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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.

Glucosinolates are the main bioactive compounds present in Brassicaceae family with remarkable protective activities against various chemical carcinogenesis and toxicities. Protective role of the hydroalcoholic extract and desulfo glucosinolate fraction from seeds of Lepidium perfoliatum were evaluated against CCl4-induced hepatotoxicity in BALB/c mice by determination of oxidative stress biomarkers and liver histopathological feature. The oral administration of different doses of the extract and desulfo glucosinolate fraction exhibited significant decrease in ROS and MDA contents of mitochondria in a dose-dependent manner, especially the doses of 200 mg/kg of the extract and 10 mg/kg of the fraction. GSH content was significantly increased (p

Hamidreza Mohammadi,1,2 Reza Heidari,1 Seyyed Vahid Niknezhad,1 Akram Jamshidzadeh,1,2 Fatemeh Farjadian1 1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, IranCorrespondence: Fatemeh FarjadianPharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P. O. Box 158371345, Karafarin Ave., Shiraz, Fars, IranTel + 987132424127 302Fax + 987132424126Email farjadian_f@sums.ac.irAkram JamshidzadehDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, P. O. Box 158371345, Karafarin Ave., Shiraz, Fars, IranEmail ajamshid@sums.ac.irPurpose: Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH4+) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH4+ is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH4+ levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons).Methods: First, MS particles containing amine groups (MS-NH2) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH2 and MS-SA particles in adsorption of NH4+ was investigated in vitro and in vivo. MS-NH2 and MS-SA were incubated with increasing concentrations (0.1– 10 mM) of NH4+, and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model.Results: It was figured out that both MS-NH2 and MS-SA significantly scavenged NH4+ in the in vitro model. However, the NH4+ scavenging capability of MS-SA was more significant. Administration of MS-NH2 and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH2 in the HE animal model.Conclusion: Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.Keywords: acute liver failure, ammonia, hyperammonemia, nanomedicine

Di-(2-ethylhexyl) phthalate (DEHP) and its main metabolite, monoethylhexyl phthalic acid (MEHP), are a serious threat to human and animals’ health in the current century. However, their exact mecha...

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

Objective Curcumin, a natural polyphenol that has anti-oxidative, anti-inflammatory and anti-cancer properties. Therapeutic potential of curcumin is substantially limited by the rather low water solubility, rapid metabolism and low bioavailability. Therefore it is necessary for its' suitable carriers. In the present study, it was aimed to assess of polymeric micelles of curcumin on experimental model of colon cancer in Rat. Method Pathogen-free male Sprague–Dawley rats divided into 4 groups. Animals from group A, B, C received DMH intraperitoneal injection once a week at a dose of 20 mg/kg body weight in 0.9% normal saline. Group A, as DMH control. B, C received Nano-micelle curcumin and 5-FU respectively 4 weeks before first carcinogen challenge and continued until week 30 of experimentation. After 4 weeks all animals were killed and their colon removed and investigated for morphological and immunohistochemistry studies of apoptosis and expression of Bcl2, BAX and Caspase9. Results It was observed significant morphological changes in Nano-curcumin groups compared with DMH group but for expression of apoptotic factors, although decrease in Bcl2 expression and increase in BAX and caspase9 observed in Nano-micelle group but these changes were not significant compared with DMH group (P > 0.05). Conclusion Results of this study indicate that Nano-micelle of curcumin has some preventive effect in experimental model of colon cancer in vivo but has not induced complete apoptotic effect and more studies that are complete are needed.

Tramadol (TR) is an analgesic drug used to treat moderate-to-severe pain but it induces seizure even at therapeutic doses. The exact mechanism of TR-inducing seizure is not clear but inhibition of the serotonin, GABA, and nitrous oxide (NOS) pathways are the commonly proposed mechanisms. Adenosinergic system has a crucial function in the modulation of seizure. Also, oxidative damage is an unavoidable effect of the seizure. This study was conducted to evaluate the role of the adenosinergic system on the seizure and oxidative stress biomarkers induced by TR using antagonist of the adenosinergic receptors in the Albino mice. For that purpose, generated clonic seizure, as seizure threshold, was evaluated by TR. Caffeine (CAF; 8 mg/kg, i.p.), a nonselective antagonist of adenosine receptors, was administered 1 hour before the seizure induction. The seizure threshold significantly increased by CAF-treated group when compared to TR group (

Pyrethroids are a class of synthetic insecticides that are used widely in and around households to control the pest. Concerns about exposure to this group of pesticides are now mainly related to their neurotoxicity and nigrostriatal dopaminergic neurodegeneration seen in Parkinson’s disease. The main neurotoxic mechanisms include oxidative stress, inflammation, neuronal cell loss, and mitochondrial dysfunction. The main neurodegeneration targets are ion channels. However, other receptors, enzymes, and several signalling pathways can also participate in disorders induced by pyrethroids. The aim of this review is to elucidate the main mechanisms involved in neurotoxicity caused by pyrethroids deltamethrin, permethrin, and cypermethrin. We also review common targets and pathways of Parkinson’s disease therapy, including Nrf2, Nurr1, and PPARγ, and how they are affected by exposure to pyrethroids. We conclude with possibilities to be addressed by future research of novel methods of protection against neurological disorders caused by pesticides that may also find their use in the management/treatment of Parkinson’s disease.

The preservation of the redox homeostasis is critical for cell survival and functionality. Redox imbalance is an essential inducer of several pathological states. CD4+ /helper T cells are highly dependent on the redox state of their surrounding milieu. The potential of the aryl hydrocarbon receptor (AhR) engagement in controlling CD4+ T-cell fate during redox alteration is still challenging. C57BL/6 mice were treated with AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ), AhR antagonist CH223191, an inhibitor of glutathione biosynthesis buthionine sulfoximine (BSO), and the antioxidant N-acetylcysteine (NAC) alone or in combination. Six days later, splenocytes were evaluated for the expression of the redox-related genes and the possible changes in T-cell subsets. FICZ like BSO significantly elevated the expression of HMOX1, GCLC, and GCLM genes but it failed to increase the expression of the Nrf2 gene. Moreover, FICZ + BSO increased while FICZ + CH223191 or NAC decreased the expression of these genes. FICZ also significantly increased Th1 cell numbers but decreased Tregs in a dose-dependent manner. Furthermore, a high dose of FICZ + CH223191 + NAC significantly enhanced Th1, Th17, and Treg cells but its low dose in such a situation increased Th2 and Th17 while decreased Treg cells. AhR engagement during redox alteration can determine the fate of CD4 + T cells, so, AhR agonists or antagonists might be useful in assessing immune responses. However, these results need further verifications in vitro and in animal models of various diseases.

Mg2+ is an important cation in our body. It is an essential cofactor for many enzymes. Despite many works, nothing is known about the protective effects of MgSO4 against hypoxia-induced lethality and oxidative damage in brain mitochondria. In this study, antihypoxic and antioxidative activities of MgSO4 were evaluated by three experimental models of induced hypoxia (asphyctic, haemic, and circulatory) in mice. Mitochondria protective effects of MgSO4 were evaluated in mouse brain after induction of different models of hypoxia. Antihypoxic activity was especially pronounced in asphyctic hypoxia, where MgSO4 at dose 600 mg/kg showed the same activity as phenytoin, which used as a positive control ( P < 0.001 ). In the haemic model, MgSO4 at all used doses significantly prolonged latency of death. In circulatory hypoxia, MgSO4 (600 mg/kg) doubles the survival time. MgSO4 significantly decreased lipid peroxidation and protein carbonyl and improved mitochondrial function and glutathione content in brain mitochondria compared to the control groups. The results obtained in this study showed that MgSO4 administration has protective effects against lethality induced by different models of hypoxia and improves brain mitochondria oxidative damage.

The wide use of phthalates, as phthalates are used in the manufacturing of not only plastics but also many others goods, has become a main concern in the current century because of their potency to induce deleterious effects on organism health. The toxic effects of phthalates such as reproductive toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, teratogenicity, and tumor development have been widely indicated by previous experimental studies. Some of the important mechanisms of toxicity by phthalates are the induction and promotion of inflammation, oxidative stress, and apoptosis. Awareness of the involved molecular pathways of these mechanisms will permit the detection of exact molecular targets of phthalates to protect or treat their toxicity. Up to now, various transcription factors and signaling pathways have been associated with phthalate-induced toxicity which by influencing on nuclear surface and the expression of different genes can alter cell hemostasis. In different studies, the role of nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), and phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathways in processes of oxidative stress, inflammation, apoptosis, and cancer has been shown following exposure to phthalates. In the present review, we aim to survey experimental studies (in vitro and in vivo) in order to show firstly the most involved receptors and also the importance and the role of the mentioned signaling pathways in phthalate-induced toxicity, and with considering this point, the future studies can focus on these molecular targets as a strategic method to reduce environmental chemicals-induced toxicity especially phthalates toxic effects.

Background Cyclophosphamide (CP), as an anticancer agent, causes ovarian toxicity and subsequent infertility in women. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties. Objective The aim of this study was to investigate the protective effect of ATV against CP-induced ovarian injury in rat. Materials and methods In this experimental study, thirty-two female Wistar rats were randomly divided into four groups as I) control, II) ATV (10 mg/kg), III) CP (150 mg/kg), and IV) CP +ATV. The ATV treated groups were received ATV for 10 days via oral gavage. In the CP+ATV group, ATV was administrated on 5 days before and 5 days after CP injection. Histological structure, apoptosis (caspase-3), oxidative stress parameters as malondialdehyde, reactive oxygen species, protein carbonyl levels and cell viability were evaluated in ovary tissue by histological scores, immunohistochemistry, histochemical and biochemical assays. The levels of estrogen and progesterone hormones were measured on the 12th day of study. Results ATV pretreatment significantly decreased the levels of oxidative stress biomarkers as malondialdehyde, reactive oxygen species and protein carbonyl levels and increased cell death in CP-treated rats as compared with the CP alone group. ATV significantly increased estrogen and progesterone levels in CP-treated rats. In addition, the histological examination showed ATV mitigated acute inflammation, degenerative cells in stroma and follicles, stromal edema, vacuolization, atresia of the follicles and congestion of blood vessels in the CP-treated animals. Furthermore, ATV significantly reduced immunoreactivity level of caspase-3 in CP-treated rats. Conclusion Our results showed that the ATV with antioxidant and anti-apoptosis (caspase-3) activities protected ovarian against CP-induced toxicity.

Cholestasis is a disorder characterized by impaired bile flow and accumulation of cytotoxic bile acids in the liver. On the other hand, oxidative stress and its deleterious consequences seem to have a significant role in cholestasis-induced organ injury. Hence, antioxidants and thiol-reducing agents could have potential protective effect against this complication. The current investigation was designed to evaluate the effect of dithiothreitol (DTT) as a safe and clinically applicable thiol-reductant in cholestatic animals. DTT is a dithiol compound which effectively reduces disulfide bonds in glutathione molecule or different proteins and preserves cellular redox environment. Bile duct ligated (BDL) mice were supplemented with DTT-containing drinking water (0.25% and 1% w: v) for 14 days. Blood, liver, kidney, and spleen samples were collected at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant elevation in plasma biomarkers of liver and kidney injury was detected in BDL animals. Liver and kidney injury was also histopathologically evident by necrosis, inflammation, and fibrosis. Furthermore, high levels of reactive oxygen species in addition to lipid peroxidation, depleted glutathione reservoirs, and impaired tissue antioxidant capacity was detected in the liver and kidney of cholestatic animals. It was found that DTT supplementation (0.25% and 1% w:v) alleviated markers of oxidative stress in the liver and kidney. Moreover, liver and kidney histopathological changes and collagen deposition were markedly attenuated by DTT treatment. The beneficial effects of DTT administration in cholestasis and its associated complications might be linked to its ability for preserving cellular redox environment and preventing oxidative stress.

Cholestasis is the stoppage of bile flow which could lead to serious clinical complications if not managed. Cytotoxic bile acids are involved in the pathogenesis of liver injury during cholestasis. There are no promising pharmacological interventions against cholestasis and its associated complications. This study examined the impact of glycine supplementation on liver mitochondria as a major target of bile acids-induced toxicity during cholestasis. Mice underwent BDL operation and received glycine (0.25% and 1% w:v in drinking water). Blood and liver samples were collected at scheduled time intervals (3, 7, and 14 days after BDL surgery). Plasma biomarkers of liver injury, along with markers of oxidative stress in the liver tissue were evaluated. Furthermore, liver mitochondria were isolated, and several mitochondrial indices were assessed. BDL-induced cholestasis was evident in mice as a significant elevation in plasma biomarkers of liver injury. Markers of oxidative stress were significantly increased in the liver of BDL animals. Liver injury was histopathologically evident by tissue necrosis, bile duct proliferation, hydropic changes, inflammation, and fibrosis. Furthermore, high level of reactive oxygen species, lipid peroxidation, depleted glutathione reservoirs, and impaired tissue antioxidant capacity were also detected in the liver of cholestatic mice. An assessment of liver mitochondrial function in BDL animals revealed an inhibition of mitochondrial dehydrogenases activity, collapse of mitochondrial membrane potential, mitochondrial swelling, and increase of reactive oxygen species (ROS), and lipid peroxidation (LPO). Furthermore, a significant decrease in mitochondrial ATP was detected in the liver mitochondria isolated from cholestatic animals. Glycine supplementation (0.25% and 1%) decreased mitochondrial swelling, ROS, and LPO. Moreover, glycine treatment improved mitochondrial membrane potential and restored liver mitochondrial ATP. On the other hand, it was found that glycine supplementation attenuated oxidative stress markers in the liver of BDL animals. Moreover, liver histopathological changes and collagen deposition were markedly mitigated by glycine treatment. The mechanisms for the beneficial effects of glycine administration in cholestatic animals might be linked to its ability for preserving cellular redox environment, preventing oxidative stress, and maintaining mitochondrial functionality.

Cyclophosphamide (CP), as a chemotherapy drug, induces hepatotoxicity through causing oxidative stress. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties. The present study was designed to investigate the protective effects of ATV against CP-induced hepatotoxicity in rat. In this experimental study, 32 rats were treated with ATV orally at a dose of 10 mg/kg for 10 consecutive days, 5 days before and 5 days after the administration of a single intraperitoneal injection of CP (150 mg/kg). The hepatoprotective effect of ATV was evaluated by measuring liver function markers, oxidative markers, histological and immunohistochemical assays. The biochemical results showed that administration of CP increased hepatic biomarkers enzymes as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels. CP increased malondialdehyde (MDA), protein carbonyl (PC) and decreased glutathione (GSH) content in rats. Moreover, administration of CP was associated with periportal leucocyte infiltration, dilation sinusoids, hepatocyte vacuolation, congestion and hemorrhage in livers of rats. CP significantly increased immunoreactivity of caspase-3 as a marker of apoptosis in liver tissue. ATV markedly mitigated liver injury through reduction in oxidative stress biomarkers, histopathological findings and apoptosis. The antioxidant and anti-apoptotic activities of ATV are main proposed mechanisms involved in its hepatoprotective effects against CP-induced hepatic injury.

Diazinon (Dz) is a widely used insecticide. It can induce nephrotoxicity and neurotoxicity via oxidative stress. Captopril, an angiotensin-converting enzyme inhibitor, is known for its antioxidant properties. In this study, we used captopril for ameliorating of Dz-induced kidney and brain toxicity in rats. Animals were divided into five groups as follows: negative control (olive oil), Dz (150 mg kg−1), captopril (60 and 100 mg kg−1) and positive control (N-acetylcysteine 200 mg kg−1) were injected intraperitoneally 30 min before Dz. After 24 h, animals were anesthetized and the brain and kidney tissues were separated. Then oxidative stress factors were evaluated. Also, blood was collected for assessment of blood urea nitrogen (BUN), creatinine (Cr) and nitric oxide (NO) levels. Dz significantly increased oxidative stress markers such as reactive oxygen species (ROS), lipid peroxidation, and protein carbonyl as well as glutathione (GSH) oxidation in both tissues. Increased levels of the BUN, Cr and...

Objectives: Organophosphate (OP) pesticides inhibit both red blood cell (RBC) and plasma cholinesterases (ChEs). Oximes, especially pralidoxime (2-PAM), are widely used as antidotes to treat OP poisoning. In addition, N-acetylcysteine (NAC) is sometimes used as an adjuvant antidote. The current study aimed to assess the feasibility of using NAC as a single therapeutic agent for OP poisoning in comparison to in vitro 2-PAM. Methods: This study was carried out at the Razi Drug Research Center of Iran University of Medical Sciences, Tehran, Iran, between April and September 2014. A total of 22 healthy human subjects were recruited and 8 mL citrated blood samples were drawn from each subject. Dichlorvos-inhibited blood samples were separately exposed to low and high doses (final concentrations of 300 and 600 μmol.L- 1 , respectively) of 2-PAM, NAC and cysteine. Plasma and RBCs were then separated by centrifugation and their ChE activity was measured using spectrophotometry. Results: Although cysteine—and not NAC—increased the ChE activity of both plasma and RBCs over those of dichlorvos, it did not increase them over those of a high dose of 2-PAM. Conclusion: These results suggest that the direct reactions of 2-PAM and cysteine with dichlorvos and the reactivation of phosphorylated ChEs occurr via an associative stepwise addition-elimination process. High therapeutic blood concentrations of cysteine are needed for the elevation of ChE activity in plasma and RBCs; however, both this agent and NAC may still be effective in the reactivation of plasma and RBC ChEs.

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.

Oxidative stress is believed to be an important cause of sperm damage during freezing. l-Carnitine (LC) may have the potential to improve sperm quality after frozen-thawed process. The present study aimed to investigate the effect of LC supplementation in cryoprotectant media of mouse epididymal sperm on post-thaw sperm quality and expression of apoptosis-related genes. Male BALB/cJ mice spermatozoa were cryopreserved in a cryoprotectant medium containing 2.5 or 5 mM LC. The untreated group was cryopreserved with the cryoprotectant medium only. Six months following cryopreservation, the samples were thawed and sperm quality parameters, chromatin and acrosome integrity, reactive oxygen species (ROS) and glutathione (GSH) levels, mitochondrial activity, and mRNA expression of Bax and Bcl-2 were assessed. The results demonstrated that the concentration of 5 mM LC in cryoprotectant media exhibited higher values for the sperm quality parameters and integrity of chromatin and acrosome in post-thaw spermatozoa than those of the untreated group. Furthermore, sperm ROS levels decreased while GSH and mitochondrial activity levels increased in 5 mM LC group compared to those in the untreated group (P 0.01). In 5 mM LC-treated group, Bax was down-regulated (P 0.05) while Bcl-2 was up-regulated (P 0.001) compared to the untreated group. Collectively, LC supplementation of cryoprotectant medium improved the quality of frozen-thawed mouse epididymal spermatozoa, as showed reduced ROS level and Bax expression as well as increased GSH, mitochondrial activity, and Bcl-2 expression.

Microbial exopolysaccharides (EPSs) have recently served as an efficient substrate for the production of biocompatible metal nanoparticles (NPs) given their favorable stabilizing and reducing properties due to the presence of polyanionic functional groups in their structure. In the present work, Pantoea sp. BCCS 001 GH was used to produce EPS-stabilized biogenic Fe NPs as a complex through a novel biosynthesis reaction. Physicochemical characterization of the EPS–Fe complex was performed, indicating high thermal stability, desirable magnetic properties due to the uniform distribution of the Fe NPs with the average size of ∼10 nm and spherical shape within the EPS matrix. In addition, the in vivo toxicity of the EPS-stabilized Fe NPs was evaluated to investigate their potential for the treatment of iron deficiency anemia. Biological blood parameters and organ histology studies confirmed very high safety of the biosynthesized composite, making EPS–Fe a suitable candidate with an economical and environment friendly synthesis method for a wide spectrum of potential fields in medicine.

Background: Cyclophosphamide (CP), as a chemotherapy drug, causes severe damage in testicular tissue through producing free radicals. Cerium oxide nanoparticles (NC) exhibit antioxidant and anti-inflammatory properties. The purpose of this study was to investigate the protective effect of NC on CP-induced testicular damage in mice. Methods: In this experimental study, thirty-two male mice were divided into four groups (eight mice in each group). The control group was received intraperitoneally (IP) normal saline, NC group was received NC for three consecutive days (100 μg/kg, IP), CP group was received CP (200 mg/kg, IP), and the CP + NC group received NC, three consecutive days before receiving CP. After 2 days, testicles were assessed for biochemical, histomorphometrical, histopathological, and immunohistochemical analyses. Results: CP administration caused statistically significant increases in sperm abnormality, malondialdehyde, protein carbonyl levels, reactive oxygen species, level and apoptosis, and decreases in sperm count, sperm viability, testosterone, glutathione activity, the mean thickness of the germinal epithelium, diameter of seminiferous tubules in mice. Degeneration, necrosis, arrest of spermatogenesis, congestion, and atrophy in testicular tissue confirmed the low Johnsen's Testicular score in CP group. Administration of NC significantly ameliorated the CP-induced adverse effects on testis compared with the CP group. In addition, pretreatment mice with NC significantly reduced caspase-3 immunoreactivity induced by CP in testis. Conclusions: This study showed that NC with scavenging free radicals and antiapoptotic properties enable to reduce the side effects of CP in the testicular tissue.

Methotrexate is a folate analog used against a wide range of diseases including malignancies and autoimmune disorders. On the other hand, clinical use of the MTX is associated with kidney injury and renal failure. There is no clear mechanism for MTX-induced renal injury. The current investigation was designed to evaluate the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of MTX-induced renal injury. Rats received MTX (a single dose of 20 or 30 mg/kg, i.p). Five days after MTX administration, serum biomarkers of kidney injury and tissue markers of oxidative stress were assessed. Moreover, kidney mitochondria were isolated, and several mitochondrial indices were determined. MTX-treated animals developed biochemical evidence of renal injury as judged by elevated serum blood urea nitrogen (BUN), creatinine (Cr) and along with hypokalemia, hypophosphatemia, hypocalcemia, and a decrease in serum glucose, and uric acid. Moreover, MTX caused an increase in kidney reactive oxygen species and lipid peroxidation. Renal glutathione reservoirs were also depleted, and tissue antioxidant capacity was decreased in MTX-treated animals. Kidney histopathological changes including interstitial inflammation, renal tubular degeneration, retraction glomeruli, and vascular congestion were also evident in MTX-treated rats. On the other hand, it was found that mitochondrial parameters including mitochondrial membrane potential, mitochondrial dehydrogenases activity, and mitochondrial glutathione and ATP content were decreased, while lipid peroxidation and mitochondrial permeabilization were increased with MTX treatment. These data suggest a role for mitochondrial dysfunction and oxidative stress in the mechanism of MTX nephrotoxicity.

Nausea and vomiting are the most common symptoms in different diseases. Medicinal plants are considered as a reliable source of new drugs to control these symptoms. In this study, we evaluated the antiemetic and neuroprotective effects of the methanolic extract of Sambucus ebulus L. fruit and relationship between emesis (retching) and oxidative stress biomarkers in the mitochondria brain of young chickens. Emesis was induced by ipecac and copper sulphate (60 and 600 mg/kg, orally), respectively, and the methanolic extracts (50, 100, 200 mg/kg) were injected intraperitoneally (i.p.). The extract showed a significant antiemetic activity against ipecac and copper sulphate-induced emesis at all doses (p

The objective of the present study was to investigate the role of nanocarrier of magnetic isotope of 25-Mg2+ (PMC16) in liver toxicity, ATP content and oxidative stress due to malathion (MAL) exposure. PMC16 nanoparticles were administered in different doses (0.05, 0.1 and 0.2 LD50) intravenously (iv) 40 minutes after a single MAL (0.25 LD50= 207 mg/kg) intraperitoneal (ip) injection as a complement to standard therapy of pralidoxime (PAM) and atropine (AT). MgSO4 was used as another supplement for comparison with PMC16. ATP/ADP ratio, antioxidant enzymes including catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and oxidative stress biomarker including lipid peroxidation (LPO) were evaluated in liver tissue cells. Results indicated that after MAL administration, ADP/ATP ratio had a significant increase in liver tissues in comparison with control but this ratio was improved using various doses of PMC16. LPO was significantly decreased at all doses of PMC16 and MgSO4 when compared with MAL-exposed group. SOD and CAT activities significantly were increased in MAL-treated group as compared to saline group. SOD was reduced by all doses of PMC16 and CAT activity was decreased in PMC16-0.1 group. These results lead us to conclude that PMC16 and MgSO4 are so useful for protection against MAL-induced liver toxicity, ATP depletion and oxidative damages.

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.

The present work was designed to examine the effect of a new (25)Mg(2+)-carrying nanoparticle (PMC16) on energy and oxidative stress parameters inside the heart of the rats exposed to acute mild toxic dose of malathion, a widely used organophosphate. Post a single intraperitoneal (ip) injection of malathion (0.25 of LD50), PMC16 at different doses (0.05, 0.1, and 0.2 of LD50) was administered intravenously (iv) as a supplement to standard therapy of atropine and pralidoxime. MgSO(4) was used as another supplement for comparison with PMC16. Oxidative stress biomarkers including lipid peroxidation (LPO) and reactive oxygen species (ROS), antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), ATP/ADP ratio, and Mg in the cardiac cells were determined. Results indicated a significant increase in LPO, ROS, ADP/ATP ratio, and a decrease in Mg post-malathion poisoning in comparison to controls. All of these parameters were improved by use of standard therapy either with MgSO4 or various doses of PMC16. The activities of SOD, CAT, and GPx did not change significantly in the present acute malathion poisoning model and neither MgSO(4) or PMC16 had no considerable improvement on these parameters. Comparing groups that received normal Mg and those of various doses of PMC16, a significant difference was found with the PMC16 (0.2 LD50) group. PMC16 0.2 reduced cardiac cells LPO and ROS of Mal-exposed animals rather than that of MgSO4. PMC16 0.2 was also significantly better than MgSO(4) in improving MAL-induced changes in ADP/ATP ratio and also intracellular Mg levels. This study illustrates that malathion-induced cardiac cells toxicity is improved by administration of Mg as a result of increasing cardiac ATP through active transport of Mg inside the cells. Finally, the results of this study support positive effects of this magnetic Mg nanoparticle carrier but do not confirm its absolute efficacy that remains to be explored by further tests in different animal models and organs before moving to a phase I human trial.

Oxidative stress is the main cause of hexavalant chromium-induced damage in chrome electroplating workers. The main goal of this study is toxicity analysis and the possibility of toxicity risk categorizing in the chrome electroplating workers based on oxidative stress parameters as prognostic variables. We assessed blood chromium levels and biomarkers of oxidative stress such as lipid peroxidation, thiol (SH) groups and antioxidant capacity of plasma. Data were subjected to principle component analysis (PCA) and artificial neuronal network (ANN) to obtain oxidative stress pattern for chrome electroplating workers. Blood chromium levels increased from 4.42 ppb to 10.6 ppb. Induction of oxidative stress was observed by increased in lipid peroxidation (22.38 ± 10.47 μM versus 14.74 ± 4.82 μM, p 0.0008), decreased plasma antioxidant capacity (3.17 ± 1.35 μM versus 7.74 ± 4.45 μM, p 0.0001) and plasma total thiol (SH groups) (0.21 ± 0.07 μM versus 0.45 ± 0.41 μM, p 0.0042) in comparison to controls. Based on the oxidative parameters, two groups were identified by PCA methods. One category is workers with the risk of oxidative stress and second group is subjects with probable risk of oxidative stress induction. ANN methods can predict oxidative-risk category for assessment of toxicity induction in chrome electroplaters. The result showed multivariate modeling can be interpreted as the induced biochemical toxicity in the workers exposed to hexavalent chromium. Different occupation groups were assessed on the basis of risk level of oxidative stress which could further justify proceeding engineering control measures.

Patulin is a secondary metabolite produced mainly in rotten parts of apples by a wide range of fungi. Due to its mutagenic and teratogenic nature and possible health risks to consumers, many countries have regulations to reduce level of patulin in apple products to as low as practically possible. A survey of the presence of patulin was conducted in 2002 on 65 locally produced commercial apple juice and apple juice concentrates purchased from retail outlets or producers in Iran. In this study 42 samples of apple juice and 23 apple juice concentrate surveyed for patulin contamination. Results of the study showed in 69% of apple juice and 78% of the apple juice concentrates level of patulin found was higher than 15 μg/l. Overall 33% of the apple juice samples had patulin levels higher than 50 μg/l with maximum level of 285 μg/l and 56% of the apple juice concentrates with patulin level of higher than 50 μg/l and maximum level of 148 μg/l. Although the mean concentration of patulin in apple juice samples surveyed was slightly lower than maximum level recommended by the Codex Alimentarious, fairly high incidence of patulin in these samples indicates the need for improving production techniques by industry in order to reduce the incidence and level of patulin contamination in apple juices.

Medical management in acute organophosphate (OP) poisoning is not always successful because of tissue hypoxia which results in a reduction of heart contractility and cell damage. This study reports improvement of malathion (MAL)-induced cardiac failure by a nanocarrier of magnetic isotope of Mg (PMC16). A rat model of acute MAL poisoning was set up. PMC16 nanoparticle at doses of 0.05, 0.1, 0.2 LD50 = 896 mg/kg) were administered intravenously (iv) 30 minutes after a single intraperitoneal (ip) injection of MAL (0.25 LD50= 207 mg/kg). Atropine (AT; 40 mg/kg, ip) plus pralidoxime (PAM; 40 mg/kg, ip) and magnesium sulfate (MgSO4; 600 mg/kg, iv) were used as standard therapy or controls. Anesthetized animals were monitored for heart rate, electrocardiogram, blood pressure, and blood oxidative stress biomarkers like cellular lipid peroxidation, total thiol molecules, antioxidant power, gamma glutamil transpeptidase, and acetylcholinesterase (AChE) as a marker of OP toxicity. Results indicated that after MAL administration, heart rate and BP decreased and R-R duration increased. PMC16 markedly restored BP at all doses as compared with MgSO4. PMC16 at the dose of 0.05 LD50 significantly increased BP in comparison to AT + PAM. PMC16 restored heart rate at dose of 0.2 LD50 and reduced lipid peroxidation at dose of 0.05 LD50 as compared to MgSO4. PMC16 also improved total antioxidant power at all doses when compared to AT + PAM and reduced GGT activity at dose of 0.2 LD50 but did not affect total thiol molecules. MgSO4could improve MAL-induced reduction of total antioxidant power. After 24 h, PMC16 significantly improved MAL-suppressed AChE activity at doses of 0.05 and 0.1 LD50. PMC16 at all doses significantly recovered MAL-induced arrhythmia when compared to standard therapies. It is concluded that PMC16 is able to control OP-induced cardiac failure and toxicity.

Aluminium phosphide (AlP) is a storage fumigant pesticide, which is used to protect stored grains especially from insects and rodents. It releases phosphine (PH 3 ) gas, a highly toxic mitochondrial poison, in contact with moisture, particularly if acidic. Although the exact mechanism of action is unknown so far, the major mechanism of PH 3 toxicity seems to be the inhibition of cytochrome-c oxidase and oxidative phosphorylation which eventually results in adenosine triphosphate (ATP) depletion and cell death. Death due to AlP poisoning seems to be as a result of myocardial damage. No efficient antidote has been found for AlP poisoning so far, and unfortunately, most of the poisoned human cases die. PH 3 , like ammonia (NH 3 ), is a Lewis base with a lone-pair electron. However, boric acid (B(OH) 3 ) is a Lewis acid with an empty p orbital. It is predicted that lone-pair electron from PH 3 is shared with the empty p orbital from B(OH) 3 and a compound forms in which boron attains its octet. In other words, PH 3 is trapped and neutralised by B(OH) 3 . The resulting polar reaction product seems to be excretable by the body due to hydrogen bonding with water molecules. The present article proposes boric acid as a non-toxic and efficient trapping agent and an antidote for PH 3 poisoning by investigating the chemical reaction between them.