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Taurine (TAU) is a sulfur-containing amino acid abundantly found in the human body. Endogenously, TAU is synthesized from cysteine in the liver. However, newborns rely entirely on TAU's dietary supply (milk). There is no investigation on the effect of long-term TAU administration on next-generation neurological development. The current study evaluated the effect of long-term TAU supplementation during the maternal gestational and litter weaning time on several neurological parameters in mice offspring. Moreover, the effects of TAU on mitochondrial function and oxidative stress biomarkers as plausible mechanisms of its action in the whole brain and hippocampus have been evaluated. TAU (0.5 % and 1 % w/v) was dissolved in the drinking water of pregnant mice (Day one of pregnancy), and amino acid supplementation was continued during the weaning time (post-natal day; PND = 21) until litters maturity (PND = 65). It was found that TAU significantly improved cognitive function, memory performance, reflexive motor activity, and emotional behaviors in F1-mice generation. TAU measurement in the brain and hippocampus revealed higher levels of this amino acid. TAU and ATP levels were also significantly higher in the mitochondria isolated from the whole brain and hippocampus. Based on these data, TAU could be suggested as a supplement during pregnancy or in pediatric formula. The effects of TAU on cellular mitochondrial function and energy metabolism might play a fundamental role in the positive effects of this amino acid observed in this investigation.
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Suplementos Nutricionais , Taurina , Recém-Nascido , Gravidez , Feminino , Criança , Camundongos , Animais , Humanos , Taurina/farmacologia , Puberdade , Encéfalo , Aminoácidos/farmacologiaRESUMO
Understanding the intricate molecular mechanisms governing aryl hydrocarbon receptor (AHR) and Wnt/ß-Catenin pathways crosstalk is of paramount importance for elucidating normal development. We investigated the repercussions of aberrant activation of these signaling pathways on kidney development. HEK-293 cells were subjected to AHR and Wnt activators and inhibitors for 3 and 24 h. Subsequently, pregnant adult female BALB/c mice were administered treatments at gestation day 9 (GD-9), and embryos were analyzed at GD-18 using a combination of cellular, molecular, stereological, and histopathological techniques. Our results demonstrated a noteworthy escalation in oxidative stress and gene expression endpoints associated with apoptosis. Moreover, stereological analyses exhibited alterations in cortex, proximal tubule, and kidney tissue vessels volumes. Remarkably, co-treatment with 6-formylindolo [3,2-b] carbazole (FICZ) and cadmium (Cd) resulted in a significant reduction in glomerulus volume, while elevating the volumes of distal tubule, Henle loop, and connective tissue, compared to the control group. Histopathological investigations further confirmed structural changes in the loop of Henle and proximal tubule, alongside a decline in glomerular volume. Additionally, the expression levels of AHR and Ctnnb1 genes significantly increased in the Cd-treated group compared to the control group. Enhanced expression of apoptosis-related genes, including Bcl-x, Bax, and Caspase3, along with alterations in mitochondrial membrane potential and cytochrome C release, was observed. In contrast, Gsk3 gene expression was significantly decreased. Our findings robustly establish that chemical pollutants, such as Cd, disrupt the AHR and Wnt/ß-Catenin physiological roles during developmental stages by inhibiting the metabolic degradation of FICZ.
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Poluentes Ambientais , Rim , Camundongos Endogâmicos BALB C , Receptores de Hidrocarboneto Arílico , Via de Sinalização Wnt , Animais , Feminino , Humanos , Camundongos , Gravidez , Apoptose/efeitos dos fármacos , beta Catenina/metabolismo , Cádmio/toxicidade , Carbazóis/farmacologia , Poluentes Ambientais/toxicidade , Células HEK293 , Rim/metabolismo , Rim/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Via de Sinalização Wnt/efeitos dos fármacos , MasculinoRESUMO
Background and objectives: Aluminum phosphide (AlP), known as "rice tablet," is widely used as an effective pesticide. However, AlP poisoning is a common cause of mortality in many countries, such as Iran. Unfortunately, there is no specific antidote for AlP toxicity to date. AlP releases phosphine gas when it is exposed to moisture or acid. Phosphine is a potent mitochondrial toxin that could significantly inhibit cellular energy metabolism. AlP poisoning is an emergency condition that needs instant and effective intervention. Dihydroxyacetone (DHA) is a simple saccharide used for several pharmacological as well as cosmetic purposes. Previously, we found that DHA could significantly prevent mitochondrial impairment induced by toxic agents such as cyanide and phosphine in various in vitro and in vivo experimental models. Methods: Hospitalized patients (n = 111) were evaluated for eligibility criteria. Among these patients, n = 35 cases were excluded due to incomplete data (n = 11) and suspicion of poisoning with poisons other than AlP (n = 24). Meanwhile, n = 76 cases with confirmed AlP poisoning were included in the study. AlP-poisoned patients who did not receive DHA (n = 18) were used as the control group.Patients (n = 58) received at least one dose of DHA (500 ml of 5 % DHA solution w/v, i.v.) as an adjuvant therapy in addition to the routine treatment of AlP poisoning. Arterial blood gas (ABG), blood pH, bicarbonate levels, and other vital signs and biochemical measurements were monitored. Moreover, the mortality rate and hospitalization time were evaluated in DHA-treated and AlP-poisoned patients without DHA administration. Several biomarkers were assessed before (upon hospitalization) and after DHA treatment. The routine tests for AlP-poisoned patients in this study were the measurement of electrolytes (K+ and Na+), WBC, RBC, hemoglobin, INR, carbonate (HCO3), blood pH, PaCO2, and PaO2 and SGPT, SGOT, BUN, Cr. Results: Upon patients' admission, significant decreases in blood pH (acidosis), blood PaO2, and HCO3 levels were the hallmarks of AlP poisoning. It was found that DHA significantly alleviated biomarkers of AlP poisoning and tremendously enhanced patients' survival rate (65.52 % in DHA-treated vs 33.34 % in the control group) compared to patients treated based on hospital routine AlP poisoning protocols (no DHA). No significant adverse effects were evident in DHA-treated patients in the current study. Interpretation and conclusions: These data suggest that parenteral DHA is a novel and effective antidote against AlP poisoning to be used as an adjuvant in addition to routine supportive treatment. Trial registration: IR.SUMS.REC.1394.102.
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Background: of the study: Hepatic encephalopathy (HE) is a complication in which brain ammonia (NH4+) levels reach critically high concentrations because of liver failure. HE could lead to a range of neurological complications from locomotor and behavioral disturbances to coma. Several tactics have been established for subsiding blood and brain NH4+. However, there is no precise intervention to mitigate the direct neurological complications of NH4+. Purpose: It has been found that oxidative stress, mitochondrial damage, and neuro-inflammation play a fundamental role in NH4+ neurotoxicity. Piracetam is a drug used clinically in neurological complications such as stroke and head trauma. Piracetam could significantly diminish oxidative stress and improve brain mitochondrial function. Research methods: In the current study, piracetam (100 and 500 mg/kg, oral) was used in a mice model of HE induced by thioacetamide (TA, 800 mg/kg, single dose, i.p). Results: Significant disturbances in animals' locomotor activity, along with increased oxidative stress biomarkers, including reactive oxygen species formation, protein carbonylation, lipid peroxidation, depleted tissue glutathione, and decreased antioxidant capacity, were evident in the brain of TA-treated mice. Meanwhile, mitochondrial permeabilization, mitochondrial depolarization, suppression of dehydrogenases activity, and decreased ATP levels were found in the brain of the TA group. The level of pro-inflammatory cytokines was also significantly high in the brain of HE animals. Conclusion: It was found that piracetam significantly enhanced mice's locomotor activity, blunted oxidative stress biomarkers, decreased inflammatory cytokines, and improved mitochondrial indices in hyperammonemic mice. These data suggest piracetam as a neuroprotective agent which could be repurposed for the management of HE.
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Ammonium ion (NH4 + ) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4 + -induced brain injury exists so far. Excitotoxicity is a well-known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N-Methyl- d-aspartate (NMDA) receptors by agents such as glutamate, an NH4 + metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4 + neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4 + were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF-α, IL-6, and IL-1ß was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.
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Encefalopatia Hepática , Ketamina , Doenças do Sistema Nervoso , Síndromes Neurotóxicas , Camundongos , Animais , Ketamina/efeitos adversos , Amônia/toxicidade , Amônia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Encéfalo/metabolismo , Inflamação/metabolismo , Estresse Oxidativo , Encefalopatia Hepática/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Biomarcadores/metabolismoRESUMO
INTRODUCTION: Cholestasis is the stoppage of bile flow, leading to the accumulation of potentially cytotoxic bile components in the liver. These cytotoxic molecules affect many organs. Cholestasis-induced lung injury is a severe complication that could lead to tissue fibrosis and respiratory distress. Substantial evidence indicates the role of oxidative stress and inflammatory response in the pathogenesis of cholestasis-associated pulmonary damage. Agmatine (AGM; 1-amino-4-guanidinobutane) is a biogenic amine endogenously synthesized in the human body. This amine provides potent anti-inflammatory and antioxidant properties. METHODS: In the current study, a series (six C57BL/6J male mice/group) of bile duct-ligated (BDL) animals were monitored at scheduled intervals (7, 14, and 28 days after the BDL operation) to ensure inflammatory response in their lung tissue (by analyzing their bronchoalveolar lavage fluid [BALF]). It was found that the level of inflammatory cells, pro-inflammatory cytokines, and IgG in the BALF reached their maximum level on day 28 after the BDL surgery. Therefore, other research groups were selected as follows: 1) Sham-operated (2.5 mL/kg normal saline, i.p., for 28 consecutive days), 2) BDL, 3) BDL + AGM (1 mg/kg/day, i.p., for 28 consecutive days), and 4) BDL + AGM (10 mg/kg/day, i.p., for 28 consecutive days). Then, the BALF was monitored at scheduled time intervals (7, 14, and 28 days post-BDL). RESULTS: It was found that pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), bile acids, bilirubin, and inflammatory cells (monocytes, neutrophils, and lymphocytes) were significantly increased in the BALF of BDL mice. Moreover, biomarkers of oxidative stress were significantly increased in the pulmonary tissue of cholestatic animals. Lung tissue histopathological changes, tissue collagen deposition, and increased TGF-ß were also detected. It was found that AGM significantly ameliorated cholestasis-induced lung injury. CONCLUSION: The effects of AGM on inflammatory indicators, oxidative stress biomarkers, and tissue fibrosis seem to play a pivotal role in its protective properties.
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Agmatina , Colestase , Lesão Pulmonar , Pneumonia , Masculino , Camundongos , Humanos , Animais , Agmatina/farmacologia , Agmatina/uso terapêutico , Agmatina/metabolismo , Camundongos Endogâmicos C57BL , Colestase/complicações , Colestase/tratamento farmacológico , Colestase/metabolismo , Fígado , Estresse Oxidativo , Fibrose , Pneumonia/tratamento farmacológico , Pneumonia/prevenção & controle , Pneumonia/complicações , Biomarcadores/metabolismo , Citocinas/metabolismo , Aminas Biogênicas/metabolismo , Aminas Biogênicas/farmacologiaRESUMO
Aim of the study: Cholestasis/cirrhosis could induce erythrocyte lysis. The incidence of various types of anemia in cirrhosis is approx. 75%. Several studies have mentioned the pivotal role of oxidative stress in this complication. Taurine (TAU) is the human body's most abundant free amino acid. TAU is known as a robust cell membrane stabilizer. Many studies have mentioned that TAU could counteract oxidative stress in various experimental models. The current study was intended to evaluate the effect of TAU on erythrocytes in cirrhotic rats. Material and methods: Bile duct ligation (BDL) surgery was carried out on rats. Then, complete blood count (CBC), hemoglobin (Hgb), hematocrit (HTC), and erythrocytes' G6PD, catalase (CAT), and superoxide dismutase (SOD) activity were measured. Moreover, biomarkers of oxidative stress were assessed, and the erythrocytes' morphological changes were monitored in the cirrhotic mice exposed to TAU (0.25%, 0.5%, and 1% w : v in drinking water). Results: Significant changes in the assessed erythrocyte parameters (G6PD activity, Hgb, HTC, and erythrocyte count) and red blood cells (RBC) morphological alterations were detected on day 42 after BDL surgery. Biomarkers of oxidative stress also did not change at the time points, except on post-BDL days 28 and 42. A significant decrease in blood parameters was evident at post-BDL day 42. All doses of TAU (0.25%, 0.5%, and 1% w : v in drinking water) significantly improved erythrocyte parameters and encountered oxidative stress in the erythrocytes of cirrhotic animals. Conclusions: These data indicate that TAU could be a safe agent to mitigate cirrhosis-induced erythrocyte damage and anemia. Further investigations are necessary to prove this in clinical settings.
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Cholestasis is a clinical complication that primarily influences the liver. However, it is well known that many other organs could be affected by cholestasis. Lung tissue is a major organ influenced during cholestasis. Cholestasis-induced lung injury could induce severe complications such as respiratory distress, serious pulmonary infections, and tissue fibrosis. Unfortunately, there is no specific pharmacological intervention against this complication. Several studies revealed that oxidative stress and inflammatory response play a role in cholestasis-induced lung injury. Carnosine (CARN) is a dipeptide found at high concentrations in different tissues of humans. CARN's antioxidant and antiinflammatory properties are repeatedly mentioned in various experimental models. This study aimed to assess the role of CARN on cholestasis-induced lung injury. Rats underwent bile duct ligation (BDL) to induce cholestasis. Broncho-alveolar lavage fluid (BALF) levels of inflammatory cells, pro-inflammatory cytokines, and immunoglobulin were monitored at scheduled intervals (7, 14, and 28 days after BDL). Moreover, lung tissue histopathological alterations and biomarkers of oxidative stress were evaluated. A significant increase in BALF inflammatory cells, TNF-α, IL-1ß, IL-6, and immunoglobulin-G (IgG) was detected in the BALF of BDL rats. Moreover, lung tissue histopathological changes, collagen deposition, increased TGF-ß, and elevated levels of oxidative stress biomarkers were evident in cholestatic animals. It was found that CARN (100 and 500 mg/kg, i.p.) significantly alleviated lung oxidative stress biomarkers, inflammatory response, tissue fibrosis, and histopathological alterations. These data indicate the potential protective properties of CARN in the management of cholestasis-induced pulmonary damage. The effects of CARN on inflammatory response and oxidative stress biomarkers seems to play a crucial role in its protective properties in the lung of cholestatic animals.
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Carnosina , Colestase , Lesão Pulmonar , Pneumonia , Camundongos , Humanos , Ratos , Animais , Carnosina/farmacologia , Carnosina/uso terapêutico , Dipeptídeos/farmacologia , Lesão Pulmonar/metabolismo , Colestase/complicações , Colestase/tratamento farmacológico , Fígado , Fibrose , Estresse Oxidativo , Pneumonia/tratamento farmacológico , Pneumonia/prevenção & controle , Biomarcadores/metabolismo , Ligadura/efeitos adversosRESUMO
Lead (Pb) is a highly toxic heavy metal. Pb exposure could adversely affect many organs, including the male reproductive system. Oxidative stress and mitochondrial impairment play a fundamental role in the pathogenesis of Pb-induced male reproductive system injury. Taurine (TAU) is abundantly found in mammalian bodies. The positive effects of TAU on oxidative stress biomarkers and mitochondrial function have been reported. The current study evaluated the effects of TAU on Pb-induced reproductive toxicity. Mice received Pb (20 mg/kg/day; gavage, 35 consecutive days). Then, sperm indices (quality and quantity) together with sperm kinetics, sperm mitochondrial parameters, testicular and sperm oxidative stress biomarkers, testis and plasma testosterone levels, and the expression of genes involved in the steroidogenesis process have been evaluated. Pb caused significant histopathological alterations and oxidative stress in male mice's reproductive system and sperm. Moreover, significant mitochondrial function impairment was evident in sperm isolated from Pb-treated mice. Pb exposure also suppressed the expression of StAR, 17ß-HSD, CYP11A, and 3ß-HSD genes in the male gonad. It was found that TAU (500 and 1000 mg/kg) significantly improved oxidative stress biomarkers in both male gonads and gametes of Pb-treated mice. TAU also significantly restored sperm mitochondrial function and kinetics. The expression of genes involved in steroidogenesis was also higher in TAU-treated animals. These data suggest TAU as an effective agent against Pb-induced reproductive toxicity. The effects of TAU on oxidative stress markers, mitochondrial function, and the steroidogenesis process seem to play a fundamental role in its protective properties. Further studies are warranted to detect the precise protective effects of this amino acid in the reproductive system. Lead (Pb) is a toxic element that adversely affects the male reproductive system. Mitochondrial impairment and oxidative stress have a crucial role in the Pb-induced reproductive toxicity. Taurine (TAU) could considerably improve the reproductive toxicity induced by Pb via enhancing mitochondrial function and mitigating oxidative stress indices. ΔΨ, mitochondrial membrane potential; ATP, adenosine triphosphate.
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Chumbo , Taurina , Masculino , Camundongos , Animais , Taurina/farmacologia , Taurina/metabolismo , Fenômenos Biomecânicos , Chumbo/toxicidade , Chumbo/metabolismo , Sêmen/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismo , Estresse Oxidativo , Mitocôndrias/metabolismo , Biomarcadores/metabolismo , Testosterona , Mamíferos/metabolismoRESUMO
Lead (Pb) is a highly toxic heavy metal widely dispersed in the environment because of human industrial activities. Many studies revealed that Pb could adversely affect several organs, including the male reproductive system. Pb-induced reproductive toxicity could lead to infertility. Thus, finding safe and clinically applicable protective agents against this complication is important. It has been found that oxidative stress plays a fundamental role in the pathogenesis of Pb-induced reprotoxicity. Glycine is the simplest amino acid with a wide range of pharmacological activities. It has been found that glycine could attenuate oxidative stress and mitochondrial impairment in various experimental models. The current study was designed to evaluate the role of glycine in Pb-induced reproductive toxicity in male mice. Male BALB/c mice received Pb (20 mg/kg/day; gavage; 35 consecutive days) and treated with glycine (250 and 500 mg/kg/day; gavage; 35 consecutive days). Then, reproductive system weight indices, biomarkers of oxidative stress in the testis and isolated sperm, sperm kinetic, sperm mitochondrial indices, and testis histopathological alterations were monitored. A significant change in testis, epididymis, and Vas deferens weight was evident in Pb-treated animals. Markers of oxidative stress were also significantly increased in the testis and isolated sperm of the Pb-treated group. A significant disruption in sperm kinetic was also evident when mice received Pb. Moreover, Pb exposure caused significant deterioration in sperm mitochondrial indices. Tubular injury, tubular desquamation, and decreased spermatogenic index were histopathological alterations detected in Pb-treated mice. It was found that glycine significantly blunted oxidative stress markers in testis and sperm, improved sperm mitochondrial parameters, causing considerable higher velocity-related indices (VSL, VCL, and VAP) and percentages of progressively motile sperm, and decreased testis histopathological changes in Pb-exposed animals. These data suggest glycine as a potential protective agent against Pb-induced reproductive toxicity. The effects of glycine on oxidative stress markers and mitochondrial function play a key role in its protective mechanism.
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Glicina , Chumbo , Humanos , Masculino , Camundongos , Animais , Chumbo/toxicidade , Chumbo/metabolismo , Glicina/farmacologia , Regulação para Baixo , Fenômenos Biomecânicos , Sementes/metabolismo , Espermatozoides , Estresse Oxidativo , Testículo , Mitocôndrias/metabolismo , Substâncias Protetoras/farmacologia , Biomarcadores/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismoRESUMO
Lung injury is a significant complication associated with cholestasis/cirrhosis. This problem significantly increases the risk of cirrhosis-related morbidity and mortality. Hence, finding effective therapeutic options in this field has significant clinical value. Severe inflammation and oxidative stress are involved in the mechanism of cirrhosis-induced lung injury. Taurine (TAU) is an abundant amino acid with substantial anti-inflammatory and antioxidative properties. The current study was designed to evaluate the role of TAU in cholestasis-related lung injury. For this purpose, bile duct ligated (BDL) rats were treated with TAU (0.5 and 1% w: v in drinking water). Significant increases in the broncho-alveolar lavage fluid (BALF) level of inflammatory cells (lymphocytes, neutrophils, basophils, monocytes, and eosinophils), increased IgG, and TNF-α were detected in the BDL animals (14 and 28 days after the BDL surgery). Alveolar congestion, hemorrhage, and fibrosis were the dominant pulmonary histopathological changes in the BDL group. Significant increases in the pulmonary tissue biomarkers of oxidative stress, including reactive oxygen species formation, lipid peroxidation, increased oxidized glutathione levels, and decreased reduced glutathione, were also detected in the BDL rats. Moreover, significant myeloperoxidase activity and nitric oxide levels were seen in the lung of BDL rats. It was found that TAU significantly blunted inflammation, alleviated oxidative stress, and mitigated lung histopathological changes in BDL animals. These data suggest TAU as a potential protective agent against cholestasis/cirrhosis-related lung injury.
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Colestase , Lesão Pulmonar , Pneumonia , Ratos , Animais , Taurina/farmacologia , Taurina/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Estresse Oxidativo , Ductos Biliares/cirurgia , Colestase/tratamento farmacológico , Colestase/metabolismo , Ligadura/efeitos adversos , Antioxidantes/uso terapêutico , Cirrose Hepática/patologia , Fibrose , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pneumonia/patologia , FígadoRESUMO
Taurine (TAU) is a free amino acid abundant in the human body. Various physiological roles have been attributed to TAU. At the subcellular level, mitochondria are the primary targets for TAU function. Meanwhile, it has been found that TAU depletion is associated with severe pathologies. Cholestasis is a severe clinical complication that can progress to liver fibrosis, cirrhosis, and hepatic failure. Bile duct ligation (BDL) is a reliable model for assessing cholestasis/cirrhosis and related complications. The current study was designed to investigate the effects of cholestasis/cirrhosis on tissue and mitochondrial TAU reservoirs. Cholestatic rats were monitored (14 and 42 days after BDL surgery), and TAU levels were assessed in various tissues and isolated mitochondria. There was a significant decrease in TAU in the brain, heart, liver, kidney, skeletal muscle, intestine, lung, testis, and ovary of the BDL animals (14 and 42 days after surgery). Mitochondrial levels of TAU were also significantly depleted in BDL animals. Tissue and mitochondrial TAU levels in cirrhotic animals (42 days after the BDL operation) were substantially lower than those in the cholestatic rats (14 days after BDL surgery). These data indicate an essential role for tissue and mitochondrial TAU in preventing organ injury induced by cholestasis/cirrhosis and could justify TAU supplementation for therapeutic purposes.
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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.
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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.
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Di-Hidroxiacetona/uso terapêutico , Fosfinas/intoxicação , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Coração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
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.
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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 SinaisRESUMO
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.
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.