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Zoledronic acid (ZLD) is a bisphosphonate drug widely administered against pathological conditions such as hypercalcemia of malignancy, osteoporosis, bone metastases from solid tumors, and multiple myeloma. Unfortunately, renal injury is a serious and dose-limiting adverse effect of ZLD. There is no specific mechanism for ZLD-induced renal damage. The current study aimed to assess the effects of ZLD (10 and 15 mg/kg, i.p., single dose) on the rat kidney. In this regard, several parameters, including oxidative stress biomarkers, serum level of BUN and creatinine, inflammatory cytokines, kidney histopathology, and indices of mitochondrial function were assessed. A significant increase in serum Cr and BUN revealed renal injury. Moreover, kidney histopathological changes, including interstitial inflammation, tissue necrosis, and tubular atrophy, were detected in ZLD-treated rats. Biomarkers of oxidative stress, including a significant increase in reactive oxygen species (ROS), depletion of kidney glutathione (GSH) stores, increased lipid peroxidation, and suppression of the total antioxidant capacity, were detected in ZLD-treated animals. ZLD also significantly increased renal levels of TNF-α, IL-6, and IL-1β. ZLD exposure was also associated with significantly decreased mitochondrial dehydrogenases activity, mitochondrial depolarization, mitochondrial permeabilization, and ATP depletion. These data highlight mitochondrial dysfunction, inflammatory response, and oxidative stress as potential mechanisms in ZLD-induced kidney injury.

Insulitis is the inflammation of beta cells of the Langerhans islets. It is well-known that insulitis is a prevalent complication of diabetes. A series of xenobiotics, including drugs, could also induce insulitis. The current study evaluated the effect of zoledronic acid (ZLD) on the pancreas in an animal model. Actually, in an attempt to evaluate the adverse effects of ZLD on the kidney, we noticed severe morphological alterations in the pancreas. Therefore, the effects of ZLD on the pancreas tissue were further investigated. Rats received ZLD (10 and 15 mg/kg, single dose, i.p) and pancreas weight index, serum biomarkers of pancreas injury, the level of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), oxidative stress biomarkers in this organ, and pancreas histopathological alterations were assessed. A significant increase in pancreas weight index was detected in ZLD-treated animals. ZLD also significantly increased serum amylase and lipase levels. No significant changes in serum glucose were detected in this study. A significant increase in reactive oxygen species, lipid peroxidation, decreased glutathione levels, and antioxidant capacity was also evident in the pancreas of ZLD-treated rats. Histopathological findings indicate the insulitis lesions of the islets of Langerhans at both doses of 10 and 15 mg/kg of ZLD. The data obtained from this study revealed insulitis as a serious adverse effect associated with high doses of ZLD. Clearly, further studies are warranted to evaluate the effects of other doses and/or patterns of administration of ZLD on pancreas tissue and, finally, the clinical significance of these data.

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.

Objective: Management of pregnancy complicated by severe early-onset fetal growth restriction (FGR) is one of the most challenging obstetrical issues. So far, there has not been a proven option for the treatment or improvement of this condition. Improper immune response during placentation leads to inadequate trophoblast invasion and impaired utero-placental perfusion. Pentoxifylline improves the endothelial function and induces vasodilation by reducing the inflammatory-mediated cytokines. We have evaluated the effect of Pentoxifylline on fetal-placental perfusion, neonatal outcome, and the level of oxidative stress markers before and after the intervention in the setting of severe early-onset FGR. Materials and methods: This study is a pilot randomized clinical trial on 40 pregnant women who had developed early-onset growth restricted fetus. Pentoxifylline and placebo were given with a dose of 400 mg per os two times daily until delivery. Serial ultrasound examination regarding fetal weight, amniotic fluid and also utero-placenta-fetal Doppler's were done. For the assessment of serum Antioxidant level, blood sampling was done once at the beginning of the study and again, at least, three weeks after the investigation. After delivery, umbilical-cord blood gas analysis, APGAR score at 1 and 5 min, NICU admission, and neonatal death were recorded and compared between the two groups. Results: Utero-placenta-fetal Doppler's in the Pentoxifylline group did not significantly change compared to the control group. Fetal weight gain was significantly higher in the Pentoxifylline group before (996.33 ± 317.41) and after (1616.89 ± 527.90) treatment (P = 0.002). Total serum antioxidant capacity significantly increased in the Pentoxifylline group (p

According to the cancer stem cell (CSC) theory, a subpopulation of cells demonstrating stem-like cell properties is responsible for tumorigenicity, self-renewal capacity, therapy resistance, and recurrence. Due to CSCs’ resistance, it’s demanded to develop drugs having appropriate efficacy. Despite cisplatin is a potent antitumor agent widely used in the treatment of different cancers, its severe side effects and resistance remain a challenge in the clinic. Research has shown that platinum (IV) has considerably fewer side effects and drug resistance. In this study, toxicity and effectiveness of [Pt(dpyam)Cl4] where dpyam is 2,2'-dipyridylamine, as a platinum (IV) agent, has been investigated to find a reliable alternative for cisplatin. To this aim, cancer stem-like cells (CS-LCs) with CD44+/CD133+ phenotype were isolated from HT1080 cells. EJ138, HT1080, and its CS-LCs were selected to compare the effectiveness of Pt (IV) complex versus cisplatin. MTT, apoptosis, and cell cycle analysis were carried out to evaluate drug toxicity. Sphere and colony formation assays confirmed the potentiality of Pt (IV) complex and cisplatin to target stemness characteristics in CS-LCs. Although toxicity results were in favor of cisplatin, the anti-cancer activity of the synthesized Pt (IV) complex was also considerable. Regarding other studies that proposed high selective toxicity of Pt (IV), they could be a volunteer for additional improvements.

Resistance of Candida species is a major problem in the management of Candida infection. This study investigated in vivo antifungal activities of several new imidazole and triazole derivatives in a C. albicans systemic infection. The efficacy of derivatives was determined against systemic infection by C. albicans in mice with cyclophosphamide-induced immunosuppression, and the antifungal activities of the synthesized compounds were evaluated in comparison with fluconazole. Compounds 3 and 8 had the highest efficacy with minimum inhibitory concentration (MIC) values of 0.5–1 μM against the C. albicans pathogen. In vivo activities in immunosuppressed mice were also greater than fluconazole. Furthermore, docking analysis was carried out to know the binding mode of imidazole and triazole derivatives to the CYP51 active site of C. albicans and dihydrofolate reductase as a valid antifungal target. The docking study found that the antifungal results are well correlated with docking results. ADMET and in silico physicochemical parameters were also performed. This study demonstrates that compounds 3 and 8 are potential antifungal candidates against the C. albicans pathogen.

Background: Cholestatic liver disease primarily affects hepatic tissue. Cholestasis could also influence the function of other organs rather than the liver. Cholestasis-induced kidney injury is a severe clinical complication known as "cholemic nephropathy" (CN). Bile duct ligation (BDL) is a trustworthy experimental model for inducing CN. Although the precise mechanism of renal injury in cholestasis is not fully recognized, several studies revealed the role of oxidative stress in CN. There is no promising pharmacological intervention against CN. Carnosine (CAR) is a peptide extensively investigated for its pharmacological effects. Radical scavenging and antioxidative stress are major features of CAR. The current study aimed to evaluate the role of CAR supplementation on the CN. Methods: CAR was administered (250 and 500 mg/kg, i.p) to BDL rats for 14 consecutive days. Urine and serum 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, lipid peroxidation, oxidized glutathione (GSSG) levels, 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 organ of cholestatic animals. Renal histopathological changes, 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 kidney of cholestatic animals. Conclusion: The antioxidative properties of this peptide might play a fundamental role in its protective properties during cholestasis.

Abstract 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).

Cyclophosphamide is one of the most prescribed antineoplastic agents. Hemorrhagic cystitis is one of the most common side effects of cyclophosphamide. Captopril is usually used as an anti-blood pressure agent. On the other hand, as a thiol group-containing agent, captopril has potent antioxidant activity. This study aims to evaluate the effect of captopril on cyclophosphamide-induced hemorrhagic cystitis in rats. Twenty-five male Sprague-Dawley rats were equally divided into five groups. Group I received saline (10 ml/kg, i.p.), Group II received a single dose of Cyclophosphamide (200 mg/kg, i.p), Groups III-V received cyclophosphamide and mesna (40 mg/kg, i.p.) or captopril (20 and 40 mg/kg, i.p.). Histopathological changes of bladder, liver, and kidney and lipid peroxidation and glutathione contents in the kidney and liver were monitored. Moreover, serum markers of organ injury were measured. It was found that captopril (20 and 40 mg/kg, i.p) and mesna (40 mg/kg, i.p), as the standard treatment of cyclophosphamide-induced hemorrhagic cystitis, conspicuously attenuated the macroscopic and microscopic damage in the bladder induced by cyclophosphamide. In contrast, mesna did not significantly improve histopathological changes. No significant difference in the serum level of liver and kidney injury biomarkers, tissue biomarkers of oxidative stress, and histopathological alteration were detected between control and cyclophosphamide-treated animals. On the other hand, both captopril and mesna alleviated histopathological bladder changes. Although the mechanism of action of captopril seems not to be mediated by alleviating oxidative stress, the present study results indicate that this drug could have a protective effect on cyclophosphamide-induced hemorrhagic cystitis.

Solenanthus circinatus root, commonly called “Azaar Choob” in Persian medicine, has a very long history of use in relieving pain and inflammation in muscle contusion and bone bruises and fractures. In this study, the analgesic effect of root extract and various fractions of S. circinatus were assessed in male rats using tail flick and formalin tests. Powdered roots of the plant was extracted with ethanol in a soxhlet apparatus and then fractionated with solvents of increasing polarity including petroleum ether, chloroform, ethyl acetate and n-butanol in a liquid-liquid extractor. Ethanolic extract and fractions were then chromatographed on silica gel TLC plates using various solvent systems. The spots on the chromatograms visualized using colour reagents which showed the presence of various compounds. In order to evaluate analgesic effect, rats were treated with 200 mg/kg of extract and fractions intraperitoneally and verified by tail-flick and formalin tests and compared with diclofenac group (25 mg/kg) as a standard drug. Extract and almost all fractions revealed significant analgesic effects compared to the control group. Based on the results, analgesic activity of root extract and fractions of S. circinatus were comparable with that of diclofenac. Petroleum ether fraction displayed higher pain relieving activity than diclofenac at 25 mg/kg in tail-flick test. Interestingly the analgesic efficacy of petroleum ether fraction surpassed other fractions at 60 min interval after injection. Ethyl acetate and petroleum ether were found to be superior to other fractions in manifestation of analgesic activity. The root extract is currently under further detailed investigation.

Cirrhosis-associated muscle mass loss or sarcopenia is a common complication (17-30% prevalence) in cirrhotic patients. However, the pathogenesis of this complication is poorly understood. Therefore, finding the mechanisms of sarcopenia could lead to the development of therapeutic strategies against this complication. In the current study, rats underwent bile duct ligation (BDL) surgery, and their skeletal muscle (gastrocnemius; GS) was isolated and assessed 28 and 56 days after BDL operation. Significant increase in biomarkers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, and increased oxidized glutathione (GSSG) levels were detected in the muscle of cirrhotic animals. Skeletal muscle tissue antioxidant capacity and reduced glutathione (GSH) were also significantly decreased in BDL rats. Moreover, deterioration of several mitochondrial indices, including mitochondrial depolarization, increased mitochondrial permeabilization, depleted ATP reservoirs, and decreased mitochondrial dehydrogenases activity, were evident in the GS isolated from cirrhotic rats. Based on these data, oxidative stress and mitochondrial impairment seem to play as primary mechanisms of cirrhosis-induced sarcopenia.

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.

Taurine (TAU) is the most abundant free amino acid in the human body. High concentrations of this amino acid are found in tissues such as the skeletal muscle, brain, and kidney. Recently, a focus has emerged on the effects of TAU on cellular mitochondria. It has been found that TAU could positively affect this organelle by enhancing mitochondrial membrane potential, increasing ATP levels, and mitigating mitochondria-mediated ROS formation. The current study aimed to evaluate the effect of a wide range of TAU concentrations (0.01 mM-1000 mM) on mitochondrial function. Mice liver mitochondria were isolated and exposed to different concentrations of TAU (30 min). Several indices, including mitochondrial depolarization, dehydrogenases activity, permeabilization, and ATP content, were monitored. It was found that TAU supplementation significantly enhanced parameters such as mitochondrial ATP levels and mitochondrial membrane potential in comparison with the control group. Moreover, TAU prevented Ca2+-induced mitochondrial permeabilization. This amino acid revealed no significant adverse effect on isolated mitochondria even at very high and supra-physiological concentrations (e.g., 100, 250, and 500 mM). These data suggest TAU as an ideal and safe agent to protect mitochondria against toxic insults or regulating cellular function in different mitochondria-linked disorders.

The present investigation was carried out to evaluate the pharmacognostic properties of Citrus aurantium seeds as well as its anti-inflammatory activities. The n-hexane fraction of seed oil extracted via a Soxhlet extractor and subjected to pharmacognostic assays, HPTLC and GC-MS analysis for determination of fatty acids and sterols. The possible anti-inflammatory and antinociceptive activities in rats were evaluated using formalin-induced paw licking, oedema and myeloperoxidase activity assessment. Total ash, acid insoluble and water soluble ash values were determined as 35.83 ± 4.92, 6.67 ± 2.89 and 28.33 ± 5.77 mg/g, respectively. HPTLC assessment revealed the presence of different fatty acids and steroidal triterpenes. The principal fatty acids of the seed oil were linoleic acid (C18:2, 50.10 ± 2.58 %) and Oleic acid (C18:1, 30.14 ± 0.39). Esterified (2.40 mg/g) and free β-sitosterol (32.90 mg/g), free campesterol (3.9 mg/g) and free stigmasterol (10.165 mg/g) were detected in the oil. Seed oil exhibited anti-inflammatory properties in the first and the second phases of formalin test. Also, it had anti-edematogenic effects but exerted no effects on myeloperoxidase activity.

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

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.

Carbon-based nanomaterials possess a remarkably high potential for biomedical applications due to their physical properties; however, their detrimental effects on reproduction are also concerned. Several reports indicate the toxicity of carbon nanotubes (CNT); nevertheless, their impact on intracellular organelles in the male reproductive organs has not been fully elucidated. Herein, we report on the reprotoxicity of single-walled (SWCNT) and multi-walled carbon nanotubes (MWCN) on several intracellular events and histological criteria in pubertal male BALB/c mice orally treated with 0, 10, and 50 mg/kg/day doses for 5 weeks. Biomarkers of oxidative stress and mitochondrial functionality, histopathological alterations, and epididymal sperm characteristics were determined. Oral administration of CNTs at 10 and 50 mg/kg evoked a significant decrement in weight coefficient, sperm viability and motility, hypo-osmotic swelling (HOS) test, sperm count, mitochondrial dehydrogenase activity, ATP content, total antioxidant capacity, and GSH/GSSH ratio in the testis and epididymal spermatozoa. On the other hand, percent abnormal sperm, testicular and sperm TBARS contents, protein carbonylation, ROS formation, oxidized glutathione level, and sperm mitochondrial depolarization were considerably increased. Significant histopathological and stereological alterations in the testis occurred in the groups challenged with CNTs. The current findings indicated that oxidative stress and mitochondrial impairment might substantially impact CNTs-induced reproductive system injury and sperm toxicity. The results can also be used to establish environmental standards for CNT consumption by mammals, produce new chemicals for controlling the rodent populations, and develop therapeutic approaches against CNTs-associated reproductive anomalies in the males exposed daily to these nanoparticles.

The aim of this study was to evaluate the effect of the hexyl acrylate conjugated polyamidoamine (PAMSM) dendrimer on different cell lines in the presence and absence of serum. Although the positively charged dendrimers including PAMAM has been considered as efficient gene carriers, their cytotoxicity is a major barrier for their clinical applications. The conjugation of hexyl acrylate on PAMAM dendrimer was carried out to improve the hydrophilic-hydrophiobic balance of the dendrimer as well as the modulation of the positive charge on the dendrimer structure. The cytotoxicity of PAMAM derivatives was evaluated using MTT test on HepG2, MCF-7 and A549 cell lines in the presence and absence of serum. The results revealed that the modified PAMAM dendrimers induced less toxic effects on the cell lines in the presence of serum. Therefore, conjugation of acrylate on the PAMAM structure could be an efficient way to reduce the dendrimer toxicity allowing the administration of more dendrimer for gene delivery.

The liver is continuously exposed to a variety of xenobiotics. Several xenobiotics are identified which act as hepatotoxicants. Hence, finding protective agents for ameliorating xenobiotics-included liver injury has a great value. Eisenia foetida, a kind of “earthworm,” is a source of a wide range of bioactive components. Several investigations have been evaluated the E. foetida extract (EFX) for biomedical and nutritional applications. The current study was designed to evaluate the potential hepatoprotective properties of EFX in two experimental models of hepatic damage. Acetaminophen (APAP; 1 g/kg, i.p) was administered as the animal model of acute liver injury in mice. Bile duct ligated (BDL) rats were used as the animal model of chronic hepatic damage. Severe elevation in tissue biomarkers of oxidative stress including lipid peroxidation and hepatic glutathione depletion was evident in both APAP-treated and BDL animals. Moreover, serum biomarkers of liver injury were drastically increased in both acute and chronic animal models of hepatotoxicity. Significant liver tissue histopathological alterations including tissue necrosis, vascular congestion, and inflammatory cells infiltration were detected in APAP-treated and BDL animals. On the other hand, it was found that EFX supplementation (100, 200, 500, and 700 mg/kg, i.p) mitigated oxidative stress markers, decreased serum biomarkers of liver injury, and alleviated liver tissue histopathological changes. The hepatoprotection provided by EFX supplementation in the current study might be mediated through its potential antioxidative mechanisms.

Background and objectives: Although weed plants are considered undesirable in a particular situation, some weed seeds can be a valuable and cheap source of therapeutic natural compounds. Securigera securidaca (L.) Degen & Dorfl (Fabaceae) is widely distributed in Europe, Australia and Asia as a weed plant. This study investigated the bioactive compounds of S. securidaca seeds as well as its potential anti-inflammatory properties. Methods: The fatty acid and sterol content were investigated with gas chromatography–mass spectrometry (GC-MS) and phenolic compounds were detected using high performance thin layer chromatography (HPTLC). The thermostability of the oil was studied using differential scanning calorimetry (DSC). Formalin-induced paw licking test and myeloperoxidase activity were investigated. The study was conducted by creating six groups of rats including a control group (vehicle-treated rats, 250 µL/kg, i.p.), formalin group (50 µL of 2.5% formalin), positive control (paracetamol, 100 mg/kg, i.p), and groups of S. securidaca seed oil (250, 500, 1000, 2000, and 4000 μl/kg, i.p). Results: S. securidaca seeds contained a high level of polyunsaturated fatty acid content including linoleic acid (64.602 ± 0.793%) and oleic acid (15.353 ± 0.461%). Stigmasterol and campesterol were not detected in the oil but it contained esterified β-sitosterol (6.621 ± 0.08 mg/g). The seed oil couldn’t create a significant reduction in the MPO activity. It showed a slight but not significant effect on formalin-induced pain reduction. Conclusion: The seed is a rich source of linoleic acid which makes it a good candidate to be used in the pharmaceutical industry.

Background: Propylthiouracil (PTU) administration is associated with several cases of hepatotoxicity, especially in children. The mechanism(s) of PTU-induced hepatotoxicity is obscure. In the current study, we aimed to assess the effect of PTU on hepatocytes mitochondria in different experimental models. Methods: Mice were treated with PTU (10, 20, 40, 80, and 100 mg/kg, i.p) then, the liver mitochondria were isolated and evaluated. Moreover, liver mitochondria were isolated from normal mice and incubated with increasing concentrations of PTU (10 µM-1 mM). Mitochondrial dehydrogenases activity, mitochondrial membrane potential, mitochondrial swelling, and mitochondrial adenosine triphosphate (ATP) content were monitored. Results: PTU hepatotoxicity was biochemically evident in mice by increased serum biomarkers of liver injury. PTU also caused a decrease in mitochondrial dehydrogenases activity, increased mitochondrial swelling, depleted mitochondrial ATP, and caused mitochondrial depolarization both in vitro and in vivo. Conclusion: Our data suggest mitochondrial dysfunction as a mechanism for PTU-induced hepatotoxicity

Context: One of the most complained skin cares in ethnic skin like Asian women is hyperpigmentation, and lightening preparations have been long-standing desired. Due to the side effects of current drugs, medicinal plants have attracted more attentions as a source of novel drugs. Mazo (Quercus infectoria galls) and Terminalia chebula fruits have been suggested in Persian Traditional Medicine as a safe treatment for hyperpigmentation. Aims: To evaluate the cytotoxicity and the effect on melanin synthesis in B16/F10 melanoma of Q. infectoria and T. chebula extracts. Methods: After collection and scientific authentication, plants were extracted by maceration method with methanol and were standardized based on total phenolic content. MTT assay and colorimetric method were used for cytotoxicity and determination of melanin content and tyrosinase activity in B16/F10 cells, respectively. Kojic acid was used as a reference compound. Results: Total phenolic content of Q. infectoria and T. chebula was determined as 287.34 ± 4.21 and 172.61 ± 8.67 mg gallic acid equivalent/g dried extract, respectively. Both plants decreased cell viability at 100 µg/mL and significantly reduced intercellular melanin to 66.25% and 71.1%, respectively in comparison to kojic acid (56.63%) at 50 µg/mL. In the same concentration, 65.7% and 71.2% tyrosinase activity was inhibited by Q. infectoria and T. chebula, which significantly were different from control (p

Fulminant hepatic failure is a deleterious clinical complication, which leads to hyperammonemia. Ammonia is a noxious neurotoxic agent, which affects brain tissue through different mechanisms. On the other hand, it is well-known that oxidative stress and its consequences play a major role in the pathogenesis of ammonia-induced brain injury. Carnosine is a dipeptide abundantly found in the human central nervous system (CNS). This peptide is widely investigated for its neuroprotective properties. The current study aimed to evaluate the effect of carnosine supplementation on oxidative stress markers in the brain tissue of a rat model of fulminant hepatic failure and hyperammonemia. Animals received thioacetamide (400 mg/kg, i.p, for three consecutive days at 24-hr intervals) as a model of acute liver failure and hyperammonemia. Several serum biochemical parameters, in addition to plasma and brain ammonia level, were monitored. On the other hand, brain tissue markers of oxidative stress including reactive oxygen species (ROS) formation, lipid peroxidation, tissue glutathione content, and total antioxidant capacity were measured. It was found that plasma and brain ammonia was increased, and serum markers of liver injury were significantly elevated in the thioacetamide-treated group. On the other hand, an increase in markers of oxidative stress, including ROS formation, lipid peroxidation, glutathione depletion, and decreased tissue antioxidant capacity, was evident in the brain of thioacetamide-treated animals. It was found that carnosine supplementation (250, 500, and 1000 mg/kg) decreased serum markers of liver injury, mitigated brain, and plasma ammonia level, and alleviated brain tissue markers of oxidative stress. These data suggest carnosine as a potential neuroprotective agent with therapeutic capability against ammonia-induced CNS injury.

Recently use of antifungal drugs in human medicine has been increased, especially with the advent of AIDS epidemic. Despite the growing list of azoles, their clinical value has been limited by their relatively high risk of toxicity and the emergence of drug resistance. Efforts have focused on the development of new, less toxic and more efficacious antifungal agents. We previously described synthesis of some new azole derivatives. We also evaluated all the synthesized compounds for their antifungal activity. Most of our compounds showed desirable activity against different species of microorganisms. Here we choose thirteen of these compounds, 5 bentriazole derivatives (1a-5a), 5 imidazole derivatives (1b-5b) and 3 triazole derivatives (1c-3c) to evaluate their cytotoxic activities against a human cancer cell line (MCF-7) using colorimetric MTT cytotoxic assay. Their cytotoxic activities were compared to clotrimazole as a positive control. Our results collectively showed that most of our synthesized compounds had less cytotoxicity against MCF-7 compared to clotrimazole.

Hepatic encephalopathy (HE) is a serious clinical complication, which could lead to coma and death if not appropriately managed. There is agreement on the predominant role of ammonia in the etiology of HE. Brain is one of the most critical organs affected by ammonia. The critical role of oxidative stress and its consequences in the pathogenesis of ammonia-induced brain injury have been revealed before. On the other hand, there is no promising therapeutic option against ammonia neurotoxicity. Taurine is one of the most abundant amino acids in the human body. Several pharmacological roles including brain protecting properties have been attributed to this amino acid. The current study was designed to evaluate the role of taurine supplementation on HE-induced oxidative stress in the brain tissue. Animals received thioacetamide (400 mg/kg, i.p, for three consecutive days at 24-hr intervals) as a model of acute liver failure and hyperammonemia. Several serum biochemical parameters, in addition to plasma and brain ammonia level, were monitored. Moreover, markers of oxidative stress in the brain of hyperammonemic animals were assessed. It was found that plasma and brain ammonia was increased, and serum markers of liver injury were significantly elevated in the thioacetamide-treated group. On the other hand, an increase in markers of oxidative stress, including reactive oxygen species formation, lipid peroxidation, glutathione depletion, and decreased tissue antioxidant capacity, was detected in the brain tissue of thioacetamide-treated animals. It was found that taurine treatment (250, 500, and 1000 mg/kg, i.p) alleviated brain tissue markers of oxidative stress and decreased serum biomarkers of liver injury. Furthermore, lower plasma and brain ammonia were detected in taurine-treated animals. These data suggest taurine as a potential protective agent with therapeutic capability against HE-associated central nervous system complications.

Valproic acid (VPA) is a widely administered drug against epilepsy and several other neurological disorders. On the other hand, liver injury is a deleterious side effect associated with VPA. Oxidative stress seems to play a critical role in VPA-induced hepatotoxicity. The current investigation was designed to evaluate if N-acetylcysteine (NAC) and dithiothreitol (DTT) as thiol reducing agents have any protective effects against VPA-induced liver injury. Isolated rat hepatocytes (in vitro) were exposed to increasing concentrations of VPA (25, 50, 100, 150, and 250 µM) and markers of cytotoxicity were evaluated. Furthermore, animals received VPA (250 and 500 mg/kg, i.p for 15 consecutive days) (in vivo) and markers of liver injury were monitored. It was found that 250 µM of VPA caused marked cytotoxicity toward isolated hepatocytes as judged by trypan blue exclusion test. Moreover, markers of oxidative stress including glutathione depletion and lipid peroxidation were detected in VPA-treated hepatocytes. On the other hand, VPA caused a significant increase in plasma markers of hepatotoxicity in drug-treated group. Liver histopathological changes and markers of oxidative stress were also detected in VPA-treated animals. It was found that administration of NAC (1 mM), and DTT (1 mM) significantly alleviated VPA-induced cytotoxicity (In vitro). NAC (250 and 500 mg/kg) and DTT (15 and 30 mg/kg) also significantly mitigated VPA hepatotoxicity (In vivo). The data obtained from the current investigation indicate potential therapeutic properties of thiol reductants against VPA-induced liver injury.

Objective(s): Comparative in vivo studies were carried out to determine the adsorption characteristics of amitriptyline (AMT) on activated charcoal (AC) and sodium polystyrene sulfonate (SPS). AC has been long used as gastric decontamination agent for tricyclic antidepressants and SPS has showed to be highly effective on in-vitro drugs adsorption. Materials and Methods: Sprague-Dawley male rats were divided into six groups. Group I: control, group II: AMT 200 mg/kg as single dose orally, group III and IV: AC 1g/kg as single dose orally 5 and 30 min after AMT administration respectively, and group 5 and 6: SPS 1 g/kg as single dose orally 5 and 30 min after AMT administration, respectively. 60 min after oral administration of AMT (Tmax of AMT determined in rats), Cmax plasma levels were determined by a validated GC-Mass method. Results: The Cmax values for groups II to IV were determined as 1.1, 0.5, 0.6, 0.1 and 0.3 µg/ml, respectively. Conclusion: AC and SPS could significantly reduce Cmax of AMT when administrated either 5 or 30 min after AMT overdose (P

The protective effects of Artemia salina L. extract was examined against carbon tetrachloride (CCl4)-induced cell toxicity. In the in vitro model of study, markers such as cell viability, cellular reduced and oxidized glutathione, and lipid peroxidation in HepG2 cells was evaluated. Human liver cancer cell line HepG2 was treated with CCl4 and Artemia salina extract, and markers of hepatotoxicity were investigated. Artemia salina extract showed significant dose-dependent protective effects against the cytotoxicity of CCl4. This extract was able to normalize the levels of GSH, and thiobarbituric acid-reactive (TBARs), which were altered due to CCl4 intoxication in HepG2 cells. As the oxidative stress markers were ameliorated, it might be concluded that Artemia salina extract possesses protective effects probably due to its antioxidant constituents.

Objective: To investigate the effects of hydroalcoholic extract of Ziziphus jujuba on the histopathological, tissue oxidative stress and inflammation plus to antioxidant pathways of colon tissue in rat with induced Ulcerative colitis. Materials and methods: Ulcerative colitis was induced in 80 rats those divided into 8 equal groups. Group 1 and 2 were negative controls receiving 1 mL/day of normal saline in enema and oral; group 3 and 4 as positive control 1 and 2 received 10 mg/kg of intra-colonic asacol and oral mesalazine; groups 5 and 6 received 20% and 40% of hydroalcoholic extract of Z. jujuba trans-rectally; group 7 and 8 received 1500 and 3000 mg/kg of hydroalcoholic extract of Z. jujuba orally, respectively. After 7 days, animals were evaluated for colon tissue histopathology, levels of malondialdehyde and IL-1β, and activities of superoxide dismutase, glutathione peroxidase and myeloperoxidase in colon tissue. Results: Hydroalcoholic extract of Z. jujuba in both forms of trans-rectal and oral administration especially in the higher doses could result into a more healing effect in damaged colonic tissue, more reduce glutathione peroxidase and IL-1β level. Also, these two doses (gel 40% and oral 3000 mg/kg) could more decrease the myeloperoxidase activity and stimulate superoxide dismutase and glutathione peroxidase activities. Also, gel 40% in transrectal administration was more potent than administration 3000 mg/kg in oral. Conclusion: The results of the present study indicated that Z. jujube may be considered as a treatment of choice for Ulcerative colitis especially in gel form and also in dose-dependent pattern. Resumo: Objetivo: Investigar os efeitos do extrato hidroalcoólico de Ziziphus jujuba no estresse oxidativo em tecido ao nível histopatológico e na inflamação, juntamente com as vias antioxidantes em tecido de cólon em ratos com colite ulcerativa induzida.Materiais e métodos: Induzimos colite ulcerativa em 80 ratos, divididos em 8 grupos iguais. Os grupos 1 e 2 eram controles negativos que receberam 1 mL/dia de salina normal em enema e por via oral; os grupos 3 e 4 eram controles positivos para 1 e 2 e receberam 10 mg/kg de asacol por via intracolônica e mesalazina oral; os grupos 5 e 6 receberam gel a 20% e 40% de extrato hidroalcoólico de Z. jujuba por via trans-retal; os grupos 7 e 8 receberam 1500 e 3000 mg/kg de extrato hidroalcoólico de Z. jujuba por via oral, respectivamente. Transcorridos 7 dias, os animais foram avaliados para histopatologia de tecido de cólon, níveis de malonildialdeído e IL-1β, e atividades de superóxido dismutase, glutátion peroxidase e mieloperoxidase no tecido colônico. Resultados: O uso do extrato hidroalcoólico de Z. jujuba, tanto na forma transretal como oral, e em especial nas doses mais altas, resultou em um efeito de cicatrização mais intensa no tecido colônico lesionado, e em maior redução nos níveis de glutátion peroxidase IL-1β. Além disso, essas duas doses (gel a 40% e 3000 mg/kg por via oral) diminuíram ainda mais a atividade de mieloperoxidase e estimularam as atividades de superóxido dismutase e glutátion peroxidase. Outro achado do estudo foi que o gel a 40% por administração trans-retal se mostrou mais potente do que a administração oral de 3000 mg/kg. Conclusão: Os resultados do presente estudo sugerem que Z. jujuba pode ser considerado como tratamento de escolha para colite ulcerativa, sobretudo em forma de gel e também em um padrão proporcional à dose administrada. Keywords: Ziziphus jujuba, Ulcerative colitis, Oxidative stress, Histopathology, Inflammation, Palavras-chave: Ziziphus jujuba, Colite ulcerativa, Estresse oxidativo, Histopatologia, Inflamação

Background: Chloroquine and amodiaquine are used in the prophylaxis and treatment of malaria. However, hepatic injury is associated with malaria drug therapy. On the other hand, there is no promising hepatoprotective agent for prophylaxis or treatment of antimalarial drugs‑induced liver injury. Carnosine is a naturally occurring peptide with pleiotropic protective properties in different tissues. This investigation aimed to evaluate the effect of carnosine administration in antimalarial drugs-induced hepatic injury in rats. Methods: Animals were treated with amodiaquine (180 mg/kg, oral) or chloroquine (970 mg/kg, oral). Carnosine (250, 500 and 1000 mg/kg, i.p) was administered as the hepatoprotective agent against antimalarial drugs liver injury. Results: Liver injury was manifested biochemically by a significant increase in serum level of ALT, LDH, and AST. In addition, hepatic tissue from antimalarial drugs‐treated rats showed a significant increase in reactive oxygen species (ROS), lipid peroxidation and protein carbonylation along with a decrease in hepatic glutathione reservoirs and total antioxidant capacity. Moreover, the liver histopathologic evaluation revealed significant congestion, inflammation, and necrosis in amodiaquine and/or chloroquine-treated animals. Carnosine administration significantly alleviated antimalarial drugs-induced pathologic changes in serum biochemistry and liver tissue. Conclusion: Our data suggest that carnosine possesses protective properties against amodiaquine and/or chloroquine‑induced liver injury possibly through mitigation of drug-induced oxidative stress and its consequent events.

Taurine (2-aminoethane sulfonic acid) is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid) is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 µM, 100 µM and 1000 µM) of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5‑Fluorouracil, Doxorubicin and Dacarbazine) via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+). Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione) were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug‑treated livers. It was found that taurine (5 and 10 mM) and glycine (5 and 10 mM) administration significantly mitigated the biomarkers of liver injury and attenuated drug‑induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

Platelet-rich plasma (PRP) is an attractive preparation in regenerative medicine due to its potential role on the healing process in different experimental models. This study was designed to investigate the wound healing activity of a new formulation of PRP. Different gel-based formulations of PRP were prepared. Open excision wounds were made on the back of male Sprague-Dawley rats, and PRP gel was administered topically once daily until the wounds healed completely (12 days). The results revealed that the tested PRP formulation significantly accelerated the wound healing process by increasing the wound contracting, tissue granulization, vascularization, and collagen regeneration. Interestingly, we found that there were no significant differences between PRP formulation and its gel base in all above mentioned parameters. Although this investigation showed that PRP formulation had significant wound healing effects, but the PRP gel base also had significant wound healing properties. This might indicate the wound healing properties of the PRP gel ingredients in the current investigation.

Hyperammonemia is associated with chronic and acute liver injury. There is no promising therapeutic agent against ammonia-induced complications. Hence, finding therapeutic molecules with safe profile of administration has clinical value. The present study was conducted to evaluate the role of taurine (TA) administration on plasma and brain ammonia and its consequent events in different models of chronic and acute liver injury and hyperammonemia. Bile duct ligated (BDL) rats were used as a model of chronic liver injury. Thioacetamide and acetaminophen-induced acute liver failure were used as acute liver injury models. A high level of ammonia was detected in blood and brain of experimental groups. An increase in brain ammonia level coincided with a decreased total locomotor activity of animals and significant changes in the biochemistry of blood and also liver tissue. TA administration (500 and 1000 mg/kg, i.p), effectively alleviated liver injury and its consequent events including rise in plasma and brain ammonia and brain edema. The data suggested that TA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia as a deleterious consequence of acute and chronic liver injury. Keywords: Amino acid, Ammonia, Brain edema, Hepatic encephalopathy, Hepatic injury, Hepatoprotective

Background/Aim: Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease with unknown etiology. Several therapeutic strategies such as consumption of medicinal plants have been used for its treatment. The aim of this study was to evaluate healing effects of Calendula officinalis hydroalcoholic extract in experimentally induced UC in rat. Materials and Methods: Ninety-six rats, weighing 200 ± 20 g, were randomly divided into eight equal groups. UC induced by 3% acetic acid and oral doses of C. officinalis extract, 1500 and 3000 mg/kg, and enema (gel 10% and 20%) were given. Two groups as positive controls were given asacol (enema) and oral mesalamine. Negative control groups were given normal saline and base gel. On days 3 and 7, intestinal histopathology and weight changes, plus oxidative stress indices including malondialdehyde (MDA) level and myeloperoxidase (MPO) activity were assayed. Results: A significant increase in the body weight of rats was seen in the group given C. officinalis extract 3000 mg/kg orally, oral mesalamine, and 20% intracolonic gel form of marigold extract compared with negative control and base gel groups during the experimental period. Acute inflammation and granular atrophy after UC induction were resolved completely completely by both 20% intracolonic gel and 3000 mg/kg orally. An increase in MPO activity and a decrease in MDA level in response to oral and intracolonic gel form of C. officinalis were observed 3 and and 7 days after treatment (P < 0.05). Conclusion: Our results indicate that oral and enema forms of hydroalcoholic extract of C. officinalis can be offered as are potential therapeutic agents for UC induced in rats.

Backgrounds & objectives: Liver damage results in a large accumulation of external cellular matrix that affects the function of this important body organ in a long term and finally stops its function completely. The growth factors existing in platelet extract are more cost-effective, available, and stable than recombinant ones. To determine whether the platelet extract effects on histological changes in liver injury induced by carbon tetrachloride (CCl4), we used immunohistochemical analysis in male rats. Methods: In this project the 28 male Wistar rats (250-300 g) were randomly divided into 4 groups, each consisting of 7 animals. The rats were divided into four experimental groups as follows: the first group (sham) intraperitoneally received only olive oil as the solvent of carbon tetrachloride; second group (CCl4) intraperitoneally received carbon tetrachloride dissolved in olive oil (ratio of about 1: 1) at a concentration of 1 ml/kg and a twice a week for eight weeks; third group subcutaneously received only platelet extract at a concentration of 0.5 ml/kg twice a week for three weeks; and fourth group received both CCl4 intraperitoneally for eight weeks and platelet extract subcutaneously for last three weeks. After 8 weeks of trial blood and liver sampling were done. Blood samples sent for enzymatic (AST, ALT) tests and liver samples tested for histological and immunohistochemical studies. The data were analyzed using one-way ANOVA followed by Tukey test by Graph pad Prism 5 software and data were considered significant at p≤ 0.05. Results: The results show that platelet extract causes a significant (p≤ 0.001) decrease in liver enzymes and albumin improves the function of liver. The level of alfa smooth muscle actin (α-SMA) as an index of hepatic stellate cell activation was decreased by platelet extract administration which eventually reduced the necrosis and fibrosis induced by carbon tetrachloride in studied rats

Azole derivatives are an important class of compounds in medicinal chemistry with a wide variety of biological activities. We previously described synthesis and antimicrobial evaluations of some new Azole derivatives. Most of our compounds showed desirable activity against different species of microorganisms. Here, we chose seventeen of these compounds, in four different groups including imidazole (group a, 1a-6a), 2-methylimidazole (group b, 1b-4b), 2-methyl-4-nitroimidazole (group c, 1c-4c) and benzimidazole (group d, 1d-3d) to further evaluate their cytotoxic activities against a human cancer cell line (HepG2) using colorimetric MTT cytotoxic assay. We also compared their cytotoxic activities with Clotrimazole to find the safer compounds as antimicrobial agents. Our results indicated that Azole compounds including 2b, 4c, 2d and 3d displayed desirable anti-tumor activities against HepG2 (IC50

The cholestatic liver disease ensues with a hepatic accumulation of cytotoxic molecules. Several hydrophobic bile acids are known as cytotoxic agents accumulated in the liver during cholestasis. Chenodeoxycholic acid (CDCA) is a toxic hydrophobic bile acid. Oxidative stress and mitochondrial dysfunction are well-known mechanisms of bile acids cytotoxicity. In the current study, CDCA effect on isolated liver mitochondria was monitored by analyzing the changes in mitochondrial dehydrogenases activity, mitochondrial permeabilization, and mitochondrial membrane potential. On the other hand, taurine (1 mM) and carnosine (1 mM) were added as potential protective agents against CDCA-induced mitochondrial dysfunction. Increasing concentrations of CDCA (100 µM - 1000 µM) impaired mitochondrial membrane potential, decreased mitochondrial dehydrogenases activity and enhanced mitochondrial permeabilization and swelling. It was found that taurine and carnosine supplementation preserved mitochondrial function in the presence of CDCA. The results mention that toxicologically relevant concentrations of CDCA impaired mitochondrial function. On the other hand, taurine and carnosine might be applicable as protective agents against bile acids-induced mitochondrial impairment and toxicity.

Carnosine is an abundantly found dipeptide present in different tissues. Several pharmacological properties have been attributed to carnosine. On the other hand, the precise mechanism of cytoprotection provided by carnosine remains obscure. The current study aimed to evaluate the direct effect of different concentrations of carnosine on cellular mitochondria as an essential target involved in the cytoprotection/cytotoxicity. Liver mitochondria were isolated and exposed to carnosine (0.01-20 mM). Mitochondrial depolarization, dehydrogenases activity, mitochondrial swelling and permeability, and ATP content were assessed. On the other hand, the effect of carnosine supplementation on calcium (Ca2+) overload-induced mitochondrial injury was evaluated. It was found that concentrations between 0.01-20 mM of this peptide preserved mitochondrial indices of functionality in a Ca2+ overloaded environment. These data represent regulation of mitochondrial function as a primary mechanism for the protective properties of carnosine.

Introduction: burn wounds are common happenings which cause many people have irreversible defects and to be death around the world every year. In this study, we evaluated the effects of Melilotus officinalis and Alpha ointment in the healing of burn wounds and compare their findings with silver sulfadiazine (SSD).Methods: Seventy-five male Sprague-Dawley rats were randomly divided into five groups, and similar burn ulcers were produced on the back of rats. The first group of rats received no treatment, base gel was used topically to group II, in groups III-V, Alpha, SSD and Melilotus officinalis preparations were applied, respectively. Wound healing, contraction and histopathological examination were evaluated at the end of 7, 14, and 21 days.Results: Alpha ointment was equally effective as Melilotus officinalis gel, while its efficacy was better compared to SSD for all parameters of wound healing on days 7, 14 and 21. Alpha and Melilotus officinalis preparations as less expensive medications which significantly improve the quality of wound healing and scar formation and also are more appropriate treatment choices than SSD.Conclusion: Alpha and Melilotus officinalis are recommended as alternative to SSD, especially in patients with low economical backgrounds or in those who show adverse reactions to SSD.

Drug-induced liver injury (DILI) is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU) are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s) of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

Objective(s): Protective effects of different extracts and essential oil from Pimpinella anisum L. seeds were examined against carbon tetrachloride (CCl4)-induced toxicity. The parameters such as serum transaminases, lactate dehydrogenase activity, hepatic glutathione content, liver lipid peroxidation and histopathological changes of liver were assessed as toxicity markers. In the in vitro model of this study, markers such as cell viability, cellular reduced and oxidized glutathione and lipid peroxidation in HepG2 cells were evaluated. Materials and Methods:Human liver cancer cell line HepG2 and male Sprague-Dawley rats were treated with extracts and essential oil, and markers of hepatotoxicity were investigated. Results: The data revealed that the n-hexane extract, effectively attenuated CCl4‑induced toxicity in both in vitro and in vivo models in current investigation. Conclusion: As the oxidative stress markers were ameliorated, it might be concluded that anise seed possesses protective effects probably due to its antioxidant constituents.

Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

Objective(s):The relationship between tramadol, as an antinociceptive drug, and locus coeruleus (LC), the main noradrenergic nucleus of the brain that affects regulation and modulation of pain through descending noradrenergic pathways was investigated. Materials and Methods: Male Sprague-Dawley rats were divided into four groups of 10 rats. The rats were fixed in stereotaxic instrument and then a probe was inserted into LC. Pain was induced by subcutaneous injection of 50 μl of 2.5% formalin 40 minutes after initiation of microdialysisin right hind paw, and nociceptivepain scores were calculated every 5 minutes. Subsequently noradrenaline (NA) and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were collected and measured by microdialysis of locus coeruleus in freely moving rats every 15 minutes during formalin injection. Results: Nociceptive pain scores observed in formalin test had the highest nociceptive sensation 5 minutes after injection. Significant rises in concentrations of NA and MHPG, in samples taken between 30 and 45 min after initiation of the locus coeruleusmicrodialysis, coincided with the peak of the pain after injection of formalin. Conclusion: According toconcurrency of the highest nociceptive sensation and peak of NE and MHPG concentrations, tramadol can indirectly affect the LC by blocking the pain signals from different parts of the brain such as periaqueductal gray mater, central nucleus of amygdale or the spinal cord.

The widespread use of pesticides in agriculture represents a threat to the human populations exposed to them. In this cross-sectional study, the hematological and biochemical parameters, plasma cholinesterase (PChE) activity, oxidative stress, genotoxicity, and NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism were measured in 100 greenhouse workers occupationally exposed to pesticide mixture and 104 normal healthy controls. There was a decrease in erythrocytes (5.45%, p = 0.026) and hemoglobin (3.26%, p = 0.025), and an increase in mean corpuscular hemoglobin (3.54%, p = 0.013) in the exposed workers. Sprayers showed a reduction in PChE (23%) and GSH (50%) levels, and an increase in lipid peroxidation (LPO) (55%), protein carbonyl (145%), Superoxide dismutase activity (61%), and total antioxidant capacity (35%) (p < 0.001 for all parameters but LPO: p = 0.009). Genotoxicity parameters were significantly high in the exposed cases (for all parameters: p < 0.001 but tail length: p = 0.002). There was a significant correlation between oxidative stress and genotoxicity parameters, and also between these biomarkers and PChE activity. The NQO1 C609T polymorphism was not significantly associated with studied biomarkers. The findings indicate that occupational exposure to a mixture of pesticides can induce hematotoxicity, oxidative stress, and genotoxicity in greenhouse workers.

Background: Cylophosphamide is used alone or in combinationwith other drugs for treatment of neoplastic diseases.Hemorrhagic cystitis is a major potential toxicity and doselimiting side effect of cyclophosphamide. The aim of thisstudy was to evaluate the effects of lycopene compared withsome antioxidants for the prevention of cyclophosphamideinduced hemorrhagic cystitis in rats.Methods: In this study, male Sparague-Dawley rats dividedinto 17 groups of six animals. Group 1 received saline (10ml/kg, i.p) as normal control, group 2 received cyclophosphamide(200 mg/kg, i.p) as a single dose, groups 3-10 receivedMesna (40 mg/kg, i.p), N-acetylcysteine (100 mg/kg i.p), dithiotheritol(50 mg/kg, i.p), L-carnitine (200 and 400 mg/kg,i.p), grape seed extract (500 mg/kg i.p) and lycopene (0.1 and0.5 mg/kg, i.p) alone. Groups 11-17 received Mesna (40 mg/kg,i.p), N-acetylcysteine (100 mg/kg, i.p), dithiotheritol (50 mg/kg,i.p), L-carnitine (400 mg/kg, i.p), grape seed extract (500mg/kg, i.p) and lycopene (0.1 and 0.5 mg/kg, i.p), 5 minutesbefore, and 2 and 6 hours after administration of 200 mg/kgcyclophosphamide. Pathological and biochemical analysis wasevaluated 24 hours after cyclophosphamide administration.Results: Mesna and N-acetylcysteine resulted in some but notfull protection against cyclophosphamide toxicity compared tothe controls. Lycopene (0.1 and 0.5 mg/kg) was efficient inprotecting the bladder from cyclophosphamide induced hemorrhagiccystitis. However, dithiotheritol, L- carnitine andgrape seed extract did not prevent hemorrhagic cystitis.Conclusion: Our results suggest that pre and co- treatment oflycopene (0.1 and 0.5 mg/kg) with cyclophosphamide mayhave therapeutic potential to inhibit the hemorrhagic cystitisby cyclophosphamide.

Platelet-rich plasma (PRP) has been of great concern to the scientists and doctors who are involved in wound healing and regenerative medicine which focuses on repairing and replacing damaged cells and tissues. Growth factors of platelet-rich plasma are cost-effective, available, and is more stable than recombinant human growth factors. Given these valuable properties, we decided to assess the effect of PRP on CCl4-induced hepatotoxicity on rats. The rats received CCl4 (1 mL/kg, i.p. 1 : 1 in olive oil) twice per week for 8 weeks. Five weeks after CCl4 injection, the rats also received PRP (0.5 mL/kg, s.c.) two days a week for three weeks. Twenty-four hours after last CCl4 injection, the animals bled and their livers dissected for biochemical and histopathological studies. Blood analysis was performed to evaluate enzyme activity. The results showed that PRP itself was not toxic for liver and could protect the liver from CCl4-induced histological damages and attenuated oxidative stress by increase in glutathione content and decrease in lipid peroxidative marker of liver tissue. The results of the present study lend support to our beliefs in hepatoprotective effects of PRP.

Background Anal fissure is a painful tear or crack in the distal part of anal canal. It usually involves the epithelium, but in the long term it may extend to the whole anal mucosa. Platelet Lysate (PL) hydrogel is a hemoderivitive pharmaceutical formulation that contains plenty of growth factors. These growth factors can induce tissue regeneration and revascularization as well as fibroblast proliferation. Objectives This study aimed to evaluate the effectiveness of PL hydrogel in the treatment of the anal fissure or retardation of its development. Patients and Methods The patients with chronic and acute anal fissure were randomly divided into groups of A and B. Group A received PL hydrogel and Rectol, while group B received placebo and Rectol. Then, they were followed and evaluated for two weeks. Results Although it was anticipated that platelet growth factors would be effective in anal fissure healing process, no significant difference was observed between the control group and the case group after the treatment. Nevertheless, a significant difference was observed within the two groups after the treatment. Conclusions PL hydrogel does not seem to have beneficial effects compared to the placebo or Rectol on the healing of anal fissure.