ABSTRACT
Organoselenium compounds modulate the metabolism by regulating carbohydrate and lipid syntheses and degradation in the liver, muscle, and adipose tissue. Notably, p-chloro-diphenyl diselenide (p-ClPhSe)2 can directly regulate the activities of enzymes involved in glucose metabolism, suggesting an insulin-like effect in rodents; however, there is still a lack of scientific evidence to confirm this hypothesis. The objective of this study was to investigate (p-ClPhSe)2 effects on glucose and lipid metabolism in Caenorhabditis elegans. The contribution of AGE-1/PI3K, AKT-1, AKT-2, PFK-1, DAF-16, and DAF-2 in the (p-ClPhSe)2 effects were also investigated. Our results demonstrate that (p-ClPhSe)2 acute exposure presented some toxicity to the worms, and therefore, lower concentrations were further used. (p-ClPhSe)2 reduced glucose and triglyceride levels to the baseline levels, after induction with glucose or fructose, in wild-type worms. This effect required proteins involved in the insulin/IGF-1 like signaling, such as the DAF-2, AGE-1, AKT-1 and AKT-2, PFK-1, but also DAF-16, which would be negatively regulated by DAF-2 activation. Moreover, the reduction in glucose and triglyceride levels, caused by (p-ClPhSe)2per se was lost in age-1/daf-16 worms, suggesting that insulin/IGF-1-like signaling in a DAF-2 and AGE-1/DAF-16 dependent-manner in C. elegans are necessary to effects of (p-ClPhSe)2. In conclusion, (p-ClPhSe)2 requires proteins involved in the IIS pathway to modulate carbohydrate and lipid metabolism.
Subject(s)
Caenorhabditis elegans Proteins , Organoselenium Compounds , Animals , Caenorhabditis elegans/metabolism , Insulin/metabolism , Insulin-Like Growth Factor I/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Lipid Metabolism , Organoselenium Compounds/pharmacology , Caenorhabditis elegans Proteins/metabolism , Glucose/metabolism , Triglycerides/metabolism , Longevity , Forkhead Transcription Factors/metabolismABSTRACT
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely used due to its specific and reproducible neurotoxic effect on the nigrostriatal system, being considered a convenient model of dopaminergic neurodegeneration to study interventions therapeutics. The purple pitanga (Eugenia uniflora) is a polyphenol-rich fruit with antioxidant and antidepressant properties, among others. Therefore, this study investigated the effect of purple pitanga extract (PPE) on acute early oxidative stress induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats. Male Wistar rats were pre-treated orally with PPE (1000 mg/kg) or vehicle. After 24 h, MPTP (0.1 mg/10µL/nostril) or vehicle was administered bilaterally into the animal's nostrils, and 6 h later, the olfactory bulb (OB), striatum (ST), and substantia nigra (SN) were collected to evaluate the oxidative stress parameters. Our findings revealed that OB and SN were the most affected areas after 6 h of MPTP infusion; an early increase in reactive oxygen species (ROS) levels was observed, while pretreatment with a single dose of PPE prevented this increment. No differences in thiobarbituric acid reactive species (TBARS) and 3-nitrotyrosine (3-NT) formation were observed, although 4-hydroxy-2-nonenal (4-HNE) levels increased, which is the most toxic form of lipid peroxidation, in the MPTP group. The PPE pretreatment could prevent this increase by increasing the NPSH levels previously decreased by MPTP. Furthermore, PPE prevents the Na+/K + ATPase strongly inhibited by MPTP, showing the neuroprotective capacity of the PPE by inhibiting the MPTP-generated oxidation. Thus, we demonstrated for the first time the antioxidant and neuroprotective effects of PPE against the early MPTP neurotoxicity.
Subject(s)
Eugenia , Neuroprotective Agents , Rats , Male , Animals , Mice , Antioxidants/pharmacology , Antioxidants/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , Eugenia/metabolism , Rats, Wistar , Oxidative Stress , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Substantia Nigra/metabolism , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Mice, Inbred C57BL , Disease Models, AnimalABSTRACT
Parkinson's disease is a multisystemic neurodegenerative disorder that includes motor and non-motor symptoms, and common symptoms include memory loss and learning difficulties. Thus, we investigated the neuroprotective potential of a hydroalcoholic extract of Brazilian purple cherry (Eugenia uniflora) (HAE-BC) on memory impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats and the involvement of hippocampal BDNF/TrkB/p75NTR pathway in its effects. Adult male Wistar rats were exposed to MPTP (1 mg/nostril) or vehicle. Twenty-four hours later, the HAE-BC treatments began at doses of 300 or 2000 mg/kg/day or vehicle for 14 days. From 7 days after the MPTP induction, the animals were subjected to behavioral tests to evaluate several cognitive paradigms. HAE-BC treatments, at both doses, blocked the MPTP-caused disruption in the social recognition memory, short- and long-term object recognition memories, and working memory. Furthermore, MPTP-induced motor deficit linked to striatal tyrosine hydroxylase levels decreased, which was blocked by HAE-BC. Our findings demonstrated that HAE-BC blocked the MPTP-induced increase in the hippocampal pro-BDNF, TrkB.t1, and p75NTR levels. The pro-BDNF/p75NTR interaction negatively regulates synaptic transmission and plasticity, and the neuroprotective effect of HAE-BC was related, at least partly, to the modulation of this hippocampal signaling pathway. Thus, our study reports the first evidence of the potential therapeutic of E. uniflora in a Parkinson's disease model in rodents.
Subject(s)
Eugenia , Neuroprotective Agents , Parkinson Disease , Rats , Animals , Male , Mice , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Brain-Derived Neurotrophic Factor/metabolism , Parkinson Disease/drug therapy , Rats, Wistar , Eugenia/metabolism , Memory Disorders/drug therapy , Memory Disorders/prevention & control , Memory Disorders/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Disease Models, Animal , Mice, Inbred C57BLABSTRACT
Magnetic nanoparticles (NPs) are suitable candidates for various medical and biological applications, despite some concerns that they may have negative impacts on human health. In this study, the toxicity effects of magnetic NPs consisting of α"-Fe16N2 captured and bioaccumulated by the nematode Caenorhabditis elegans (C. elegans) in the early larval stage are evaluated. The choice of α"-Fe16N2 NPs is based on their good structural stability when stored in saline solution and high magnetic performance. The uptake and bioaccumulation of α"-Fe16N2 NPs in intestinal cells of C. elegans was evidenced by transmission electron microscopy. After exposure to NPs up to 40 mg mL-1, C. elegans larval development, survival, feeding behavior, defecation cycles, movement and reproduction were monitored. C. elegans survival and other monitored behavioral evolutions do not show significant changes, except for a slight statistical reduction in the reproductive profile. Therefore, the present results are promising and very encouraging for investigations of applications of α"-Fe16N2 NPs in the biomedical area.
Subject(s)
Magnetite Nanoparticles , Nanoparticles , Animals , Caenorhabditis elegans , Humans , Iron/toxicity , Magnetite Nanoparticles/toxicity , Nanoparticles/toxicity , Reproduction , Saline SolutionABSTRACT
In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer's Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aß) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 µM and after 48 h the maintenance temperature was increased to 25 ° C for Aß expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aß toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aß aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Organoselenium Compounds/pharmacology , Pyrimidinones/pharmacology , Acetylcholinesterase/metabolism , Amyloid beta-Peptides/metabolism , Animals , Caenorhabditis elegans , Disease Models, Animal , Levamisole/pharmacology , Neuroprotective Agents/adverse effects , Organisms, Genetically Modified , Organoselenium Compounds/adverse effects , Oviposition/drug effects , Pyrimidinones/adverse effectsABSTRACT
AChE inhibition caused by exposure to organophosphate (OP) compounds is strongly related to behavioural disorders such as depression. Malathion is an OP that already has a relationship between its exposure and behavioural changes, although few data still have its effects in a longer exposure protocol. In addition, intoxication therapy is based on the use of atropine-oxime which still has its controversial efficacy depending on the type of compound. For this, (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Câ-HIN), a compound that has properties of isatin and oxime in its structure, have shown reactivating properties in the activity of AChE that have been added to antidepressant-like effects in rats exposed to malathion in acute protocol. In this sense, effects of Câ-HIN on the depressive-like behaviour and AChE activity were evaluated in a protocol of subchronic exposure to malathion in rats. Male wistar rats were co-treated with Câ-HIN [5 mg/kg, p.o.] and/or malathion [1 or 10 mg/kg, i.p] for 20 days. The exposure to both doses of malathion increased immobility time of rats on the forced swimming test (FST). Besides, malathion inhibited the AChE activity in the prefrontal cortex of rats, but any significant difference was observed in the hippocampus. Câ-HIN protected against increased immobility time in the FST of those rats exposed to a dose of 1 mg/kg of malathion. Similarly, Câ-HIN was able to reactivate AChE activity only in that group exposed to the lowest dose of malathion. Collectively, the results of this study suggest that Câ-HIN is an oxime capable of reactivating AChE inhibited and presents na antidepressant-like effect in cases of prolonged exposure to malathion.
Subject(s)
Acetylcholinesterase/drug effects , Behavior, Animal/drug effects , Hippocampus/drug effects , Malathion/pharmacology , Oxindoles/pharmacology , Acetylcholinesterase/metabolism , Animals , Antidepressive Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Hippocampus/metabolism , Rats, WistarABSTRACT
Alzheimer's disease (AD) is a progressive brain disorder and complex mechanisms are involved in the physiopathology of AD. However, there is data suggesting that inflammation plays a role in its development and progression. Indeed, some non-steroidal anti-inflammatory drugs, such as meloxicam, which act by inhibiting cyclooxygenase-2 (COX-2) have been used as neuroprotective agents in different neurodegenerative disease models. The purpose of this study was to investigate the effects of co-nanoencapsulated curcumin and meloxicam in lipid core nanocapsules (LCN) on cognitive impairment induced by amyloid-beta peptide injection in mice. LCN were prepared by the nanoprecipitation method. Male Swiss mice received a single intracerebroventricular injection of amyloid-beta peptide aggregates (fragment 25-35, 3 nmol/3 µL) or vehicle and were subsequently treated with curcumin-loaded LCN (10 mg/kg) or meloxicam-loaded LCN (5 mg/kg) or meloxicam + curcumin-co-loaded LCN (5 and 10 mg/kg, respectively). Treatments were given on alternate days for 12 days (i.e., six doses, once every 48 hours, by intragastric gavage). Our data showed that amyloid-beta peptide infusion caused long-term memory deficits in the inhibitory avoidance and object recognition tests in mice. In the inhibitory avoidance test, both meloxicam and curcumin formulations (oil or co-loaded LCN) improved amyloid-beta-induced memory impairment in mice. However, only meloxicam and curcumin-co-loaded LCN attenuated non-aversive memory impairment in the object recognition test. Moreover, the beneficial effects of meloxicam and curcumin-co-loaded LCN could be explained by the anti-inflammatory properties of these drugs through cortical COX-2 downregulation. Our study suggests that the neuroprotective potential of meloxicam and curcumin co-nanoencapsulation is associated with cortical COX-2 modulation. This study was approved by the Committee on Care and Use of Experimental Animal Resources, the Federal University of Pampa, Brazil (approval No. 02-2015) on April 16, 2015.
ABSTRACT
Plants are widely used in folk medicine because of their pharmacological properties. Ceiba speciosa, popularly known as paineira-rosa or tree-of-wool, is a species found in the Northwest of Rio Grande do Sul, being native of the upper Uruguay River, Brazil. The tea obtained from the stem bark is employed in folk medicine to reduce cholesterol, triacylglycerides, and glucose levels. However, there are no studies in the literature proving its efficacy or the safety of its use. For this study, we used Caenorhabditis elegans as an animal model considering its advantages for risk assessment and pharmacological screenings. For the toxicological tests, C. elegans N2 (wild type) was treated with the aqueous extract of the stem bark of C. speciosa (ECE) at the first larval stage (L1) at concentrations of 5, 25, 50, and 250 µg/mL. To evaluate biological activities, we challenged the extract for oxidative stress resistance in the presence of paraquat (0.5 mM), H2O2 (1 mM), and against glucose-induced toxicity. Our results demonstrated that ECE did not alter survival rate, pharyngeal pumping, and reproduction of the nematodes. The extract was not able to protect the nematodes against the toxicity induced by prooxidants. Notably, ECE protected against glucotoxicity by increasing worms' life span and by reducing glucose levels. On the other hand, ECE treatment did not reduce lipid accumulation induced by exogenous glucose feeding, as observed in worms which lipid droplets were tagged with GFP. Based on our results, we believe that the extract is indeed promising for further studies focusing on carbohydrates metabolism; however, it needs to be carefully evaluated since the extract does not seem to modulate lipid accumulation.
Subject(s)
Caenorhabditis elegans/drug effects , Ceiba/chemistry , Plant Extracts/pharmacology , Protective Agents/pharmacology , Animals , Caenorhabditis elegans/growth & development , Ceiba/metabolism , Glucose/pharmacology , Larva/drug effects , Larva/metabolism , Lethal Dose 50 , Longevity/drug effects , Oxidative Stress/drug effects , Paraquat/toxicity , Plant Bark/chemistry , Plant Bark/metabolism , Plant Extracts/chemistryABSTRACT
Organic selenium, tellurium and sulfur compounds have been studied due to their pharmacological properties. For instance, the ß-aryl-chalcogenium azide compounds have demonstrated antitumoral action in vitro. However, yet no pharmacological actions of this class of compounds were determined in vivo. Caenorhabditis elegans is a nematode that presents innumerable advantages in relation to mammalian models, such as having a small and transparent body, which allows the visualization of its internal anatomy, besides short life and low cost. Based on that, the aim of this work was to investigate the pharmacological and toxicological properties of ß-aryl-chalcogenium azide compounds in C. elegans. As well, to evaluate the capacity of organochalcogenium compounds to repair oxidative damage induced by hydrogen peroxide and the possible mechanism of action of these compounds using CF1553 transgenic strain with superoxide dismutase (SOD-3) tagged with GFP. Our results showed that ß-aryl-chalcogenium azide have low toxicity in wild-type worms and the pre-treatment protected against the damage induced by hydrogen peroxide at higher tested concentration. Associated with this, we observed that this protection is due in part to the increased expression of the antioxidant enzyme SOD-3. In conclusion, ß-aryl-chalcogenium azide compounds caused low toxicity and induced stress-resistance by modulating SOD-3 expression in C. elegans.
Subject(s)
Caenorhabditis elegans , Animals , Antioxidants , Azides , Superoxide DismutaseABSTRACT
BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Câ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Câ-HIN on the AChE activity and the BDNF-Trkß pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Câ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Câ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Câ-HIN. The cortical AChE activity was reactivated by Câ-HIN in rats exposed to malathion. Malathion induced an increase in Trkß and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Câ-HIN. CONCLUSION: These findings support the hypothesis that Câ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkß signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Câ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.
Subject(s)
Acetylcholinesterase/metabolism , Antidepressive Agents/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Indoles/pharmacology , Malathion/toxicity , Oxindoles/pharmacology , Receptor, trkB/metabolism , Signal Transduction , Animals , Antidepressive Agents/administration & dosage , Antidepressive Agents/chemistry , Antidepressive Agents/therapeutic use , Behavior, Animal/drug effects , Depression/drug therapy , Indoles/administration & dosage , Indoles/chemistry , Indoles/therapeutic use , Male , Motor Activity/drug effects , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Oxindoles/administration & dosage , Oxindoles/chemistry , Oxindoles/therapeutic use , Rats, Wistar , Signal Transduction/drug effectsABSTRACT
Glutaric acidaemia type I (GA-I) is a cerebral organic disorder characterized by the accumulation of glutaric acid (GA) and seizures. As seizures are precipitated in children with GA-I and the mechanisms underlying this disorder are not well established, we decided to investigate the role of nitric oxide (NO) in GA-induced convulsive behaviour in pup rats. Pup male Wistar rats (18-day-old) were anesthetized and placed in stereotaxic apparatus for cannula insertion into the striatum for injection of GA. The experiments were performed 3 days after surgery (pup rats 21-day-old). An inhibitor of NO synthesis (N-G-nitro-l-arginine methyl ester-L-NAME, 40 mg/kg) or saline (vehicle) was administered intraperitoneally 30 min before the intrastriatal injection of GA (1 µl, 1.3 µmol/striatum) or saline. Immediately after the intrastriatal injections, the latency and duration of seizures were recorded for 20 min. The administration of L-NAME significantly increased the latency to the first seizure episode and reduced the duration of seizures induced by GA in pup rats. The administration of the NO precursor l-arginine (L-ARG; 80 mg/kg) prevented the effects of L-NAME. Besides, GA significantly increased nitrate and nitrite (NOx) levels in the striatum of pup rats and the preadministration of L-NAME prevented this alteration. L-ARG blocked the reduction of striatal NOx provoked by L-NAME. These results are experimental evidence that NO plays a role in the seizures induced by GA in pup rats, being valuable in understanding the physiopathology of neurological signs observed in children with this organic acidaemia and to develop new therapeutic strategies.
Subject(s)
Nitric Oxide , Seizures , Animals , Arginine , Enzyme Inhibitors/pharmacology , Glutarates , Male , NG-Nitroarginine Methyl Ester/pharmacology , Rats , Rats, Wistar , Seizures/chemically inducedABSTRACT
Dexamethasone (DEX) is a synthetic agonist of glucocorticoid receptors that has been associated with neurotoxicity and neuropsychiatric diseases. (p-ClPhSe)2 is an organoselenium compound reported to have antioxidant, antidepressant-like, and neuroprotective actions. This study investigated whether antioxidant activity and modulation of the glutamatergic system contribute to the antidepressant-like effect of (p-ClPhSe)2 in mice subchronically exposed to DEX. Swiss mice received intraperitoneal injections of DEX (2â¯mg/kg) or saline (vehicle) once a day for 21 days. After, the mice received (p-ClPhSe)2 (1-10â¯mg/kg) or mineral oil (vehicle) by the intragastric route (i.g.) for 7 days. The mice exposed to DEX were treated with fluoxetine (20â¯mg/kg, i.g.) once a day for 7 days. 24â¯h after the last treatment, the animals performed the locomotor activity (LMA), tail suspension, and forced swimming tests. Ex vivo assays were performed in samples of prefrontal cortex (PFC). The results show that (p-ClPhSe)2 reversed depressive-like behavioral phenotype induced by DEX without affecting LMA. Further, (p-ClPhSe)2â¯at all doses reduced ROS levels and increased CAT activity in the PFC of DEX-exposed mice. The highest dose of (p-ClPhSe)2 was effective against the decrease of SOD activity in the PFC of mice exposed to DEX. (p-ClPhSe)2 increased the [3H] glutamate uptake/release and decreased the Na+/K+-ATPase activity as well as the EAAT1 and NMDA R2A protein contents in the PFC of DEX-exposed mice. Regarding the NMDA R2B levels, there was no difference among experimental groups. In conclusion, this study reveals the effectiveness of (p-ClPhSe)2 in reversing the depressive-like phenotype of DEX-exposed mice. In addition, (p-ClPhSe)2 modulated oxidative stress and glutamate neurotransmission in the PFC of mice subchronically exposed to DEX.
Subject(s)
Antidepressive Agents/pharmacology , Antioxidants/pharmacology , Behavior, Animal/drug effects , Depression/drug therapy , Dexamethasone/pharmacology , Fluoxetine/pharmacology , Glucocorticoids/pharmacology , Glutamic Acid/metabolism , Locomotion/drug effects , Organoselenium Compounds/pharmacology , Prefrontal Cortex/drug effects , Synaptic Transmission/drug effects , Animals , Antidepressive Agents/administration & dosage , Antioxidants/administration & dosage , Depression/chemically induced , Dexamethasone/administration & dosage , Disease Models, Animal , Fluoxetine/administration & dosage , Glucocorticoids/administration & dosage , Male , Mice , Organoselenium Compounds/administration & dosage , PhenotypeABSTRACT
The current study evaluated whether fructose supplementation affects oxidative stress and metabolic parameters in the liver and gastrocnemius muscle of rats subjected to swimming exercise. Male adult Wistar rats received a fructose solution (10%) or water during 1 h before exercise and during the rest interval by the intragastric route. The swimming protocol consisted of 6 days: each day, rats underwent 3 sessions of 17 min each, with a load of 5% of body mass, and rest intervals of 3 min. Fructose supplementation changed metabolic and oxidative parameters in the liver and gastrocnemius muscle of sedentary rats. Swimming exercise counteracted the increase of triglyceride levels in plasma and liver induced by fructose supplementation. It also reduced thiobarbituric acid reactive species levels in the liver, and catalase and superoxide dismutase activities in the gastrocnemius muscle of supplemented rats. However, fructose supplementation worsened metabolic (hepatic triglyceride levels) and oxidative parameters (thiobarbituric acid reactive species levels) in the liver and gastrocnemius of exercised rats. This study demonstrates that oxidative stress and metabolic parameters were differently affected by fructose supplementation when rats were kept sedentary or underwent swimming exercise. The present results indicate the need of a new insight of the role of fructose supplementation during physical exercise.
Subject(s)
Fructose/pharmacology , Oxidative Stress/drug effects , Physical Conditioning, Animal , Sedentary Behavior , Swimming , Animals , Liver/drug effects , Liver/metabolism , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Rats , Rats, Wistar , Triglycerides/metabolismABSTRACT
Despite resistance exercises being associated with health outcomes, numerous issues are still unresolved and further research is required before the exercise can faithfully be prescribed as medicine. The goal of this study was to investigate whether there are sex differences in resistance training effects on metabolic alterations induced by monosodium glutamate (MSG), a model of obesity, in male and female rats. Male and female Wistar rats received MSG (4 g/kg body weight/day, s.c.) from postnatal day 1 to 10. After 10 days from MSG administration, the rats were separated into two groups: MSG-sedentary and MSG-exercised. At postnatal day 60, the animals started a resistance training protocol in an 80 degrees inclined vertical ladder apparatus and performed it for 7 weeks. Control rats received saline solution and were divided in saline-sedentary and saline-exercised. Resistance training restored all plasma biochemical parameters (glucose, cholesterol, triglycerides, aspartate aminotransferase, and alanine aminotransferase) increased in male and female rats treated with MSG. The MSG administration induced hyperglycemia associated with a decrease in the skeletal muscle glucose transporter 4 (GLUT4) levels and accompanied by deregulation in proteins, G-6Pase, and tyrosine aminotransferase, involved in hepatic glucose metabolism of male and female rats. MSG induced dyslipidemia and lipotoxicity in the liver and skeletal muscle of male rats. Regarding female rats, lipotoxicity was found only in the skeletal muscle. The resistance training had beneficial effects against metabolic alterations induced by MSG in male and female rats, through regulation of proteins (GLUT2, protein kinase B, and GLUT4) involved in glucose and lipid pathways in the liver and skeletal muscle.
Subject(s)
Liver/metabolism , Metabolome/genetics , Obesity/therapy , Resistance Training/methods , Alanine Transaminase/metabolism , Animals , Animals, Newborn , Aspartate Aminotransferases/metabolism , Blood Glucose , Cholesterol/metabolism , Female , Glucose/metabolism , Humans , Insulin/metabolism , Liver/pathology , Male , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Obesity/chemically induced , Obesity/physiopathology , Physical Conditioning, Animal , Rats , Sex Characteristics , Sodium Glutamate , Triglycerides/metabolismABSTRACT
The ethanolic extract obtained from purple pitanga fruit (Eugenia uniflora - PPE) has been previously described by its potential to reduce lipid accumulation in vitro. In this study, we aimed to study this potential in vivo using Caenorhabditis elegans as animal model. Considering the low pH of the extract, its hydrophilic characteristic, its absorption by the medium where the worms are cultivated and the need of a chronic exposure in the worms solid medium, we have loaded liposomes with PPE and investigated its potential for oral administration. Following 48 h exposure to the PPE-loaded liposomes on worms nematode growth medium, we did not observe any toxic effects of the formulation. Under high cholesterol diet, which increased worms total lipid and also triacylglycerides levels, liposomes containing PPE were able to significantly attenuate these alterations, which could not be observed when worms were treated with free PPE. Furthermore, we could evidence that liposomes were ingested by worms through their labelling to uranin fluorescence dye. Through total phenolic compounds quantification, we estimated an entrapment efficacy of PPE into liposomes of 87.7%. The high levels of phenolic compounds present in PPE, as previously described by our group, indicate that these antioxidants may interfere in worms lipid metabolism, which may occur through many and intricated mechanisms. Although the use of conventional liposomes for human consumption may not be pragmatic, its application for oral delivery of a hydrophilic substance in C. elegans was absolutely critical for our experimental design and has proven to be efficient.
Subject(s)
Caenorhabditis elegans/drug effects , Ethanol/chemistry , Eugenia/chemistry , Hypolipidemic Agents/chemistry , Lecithins/chemistry , Liposomes/chemistry , Phenols/chemistry , Plant Extracts/chemistry , Animals , Antioxidants/administration & dosage , Antioxidants/chemistry , Antioxidants/toxicity , Fruit/chemistry , Hydrophobic and Hydrophilic Interactions , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/toxicity , Particle Size , Phenols/administration & dosage , Phenols/toxicity , Plant Extracts/administration & dosage , Plant Extracts/toxicity , Solvents , Triglycerides/metabolismABSTRACT
Although cisplatin (CIS) has been associated with serious adverse effects, such as hepatotoxicity and nephrotoxicity in adult rats, there is few reports on its use in newborn rats. The aim of this study was to evaluate acute toxic effects of CIS in newborn rats. Adult and newborn Wistar rats received CIS by the i. p. route, at the dose of 5 or 10â¯mg/kg. After 24â¯h of treatment, blood, kidney, and liver were excised from the animals and parameters of renal and hepatic functions, oxidative stress markers were determined. Acute administration of CIS caused an increase of AST activity and urea levels, suggesting hepatorenal toxicity in newborn and adult rats. However, the pattern and intensity of damage was different between ages and tissues. Newborn rats showed more pronouncedly oxidative stress damage, characterized by an increase in reactive species and protein carbonyl levels, lower NPSH content and highest inhibition in δ-ALA-D and CAT activities. Besides that, it was observed a faster molecular response in protein levels involved with apoptosis and oxidative stress response; whereas in the beginning the damage was less severe in the kidney than in the liver of adult rats. Thus, the present study shows that there are body response differences between adult and newborn rats to CIS acute exposure being that newborn rats are more susceptible than adults.
Subject(s)
Antineoplastic Agents/toxicity , Cisplatin/toxicity , Kidney/drug effects , Liver/drug effects , Alanine Transaminase/metabolism , Animals , Animals, Newborn , Aspartate Aminotransferases/metabolism , Catalase/metabolism , Female , Kelch-Like ECH-Associated Protein 1/metabolism , Kidney/metabolism , Liver/metabolism , Male , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Porphobilinogen Synthase/metabolism , Rats , Rats, Wistar , Sodium-Potassium-Exchanging ATPase/metabolism , Sulfhydryl Compounds/metabolism , Superoxide Dismutase/metabolismABSTRACT
Obesity is a chronic and complex medical condition characterized by excessive fat accumulation and its complications include metabolic syndrome, diabetes and chronic inflammation. The aim of this study was to expand the knowledge about p-chloro-diphenyl diselenide (p-ClPhSe)2 effects on enzymes and proteins involved in the metabolism of lipids and carbohydrates in a model of neuroendocrine obesity induced by MSG. Male Wistar rats were treated during the first ten postnatal days with MSG (4â¯g/kg, s.c.) and received (p-ClPhSe)2 (10â¯mg/kg, i.g.) from 90th to 97th postnatal day. The hypothalamic function, insulin resistance and other biochemical parameters were determined in the rat blood, liver and skeletal muscle. The MSG administration induced hypothalamic neurotoxicity accompanied by metabolic disorders, including obesity, a transient insulin resistance, and metabolic alterations, demonstrated in the blood, liver and skeletal muscle, and lipotoxicity, characterized in the liver and skeletal muscle. The metabolic disorders in the liver and skeletal muscle were accompanied by the decrease in AMPK phosphorylation and activation of Akt. (p-ClPhSe)2 restored most of metabolic parameters altered by MSG administration in rats. The hypothalamic neurotoxicity induced by MSG was accompanied by metabolic disorders in rats, which were regulated by (p-ClPhSe)2.
Subject(s)
Metabolic Diseases/drug therapy , Metabolic Diseases/metabolism , Obesity/drug therapy , Obesity/metabolism , Organoselenium Compounds/therapeutic use , Sodium Glutamate/administration & dosage , Alanine Transaminase/blood , Animals , Animals, Newborn , Aspartate Aminotransferases/blood , Cholesterol/blood , Creatinine/blood , Disease Models, Animal , Feeding Behavior/drug effects , Glucose Tolerance Test , Glucose-6-Phosphatase/metabolism , Glycated Hemoglobin/metabolism , Homeostasis , Hypothalamus/drug effects , Liver/drug effects , Liver/enzymology , Liver Glycogen/metabolism , Male , Metabolic Diseases/chemically induced , Muscle, Skeletal/metabolism , Obesity/chemically induced , Organoselenium Compounds/pharmacology , Rats, Wistar , Triglycerides/blood , Triglycerides/metabolismABSTRACT
Bisphenol A (BPA) is a chemical toxicant that has deleterious effects on human. BPA causes oxidative stress in tissues, including the liver. Diphenyl diselenide (PhSe)2 improves the antioxidant response via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein (keap 1) pathway in macrophage cells. In the present study, we investigated whether (PhSe)2 counteracts hepatic oxidative stress induced by BPA in male and female Swiss mice. Three-week-old mice received by the intragastric (i.g.) route BPA (5â¯mg/kg) from 21st to 60th postnatal day (PND). At PND 61, the mice were treated with (PhSe)2 (1â¯mg/kg, i.g.) for seven days. Parameters of hepatic damage and oxidative stress were determined in male and female mice. The results show that BPA increased the activity of aspartate aminotransferase in female mice, and in male mice the activity of alanine aminotranseferase was increased. Male and female mice had an increase in fat mass accumulation. Male mice showed an increase in hepatic oxidative damage of proteins and a decrease in non-enzymatic (ascorbic acid and non-protein thiol) and enzymatic (superoxide dismutase) defenses, which are consistent with oxidative stress status. Male mice were more susceptible than female mice to hepatic oxidative stress induced by BPA. BPA decreased Nrf2/Keap1 protein content in male mice. (PhSe)2 reduced hepatic oxidative stress induced by BPA in male mice. Our results demonstrate that male mice were more susceptible to hepatic oxidative stress induced by BPA than female mice. (PhSe)2 regulated Nrf2/Keap-1 signaling pathway and countered hepatic oxidative stress induced by BPA in male mice.
Subject(s)
Benzene Derivatives , Benzhydryl Compounds , Kelch-Like ECH-Associated Protein 1 , NF-E2-Related Factor 2 , Organoselenium Compounds , Oxidative Stress , Phenols , Signal Transduction , Animals , Benzene Derivatives/pharmacology , Benzhydryl Compounds/toxicity , Female , Kelch-Like ECH-Associated Protein 1/drug effects , Kelch-Like ECH-Associated Protein 1/metabolism , Liver/drug effects , Liver/metabolism , Male , Mice , NF-E2-Related Factor 2/drug effects , NF-E2-Related Factor 2/metabolism , Organoselenium Compounds/pharmacology , Phenols/toxicity , Signal Transduction/drug effectsABSTRACT
The modern life leads to excess consumption of food rich in fructose; however, the long-term changes in carbohydrate and lipid metabolism could lead to metabolic dysfunction in humans. The present study evaluated the in vitro insulin-mimetic action of p-chloro-diphenyl diselenide (p-ClPhSe)2. The second aim of this study was to investigate if (p-ClPhSe)2 reverses metabolic dysfunction induced by fructose load in Wistar rats. The insulin-mimetic action of (p-ClPhSe)2 at concentrations of 50 and 100 µM was determined in slices of rat skeletal muscle. (p-ClPhSe)2 at a concentration of 50 µM stimulated the glucose uptake by 40% in skeletal muscle. A dose-response curve revealed that (p-ClPhSe)2 at a dose of 25 mg/kg reduced (â¼20%) glycemia in rats treated with fructose (5 g/kg, i.g.). The administration of fructose impaired the liver homeostasis and (p-ClPhSe)2 (25 mg/kg) protected against the increase (â¼25%) in the G-6-Pase and isocitrate dehydrogenase activities and reduced the triglyceride content (â¼25%) in the liver. (p-ClPhSe)2 regulated the liver homeostasis by stimulating hexokinase activity (â¼27%), regulating the TCA cycle activity (increased the ATP and citrate synthase activity (â¼15%)) and increasing the glycogen levels (â¼67%). In conclusion, (p-ClPhSe)2 stimulated carbohydrate metabolism and reversed metabolic dysfunction in rats fed with fructose.
Subject(s)
Carbohydrate Metabolism/drug effects , Fructose/adverse effects , Metabolic Diseases/drug therapy , Organoselenium Compounds/administration & dosage , Animals , Fructose/metabolism , Hexokinase/metabolism , Homeostasis/drug effects , Humans , Isocitrate Dehydrogenase/metabolism , Liver/drug effects , Liver/enzymology , Liver/metabolism , Male , Metabolic Diseases/enzymology , Metabolic Diseases/etiology , Metabolic Diseases/metabolism , Rats , Rats, Wistar , Triglycerides/metabolismABSTRACT
NEW FINDINGS: What is the central question of this study? Monosodium glutamate causes cognitive impairment. Does resistance exercise improve the performance of rats treated with monosodium glutamate? What is the main finding and its importance? Resistance exercise is effective against monosodium glutamate-induced memory impairment in male and female rats. Monosodium glutamate (MSG), a flavour enhancer in diets, causes cognitive impairment in rodents. Exercise has been reported to protect against impairment of memory in humans. In this study, we investigated whether resistance exercise improves the performance of male and female rats treated with MSG in tests of memory and motor co-ordination. Wistar rats received MSG [4 g (kg body weight)-1 day-1 , s.c.] from postnatal day 1 to 10. At postnatal day 60, the animals started a resistance exercise protocol in an 80 deg inclined vertical ladder apparatus and performed it during 7 weeks. Rats performed object recognition and location memory tests. Resistance exercise reduced impairment in motor co-ordination of male and female rats treated with MSG. Resistance exercise was effective against the decrease in exploratory preference in the long-term recognition memory for novel objects of male rats treated with MSG. In MSG-treated female rats, resistance exercise was effective against the decrease in exploratory preference in the novel object location test. The exploratory preference of female rats in the long-term recognition memory test was similar in all groups. The short-term memory was not altered by MSG or resistance exercise in male and female rats. This study demonstrates that MSG affected the memory of male and female rats in different ways. Resistance exercise was effective against the decrease in recognition for male rats and in location memory for female rats treated with MSG. This report demonstrates the beneficial effects of resistance exercise against the prejudice of motor condition and impairment of memory induced by MSG in male and female rats.