Lipoic acid and Calligonum comosumon attenuate aroclor 1260-induced testicular toxicity in adult rats.

Aroclor 1260 is one of the more representative polychlorinated biphenyls found in biota. This study was designed to delineate the testicular toxicity of Aroclor 1260 and to elucidate the potential protective role of Calligonum comosum (C. comosum) and lipoic acid in adult rats. Aroclor 1260 was dissolved in corn oil and given to rats by gavage at doses 0, 20, 40, or 60 mg/kg/day for 15 consecutive days (Groups I, II, III, and IV, respectively). Groups V and VI were pretreated with C. comosum (200 mg/kg/day) and lipoic acid (35 mg/kg/day) respectively 24 h before Aroclor 1260 (40 mg/kg/day) treatment for 15 consecutive days. Aroclor 1260 (20, 40 or 60 mg/kg/day) treatment significantly decreased testes weight, sperm count and motility and daily sperm production. Serum testosterone was significantly decreased in response to treatment with 40 and 60 mg/kg/day of Aroclor 1260. LDH-X activity was significantly decreased at the three dose levels. Hydrogen peroxide (H2 O2 ) production (in a dose-related manner) and lipid peroxidation were significantly increased in response to Aroclor 1260 (20, 40, or 60 mg/kg/day) treatment. Aroclor 1260 at the three dose levels decreased the activities of the antioxidant enzymes SOD, CAT, GPx, and GR and the non-enzymatic antioxidant GSH level. CAT, GPx and GSH showed a dose-response effect. These abnormalities were effectively attenuated by pretreatment with C. comosum (200 mg/kg/day) or lipoic acid (35 mg/kg/day). Histopathological examination showed a dose-related increase in morphological abnormalities of the testis in response to Aroclor 1260 treatment. In conclusion, Aroclor 1260 induced testicular toxicity at least, in part, by induction of oxidative stress. By reversal of biochemical and morphological changes towards normalcy, the cytoprotective role of C. comosum and lipoic acid is illuminated. In comparison, lipoic acid was more protective than C. comosum extract against testicular toxicity induced by Aroclor 1260. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1147-1157, 2017.

Adverse testicular effects of Botox® in mature rats.

Botox® injections are taking a consistently increasing place in urology. Intracremasteric injections, particularly, have been applied for cryptorchidism and painful testicular spasms. Studies outlining their safety for this use are, however, scanty. Thus, the present study aimed at evaluating possible testicular toxicity of Botox® injections and their effect on male fertility. Mature rats were given intracremasteric Botox® injections (10, 20 and 40 U/kg) three times in a two-week interval. Changes in body and testes weights were examined and gonadosomatic index compared to control group. Semen quality, sperm parameters, fructose, protein, cholesterol and triglycerides contents were assessed. Effects on normal testicular function were investigated by measuring testosterone levels and changes in enzyme activities (lactate dehydrogenase-X and acid phosphatase). To draw a complete picture, changes in oxidative and inflammatory states were examined, in addition to the extent of connective tissue deposition between seminiferous tubules. In an attempt to have more accurate information about possible spermatotoxic effects of Botox®, flowcytometric analysis and histopathological examination were carried out. Botox®-injected rats showed altered testicular physiology and function. Seminiferous tubules were separated by dense fibers, especially with the highest dose. Flowcytometric analysis showed a decrease in mature sperms and histopathology confirmed the findings. The oxidative state was, however, comparable to control group. This study is the first to show that intracremasteric injections of Botox® induce adverse testicular effects evidenced by inhibited spermatogenesis and initiation of histopathological changes. In conclusion, decreased fertility may be a serious problem Botox® injections could cause.

Cardioprotective role of the coenzyme Q10 and coconut oil in acute aluminum phosphide poisoning: a randomized controlled clinical trial.

Aluminum phosphide (ALP)-induced cardiotoxicity is a major cause of high mortality rates. As there is no specific antidote, restoring cardiac hemodynamics is the cornerstone for saving patients. Based on oxidative stress theory in acute ALP poisoning, we examined the cardioprotective role of coconut oil and Coenzyme Q10 (COQ10) in ALP poisoning, focusing on their antioxidant capacity. This study was a randomized, controlled, single-blind, phase II clinical trial conducted at Tanta Poison Control Center over 1 year. Eighty-four ALP poisoned patients received supportive treatment and were randomly allocated to three equal groups. Gastric lavage was performed using sodium bicarbonate 8.4% with saline in group I. Alternatively, group II received 50 ml coconut oil, and group III initially received 600 mg CoQ10 dissolved in 50 ml coconut oil; and repeated 12 hours later. In addition to patient characteristics, clinical, laboratory, electrocardiography (ECG), and total antioxidant capacity (TAC) data were recorded and repeated 12 hours later. Patient outcomes were evaluated. There was no significant difference among groups considering patient characteristics, initial cardiotoxicity severity, vital, laboratory data, ECG changes, and TAC. However, 12 hours post-admissions, group III was significantly improved in all clinical, laboratory, and ECG parameters than comparable groups. Significant correlations were observed between elevated TAC in groups II and III with hemodynamic, serum troponin, and ECG variables. Accordingly, the need for intubation, mechanical ventilation, and the total vasopressor dose was significantly decreased in group III compared with other groups. Therefore, coconut oil and COQ10 are promising cardioprotective adjuvant therapy ameliorating the ALP-induced cardiotoxicity.

Evaluation of the potential cardioprotective activity of some Saudi plants against doxorubicin toxicity.

Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumours. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. The local Saudi flora is very rich in a variety of plants of quite known folkloric or traditional medicinal uses. Tribulus macropterus Boiss., Olea europaea L. subsp. africana (Mill.) P. S. Green, Tamarix aphylla (L.) H. Karst., Cynomorium coccineum L., Cordia myxa L., Calligonum comosum L' Hér, and Withania somnifera (L.) Dunal are Saudi plants known to have antioxidant activities. The aim of the current study was to explore the potential protective effects of methanolic extracts of these seven Saudi plants against DOX-induced cardiotoxicity in rats. Two plants showed promising cardioprotective potential in the order Calligonum comosum > Cordia myxa. The two plant extracts showed potent in vitro radical scavenging and antioxidant properties. They significantly protected against DOX-induced alterations in cardiac oxidative stress markers (GSH and MDA) and cardiac serum markers (CK-MB and LDH activities). Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. In conclusion, C. comosum and C. myxa exerted protective activity against DOX-induced cardiotoxicity, which is, at least partly, due to their antioxidant effect.

Potential role of paraffin oil gastric lavage in acute aluminum phosphide poisoning: a randomized controlled trial.

Aluminum phosphide (ALP) poisoning is a true medical emergency associated with high mortality. The lack of a specific antidote for ALP poisoning mandates searching for new treatment modalities. This study aimed to evaluate the effectiveness and safety of gastric decontamination by paraffin oil in cases with acute ALP poisoning. This study was a randomized, controlled, parallel-group, single-blind, phase II clinical trial conducted over a period of 6 months. Sixty-two patients with acute ALP poisoning were randomly allocated into two equivalent groups. In both groups, the standard ALP treatment was given. Gastric decontamination in the control group was performed by saline and sodium bicarbonate 8.4%, while in the intervention group, it was done by paraffin oil and sodium bicarbonate 8.4%. All patients were subjected to history taking, clinical examination, and laboratory investigations. The outcomes were evaluated. The median age of the studied patients was 20 years. Most of the studied cases were females, single, and from rural areas. The median delay time was 1 h. All patients included in the study alleged ingestion of ALP during suicidal attempts. Twelve hours after admission, many clinical and laboratory findings were significantly better in the intervention group. The need for intubation, mechanical ventilation, and total amount of vasopressors was significantly lower, and the mortality rate was non-significantly lower in the intervention group compared to the control. The median length of hospital stay was significantly shorter in the control group. Gastric decontamination with paraffin oil and sodium bicarbonate 8.4% could be valuable in reducing ALP poisoning severity, the need for intubation, mechanical ventilation, and vasopressors.

Protective effect of bilberry (Vaccinium myrtillus) against doxorubicin-induced oxidative cardiotoxicity in rats.

BACKGROUND: Doxorubicin (DOX) is a commonly used chemotherapeutic agent. It is associated with serious dose-limiting cardiotoxicity, which is at least partly caused by generation of reactive oxygen species (ROS). Supplementations with bilberries were effective in reducing oxidative stress in many tissue injuries due their high content of antioxidants. The present study investigated the potential protective effect of bilberry extract against DOX-induced cardiotoxicity in rats. MATERIAL/METHODS: Rats were treated orally with a methanolic extract of bilberry for 10 days. DOX was injected intraperitoneally on day 7. Twenty-four hours after the last bilberry administration, rats were subjected to ECG study. Blood was then withdrawn and cardiac tissues were dissected for assessment of oxidative stress and cardiac tissue injury. Cardiac tissues were also subjected to histopathological examination. RESULTS: Bilberry extract significantly inhibited DOX-provoked reduced glutathione depletion and accumulation of oxidized glutathione, malondialdehyde and protein carbonyls in cardiac tissues. This was accompanied by significant amelioration of reduced cardiac catalase, superoxide dismutase, and glutathione peroxidase activities; and increased cardiac myeloperoxidase activity in response to DOX challenge. Pretreatment with bilberry significantly guarded against DOX-induced increase in serum activities of lactate dehydrogenase, creatine phosphokinase and creatine kinase-MB, as well as the level of troponin I. Bilberry alleviated ECG changes in rats treated with DOX and attenuated its pathological changes. CONCLUSIONS: Bilberry protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to its antioxidant activity.

Amelioration of tamoxifen-induced liver injury in rats by grape seed extract, black seed extract and curcumin.

Liver injury was induced in female rats using tamoxifen (TAM). Grape seeds (Vitis vinifera) extract (GSE), black seed (Nigella sativa) extract (NSE), curcumin (CUR) or silymarin (SYL) were orally administered to TAM-intoxicated rats. Liver histopathology of TAM-intoxicated:rats showed pathological changes. TAM-intoxication elicited declines in liver antioxidant enzymes levels (glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase), reduced glutathione (GSH) and GSH/GSSG ratio plus the hepatic elevations in lipid peroxides, oxidized glutathione (GSSG), tumor necrosis factor-alpha (TNF-alpha) and serum liver enzymes; alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase levels. Oral intake of NSE, GSE, CUR or SYL to TAM-intoxicated rats, attenuated histopathological changes and corrected all parameters mentioned above. Improvements were prominent in case of NSE (similarly SYL) > CUR > GSE. Data indicated that NSE, GSE or CUR act as free radicals scavengers and protect TAM-induced liver injury in rats.

Dibromoacetonitrile-induced protein oxidation and inhibition of proteasomal activity in rat glioma cells.

Dibromoacetonitrile (DBAN) is a disinfection byproduct of water chlorination. The present study was designed to investigate the potential oxidative protein modifications and alterations in proteasomal activity induced by DBAN in C6 glioma cells (C6 cells). Cells were exposed to 50-400 ppb DBAN for 24 h or 48 h. Cellular viability and lactate dehydrogenase (LDH) leakage were unaffected at 24 h. However, at 48 h after exposure to high concentrations of DBAN, there was a significant decrease in cell viability accompanied by a significant increase in LDH leakage. Exposure to DBAN for 48 h significantly enhanced formation of reactive oxygen species (ROS) in a concentration-related manner. Incubation of C6 cells for 24h or 48 h caused 1.3-2.4-fold increase in levels of lipid peroxidation as indicated by malondialdehyde (MDA)+4-hydroxy-2(e)-nonenal (4-HNE). Further, DBAN induced a concentration and time-dependent increase (1.6-6-folds) in the levels of protein carbonylation. At 48 h, proteasomal activities were found to decrease to 80%, 72%, 46%, and 34% of control with 50 ppb, 100 ppb, 200 ppb, 400 ppb DBAN, respectively. In conclusion, the present study indicates that exposure of C6 cells to DBAN results in generation of ROS, lipid peroxidation, accumulation of oxidized proteins and inhibition of proteasomal activity.

Gingerol protects against experimental liver fibrosis in rats via suppression of pro-inflammatory and profibrogenic mediators.

6-Gingerol (Gin) is known to possess hepatoprotective effects. Liver fibrosis is a major health concern that results in significant morbidity and mortality. There is no FDA-approved medication for liver fibrosis. The present work aimed at exploring the beneficial effects of Gin against liver fibrosis in rats. Experimental fibrosis was induced by challenging animals with CCl4 for 6 weeks. Gin significantly ameliorated the increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, albumin, total cholesterol (TC) and triglyceride (TG) concentrations, and liver index. These effects were confirmed by light and electron microscopic examinations. The antifibrotic effects were confirmed by examining Masson trichrome-stained liver sections which indicated reduced collagen deposition in Gin-treated animals. Further, Gin administration hampered alpha-smooth muscle actin (α-SMA) expression and significantly reduced hepatic content of transforming growth factor-beta (TGF-ß). Also, Gin elicited profound antioxidant actions as indicated by preventing reduced glutathione (GSH) depletion and lipid peroxide accumulation. The observed antifibrotic activities involved decreased production of nuclear factor κB (NF-κB), tumor necrosis factor alpha (TNF-α), expression of toll-like receptor 4 (TLR4), intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM). Involvement of Gin anti-inflammatory activity was verified by the decreased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in livers of animals treated with Gin. Thus, it can be concluded that Gin protects against CCl4-induced liver fibrosis in rats. This can be ascribed, at least partly, to its antioxidant, anti-inflammatory effects as well as the inhibition of NF-κB/TLR-4 expression.

Nimesulide improves the symptomatic and disease modifying effects of leflunomide in collagen induced arthritis.

Nimesulide is a COX-2 inhibitor used for symptomatic relief of rheumatoid arthritis. Leflunomide is an anti-pyrimidine used to manage the progression of rheumatoid arthritis. Herein we studied the influence of nimesulide and leflunomide combination in terms of disease symptoms and progression using collagen-induced arthritis model in mice, as a model for rheumatoid arthritis. Collagen induced arthritis was induced by immunization with type II collagen. Assessment of joint stiffness and articular hyperalgesia were evaluated using a locomotor activity cage and the Hargreaves method, respectively. Disease progression was assessed via arthritic index scoring, X-ray imaging, myeloperoxidase enzyme activity and histopathologic examination. Nimesulide induced only transient symptomatic alleviation on the top of decreased leucocytic infiltration compared to arthritis group. However, nimesulide alone failed to induce any significant improvement in the radiological or pathological disease progression. Leflunomide alone moderately alleviates the symptoms of arthritis and moderately retarded the radiological and pathological disease progression. Combination of nimesulide and leflunomide significantly improved symptomatic (analgesia and joint stiffness) and arthritic disease progression (radiological, pathological and Myeloperoxidase enzyme activity) in collagen induced arthritis animal model.

Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats.

Doxorubicin (DOX) is a widely used cancer chemotherapeutic agent. However, it generates free oxygen radicals that result in serious dose-limiting cardiotoxicity. Supplementations with berries were proven effective in reducing oxidative stress associated with several ailments. The aim of the current study was to investigate the potential protective effect of cranberry extract (CRAN) against DOX-induced cardiotoxicity in rats. CRAN was given orally to rats (100mg/kg/day for 10 consecutive days) and DOX (15mg/kg; i.p.) was administered on the seventh day. CRAN protected against DOX-induced increased mortality and ECG changes. It significantly inhibited DOX-provoked glutathione (GSH) depletion and accumulation of oxidized glutathione (GSSG), malondialdehyde (MDA), and protein carbonyls in cardiac tissues. The reductions of cardiac activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were significantly mitigated. Elevation of cardiac myeloperoxidase (MPO) activity in response to DOX treatment was significantly hampered. Pretreatment of CRAN significantly guarded against DOX-induced rise of serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), creatine kinase-MB (CK-MB) as well as troponin I level. CRAN alleviated histopathological changes in rats' hearts treated with DOX. In conclusion, CRAN protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to CRAN's antioxidant activity.

Antihepatotoxic effect of marrubium vulgare and withania somnifera extracts on carbon tetrachloride-induced hepatotoxicity in rats.

Marrubium vulgare and Withania somnifera are used in folk medicine of several countries. Many researches showed that they are used for the treatment of variety of diseases due to their antioxidant effects. The present aim of this study was to evaluate the antihepatotoxic and antioxidant activities of the both extracts against carbon tetrachloride (CCl4)-induced hepatic damage in rats. Both extracts were given orally in a dose of 500 mg/kg/day for 4 weeks along with CCl4 started at the 7th week of induction of hepatotoxicity. The antihepatotoxic activity was assessed by measuring aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), reduced glutathione (GSH), tissue content and malondialdehyde (MDA) as well as histopathological examination. Both extracts showed a significant antihepatotoxic effect by reducing significantly the levels of AST, ALT and LDH. However, ALP levels were decreased non-significantly. Regarding the antioxidant activity, they exhibited significant effects by increasing the GPx, GR and GST activities with increased GSH tissue contents and decreased production of MDA level. Furthermore, both extracts alleviated histopathological changes in rats' liver treated with CCl4. M. vulgare and W. somnifera protect the rats' liver against CCl4-induced hepatotoxicity. This effect may be attributed, at least in part, to the antioxidant activities of these extracts.

Caffeic acid phenethyl ester protects against tamoxifen-induced hepatotoxicity in rats.

Tamoxifen (TAM) is widely used in the treatment and prevention of breast cancer. Adverse effects of TAM include hepatotoxicity. Caffeic acid phenethyl ester (CAPE), an active component of propolis, has been used in folk medicine for diverse ailments. In the current study, the protective effects of CAPE against TAM-induced hepatotoxicity in female rats were evaluated. TAM (45 mg/kg/day, i.p., for 10 consecutive days) resulted in an elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), depletion of liver reduced glutathione (GSH) and accumulation of oxidized glutathione (GSSG) and lipid peroxidation (LPO). Also, TAM treatment resulted in inhibition of hepatic activity of glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT). Further, it raised liver tumor necrosis factor-alpha (TNF-alpha) level and induced histopathological changes. Pretreatment with CAPE (2.84 mg/kg/day; i.p., for 20 consecutive days, starting 10 days before TAM injection) significantly prevented the elevation in serum activity of the assessed enzymes. CAPE significantly inhibited TAM-induced hepatic GSH depletion and GSSG and LPO accumulation. Consistently, CAPE normalized the activity of GR, GPx, SOD and CAT, inhibited the rise in TNF-alpha and ameliorated the histopathological changes. In conclusion, CAPE protects against TAM-induced hepatotoxicity.

Chloroacetonitrile induces oxidative stress and apoptosis in mouse fetal liver.

Chloroacetonitrile (CAN) is a disinfection by-product of chlorination of drinking water. The present study was designed to investigate the potential adverse effects of maternal exposure to CAN on fetal liver in mice. Based on an initial dose-response experiment, CAN (25mg/(kgday)) was given orally to pregnant mice at gestation day (GD) 6, till GD 18. Fetuses were collected and fetal livers were used for assessing oxidative status, apoptosis and histopathological changes. Maternal exposure to CAN resulted in observed oxidative stress and redox imbalance in fetal liver tissues as marked by significant decrease in reduced glutathione (GSH) and elevation of oxidized glutathione (GSSG), malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in genomic DNA. Further, CAN induced apoptosis as indicated by a significant increase in binding of Hoechst reagent to damaged DNA fragments of fetal liver and enhancement of the activity of caspase-3 in cytosolic fractions of fetal livers. Histopathological examination of fetal livers of CAN-treated mice showed hepatocytes with vacuolated cytoplasm, karyolysis and karyorrhexis as well as depletion of their glycogen content. In conclusion, maternal exposure to CAN adversely affects mouse fetal livers as evidenced by the induction of oxidative stress, apoptosis and histopathological changes.