain values of indices of oxidative stress that were lower than those attained with MET alone, although generally not to a statistically significant degree.


Subject(s)
Brain/drug effects , Diabetes Mellitus, Experimental/complications , Metformin/pharmacology , Oxidative Stress/drug effects , Taurine/pharmacology , Animals , Antioxidants/pharmacology , Brain/metabolism , Hypoglycemic Agents/pharmacology , Male , Rats , Rats, Sprague-Dawley
7.
Adv Exp Med Biol ; 975 Pt 1: 337-351, 2017.
Article in English | MEDLINE | ID: mdl-28849468

ABSTRACT

This study has examined the acute effects of taurine (TAU) and of its two immediate homologs aminomethanesulfonic acid (AMSA) and homotaurine (HTAU) on the oxidative stress that develops in the brain of rats as a result of type 2 diabetes mellitus. Male Sprague-Dawley rats, 220-225 g in weight, were divided into groups of 6 each, and treated with a single intraperitoneal (i.p.) dose of streptozotocin (STZ) in 10 mM citrate buffer pH 4.5 (60 mg/kg). The treatment compound (AMSA, HTAU or TAU) was administered by the i.p. route in two equal doses (1.2 mM/kg each) at 75 and 45 min before STZ. Control rats received only 10 mM citrate buffer pH 4.5 or only STZ by the i.p. route. The rats were sacrificed at 24 h after a dosing with STZ under general anesthesia, and their brains and spinal cords collected by the freeze clamp technique. A portion of brain, of a brain area (cerebellum, cortex, brain stem) or of spinal cord from each animal was extracted into 0.1 M PBS pH 7.4, and the extract was used for the assay of malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). An extract for the assay of the reduced (GSH) and disulfide (GGSG) forms of glutathione was prepared in similar manner but using 2% metaphosphoric acid plus 0.1 M PBS pH 8.0 as the extracting medium. Diabetes was found to markedly increase the formation of MDA (by 160-202%), NO (by 138-313%) and GSSG (by 103-241%), and to lower the values of GSH (by 57-65%), GSH/GSSG ratio (79-89%) and activities of CAT (by 61-69%), GPx (by 52-66%) and SOD (by 55-68%) in the brain, brain areas and spinal cord relative to corresponding control values (all at p < 0.001). These effects were reduced to values that were generally at least one-half of those seen in untreated diabetic rats, with TAU providing a greater attenuation of the formation of MDA and NO, an about similar action on the depletion of GSH, and a lower action on the decrease in the GSH/GSSG ratio caused by diabetes than either AMSA or HMTAU. In contrast AMSA and HMTAU were about equipotent with each other and more potent than TAU in preventing the loss of antioxidant enzyme activities associated with diabetes. In short, pretreating diabetic rats with AMSA, HMTAU or TAU is found to protect the brain against changes in biochemical parameters indicative of oxidative stress, with potency differences among the test compounds varying within a narrow range.


Subject(s)
Brain/drug effects , Diabetes Mellitus, Type 2/complications , Oxidative Stress/drug effects , Spinal Cord/drug effects , Taurine/pharmacology , Animals , Diabetes Mellitus, Experimental/complications , Male , Rats , Rats, Sprague-Dawley , Sulfonic Acids/pharmacology , Taurine/analogs & derivatives
8.
Exp Toxicol Pathol ; 68(2-3): 103-12, 2016.
Article in English | MEDLINE | ID: mdl-26616540

ABSTRACT

This study has comparatively evaluated the antiradical and antilipid peroxidizing actions of taurine (TAU) and its N-pantoyl analog pantoyltaurine (PTAU) in vitro, and has determined the extent to which these findings agree with the in vivo ability of these compounds to prevent changes in plasma glucose and in indices of oxidative stress in the plasma, brain and spinal cord induced by the diabetogen streptozotocin (STZ) in Sprague-Dawley rats. Using free radical-generating and oxidizing systems, PTAU was found more effective than TAU in scavenging DPPH, hydroxyl, peroxyl, and superoxide anion radicals and peroxynitrite, and in preventing lipid peroxidation of a brain homogenate by iron (III)-dopamine and the oxidation of dopamine by iron (III). On the other hand, when administered intraperitoneally (i.p.) at a 1.2mM/kg dose, 75min and 45min before a single i.p., 60mg/kg, dose of (STZ), TAU was about equipotent with PTAU in attenuating STZ-induced increases in glucose, malondialdehyde (MDA) and nitric oxide (NO), and the loss of reduced glutathione (GSH) in plasma collected at 24h post STZ. Moreover, the analysis of concurrently collected brain and spinal cords samples revealed that both TAU and PTAU were able to equally reverse the increases in MDA and NO concentrations and to effectively counteract the decrease in the GSH/GSSG ratio caused by STZ. Likewise, both compounds were very effective in preventing the losses of tissue catalase, glutathione peroxidase and superoxide dismutase activities. A comparison of the results for spinal cord and for brain parts such as the cerebellum, cortex and brain stem suggested the existence of regional differences in antioxidant potency between TAU and PTAU, especially in terms of antioxidant enzymes. In general, differences in antiradical and antioxidant potencies between TAU and PTAU derived from in vitro test are not reliable indicators of the antioxidant potencies these compounds may subsequently manifest in a living organism.


Subject(s)
Antioxidants/therapeutic use , Brain/drug effects , Diabetes Mellitus, Experimental/metabolism , Spinal Cord/drug effects , Taurine/analogs & derivatives , Taurine/therapeutic use , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacology , Blood Glucose/metabolism , Brain/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Male , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Spinal Cord/metabolism , Streptozocin/pharmacology , Taurine/administration & dosage , Taurine/pharmacology
13.
Adv Exp Med Biol ; 776: 199-215, 2013.
Article in English | MEDLINE | ID: mdl-23392884

ABSTRACT

The present study was carried out to ascertain the impact of replacing the sulfonate group of TAU with thiosulfonate, as present in thiotaurine (TTAU), on the protective actions of TAU against hepatocellular damage and biochemical alterations related to oxidative stress and glutathione redox cycling, synthesis, and utilization caused by a high dose of acetaminophen (APAP). To this end, male Sprague-Dawley rats, 225-250 g, were intraperitoneally treated with a 2.4 mmol/kg dose of TAU (or TTAU), followed 30 min later by 800 mg/kg of APAP. A reference group received 2.4 mmol/kg of N-acetylcysteine (NAC) prior to APAP. Naive rats served as controls. The animals were sacrificed 6 h after receiving APAP and their blood and livers were collected. Plasma and liver homogenates were analyzed for indices of cell damage (plasma transaminases, plasma lactate dehydrogenase), -oxidative stress (malondialdehyde = MDA, reduced glutathione = GSH, glutathione disulfide = GSSG, catalase, glutathione peroxidase, superoxide dismutase), glutathione cycling (glutathione reductase), utilization (glutathione S-transferase), and synthesis (γ-glutamylcysteine synthetase) activities. APAP increased MDA formation and lowered the GSH/GSSG ratio and all enzyme activities, especially those of antioxidant enzymes. In general, TTAU was equipotent with NAC and more potent than TAU in protecting the liver. Taken into account the results of a previous study comparing the actions of TAU and hypotaurine (HTAU), the sulfinate analog of TAU, it appears that the sulfinate and thiosulfonate analogs are somewhat more effective than the parent sulfonate TAU in counteracting APAP-induced hepatic alterations in the liver and plasma.


Subject(s)
Acetaminophen/adverse effects , Antioxidants/metabolism , Glutathione/metabolism , Liver/enzymology , Liver/pathology , Taurine/analogs & derivatives , Taurine/pharmacology , Acetylcysteine/pharmacology , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Catalase/blood , Glutamate-Cysteine Ligase/blood , Glutathione/blood , Glutathione Disulfide/blood , Glutathione Reductase/blood , Glutathione Transferase/blood , L-Lactate Dehydrogenase/blood , Liver/drug effects , Male , Malondialdehyde/blood , Oxidation-Reduction/drug effects , Rats , Rats, Sprague-Dawley , Superoxide Dismutase/blood
14.
Adv Exp Med Biol ; 775: 321-43, 2013.
Article in English | MEDLINE | ID: mdl-23392946

ABSTRACT

In this study, the actions of taurine (TAU), a sulfonate, and thiotaurine (TTAU), a thiosulfonate, on diabetes-mediated biochemical alterations in red blood cells (RBCs) and plasma and on the RBC membrane, morphology and spectrin distribution were examined in rats. Diabetes was induced in male Sprague-Dawley rats with streptozotocin (60 mg/kg i.p.) and allowed to progress for 14 days. From days to 56, the rats received a daily, 2.4 mmol/kg, oral dose of TAU or TTAU, 2 mL oral dose of physiological saline or 4 U/kg subcutaneous dose of isophane insulin (INS). Naive rats served as the control group. The rats were sacrificed on day 57 and their blood was collected to measure HbA(1c), to isolate intact RBCs, and to obtain plasma. A 6-weeks treatment with INS effectively lowered the elevations in plasma glucose, cholesterol, triglycerides, and plasma and RBC malondialdehyde and glutathione disulfide while effectively counteracting the decreases in plasma INS, plasma and RBC glutathione redox status, and plasma and RBC activities of antioxidant enzymes caused by diabetes. Also, INS returned the echynocytic appearance and peripheral location of spectrin seen in RBCs from diabetic rats to the normal discocytic shape and uniform distribution. TAU and TTAU were as effective as INS in inhibiting malondialdehyde formation, changes in redox status and oxidative stress in both the plasma and RBC, but were much less effective in controlling hyperglycemia and hypoinsulinemia. Furthermore TTAU was more effective than INS or TAU in lowering the increase in cholesterol to phospholipids ratio in the RBC membrane and, unlike TAU, it was able to normalize the RBC morphology and spectrin distribution.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Protective Agents/therapeutic use , Taurine/analogs & derivatives , Animals , Antioxidants/metabolism , Blood Glucose/metabolism , Catalase/metabolism , Cell Shape , Cholesterol/blood , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/enzymology , Disease Models, Animal , Erythrocytes/drug effects , Erythrocytes/metabolism , Erythrocytes/ultrastructure , Glutathione Disulfide/blood , Glutathione Peroxidase/metabolism , Glycated Hemoglobin/metabolism , Insulin/blood , Insulin/pharmacology , Lipid Peroxidation/drug effects , Male , Phospholipids/blood , Protective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Spectrin/metabolism , Superoxide Dismutase/metabolism , Taurine/pharmacology , Taurine/therapeutic use , Triglycerides/blood
15.
Adv Exp Med Biol ; 775: 345-69, 2013.
Article in English | MEDLINE | ID: mdl-23392947

ABSTRACT

This study has compared the actions of the sulfur-containing compounds taurine (TAU) and thiotaurine (TTAU) with those of insulin (INS) on the oxidative stress that develops in the aorta and heart as a result of diabetes. Diabetes was induced in male Sprague-Dawley rats with streptozotocin (60 mg/kg, i.p.). Starting on day 15, and continuing for the next 41 days, the diabetic rats received each day 2 mL of physiological saline or 2.4 mmol/kg/2 mL of TAU (or TTAU) p.o. or 4 U/kg of isophane INS s.c. Normal rats served as controls. The rats were sacrificed on day 57 to collect blood, heart and thoracic aorta samples. Untreated diabetic rats exhibited a lower body weight gain (by 34%), higher than normal plasma glucose (by ∼4-fold), cholesterol (by 66%) and triglycerides (by 188%) levels, and lower INS levels (by 76%). Also there was a marked increase in catalase activity (≥90%); and clear decreases in nitrite (≥40%), glutathione redox status (≥67%), and glutathione peroxidase (≥66%) and superoxide dismutase (≥51%) activities in both the aorta and heart. With only a few isolated instances (plasma lipids), TTAU was either markedly more effective (plasma glucose, plasma INS, aorta and heart glutathione, aorta redox status, and antioxidant enzymes) or marginally more effective (heart redox status) than TAU in attenuating the alterations brought about by diabetes. These results suggest that replacing the sulfonic acid group of TAU by thiosulfonic acid can lead to a greater potency against diabetes-related biochemical changes in the plasma, heart and aorta. However, except for effects on plasma lipids, these sulfur-containing compounds were less effective than INS in counteracting diabetes-related changes.


Subject(s)
Aorta/drug effects , Aorta/pathology , Diabetes Mellitus, Experimental/pathology , Myocardium/pathology , Oxidative Stress/drug effects , Taurine/analogs & derivatives , Animals , Aorta/enzymology , Blood Glucose/metabolism , Catalase/metabolism , Cholesterol/blood , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/enzymology , Disease Models, Animal , Glutathione Disulfide/metabolism , Glutathione Peroxidase/metabolism , Insulin/blood , Male , Malondialdehyde/metabolism , Myocardium/enzymology , Nitric Oxide/metabolism , Nitrites/metabolism , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Superoxide Dismutase/metabolism , Taurine/pharmacology , Triglycerides/blood , Weight Gain/drug effects
16.
Adv Exp Med Biol ; 775: 371-94, 2013.
Article in English | MEDLINE | ID: mdl-23392948

ABSTRACT

Taking into account the proven effectiveness of antioxidants in preventing experimentally induced diabetes in laboratory animals, this study was carried out with the specific purpose of comparing the effectiveness of two known antioxidants, the ß-aminosulfonate taurine (TAU) and ß-aminothiosulfonate thiotaurine (TTAU), in preventing biochemical, functional and histological alterations indicative of -diabetic nephropathy. In the study, streptozotocin (60 mg/kg, orally) was used to induce type 2 diabetes mellitus in Sprague-Dawley rats. Starting on day 15 and continuing up to day 56, the rats received a daily single 2.4 mmol/kg oral dose of a sulfur-containing compound (TAU or TTAU) or 4 U/kg subcutaneous dose of isophane insulin (INS). Rats not receiving any treatment served as controls. After obtaining a 24 h urine sample, the animals were sacrificed by decapitation on day 57, and their blood and kidneys immediately collected. Diabetic rats exhibited marked hyperglycemia, hypoinsulinemia, hypoproteinemia, hyponatremia, hyperkalemia, azotemia, hypercreatinemia, increased plasma TGF ß(1), lipid peroxidation, plasma and kidney nitrite, and urine output; decreased glutathione redox status in plasma and kidney, decreased urine Na(+) and K(+), proteinuria and hypocreatinuria. Without exceptions, all the treatment compounds were found to markedly and variously attenuate these changes. Confirmation of protection by INS, TAU and TTAU was provided by the results of histological examination of kidney sections and which showed a more normal appearance than sections from diabetic animals. In most instances protection by TTAU was about equal to that by INS but greater than that by TAU.


Subject(s)
Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/pathology , Protective Agents/therapeutic use , Taurine/analogs & derivatives , Taurine/therapeutic use , Animals , Blood Glucose/metabolism , Blood Urea Nitrogen , Creatinine/blood , Creatinine/urine , Diabetic Nephropathies/blood , Diabetic Nephropathies/urine , Disease Models, Animal , Glutathione Disulfide/blood , Glycated Hemoglobin/metabolism , Insulin/blood , Insulin/pharmacology , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Malondialdehyde/blood , Nitric Oxide/blood , Protective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Taurine/pharmacology , Transforming Growth Factor beta1/blood , Weight Gain/drug effects
17.
ScientificWorldJournal ; 2012: 145651, 2012.
Article in English | MEDLINE | ID: mdl-22619591

ABSTRACT

A simple reversed-phase HPLC method for measuring hepatic levels of acetaminophen- (APAP-) protein adduct following an overdose of APAP was developed. An aliquot of liver homogenate in phosphate-buffered saline pH 7.4 (PBS) was placed on a Nanosep centrifugal device, which was centrifuged to obtain a protein residue. This residue was incubated with a solution of p-aminobenzoic acid (PABA), the internal standard, and bacterial protease in PBS, transferred to a Nanosep centrifugal device, and centrifuged. A 100 µL portion of the filtrate was analyzed on a YMC-Pack ODS-AMQ C18 column, using 100 mM potassium dihydrogen phosphate-methanol-acetic acid (100 : 0.6 : 0.1) as the mobile phase, a flow rate of 1 mL/min, and photometric detection at 254 nm. PABA and APAP-cystein-S-yl (APAP-Cys) eluted at ~14.7 min and 22.7 min, respectively. Method linearity, based on on-column concentrations of APAP-Cys, was observed over the range 0.078-40 µg. Recoveries of APAP-Cys from spiked blank liver homogenates ranged from ~83% to 91%. Limits of detection and of quantification of APAP-Cys, based on column concentrations, were 0.06 µg and 0.14 µg, respectively. RSD values for interday and intraday analyses of a blank liver homogenate spiked with APAP-Cyst at three levels were, in all cases, ≤1.0% and <1.5%, respectively. The proposed method was found appropriate for comparing the antidotal properties of N-acetylcysteine and taurine in a rat model of APAP poisoning.


Subject(s)
Acetaminophen/metabolism , Chromatography, High Pressure Liquid/methods , Liver/metabolism , Proteins/metabolism , Animals , Limit of Detection , Male , Rats , Rats, Sprague-Dawley
18.
Chem Biol Drug Des ; 79(4): 488-96, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22177599

ABSTRACT

A group of novel N-1-substituted indazole-3-carboxamide derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy was applied to a weakly active unsubstituted 1H-indazole-3-carboxamide 2, by introducing a three carbon linker between 1H-indazole-3-carboxamide and different heterocycles, and led to compounds 4 [1-(3-(piperidine-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) =36µm] and 5 [1-(3-(2,3-dioxoindolin-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) = 6.8µm]. Compound 5 was evaluated in rats for its protective action against diabetes induced by a treatment with streptozotocin, a known diabetogenic agent. In addition to preserving the ability of the pancreas to secrete insulin, compound 5 was also able to attenuate the ensuing hyperglycemic response to a significant extent.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Indazoles/chemistry , Indazoles/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Diabetes Mellitus, Experimental/enzymology , Drug Design , Hypoglycemic Agents/pharmacology , Indazoles/pharmacology , Insulin/metabolism , Male , Models, Molecular , Poly(ADP-ribose) Polymerases/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
19.
Chem Biol Drug Des ; 77(5): 361-72, 2011 May.
Article in English | MEDLINE | ID: mdl-21352503

ABSTRACT

GPR40, a G-protein-coupled receptor has been well established to play a crucial role in regulating blood glucose levels. Hence, GPR40 is a potential target for future antidiabetic agents. The present 3D QSAR study is aimed at delineating structural parameters governing GPR40 agonistic activity. To meet this objective, a comparative molecular similarity indices analysis for 63 different GPR40 agonists was performed using two methods; a ligand-based 3D QSAR model employing the atom fit alignment method and a receptor-based 3D QSAR model that was derived from the predicted binding conformations obtained by docking all the GPR40 agonists at the active site of GPR40. The results of these studies showed the ligand-based model to be superior (r(cv)(2) value of 0.610) to the receptor-based model (r(cv)(2) value of 0.519) in terms of statistical data. The predictive ability of these models was evaluated using a test set of 15 compounds not included in the preliminary training set of 48 compounds. The predictive r(2) values for the ligand- and the receptor-based models were found to be 0.863 and 0.599, respectively. Further, interpretation of the comparative molecular similarity indices analysis contour maps with reference to the active site of GPR40 provided an insight into GPR40-agonist interactions.


Subject(s)
Carboxylic Acids/metabolism , Hydrocarbons, Aromatic/metabolism , Receptors, G-Protein-Coupled , Binding Sites , Blood Glucose/metabolism , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Catalytic Domain , Computer Simulation , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Diabetes Mellitus/physiopathology , Humans , Hydrocarbons, Aromatic/chemistry , Hydrocarbons, Aromatic/pharmacology , Ligands , Models, Molecular , Molecular Conformation/drug effects , Protein Binding/drug effects , Quantitative Structure-Activity Relationship , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism
20.
J Biomed Sci ; 17 Suppl 1: S16, 2010 Aug 24.
Article in English | MEDLINE | ID: mdl-20804590

ABSTRACT

BACKGROUND: Poly(ADP-ribose) is a NAD+-requiring, DNA-repairing, enzyme playing a central role in pancreatic beta-cell death and in the development of endothelial dysfunction in humans and experimental animals. PARP activation is also relevant to the development of complications of diabetes. Hence, agents capable of inhibiting PARP may be useful in preventing the development of diabetes and in slowing down complications of diabetes. METHODS: PARP inhibition was assessed with a colorimetric assay kit. Molecular docking studies on the active site of PARP were conducted using the crystalline structure of the enzyme available as Protein Data Bank Identification No. 1UK1. Type 2 diabetes was induced in male Sprague-Dawley rats with streptozotocin (STZ, 60 mg/kg, i.p.). The test compounds (3-aminobenzamide = 3-AB, nicotinamide = NIC, taurine = TAU) were given by the i.p. route 45 min before STZ at 2.4 mM/kg (all three compounds) or 1.2 and 3.6 mM/kg (only NIC and TAU). Blood samples were collected at 24 hr after STZ and processed for their plasma. The plasma samples were used to measure glucose, insulin, cholesterol, triglycerides, malondialdehyde, nitric oxide, and glutathione levels using reported methods. RESULTS: 3-AB, NIC and TAU were able to inhibit PARP, with the inhibitory potency order being 3-AB>NIC> or =TAU. Molecular docking studies at the active site of PARP showed 3-AB and NIC to interact with the binding site for the nicotinamide moiety of NAD+ and TAU to interact with the binding site for the adenine moiety of NAD+. While STZ-induced diabetes elevated all the experimental parameters examined and lowered the insulin output, a pretreatment with 3-AB, NIC or TAU reversed these trends to a significant extent. At a dose of 2.4 mm/kg, the protective effect decreased in the approximate order 3-AB>NIC> or =TAU. The attenuating actions of both NIC and TAU were dose-related except for the plasma lipids since NIC was without a significant effect at all doses tested. CONCLUSIONS: At equal molar doses, 3-AB was generally more potent than either TAU or NIC as an antidiabetogenic agent, but the differences were not as dramatic as would have been predicted from their differences in PARP inhibitory potencies. NIC and TAU demonstrated dose-related effects, which in the case of TAU were only evident at doses > or =2.4 mM/kg. The present results also suggest that in the case of NIC and TAU an increase in dose will enhance the magnitude of their attenuating actions on diabetes-related biochemical alterations to that achieved with a stronger PARP inhibitor such as 3-AB. Hence, dosing will play a critical role in clinical studies assessing the merits of NIC and TAU as diabetes-preventing agents.


Subject(s)
Benzamides , Diabetes Mellitus, Experimental/prevention & control , Niacinamide , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/metabolism , Taurine , Animals , Benzamides/chemistry , Benzamides/metabolism , Benzamides/therapeutic use , Blood Glucose/drug effects , Blood Glucose/metabolism , Catalytic Domain , Cholesterol/blood , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Glutathione/blood , Humans , Insulin/blood , Male , Models, Molecular , Neuroprotective Agents/chemistry , Neuroprotective Agents/metabolism , Neuroprotective Agents/therapeutic use , Niacinamide/chemistry , Niacinamide/metabolism , Niacinamide/therapeutic use , Poly(ADP-ribose) Polymerases/chemistry , Rats , Rats, Sprague-Dawley , Streptozocin/pharmacology , Taurine/chemistry , Taurine/metabolism , Taurine/therapeutic use , Triglycerides/blood , Vitamin B Complex/chemistry , Vitamin B Complex/metabolism , Vitamin B Complex/therapeutic use
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