Glycine protects the male reproductive system against lead toxicity via alleviating oxidative stress, preventing sperm mitochondrial impairment, improving kinematics of sperm, and blunting the downregulation of enzymes involved in the steroidogenesis.

Lead (Pb) is a highly toxic heavy metal widely dispersed in the environment because of human industrial activities. Many studies revealed that Pb could adversely affect several organs, including the male reproductive system. Pb-induced reproductive toxicity could lead to infertility. Thus, finding safe and clinically applicable protective agents against this complication is important. It has been found that oxidative stress plays a fundamental role in the pathogenesis of Pb-induced reprotoxicity. Glycine is the simplest amino acid with a wide range of pharmacological activities. It has been found that glycine could attenuate oxidative stress and mitochondrial impairment in various experimental models. The current study was designed to evaluate the role of glycine in Pb-induced reproductive toxicity in male mice. Male BALB/c mice received Pb (20 mg/kg/day; gavage; 35 consecutive days) and treated with glycine (250 and 500 mg/kg/day; gavage; 35 consecutive days). Then, reproductive system weight indices, biomarkers of oxidative stress in the testis and isolated sperm, sperm kinetic, sperm mitochondrial indices, and testis histopathological alterations were monitored. A significant change in testis, epididymis, and Vas deferens weight was evident in Pb-treated animals. Markers of oxidative stress were also significantly increased in the testis and isolated sperm of the Pb-treated group. A significant disruption in sperm kinetic was also evident when mice received Pb. Moreover, Pb exposure caused significant deterioration in sperm mitochondrial indices. Tubular injury, tubular desquamation, and decreased spermatogenic index were histopathological alterations detected in Pb-treated mice. It was found that glycine significantly blunted oxidative stress markers in testis and sperm, improved sperm mitochondrial parameters, causing considerable higher velocity-related indices (VSL, VCL, and VAP) and percentages of progressively motile sperm, and decreased testis histopathological changes in Pb-exposed animals. These data suggest glycine as a potential protective agent against Pb-induced reproductive toxicity. The effects of glycine on oxidative stress markers and mitochondrial function play a key role in its protective mechanism.

N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats.

Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.

Antidotal effect of dihydroxyacetone against phosphine poisoning in mice.

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

Disturbed mitochondrial redox state and tissue energy charge in cholestasis.

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.

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 µM and 0.17 µM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 µM for l-tyrosine and 9.30 µM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 µM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.

α-Melanocyte-Stimulating Hormone Triggers Melanogenesis Via Activation of the Aryl Hydrocarbon Receptor Pathway in B16F10 Mouse Melanoma Cells.

Melanin is a group of natural pigments that determines the human skin color and provides fundamental protection against the harmful impacts of physical and chemical stimuli. The aim of this study was to establish the regulatory role of aryl hydrocarbon receptor (AhR) in α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis. In the present study, following knockdown of AhR, murine B16F10 cells were treated with α-MSH (200 nM) and tyrosinase activities, cellular melanin content, mRNA levels of several important genes involved in melanogenesis including AhR, CTNNB1, TYR2, and microphthalmia-associated transcription factor (MITF) were measured as endpoints. Exposure to α-MSH led to elevated expression of AhR, CTNNB1, MITF, and TYR in accordance with increased tyrosinase enzyme activity as well as a significant rise in the total melanin content. Our results suggest that AhR plays a regulatory role in α-MSH-stimulated melanogenesis.

The mechanisms of arsenic-induced ovotoxicity, ultrastructural alterations, and autophagic related paths: An enduring developmental study in folliculogenesis of mice.

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.

Taurine prevents mitochondrial membrane permeabilization and swelling upon interaction with manganese: Implication in the treatment of cirrhosis-associated central nervous system complications.

Brain tissue manganese (Mn) accumulation is a cirrhosis-associated complication. Cellular mitochondria are among the potential targets for Mn-induced cytotoxicity. Taurine is one of the most abundant amino acids with high concentrations in human brain tissue. Several pharmacological properties including regulation of mitochondrial function are attributed to taurine. The current investigation was designed to evaluate the effect of taurine on Mn-induced mitochondrial impairment in isolated mice brain mitochondria. The brain mitochondria were exposed to increasing concentrations of Mn (0.1-10 mM). Taurine (0.1, 1, and 10 mM) was added as the protective agent. The severe collapse of mitochondrial membrane potential, decreased mitochondrial dehydrogenases activity, mitochondrial swelling, and depleted mitochondrial adenosine triphosphate (ATP) were evident in Mn-exposed mitochondria. It was found that taurine administration preserved mitochondrial ATP, prevented mitochondrial depolarization and swelling, and increased mitochondrial dehydrogenases activity. These data suggest mitochondrial protection as an underlying mechanism for the protective effects of taurine against Mn toxicity.

Concurrent assessment of calpain and caspase3 activities in brains of mice with acetaminophen-induced acute hepatic encephalopathy.

To develop pharmacological therapy for acute hepatic encephalopathy (AHE), understanding the molecular basis for cell injury is essential. Excitotoxic neural cell injury mediated by calpain as a post- receptor mechanism has been proposed as a player in neuronal injury in AHE. Concurrent assessment of Calpain and Caspase3 activities in the brain of AHE mice in acetaminophen- induced mourine model was performed. After induction of AHE by acetaminophen in mice, the model was confirmed by histopathological, biochemical and behavioural studies. The brains were removed, western blot analysis was done and the relative activity of calpain and caspase was estimated and compared to control group calpain but not caspase 3 activity was significantly increased in the AHE group compared to the control brains. Experimentally, this finding is the first to report. Increased calpain activity in liver has been previously reported. To translate both finding it can be suggested that calpain inhibition can be an investigational intervention in saving lives in AHE. To confirm the results, besides more advanced toxicodynamic studies on acetaminophen, the results should be confirmed in other models of AHE in future.

Prevention of phosphine-induced cytotoxicity by nutrients in HepG2 cells.

BACKGROUND & OBJECTIVES: Phosphides used as an insecticide and rodenticide, produce phosphine (PH3) which causes accidental and intentional poisoning cases and deaths. There is no specific treatment or antidote available for PH3poisoning. It is suggested that PH3-induced toxicity is associated with adenosine triphosphate (ATP) depletion; therefore, in this study the effect of some nutrients was evaluated on PH3cytotoxicity in a cell culture model. METHODS: PH3was generated from reaction of zinc phosphide (10 mM) with water in the closed culture medium of HepG2 cells, and cytotoxicity was measured after one and three hours of incubation. ATP, glutathione (GSH) and lipid peroxidation were also assessed at one or three hours post-incubation. ATP suppliers including dihydroxyacetone, glyceraldehyde and fructose were added to the culture medium 10 min before PH3generation to prevent or reduce phosphine-induced cytotoxicity. RESULTS: Phosphine caused about 30 and 66 per cent cell death at one and three hours of incubation, respectively. ATP content of the cells was depleted to 14.7 per cent of control at one hour of incubation. ATP suppliers were able to prevent cytotoxicity and ATP depletion induced by PH3. Dihydroxyacetone, α-ketoglutarate, fructose and mannitol restored the ATP content of the cells from 14.7 per cent to about 40 , 34 , 32 and 30 per cent, respectively. Lipid peroxidation and GSH depletion were not significantly induced by zinc phosphide in this study. INTERPRETATION & CONCLUSIONS: The results supported the hypothesis that phosphine-induced cytotoxicity was due to decrease of ATP levels. ATP suppliers could prevent its toxicity by generating ATP through glycolysis. α-keto compounds such as dihydroxyacetone and α-ketoglutarate may bind to phosphine and restore mitochondrial respiration.

Carbonyl traps as potential protective agents against methimazole-induced liver injury.

Liver injury is a deleterious adverse effect associated with methimazole administration, and reactive intermediates are suspected to be involved in this complication. Glyoxal is an expected reactive intermediate produced during methimazole metabolism. Current investigation was undertaken to evaluate the role of carnosine, metformin, and N-acetyl cysteine as putative glyoxal (carbonyl) traps, against methimazole-induced hepatotoxicity. Methimazole (100 mg/kg, intraperitoneally) was administered to intact and/or glutathione (GSH)-depleted mice and the role of glyoxal trapping agents was investigated. Methimazole caused liver injury as revealed by an increase in serum alanine aminotransferase and aspartate aminotransferase. Moreover, lipid peroxidation and protein carbonylation occurred significantly in methimazole-treated animals' liver. Hepatic GSH reservoirs were decreased, and inflammatory cells infiltration was observed in liver histopathology. Methimazole-induced hepatotoxicity was severe in GSH-depleted mice and accompanied with interstitial hemorrhage and necrosis of the liver. Glyoxal trapping agents effectively diminished methimazole-induced liver injury both in intact and/or GSH-depleted animals.

A comparison between the nephrotoxic profile of gentamicin and gentamicin nanoparticles in mice.

Aminoglycoside antibiotics are widely used against Gram-negative infections. On the other hand, nephrotoxicity is a deleterious side effect associated with aminoglycoside therapy. Gentamicin is the most nephrotoxic aminoglycoside. Because of serious health complications ensue the nephrotoxicity induced by aminoglycosides, finding new therapeutic strategies against this problem has a great clinical value. This study has attempted to compare the nephrotoxic properties of gentamicin and a new nanosized formulation of this drug in a mice model. Animals were treated with gentamicin (100 mg/kg, i.p. for eight consecutive days) and nanogentamicin (100 mg/kg, i.p. for eight consecutive days). Blood urea nitrogen (BUN), plasma creatinine levels, and histopathological changes of kidney proximal tubule were monitored. It was found that gentamicin caused severe degeneration of kidney proximal tubule cells and an increase in serum creatinine and BUN. No severe injury was observed after nanogentamicin administration. This study proved that nanosized gentamicin is less nephrotoxic.

Amitriptyline, clomipramine, and doxepin adsorption onto sodium polystyrene sulfonate.

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.

Carnitine in Alleviation of Complications Caused by Acute Valproic Acid Toxicity; an Exprimental Study on Mice.

Introduction: Hyperammonemia and hepatotoxicity are well-known complications of valproic acid (VPA) poisoning. The objective of this study is to evaluate the potential role of carnitine in mitigating the adverse effects of acute VPA toxicity in mice. Methods: 54 male mice (25-30 g) were randomly assigned to one of three categories, including acute, sub-acute, and chronic poisoning. Each category contained 3 groups, each consisting of 6 mice (Group 1: control, Group 2: VPA treated, and Group 3: VPA + carnitine treated). The animals were sacrificed 24 hours after the initial injection, and their blood, liver, and brain samples were compared between groups of each category regarding liver function biomarkers, oxidative stress markers, ammonia level, and liver histopathologic changes using one-way ANOVA followed by Tukey's multiple comparison test. Results: The administration of VPA increased the serum level of aspartate aminotransferase (AST) (p=0.003) and alanine aminotransferase (ALT) (p=0.001), as well as serum, and brain level of ammonia (p=0.0001 for both) in the intervention group. Elevated levels of lipid peroxidation and oxidative stress (p=0.0001 for both) in the liver tissue, decreased liver glutathione (p=0.0001) and ferric ion-reducing antioxidant power (FRAP) (p=0.0001), and histopathologic changes in the form of moderate to severe inflammation were observed. Administration of VPA + carnitine reduced AST (p=0.05) and ALT (p=0.01), increased the FRAP, reduced free oxygen radicals and liver lipid peroxidation (p=0.0001 for all), and decreased tissue damage in the form of moderate inflammation. The administration of carnitine was ineffective in reducing brain or plasma ammonia levels in acute VPA-treated animals (p = 0.0115). Conclusions: Although the administration of carnitine has been suggested as a protective remedy in cases of VPA toxicity, according to the present study, it did not have an antidotal effect and did not prevent encephalopathy or liver injury in acute VPA toxicity.

New immunological investigations on Helicobacter pylori-induced gastric ulcer in patients.

Although Helicobacter pylori (Hp) plays an important role in the pathogenesis of chronic gastritis and gastric ulcer, little is known about the probable mechanisms of these types of gastrointestinal damage. To determine the precise mechanisms involved in ulcer formation, immune responses in patients with gastric ulcer (GUP) caused by Hp infection (Hp(+)) were compared with those of other gastritis patients (GP). The sensitivity and proliferation of peripheral blood mononuclear cells (PBMNCs) obtained from patients were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against exposure with complex Hp crude antigen (HPCA) and mitogen (phytohemagglutinin, PHA). Production of inflammatory cytokines, including interleukin (IL)-1ß and IL-8, in serum and supernatants of PBMNCs were then measured by ELISA. It was found that, after stimulation with PHA, both IL-8 and IL-1ß concentrations in sera and supernatants as well as proliferation and sensitivity were statistically greater in GUP Hp(+) than GP Hp(-) . Furthermore, HPCA inhibited the proliferation of PBMNCs dose-dependently; however, it stimulated IL-8 and IL-1ß production in supernatants of mononuclear cells. Therefore, the up-regulated concentrations of IL-8 and IL-1ß may have been caused by increase in the size of mononuclear cell subpopulations or in their cytokine secretory activity, indicating the greatest cell responsiveness in GUP Hp(+) patients. These results suggest that tissue damage and ulcers occur in patients who produce more IL-8 and IL-1ß than patients who do not develop ulcers; the former consequently have more activated immune cells at the site of infection. Therefore, both host responses and Hp virulence factors may be involved in the development of gastric ulcers.

Taurine Improves Sperm Mitochondrial Indices, Blunts Oxidative Stress Parameters, and Enhances Steroidogenesis and Kinematics of Sperm in Lead-Exposed Mice.

Lead (Pb) is a highly toxic heavy metal. Pb exposure could adversely affect many organs, including the male reproductive system. Oxidative stress and mitochondrial impairment play a fundamental role in the pathogenesis of Pb-induced male reproductive system injury. Taurine (TAU) is abundantly found in mammalian bodies. The positive effects of TAU on oxidative stress biomarkers and mitochondrial function have been reported. The current study evaluated the effects of TAU on Pb-induced reproductive toxicity. Mice received Pb (20 mg/kg/day; gavage, 35 consecutive days). Then, sperm indices (quality and quantity) together with sperm kinetics, sperm mitochondrial parameters, testicular and sperm oxidative stress biomarkers, testis and plasma testosterone levels, and the expression of genes involved in the steroidogenesis process have been evaluated. Pb caused significant histopathological alterations and oxidative stress in male mice's reproductive system and sperm. Moreover, significant mitochondrial function impairment was evident in sperm isolated from Pb-treated mice. Pb exposure also suppressed the expression of StAR, 17ß-HSD, CYP11A, and 3ß-HSD genes in the male gonad. It was found that TAU (500 and 1000 mg/kg) significantly improved oxidative stress biomarkers in both male gonads and gametes of Pb-treated mice. TAU also significantly restored sperm mitochondrial function and kinetics. The expression of genes involved in steroidogenesis was also higher in TAU-treated animals. These data suggest TAU as an effective agent against Pb-induced reproductive toxicity. The effects of TAU on oxidative stress markers, mitochondrial function, and the steroidogenesis process seem to play a fundamental role in its protective properties. Further studies are warranted to detect the precise protective effects of this amino acid in the reproductive system. Lead (Pb) is a toxic element that adversely affects the male reproductive system. Mitochondrial impairment and oxidative stress have a crucial role in the Pb-induced reproductive toxicity. Taurine (TAU) could considerably improve the reproductive toxicity induced by Pb via enhancing mitochondrial function and mitigating oxidative stress indices. ΔΨ, mitochondrial membrane potential; ATP, adenosine triphosphate.

Dextromethorphan improves locomotor activity and decreases brain oxidative stress and inflammation in an animal model of acute liver failure.

Introduction: Hepatic encephalopathy (HE) is a serious clinical problem leading to severe neurological disorders and death. No specific treatment is available for the management of HE-associated neurological damage. This study aimed to evaluate the effect of dextromethorphan (DXM) on oxidative stress and disturbed locomotor activity in an animal model of HE. Material and methods: In the current study, BALB/c mice received acetaminophen (APAP; 1000 mg/kg, intraperitoneally [IP]). Dextromethorphan (0.5, 1, 5, 10 mg/kg, subcutaneously [SC]) was injected in three doses (every 6 h), starting two hours after acetaminophen. Animals' locomotor activity, brain and plasma ammonia levels, as well as biomarkers of oxidative stress and inflammatory cytokines in the brain tissue, were assessed 24 hours after acetaminophen injection. Results: It was found that APAP administration was significantly associated with liver damage and increased plasma biomarkers of liver injury. Ammonia levels in plasma and brain tissue of APAP-treated mice also increased significantly. There was also a significant difference in motor activity between the control and APAP-treated animals. The acute liver injury also increased the brain level of pro-inflammatory cytokines (tumor necrosis factor a [TNF-a], interleukin 6 [IL-6], and interleukin 1b [IL-1b]). It was found that DXM could significantly improve the motor activity of animals in all doses and decrease the biomarkers of inflammation and oxidative stress in the brain tissue of animals with hyperammonemia. Conclusions: The effect of dextromethorphan on oxidative stress and inflammation seems to be a major mechanism for its neuroprotective properties in HE. Based on these data DXM could be applied as an effective pharmacological option against HE-associated brain injury.

Influence of cellular redox environment on aryl hydrocarbon receptor ligands induced melanogenesis.

Many environmental pollutants, natural compounds, as well as endogenous chemicals exert their biological/toxicological effects by reacting with the aryl hydrocarbon receptor (AhR). Previous evidence shed new light on the role of AhR in skin physiology by regulating melanin production. In this study, we investigated the effect of oxidative imbalance induced by AhR ligands on the melanogenesis process in B16 murine melanoma cells. Exposure to 6-formylindolo[3,2-b] carbazole (FICZ) or benzo-α-pyrene (BαP) led to enhanced expression of CTNNB1, MITF, and TYR genes following increased tyrosinase enzyme activity and melanin content in an AhR-dependent manner. Analysis of the presence of reactive oxygen species (ROS) as well as reduced glutathione (GSH) / oxidized glutathione (GSSG) ratio revealed that treatment with AhR ligands is associated with oxidative stress which can be ameliorated with NAC (N-acetyl cysteine) or diphenyleneiodonium chloride (DPI). On the other hand, NAC and DPI enhanced melanogenesis induced by AhR ligands by reducing the level of ROS. We have shown for the first time that a cellular redox status is a critical event during AhR ligand-induced melanogenesis.

The effect of taurine supplementation on delirium post liver transplantation: A randomized controlled trial.

BACKGROUND & AIMS: Delirium is a prevalent complication of liver transplantation (LT). It may enhance the risk of morbidity and mortality. Taurine is considered to have antioxidant and neuroprotective activities. The aim of this study was to evaluate taurine supplementation effect on post-LT delirium. METHODS: Patients older than 18 years old who had received LT in Abu-Ali Sina transplantation center in Shiraz, Iran from September 2020 to June 2021, were enrolled in this double-blinded randomized clinical trial. Exclusion criteria was known hypersensitivity to taurine, pregnancy or breast-feeding and death within 72 h post-LT. Patients were randomly divided into two groups, each received 2 g/day placebo or taurine from the first day post-LT for 30 days. Delirium was assessed using Confusion Assessment Method-Intensive Care Unit (CAM-ICU). Mortality and rejection rates and length of Intensive Transplantation Unit (ITU) and hospital stays were evaluated within one month after transplantation. RESULTS: Two hundred and seven patients were divided into two groups. Twenty-eight and 23 patients were excluded due to their refuse to participate in the study and death within 72 h post-LT, respectively. Delirium rate within the first month was 23.08% and was significantly lower in taurine group (9.46%) compared with placebo (35.36%, P = 0.012). Length of ITU stay was significantly higher among delirious patients (P = 0.015) in this analysis. CONCLUSION: we reached to the result that taurine can prevent post-LT delirium, dramatically. Placebo receiving and longer stay in ITU were the only independent risk factors in this trial. REGISTRATION NUMBER OF CLINICAL TRIAL: The study was registered at the Iranian Registry of Clinical Trials (IRCT20200312046755N1; http://www.irct.ir/).

Cellular and mitochondrial taurine depletion in bile duct ligated rats: a justification for taurine supplementation in cholestasis/cirrhosis.

Taurine (TAU) is a free amino acid abundant in the human body. Various physiological roles have been attributed to TAU. At the subcellular level, mitochondria are the primary targets for TAU function. Meanwhile, it has been found that TAU depletion is associated with severe pathologies. Cholestasis is a severe clinical complication that can progress to liver fibrosis, cirrhosis, and hepatic failure. Bile duct ligation (BDL) is a reliable model for assessing cholestasis/cirrhosis and related complications. The current study was designed to investigate the effects of cholestasis/cirrhosis on tissue and mitochondrial TAU reservoirs. Cholestatic rats were monitored (14 and 42 days after BDL surgery), and TAU levels were assessed in various tissues and isolated mitochondria. There was a significant decrease in TAU in the brain, heart, liver, kidney, skeletal muscle, intestine, lung, testis, and ovary of the BDL animals (14 and 42 days after surgery). Mitochondrial levels of TAU were also significantly depleted in BDL animals. Tissue and mitochondrial TAU levels in cirrhotic animals (42 days after the BDL operation) were substantially lower than those in the cholestatic rats (14 days after BDL surgery). These data indicate an essential role for tissue and mitochondrial TAU in preventing organ injury induced by cholestasis/cirrhosis and could justify TAU supplementation for therapeutic purposes.