The renoprotective effects of taurine against diabetic nephropathy via the p38 MAPK and TGF-ß/Smad2/3 signaling pathways.

Diabetic nephropathy (DN), a severe diabetes complication, causes kidney morphological and structural changes due to extracellular matrix accumulation. This accumulation is caused mainly by oxidative stress. Semi-essential amino acid derivative taurine has powerful antioxidant and antifibrotic effects. The aim of this study was to investigate the renoprotective effects of taurine through its possible roles in oxidative stress, extracellular matrix proteins, and the signaling pathways associated with the accumulation of extracellular matrix proteins in DN rats. 29 Wistar albino rats were randomly separated into control, taurine, diabetes, and diabetes + taurine groups. Diabetes animals were injected 45 mg/kg streptozosine. Taurine is given by adding to drinking water as 1% (w/v). Urine, serum, and kidney tissue were collected from rats for biochemical and histological analysis after 12 weeks. According to the studies, taurine significantly reduces the levels of malondialdehyde (MDA), total oxidant status (TOS), and protein expression of NADPH oxidase 4 (NOX4) that increase in diabetic kidney tissue. Also, decreased superoxide dismutase (SOD) activity levels significantly increased with taurine in diabetic rats. Moreover, increased mRNA and protein levels of fibronectin decreased with taurine. The matrix metalloproteinase (MMP)-2 and MMP-9 activities and their mRNA levels increased significantly, and this increase was significantly summed with taurine. There was a decrease in mRNA expression of Extracellular matrix metalloproteinase inducer (EMMPRIN). Taurine significantly increased this decrease. Diabetes increased mRNA expressions of transforming growth factor (TGF)-ß and Smad2/3. Taurine significantly reduced this induction. TGF-ß protein expression, p38, and Smad2/3 activations were also inhibited, but taurine was suppressed significantly. All these findings indicate that taurine may be an effective practical strategy to prevent renal diabetic injury.

The healing effect of topical tea tree oil on pressure ulcers in a rat model.

Objective: The effects of topical tea tree oil (TTO) on the healing of pressure ulcers (PUs) in an animal model was evaluated. Method: To induce PUs, ischaemia-reperfusion cycles were performed by the external application of magnetic plates, with an ischaemic period of eight hours and a reperfusion period of 16 hours. Male and female Wistar rats were divided into three equally sized groups (n=20): one group received topical glycerin twice daily, another group received topical 10% (volume/volume (v/v)) TTO in glycerin twice daily; and the remaining group was untreated. The animals were assessed after one, four, seven and 14 cycles of ischaemia-reperfusion by thermal camera imaging, and then euthanised and sampled to investigate the degree of inflammation, collagen synthesis and apoptosis in the PUs. Results: Although topical glycerin alone suppressed local inflammation and apoptosis, this suppressive effect was accentuated at all timepoints by the application of topical TTO + glycerin. Similarly, an increase in collagen synthesis was observed in the glycerin group and this was accentuated by TTO at all timepoints. Parallel to the histological findings, the local temperature had decreased significantly on days 4 and 7 for both treatment groups (glycerin and TTO+glycerin). Conclusion: In this study, treatment with 10% (v/v) TTO in glycerin effectively suppressed skin inflammation and apoptosis, while it increased collagen synthesis during PU formation.

Ocular toxicity of intravitreal golimumab in a rabbit model

Background/aim: To investigate the effect of intravitreal golimumab on rabbit retina histopathology. Materials and methods: Sixteen albino New Zealand rabbits were divided into three groups. The right eye of each rabbit in groups I, II, and III received a single intravitreal injection of 5 mg/0.05 mL (6 eyes), 10 mg/0.1 mL (6 eyes), or 20 mg/0.2 mL (4 eyes) golimumab, while left eyes served as controls with the same volume of a balanced salt solution injection. All animals were examined using slit-lamp biomicroscopy and indirect ophthalmoscopy before and after intravitreal injection and at days 1 and 7. Animals were euthanized on day 7 and the eyes were enucleated for immunohistochemistry evaluation and electron microscopic examination of the retinas. Results: For groups I, II, and III, the number of cells in the outer nuclear layer and the inner nuclear layer was decreased compared to those in the control groups. In group I, the percentage of caspase-3 staining of the outer nuclear layer was significantly higher than that in the control. For groups II and III, TUNEL and caspase-3 staining percentages in the outer and inner nuclear layers were found to be significantly higher than those for the control groups. In the ganglion cell layer, for groups I, II, and III, neither TUNEL nor caspase-3 staining percentages showed any significant difference between two groups. No significant dose-dependent relationship was found for increasing doses of golimumab in all layers. Myelin figures and karyorrhexis in the photoreceptor cells were prominent in electron microscopy of the golimumab-injected eyes. Conclusion: Golimumab caused apoptosis in both photoreceptors and bipolar cells of the rabbit retina. Potential retinal toxicity of intravitreal golimumab should be considered if an intravitreal administration is planned.

Design and development of a self-microemulsifying drug delivery system of olmesartan medoxomil for enhanced bioavailability.

Olmesartan medoxomil (OM) is a hydrophobic antihypertensive drug with low bioavailability (26%) and is known to have adverse effects such as celiac disease and enteropathy. The purpose of this study was to develop SMEDDS to increase bioavailability and decrease potential side effects of OM. Hydrophilic lipophilic balance was calculated by testing solubility of OM in different oils, surfactants, and cosurfactants to obtain the most suitable combination of SMEDDS. Pseudoternary phase diagram was used to select the better oil/water formulation of SMEDDS. After a test for 3-month stability, dissolution tests and parallel artificial membrane permeability assay (PAMPA) were conducted to investigate drug solubility and permeability. Biodistribution of fluorescent marked SMEDDS was observed by using in vivo imaging system. The pharmacodynamics of the drug were determined by measuring blood pressure from tails of rats. At the end of the experiment, intestines were examined for adverse effects of OM. Compared with tablet formulation according to the dissolution study, SMEDDS formulation showed 1.67 times improvement in solubility of OM. PAMPA studies suggested a much faster permeability rate for OM SMEDDS compared to the suspension form. Labeled SMEDDS gave 3.96 times stronger fluorescent emission than control dye administered mice in in vivo imaging system (IVIS®) studies, indicating an increased bioavailability. Treating effect of SMEDDS was 3.1 times more efficient compared to suspension in hypertensive rats. It caused neither celiac-like enteropathy nor diarrhea, during 21-day noninvasive blood pressure system (NIBP) assay. Our results suggest that SMEEDS formulation improves dissolution and oral bioavailability of OM while reducing its adverse effects.

Renal complications of lipodystrophy: A closer look at the natural history of kidney disease.

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.

Inhibitory effect of adenosine on intimal hyperplasia and proliferation of smooth muscle cells in a carotid arterial anastomosis animal model.

PURPOSE: The effect of adenosine (9-ß-0-ribifuranosyladenine) on the endothelial cell proliferation and neointimal hyperplasia is investigated in the rabbit carotid artery anastomosis model. METHODS: Twenty-eight New Zealand white rabbits were arranged in four groups of seven animals each. The right carotid arteries of each animal were transsected and re-anastomosed. The left sides remained as control. In Group A, no medication was used. In Group B, subcutaneous Adenosine was applied for 3 days. In Group C, the same dose was applied for 7 days, and in Group D for 21 days. After 28 days, the luminal diameters, luminal areas, intima/media ratios were all measured by using histopathological evaluation. FINDINGS: The mean luminal diameters and areas of the four groups were smaller than the control ones. Massive thickening of smooth muscle cell proliferation and dense intensifying in the connecting tissues were observed most prominently in Group A, in decreasing degrees within other groups. Intima/media ratio was highest in Group A. Scoring the quantity of e-NOS positive staining also revealed a significant difference between the experimental groups and their control associates. CONCLUSION: The process of endothelial cell proliferation and neointimal hyperplasia can be significantly reduced by the use of adenosine.

Effects of lipoic acid in an experimentally induced hypertensive and diabetic rat model.

In this study, experimental diabetes and nephrectomy have been applied separately and together in order to investigate the possible therapeutic effects of lipoic acid (LA) on hypertensive and diabetic rat kidneys. Wistar rats were divided into eight groups: control, diabetes mellitus (DM), 5/6 nephrectomy, DM + 5/6 nephrectomy, LA administration, DM + LA treated, 5/6 nephrectomy + LA treated, and DM + 5/6 nephrectomy + LA-treated groups, respectively. Renal damage was evaluated histomorphometrically, ultrastructurally, and biochemically. Our findings supported that diabetes and hypertension together increased the rate of renal injury, and LA had therapeutic effects on hypertensive and diabetic rat kidneys.

The effects of exposure to electromagnetic field on rat myocardium.

Exposure to electromagnetic fields (EMFs) causes increased adverse effects on biological systems. The aim of this study was to investigate the effects of EMF on heart tissue by biochemical and histomorphological evaluations in EMF-exposed adult rats. In this study, 28 male Wistar rats weighing 200-250 g were used. The rats were divided into two groups: sham group (n = 14) and EMF group (n = 14). Rats in sham group were exposed to same conditions as the EMF group except the exposure to EMF. Rats in EMF group were exposed to a 50-Hz EMF of 3 mT for 4 h/day and 7 days/week for 2 months. After 2 months of exposure, rats were killed; the hearts were excised and evaluated. Determination of oxidative stress parameters was performed spectrophotometrically. To detect apoptotic cells, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and caspase-3 immunohistochemistry were performed. In EMF-exposed group, levels of lipid peroxidation significantly increased and activities of superoxide dismutase and glutathione peroxidase decreased compared with sham group. The number of TUNEL-positive cells and caspase-3 immunoreactivity increased in EMF-exposed rats compared with sham. Under electron microscopy, there were mitochondrial degeneration, reduction in myofibrils, dilated sarcoplasmic reticulum and perinuclear vacuolization in EMF-exposed rats. In conclusion, the results show that the exposure to EMF causes oxidative stress, apoptosis and morphologic damage in myocardium of adult rats. The results of our study indicate that EMF-related changes in rat myocardium could be the result of increased oxidative stress. Further studies are needed to demonstrate whether the exposure to EMF can induce adverse effects on myocardium.

The effects of dexmedetomidine on secondary acute lung and kidney injuries in the rat model of intra-abdominal sepsis.

In the present study, the effects of dexmedetomidine on secondary lung and kidney injuries were studied in the rat model of intra-abdominal sepsis by immunohistological and biochemical examinations. We measured serum creatinine, kidney tissue malondialdehide and plasma neutrophil gelatinase-associated lipocalin levels. In order to evaluate tissue injury we determined kidney tissue mononuclear cell infiltration score, alveolar macrophage count, histological kidney and lung injury scores and kidney and lung tissue immunoreactivity scores. We demonstrated that dexmedetomidine attenuates sepsis-induced lung and kidney injuries and apoptosis in the rat model of sepsis. There is still need for comparative studies in order to determine the effects of dexmedetomidine on organ functions in early human sepsis.

Effect of the selective mitochondrial KATP channel opener nicorandil on the QT prolongation and myocardial damage induced by amitriptyline in rats.

OBJECTIVES: The aim of this study is to evaluate the protective effect of nicorandil, a selective mitochondrial KATP channel opener, on QT prolongation and myocardial damage induced by amitriptyline. METHODS: The dose of amitriptyline (intraperitoneal, i.p.) that prolong the QT interval was found 75 mg/kg. Rats were randomized into five groups the control group, amitriptyline group, nicorandil (selective mitochondrial KATP channel opener, 3 mg/kg i.p.) + amitriptyline group, 5-hdyroxydecanoate (5-HD, selective mitochondrial KATP channel blocker, 10 mg/kg i.p.) + amitriptyline group and 5-HD + nicorandil + amitriptyline group. Cardiac parameters, biochemical and histomorphological/immunohistochemical examinations were evaluated. p < 0.05 was accepted as statistically significant. KEY FINDINGS: Amitriptyline caused statistically significant prolongation of QRS duration, QT interval and QTc interval (p < 0.05). It also caused changes in tissue oxidant (increase in malondialdehyde)/anti-oxidant (decrease in glutathione peroxidase) parameters (p < 0.05), myocardial damage and apoptosis (p < 0.01 and p < 0.001). While nicorandil administration prevented amitriptyline-induced QRS, QT, QTc prolongation (p < 0.05), myocardial damage and apoptosis (p < 0.05), it did not affect the changes in oxidative parameters (p > 0.05). CONCLUSIONS: Our results suggest that nicorandil, a selective mitochondrial KATP channel opener, plays a protective role in amitriptyline-induced QT prolongation and myocardial damage. Mitochondrial KATP channel opening and anti-apoptotic effects may play a role in the cardioprotective effect of nicorandil.

Exposure to Fumes of a Vegetable Margarine for Frying: Respiratory Effects in an Experimental Model.

Deep frying is one of the strongest emission sources into indoor air. A vegetable margarine has recently been used in commercial kitchens. This study investigated the respiratory effects of exposure to its fumes in an experimental model. A setup with glass chambers was constructed. A chamber housed a fryer. The fumes were transported to the other chamber where 24 Wistar albino rats were placed in four randomized groups: acute, subacute, chronic, and control for the exposure durations. PM10 concentration in the exposure chamber was monitored to ensure occupational levels were obtained. Sacrification was performed 24 h after exposure. Lung, trachea, and nasal concha specimens were evaluated by two blinded histologists under a light microscope with hematoxylin-eosin. Mild mononuclear cell infiltration, alveolar capillary membrane thickening, alveolar edema, and diffuse alveolar damage, along with diffuse hemorrhage, edema, and vascular congestion in the interstitium were observed in the acute and subacute groups, and were overexpressed in the chronic group, whereas normal lung histology was observed in the control group. The results indicate that exposure to fumes of vegetable margarine for frying in commercial kitchens may cause pulmonary inflammation that becomes severe as the duration of the exposure increases.

Effects of nicorandil on QT prolongation and myocardial damage caused by citalopram in rats.

Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial KATP (mito-KATP) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.

Histomorphological Investigation of Microfracture Location in a Rabbit Osteochondral Defect Model.

BACKGROUND: Microfracture is the most common treatment for cartilage defects of the knee. In microfracture surgery, holes are randomly drilled into the subchondral bone. The effect of the hole's location on its interaction with the cartilage defect site and its influence on the healing process is currently uncertain. PURPOSE: To investigate the effects of different microfracture locations on healing in a rabbit knee osteochondral defect model. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 29 adult New Zealand White rabbits were divided into 5 groups. In the healthy cartilage control group (n = 5), no surgical procedure was performed. Cylindrical full-thickness cartilage defects (5 × 3 mm) were created in the patellar groove of the remaining 24 rabbits. In the defect control group (n = 6), only the defect was created. A microfracture was performed at the 12-o'clock position (group peripheral single; n = 6), centrally (group central; n = 6), and at the 12- and 6-o'clock positions (group peripheral double; n = 6) of the defect. The animals were sacrificed after 8 weeks. Cartilage healing was evaluated by International Cartilage Regeneration & Joint Preservation Society (ICRS) score, modified O'Driscoll score, immunohistochemical analysis (type 1 collagen, type 2 collagen, and aggrecan), and scanning electron microscopy analysis. RESULTS: In group peripheral double, better cartilage healing was observed in all parameters compared with the other groups (P < .05). Group peripheral double had the greatest amount of filling, with 79% of the defect area filled with fibrocartilage repair tissue. Group peripheral single demonstrated filling of 73% of the defect area, group central 56%, and the defect control group 45%. The ICRS score was significantly higher in group peripheral single compared with group central and the defect control group. Type 2 collagen and aggrecan immunoreactivity were significantly stronger in group central than group peripheral single and the defect control group (P < .05). CONCLUSION: Microfracture performed at the peripheral margin of the defect had better filling characteristics in a rabbit model. This study suggests that interaction of pluripotent cells released from the microfracture site with the intact cartilage may enhance the quality of the repair tissue. CLINICAL RELEVANCE: The location of microfracture holes in relation to the peripheral border of the osteochondral defect (to the intact cartilage) is important in both the quality and the quantity of the newly formed repair tissue.

The effects of α-lipoic acid against testicular ischemia-reperfusion injury in Rats.

Testicular torsion is one of the urologic emergencies occurring frequently in neonatal and adolescent period. Testis is sensitive to ischemia-reperfusion injury, and, therefore, ischemia and consecutive reperfusion cause an enhanced formation of reactive oxygen species that result in testicular cell damage and apoptosis. α-lipoic acid is a free radical scavenger and a biological antioxidant. It is widely used in the prevention of oxidative stress and cellular damage. We aimed to investigate the protective effect of α-lipoic acid on testicular damage in rats subjected to testicular ischemia-reperfusion injury. 35 rats were randomly divided into 5 groups: control, sham operated, ischemia, ischemia-reperfusion, and ischemia-reperfusion +lipoic acid groups, 2 h torsion and 2 h detorsion of the testis were performed. Testicular cell damage was examined by H-E staining. TUNEL and active caspase-3 immunostaining were used to detect germ cell apoptosis. GPx , SOD activity, and MDA levels were evaluated. Histological evaluation showed that α-lipoic acid pretreatment reduced testicular cell damage and decreased TUNEL and caspase-3-positive cells. Additionally, α-lipoic acid administration decreased the GPx and SOD activity and increased the MDA levels. The present results suggest that LA is a potentially beneficial agent in protecting testicular I/R in rats.

The effect of post-reperfusion levosimendan in an experimental intestinal ischemia-reperfusion model.

BACKGROUND: Levosimendan has been reported to have a positive effect on ischemia-reperfusion injury. Herein, we aimed to evaluate the effects of levosimendan applied after reperfusion in an experimental intestinal injury-reperfusion (IR) model. METHODS: Twenty-one Wistar-albino male rats were separated into three groups: Sham group (n = 7): solely superior mesenteric artery (SMA) was dissected after laparotomy; intestinal ischemia-reperfusion group (IIR, n = 7): SMA was clamped for 60 min and unclamped for 120 min to cause ischemia-reperfusion; IIR + levosimendan group (IIR + L, n = 7): levosimendan was administered in ischemia-reperfusion model. The mean arterial pressures (MAP) were measured in all groups. MAP measurements were performed at the end of stabilization, at the 15th, 30th, and 60th minute of ischemia; at the 15th, 30th, 60th, and 120th minute of reperfusion; and at the end of levosimendan bolus application and when levosimendan infusion concluded. Reperfusion injury was evaluated with tissue malondialdehyde (MDA) and by Chiu score. RESULTS: MAP at 15 min, 30 min, and 60 min of reperfusion was lower in IIR and IIR + L groups compared with basal inter-group measurements. Decline in MAP at 30 min after reperfusion was statistically significant in IIR and IIR + L groups when compared with the sham group. There was no significant difference between MDA levels in the groups. Chiu score was significantly lower in the sham group when compared to IIR and IIR + L groups and higher in IIR when compared to the IIR + L group. CONCLUSION: Levosimendan leads to a decrease in intestinal damage although it did not affect lipid peroxidation and MAP when administered after reperfusion in an experimental intestinal IR model.

A New Approach in the Treatment of Traumatic Brain Injury: The Effects of Levosimendan on Necrosis, Apoptosis, and Oxidative Stress.

OBJECTIVE: Traumatic brain injury (TBI) is an essential and common health problem worldwide. Levosimendan is an inotropic and vasodilator drug used to treat heart failure. Moreover, it exerts pleiotropic effects and, thus, protective effects on many organs. The present study aimed to investigate the effect of levosimendan on necrosis, apoptosis, and reactive oxygen species in rats with TBI. METHODS: The study included 28 female Wistar-Albino rats weighing 200-250 g. The rats were divided into 4 groups with 7 rats each as follows: Group 1: No trauma group (Control), Group 2: Traumatized, untreated group (T), Group 3: Levosimendan was administered at a dose of 12 µg/kg intraperitoneally 1 hour after the trauma (L1), Group 4: Levosimendan was administered at a dose of 12 µg/kg intraperitoneally 2 hours after the concussion (L2). After the experiment, the rats were decapitated, and the brain tissue was removed. Necrosis was assessed with Cresyl violet staining, apoptosis was assessed with immunohistochemical analysis, superoxide dismutase and catalase levels were measured with the spectrophotometric method, and malondialdehyde (MDA) levels were assessed by High-Performance Liquid Chromatography. RESULTS: The number of necrotic cells in the L1 and L2 groups was significantly lower than in the K and T groups (P = 0.015 and P = 0.03, respectively). Although the active caspase-3 level was signified considerably in the T, L1, and L2 groups compared to the K group, no significant difference was found among these 3 groups (P > 0.05). The results of superoxide dismutase levels were similar to those of active caspase-3. catalase level was significantly higher in the K group than in the T and L2 groups (P = 0.045). Malondialdehyde activity was considerably higher in the L1 and L2 groups compared to the K group (P = 0.023). CONCLUSIONS: Our results indicated that levosimendan may exert a neuroprotective effect by reducing necrosis in TBI and that levosimendan does not affect apoptosis and antioxidant levels in TBI. Comprehensive studies are needed to elucidate the effect of levosimendan on TBI fully.

Fabrication of 3D Printed poly(lactic acid) strut and wet-electrospun cellulose nano fiber reinforced chitosan-collagen hydrogel composite scaffolds for meniscus tissue engineering.

The main goal of the study was to produce chitosan-collagen hydrogel composite scaffolds consisting of 3D printed poly(lactic acid) (PLA) strut and nanofibrous cellulose for meniscus cartilage tissue engineering. For this purpose, first PLA strut containing microchannels was incorporated into cellulose nanofibers and then they were embedded into chitosan-collagen matrix to obtain micro- and nano-sized topographical features for better cellular activities as well as mechanical properties. All the hydrogel composite scaffolds produced by using three different concentrations of genipin (0.1, 0.3, and 0.5%) had an interconnected microporous structure with a swelling ratio of about 400% and water content values between 77 and 83% which is similar to native cartilage extracellular matrix. The compressive strength of all the hydrogel composite scaffolds was found to be similar (∼32 kPa) and suitable for cartilage tissue engineering applications. Besides, the hydrogel composite scaffold comprising 0.3% (w/v) genipin had the highest tan δ value (0.044) at a frequency of 1 Hz which is around the walking frequency of a person. According to the in vitro analysis, this hydrogel composite scaffold did not show any cytotoxic effect on the rabbit mesenchymal stem cells and enabled cells to attach, proliferate and also migrate through the inner area of the scaffold. In conclusion, the produced hydrogel composite scaffold holds great promise for meniscus tissue engineering.

Comparison of Pharmacodynamics and Celiac Effects of Olmesartan Medoxomil Formulations by using Olmesartan-induced Celiac-rat-model.

INTRODUCTION: Olmesartan Medoxomil (OM) is an angiotensin receptor blocker and has the adverse effect of celiac like enteropathy which was accepted by the FDA in 2013. This disease is characterized by severe diarrhea, weight loss and enteropathy. Although there are many case reports associated with olmesartan-related enteropathy in humans, it has not been described in a long-term animal model study so far. AIM: We developed a self-microemulsifying drug delivery system (OM-SMEDDS) in our previous study to reduce this side effect of the drug and to enhance bioavailability. METHODS: In this study, an artificial hypertension model was established with a dose of 185 µmol /kg L-NAME (N ω-nitro-L-arginine methyl ester) twice in a day intraperitoneally in Wistar albino rats. To determine and compare side effects, the OM-Suspension and OM-SMEDDS were administered at 1.3 mg/kg therapeutic dose during one-month period to the rats. RESULTS: Tension of rats was recorded by measuring from their tails with non invasive blood pressure system. We observed celiac like enteropathy findings like villous atrophy and intraepithelial lymphocytosis and clinical changes like weight loss and severe diarrhea after the treatment with OM-Suspension during one-month experiment. It was also observed that the antihypertensive efficacy of the OM-SMEDDS formulation was higher than the suspension during the experiment, which did not cause enteropathy, diarrhea and weight loss by reducing intestinal exposure. CONCLUSION: Hereby, we evaluated the side effects of two different pharmaceutical forms by designing a sustainable and reproducible celiac rat model that can be induced with olmesartan medoxomil.

Alpha lipoic acid attenuates iron induced oxidative acute kidney injury in rats.

Iron has been implicated in oxidative tissue injury owing to its ability to generate reactive oxygen species (ROS). We investigated the reno-protective effects of alpha lipoic acid (ALA) by investigating its effects on the kidney isoform of NADPH oxidase (Nox4) and the specific signaling pathways, p38 MAPK and PI3K/Akt, which participate in apoptosis and survival, respectively. We established four groups of seven rats: control, 100 mg/kg ALA, 80 mg/kg iron sucrose (IS) and IS + ALA. IS and ALA were injected intravenously and rats were sacrificied after 6 h. The mRNA expression of the subunits of NADPH oxidase, Nox4 and p22phox; tumor necrosis factor-alpha (TNF-α); and kidney injury molecule-1 (KIM-1) were measured using quantitative real time polymerase chain reaction (qRT-PCR). Active caspase-3 protein expression was evaluated by immunostaining. Also, p38 MAPK and PI3K/Akt signaling pathways were analyzed using western blot. ALA suppressed the mRNA expression of Nox4, p22phox, TNF-α and KIM-1. Active caspase-3 protein expression induced by IS was decreased by ALA. ALA also suppressed p38 MAPK and activated the PI3K/Akt signaling pathway following IS administration. We found that ALA may be an effective strategy for preventing oxidative acute kidney injury caused by IS.

Protective effect of an adenosine A1 receptor agonist against metamidophos-induced toxicity and brain oxidative stress.

The aim of this study was to evaluate the effects of different doses of an adenosine A(1) selective agonist, phenylisopropyl adenosine (PIA), on metamidophos-induced cholinergic symptoms, mortality, diaphragm muscle necrosis, and brain oxidative stress. A LD(50) dose of metamidophos (20 mg/kg body weight, p.o.) was followed by 1 mL/kg body weight of 0.9% NaCl or 1 mg/kg, 2 mg/kg, 3 mg/kg, or 5 mg/kg body weight PIA ip. Incidence of clinical signs including chewing, salivation, convulsion, and respiratory distress did not show any significant difference among all treatment groups (p > 0.05). PIA was found to be effective to reverse the necrotic changes in diaphragm muscle induced by metamidophos significantly in all groups. Brain Thiobarbituric Acid Reactive Substance (TBARS) levels were significantly increased after the metamidophos poisoning. Administration of 2 to 5 mg/kg body weight PIA decreased brain TBARS levels compared to 0.9% NaCl treated rats. The results indicate that, although different doses of PIA reduced the OP-induced oxidative stress and diaphragm necrosis, a single dose of PIA was not able to recover cholinergic signs and symptoms of metamidophos poisoning.