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1.
Toxicol Res (Camb) ; 10(4): 911-927, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34484683

RESUMO

Cholestasis is a severe clinical complication that severely damages the liver. Kidneys are also the most affected extrahepatic organs in cholestasis. The pivotal role of oxidative stress has been mentioned in the pathogenesis of cholestasis-induced organ injury. The activation of the nuclear factor-E2-related factor 2 (Nrf2) pathway is involved in response to oxidative stress. The current study was designed to evaluate the potential role of Nrf2 signaling activation in preventing bile acids-induced toxicity in the liver and kidney. Dimethyl fumarate was used as a robust activator of Nrf2 signaling. Rats underwent bile duct ligation surgery and were treated with dimethyl fumarate (10 and 40 mg/kg). Severe oxidative stress was evident in the liver and kidney of cholestatic animals (P < 0.05). On the other hand, the expression and activity of Nrf2 and downstream genes were time-dependently decreased (P < 0.05). Moreover, significant mitochondrial depolarization, decreased ATP levels, and mitochondrial permeabilization were detected in bile duct-ligated rats (P < 0.05). Histopathological alterations included liver necrosis, fibrosis, inflammation and kidney interstitial inflammation, and cast formation. It was found that dimethyl fumarate significantly decreased hepatic and renal injury in cholestatic animals (P < 0.05). Based on these data, the activation of the cellular antioxidant response could serve as an efficient therapeutic option for managing cholestasis-induced organ injury.

2.
J Biochem Mol Toxicol ; : e22897, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448514

RESUMO

Phosphine (PH3 ) is widely used as an insecticide and rodenticide. On the contrary, many cases of PH3 poisoning have been reported worldwide. Unfortunately, there is no specific antidote against PH3 toxicity. Disruption of mitochondrial function and energy metabolism is a well-known mechanism of PH3 cytotoxicity. Dihydroxyacetone (DHA) is an adenosine triphosphate supplying agent which significantly improves mitochondrial function. The current study was designed to evaluate DHA's effect on inhalational PH3 poisoning in an animal model. DHA was injected into BALB/c mice before and/or after the start of the PH3 inhalation. The cytochrome c oxidase activity was assessed in the animals' brain, heart, and liver exposed to PH3 (for 15, 30, and 60 min, with and without the antidote). The LC50 of PH3 was calculated to be 18.02 (15.42-20.55) ppm over 2 h of exposure. Pretreatment of DHA (1 or 2 g/kg) increased the LC50 of PH3 by about 1.6- or 3-fold, respectively. Posttreatment with DHA (2 g/kg) increased the LC50 of PH3 by about 1.4-fold. PH3 inhibited the activity of cytochrome c oxidase in the assessed organs. It was found that DHA treatment restored mitochondrial cytochrome c oxidase activity. These findings suggested that DHA could be an effective antidote for PH3 poisoning.

3.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
5.
Front Vet Sci ; 8: 603262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33842567

RESUMO

Lithium (Li+) is prescribed against a wide range of neurological disorders. Besides its excellent therapeutic properties, there are several adverse effects associated with Li+. The impact of Li+ on renal function and diabetes insipidus is the most common adverse effect of this drug. On the other hand, infertility and decreased libido is another complication associated with Li+. It has been found that sperm indices of functionality, as well as libido, is significantly reduced in Li+-treated men. These adverse effects might lead to drug incompliance and the cessation of drug therapy. Hence, the main aims of the current study were to illustrate the mechanisms of adverse effects of Li+ on the testis tissue, spermatogenesis process, and hormonal changes in two experimental models. In the in vitro experiments, Leydig cells (LCs) were isolated from healthy mice, cultured, and exposed to increasing concentrations of Li+ (0, 10, 50, and 100 ppm). In the in vivo section of the current study, mice were treated with Li+ (0, 10, 50, and 100 ppm, in drinking water) for five consecutive weeks. Testis and sperm samples were collected and assessed. A significant sign of cytotoxicity (LDH release and MTT assay), along with disrupted testosterone biosynthesis, impaired mitochondrial indices (ATP level and mitochondrial depolarization), and increased biomarkers of oxidative stress were detected in LCs exposed to Li+. On the other hand, a significant increase in serum and testis Li+ levels were detected in drug-treated mice. Moreover, ROS formation, LPO, protein carbonylation, and increased oxidized glutathione (GSSG) were detected in both testis tissue and sperm specimens of Li+-treated mice. Several sperm anomalies were also detected in Li+-treated animals. On the other hand, sperm mitochondrial indices (mitochondrial dehydrogenases activity and ATP levels) were significantly decreased in drug-treated groups where mitochondrial depolarization was increased dose-dependently. Altogether, these data mention oxidative stress and mitochondrial impairment as pivotal mechanisms involved in Li+-induced reproductive toxicity. Therefore, based on our previous publications in this area, therapeutic options, including compounds with high antioxidant properties that target these points might find a clinical value in ameliorating Li+-induced adverse effects on the male reproductive system.

6.
Naunyn Schmiedebergs Arch Pharmacol ; 394(6): 1301-1314, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33538845

RESUMO

Bile duct obstruction or cholestasis can occur by several diseases or xenobiotics. Cholestasis and the accumulation of the bile constituents in the liver primarily damage this organ. On the other hand, extrahepatic organs are also affected by cholestasis. The kidney is the most affected tissue during cholestatic liver injury. Cholestasis-associated renal injury is known as cholemic nephropathy (CN). Several lines of evidence specify the involvement of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to assess the role of silymarin as a potent antioxidant on CN-induced oxidative stress and mitochondrial dysfunction in the kidney. Bile duct ligated (BDL) rats were treated with silymarin (10 and 100 mg/kg, oral) for seven consecutive days. A significant increase in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and oxidized glutathione (GSSG) levels were evident in the kidney of BDL animals. Moreover, reduced glutathione (GSH) content and total antioxidant capacity were significantly decreased in the kidney of cholestatic rats. Mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depleted ATP stores were detected in the kidney mitochondria isolated from BDL animals. Kidney histopathological alterations, as well as serum and urine levels of renal injury biomarkers, were also significantly different in the BDL group. It was found that silymarin treatment significantly ameliorated CN-induced renal injury. The antioxidant effects of silymarin and its positive impact on mitochondrial indices seem to play a significant role in its renoprotective effects during cholestasis.

7.
Biol Trace Elem Res ; 199(5): 1908-1918, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32712907

RESUMO

Lithium is abundantly administered against bipolar disorder. On the other hand, the lithium-induced renal injury is a clinical complication which commonly reveals as drug-induced diabetes insipidus. However, lithium-induced cytotoxicity might also play a role in the adverse effects of this drug on the kidney. There is no clear cellular and molecular mechanism(s) for lithium-induced nephrotoxicity. The current study was designed to assess the effect of lithium on kidney tissue oxidative stress biomarkers and mitochondrial function and its relevance to drug-induced nephrotoxicity and electrolyte imbalance. Rats were treated with lithium (lithium carbonate, 25 and 50 mg/kg/day, i.p., for 28 consecutive days). Kidney mitochondria were also isolated from rats and exposed to increasing concentrations of lithium (0.01-10 mM). Serum and urine biomarkers of kidney injury, kidney tissue markers of oxidative stress, and renal histopathological changes were assessed. Moreover, several mitochondrial indices were monitored. Lithium-induced renal injury revealed a significant increase in urine and serum biomarkers of renal impairment. Lithium caused an increase in the kidney reactive oxygen species (ROS) level and lipid peroxidation (LPO). Renal glutathione (GSH) reservoirs were also depleted, and tissue antioxidant capacity decreased in lithium-treated animals. Significant tissue histopathological changes, including necrosis, Bowman capsule dilation, and interstitial inflammation, were evident in lithium-treated animals. On the other hand, significant alterations in kidney mitochondrial function were detected in lithium-treated groups. These data mention oxidative stress, mitochondrial dysfunction, and cellular energy crisis as the potential primary mechanisms for lithium-induced renal injury.


Assuntos
Lítio , Mitocôndrias , Animais , Antioxidantes/metabolismo , Rim/metabolismo , Peroxidação de Lipídeos , Lítio/toxicidade , Mitocôndrias/metabolismo , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismo
8.
Clin Exp Hepatol ; 6(3): 207-219, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33145427

RESUMO

Cirrhosis-induced heart injury and cardiomyopathy is a serious consequence of this disease. It has been shown that bile duct ligated (BDL) animals could serve as an appropriate experimental model to investigate heart tissue injury in cirrhosis. The accumulation of cytotoxic chemicals (e.g., bile acids) could also adversely affect the heart tissue. Oxidative stress and mitochondrial impairment are the most prominent mechanisms of bile acid cytotoxicity. Taurine (Tau) is the most abundant non-protein amino acid in the human body. The cardioprotective effects of this amino acid have repeatedly been investigated. In the current study, it was examined whether mitochondrial dysfunction and oxidative stress are involved in the pathogenesis of cirrhosis-induced heart injury. Rats underwent BDL surgery. BDL animals received Tau (50, 100, and 500 mg/kg, i.p.) for 42 consecutive days. A significant increase in oxidative stress biomarkers was detected in the heart tissue of BDL animals. Moreover, it was found that heart tissue mitochondrial indices of functionality were deteriorated in the BDL group. Tau treatment significantly decreased oxidative stress and improved mitochondrial function in the heart tissue of cirrhotic animals. These data provide clues for the involvement of mitochondrial impairment and oxidative stress in the pathogenesis of heart injury in BDL rats. On the other hand, Tau supplementation could serve as an effective ancillary treatment against BDL-associated heart injury. Mitochondrial regulating and antioxidative properties of Tau might play a fundamental role in its mechanism of protective effects in the heart tissue of BDL animals.

9.
Clin Exp Hepatol ; 6(2): 106-115, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32728627

RESUMO

Aim of the study: Acute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4 +) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4 + is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4 +-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE. Material and methods: Acetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4 + were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed. Results: A significant increase in plasma and brain NH4 + was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals. Conclusions: These data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.

10.
Toxicol Lett ; 330: 144-158, 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32422328

RESUMO

Cholestatic liver disease is a clinical complication with a wide range of etiologies. The liver is the primary organ influenced by cholestasis. Other organs, rather than the liver (e.g., kidneys), could also be affected by cholestatic liver disease. Cholestasis-induced renal injury is known as cholemic nephropathy (CN). Although the structural and functional alterations of the kidney in cholestasis have been well described, the cellular and molecular mechanisms of CN are not well understood. Some studies mentioned the role of oxidative stress and mitochondrial impairment in CN. Several cellular targets, including proteins, lipids, and DNA, could be affected by oxidative stress. Poly (ADP-Ribose) polymerase-1 (PARP-1) is an enzyme that its physiological activity plays a fundamental role in DNA repair. However, PARP-1 overexpression is associated with enhanced oxidative stress and cell death. The current study was designed to evaluate the role of PARP-1 activity in the pathogenesis of CN. Bile duct ligated (BDL) rats were treated with nicotinamide (NA) as a PARP-1 inhibitor. Kidney, urine, and plasma samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Serum and urine biomarkers of kidney injury, markers of oxidative stress and DNA damage, PARP-1 expression and activity in the kidney tissue, inflammatory response, renal fibrosis markers, and kidney histopathological alterations were assessed. Significant changes in the serum and urine biomarkers of kidney injury were evident in the BDL rats. Markers of oxidative stress were increased, and tissue ATP levels and antioxidant capacity were decreased in the kidney of cholestatic animals. A significant increase in PARP-1 expression and activity was evident in BDL rats (3, 7, 14, and 28 days after BDL). Moreover, inflammatory response (IL-1ß and TNF-α expression; and myeloperoxidase activity), renal tissue histopathological alterations, and kidney fibrosis (α-SMA and TGF-ß expression, as well as collagen deposition) were detected in cholestatic animals. It was found that the PARP-1 inhibitor, NA (50 and 100 mg/kg, i.p), significantly mitigated cholestasis-induced renal injury. The positive effects of NA were more significant at a lower dose and the early stage of CN. These data indicate a pathogenic role for PARP-1 overexpression in CN.

11.
Complement Ther Med ; 49: 102324, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32147070

RESUMO

OBJECTIVES: The roots and rhizomes of licorice (Glycyrrhiza glabra L.) are used in traditional Persian medicine for the treatment of numerous diseases. A chronic cough is a non-specific reaction to irritation anywhere in the respiratory system. It usually lasts for more than eight weeks. The current study aimed to evaluate the effect of a modified traditional Persian medicine preparation, licorice pastille, in healing a chronic cough. METHODS: Through a randomized, double-blinded, placebo-controlled clinical trial was performed in a respiratory disease clinic in Shiraz, Iran; between October 2016 and December 2017. Seventy participants with a chronic cough took part in the trial. The outcome measures were as the daily cough scores (the score being logged via patient symptoms, diary, and the visual analogue scale) and the quality of life measure of chronic cough according to the Leicester Cough Questionnaire. RESULTS: At baseline, there were no significant differences in the demographic or clinical (cough score) characteristics between the two groups. There was complete adherence to protocol in both groups but, the drop-out rate was 4 patients in the placebo and 6 ones in the intervention groups. The results at the end of the trial (Week 2) and follow-up (Week 4) demonstrated the efficacy of the licorice pastille in terms of the cough severity score against the placebo group. This item showed a significant decrease in the intervention group (1.2 ±â€¯0.93) comparing to the placebo one (1.8 ±â€¯1.03) at follow-up time. No major side effects were reported during the study and follow-up time. CONCLUSIONS: Licorice pastille could be a promising choice in the treatment of a chronic cough of unknown origin.


Assuntos
Tosse/tratamento farmacológico , Glycyrrhiza , Extratos Vegetais/uso terapêutico , Adolescente , Adulto , Idoso , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Irã (Geográfico) , Masculino , Medicina Tradicional , Pessoa de Meia-Idade , Qualidade de Vida , Rizoma , Inquéritos e Questionários , Adulto Jovem
12.
Nutr Neurosci ; 23(9): 731-743, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30856059

RESUMO

Objective(s): Manganese (Mn) is an essential trace element physiologically incorporated in the structure of several vital enzymes. Despite its essentiality, excessive Mn exposure is toxic with brain tissue as the primary target organ. There is no specific and clinically available therapeutic/preventive option against Mn neurotoxicity. Carnosine is a neuropeptide with several physiological roles. The neuroprotective properties of this peptide have been evaluated in different experimental models. The current study was designed to investigate the effect of carnosine supplementation and its potential mechanisms of action in an animal model of Mn-induced neurotoxicity. Materials and Methods: Male C57BL/6 mice received Mn (100 mg/kg, s.c) alone and/or in combination with carnosine (10, 50, and 100 mg/kg, i.p). Several locomotor activity indices were monitored. Moreover, biomarkers of oxidative stress and mitochondrial function were assessed in the brain tissue of Mn-exposed animals. Results: Significant locomotor dysfunction was revealed in Mn-exposed animals. Furthermore, brain tissue biomarkers of oxidative stress were significantly increased, and mitochondrial indices of functionality were impaired in Mn-treated animals. It was found that carnosine supplementation (10, 50, and 100 mg/kg, i.p) alleviated the Mn-induced locomotor deficit. Moreover, this peptide mitigated oxidative stress biomarkers and preserved brain tissue mitochondrial functionality in the animal model of manganism. Conclusion: These data indicate that carnosine is a potential neuroprotective agent against Mn neurotoxicity. Antioxidative and mitochondria protecting effects of carnosine might play a fundamental role in its neuroprotective properties against Mn toxicity.


Assuntos
Antioxidantes/administração & dosagem , Carnosina/administração & dosagem , Manganês/toxicidade , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
13.
Toxicol Lett ; 316: 60-72, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520699

RESUMO

Cholestasis is a significant decrease in bile flow. The liver is the primary organ affected by cholestasis. Chronic cholestasis could entail to tissue fibrotic changes and liver cirrhosis. Other organs, including heart, kidneys, nervous system, skeletal muscles, as well as the reproductive system, might also be affected during cholestasis. Although the cholestasis-associated pathological and biochemical alterations in organs such as liver have been widely investigated, there is little information about complications such as cholestasis-induced reproductive toxicity. The current study aimed to evaluate the pathologic effects of cholestasis on reproductive organs in both male and female animals. Rats underwent bile duct ligation (BDL) surgery. Markers of reproductive toxicity, including serum hormonal changes, tissue histopathological alterations, biomarkers of oxidative stress, and markers of mitochondrial impairment, were evaluated. Increased serum markers of liver injury and elevated level of cytotoxic molecules such as bile acids and bilirubin were evident in BDL animals. On the other hand, the serum level of hormones such as testosterone was suppressed in BDL rats. Significant histopathological alterations were also evident in the testis and ovary of BDL animals. A significant increase in oxidative stress markers, including ROS formation, lipid peroxidation, protein carbonylation, and depleted glutathione and antioxidant reservoirs were also detected in BDL rats. Moreover, mitochondrial depolarization decreased dehydrogenases activity, and depleted ATP content was detected in sperm isolated from the BDL group. These data indicate that cholestasis-associated reproductive toxicity in male and female rats is restrictedly coupled with severe oxidative stress and mitochondrial impairment.


Assuntos
Colestase/metabolismo , Mitocôndrias/metabolismo , Ovário/metabolismo , Estresse Oxidativo , Reprodução , Espermatozoides/metabolismo , Testículo/metabolismo , Animais , Colestase/etiologia , Colestase/fisiopatologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Feminino , Ligadura , Peroxidação de Lipídeos , Masculino , Mitocôndrias/patologia , Ovário/patologia , Ovário/fisiopatologia , Carbonilação Proteica , Ratos Sprague-Dawley , Medição de Risco , Testículo/patologia , Testículo/fisiopatologia
14.
Clin Exp Hepatol ; 5(2): 109-117, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31501786

RESUMO

Aim of the study: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome ensuing from liver failure. The liver is the major site of ammonia detoxification in the human body. Hence, acute and chronic liver dysfunction can lead to hyperammonemia. Manganese (Mn) is a trace element incorporated in several physiological processes in the human body. Mn is excreted through bile. It has been found that cirrhosis is associated with hyperammonemia as well as body Mn accumulation. The brain is the primary target organ for both ammonia and Mn toxicity. On the other hand, brain mitochondria impairment is involved in the mechanism of Mn and ammonia neurotoxicity. Material and methods: The current study was designed to evaluate the effect of Mn and ammonia and their combination on mitochondrial indices of functionality in isolated brain mitochondria. Isolated brain mitochondria were exposed to increasing concentrations of ammonia and Mn alone and/or in combination and several mitochondrial indices were assessed. Results: The collapse of mitochondrial membrane potential, increased mitochondrial permeabilization, reactive oxygen species formation, and a significant decrease in mitochondrial dehydrogenase activity and ATP content were evident in Mn-exposed (0.005-1 mM) brain mitochondria. On the other hand, ammonia (0.005-0.5 mM) caused no significant changes in brain mitochondrial function. It was found that co-exposure of the brain mitochondria to Mn and ammonia causes more evident mitochondrial impairment in comparison with Mn and/or ammonia alone. Conclusions: These data indicate additive toxicity of ammonia and Mn in isolated brain mitochondria exposed to these neurotoxins.

15.
Adv Pharm Bull ; 9(2): 294-301, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31380256

RESUMO

Purpose: Manganese (Mn) is a neurotoxic chemical which induces a wide range of complications in the brain tissue. Impaired locomotor activity and cognitive dysfunction are associated with high brain Mn content. At the cellular level, mitochondria are potential targets for Mn toxicity. Carnosine is a dipeptide abundantly found in human brain. Several pharmacological properties including mitochondrial protecting and antioxidative effects have been attributed to carnosine. The current study aimed to evaluate the effect of carnosine treatment on Mn-induced mitochondrial dysfunction in isolated brain mitochondria. Methods: Mice brain mitochondria were isolated based on the differential centrifugation method and exposed to increasing concentrations of Mn (10 µM-10 mM). Carnosine (1 mM) was added as the protective agent. Mitochondrial indices including mitochondrial depolarization, reactive oxygen species (ROS) formation, mitochondrial dehydrogenases activity, ATP content, and mitochondrial swelling and permeabilization were assessed. Results: Significant deterioration in mitochondrial indices were evident in Mn-exposed brain mitochondria. On the other hand, it was found that carnosine (1 mM) treatment efficiently prevented Mn-induced mitochondrial impairment. Conclusion: These data propose mitochondrial protection as a fundamental mechanism for the effects of carnosine against Mn toxicity. Hence, this peptide might be applicable against Mn neurotoxicity with different etiologies (e.g., in cirrhotic patients).

16.
Heliyon ; 5(6): e01996, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31294126

RESUMO

Imatinib is a tyrosine kinase inhibitor widely administered against chronic myeloid leukemia. On the other hand, drug-induced kidney proximal tubular injury, electrolytes disturbances, and renal failure is a clinical complication associated with imatinib therapy. There is no precise cellular mechanism(s) for imatinib-induced renal injury. The current investigation aimed to evaluate the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of imatinib nephrotoxicity. Rats received imatinib (50 and 100 mg/kg, oral, 14 consecutive days). Serum and urine biomarkers of renal injury and markers of oxidative stress in the kidney tissue were assessed. Moreover, kidney mitochondria were isolated, and mitochondrial indices, including mitochondrial depolarization, dehydrogenases activity, mitochondrial permeabilization, lipid peroxidation (LPO), mitochondrial glutathione levels, and ATP content were determined. A significant increase in serum (Creatinine; Cr and blood urea nitrogen; BUN) and urine (Glucose, protein, gamma-glutamyl transferase; γ-GT, and alkaline phosphatase; ALP) biomarkers of renal injury, as well as serum electrolytes disturbances (hypokalemia and hypophosphatemia), were evident in imatinib-treated animals. On the other hand, imatinib (100 mg/kg) caused an increase in kidney ROS and LPO. Renal tubular interstitial nephritis, tissue necrosis, and atrophy were evident as tissue histopathological changes in imatinib-treated rats. Mitochondrial parameters were also adversely affected by imatinib administration. These data represent mitochondrial impairment, renal tissue energy crisis, and oxidative stress as possible mechanisms involved in the pathogenesis of imatinib-induced renal injury and serum electrolytes disturbances.

17.
Methods Mol Biol ; 1981: 117-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016651

RESUMO

The blockage of bile flow, cholestasis, could lead to serious clinical outcomes, including severe liver injury. Accumulation of the cytotoxic molecules, such as bile acids, during cholestasis, not only impairs liver function, but also affects other organs, including the kidneys. Although the precise mechanisms of cytotoxicity and organ injury in cholestasis are far from clear, oxidative stress and its subsequent events seem to play a central role in this complication. Oxidative stress acts as a signaling path which could finally lead to cell death and organ injury. At the cellular level, mitochondria are major targets affected by cytotoxic molecules. Mitochondrial impairment could lead to severe outcomes, including cellular energy crisis and release of cell death mediators from this organelle. Therefore, targeting oxidative stress and mitochondrial dysfunction might serve as a therapeutic point of intervention against cholestasis-associated organ injury. In this protocol, an animal model of cholestasis is described, and the techniques for liver mitochondria isolation, evaluating mitochondrial indices of functionality, and assessing biomarkers of oxidative stress in the liver tissue are outlined.


Assuntos
Colestase/metabolismo , Mitocôndrias/metabolismo , Animais , Apoptose , Ácidos e Sais Biliares/metabolismo , Colestase/patologia , Humanos , Mitocôndrias/patologia , Estresse Oxidativo/fisiologia
18.
Biomed Pharmacother ; 109: 271-280, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30396085

RESUMO

Cholemic nephropathy (CN) is a clinical complication associated with cholestasis and chronic liver diseases. CN could lead to renal failure and the need for kidney transplantation if not appropriately managed. On the other hand, although the clinical features of CN are well described, there is no clear idea on the precise cellular and molecular mechanisms of CN. The current study was designed to evaluate kidney mitochondrial function in cholestasis-associated CN. Rats underwent bile duct ligation (BDL) surgery, and kidney mitochondria were isolated at scheduled time intervals (14, 28, and 42 days after BDL operation). Several mitochondrial indices including mitochondrial permeabilization and swelling, glutathione and ATP content, mitochondrial depolarization, and lipid peroxidation were evaluated. Renal tissue markers of oxidative stress along with tissue histopathological changes and serum biochemistry were also analyzed. Severe kidney tissue histopathological alterations including interstitial inflammation, necrosis, and Bowman capsule dilation were detected in the BDL animals. Moreover, drastic elevation in renal fibrosis and collagen deposition was detected in BDL rats. Oxidative stress markers were also significantly enhanced in the kidney tissue of BDL animals. On the other hand, it was found that mitochondrial indices of functionality were significantly deteriorated in BDL rats. These data introduce mitochondrial dysfunction and energy metabolism disturbances as a fundamental mechanism involved in the pathogenesis of bile acids-associated renal injury during cholestasis.


Assuntos
Injúria Renal Aguda/metabolismo , Colestase/metabolismo , Cirrose Hepática/metabolismo , Mitocôndrias/metabolismo , Injúria Renal Aguda/patologia , Animais , Colestase/patologia , Peroxidação de Lipídeos/fisiologia , Cirrose Hepática/patologia , Masculino , Mitocôndrias/patologia , Ratos , Ratos Sprague-Dawley
19.
Biol Trace Elem Res ; 190(2): 384-395, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30357569

RESUMO

Manganese (Mn) is a trace element involved in many physiological processes. However, excessive Mn exposure leads to neurological complications. Although no precise mechanism(s) has been found for Mn-induced neurotoxicity, oxidative stress and mitochondrial injury seem to play a relevant role in this complication. On the other hand, there is no protective strategy against Mn neurotoxicity so far. Taurine is an amino acid with significant neuroprotective properties. The current study was designed to evaluate the effect of taurine supplementation and its potential mechanism(s) of action in a mouse model of manganism. Animals were treated with Mn (100 mg/kg, s.c) alone and/or in combination with taurine (50, 100, and 500 mg/kg, i.p, for eight consecutive days). Severe locomotor dysfunction along with a significant elevation in brain tissue biomarkers of oxidative stress was evident in Mn-exposed mice. On the other hand, it was revealed that mitochondrial indices of functionality were hampered in Mn-treated animals. Taurine supplementation (50, 100, and 500 mg/kg, i.p) alleviated Mn-induced locomotor deficit. Moreover, this amino acid mitigated oxidative stress biomarkers and preserved brain tissue mitochondrial indices of functionality. These data introduce taurine as a potential neuroprotective agent against Mn neurotoxicity. Antioxidative and mitochondria protecting effects of taurine might play a fundamental role in its neuroprotective properties against Mn toxicity.


Assuntos
Modelos Animais de Doenças , Manganês/toxicidade , Fármacos Neuroprotetores/farmacologia , Taurina/farmacologia , Animais , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Locomoção/efeitos dos fármacos , Masculino , Manganês/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Taurina/administração & dosagem
20.
Drug Chem Toxicol ; 42(6): 615-623, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29722569

RESUMO

Drug-induced liver injury is a major concern in clinical studies as well as in post-marketing surveillance. Previous evidence suggested that drug exposure during periods of inflammation could increase an individual's susceptibility to drug hepatoxicity. The antithyroid drugs, methimazole (MMI) and propylthiouracil (PTU) can cause adverse reactions in patients, with liver as a usual target. We tested the hypothesis that MMI and PTU could be rendered hepatotoxic in animals undergoing a modest inflammation. Mice were treated with a nonhepatotoxic dose of LPS (100 µg/kg, i.p) or its vehicle. Nonhepatotoxic doses of MMI (10, 25 and 50 mg/kg, oral) and PTU (10, 25 and 50 mg/kg, oral) were administered two hours after LPS treatment. It was found that liver injury was evident only in animals received both drug and LPS, as estimated by increases in serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and TNF-α. An increase in liver myeloperoxidase (MPO) enzyme activity and tissue lipid peroxidation (LPO) in addition of liver glutathione (GSH) depletion were also detected in LPS and antithyroid drugs cotreated animals. Furthermore, histopathological changes including, endotheliitis, fatty changes, severe inflammatory cells infiltration (hepatitis) and sinusoidal congestion were detected in liver tissue. Methyl palmitate (2 g/kg, i.v, 44 hours before LPS), as a macrophage suppressor, significantly alleviated antithyroids hepatotoxicity in LPS-treated animals. The results indicate a synergistic liver injury from antithyroid drugs and bacterial lipopolysaccharide coexposure.


Assuntos
Antitireóideos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Inflamação/complicações , Metimazol/toxicidade , Propiltiouracila/toxicidade , Animais , Antitireóideos/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/patologia , Relação Dose-Resposta a Droga , Lipopolissacarídeos/toxicidade , Masculino , Metimazol/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Propiltiouracila/administração & dosagem
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