Taurine protects against perfluorooctanoic acid-induced hepatotoxicity via inhibition of oxidative stress, inflammatory, and apoptotic pathways.

We are constantly encountering with low doses of chemicals in everyday life rather than toxic doses at a time. So, ongoing low-dose exposures of environmental chemicals commonly encountered are very likely to cause an adverse health effects. Perfluorooctanoic acid (PFOA) is frequently used for production of an array of consumer products and industrial processes. The present study evaluated the underlying mechanisms of PFOA-induced liver damage and also potential protection by taurine. Male Wistar rats were exposed to PFOA alone and in combination with taurine (25, 50, and 100 mg/kg/day) by gavage for 4 weeks. Liver function tests as well as histopathological examinations were studied. Also, oxidative stress markers, mitochondrial function, and nitric oxide (NO) production in liver tissues were measured. In addition, the expression of apoptosis-related genes (caspase-3, Bax, and Bcl-2), inflammation-associated genes (TNF-α, IL-6, NF-B), and c-Jun-N-terminal kinase (JNK) were evaluated. Taurine significantly reversed serum biochemical and histopathological alterations in the liver tissue following exposure to PFOA (10 mg/kg/day). Similarly, taurine alleviated mitochondrial oxidative damage-induced by PFOA in the liver tissue. An increased Bcl2: Bax ratio with decrees in the expression level of caspase-3, and decreased expression of inflammatory markers (TNF-α and IL-6), NF-B, and JNK were also observed following the administration of taurine. These findings suggest a protective role of taurine against PFOA-induced hepatotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis.

Choosing the Right Protocol to Establish MCF-7 Tumor Xenograft in Nude Mice.

BACKGROUND: Xenografts of various human cancers in nude mice provide a helpful model in cancer research. This study aimed to develop a xenograft mouse model of MCF-7 breast cancer using injectable estradiol valerate. METHODS: Thirty healthy female C57 nu/nu mice were engrafted with three protocols to establish an MCF-7 tumor. Injectable estradiol valerate (10 mg/ml) was used as a substitute for estradiol pellets. The development of tumors was recorded daily, and data were statistically analyzed. Histology of bladder, kidney, and tumors was used to estimate tumor establishment and probable urinary adverse effects. RESULTS: According to the findings, the duration of MCF-7 tumor growth was the lowest for protocol B (tumor tissue). Also, this protocol had the highest xenograft yield within the shortest time duration (37 days for protocol B vs. 73 days for protocol A) without causing urinary adverse effects. CONCLUSION: Our findings revealed that estradiol valerate, which is way less expensive than estradiol pellets, can be used as a tumor proliferator to establish MCF-7 tumors with the highest yield when MCF-7 tumors have been used for xenograft.

Sodium arsenite accelerates D-galactose-induced aging in the testis of the rat: Evidence for mitochondrial oxidative damage, NF-kB, JNK, and apoptosis pathways.

Aging inhibits male reproductive function and can have an impact on fertility. This study elucidated the accelerating role of sodium arsenite (As3+) on D-galactose-induced reproductive aging in male rats. The rats in the study are divided into nine groups. Group I is young control. Group II is naturally aged 24-month-old rats, other animal groups received As3+ (0.5, 1, and 2 mg/kg/day, i.p.) and/or D-galactose (DG) (50 mg/kg/day, i.p.) for 8 weeks. Then, sperm parameters, histopathological manifestations, oxidative stress markers, and gene expression of inflammatory factors (TNF-α, IL-6, and NF-ƙB), apoptosis-related genes (Bcl-2 and Bax), and C-Jun N-terminal kinase (JNK) were evaluated in testis tissue. As3+ (1 and 2 mg/kg) induced significant changes in evaluated factors compared to control group. Co-treatment with DG and As3+ caused morphological changes as well as a significant decrease in sperm motility and count. In DG + As3+ group, histopathological changes were also more obvious. Moreover, as compared to the DG group, co-treated animals exhibited a significant increase in oxidant markers and a decrease in antioxidant levels. Accordingly, DG co-exposure with As3+ markedly enhances the expressions of TNF-α, IL-6, and NF-ƙB compared to DG alone. Likewise, in the testis of rats treated with As3 + plus DG compared to DG alone, there was up-regulation of Bax (pro-apoptotic), down-regulation of Bcl-2 (anti-apoptotic), and elevation of JNK expression. These findings suggest sodium arsenite as an accelerating cause for D-galactose-induced aging process in testis tissue.

Radioprotective Effect of Febuxostat Against Testicular Damage Induced by Ionizing Radiation in Mice.

BACKGROUND: The testis is one of the most radiosensitive tissues in pelvic radiotherapy, especially in prostate cancer. Febuxostat (FBX), as an inhibitor of xanthine oxidase, has anti-inflammatory, antioxidant, and anti-apoptosis properties. OBJECTIVES: The aim of this research was to survey the protective effect of FBX against irradiation (IR)-induced testis damage via the attenuation of oxidative stress. METHODS: Male adult mice were randomly assigned into eight groups: control, FBX with three doses of 5, 10, and 15 mg/kg, IR with 6 Gy, IR + FBX (IR + FBX in three doses), respectively. In the IR + FBX groups, FBX was administrated for 8 consecutive days, and then mice were exposed to IR at a dose of 6 Gy on the 9th day. One day after irradiation, biochemical parameters were evaluated in the testis of animals, while histopathological assessment had been performed on 14th day. RESULTS: Irradiation led to the induction of testicular toxicity. FBX significantly protected histopathological alterations and decreased oxidative stress parameters in irradiated testis. Besides, FBX increased the diameter and germinal epithelial thickness of seminiferous tubules and Johnson's score in irradiated mice. CONCLUSION: Data showed that FBX markedly protected testicular injury induced by IR by inhibiting oxidative stress and may be considered as an infertility inhibitor in cancer patients, especially prostate cancer.

Synthesis and Biological Evaluation of 99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging.

With a poor prognosis, glioblastoma multiforme is the most aggressive tumor of the central nervous system in humans. The aim of this study was to develop novel tracers for the tumor targeting and imaging of overexpressed serotonin-7 receptors (5-HT7Rs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as PHH and MPHH were designed, and the corresponding radiotracers 99mTc-PHH and 99mTc-MPHH were synthesized in high radiochemical purity (>95%). 99mTc-MPHH showed a higher affinity to 5-HT7Rs on U-87 MG cells compared to 99mTc-PHH. In biodistribution studies, the radiocomplexes showed good brain uptake at 15 min combined with good radioactivity retention in the brain for 240 min. Regional rabbit brain studies indicated a higher radioactivity concentration in the hippocampus and diencephalon than in the cerebellum. Compared to 99mTc-MPHH, the 99mTc-PHH exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of 99mTc-MPHH led to enhanced tumor-to-muscle ratios at 240 min. A significant reduction in tumor uptake 60 min after an injection of pimozide (5-HT7 receptor antagonist) confirms the tumor uptake was receptor-mediated specifically. The tumor-to-contralateral muscle tissue ratio of 99mTc-PHH and 99mTc-MPHH in nude mice with U-87 MG xenograft was measured (5.25 and 4.65) at 60 min as well as (6.25 and 6.76) at 240 min, respectively.

Itraconazole synergistically increases therapeutic effect of paclitaxel and 99mTc-MIBI accumulation, as a probe of P-gp activity, in HT-29 tumor-bearing nude mice.

P-glycoprotein (P-gp), is an important efflux pump involved in chemotherapy resistance in human colon cancer. We investigated the efficacy of itraconazole as a P-gp inhibitor and its therapeutic synergistic relationship to paclitaxel through 99mTc-MIBI accumulation in HT-29 tumor-bearing nude mice. Histopathological screening along with in vitro experiments was done for further assessment. Itraconazole successfully inhibited P-gp mediated 99mTc-MIBI efflux, increasing its in vitro accumulation in itraconazole-receiving dishes. Notably, the co-administration of itraconazole with paclitaxel significantly enhanced the in vitro cytotoxicity effect of paclitaxel in itraconazole + paclitaxel wells containing HT-29 cells. Compared to the control, tumor volume in mice treated with itraconazole, paclitaxel and itraconazole +paclitaxel showed growth suppression approximately by 36.21, 60.02, and 73.3% respectively. And compared to paclitaxel group, the nude mice co-treated with paclitaxel and itraconazole showed suppression of tumor growth by about 33.31 % at the end of the treatment period. Also the biodistribution result showed that the co-administration of itraconazole with paclitaxel raised the mean tumor radioactivity accumulation compared to control and paclitaxel group. When given paclitaxel alone, the ID% of hepatic and cardiac tissue was reduced while co-administration of itraconazole with paclitaxel increased 99mTc-MIBI accumulation in these organs. Furthermore, the histopathological findings confirmed the biodistribution results. These results demonstrate that although monotherapy with itraconazole or paclitaxel has anti-tumor activity against HT-29 human colorectal cancer, a synergistic anti-tumor activity can be achieved when itraconazole is co-administered with paclitaxel. Also, 99mTc-MIBI is an effective radiotracer for monitoring response to treatment in MDR tumors.

Ginkgo biloba attenuated hepatotoxicity induced by combined exposure to cadmium and fluoride via modulating the redox imbalance, Bax/Bcl-2 and NF-kB signaling pathways in male rats.

Aim of this study was to investigate the efficacy of Ginkgo Biloba (G.B) hydro-ethanolic extract against hepatotoxicity induced by combined exposure to cadmium (Cd) and fluoride (F) in Wistar rats. Animals were exposed to F (30 mg/L) + Cd (40 mg/L), F + Cd plus G.B (50,100 and 200 mg/kg), G.B (200 mg/kg), F + Cd plus Vit C(1000 mg/L) in drinking water for 42 days. Significant raise in liver enzymes and histopathological changes were observed in F + Cd treated rats. F + Cd exposure enhanced protein and glutathione oxidation, lipid peroxidation and decreased superoxide dismutase activity. F and Cd combination also caused mitochondrial dysfunction, swelling and mitochondrial membrane potential collapse in liver isolated mitochondria. Up-regulation of inflammatory genes (TNF-α, IL-1ß and NF-kB) and pro-apoptotic Bax as well as down-regulation of anti-apoptotic Bcl-2 were detected after co-exposure to F and Cd. Interestingly, G.B alleviated F + Cd induced liver oxidative stress, mitochondrial damage and prevented inflammation and apoptosis. Furthermore, decrease in serum liver enzymes and improvement of histopathologic lesions were observed in G.B treated rats. This study explored the potential beneficial role of G.B on F + Cd combined hepatotoxic effects via considering its possible antioxidant, anti-inflammatory, mitochondrial protection and anti-apoptotic effects.

Investigating the skin penetration and wound healing properties of niosomal pentoxifylline cream.

Wounds are defined as any injuries to the skin. Wounds can cause great inconvenience and health problems for the patients depending on the healing time and severity. This makes wound healing and the strategies to treat a wound or reduce their treatment time, an important concern in health care systems. Pentoxifylline (PTX) has been reported to facilitate the wound healing in systemic administration. Different cellular and immunological mechanisms have been reported and suggested regarding the promising effects of PTX. On the other hand, the topical application of PTX seems to improve its therapeutic efficiency by localizing the drug on the wound site. In this study, PTX-niosomes were prepared and characterized. Niosomes with Zavg of 150, 200, and 300 nm were incorporated into the base cold cream. In-vitro release of PTX from these formulations was obtained between 70 -100%. Ex-vivo penetration/retention studies showed that niosomal formulations (F6 and F7) increased penetration of PTX by 1.8 and 1.2 times, respectively in comparison with the PTX-conventional cream. Retention of PTX from both niosomal creams was about 2 times higher than the PTX-conventional cream. In -vivo studies on the full-thickness wound in BALB/c mice showed that PTX-niosomal creams shortened the duration of wound healing by two days compared to control groups (PTX-conventional cream, base cream, and no treatment). The final wound size in the niosomal cream-treated group was also significantly smaller than the control groups. Histological analysis of the wounds confirmed the results of in-vivo studies.

Co-exposure to non-toxic levels of cadmium and fluoride induces hepatotoxicity in rats via triggering mitochondrial oxidative damage, apoptosis, and NF-kB pathways.

Fluoride (F) and cadmium (Cd) are two common water pollutants. There is low information about their co-exposure in low doses. So, in this study, we evaluated the combination effects of non-toxic doses of F and Cd and the possible mechanism of their combined interaction. Male rats were exposed to non-toxic doses of sodium fluoride (30 mg/l) and/or cadmium chloride (40 mg/l) in drinking water for 6 weeks. Then, liver tissues were separated and several factors including oxidative stress, mitochondrial toxicity, inflammation, apoptosis, and biochemical and histopathological changes were evaluated. Cd and F alone did not induce any significant changes in evaluated factors compared to control group, while significant elevation in liver enzymes as well as histopathological changes were observed in rats treated with F+Cd. Also, a remarkable increase in oxidative stress markers including reactive oxygen species, lipid peroxidation, and protein carbonyl and also decreasing glutathione and superoxide dismutase levels were detected following co-exposure to F and Cd. Furthermore, a combination of F and Cd resulted in mitochondrial dysfunction, swelling, as well as a reduction in mitochondrial membrane potential in isolated liver mitochondria. On the other hand, TNF-α, IL-1ß, and NF-kB inflammatory genes were upregulated in the liver after combined exposure to F and Cd compared to individual treatments. Also, F+Cd treatment increased the Bax expression but decreased the expression of Bcl-2 significantly. These findings suggest that Cd and F can potentiate their individual toxic effects on the liver tissue through disruption of the cellular redox status, inflammation, and apoptosis pathway.

Radioprotective effect of diethylcarbamazine on radiation-induced acute lung injury and oxidative stress in mice.

The present study was designed to evaluate the radioprotective effect of diethylcarbamazine (DEC) against oxidative stress and acute lung injury induced by total body radiation (TBI) in mice. For study the optimum dose for radiation protection of DEC, mice were administrated with three dose of DEC (10, 50 and 100 mg/kg), once daily for eight consecutive days. Animals were exposed whole body to 5 Gy X-radiation on the 9 day. The radioprotective potential of DEC in lung tissues was assessed using oxidative stress examinations at 24 h after TBI and histopathological assay also was analyzed one week after TBI. Results from biochemical analyses demonstrated increased malonyldialdehyde (MDA), nitric oxide (NO) and protein carbonyl (PC) levels of lung tissues in only irradiated group. Histopathologic findings also showed an increase in the number of inflammatory cells and the acute lung injury in this group. DEC pretreatment significantly mitigated the oxidative stress biomarkers as well as histological damages in irradiated mice. The favorable radioprotective effect against lungs injury was observed at a dose of 10 mg/kg of DEC in mice as compared with two other doses (50 and 100 mg/kg). The data of this study showed that DEC at a dose of 10 mg/kg with having antioxidant and anti-inflammatory properties can be used as a therapeutic candidate for protecting the lung from radiation-induced damage.

Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model.

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

Effects of Olive Oil supplementation on Sodium Arsenate-induced Hepatotoxicity in Mice.

BACKGROUND: Sodium arsenate (As), a toxic substance with induced oxidative stress, lead to hepatotoxicity. Olive oil (OO) with antioxidant property has protective effect on toxicity. The aim of this study was to investigate protective effect of OO on sodium As-induced hepatotoxicity in mice. SUBJECTS AND METHODS: In this experimental study, 32 adult male BALB/c mice were divided randomly into four groups: control group (received only normal saline, the same volume as other groups), OO (0.4 mL/day, gavage), sodium As (15 mg/kg, gavage), and OO + sodium As (received OO 1 h before sodium As). Drugs were given for 30 consecutive days. After the last receipt of the drugs, oxidative stress parameters [malondialdehyde (MDA), glutathione (GSH)] in tissue, liver function parameters [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP)] in serum, ferric reducing ability of plasma (FRAP) in plasma, and histopathological assays were performed. RESULTS: Sodium As induced hepatic injury as indicated by significant increase in AST, ALT, ALP, and LDH in serum and pathologic evidences. It also induces hepatic oxidative stress biomarkers as indicated by significant increase in levels of MDA and significant decrease in FRAP and GSH concentration. OO administration significantly improved oxidative stress parameters, histopathological changes, and enzymatic markers of liver injury. CONCLUSIONS: It was concluded that antioxidant activity of OO has hepatoprotective effect on As-induced hepatic injury.

Zatariamultiflora ameliorates cisplatin-induced testicular damage via suppression of oxidative stress and apoptosis in a mice model.

OBJECTIVES: Cisplatin (CP), as an anti-neoplastic drug, causes testicular damage. Zataria multiflora Boiss (ZM), a medicinal plant, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of ZM against CP-induced testicular toxicity. MATERIALS AND METHODS: In this experimental study, thirty-two adult male mice were randomly divided into four groups. The control group received normal saline with oral gavage during 7 days; ZM group received ZM (200 mg/kg) during 7 days by gavage; CP group received CP (10 mg/kg) intraperitoneally (IP) in the 5th day of study; ZM + CP group received ZM during 7 days and CP was injected in 5th day. Sperm parameters, biochemical (MDA, GSH, and PC) levels, serum testosterone levels, and histopathological and immunohistochemical assays of testis were examined one day after the last drug treatment. RESULTS: CP treatment caused significant damage via changed sperm parameters (sperm motility, count, viability rate, and abnormalities), increased oxidative stress (increased MDA and PC levels, and decreased GSH level), histological changes (degeneration, necrosis, arrest of spermatogenesis, congestion, and decrease in thickness of the germinal epithelium, diameter of seminiferous tubules, and Johnsen's Score), decreased serum testosterone level, and increased caspase-3 immunoreactivity. ZM preserved spermatogenesis and mitigated the toxic effects of CP on the testis tissue. In addition, treatment with ZM significantly reduced caspase-3 immunoreactivity. CONCLUSION: The findings of this study suggest that ZM as a potential antioxidant compound and due to free radicals scavenging activities has a protective effect against CP-induced testicular toxicity.

99mTc-Glucarate for assessment of paclitaxel therapy in human ovarian cancer in mice.

OBJECTIVES: The monitoring of cancer treatment response to chemotherapy is considered an essential strategy for follow-up of patients. The aim of this study was to evaluate the use of 99mTc-glucarate as a radiotracer for in vivo quantification and visualization of necrotic area and therapeutic effect of paclitaxel in ovarian cancer xenografted nude mice. MATERIALS AND METHODS: After implantation of human ovarian cancer (SKOV-3) in nude mice, tumor xenografted mice were enrolled in two groups as control and treatment (paclitaxel) groups. 99mTc-glucarate uptakes were quantified in tumors of control and treatment groups and also tumor imaging was performed with a gamma camera. The necrotic and viable areas of tumor and tumoral masses were evaluated through histopathological and macroscopic observations, respectively. RESULTS: 99mTc-glucarate uptake in tumor of treatment group was higher than control group.99mTc-glucarate uptake in ovarian tumor was clearly visualized with gamma imaging in both groups, but paclitaxel treated group showed higher radioactive uptake than control mice. The necrotic area in tumoral mass of mice treated with paclitaxel was confirmed by histopathological observations. CONCLUSION: 99mTc-glucarate is an effective radiotracer for evaluation and monitoring of tumor necrosis caused by chemotherapy, and it may be helpful for therapy monitoring in patients with cancer.

Deltamethrin-Induced Hepatotoxicity and Virgin Olive Oil Consumption: An Experimental Study.

BACKGROUND: Deltamethrin (DM) is a synthetic pyrethroid insecticide which can lead to pathological effects in mammals through oxidative stress. On the other hand, virgin olive oil (VOO) is a rich source of phenolic compounds with antioxidants. The aim of the present study was to determine the protective effects of VOO against DM-induced hepatotoxicity. METHODS: Thirty-six mice were randomly separated into 4 groups: vehicle group, VOO group, DM group, and DM plus VOO group. Immunohistochemistry of PARP, COX-2, and caspase-3 with the biochemical analysis of malondialdehyde and total antioxidant capacity levels were performed in the liver samples 5 weeks after gavaging. Statistical analysis was performed using SPSS, version 15. The data were compared between the groups using the Tukey multiple comparison tests and the analysis of the variance. A P value <0.05 was considered significant. RESULTS: The malondialdehyde level in the liver was increased in the DM group (71.18±0.01), whereas it was significantly (P=0.001) decreased after VOO administration in the DM plus VOO group (39.59±2.43). While the total antioxidant capacity level in the liver was decreased in the DM group (3.05±0.05), it was significantly increased (P=0.03) after VOO administration in the DM plus VOO group (3.95±0.04). A greater expression of caspase-3 (P=0.008), COX-2 (P =0.004), and PARP (P 0.006) could be detected in the DM group, while it was significantly (P=0.009) attenuated in the DM plus VOO group. Also, the degeneration of hepatocytes, which was detected in the DM group, was attenuated after VOO consumption. CONCLUSIONS: VOO exerted protective effects against DM-induced hepatotoxicity, which might be associated with its anti-apoptotic, anti-inflammatory, and antioxidative properties.