Nephroprotective effects of Acacia senegal against aflatoxicosis via targeting inflammatory and apoptotic signaling pathways.

Aflatoxin B1 (AFB1) is a common environmental pollutant that poses a major hazard to both humans and animals. Acacia senegal (Gum) is well-known for having antioxidant and anti-inflammatory bioactive compounds. Our study aimed to scout the nephroprotective effects of Acacia gum (Gum) against AFB1-induced renal damage. Four groups of rats were designed: Control, Gum (7.5 mg/kg), AFB1 (200 µg/kg b.w) and AFB1-Gum, rats were co-treated with both Gum and AFB1. Gas chromatography-mass spectrometry (GC/MS) analysis was done to determine the phytochemical constituents in Gum. AFB1 triggered profound alterations in kidney function parameters (urea, creatinine, uric acid, and alkaline phosphatase) and renal histological architecture. Additionally, AFB1 exposure evoked up-regulation of mRNA expression levels of inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), and nuclear factor kB p65 (NF-κB/P65) in renal tissue. The oxidative distress and apoptotic cascade are also instigated by AFB1 intoxication as depicted in down-regulated protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase type 1 (SOD1) along with upregulation of cytochrome c (Cyto c), and cleaved Caspase3 (Casp3-17 and 19) in renal tissue. In conclusion, current study obviously confirms the alleviating effects of Gum supplementation against AFB1-induced renal dysfunction, oxidative harm, inflammation, and cell death. These mitigating effects are suggested to be attributed to Gum's antioxidant and anti-inflammatory activities. Our results recommend Gum supplementation as add-on agents to food that might aid in protection from AFB1-induced nephrotoxicity.

Arabic Gum Could Alleviate the Aflatoxin B1-provoked Hepatic Injury in Rat: The Involvement of Oxidative Stress, Inflammatory, and Apoptotic Pathways.

Aflatoxin B1 (AF) is an unavoidable environmental pollutant that contaminates food, feed, and grains, which seriously threatens human and animal health. Arabic gum (AG) has recently evoked much attention owing to its promising therapeutic potential. Thus, the current study was conducted to look into the possible mechanisms beyond the ameliorative activity of AG against AF-inflicted hepatic injury. Male Wistar rats were assigned into four groups: Control, AG (7.5 g/kg b.w/day, orally), AF (200 µg/kg b.w), and AG plus AF group. AF induced marked liver damage expounded by considerable changes in biochemical profile and histological architecture. The oxidative stress stimulated by AF boosted the production of plasma malondialdehyde (MDA) level along with decreases in the total antioxidant capacity (TAC) level and glutathione peroxidase (GPx) activity. Additionally, AF exposure was associated with down-regulation of the nuclear factor erythroid2-related factor2 (Nrf2) and superoxide dismutase1 (SOD1) protein expression in liver tissue. Apoptotic cascade has also been evoked following AF-exposure, as depicted in overexpression of cytochrome c (Cyto c), cleaved Caspase3 (Cl. Casp3), along with enhanced up-regulation of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappa-B transcription factor/p65 (NF-κB/p65) mRNA expression levels. Interestingly, the antioxidant and anti-inflammatory contents of AG may reverse the induced oxidative damage, inflammation, and apoptosis in AF-exposed animals.

Chitosan and EDTA conjugated graphene oxide antinematodes in Eggplant: Toward improving plant immune response.

A new strategy regarding the fabrication of chitosan (CS) or ethylene diamine tetraacetic acid (EDTA) on graphene oxide (GO) was performed. The nematocidal potential against Meloidogyne incognita causing root-knot infection in eggplant was tested. The plant immune response was investigated through measuring the photosynthetic pigments, phenols and proline contents, oxidative stress, and antioxidant enzymes activity. Results indicating that, the treatment by pure GO recorded the most mortality percentages of M. incognita 2nd juveniles followed by GO-CS then GO-EDTA. In vivo greenhouse experiments reveals that, the most potent treatment in reducing nematodes was GO-CS which recorded 85.42%, 75.3%, 55.5%, 87.81%, and 81.32% in numbers of 2nd juveniles, galls, females, egg masses and the developmental stage, respectively. The highest chlorophyll a (104%), chlorophyll b (46%), total phenols (137.5%), and free proline (145.2%) were recorded in GO-CS. The highest malondialdehyde (MDA) value was achieved by GO-EDTA (7.22%), and hydrogen peroxide (H2O2) content by 47.51% after the treatment with pure GO. Treatment with GO-CS increased the activities of catalase (CAT) by 98.3%, peroxidase (POD) by 97.52%, polyphenol oxidase (PPO) by 113.8%, and superoxide dismutase (SOD) by 42.43%. The synthesized nanocomposites increases not only the nematocidal activity but also the plant systematic immune response.

Graphene oxide and its nanocomposites with EDTA or chitosan induce apoptosis in MCF-7 human breast cancer.

To achieve the advanced anticancer activity of nanocomposites fabricated with graphene oxide (GO), a novel procedure was used during the fabrication of chitosan (CS) or ethylene diamine tetra acetic acid (EDTA). The synthesized GO-based nanocomposites were distinguished through different analytical techniques. The cytotoxic activity was examined using MTT assays against three different cancer cell lines. Cell cycle distribution and apoptosis were studied by flow cytometry. Caspase-8, caspase-9, and VEGFR-2 levels were determined using the ELISA technique. HRTEM results revealed a regular 2D thin sheet with a transparent surface in non-modified GO and for GO-CS, the surface of GO has clear cuts and lines had developed due to CS insertion. Concerning the MCF-7 breast cancer cell line, the lowest IC50 values were recorded, suggesting the most powerful cytotoxic effect on breast cancer cells. Treatment with GO-EDTA resulted in the lowest IC50 value of 3.8 ± 0.18 µg mL-1. As indicated by the annexin V-FITC apoptosis assay, the total apoptosis highest percentage was in GO-EDTA treatment (30.12%). In addition, the study of cell cycle analysis showed that GO-EDTA arrested the cell cycle primarily in the G0/G1 phase (33.74%). CS- and EDTA-conjugated GO showed an anti-cancer activity through their cytotoxic effect against the MCF-7 breast cancer cell line.

Graphene oxide-based nanocomposites (GO-chitosan and GO-EDTA) for outstanding antimicrobial potential against some Candida species and pathogenic bacteria.

To obtain the synergistic antimicrobial potential of nano-composites conjugated with graphene oxide (GO), an alternative approach was developed throughout the hybridization of chitosan (CS) or ethylene diamine tetraacetic acid (EDTA) with GO. The synthesized GO-nanocomposites were identified by XRD, HRTEM, SEM, FTIR, Zeta potential, and Raman spectroscopy. The antimicrobial activity of GO, GO-CS, and GO-EDTA was investigated against some pathogenic bacteria and Candida sp. Results showed that nano-composites looked flattened and clear, with some lines and folds on the exterior part. SEM images show the basic morphology of GO which owns remarkable holes, crevasses, and indeclinable internal structure. GO-EDTA and GO-CS possess a promising antimicrobial activity against all pathogenic microbes. In-vitro ZOI result verified that they exhibited activity against Escherichia coli (22.0 mm for GO-EDTA and 11.0 mm for GO-CS), Staphylococcus aureus (15.0 mm for GO-EDTA and 10.0 mm for GO-CS) and Candida albicans (22.0 mm for GO-EDTA and 16.0 mm for GO-CS). Microbial cells may be ultimately-damaged when they interact with GO-based nanocomposites due to different mechanisms such as oxidative and membrane stress and wrapping isolation. This work provides revolutionary GO-nanocomposites for increasing the antimicrobial activity against some pathogenic microbes with a cost-effective and eco-friendly approach.

Effects of several organophosphates on hepatic cytochrome P450 activities in rats.

Four commonly used organophosphates (fenitrothion, dichlorvos, chlorpyrifos, and trichlorfon) were orally administered to male Sprague-Dawley rats for five days in order to explore their effects on the activities of liver cytochrome P450 (CYP). In addition, Michaelis-Menten kinetics of the metabolic reactions catalyzed by liver CYPs were analyzed following the addition of these compounds to the assay system to examine their potential inhibitory effects on liver CYPs activities. These reactions included ethoxyresorufin O-deethylation, midazolam 4-hydroxylation, tolbutamide hydroxylation, and bufuralol 1'-hydroxylation for CYP1A, 3A, 2C, and 2D activities, respectively. Total CYP content was also examined after oral administration of each organophosphate. Results revealed that oral giving of fenitrothion inhibited significantly CYP1A and 3A activities while elevated activity of CYP2C. Fenitrothion is a potent inhibitor for CYP1A and 2C with Ki values of 0.42 and 36.1 µM, respectively but had a weak inhibitory effect on CYP2D and 3A with Ki values of 290 and 226 µM, respectively. Chlorpyrifos is a potent inhibitor of CYP1A with Ki 0.24 µM and moderately inhibited CYP2C or 3A with Ki values of 84.8 and 77.7 µM, respectively. On the other hand, dichlorvos and trichlorfon caused extremely low or negligible inhibition of different CYP activities. From these results, it is concluded that both fenitrothion and chlorpyrifos may increase the toxicity of chemicals in environmental living organisms through their potent inhibitory effects on these CYP activities, but dichlorvos and trichlorfon may not.

Subacute Toxicity of Nerium oleander Ethanolic Extract in Mice.

Nerium oleander (N. oleander) is a well-known poisonous shrub that is frequently grown in gardens and public areas and contains numerous toxic compounds. The major toxic components are the cardiac glycosides oleandrin and neriin. The aim of our study was to evaluate the toxic effects of an ethanolic N. oleander leaf extract on haematological, cardiac, inflammatory, and serum biochemical parameters, as well as histopathological changes in the heart. N. oleander extract was orally administered for 14 and 30 consecutive days at doses of 100 and 200 mg of dried extract/kg of body weight in 0.5 mL of saline. The results showed significant increases in mean corpuscular volume, white blood cell counts, platelet counts, interleukins (IL-1 and IL-6), tumour necrosis factor alpha, C reactive protein, alanine aminotransferase, lactate dehydrogenase, creatine kinase and creatine kinase MB, especially at high doses. Marked pathological changes were perceived in the heart tissue. Thus, it can be concluded that exposure to N. oleander leaf extract adversely affects the heart and liver.

Anti-rheumatoid Activity of Secondary Metabolites Produced by Endophytic Chaetomium globosum.

The aim of the present study was to investigate the anti-rheumatoid activity of secondary metabolites produced by endophytic mycobiota in Egypt. A total of 27 endophytic fungi were isolated from 10 dominant medicinal plant host species in Wadi Tala, Saint Katherine Protectorate, arid Sinai, Egypt. Of those taxa, seven isolates of Chaetomium globosum (CG1-CG7), being the most frequent taxon, were recovered from seven different host plants and screened for production of active anti-inflammatory metabolites. Isolates were cultivated on half - strength potato dextrose broth for 21 days at 28°C on a rotatory shaker at 180 rpm, and extracted in ethyl acetate and methanol, respectively. The probable inhibitory effects of both extracts against an adjuvant induced arthritis (AIA) rat model were examined and compared with the effects of methotrexate (MTX) as a standard disease-modifying anti-rheumatoid drug. Disease activity and mobility scoring of AIA, histopathology and transmission electron microscopy (TEM) were used to evaluate probable inhibitory roles. A significant reduction (P < 0.05) in the severity of arthritis was observed in both the methanolic extract of CG6 (MCG6) and MTX treatment groups 6 days after treatment commenced. The average arthritis score of the MCG6 treatment group was (10.7 ± 0.82) compared to (13.8 ± 0.98) in the positive control group. The mobility score of the MCG6 treatment group (1.50 ± 0.55) was significantly lower than that of the positive control group (3.33 ± 0.82). In contrast, the ethyl acetate extract of CG6 (EACG6) treatment group showed no improvements in arthritis and mobility scores in AIA model rats. Histopathology and TEM findings confirmed the observation. Isolate CG6 was subjected to sequencing for confirmation of phenotypic identification. The internal transcribed spacer (ITS) 1-5.8 s - ITS2 rDNA sequences obtained were compared with those deposited in the GenBank Database and registered with accession number KC811080 in the NCBI Database. The present study revealed that the methanol extract of endophytic fungus C. globosum (KC811080) recovered from maidenhair fern has an inhibitory effect on inflammation, histopathology and morphological features of rheumatoid arthritis in an AIA rat model.

Ceftiofur pharmacokinetics in Nile tilapia Oreochromis niloticus after intracardiac and intramuscular administrations.

Ceftiofur is a broad-spectrum third generation cephalosporin, which acts by inhibiting bacterial cell wall synthesis. It is active against Gram-positive and Gram-negative bacteria such as Aeromonas hydrophila and ß-lactamase-producing strains, which are common pathogens in freshwater fish. Ceftiofur pharmacokinetics in Nile tilapia Oreochromis niloticus were studied following single intracardiac (i.c.) or intramuscular (i.m.) administration of ceftiofur sodium (NAXCEL®) in a dose of 5 mg ceftiofur kg-1 body weight. After i.c. injection, ceftiofur plasma concentrations decreased biexponentially, suggesting a 2-compartmental open model. Distribution and elimination half-lives (t0.5(α) and t0.5(ß)) were 0.61 ± 0.22 and 0.14 ± 0.03 h mean ±SD, respectively. Elimination constant (Kel) and total body clearances (Cltot) were 3.22 ± 0.48 h-1 and 1.64 ± 0.47 l h-1 kg-1, respectively. Volume of distribution (Vss) and areas under curves (AUC) were 0.12 ± 0.03 l kg-1 and 24.18 ± 8.81 µg ml-1 h, respectively. Following i.m. injection of ceftiofur, plasma concentrations were best described by a 1-compartment open model with a first order absorption; bioavailability was quite high (96.85 ± 23.74%). Plasma maximum concentration (Cmax) was 12.32 ± 6.53 µg ml-1; achieved at time of maximum concentration (Tmax) of 0.74 ± 0.04 h. Absorption and elimination half-lives (t0.5ab and t0.5ß) were 0.49 ± 0.06 and 0.53 ± 0.03 h, respectively. In conclusion, i.m. injection of ceftiofur sodium produced extremely high bioavailability with high plasma concentrations that persisted up to 6 h post injection, which may make ceftiofur a useful alternative antibiotic for treatment of brood stock or important ornamental fishes.

Remote effect of kidney ischemia-reperfusion injury on pancreas: role of oxidative stress and mitochondrial apoptosis.

INTRODUCTION: Recent studies have demonstrated remote effects of renal ischemia/reperfusion (IR) injury on some organs such as brain, liver, and lungs. Oxidative stress is reported to be the cornerstone in such ischemic conditions. Associated apoptosis is also reported in remote lung, liver and myocardial injury after acute kidney injury. So, we postulated that renal IR may affect the pancreas by its remote effect. Oxidative stress and mitochondrial mediated apoptosis may play a crucial role in this injury. We investigated the effects of kidney IR on pancreatic exocrine and endocrine functions, antioxidant enzyme activity, and apoptosis. MATERIAL AND METHODS: The protective effect of vitamin C was also investigated. The animals were submitted to non-traumatic bilateral renal IR, sham operation or treatment with vitamin C after IR. Rats were sacrificed on the 1(st), 3(rd), and 7(th) days of the experiment to evaluate the parameters of oxidative stress (catalase, lipid peroxidase, reduced glutathione and superoxide dismutase), pancreatic endocrine and exocrine function (amylase, insulin and fasting blood glucose), renal functions (serum creatinine and blood urea nitrogen), cellular injury and apoptotic markers (Bcl-2, Bax and caspase-3). RESULTS: Kidney I/R significantly increased the renal and pancreatic functions at 1, 3 and 7 days, while fasting insulin was significantly increased at day 3 after ischemia. Moreover, I/R significantly increased the studied oxidative stress markers and decreased the antioxidant capacity in pancreatic tissues. In addition, renal I/R induced numerous histopatological lesions in pancreatic tissues and increased the apoptosis-related genes. Treating the rats with vitamin C (100 mg/kg) significantly restored the renal and pancreatic functions, improved the pancreatic antioxidant capacity and protected the pancreatic tissues from apoptotic necrosis. CONCLUSIONS: The results suggested that bilateral renal ischemia for 45 min caused significant impairment of pancreatic function and structure as indicators of acute pancreatitis. While IR enhances oxidative stress and apoptosis, vitamin C appears to play a cytoprotective role.

Toxicological and biochemical studies on Schinus terebinthifolius concerning its curative and hepatoprotective effects against carbon tetrachloride-induced liver injury.

BACKGROUND: Recently, many efforts have been made to discover new products of natural origin which can limit the xenobiotic-induced hepatic injury. Carbon tetrachloride (CCl4) is a highly toxic chemical that is widely used to study hepatotoxicity in animal models. OBJECTIVE: The present study was conducted to investigate the curative and protective effects of Schinus terbenthifolius ethanolic extract against CCl4 -induced acute hepatotoxicity in rats. MATERIALS AND METHODS: S. terbenthifolius extract was orally administered in a dose of 350 mg dried extract/kg b.wt. before and after intoxication with CCl4 for curative and protective experiments, respectively. A group of hepatotoxicity indicative enzymes, oxidant-antioxidant capacity, DNA oxidation, and apoptosis markers were measured. RESULTS: CCl4 increased liver enzyme leakage, oxidative stress, hepatic apoptosis, DNA oxidation, and inflammatory markers. Administration of S. terebinthifolius, either before or after CCl4 intoxication, significantly decreased elevated serum liver enzymes and reinstated the antioxidant capacity. Interestingly, S. terebinthifolius extract inhibited hepatocyte apoptosis as revealed by approximately 20 times down-regulation in caspase-3 expression when compared to CCl4 untreated group. On the other hand, there was neither protective nor curative effect of S. terebinthifolius against DNA damage caused by CCl4. CONCLUSION: The present study suggests that S. terebinthifolius extract could be a substantially promising hepatoprotective agent against CCl4 toxic effects and may be against other hepatotoxic chemical or drugs.

Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs.

The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans.