Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carboplatin preferentially destroys inner hair cells (IHCs) and type-I spiral ganglion neurons while sparing outer hair cells (OHCs). Loss of IHCs and type-I ganglion cells is associated with a significant reduction of the compound action potential (CAP). However, the cochlear microphonic (CM) potential and distortion product otoacoustic emissions (DPOAEs) remain normal, indicating that the OHCs are functionally intact. In the vestibular system, carboplatin selectively destroys type-I hair cells and their afferent neurons. Damage of type-I vestibular hair cells and their afferent terminals is associated with significant depression of nystagmus induced by cold, caloric stimulation. Histochemical studies revealed a rapid decrease in succinate dehydrogenase (SDH) staining in IHCs soon after carboplatin treatment, and staining intensity remained depressed in surviving IHCs for at least 1 month after carboplatin treatment. These results suggest that carboplatin depresses the metabolic function in surviving IHCs. Several lines of evidence suggest that free radicals may contribute to carboplatin-induced sensory cell damage. Intracochlear infusion of L-buthionine-[S,R]-sulfoximine (BSO), which depletes intracellular glutathione (GSH), increases IHC and OHC loss. Previous in vitro studies have shown that neurotrophin 4/5 (NT-4/5) promotes the survival of spiral ganglion neurons from cisplatin ototoxicity. In vivo perfusion of NT-4/5 promoted the survival of spiral ganglion neurons, but did not protect the hair cells.
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PMID:Selective loss of inner hair cells and type-I ganglion neurons in carboplatin-treated chinchillas. Mechanisms of damage and protection. 1084 92

We recently reported a cardioselective and cumulative oxidation of cardiac mitochondrial DNA (mtDNA) following subchronic administration of doxorubicin to rats. The mtDNA adducts persist for up to 5 weeks after cessation of doxorubicin treatment. Since the evidence suggests that this persistence of mtDNA adducts cannot be attributed to a lack of repair and replication, we investigated whether it might reflect a long-lasting stimulation of free radical-mediated adduct formation. Male Sprague-Dawley rats received weekly s.c. injections of either doxorubicin (2 mg/kg) or an equivalent volume of saline. Cardiac myocytes isolated from rats following 6 weekly injections of doxorubicin expressed a much higher rate of reactive oxygen species (ROS) formation compared to saline controls. This higher rate of ROS formation persisted for 5 weeks following the last injection. Associated with this was a persistent depression of GSH in heart tissue, while protein-thiol content was not markedly altered. These data suggest that the accumulation and persistence of oxidized mtDNA may be due, not to the stability of the adducts, but to some as yet undefined toxic lesion that causes long-lasting stimulation of ROS generation by doxorubicin. This persistent generation of ROS may contribute to the cumulative and irreversible cardiotoxicity observed clinically with the drug.
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PMID:Doxorubicin-induced persistent oxidative stress to cardiac myocytes. 1136 69

The present study was designed to investigate the role of captopril in an in vivo model of myocardial ischaemic-reperfusion injury with respect to its time of administration. In open-chest pentobarbitone anaesthetized cats, the left anterior descending coronary artery was occluded for 15 min followed by 60 min of reperfusion. Vehicle (saline) or captopril (4 mg kg(-1)) was administered 10 min before instituting ischaemia (pre-treatment) or 5 min before reperfusion (post-treatment). In the vehicle-treated group, ischaemic-reperfusion injury (IRI) was evidenced by enhanced plasma renin activity, depression of global haemodynamic function (mean arterial pressure, left ventricular-end-diastolic-pressure, peak positive and negative dP/dt) along with depletion of myocardial high energy phosphate (HEP) compounds. Oxidant stress in IRI was evidenced by raised levels of myocardial thiobarbituric acid reactive substances (TBARS) and depletion of endogenous myocardial antioxidants (glutathione, superoxide dismutase and catalase). Pre-treatment with captopril prevented (i) loss of myocardial haemodynamic function, (ii) rise in TBARS and (iii) depletion of myocardial HEP compounds. However, in the post-treatment group, only partial recovery of myocardial haemodynamic function, with no significant reduction in TBARS, was observed. Glutathione, superoxide dismutase and catalase were unaffected by either treatment schedules. The results of the present study suggest that captopril is more effective in attenuating ischaemic-reperfusion injury when administered before ischaemia rather than before reperfusion.
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PMID:Captopril and its time of administration in myocardial ischaemic-reperfusion injury. 1151 62

Because the role of elemental sulfur in human nutrition has not been studied extensively, it is the purpose of this article to emphasize the importance of this element in humans and discuss the therapeutic applications of sulfur compounds in medicine. Sulfur is the sixth most abundant macromineral in breast milk and the third most abundant mineral based on percentage of total body weight. The sulfur-containing amino acids (SAAs) are methionine, cysteine, cystine, homocysteine, homocystine, and taurine. Dietary SAA analysis and protein supplementation may be indicated for vegan athletes, children, or patients with HIV, because of an increased risk for SAA deficiency in these groups. Methylsulfonylmethane (MSM), a volatile component in the sulfur cycle, is another source of sulfur found in the human diet. Increases in serum sulfate may explain some of the therapeutic effects of MSM, DMSO, and glucosamine sulfate. Organic sulfur, as SAAs, can be used to increase synthesis of S-adenosylmethionine (SAMe), glutathione (GSH), taurine, and N-acetylcysteine (NAC). MSM may be effective for the treatment of allergy, pain syndromes, athletic injuries, and bladder disorders. Other sulfur compounds such as SAMe, dimethylsulfoxide (DMSO), taurine, glucosamine or chondroitin sulfate, and reduced glutathione may also have clinical applications in the treatment of a number of conditions such as depression, fibromyalgia, arthritis, interstitial cystitis, athletic injuries, congestive heart failure, diabetes, cancer, and AIDS. Dosages, mechanisms of action, and rationales for use are discussed. The low toxicological profiles of these sulfur compounds, combined with promising therapeutic effects, warrant continued human clinical trails.
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PMID:Sulfur in human nutrition and applications in medicine. 1189 44

We examined the effects of chronic cerebral hypoperfusion on the endogenous oxidative stress-related indices, nitrite and nitrate (NOx) concentration, glutathione (GSH) content, superoxide dismutase and catalase activities, and thiobarbituric acid-reactive substances level in the rat striatum, to clarify the participation of oxidative stress in the chronic cerebral hypoperfusion-induced alterations. Our present results indicate that chronic cerebral hypoperfusion produces oxidative stress and disturbs intracellular redox regulation in two distinct phases: at 1 day, "acute" and at 6 weeks, "chronic" alterations after the operation. Therefore, striatal neural cell damage may be mainly attributed to the transient increase of NOx production at 1 day after, and the delayed reduction of muscarinic acetylcholine receptor binding in the striatum may be mostly attributed to the continuous depression of GSH content from the 1st to the 6th postoperative week. In particular, the continuous GSH depression may be considered to accompany the pathophysiology of chronic cerebral hypoperfusion.
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PMID:Chronic cerebral hypoperfusion induces striatal alterations due to the transient increase of NO production and the depression of glutathione content. 1195 36

When male rats were given a single dose of cadmium (Cd) (3.58 mg CdCl2 x H2O/kg, i.p.) 72 hr prior to sacrifice, the testicular 7-ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities toward the substrates 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (EPNP), and cumene hydroperoxide (CHPx) decreased significantly as compared to controls. Cd also inhibited reduced glutathione (GSH) level while increasing the lipid peroxidation (LP) level significantly. When the animals were given a single dose of nickel (Ni) (59.5 mg NiCl2 x 6H2O/kg, i.p.) 16 hr prior to sacrifice, significant decreases were observed in EROD and GST activities toward CDNB, EAA, EPNP, and CHPx, and GSH level. No significant alterations were noted in DCNB GST activity and LP level by Ni. For the combined treatment, rats received the single dose of Ni 56 hr after the single dose of Cd and were killed 16 hr later. In these animals, lesser depressions were observed on EROD activity and LP level than those of Cd alone. The combination of metals significantly inhibited GST activities and GSH level but not to a greater degree than noted by Cd or Ni alone. Plasma testosterone levels of Cd-, Ni-, and combination-treated rats decreased significantly compared to controls. The strongest depression was achieved by Cd alone. Cd, both alone and in combination with Ni, increased the tissue Ni uptake significantly. Ni, however, did not produce such an effect on the tissue uptake of Cd in either case. Cd treatment caused interstitial edema and coagulation necrosis in seminiferous tubules and also caused fibrinoidal necrosis in vascular endothelium. Ni treatment did not produce any pathological testicular alterations compared to controls. Combined treatment produced fewer pathological alterations (i.e., only interstitial edema) than that of Cd treatment. These results reveal that the combination of Cd and Ni does nothave a synergistic effect on testicular xenobiotic metabolizing enzymes, and in contrast, Ni has an ameliorating effect on pathological disturbances caused by Cd alone in the rat testis.
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PMID:Combined effects of cadmium and nickel on testicular xenobiotic metabolizing enzymes in rats. 1244 41

The aim of this work was to evaluate the effect of a cycle of estivation and awakening on free radical metabolism in selected organs of the land snail Helix aspersa. Estivation for 20 days induced a 4.9- and 1.8-fold increase in selenium-dependent glutathione peroxidase activity (Se-GPX) and in total glutathione levels (GSH-eq), respectively, in hepatopancreas when compared to activity in active animals 24 h after awakening. Foot muscle Se-GPX activity was also increased 3.9-fold during estivation, whereas GSH-eq did not vary. The activities of other antioxidant enzymes (catalase, superoxide dismutase, glutathione reductase and glutathione S-transferase) and glucose 6-phosphate dehydrogenase were unchanged in both organs. After 15 min of awakening, the glutathione disulphide (GSSG)/GSH-eq ratio increased significantly by 55% in hepatopancreas, slowly returning to the levels observed during estivation. The higher GSSG/GSH-eq ratio may be caused by increased formation of reactive oxygen species (ROS) during awakening. The levels of thiobarbituric acid reactive substances (TBARS) decreased from 49 to 30.7 nmol g(-1) wet mass in hepatopancreas after 5 min arousal and, after 30 min, TBARS rose significantly to 39.6 nmol g(-1) wet mass, gradually declining thereafter. The levels of lipid hydroperoxides in hepatopancreas and of carbonyl protein in foot muscle both decreased during awakening. The higher levels of products of free radical damage during estivation may have resulted from low levels of ROS formation associated with decreased rates of lipid hydroperoxide detoxification and oxidized protein turnover caused by metabolic depression. The regulation of the antioxidant system during hypometabolism may constitute a mechanism to minimize oxidative stress during cycles of estivation and awakening.
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PMID:Hypometabolism, antioxidant defenses and free radical metabolism in the pulmonate land snail Helix aspersa. 1251 85

Capsaicin is a common dietary constituent and a popular homeopathic treatment for chronic pain. Exposure to capsaicin has been shown to cause various dose-dependent acute physiological responses including the sensation of burning and pain, respiratory depression, and death. In this study, the P450-dependent metabolism of capsaicin by recombinant P450 enzymes and hepatic and lung microsomes from various species, including humans, was determined. A combination of LC/MS, LC/MS/MS, and LC/NMR was used to identify several metabolites of capsaicin that were generated by aromatic (M5 and M7) and alkyl hydroxylation (M2 and M3), O-demethylation (M6), N- (M9) and alkyl dehydrogenation (M1 and M4), and an additional ring oxygenation of M9 (M8). Dehydrogenation of capsaicin was a novel metabolic pathway and produced unique macrocyclic, diene, and imide metabolites. Metabolism of capsaicin by microsomes was inhibited by the nonselective P450 inhibitor 1-aminobenzotriazole (1-ABT). Metabolism was catalyzed by CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Addition of GSH (2 mM) to microsomal incubations stimulated the metabolism of capsaicin and trapped several reactive electrophilic intermediates as their GSH adducts. These results suggested that reactive intermediates, which inactivated certain P450 enzymes, were produced during catalytic turnover. Comparison of the rate and types of metabolites produced from capsaicin and its analogue, nonivamide, demonstrated similar pathways in the P450-dependent metabolism of these two capsaicinoids. However, production of the dehydrogenated (M4), macrocyclic (M1), and omega-1-hydroxylated (M3) metabolites was not observed for nonivamide. These differences may be reflective of the mechanism of formation of these metabolites of capsaicin. The role of metabolism in the cytotoxicity of capsaicin and nonivamide was also assessed in cultured lung and liver cells. Lung cells were markedly more sensitive to cytotoxicity by capsaicin and nonivamide. Cytotoxicity was enhanced 5 and 40% for both compounds by 1-ABT in BEAS-2B and HepG2, respectively. These data suggested that metabolism of capsaicinoids by P450 in cells represented a detoxification mechanism (in contrast to bioactivation).
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PMID:Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated metabolites and decreases cytotoxicity to lung and liver cells. 1264 34

Depression of metabolism by hypothyroidism decreases oxidant production and thus protects tIssues against oxidant damage. Moreover, it is well-known that abnormal gut motility is a common manifestation in hypo/hyperthyroidism. In this study, we aimed to investigate the putative beneficial effects of methimazole on oxidative injury and dysmotility in a rat colitis model. Methimazole (0.04%) was administered in drinking water starting 15 days prior to induction of colitis. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid (30 mg/ml; 0.8 ml) in ethanol. Six days after the induction of colitis, the fecal output was measured and used as an index for colonic motility. All rats were decapitated on the seventh day. The distal colon was weighed and the mucosal lesions were scored. Colonic lipid peroxidation (LP) and glutathione (GSH) measurements were performed. The macroscopic score, the colonic wet weight and LP values of the euthyroid colitis group were found to be higher than those of the control group (P<0.05-0.001). All these parameters were reduced in the methimazole-treated colitis group (P<0.01-0.001). The decrease in colonic GSH levels in the colitis group was completely abolished in the methimazole-treated colitis rats (P<0.01). Induction of colitis increased the average fecal output compared with the control group (P<0.05) and methimazole in the colitis group exaggerated the fecal output (P<0.001). In conclusion, methimazole reduces colonic oxidative injury probably due to hypometabolism, which is associated with a decrease in the production of reactive oxygen intermediates and an increase in the response of antioxidant systems.
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PMID:Methimazole-induced hypothyroidism in rats ameliorates oxidative injury in experimental colitis. 1277 28

Many individuals with cardiovascular diseases undergo periodic physical conditioning with or without medication. Therefore, this study investigated the interaction of exercise training and chronic nitroglycerin treatment on blood pressure (BP) and alterations in nitric oxide (NO), glutathione (GSH), antioxidant enzyme activities and lipid peroxidation in rats. Fisher 344 rats were divided into four groups: (1) sedentary control, (2) exercise training for 8 weeks, (3) nitroglycerin (15 mg/kg, s.c. for 8 weeks) and (4) training + nitroglycerin for 8 weeks. BP, heart rate (HR) and respiratory exchange ratio (RER) were monitored weekly for 8 weeks using tail-cuff method and oxygen/carbon dioxide analyzer, respectively. The animals were sacrificed 24 h after last treatments and plasma isolated and analyzed using HPLC, ELISA and UV-VIS spectrophotometric techniques. The results show that exercise conditioning significantly enhanced NO production (p < 0.001), GSH levels (p < 0.001), GSH/GSSG ratio (p < 0.05) and the up-regulation of the activities of catalase (CAT) (p < 0.05), glutathione peroxidase (GSH-Px) (p < 0.001), and glutathione reductase (GR) (p < 0.05), and depression of lactate levels (p < 0.001) in the plasma of the rat. These biochemical changes were accompanied by a significant increase in RER (p < 0.001) without a significant change in BP and HR. Chronic nitroglycerin administration significantly increased NO levels (p < 0.05), GSH levels (p < 0.001), superoxide dismutase (SOD) activity (p < 0.05), GST activity (p < 0.05), and decreased MDA levels (p < 0.05). These biochemical changes were accompanied by a significant decrease in BP (p < 0.05) and without any significant changes in HR and RER. Interaction of exercise training and chronic nitroglycerin treatment resulted in normalization of plasma NO, MDA, lactate levels, and CAT activity. The combination of exercise and nitroglycerin significantly enhanced GSH levels (p < 0.05), and the up-regulation of SOD (p < 0.001), GSH-Px (p < 0.05), GR (p < 0.05) and GST (p < 0.001) activities. These biochemical changes were accompanied by normalization of BP and a significant increased in RER (p < 0.001). The data suggest that the interaction of physical training and chronic nitroglycerin treatment resulted in the maintenance of BP and the up-regulation of plasma antioxidant enzyme activities and GSH levels in the rat.
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PMID:Interaction of physical training and chronic nitroglycerin treatment on blood pressure and plasma oxidant/antioxidant systems in rats. 1284 29


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