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Background and aim Cholestasis-associated renal injury or cholemic nephropathy (CN) is a serious clinical problem. Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN. There is no specific pharmacological intervention for CN. Metformin is an anti-diabetic drug administered for decades. On the other hand, novel pharmacological properties have emerged for this drug. The effect of metformin on oxidative stress parameters has been well-recognized in different experimental models. It has also been found that metformin positively affected mitochondrial function. The current study aimed to evaluate the effects of metformin in an animal model of CN. Methods Rats underwent bile duct ligation (BDL) and were treated with metformin (250 and 500 mg/kg) for 14 consecutive days. Two weeks after the BDL operations, urine, serum, and kidney samples were collected and analyzed. Results Markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, depleted antioxidant capacity, and decreased glutathione (GSH) levels were detected in BDL animals. Moreover, mitochondrial indices, including adenosine triphosphate (ATP) level, dehydrogenase activity, mitochondrial membrane potential, and mitochondrial permeability, were impaired in the kidney of cholestatic rats. Renal histopathological alterations in cholestatic animals included tubular degeneration and interstitial inflammation, cast formation, and fibrosis. It was found that metformin significantly alleviated oxidative stress and improved mitochondrial indices in the kidney of cholestatic rats. Tissue histopathological alterations were also mitigated in metformin-treated groups. Conclusions Metformin could be a candidate for managing CN. The nephroprotective role of metformin is primarily associated with its effects on oxidative stress parameters and mitochondrial function.

The ovariectomized rat is a widely used preclinical model for studying postmenopausal and its complications. In this study, the therapeutic effect of flaxseed oil on the ovariectomized adult rats was investigated. Our results showed that biochemical parameters including calcium, oestrogen and progesterone levels increase 8 weeks after ovariectomy in rats. Also, the amount of alkaline phosphatase decreased significantly after 8 weeks compared with the OVX rat. The healing potential of flaxseed oil was proven by successfully recovering the affected tissue and preventing the unpleasant symptoms of ovariectomized rats. The biological effects of flaxseed oil may be due to high amounts of fatty acids, phytoestrogens and an array of antioxidants. The results suggest that flaxseed oil can mimic the action of oestrogen and can be a potential treatment for hormone replacement therapy (HRT)., The potential use of flaxseed oil as the natural source for hormone replacement therapy on the ovariectomized rat model was investigated.The antioxidant properties and biochemical parameters including alkaline phosphatase, calcium, estrogen, and progesterone levels were determined in ovariectomy rats.

Introduction: The cholestatic liver disease primarily affects hepatic tissue. Cholestasis could also influence the function of other organs rather than the liver. Cholestasis-induced renal injury is a severe clinical complication known as "cholemic nephropathy" (CN). Bile duct ligation (BDL) is a reliable experimental tool for inducing CN. Although the precise mechanism of renal injury in cholestasis is not fully recognized, several studies mentioned the role of oxidative stress in this complication. There is no promising pharmacological intervention against CN. Carnosine (CAR) is a dipeptide widely investigated for its pharmacological effects. Radical scavenging and antioxidative stress are major features of CAR. The current study was designed to evaluate the role of CAR supplementation on the CN. Methods: CAR (250 and 500 mg/kg, i.p) was administered to BDL rats for 14 consecutive days. Serum and urine markers of renal injury, biomarkers of oxidative stress in the kidney tissue, and renal histopathological alterations were monitored. Results: Significant elevation in oxidative stress biomarkers, including ROS formation, oxidized glutathione (GSSG) levels, lipid peroxidation, and protein carbonylation were found in the kidney of BDL rats. Moreover, renal tissue antioxidant capacity and reduced glutathione (GSH) levels were significantly decreased in the renal tissue of cholestatic animals. Renal histopathological alterations, including tubular atrophy, interstitial inflammation, tissue fibrosis, and cast formation, were detected in the kidney of BDL rats. It was found that CAR administration significantly protected the renal tissue of cholestatic animals. Conclusion: The antioxidative properties of this peptide might play a fundamental role in its protective properties during cholestasis.

Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues' AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease. Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.

Cholestasis is the stoppage of bile flow that primarily affects liver function. On the other hand, kidneys are also severely influenced during cholestasis. Cholestasis-induced kidney injury is known as cholemic nephropathy (CN). There is no precise pharmacological option in CN. Previous studies revealed that oxidative stress plays a crucial role in the pathogenesis of CN. On the other hand, the positive effects of pentoxifylline (PTX) against renal injury with different etiologies have been frequently reported. In the current study, the potential nephroprotective role of PTX in cholestasis-induced renal injury is investigated.Bile duct ligated (BDL) rats were treated with PTX (10, 50, and 100 mg/kg), and renal markers of oxidative stress, urine level of inflammatory cytokines, as well as renal histopathological alterations were monitored.Significant changes in oxidative stress markers were detected in the BDL group. On the other hand, it was found that PTX (10, 50, and 100 mg/kg) significantly ameliorated cholestasis-induced oxidative stress in renal tissue. Renal histopathological changes, including interstitial inflammation, tubular atrophy, fibrosis, and cast formation, were detected in the BDL rats. Moreover, urine pro-inflammatory cytokines [interleukin (IL)-1, IL-9, IL-18, tumor necrosis factor α (TNF-α), and interferon γ (INF-γ)] were significantly increased in the cholestatic animals. PTX (10, 50, and 100 mg/kg, 14 days) significantly ameliorated renal histopathological alterations and urine levels of inflammatory cytokines.These data indicate a potential nephroprotective role for PTX in cholestasis. The effects of PTX on oxidative stress parameters and the inflammatory response could play a primary role in its renoprotective mechanisms.

Background. Treating nonalcoholic fatty liver disease (NAFLD) is considered one of the public health priorities in the past decade. So far, probiotics have represented promising results in controlling the signs and symptoms of NAFLD. However, attempts to find the ideal probiotic strain are still ongoing. The present study is designed to find the best strain amongst suitable probiotic strains according to their ability to ameliorate histopathological and oxidative stress biomarkers in hepatic steatosis-induced rats. Methods. Initially, four probiotics species, including Lactobacillus (L.) acidophilus, L. casei, L. reuteri, and Bacillus coagulans, were cultured and prepared as a lyophilized powder for animals. The experiment lasted for fifty days. Initially, hepatic steatosis was induced by excessive ingestion of D-fructose in rats for eight weeks, followed by eight weeks of administering probiotics and D-fructose concurrently. Forty-two six-week-old male rats were alienated to different groups and were supplemented with different probiotics ( 1 ∗ 10 9 CFU in 500 mL drinking water). After eight weeks, blood and liver samples were taken for further evaluation, and plasma and oxidative stress markers corresponding to liver injuries were examined. Results. Administration of probiotics over eight weeks reversed hepatic and blood triglyceride concentration and blood glucose levels. Also, probiotics significantly suppressed markers of oxidative stress in the liver tissue. Conclusions. Although some of the single probiotic formulations were able to mitigate oxidative stress markers, mixtures of probiotics significantly ameliorated more symptoms in the NAFLD animals. This enhanced effect might be due to probiotics’ cumulative potential to maintain oxidative stress and deliver improved lipid profiles, liver function markers, and inflammatory markers.

Purpose Hepatic encephalopathy (HE) is described as impaired brain function induced by liver failure. Ammonia is the most suspected chemical involved in brain injury during HE. Although the precise mechanism of HE is not clear, several studies mentioned the role of oxidative stress in ammonia neurotoxicity. In animal models, the use of some compounds with antioxidant properties was reported to reduce the neurotoxic effects of ammonia, improve energy metabolism, and ameliorate the HE symptoms. Citicoline is a principal intermediate in the biosynthesis pathway of phosphatidylcholine that acts as neurovascular protection and repair effects. Various studies mentioned the neuroprotective and antioxidative effects of citicoline in the central nervous system. This study aims to investigate the potential protective effects of citicoline therapeutic in an animal model of HE. Materials and methods Mice received acetaminophen (APAP,1g/kg, i. p.) and then treated with citicoline (500 mg/kg, i.p) one and two hours after APAP. Animals were monitored for locomotor activity and blood and brain ammonia levels. Moreover, markers of oxidative stress were assessed in the brain tissue. Results The result of the study revealed that plasma and brain ammonia and the liver injury markers increased, and locomotor activity impaired in the APAP-treated animals. Besides, an increase in markers of oxidative stress was evident in the brain of the APAP-treated mice. It was found that citicoline supplementation enhanced the animal's locomotor activity and improved brain tissue markers of oxidative stress. Conclusion These data propose citicoline as a potential protective agent in HE. The effects of citicoline on oxidative stress markers could play a fundamental role in its neuroprotective properties during HE.

Cholestasis-associated renal injury, known as cholemic nephropathy (CN), is a severe clinical complication. CN could lead to acute kidney injury. However, there is no specific pharmacological intervention for cholestasis-induced renal injury. Oxidative stress and mitochondrial impairment seem to play a role in the pathogenesis of CN. Betaine (3-methyl glycine; BET) is an amino acid derivative with a wide range of pharmacological actions. Several studies mentioned the effects of BET on oxidative stress in different experimental models. It has also been found that BET positively affected mitochondrial function. The current study aimed to evaluate the effects of BET supplementation on CN in the bile duct ligation (BDL) model of cholestasis. BET (0.25% and 1% w: v in drinking water) was administered to BDL animals for seven consecutive days. Biomarkers of oxidative stress and mitochondrial indices were evaluated in cholestatic animals. Significant elevation in reactive oxygen species formation, lipid peroxidation, and oxidized glutathione (GSSG) was evident in BDL rats. Moreover, reduced glutathione (GSH) levels and renal antioxidant capacity were decreased in cholestatic animals. Mitochondrial depolarization, mitochondrial permeabilization, decreased mitochondrial dehydrogenases activity, and lipid peroxidation was also detected in the kidney of BDL rats. Tubular atrophy, interstitial inflammation, and renal fibrosis were also detected in BDL rats. BET alleviated biomarkers of oxidative stress, improved mitochondrial indices, and decreased renal histopathological alterations in BDL animals. The antioxidant effects and the positive effects of BET on cellular mitochondria seem to play a fundamental role in its nephroprotective role during cholestasis.

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.

Manganese (Mn) is an essential element that is incorporated in various metabolic pathways and enzyme structures. On the other hand, a range of adverse effects has been described in association with Mn overexposure. Mn is a well-known neurotoxic agent in mammals. Renal injury is another adverse effect associated with Mn intoxication. No precise mechanism for Mn nephrotoxicity has been identified so far. The current study was designed to evaluate the potential mechanisms of Mn-induced renal injury. Rats were treated with Mn (20 and 40 mg/mL, respectively, in drinking water) for 30 consecutive days. Markers of oxidative stress, as well as several mitochondrial indices, were assessed in the kidney tissue. Renal injury was evident in Mn-treated animals, as judged by a significant increase in serum BUN and creatinine. Moreover, urinalysis revealed a significant increase in urine glucose, phosphate, and protein in Mn-treated rats. Kidney histopathological alterations, including tubular atrophy, interstitial inflammation, and necrosis, were also detected in Mn-treated animals. Biomarkers of oxidative stress, including an increment in reactive oxygen species (ROS), lipid peroxidation, and oxidized glutathione (GSSG), were detected in Mn-treated groups. On the other hand, kidney glutathione (GSH) stores and total antioxidant capacity were depleted in Mn groups. Mn exposure was associated with significant mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depletion of adenosine tri-phosphate (ATP) content. These data highlight oxidative stress and mitochondrial impairment as potential mechanisms involved in Mn-induced renal injury.

It has been well documented that cirrhosis is associated with the intestinal injury. Intestinal injury in cirrhosis could lead to bacterial lipopolysaccharide (LPS) translocation to the systemic circulation. It has been found that high plasma LPS is connected with higher morbidity and mortality in cirrhotic patients. Therefore, finding therapeutic approaches to mitigate this complication has great clinical value. Several investigations mentioned the pivotal role of oxidative stress in cirrhosis-associated intestinal injury. It has been well-known that the redox balance of enterocytes is disturbed in cirrhotic patients. In the current study, the effects of thiol-reducing agents N-acetylcysteine (NAC) (0.5 and 1% w: v) and dithiothreitol (DTT) (0.5 and 1% w: v) on biomarkers of oxidative stress, tissue histopathological alterations, and LPS translocation is investigated in a rat model of cirrhosis. Bile duct ligation (BDL) surgery was used to induce cirrhosis in male Sprague-Dawley rats. Animals (n ​= ​48; 8 animals/group) were supplemented with NAC and DTT for 28 consecutive days. Significant changes in ileum and colon markers of oxidative stress were evident in BDL rats as judged by increased reactive oxygen species (ROS), lipid peroxidation, oxidized glutathione (GSSG), and protein carbonylation along with decreased antioxidant capacity and glutathione (GSH) content. Blunted villus, decreased villus number, and inflammation was also detected in the intestine of BDL animals. Moreover, serum LPS level was also significantly higher in BDL rats. NAC and DTT administration (0.5 and 1% w: v, gavage) significantly decreased biomarkers of oxidative stress, mitigated intestinal histopathological alterations, and restored tissue antioxidant capacity. Moreover, NAC and/or DTT significantly suppressed LPS translocation to the systemic circulation. The protective effects of thiol reducing agents in the intestine of cirrhotic rats could be attributed to the effect of these chemicals on the cellular redox environment and biomarkers of oxidative stress., Graphical abstract Image 1Oxidative stress and disturbed cellular thiol redox state are involved in the mechanisms of cholestasis/cirrhosis-induced gut permeability and lipopolysaccharide (LPS) translocation to the systemic circulation. In the current study, we found that the oral administration of thiol reducing agents such as N-acetylcysteine (NAC) and dithiothreitol (DTT) significantly mitigated intestinal tissue oxidative stress and serum LPS level in the bile duct ligation (BDL) model of cirrhosis., Highlights • Gut permeability is a clinical complication in cholestasis/cirrhosis • Intestinal injury leads to lipopolysaccharide (LPS) translocation to the bloodstream • LPS translocation to the systemic circulation could cause systemic inflammation • Oxidative stress is involved in the mechanisms of cirrhosis-induced gut permeability • Oral administration of thiol-reducing agents mitigated intestinal tissue oxidative stress • Serum LPS levels were lower in thiol reducing agents-treated animals

Chlorogenic acid (CA), is a polyphenol abundantly found in several foods. Different pharmacological roles of CA, including its effect on body weight, become a subject of research interest. In the current study, the effect of CA supplementation was evaluated on the muscle mitochondria function in an animal model of resistance training (RT). Rats were allotted into control, CA (100 mg/kg) without RT, RT, RT + CA 10 mg/kg, RT + CA 50 mg/kg, and RT + CA 100 mg/kg. It was found that CA supplementation (10, 50, and 100 mg/kg, gavage, 56 consecutive days) significantly improved muscle strength and mitochondrial function, especially when it was co-administered with the RT program. The present findings suggest that CA supplementation with RT improved muscle function by regulating mitochondrial function and cellular energy metabolism. Therefore, CA could be a promising, supplementary/therapeutic agent against a variety of skeletal muscle-associated complications.

Background: Nanotechnology and nanobiotechnology have emerged as novel technologies for the production and application of nanoscale materials in different pharmaceutical, medical, and biological fields. Besides, there are a bunch of recently published patents in this field. Although Carbon Nanotubes (CNTs) have various advantages and can be applied for a wide variety of purposes, their toxicity on humans is a matter of concern. Objective: This study aimed to evaluate six different types of CNTs, including pristine, carboxylated, and hydroxylated single-walled CNTs (SWCNTs) and multi-walled CNTs (MWCNTs) on three human cell lines. Methods: MTT assay was employed to assess the cytotoxicity of six types of CNTs, including pristine, carboxylated, and hydroxylated forms of SWCNTs and MWCNTs on three different human cell lines. Results: The findings of the MTT assay showed that the six different types of CNTs (100- 600 μg/mL) exhibited different levels of cytotoxicity on the three human cell lines. The observed trend presented dose-dependent cytotoxicity on the three studied cell lines, including pulmonary, skin, and gastrointestinal cell lines. SWCNT-COOH and MWCNTs accounted for the lowest cell viability in the three human cell lines. Conclusion: In conclusion, researchers and industrial workers are recommended to be cautious while working with different types of CNT because all their toxicity dimensions have not been determined yet.

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.

Background Ifosfamide (IFO) is an alkylating agent administered against different types of malignancies. Several cases of renal injury and serum electrolytes disturbances have been reported in IFO-treated patients. Oxidative stress and mitochondrial dysfunction are suspected of being involved in the mechanism of IFO nephrotoxicity. Carnosine is a dipeptide which its antioxidant and mitochondria protecting properties have been mentioned in different experimental models. The current study aimed to evaluate the nephroprotective properties of carnosine against IFO-induced renal injury. Methods Rats were treated with IFO (50 mg/kg, i.p) alone or in combination with carnosine. Serum and urine biomarkers of renal injury in addition to kidney markers of oxidative stress were evaluated. Moreover, kidney mitochondria were isolated, and some mitochondrial indices were assessed. Results Elevated serum creatinine and BUN, hypokalemia, and hypophosphatemia, in addition, to an increase in urine glucose, protein, γ-GT, and alkaline phosphatase (ALP), were evident in IFO-treated animals. IFO also caused an increase in kidney reactive oxygen species (ROS) and lipid peroxidation (LPO). Renal GSH levels and antioxidant capacity were also depleted with IFO therapy. Mitochondrial dehydrogenase activity, GSH level, membrane potential, and ATP content were decreased while mitochondrial LPO and permeabilization were increased in IFO group. Carnosine (250 and 500 mg/kg, i.p) mitigated IFO-induced oxidative stress and mitochondrial impairment in renal tissue. Conclusion Our data suggest mitochondrial dysfunction and oxidative stress as fundamental mechanisms of renal injury induced by IFO. On the other hand, carnosine supplementation protected kidneys against IFO-induced injury through regulating mitochondrial function and mitigating oxidative stress.

Exposure to arsenic (AS) causes abnormalities in the reproductive system; however, the precise cellular pathway of AS toxicity on steroidogenesis in developing F1-male mice has not been clearly defined. In this study, paternal mice were treated with arsenic trioxide (As2O3; 0, 0.2, 2, and 20 ppm in drinking water) from 5 weeks before mating until weaning and continued for male offspring from weaning until maturity (in vivo). Additionally, Leydig cells (LCs) were isolated from the testes of sacrificed F1-intact mature male mice and incubated with As2O3 (0, 1, 10, and 100 μM) for 48 h (in vitro). Biomarkers of mitochondrial impairment, oxidative stress, and several steroidogenic genes, including the steroidogenic acute regulatory (StAR) protein, cytochrome P450 side-chain cleaving enzyme (P450scc; Cyp11a), 3β-hydroxysteroid dehydrogenase (3β-HSD), and 17β-hydroxysteroid dehydrogenase (17β-HSD), were evaluated. High doses of As2O3 interrupted testosterone (T) biosynthesis and T-related gene expression in these experimental models. Altogether, overconsumption of As2O3 can cause testicular and LC toxicity through mitochondrial-related pathways and oxidative stress indices as well as downregulation of androgenic-related genes in mice and isolated LCs. These results could lead to the development of preventive/therapeutic procedures against As2O3-induced reproductive toxicity.

The liver is the primary organ affected by cholestasis. However, the brain, skeletal muscle, heart, and kidney are also severely influenced by cholestasis/cirrhosis. However, little is known about the molecular mechanisms of organ injury in cholestasis. The current study was designed to evaluate the mitochondrial glutathione redox state as a significant index in cell death. Moreover, tissue energy charge (EC) was calculated. Rats underwent bile duct ligation (BDL) and the brain, heart, liver, kidney, and skeletal muscle mitochondria were assessed at scheduled time intervals (3, 7, 14, and 28 days after BDL). A significant decrease in mitochondrial glutathione redox state and EC was detected in BDL animals. Moreover, disturbed mitochondrial indices were evident in different organs of BDL rats. These data could offer new insight into the mechanisms of organ injury and the source of oxidative stress during cholestasis and might provide novel therapeutic strategies against these complications.

Background: Pistacia atlantica (PA) trees grow in all areas of Iran. Pistacia atlantica fruit is edible and mostly consumed by residents. Also, PA leaves, gum, and fruit are considered to have medicinal value in traditional medicine. Objectives: This study was designed to evaluate the analgesic effects of the hydroalcoholic extract of PA leaves, gum, and fruit. Methods: Seventy-two adult male Sprague-Dawley rats were divided into 12 groups, including control and test groups. In the positive control group, the rats received the standard drug paracetamol at a dose of 100 mg/kg, IP. In the test groups, the rats received leaves, gum, and fruit extracts at the doses of 25, 50, and 100 mg/kg, IP. Then, the rats were assessed for antinociception by the tail-flick and formalin tests. In this study, the ethical guidelines approved by the Ethics Committee of Shiraz University of Medical Sciences regarding the use of animals in experimental studies were followed. Results: The results showed that the leaves extract at the doses of 25 and 50 mg/kg and the gum extract at the dose of 100 mg/kg had a substantial analgesic effect, as demonstrated by the increase in the latency time in the tail-flick test and the decrease in the pain sensitivity in the formalin test (P < 0.05). The fruit extract, compared with the other parts of the plant, had no analgesic effect. Conclusions: The stronger analgesic effects of PA leaves extract, compared to those observed for the extracts of other parts of PA, might be due to the higher concentration of components with analgesic properties in PA leaves.

Objective. Manganese (Mn) has been reported, through dietary and occupational overexposure, to induce neurotoxicity named manganism. Pentoxifylline (PTX) administration attracts much attention considering the beneficial properties of PTX, as an anti-inflammatory and smooth muscle relaxation agent. This in vivo study aims to evaluate the effect of PTX on manganism in rat model. Materials and Methods. Thirty adult male Sprague Dawley rats received MnCl2 (100 mg/kg, i.p. on days 1, 3, and 7) during a week alone or in combination with PTX (300 mg/kg, i.p. every day for 8 consecutive days on manganism rat model). Several locomotor activity indices, as well as biomarkers of oxidative stress, were monitored in the brain tissue of Mn-exposed animals. Results. It was found that PTX supplementation (300 mg/kg, i.p.) deteriorated the Mn-induced locomotor deficit. This drug also increased the Mn brain accumulation as well as reactive oxygen species (ROS) and lipid peroxidation products in the manganism rat model. Moreover, the levels of total antioxidant capacity (TAC) and glutathione (GSH) were shown to be reduced significantly compared to the control group. Conclusion. The results of this study revealed that PTX at a high dose (300 mg/kg) might increase manganism complications. PTX lowers the blood viscosity, improves the tissue perfusion, and increases the Mn levels in the brain.

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.

Arsenic (As) exerts a wide range of adverse effects on biological systems, including the reproductive organs in males and females. However, the mechanisms of As-induced reproductive toxicity are mostly obscure. Recently, we showed that autophagy is an essential route for As2O3-induced reprotoxicity through the hypothalamic-pituitary-gonadal-sperm (HPG-S) axis in pubertal and matured F1-male mice. However, the role of autophagy in As2O3- induced ovarian toxicity is mostly unknown. Hence, this study aimed to elucidate the role of oxidative stress, mitochondrial impairment, and autophagic processes in the ovary of As-exposed female mice. For this purpose, mature female mice were challenged with 0, low (0.2), medium (2), and high (20 ppm) As2O3 from 35-days before mating till weaning their pups, and the F1- females from weaning until maturity. Then, all the mice were sacrificed, and oxidative stress parameters, mitochondrial indices, electron microscopic evaluation of the ovaries, expression of autophagic-related genes and proteins, and autophagosome formation were assessed. It was shown that medium and high As2O3 doses were a potent inducer of oxidative stress, mitochondrial dysfunction, and autophagy in the ovary of F1-generation. A dose-dependent increment in the gene expression of PDK1, PI3K, TSC2, AMPK, ULK1, ATG13, Beclin1, ATG12, ATG5, LC3, P62, ATG3, ATG7, and p62, as well as protein expression of Beclin1, and LC3- I, II, was evident in the ovaries of the As-treated animals. Moreover, a dose-dependent decrease in the expression of mTOR and Bcl-2 genes, and mTOR protein was detected with increasing doses of As, suggesting that As treatment-induced autophagy. Along with a dose-dependent increase in the number of MDC-labeled autophagic vacuoles, transmission electron microscopy also confirmed more autophagosomes and injured mitochondria in medium and high As2O3 doses groups. As2O3 also negatively affected the mean body weight, litter size, organ coefficient, and stereological indices in female mice. Finally, in physiological conditions, arsenic trioxide (As2O3) leads to an increased level of autophagy in the oocyte when many oocytes were being lost. These findings indicated that an imbalance in the oxidant-antioxidant system, mitochondrial impairment, and the autophagic process, through inhibition of mTOR, dependent and independent pathways, and Bcl-2, as well as activation of AMPK/PI3K/Beclin1/LC3 routes, could play a pivotal role in As-induced reproductive toxicity through ovarian dysfunction in females.

Purpose Hepatic encephalopathy (HE) is described as impaired brain function induced by liver failure. Ammonia is the most suspected chemical involved in brain injury during HE. Although the precise mechanism of HE is not clear, several studies mentioned the role of oxidative stress in ammonia neurotoxicity. In animal models, the use of some compounds with antioxidant properties was reported to reduce the neurotoxic effects of ammonia, improve energy metabolism, and ameliorate the HE symptoms. Citicoline is a principal intermediate in the biosynthesis pathway of phosphatidylcholine that acts as neurovascular protection and repair effects. Various studies mentioned the neuroprotective and antioxidative effects of citicoline in the central nervous system. This study aims to investigate the potential protective effects of citicoline therapeutic in an animal model of HE. Materials and Methods Mice received acetaminophen (APAP,1g/kg, i. p.) and then treated with citicoline (500 mg/kg, i.p) one and two hours after APAP. Animals were monitored for locomotor activity and blood and brain ammonia levels. Moreover, markers of oxidative stress were assessed in the brain tissue. Results The result of the study revealed that plasma and brain ammonia and the liver injury markers increased, and locomotor activity impaired in the APAP-treated animals. Besides, an increase in markers of oxidative stress was evident in the brain of the APAP-treated mice. It was found that citicoline supplementation enhanced the animal’s locomotor activity and improved brain tissue markers of oxidative stress. Conclusion These data propose citicoline as a potential protective agent in HE. The effects of citicoline on oxidative stress markers could play a fundamental role in its neuroprotective properties during HE.

Lung injury in rats challenged with paraquat at 20 mg kg−1 body weight was histopathologically evident by inflammation, hemorrhage, and vascular congestion. Increased levels of reactive oxygen spec...

Background The cholestatic liver disease could develop in association with a wide range of etiologies. The liver is the most affected organ by cholestasis. It has also been found that the kidney is severely injured during cholestasis. Oxidative stress seems to play a fundamental role in the pathogenesis of cholestasis-induced hepatic and renal injury. The current study was designed to evaluate the effects of agmatine supplementation on hepatic and renal injury and its potential mechanisms of action. Methods Rats underwent bile duct ligation (BDL) surgery. BDL animals were treated with agmatine (5, 10, and 20 mg/kg, gavage) for seven consecutive days. Results Significant reactive oxygen species formation, lipid peroxidation, increased oxidized glutathione level, decreased tissue antioxidant capacity and depleted reduced glutathione (GSH) were detected in cholestatic animals. Moreover, mitochondrial indices, including ATP level, membrane potential, lipid peroxidation, and swelling, were deteriorated in both liver and kidney of cholestatic rats. Liver fibrosis and renal tissue histopathological changes were also evident in BDL rats. It was found that agmatine supplementation significantly alleviated cholestasis-induced hepatic and renal injury. Conclusion The mechanism of action of agmatine could be related to its antioxidant properties and the positive effects of this amine on mitochondrial indices.

The original version of this article unfortunately contained a mistake. The “Funding Information” section is missing.

Gut barrier dysfunction and bacterial endotoxin (Lipopolysaccharide; LPS) translocation to the systemic circulation are prominent clinical challenges in cirrhotic patients. Several investigations mentioned the role of oxidative stress in this complication. In the current study, the effects of BET (0.5 and 1 % w: v, gavage) on biomarkers of oxidative stress, tissue histopathological alterations, and LPS translocation in cirrhotic rats was evaluated. Rats underwent bile duct ligation (BDL) and supplemented with BET for 28 consecutive days. Significant increase in ileum and colon reactive oxygen species, lipid peroxidation, oxidized glutathione levels, and protein carbonylation along with decreased antioxidant capacity and reduced glutathione content were evident in BDL rats. Mitochondrial indices were also significantly different in the intestine of BDL animals. Blunted villus, decreased villus number, and inflammation was also detected in the intestine of BDL animals. The serum LPS level was also significantly higher in the BDL group. BET treatment decreased biomarkers of oxidative stress, enhanced mitochondrial function, and mitigated intestinal histopathological alterations. Moreover, BET significantly suppressed LPS translocation to the systemic circulation. The protective role of BET in the intestine of cirrhotic animals could be attributed to the effect of this compound on oxidative stress and its associated events in enterocytes.

Betaine is a derivative of the amino acid glycine widely investigated for its hepatoprotective properties against alcoholism. The protective properties of betaine in different other experimental models also have been documented. On the other hand, the exact cellular mechanism of cytoprotection provided by betaine is obscure. The current study was designed to evaluate the hepatoprotective effects of betaine and its potential mechanisms of hepatoprotection in two animal models of acute and chronic liver injury. Bile duct ligation (BDL) was used as a model of chronic liver injury and thioacetamide (TAA)-induced hepatotoxicity was applied as the acute liver injury model. Severe increase in serum markers of liver tissue damage along with significant liver tissue histopathological changes were evident in both acute and chronic models of hepatic injury. It was also found that tissue markers of oxidative stress were significantly increased in BDL and TAA-treated animals. Moreover, liver mitochondrial indices of functionality were deteriorated in both investigated models. Betaine supplementation (10 and 50 mg/kg, i.p) ameliorated hepatic injury as judged by decreased liver tissue histopathological alterations, a significant decrease in tissue markers of oxidative stress, and mitigation of serum biomarkers of hepatotoxicity. On the other hand, betaine (10 and 50 mg/kg, i.p) protected hepatocytes mitochondria in both chronic and acute models of hepatotoxicity. These data indicate that the antioxidative and mitochondria regulating properties of betaine could play a primary role in its mechanisms of hepatoprotection.

Taurine (β-amino sulfonic acid; TAU) is the most abundant amino acid in the human body. Recently, the positive effects of TAU on cellular mitochondria has been considered as an interesting mechanism for its beneficial effects. On the other hand, skeletal muscle disorders are debilitating complications, which could affect patients’ quality of life. Moreover, increasing muscle performance and stamina without violating standard rules are of particular interest in athletes. The current study was designed to evaluate the effect of resistance training (RT) with and without TAU supplementation on skeletal muscle function. Rats underwent RT training for eight weeks. Concurrently, animals received TAU (100, 500, and 1000 mg/kg/day, gavage). It was found that TAU treatment significantly decreased animals weight gain and enhanced the weight carrying capacity in RT rats. Mitochondrial indices, including dehydrogenases activity, ATP level, and membrane potential were significantly increased upon TAU treatment. These data indicate the positive effects of TAU on skeletal muscle function and provide insight into its potential mechanism of action. Therefore, TAU could be feasibly used to enhance muscle function and stamina. Moreover, TAU could be considered as a potential preventive/therapeutic agent against muscle disorders linked to mitochondrial impairment and disrupted cellular energy metabolism.

Purpose of the study: Comparative in vitro studies were carried out to determine the adsorption characteristics of 3 drugs on activated charcoal (AC) and sodium polystyrene sulfonate (SPS). Activated charcoal (AC) has been long used as gastric decontamination agent for tricyclic antidepressants (TCA). Methods: Solutions containing drugs (amitriptyline, clomipramine, or doxepin) and variable amount of AC or SPS were incubated for 30 minutes. Results: At pH 1.2 the adsorbent: drug mass ratio varied from 2 : 1 to 40 : 1 for AC, and from 0.4 : 1 to 8 : 1 for SPS. UV–VIS spectrophotometer was used for the determination of free drug concentrations. The qmax of amitriptyline was 0.055 mg/mg AC and 0.574 mg/mg SPS, qmax of clomipramine was 0.053 mg/mg AC and 0.572 mg/mg SPS, and qmax of doxepin was 0.045 mg/mg AC and 0.556 mg/mg SPS. The results of adsorption experiments with SPS revealed higher values for the qmax parameters in comparison with AC. Conclusion: In vitro gastric decontamination experiments for antidepressant amitriptyline, clomipramine, and doxepin showed that SPS has higher qmax values than the corresponding experiments with AC. Therefore, we suggest SPS is a better gastric decontaminating agent for the management of acute TCA intoxication.