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Background: Ambient air pollution (AAP) is an essential global problem that afects most of the body's organs, including the kidneys. We investigated the efects of AAP, sulfur dioxide (SO2), and ozone (O3) on kidney functions, histology, antioxidant enzymes, and apoptosis gene expressions in Wistar rats. Methods: The rats were divided into 4 groups (n = 8): control, AAP, SO2 (10 ppm), and O3 (0.6 ppm) groups. Blood urea and creatinine, kidney tissue superoxide dismutase, total antioxidant capacity, glutathione peroxidase activities, and malondialdehyde were determined afer exposure to AAP, SO2, or O3 for 3 hours per day for 5 weeks. Kidney tissue was examined by light microscopy, and the expression of BCL-2, BAX, and caspases-3,-8, and caspase-9 were evaluated by the reverse transcription quantitative polymerase chain reaction technique. Results: Mild to moderate histopathological changes in AAP and moderate-to-severe changes in SO2 and O3 groups were reported. Increment of serum urea in SO2 and AAP groups (P = .017 and P = .045), kidney catalase in AAP group (P = .008), total antioxidant capacity in O3 group (P < .001), caspase-8 expression in SO2 group (P = .035), caspase-8, and caspase-9 expressions in O3 group (P < .001 and P = .003) were signifcant. p53 expression in the kidney of the AAP group was less than that of the control group (P = .018). Conclusion: Ambient air pollution, SO2, and O3 exposures in the concentrations used in our study cause kidney dysfunction, stimulate oxidative stress defense enzymes, cause histopathological changes, and downregulate kidney p53 expression. [ABSTRACT FROM AUTHOR]

In the last decades, numerous studies have focused on the search for new agents to suppress the growth of cancer cells. In this study, we investigated the effect of two novel synthetic coumarin derivatives, namely 2-amino-4- (4-(2-hydroxyethoxy)-3-methoxyphenyl)-5-oxo-4H,5H-pyrano[3,2-c]coumarin-3-carbonitrile and 2-amino-4-(4-hydroxyphenyl)-5-oxo-4H,5H-pyrano[3,2-c]coumarin-3-carbonitrile, on the induction of apoptosis in breast cancer in a mouse model. Breast cancer was induced in BALB/c mice, which were randomly divided into six groups and then underwent the experiment. The groups and treatments included A1 : coumarin A with a low dose (10 µm), A2: coumarin A with a high dose (1 mM), B1: coumarin B with a low dose (10 µm), B2: coumarin B with a high dose (1 mM), D: doxorubicin, and C: cancer control/ treatment with normal saline. The samples underwent treatments for 5 weeks. Animals were euthanized, and tissue samples, including the lung, liver, and tumor mass, were collected for histopathological examination. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine some apoptotic markers, such as BCL-2, caspase-9, COX-2, and c-Myc. The qRT- PCR presented that both coumarin compounds could significantly alter the expression levels of BCL-2, caspase-9, COX-2, and c-Myc. Consistent with these results, histopathological observations showed a significant reduction in pathological lesions and severity of malignancy of the tumor mass, as well as a decrease in microscopic metastases in the lung and liver. This suggests that the present new coumarin compounds may induce apoptosis in breast cancer cells by altering some apoptosis-related genes that may play a chemotherapeutic role in breast cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Purpose: This study was aimed to evaluate the site-specific drug delivery of 5-FU with chitosan (CS) as a carrier and quercetin (Qu) against induced colon cancer in Wistar rats. Methods: Cross-linked CS-Qu nanoparticles (NPs) were prepared by ionotropic gelation method. Physicochemical characterization of NPs was performed by Fourier-transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), in vitro drug release, and drug loading efficiency (LE). 1, 2-Dimethylhydrazine (DMH) and dextran sulfate sodium (DSS) were applied to induce adenocarcinoma tumors on inbred male Wistar rats’ colon. The treatment group of rats was administered through enema with NPs dispersion. Hematoxylin and eosin staining were performed to the histopathological examination of tumors. Results: Zeta potential and particle size for NPs were +53.5 ± 5 mV and 179 ± 28 nm, respectively. About 96% Qu LE was obtained with a maximum release of 5.63 ±1.59% and 4.62 ± 1.33% after 24 hours in PB solution with pH values of 6 and 7.4, respectively. The numbers of 8 to 21 tumors were observed in all rats administered with DMH and DSS. Significantly decreasing of microvascular density and mitosis count was detected in the treatment group in comparison with cancerous group (P = 0.032 for the former compared to P = 0.016 for the later), respectively. Furthermore, the treatment group showed a high apoptosis rate (P = 0.038). Conclusion: The developed Qu-loaded CS NPs were good candidates for site-specific and sustained drug release in enema treatment. Decreasing of microvascular density and mitosis count, along with increasing the apoptosis percent in the treatment group proved that the NPs could have promising results in site-specific and sustained drug delivery against colorectal cancer. [ABSTRACT FROM AUTHOR]

Objective(s): Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, possesses verified anti-inflammatory and anti-oxidative stress effects against diabetic nephropathy. The present investigation aims to examine empagliflozin effects on the renal levels of high mobility group box-1 (HMGB1), a potent inflammatory cytokine, and its respective receptor toll-like receptor-4 (TLR-4) in STZ-induced diabetic rats. Materials and Methods: Empagliflozin at 10 mg/kg per os (p.o.) was administered for 4 weeks, starting 8 weeks after the induction of diabetes. Renal function, kidney inflammation, oxidative stress, and apoptosis markers as well as renal HMGB1, receptor for advanced glycation end products (RAGE), and TLR-4 levels were assessed. Results: In addition to down-regulating NF-κB activity in renal cortices, empagliflozin reduced renal levels of HMGB1, RAGE, and TLR-4. It alleviated renal inflammation as indicated by diminished renal expressions of inflammatory cytokines and chemokines like tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) and also decreased urinary levels of interleukin-6 (IL-6) and alpha-1 acid glycoprotein (AGP). Moreover, empagliflozin ameliorated renal oxidative stress as demonstrated by decreased renal malondialdehyde (MDA) and elevated renal activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). It also suppressed renal caspase-3, the marker of apoptosis; and furthermore, enhanced renal function noticed by the declined levels of serum urea and creatinine. Conclusion: These findings underline that empagliflozin is able to attenuate diabetes-related elevations in renal HMGB1 levels, an influential inflammatory cytokine released from the necrotic and activated cells, and its correspondent receptors, i.e., RAGE and TLR-4. [ABSTRACT FROM AUTHOR]

Cisplatin (Cis) has serious adverse side-effects that limit its clinical use. The mechanism underlying the effects is complex, including mitochondrial oxidative stress and inflammation. This study investigated whether Cornus mas, a fruit with high antioxidant contents, hydro-methanolic extract (CME) can modulate the cisplatin-induced changes. Forty Wistar rats were divided into a control group, Cis group, CME group, CME 300 + Cis group, and the CME 700 + Cis group. After the intervention, blood samples were taken for biochemical and hematological analysis. CME analysis showed noticeable total phenol and total antioxidant contents. The plasma glutathione peroxidase and catalase levels were significantly decreased and malondialdehyde and blood hemoglobin levels were significantly increased in the Cis group, which were reversed to the control levels in the CME + Cis groups. In the CME group, the red blood cell count was significantly lower and the red cell distribution width and hemoglobin distribution width levels were significantly higher. In the Cis-treated group, white blood cells, neutrophils, monocytes, basophils, and large unstained cells were significantly increased and lymphocytes were significantly decreased when compared with the control group that was reached to non-significant levels in CME 700 + Cis group. The blood cholesterol and high density lipoprotein in all CME-treated groups were significantly decreased. The eosinophils increased in the CME group significantly. The results showed considerable total antioxidant and total phenol contents and relative protective effects of CME against Cis-induced antioxidant and hematologic changes in rats. [ABSTRACT FROM AUTHOR]

Purpose: Methotrexate (MTX) is prescribed in many diseases and can result in oxidative stress (OS) followed by injuries in some tissues. Antioxidants administration are effective in reducing OS. Pomegranate exhibits high anti-oxidant capacities. This study investigated whether pomegranate seed and peel methanolic extracts (PSE and PPE) could protect against MTX-induced OS and lipid profile changes in rats. Methods: Forty-eight rats were randomly divided into 6 groups: control group (normal salin), PSE group (500 mg/kg, orally), PPE group (500 mg/kg, orally), MTX group (10 mg/kg, IM), MTX and PSE group, and MTX and PPE group. Blood samples were taken for analysis in the end of the procedure. Results: The findings showed a significant reduction in Glutathione peroxidase (GPx) and Superoxide dismutase (SOD), and an enhancement in malondialdehyde (MDA) values after MTX treatment (p < 0.05). SOD and GPx levels reached the levels of the control group in MTX+SPE and MTX+PPE groups. No significant differences were observed in catalase (CAT) and total antioxidant capacity (TAC) levels between groups. The results showed a significant decrease in total cholesterol (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) in the MTX treated group (p < 0.01). The values of TC, HDL, and LDL became elevated to the normal control levels in the MTX+PSE and MTX+PPE treated groups. Conclusion: The results showed the OS induced by MTX and the protective effects of PSE and PPE against MTX-induced serum oxidative stress and lipid profile changes in rats. [ABSTRACT FROM AUTHOR]

Statement of the Problem: Various researchers have suggested the use of β2- adrenergic receptor antagonists in prevention or treatment of bone resorption. Purpose: This study aimed to evaluate the effect of β2-adrenergic receptor antagonists on number of osteoclasts and osteoblasts involved in the healing of extraction socket of maxillary first molar in rats. Materials and Method: Maxillary first molars of 40 rats were extracted and divided into two groups. The test group received 0.1 mg/kg propranolol intraperitoneally daily. The controls received normal saline. At days 7, 14, 21 and 28 post-extraction, 5 rats were euthanized from each group. Maxillary bone was resected and the mean number of osteoblasts and osteoclasts in tooth socket was measured. Results: After 1 week, the number of osteoclasts in the controls was significantly higher than the test group. A significant increase in the number of osteoclasts in both groups at week 1 was observed compared to the following weeks (p< 0.05). The number of osteoblasts in the controls at second week reached its maximum rate but stayed constant in the 3rd and 4th weeks. Osteoblasts in the test group increased similar to the controls but reached its maximum at 3rd week and showed a significant increase compared to the controls (p< 0.05). Conclusion: β2 adrenergic receptor antagonists decrease the number of osteoclasts and increase the number of osteoblasts during extraction socket healing. [ABSTRACT FROM AUTHOR]

Purpose: Nanostructured lipid carriers (NLCs) composed of solid lipid and oil are a new generation of lipid nanoparticles which have exhibited some merits over traditional used lipid nanoparticles in fortifying food and beverages and nutraceuticals delivery systems such as liposomes and solid lipid nanoparticles. Methods: In this study, Precirol and Compritol as solid lipids, Miglyol and Octyloctanoat as liquid lipids, Tween80, Tween20 and Poloxamer407 as surfactants were used to prepare vitamin D3-loaded NLC dispersion using hot homogenization method. The particle size and size distribution for all formulations were evaluated by immediately after production and during a storage period of 60 days. Results: The Precirol-based NLC showed superiority over Compritol-based NLC in the point of physical stability. Results clearly suggested that an optimum concentration of 3% of Poloxamer407 or 2% of Tween20 was sufficient to cover the surface of nanoparticles effectively and prevent agglomeration during the homogenization process. Octyloctanoat was introduced for the first time as a good substituent for Miglyol in the preparation of NLC formulations. The vitamin D3 Intestinal absorption enhanced by the incorporating in NLCs. Conclusion: It was concluded that NLC showed a promising approach for fortifying beverages by lipophilic nutraceuticals such as vitamin D. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) is a membrane transporter responsible for the active efflux from the cell. Inhibition of the activity may lead to clinically significant drug-drug interactions. This study was performed to investigate the effects of atorvastatin and ezetimibe on the function and expression of P-gp. The in vitro rhodamine-123 (Rho123) efflux assay and Western blot in Caco-2 cells, and the in situ rat single-pass intestinal permeability model followed by high performance liquid chromatography were developed. Rho123 intracellular accumulation in 100 µM of atorvastatin- and ezetimibe-treated cells was significantly higher than that in control cells (p<0.05). P-gp expression was decreased by 100 µM atorvastatin and ezetimibe. Intestinal effective permeability of digoxin in the presence of atorvastatin (3 and 100 µM), ezetimibe (10 and 100 µM) was significantly increased (p<0.05). Both drugs inhibited P-gp activity in vitro and in situ. Atorvastatin and ezetimibe downregulated the expression of P-gp in vitro. [ABSTRACT FROM AUTHOR]

Statement of the Problem: Oral cancer is among the ten most common cancers worldwide. It affects the life quality of patients in many ways. Purpose: The aim of this study was to compare the effects of two different systemic doses of Viola Odorata syrup on the prevention of 4-Nitroquinoline-1-oxide (4NQO) induced tongue dysplasia in rats. Materials and Method: Forty-eight male Wistar rats were divided into four groups of A, B, C and D. Group A served as the control group. The rats in groups B to D received 30 ppm of 4-NQO in drinking water for 12 weeks. Additionally, the rats in groups B and C received Viola Odorata syrup at doses of 15 and 5 ml/kg, respectively, 3 times a week. Body weights were measured three times a week. At the end, the rats were euthanized and the tongue was removed. Histological evaluations for carcinogenesis were carried out under a light microscope. Results: The mean body weight of the rats in groups B, C, and D were lower than that in group A (p< 0.01). After 12 weeks of treatment, microscopically no histological changes of the tongue base epithelia were observed in the control group. The rats in group B did not show severe dysplastic changes; only mild to moderate histological changes including hyperplasia and hyperkeratosis were evident. These incidences were significantly more apparent in groups C with moderate to severe changes (p< 0.05) and group D with severe dysplastic changes (p< 0.01). Almost all rats in group D had hyperplasia and manifested all of the stages of dysplasia. Conclusion: Viola Odorata extract has dose-dependent inhibitory effects on the development of tongue induced dysplasia. [ABSTRACT FROM AUTHOR]

Introduction: Nephrotoxicity as a side effect caused by the immunosuppressive drug, cyclosporine-A (CsA), can be a major problem in transplant medicine. Oxidative stress may play an important role in the CsA-induced nephrotoxicity. It has been shown that the antihypertensive drug, valsartan (Val), has also renoprotective effects but, its molecular mechanism is largely unknown. In the present study, it was aimed to evaluate the Val effect in the alleviation of CsA nephrotoxicity via probable renal glutathione peroxidase (GPx) upregulation and oxidative stress decrease. Methods: Thirty-two Sprague-Dawley rats were divided into four groups based on CsA and/or Val administration: group A (Control, 1 mL/kg/day of olive oil as vehicle), group B (CsA, 30 mg/kg/day), group C (CsA+Val, 30+30 mg/kg/day), and group D (Val, 30 mg/kg/day). After the administration period (six weeks), renal GPx expression was evaluated by real-time polymerase chain reaction (PCR). Plasma levels of GPx and 8-Hydroxydeoxyguanosine (8-OHdG) were measured by enzyme-linked immunosorbent assay (ELISA). Malondialdehyde (MDA) and protein carbonyl groups (PCG) were measured by spectrophotometer. Plasma levels of urea and creatinine were measured by an autoanalyzer. Results: CsA treatment led to the decrease in renal expression and plasma levels of GPx in comparison to other study groups. Rats received CsA were detected to have significantly (p<0.05) higher plasma 8-OHdG, MDA, PCG, urea, and creatinine levels in comparison to other groups. Plasma urea and creatinine levels were negatively correlated with renal GPx expression and positively correlated with the oxidative stress markers. Conclusion: Administration of Val may result in attenuating the nephrotoxic side effect of CsA via probable renal GPx upregulation, and subsequently oxidative stress decrease. [ABSTRACT FROM AUTHOR]

Epidemiological and clinical studies indicate a close relationship between obesity and asthma. Here, we determined the impact of diet-induced obesity on the expression levels of IL-1β, IRAK-1 and TRAF-6 mRNA as well as IL-1β protein level and pathological changes in male Wistar rat's lung after sensitization with ovalbumin (OVA). Twenty male Wistar rats divided into four groups, control with normal diet (C+ND), OVA-sensitized with normal diet (S+ND), control with high-fat diet (C+HFD), and OVA-sensitized with high-fat diet (S+HFD). All rats fed for 12 weeks with standard pellets or high-fat diet while sensitization and challenging with OVA or saline were done for groups in the last month. In the end of intervention, lung was isolated and tested for the expression levels of IL-1β, IRAK-1 and TRAF-6 mRNA with real time-PCR method, and pathological changes were determined. Diet-induced obesity groups showed increased weight, obesity indexes and lipid profiles The expression levels of IL-1β mRNA in OVA-sensitization groups (S+ND and S+HFD) showed a significant increase compared with other groups. Also in S+HFD group, expression level of IRAK-1 and TRAF-6 mRNA were markedly higher than other groups (p<0.001). The pathological changes were marked in sensitized groups compared to non-sensitized groups; with marked increase in obese sensitized rat. The results showed that high fat diet caused overexpression of IL-1β, IRAK-1 and TRAF-6 mRNA as well as IL-1β protein in an experimental model of asthma. Our results suggest that obese-asthmatic conditions may lead to the local production and activation of pro-inflammatory agents. [ABSTRACT FROM AUTHOR]

Objective(s): Transporters have an important role in pharmacokinetics of drugs. Inhibition or induction of drug transporters activity can affect drug absorption, safety, and efficacy. P-glycoprotein (P-gp) is the most important membrane transporter that is responsible for active efflux of drugs. It is important to understand which drugs are substrates, inhibitors, or inducers of P-gp to minimize or avoid unwanted interactions. The aim of this study was to investigate the effects of clemastine on the expression and function of P-gp. Materials and Methods: The effect of clemastine on P-gp function and expression was evaluated in vitro byrhodamine-123 (Rho123) efflux assay in Caco-2 cells and Western blot analysis. Rat in situ single pass intestinal permeability model was used to investigate the clemastine effect on digoxin Peff, as a known P-gp substrate. Digoxin levels in intestinal perfusates were assayed by high performance liquid chromatography (HPLC) method. Results: The Caco-2 intracellular accumulation of Rho123 in clemastine and verapamil treated cells was 90.8 ± 9.8 and 420.6±25.4 pg/mg protein, respectively which was significantly higher than that in control cells (50.2±6.0; P<0.05). Immunoblotting results indicated that clemastine decreased expression of P-gp in Caco-2 cells in vitro. More over effective intestinal permeability (Peff) of digoxin in the presence of clemastine, was significantly increased compare to control group. Conclusion: Findings of our study suggested dose dependent P-gp inhibition activity for clemastine in vitro and in situ. Therefore co-administration of clemastine with P-gp substrates may result in unwanted interactions and side effects. [ABSTRACT FROM AUTHOR]