Fabrication and application of targeted ciprofloxacin nanocarriers for the treatment of chronic bacterial prostatitis.

Pathogenic bacteria cause chronic bacterial prostatitis (CBP). CPB is characterized by urinary tract infection and persistence of pathogenic bacteria in prostatic secretion. Owing to poor blood supply to the prostate gland and limited drug penetration, CBP treatment is difficult. Transferosomes are ultradeformable vesicles for nanocarrier applications, which have become an important area of nanomedicine. Such carriers are specifically targeted to the pathological area to provide maximum therapeutic efficacy. It consists of a lipid bilayer soybean lecithin phosphatidylcholine (PC), an edge activator Tween 80 with various ratios, and a chloroform/methanol core. Depending on the lipophilicity of the active substance, it can be encapsulated within the core or among the lipid bilayer. Due to their exceptional flexibility, which enables them to squeeze themselves through narrow pores that are significantly smaller than their size, they can be a solution. One formulation (Cipro5 PEG) was selected for further in vitro analysis and was composed of phosphatidylcholine (PC), Tween 80, and polyethylene glycol-6 stearate (PEG-6 stearate) in a ratio of 3:3:1 in a chloroform/methanol mixture (1:2 v/v). In vitro, the results showed that PEGylated transferosomes had faster drug release, higher permeation, and increased bioavailability. The transferosomes were quantified with a particle size of 202.59 nm, a zeta potential of-49.38 mV, and a drug entrapment efficiency of 80.05%. The aim of this study was to investigate drug targeting. Therefore, Monoclonal antibody IgG was coupled with Cipro5 PEG, which has specificity and selectivity for conjugated nanoparticles. In vivo, a total of twenty-five adult Wistar rats were obtained and randomly divided into 5 groups, each of 5 rats at random: the control group, blank group, positive control group, Cipro 5PEG group, and Cipro 5PEG coupled with IgG antibody group. The cytokines levels (IL-1ß, IL-8, and TNF-α) in the serum were detected by analysis kits. Compared with the control group, treatment with Cipro 5PEG coupled with the IgG antibody could significantly inhibit cytokines, according to histological analysis. Cipro 5PEG, coupled with the IgG antibody group, reduced prostate tissue inflammation. Hence, our results show a promising approach to delivering antibiotics for the targeted therapy of CBP.

miRNA-1246, HOTAIR, and IL-39 signature as potential diagnostic biomarkers in breast cancer.

The molecular alterations in noncoding RNA can lead to a cellular storm that is correlated to higher mortality and morbidity rates and contributes to the progression and metastasis of cancer. Herein, we aim to evaluate the expression levels and correlations of microRNA-1246 (miR-1246), HOX transcript antisense RNA (HOTAIR), and interleukin-39 (IL-39) in patients with breast cancer (BC). In this study, 130 participants were recruited, including 90 breast cancer patients and 40 healthy control participants. Serum levels of miR-1246 and HOTAIR expression were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Also, the level of IL-39 expression was evaluated using a Western blot. All BC participants demonstrated a remarkable elevation in miR-1246 and HOTAIR expression levels. Moreover, IL-39 expression levels demonstrated a noticeable decline in BC patients. Furthermore, the differential expression fold of miR-1246 and HOTAIR revealed a strong positive correlation among breast cancer patients. In addition, a negative relationship between the IL-39 and the miR-1246 and HOTAIR differential expression was also noticed. This study revealed that HOTAIR/miR-1246 exerts an oncogenic impact in patients with breast cancer. The expression levels of circulation miR-1246, HOTAIR, and IL-39 could be considered early diagnostic biomarkers in BC patients.

Diosmin and Trolox Have Anti-Arthritic, Anti-Inflammatory and Antioxidant Potencies in Complete Freund's Adjuvant-Induced Arthritic Male Wistar Rats: Roles of NF-κB, iNOS, Nrf2 and MMPs.

Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disease caused by a malfunction of the immune system. The aim of this study was to examine the anti-arthritic effects and suggest the mechanisms of actions of diosmin and trolox in male Wistar rats. Complete Freund's adjuvant (CFA) was used to establish RA in the animals by subcutaneous injection of 100 µL CFA/rat into plantar region of right hind leg in two consecutive days. Diosmin and/or trolox were administered orally at a dosage of 20 mg/kg/day to CFA-induced arthritic rats for 2 weeks. The normal and arthritic control groups were orally given the same equivalent volume of a vehicle (1% carboxymethyl cellulose) in which treatment agents were dissolved. At the end of the experiment, blood samples were collected from the jugular vein for the detection of the total leukocyte count (TLC) and differential leukocyte count (DLC) in blood and the detection of rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), tumor necrosis factor-α (TNF-α), interleukin-13 (IL-13), and interleukin-17 (IL-17) levels by enzyme-linked immunosorbent assay (ELISA), as well as markers of oxidative stress and the antioxidant defense system in serum. The right hind ankle regions of three rats from each group were dissected out and fixed in 10% neutral-buffered formalin for histological examination and the other three were kept at -30 °C for Western blot analysis of nuclear factor-kappa B (NF-κB) protein 50 (NF-κB p50), NF-κB p65, inducible nitric oxide synthase (iNOS), nuclear factor erythroid-2-related factor 2 (Nrf2), and matrix metalloproteinase (MMP)-1 (MMP-1), MMP-3, and MMP-9. The CFA injection was deleterious to the ankle joint's histological architecture, manifesting as infiltration of inflammatory cells into the articular cartilage, hyperplasia of the synovium, and erosion of the cartilage. All these effects were ameliorated by diosmin and/or trolox, with the combined dose being the most effective. The two compounds significantly lowered the elevated serum levels of RF, ACPA, TNF-α, and IL-17, as well as other pro-inflammatory mediators, such as NF-κB p50, NF-κB p65, iNOS, MMP-1, MMP-3 and MMP-9. They also increased the levels of the anti-inflammatory cytokine, IL-13, and the cytoprotective transcription factor Nrf2. The compounds stimulated higher activities of antioxidants, such as glutathione, glutathione-S-transferase, catalase, and superoxide dismutase, and reduced lipid peroxidation in the serum of arthritic rats. In conclusion, diosmin, trolox, and their combination, which was the most potent, exerted anti-arthritic, anti-inflammatory and antioxidant effects by suppressing NF-κB signaling, inhibiting matrix metalloproteinases, and activating Nrf2.

Adsorptive recovery of arsenic (III) ions from aqueous solutions using dried Chlamydomonas sp.

The present study aimed to descry the effectiveness of dried microalga Chlamydomonas sp. for disposing of arsenic from aqueous solution. The study included examining the impact of some factors on algae's adsorption capacity (optimization study), such as initial concentrations of heavy metal, biosorbent doses, pH and contact time. All trials have been performed at constant temperature 25 °C and shaking speed of 300 rpm. The optimization studying indicated the pH 4, contact time at 60 min, temperature 25 °C and biomass concentration of 0.6 g/l were the best optimum conditions for the bioremediation activity with maximum removal percentage 95.2% and biosorption capacity 53.8 mg/g. Attesting of biosorption by applying FTIR (Fourier transfigure infrared), XRD (X-ray diffraction), SEM-EDX (Scanning Electron Microscope - Energy Dispersive X-ray), DLS (Dynamic light scarring) and ZP (Zeta Potential) was conducted. Also, Kinetics, isotherm equilibrium and thermodynamics were carried out to explain the plausible maximum biosorption capacity and biosorption rate of biosorbent q maximum.

Naringin and Hesperidin Counteract Diclofenac-Induced Hepatotoxicity in Male Wistar Rats via Their Antioxidant, Anti-Inflammatory, and Antiapoptotic Activities.

This study is aimed at evaluating the preventive effect and at suggesting the mode of actions of naringin and hesperidin and their combination in diclofenac-induced hepatotoxicity. Male Wistar rats, intraperitoneally injected with diclofenac sodium (3 mg/kg b.wt/day), were orally treated with naringin (20 mg/kg b.wt/day) and hesperidin (20 mg/kg b.wt/day) and their combination for 4 weeks. The administrations of naringin and hesperidin to diclofenac-injected rats led to a significant decrease in the elevated serum ALT, AST, LDH, ALP, GGT, total bilirubin, TNF-α, and IL-17 levels as well as liver lipid peroxidation and liver p53 and caspase-3 mRNA expressions. In contrast, serum IL-4 level, liver GSH content, and liver GPx and SOD activities increased. In association, diclofenac-induced deleterious histological alterations including hydropic degeneration, cytoplasmic vacuolization, apoptosis, and focal hepatic necrosis of hepatocytes associated with inflammatory cells' infiltration were remarkably improved by treatments with naringin and hesperidin. In conclusion, naringin, hesperidin, and their combination, which was the most potent, counteract diclofenac-induced liver injury via antioxidant, anti-inflammatory, and antiapoptotic actions. Thus, this study recommends the use of naringin and hesperidin or their combination to resolve the side effects of drugs like diclofenac on the liver.

Aromatase inhibitor letrozole: a novel treatment for ectopic pregnancy.

OBJECTIVE: To study the use of the aromatase inhibitor letrozole for treatment of ectopic pregnancy compared with methotrexate. DESIGN: Nonrandomized prospective cohort study. SETTING: University hospital. PATIENT(S): A series of 42 consecutive patients with undisturbed ectopic pregnancy. INTERVENTION(S): Counseling on treatment options, including surgical treatment (control group) versus medical treatment with methotrexate (group 1) or letrozole (group 2). MAIN OUTCOME MEASURE(S): Primary outcome: complete resolution of ectopic pregnancy determined by serum human chorionic gonadotropin (ß-hCG) levels below laboratory immunoassay detection. SECONDARY OUTCOMES: changes in the biochemical parameter of ovarian reserve, antimüllerian hormone (AMH), and hematologic changes associated with the two medical treatments compared with surgical treatment. RESULT(S): Each treatment group included 14 patients, and each patient made her own treatment choice. Complete resolution of ectopic pregnancy occurred in an equal number of patients: 12 out of 14 (86%) in each of the two medical treatment groups. Methotrexate treatment was associated with statistically significantly higher liver enzymes and lower blood platelets count. The decline in ß-hCG levels was faster in the letrozole group when compared with the methotrexate group. Three months after treatment, AMH levels were lower in the methotrexate group when compared with the letrozole and the surgery groups. However, the decline in ß-hCG and AMH levels was not statistically significant. CONCLUSION(S): To our knowledge, this is the first report in the literature on the success of letrozole for the medical treatment of ectopic pregnancy. The promisingly high resolution rate and better safety profile that letrozole has compared with a chemotherapeutic agent such as methotrexate should encourage further studies.

Chicoric acid prevents methotrexate hepatotoxicity via attenuation of oxidative stress and inflammation and up-regulation of PPARγ and Nrf2/HO-1 signaling.

Chicoric acid (CA) is a natural antioxidant with promising hepatoprotective activity. We investigated the potential of CA to prevent methotrexate (MTX) hepatotoxicity, pointing to the role of Nrf2/HO-1 signaling and PPARγ. Rats received CA for 15 days and were then injected with MTX at day 16. Blood and tissue samples were collected for analysis at day 19. CA ameliorated liver function markers and mitigated histological alterations in MTX-induced rats. Pre-treatment with CA suppressed reactive oxygen species and lipid peroxidation and enhanced antioxidants in MTX-induced rats. Moreover, CA upregulated hepatic Nrf2, HO-1, NQO-1, and PPARγ, and attenuated inflammation. Consequently, CA inhibited apoptosis by increasing Bcl-2 expression and suppressing Bax, cytochrome c, and caspase-3 in MTX-administered rats. In conclusion, CA prevented oxidative stress, inflammation, and liver injury induced by MTX by activating Nrf2 /HO-1 signaling and PPARγ.

Evaluation of the Cytotoxicity and Apoptotic Induction in Human Liver Cell Lines Exposed to Three Food Additives.

BACKGROUND: Rapid lifestyle, especially among people living in urban areas, has led to increasing reliance on the processed food market. Unfortunately, harmful effects caused by the excessive use of food additives in such type of industry are often neglected. OBJECTIVE: This proposal investigates in vitro cytotoxic and apoptotic effects of three food preservatives commonly consumed in daily meals; sodium sulphite, boric acid, and benzoic acid. METHODS: The effect of the three preservatives on cell viability was tested on two different cell lines; normal liver cell line THLE2 and human hepatocellular carcinoma cancer cell line HepG2 using MTT assay. Cell cycle arrest was measured using flow cytometry by propidium iodide. Measurement of expression levels of two central genes, p53 and bcl-2 that play key roles in cell cycle and apoptosis was carried out in HepG2 cells using real time-PCR. RESULTS: Although the effect was more significantly realized in the HepG2 cell line, the viability of both cell lines was decreased by all of the three tested compounds. Flow cytometric analysis of HepG2 cells treated with sodium sulphite, boric acid, and benzoic acid has revealed an increase in G2/M phase cell cycle arrest. In Sodium sulphite and boric acid-treated cells, expression levels of p53 were up-regulated, while that of the Bcl2 was significantly down-regulated. On the other hand, Benzoic acid has shown an anti-apoptotic feature based on the increased expression levels of Bcl-2 in treated cells. CONCLUSION: In conclusion, all of the tested compounds have decreased the cell line viability and induced both cell cycle arrest and apoptotic events indicating their high potential of being cytotoxic and genotoxic materials.

Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats.

Liver injury is one of the adverse effects of methotrexate (MTX). Ferulic acid (FA) is an antioxidant phytochemical that confers hepatoprotective efficacy; however, its effect against MTX hepatotoxicity remains unexplored. This study investigated the role of FA in modulating oxidative stress, inflammation, Nrf2/HO-1 signaling, and PPARγ in MTX-administered rats. Following oral FA supplementation for 15 days, rats received a single dose of MTX at day 16 and samples were collected at day 19. MTX provoked multiple histological manifestations, including degenerative changes, steatosis, inflammatory cells infiltration and hemorrhage, and altered serum transaminases, bilirubin, and albumin. Reactive oxygen species, lipid peroxidation, and nitric oxide were increased in the liver of rats that received MTX. FA prevented all histological alterations, ameliorated liver function markers, suppressed oxidative stress, and boosted antioxidants in MTX-induced rats. FA reduced serum TNF-α and IL-1ß, and hepatic NF-κB p65, Bax, and caspase-3, whereas increased Bcl-2, Nrf2, NQO1, HO-1, and PPARγ. In conclusion, FA prevented MTX hepatotoxicity by activating Nrf2/HO-1 signaling and PPARγ, and attenuating oxidative stress, inflammation, and cell death.

Patterns of Toll-Like Receptor Expressions and Inflammatory Cytokine Levels and Their Implications in the Progress of Insulin Resistance and Diabetic Nephropathy in Type 2 Diabetic Patients.

Background: Diabetic nephropathy (DNP) is a type 2 diabetes mellitus (T2DM) chronic complication, which is the largest single cause of end-stage kidney disease. There is an increasing evidence of the role of inflammation and Toll-like receptors (TLRs) as part of innate immune system in its development and progression. In addition, Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) downward signaling causes the production of proinflammatory cytokines, which can induce insulin (INS) resistance in T2DM. Objective: The goal of this study was to estimate the expression of TLRs (TLR2 and TLR4) in relation to inflammation and INS resistance in nephrotic type 2 diabetic patients with or without renal failure and to discuss the role of these TLRs in DNP progression. Patients and Methods: In this study, blood samples were obtained from type 2 diabetic patients with or without renal failure, and patients with non-diabetic renal failure were compared to healthy controls. All participants were tested for analysis of fasting plasma glucose and serum insulin, kidney function tests, C-reactive protein (CRP), and proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and interleukin 6 (IL-6) as well as expression of TLR2 and TLR4 in peripheral blood (PB). Statistical analysis of data was done by using SPSS. Results: Diabetic patients with renal failure exhibited significant increase in TLR2, TLR4 mRNA expression in PB in comparison with normal subjects, diabetic patients without renal failure and non-diabetic patients with renal failure. Both diabetic patients with or without kidney failure and non-diabetic patients with renal failure had increased TLR2 and TLR4 mRNA expression in association with increased levels of proinflammatory cytokines (TNF-α, IFN-γ, and IL-6) compared to normal subjects. The diabetic patients with kidney failure exhibited the highest elevation of TLRs, Th1 cytokines and CRP in association the highest record of insulin resistance. Conclusion: Toll-like receptor 2 and Toll-like receptor 4 increased expression and Th2 cytokines may have an important role in the progression of DNP and deteriorations in insulin resistance in type 2 diabetic patients. Therefore, TLR2 and TLR4 may be a promising therapeutic target to prevent or retard DNP in type 2 diabetic patients.

Mesoporous Silica Nanoparticles Trigger Liver and Kidney Injury and Fibrosis Via Altering TLR4/NF-κB, JAK2/STAT3 and Nrf2/HO-1 Signaling in Rats.

Mesoporous silica nanoparticles (MSNs) represent a promising inorganic platform for multiple biomedical applications. Previous studies have reported MSNs-induced hepatic and renal toxicity; however, the toxic mechanism remains unclear. This study aimed to investigate MSNs-induced hepatic and nephrotoxicity and test the hypothesis that altered TLR4/MyD88/NF-κB, JAK2/STAT3, and Nrf2/ARE/HO-1 signaling pathways mediate oxidative stress, inflammation, and fibrosis induced by MSNs. Rats were administered 25, 50, 100, and 200 mg/kg MSNs for 30 days, and samples were collected for analyses. MSNs induced functional and histologic alterations, increased the levels of reactive oxygen species (ROS), lipid peroxidation and nitric oxide, suppressed antioxidants, and Nrf2/HO-1 signaling in the liver and kidney of rats. MSNs up-regulated the expression of liver and kidney TLR4, MyD88, NF-κB p65, and caspase-3 and increased serum pro-inflammatory cytokines. In addition, MSNs activated the JAK2/STAT3 signaling pathway, down-regulated peroxisome proliferator activated receptor gamma (PPARγ), and promoted fibrosis evidenced by the increased collagen expression and deposition. In conclusion, this study conferred novel information on the role of ROS and deregulated TLR4/MyD88/NF-κB, JAK2/STAT3, PPARγ, and Nrf2/ARE/HO-1 signaling pathways in MSNs hepatic and nephrotoxicity. These findings provide experimental evidence for further studies employing genetic and pharmacological strategies to evaluate the safety of MSNs for their use in nanomedicine.

Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARγ, and suppression of NF-κB/NLRP3 inflammasome axis.

Drug-induced nephrotoxicity contributes to acute kidney injury (AKI) and represents a major problem in the clinical setting. We investigated the possible involvement of NLRP3 inflammasome activation in methotrexate (MTX)-induced nephrotoxicity and the protective potential of ferulic acid (FA), pointing out the role of PPARγ and Nrf2/HO-1 signaling. Rats that received MTX showed a significant increase in circulating creatinine and urea, and kidney Kim-1 levels along with multiple histological alterations. Reactive oxygen species (ROS), malondialdehyde and nitric oxide levels showed a significant increase in the kidney of rats that received MTX, while antioxidant defenses were diminished. FA ameliorated kidney function markers, prevented histological alterations, suppressed ROS production and enhanced antioxidant defenses. FA inhibited MTX-induced inflammasome activation as showed by the decreased phosphorylation of NF-κB, and expression of NLRP3, caspase-1 and IL-1ß. MTX caused apoptosis marked by increased expression of BAX, cytochrome c and caspase-3, and suppressed Bcl-2, effects that were significantly reversed in FA-treated groups. In addition, FA up-regulated Nrf2/ARE/HO-1 signaling and PPARγ expression in the kidney of MTX-induced rats. In conclusion, activation of NLRP3 inflammasome may represent a new mechanism for MTX nephrotoxicity. FA up-regulated PPARγ and Nrf2 signaling, prevented overproduction of ROS, and suppressed NF-κB/NLRP3 inflammasome axis and apoptosis in the kidney of MTX-induced rats.

Chicoric acid prevents methotrexate-induced kidney injury by suppressing NF-κB/NLRP3 inflammasome activation and up-regulating Nrf2/ARE/HO-1 signaling.

OBJECTIVE: Chicoric acid (CA) is a natural product with promising antioxidant and anti-inflammatory properties; however, its protective effect on methotrexate (MTX)-induced acute kidney injury (AKI) hasn't been reported. We investigated the effect of CA on MTX-induced AKI in rats, pointing to the role of NF-κB/NLRP3 inflammasome and Nrf2/ARE/HO-1 signaling. MATERIALS AND METHODS: Wistar rats received 25 mg/kg and 50 mg/kg CA for 15 days and a single injection of MTX at day 16. At day 19, the rats were killed, and samples were collected for analyses. RESULTS: MTX induced a significant increase in serum creatinine and urea, and kidney Kim-1, reactive oxygen species (ROS), malondialdehyde and nitric oxide levels. In addition, MTX-induced rats exhibited multiple histopathological alterations, diminished antioxidant defenses, and decreased expression of Nrf2, NQO-1 and HO-1. CA prevented histological alterations, ameliorated kidney function markers, attenuated ROS production and lipid peroxidation, and boosted antioxidant defenses. CA suppressed the expression of NF-κB p65, NLRP3, caspase-1 and IL-1ß in the kidney of MTX-induced rats. Furthermore, CA inhibited MTX-induced apoptosis as evidenced by the decreased expression of BAX and caspase-3, and increased Bcl-2 gene expression. CONCLUSIONS: CA prevented MTX-induced AKI through activation of Nrf2/ARE/HO-1 signaling, and attenuation of ROS-induced activation of NF-κB/NLRP3 inflammasome signaling.

Umbelliferone Ameliorates CCl4-Induced Liver Fibrosis in Rats by Upregulating PPARγ and Attenuating Oxidative Stress, Inflammation, and TGF-ß1/Smad3 Signaling.

Umbelliferone (UMB) is a natural coumarin that has diverse biological activities. However, its potential to protect against liver fibrosis has not been reported yet. This study aimed to investigate the protective effect of UMB against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats received CCl4 and UMB for 8 weeks and samples were collected for analyses. CCl4 induced a significant increase in serum levels of liver function markers and pro-inflammatory cytokines. Treatment with UMB significantly ameliorated liver function markers and pro-inflammatory cytokines and prevented CCl4-induced histological alterations. CCl4 promoted significant upregulation of α-smooth muscle actin (SMA), collagen I, collagen III, NF-κB p65, TGF-ß1, and p-Smad3. Masson's trichrome staining revealed a significant fibrogenesis in CCl4-induced rats. Treatment with UMB suppressed TGF-ß1/Smad3 signaling and downregulated α-SMA, collagen I, collagen III, and NF-κB p65. In addition, UMB diminished malondialdehyde and nitric oxide levels, boosted reduced glutathione and antioxidant enzymes, and upregulated the expression of PPARγ. In conclusion, our results demonstrated that UMB prevented CCl4-induced liver fibrosis by attenuating oxidative stress, inflammation, and TGF-ß1/Smad3 signaling, and upregulating PPARγ. Therefore, UMB may be a promising candidate for preventing hepatic fibrogenesis, given that further research is needed to delineate the exact molecular mechanisms underlying its antifibrotic efficacy.

Cardiac and pulmonary toxicity of mesoporous silica nanoparticles is associated with excessive ROS production and redox imbalance in Wistar rats.

Mesoporous silica nanoparticles (MSNs) represent one of the most promising drug delivery systems. MSNs have attracted considerable attention in recent years both in industry and biomedicine due to their unique properties. Thus, evaluation of the toxic effects of MSNs is necessary before the biomedical and clinical applications. We investigated the in vivo effect of MSNs on the production of reactive oxygen species (ROS), antioxidant defenses and histology of the heart and lung. Rats received 25, 50, 100 and 200 mg/kg body weight of synthesized MSNs intraperitoneally for 30 days and samples were collected for analysis. MSNs induced significant increase in serum cardiac function markers, tumor necrosis factor alpha and lipids. MSNs-induced rats exhibited anemia, thrombocytopenia, leukocytosis, significantly increased ROS, malondialdehyde and nitric oxide, and declined antioxidant defenses in the heart and lung of rats. In addition, MSNs induced histological alterations in the heart and lung of rats. In conclusion, our results demonstrated that MSNs induce cardiotoxicity and pulmonary toxicity via excessive generation of ROS, suppressed antioxidants, inflammation and histological alterations. Further investigations are recommended to understand the molecular mechanism underlying the toxic effects of MSNs and to improve the performance of nanomedicine.

Ameliorative effects of bee pollen and date palm pollen on the glycemic state and male sexual dysfunctions in streptozotocin-Induced diabetic wistar rats.

This study aimed to assess the effects of bee pollen (BP) and/or date palm pollen (DPP) suspensions on the glycemic state, testicular dysfunctions, oxidative stress and antioxidant defense system in streptozotocin (STZ)-induced diabetic male Wistar rats. Diabetes mellitus was induced by single intraperitoneal injection of STZ to overnight-fasted rats at dose of 40mg/kg body weight. After 1 week of STZ injection, diabetic rats were treated with BP and/or DPP suspensions at dose levels of 100mg/kg body weight/day for 4 weeks. The STZ-induced diabetes significantly increased blood glucose levels and testicular nitric oxide (NO) and malondialdehyde (MDA) levels parallel with disrupted testicular and pancreatic histological architecture and integrity. On the other hand, STZ-induced diabetes significantly decreased body weight, testis and pancreas weights, levels of serum insulin, testosterone, luteinizing hormone (LH) & follicle stimulating hormone (FSH) as well as sperm count, motility and viability. The administration of BP and DPP suspensions resulted in a significant recovery of the above mentioned parameters as compared to the diabetic control group. These improvements were associated with enhancement of the testicular antioxidant system manifested by an increase in the lowered glutathione content (GSH) and glutathione-S-transferase (GST), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities in diabetic rats as a result of treatments with BP and DPP suspensions. Thus, it can be concluded that BP and/or DPP suspensions may have potential protective role against diabetes-induced pituitary testicular axis dysfunction and testicular histological deleterious changes in association with antihyperglycemic actions via their antioxidant properties and their efficiency to improve blood insulin level and beta cell function.

Berberine ameliorates methotrexate-induced liver injury by activating Nrf2/HO-1 pathway and PPARγ, and suppressing oxidative stress and apoptosis in rats.

Berberine (BBR) is a natural isoquinoline alkaloid with very impressive health benefits. It is one of the most effective natural supplements available; however, its ameliorative mechanism against methotrexate (MTX)-induced liver injury is not well defined. This study investigated the protective effect of BBR against MTX hepatotoxicity, focusing on its ability to attenuate oxidative stress and apoptosis and to activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and peroxisome proliferator activated receptor gamma (PPARγ). Rats received BBR (25 and 50mg/kg) orally for 7days before MTX injection. Other groups received MTX followed by BBR (25 and 50mg/kg) orally for 7 days. MTX-induced rats showed significant body weight loss, increased serum liver function marker enzymes, bilirubin and tumor necrosis factor alpha (TNF-α). Liver lipid peroxidation, nitric oxide (NO) and caspase-3 were significantly increased following MTX administration. BBR supplemented either before or after MTX significantly ameliorated body weight, liver function markers, TNF-α, lipid peroxidation, NO and caspase-3. BBR increased serum albumin and liver antioxidant defenses in MTX-induced rats. Histological and immunohistochemical examination showed improved histological structure and decreased expression of Bax in liver of MTX-induced rats treated with BBR. In addition, BBR up-regulated Nrf2, HO-1 and PPARγ expression in the liver of MTX-induced rats. In conclusion, BBR attenuated MTX-induced oxidative stress and apoptosis, possibly through up-regulating Nrf2/HO-1 pathway and PPARγ. Therefore, BBR can protect against MTX-induced liver injury.

Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: Protective effect of 18ß-Glycyrrhetinic acid.

18ß-glycyrrhetinic acid (18ß-GA) is a bioactive component of licorice with promising hepatoprotective activity. However, its protective mechanism on methotrexate (MTX) hepatotoxicity in not well defined. We investigated the hepatoprotective effect of 18ß-GA, pointing to the role of peroxisome proliferator activated receptor gamma (PPARγ) and the redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2). Wistar rats were orally administered 18ß-GA (50 and 100 mg/kg) 7 days either before or after MTX injection. MTX induced significant increase in circulating liver function marker enzymes and bilirubin with concomitant declined albumin levels. Serum pro-inflammatory cytokines, and liver malondialdehyde and nitric oxide were significantly increased in MTX-induced rats. Treatment with 18ß-GA significantly reduced serum enzymes of liver function, bilirubin and pro-inflammatory cytokines. 18ß-GA attenuated MTX-induced oxidative stress and restored the antioxidant defenses. In addition, 18ß-GA improved liver histological structure and decreased the expression of Bax whereas increased Bcl-2 expression. MTX-induced rats showed significant down-regulation of Nrf2, hemoxygenase-1 and PPARγ, an effect that was markedly reversed by 18ß-GA supplemented either before or after MTX. In conclusion, 18ß-GA protected against MTX-induced liver injury, possibly by activating Nrf2 and PPARγ, and subsequent attenuation of inflammation, oxidative stress and apoptosis. Therefore, 18ß-GA can provide protection against MTX-induced hepatotoxicity.

18ß-Glycyrrhetinic acid protects against methotrexate-induced kidney injury by up-regulating the Nrf2/ARE/HO-1 pathway and endogenous antioxidants.

OBJECTIVES: 18ß-glycyrrhetinic acid (18ß-GA) has multiple beneficial and therapeutic effects. However, its protective roles on methotrexate (MTX)-induced renal injury are not well defined. In the present study, we investigated the possible protective effects of 18ß-GA against MTX-induced nephrotoxicity in rats. MATERIALS: 18ß-GA (50 and 100 mg/kg) was administered for 7 days either before or after MTX. The rats were decapitated and kidney and serum samples were collected. RESULTS: MTX-induced renal injury in rats was evidenced by the significant (p < 0.001) increase in circulating kidney function markers and tumor necrosis factor alpha (TNF-α), as well as the histopathological alterations. MTX-induced rats exhibited significantly increased lipid peroxidation (p < 0.05) and nitric oxide (p < 0.001) levels, with concomitant marked (p < 0.001) decline in the antioxidant defenses. 18ß-GA, administered either before or after MTX, produced a significant amelioration of circulating kidney function markers, TNF-α, kidney lipid peroxidation, nitric oxide, and antioxidant defenses. In addition, 18ß-GA supplementation significantly up-regulated the mRNA abundance of both nuclear factor-erythroid 2-related factor 2 (Nrf2) and hemoxygenase 1 (HO-1) in the kidney of MTX-induced rats. CONCLUSIONS: These results indicate that 18ß-GA has a protective effect on MTX-induced nephrotoxicity with possible mechanisms of attenuating oxidative stress and inflammation through up-regulating the Nrf2/ARE signaling. These findings make 18ß-GA candidate as a potent agent in preventing MTX-induced kidney injury.