Receptor mediated targeting of EGF-conjugated alginate-PAMAM nanoparticles to lung adenocarcinoma: 2D/3D in vitro and in vivo evaluation.

Carboplatin (cis-diamine (1,1-cyclobutandicarboxylaso)­platinum (II)) is a second-generation antineoplastic drug, which is widely used for chemotherapy of lung, colon, breast, cervix, testicular and digestive system cancers. Although preferred over cisplatin due to the lower incidence of nephrotoxicity and ototoxicity, efficient carboplatin delivery remains as a major challenge. In this study, carboplatin loaded alginate- poly(amidoamine) (PAMAM) hybrid nanoparticles (CAPs) with mean sizes of 192.13 ± 4.15 nm were synthesized using a microfluidic platform, then EGF was conjugated to the surface of CAPs (EGF-CAPs) for the receptor-targeted delivery. Hence, increased FITC+ cell counts were observed in A549 spheroids after EGF-CAP treatment compared to CAP in the 3D cellular uptake study. As such, the cytotoxicity of EGF-CAP was approximately 2-fold higher with an IC50 value of 35.89 ± 10.37 µg/mL compared to the CAPs in A549 spheroids. Based on in vivo experimental animal model, anti-tumor activities of the group treated with CAP decreased by 61 %, whereas the group treated with EGF-CAP completely recovered. Additionally, EGF-CAP application was shown to induce apoptotic cell death. Our study provided a new strategy for designing a hybrid nanoparticle for EGFR targeted carboplatin delivery with improved efficacy both in vitro and in vivo applications.

Single and repeat-dose toxicity and local tolerance assessment of newly developed oil emulsion adjuvant formulations for veterinary purposes.

Adjuvants are components of vaccines that boost the intensity, duration, and breadth of the immune response. Insight into the mechanisms responsible for the immunotoxicity of both local and systemic adverse reactions following the use of adjuvants has been gained through research over the past twenty years. In the present study, single and repeated-dose toxicity and local tolerance of newly developed Water-in-Oil (W/O) and Water-in-Oil-in-Water (W/O/W) Emulsion adjuvants (Coralvac RZ 528, Coralvac RZ 506, Coralvac AT 318, Coralvac AT 318 SIS and Coralvac 252) by Coral Biotechnology Industry and Trade Incorporated Company were demonstrated after intramuscular injection in mice. In both toxicity studies, no adverse reactions such as death, general appearance, behavior, or weight loss were observed in the mice in the experimental groups. The results indicate that clinical chemistry parameters demonstrated normal function of the major organs and no irreversible damage to the mice in all adjuvant groups compared to the control group. In histopathologic investigation of single dose toxicity study, inflammation, edema, and large amounts of lipid droplets were observed on the 7th day in all experimental groups. On the 14th day, when the control group and the experimental groups were compared, it was seen that inflammation and edema had decreased considerably. Similarly, repeated dose toxicity study showed mild inflammation and edema in the control group, while quite widespread and severe inflammation, edema, and diffuse lipid droplets of varying sizes were observed in all adjuvant groups compared to the control group. These observations would be useful for the future development of oil-based adjuvants and their use in veterinary inactive vaccines.

Fluvastatin alleviates doxorubicin-induced cardiac and renal toxicity in rats via regulation of oxidative stress, inflammation, and apoptosis associated genes expressions.

Doxorubicin (DOXO) is a cytostatic agent used in the chemotherapy protocol of several cancers for more than 40 years, but usage of this drug in cancer treatment has been limited due to severe renal and cardiac tissue toxicities that may result in death in patients. Fluvastatin (FV) is a fully synthetic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor used as a cholesterol-lowering agent in patients with hypercholesterolemia. Previous studies revealed that FV also exhibits antioxidant, anti-inflammatory, and antitumor activity. Additionally, our previous study indicated that FV exerts a prophylactic effect on DOXO-induced testicular toxicity by preventing lipid peroxidation, supporting the antioxidant system, and regulating the blood-testis barrier-associated genes expression. Herein, we purposed to evaluate the possible therapeutic and the protective effects of FV on the DOXO-induced cardiac and renal toxicitiy model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction (real-time PCR) analyses. Results point out protective use of FV exerts a beneficial effect by repressing lipid peroxidation and by regulating the inducible nitric oxide synthase (iNOS), nitric oxide synthase endothelial (eNOS), nuclear factor kappa-B (NF-κB), and Caspase-3 (Casp3) protein and mRNA expressions, which play an important role in mediating DOXO-induced renal and cardiac toxicity mechanisms. In conclusion, FV may be a candidate agent for the prevention of renal and cardiac toxicities in cancer patients receiving DOXO chemotherapy.

The regulatory effects of clomiphene and tamoxifen on mTOR and LC3-II expressions in relation to autophagy in experimental polycystic ovary syndrome (PCOS).

BACKGROUND: Polycystic ovary syndrome (PCOS) is a metabolic disease that causes infertility due to anovulation in women in reproductive age. It is known that clomiphene citrate (CC) and tamoxifen citrate (TMX) induce ovulation in women with PCOS. In this study, we aimed to investigate the effects of CC and TMX on the autophagy pathway in PCOS. METHODS AND RESULTS: Experimental PCOS model was induced by letrozole (1 mg/kg) in rats by gavage for 21 days. After the last letrozole administration, rats were treated TMX (1 mg/kg) or CC (1 mg/kg) for 5 days. At the end of the experimental procedures, rats in all groups were sacrificed and ovarian tissues were removed. It was observed that mRNA and protein expressions of LC3-II were significantly higher in TMX and CC groups than control and PCOS groups (p < 0.05), while mRNA and protein expressions of mTOR in TMX and CC groups were found significantly lower than control and PCOS groups (p < 0.05). CONCLUSIONS: In conclusion, present study suggests that TMX and CC induce autophagy in ovaries with PCOS. Autophagy is a promising target for understanding pathophysiology of this disease and for developing more effective and safe new protocols for the treatment of PCOS-related anovulation.

The neuro-restorative effect of adipose-derived mesenchymal stem cell transplantation on a mouse model of diabetic neuropathy.

Diabetic neuropathy (DN) is the most common degenerative complication associated with Diabetes Mellitus. Despite widespread awareness about DN, the only effective treatments are blood glucose control and pain management. The aim of the current study was to determine the effect of intramuscular adipose-derived mesenchymal stem cell (AMSC) transplantation on sciatic nerves in DN using EMG and histological analyses. A total of 27 mice were randomly divided into three groups: control group, DN group and AMSC group. In EMG, CMAP amplitude in the sciatic nerves was lower, but distal latency was higher in the DN group compared with the control group. CMAP amplitude in the sciatic nerves was higher in the AMSC group compared with the DN group. Distal latency in the sciatic nerve was lower in the AMSC group compared with the DN group. Histologic examination of the tissues in the animals treated with AMSC showed a remarkable improvement in microscopic morphology. Fluorescence microscopy analyses demonstrated that intramuscularly transplanted AMSC was selectively localized in the sciatic nerves. Transplantation of AMSC increased protein expression of S100, cdk2, NGF and DHH, all of which, interfered with DN onset in sciatic nerves. The findings of the present study suggest that AMSC transplantation improved DN through a signal-regulatory effect on Schwann cells, neurotrophic actions and restoration of myelination.

Ameliorative effect of edible Halopteris scoparia against cadmium-induced reproductive toxicity in male mice: A biochemical and histopathologic study.

Cadmium (Cd) is a toxic metal affecting the reproductive system. Halopteris scoparia (brown algae) is generally consumed as a salad in the Far East countries. This study was conducted to compare and determine the possible protective effects of H. scoparia and vitamin E and C combination (VEC) against cadmium chloride (CdCl2 )-induced reproductive toxicity. A total of 36 male mice were equally divided into as control, CdCl2 (2 mg/kg), CdCl2  + H. scoparia (900 mg/kg), CdCl2  + VEC (200 mg/kg), H. scoparia alone and VEC alone groups. Blood and testis samples were taken for biochemical, histochemical and immunohistochemical analyses. H. scoparia was also examined for antioxidant activity (by DPPH assay) and mineral/trace element content (by ICP-MS method). CdCl2 exposure caused a significant deterioration in body weight, sperm parameters (count, motility, viability and morphology) (p < .001), histopathology, immunoreactivity and testosterone levels. However, H. scoparia improved CdCl2 -induced deterioration effects more successfully than VEC-treated group. The present study suggests that edible H. scoparia can be used as a natural protective agent against Cd-induced testicular damage by possibly enhancing essential element levels or increasing antioxidant defence system.

Mid-dose losartan mitigates diabetes-induced hepatic damage by regulating iNOS, eNOS, VEGF, and NF-κB expressions

Background/aim: Losartan, an antihypertensive drug, is highly preferred in patients with diabetes mellitus (DM) and hypertension because of its retarding effect on diabetic nephropathy. In this study, we investigated the potential therapeutic effect of different doses of losartan on hepatic damage in a streptozotocin (STZ, 50 mg/kg)-induced DM model in rats. Materials and methods: In this study, five different groups were formed: control, DM, low-dose losartan (5 mg/kg), mid-dose losartan (20 mg/kg), and high-dose losartan (80 mg/kg). Liver tissues of experimental groups were evaluated immunohistochemically for TUNEL, iNOS, eNOS, VEGF, and NF-κB pathways. In addition to immunohistochemical analysis, analyses of SOD and MDA, which are oxidative stress markers, were also performed and the results were evaluated together. Results: When biochemical and immunohistochemical findings were evaluated together, it was found that the results obtained from the mid-dose losartan group were closer to those of the control than the other groups. Conclusion: This study indicated that mid-dose losartan administration may have a therapeutic effect by inhibiting apoptosis and regulating iNOS, eNOS, VEGF, and NF-κB protein expressions in DM-induced hepatic damage.

Fluvastatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood-testis barrier via mTOR signaling pathway.

Doxorubicin (DOX) is an anthracycline derivative antibiotic that still frequently used in the treatment of solid tumors and hematological malignancies. The clinical use of DOX is largely restricted due to acute and chronic renal, cardiac, hematological, and testicular toxicities. Previous studies have indicated that oxidative stress, lipid peroxidation, and apoptosis in germ cells are the main factors in DOX-induced testicular toxicity, but the entire molecular mechanisms that responsible for DOX-induced testicular damage are not yet fully understood. Fluvastatin is a cholesterol-lowering agent that acts by inhibiting hydroxylmethyl glutaryl coenzyme A, the key enzyme for cholesterol biosynthesis. In addition to its cholesterol-lowering effect, fluvastatin showed an antioxidant effect by cleaning hydroxyl and superoxide radicals and this drug could have a protective effect by acting on the mammalian target of rapamycin (mTOR) signal pathway in testicular damage caused by obesity. This study aimed to investigate the possible protective and therapeutic effects of fluvastatin on the DOX-induced testicular toxicity model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction analyses. The present study indicates that fluvastatin may have a protective and therapeutic effect by removing reactive oxygen species and by regulating the mTOR, connexin 43, and matrix metalloproteinase 9 protein and messenger ribonucleic acid expressions, which play an important role in regulating the blood-testis barrier. On the other hand, the use of fluvastatin as a protective/prophylactic agent was found to be more effective than the use of this drug for treatment. In light of this information, fluvastatin may be a candidate agent that can be used to prevent testicular toxicity observed in men receiving DOX treatment.

Exenatide preserves trabecular bone microarchitecture in experimental ovariectomized rat model.

PURPOSE: The aim of this study is to investigate effects of exenatide (Glucagon-Like Peptide Agonist) replacement on bone mineral density (BMD) and microarchitecture in a surgical menopause-induced osteoporosis model in rats. METHODS: In this study, 24 female Sprague-Dawley albino mature rats were used. Rats were assigned either to the group ovariectomized administered exenatide or to the control group. Bone Mineral Density (BMD), plasma cytokine levels and histomorphometric analysis were measured. RESULTS: Ovariectomized rats showed significant decrease BMD values, trabecular counts, trabecular thickness and trabecular area. Also, significant increase trabecular separation and plasma TNF-α (Tumor Necrosis Factor) and IL-6 (Interleukin) levels. Exenatide treatment reversed these changes and it showed a considerable protective effect on trabecular bone microarchitecture. CONCLUSIONS: Exenatide may be a candidate for use in the treatment of postmenopausal osteoporosis and anti-inflammatory properties can be attributed this effects.

Repression of the Notch pathway prevents liver damage in streptozotocin-induced diabetic mice.

INTRODUCTION: Sunitinib is an oral inhibitor of vascular endothelial growth factor that is used to treat a variety of cancer. There are limited data regarding the effect of sunitinib on diabetes. In the liver, Notch signaling plays an important role in liver tissue development and homeostasis and its dysfunction is associated with liver pathol-ogies. The aim of the present study is to investigate the effects of sunitinib on streptozotocin (STZ)-induced diabetic liver in mice models. MATERIAL AND METHODS: An experimental diabetes mellitus (DM) model was created in 28 male CD-1 mice. Twenty-eight male CD-1 mice divided in four groups (n = 7 each) were used; control mice (C), control mice treated with sunitinib (C + S), diabetic mice (DM), and diabetic mice treated with sunitinib (DM + S) for four weeks. The histopathological changes in the liver were examined by histochemistry and immunohistochemistry. Immunoreactivity of Notch1, Jagged1, DLL-1 and VEGF were evaluated in control and diabetic mice after sunitinib treatment. RESULTS: The significant morphological changes in the liver were mostly seen in hepatocytes that were hyper-trophied in the DM mice, with an increased amount of eosinophilic granules; moreover, some hepatocytes contained empty vacuole-like structures. The livers of the DM mice revealed increased deposition of collagen fibers. After sunitinib treatment the hepatocytes and hepatic lobules had almost similar morphology to control mice. The immunoreactivities of Notch1, Jagged1, DLL-1 and VEGF in hepatocytes were significantly lower in the DM group when compared with the C, DM + S and C + S group treated with sunitinib. CONCLUSIONS: These results suggest that sunitinib effectively protects the liver from diabetes-induced damage through the inhibition of the Notch pathway.

The antioxidant role of agomelatine and gallic acid on oxidative stress in STZ induced type I diabetic rat testes.

Diabetes is a multisystem disorder and its effects are observed on the reproductive system. One of the main causes of testicular tissue damage is diabetes-induced overproduction of reactive oxygen species and glycated end products. The main objectives of this study were to investigate the possible effects of agomelatine (AG) and gallic acid (GA) in suppressing oxidative stress in Type I diabetes induced testicular damage. A total of 28 adult male rats were included in the study. Diabetes was induced by intraperitoneal injection of streptozocin (STZ, 55mg/kg) to 21 rats, which were then randomly assigned to 3 groups; 1mL saline solution was given to the diabetes+saline group by oral gavage, 20mg/kg/day oral AG was given to the diabetes+AG group, and 20mg/kg/day oral GA was given to the diabetes+GA group for 4 weeks. Tumor necrosis factor α (TNFα), nitric oxide synthase 2 (NOS2), fibronectin and vascular endothelial growth factor (VEGF) were used for the investigation of inflammation, fibrosis and vascular structures. The terminal-deoxynucleoitidyl-transferase mediated nick end-labeling assay (TUNEL) was used to detect apoptosis. Testicular tissue total antioxidant capacity values were tested by biochemical analysis. AG treatment showed an improvement on biochemical parameters and histopathological appearance on the rat testes. GA showed dose-related regenerative effects on biochemical parameters. Histologically, a minimal healing effect was determined on the testes damage. In conclusion, it was observed that AG is a potentially beneficial agent for reducing testicular damage by decreasing oxidative stress level. However, GA was seen to have a poor therapeutic effect.

Oxytocin provides protection against diabetic polyneuropathy in rats.

PURPOSE: The aim of the present study is to investigate the protective effects of oxytocin (OT) on diabetic neuropathy (DNP) in rats. MATERIALS AND METHODS: Eighteen rats were used to induce diabetes using single dose streptozotocin (STZ, 60 mg/kg). Diabetic DNP was verified by electromyography (EMG) and motor function test on 21st day following STZ injection. Six rats served as naïve control group and received no drug (n = 6). Following EMG, diabetic rats were randomly divided into three groups and administered with either 1 ml/kg saline or 80 µg/kg OT or 160 µg/kg OT intraperitoneally for four weeks. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and glutathione), histological, and immunohistochemical analysis of sciatic nerves (bax, caspase 3, caspase 9, and NGF) were performed. RESULTS: Diabetic rats developed neuropathy, which was apparent from decreased compound muscle action potentials amplitudes and prolonged distal latency in saline-treated rats (p < 0.001) whereas 160 µg/kg OT significantly improved EMG findings. OT treatment significantly lessened the thickening of perineural fibrosis when compared with saline group (p < 0.001). Besides, OT significantly reduced plasma lipid peroxides (p < 0.05) and increased glutathione levels in diabetic rats (p < 0.001). The sciatic nerves of saline-treated rats showed considerable increase in bax, caspase 3 and caspase 8 expressions (p < 0.001) while OT treatment significantly suppressed these apoptosis markers. Also, OT improved NGF expression in diabetic rats compared to saline group. CONCLUSION: Present results demonstrate that OT appears to alleviate harmful effects of hyperglycemia on peripheral neurons by suppressing inflammation, oxidative stress and apoptotic pathways.

Comparison of cell cycle components, apoptosis and cytoskeleton-related molecules and therapeutic effects of flavopiridol and geldanamycin on the mouse fibroblast, lung cancer and embryonic stem cells.

Similarities and differences in the cell cycle components, apoptosis and cytoskeleton-related molecules among mouse skin fibroblast cells (MSFs), mouse squamous cell lung carcinomas (SqCLCs) and mouse embryonic stem cells (mESCs) are important determinants of the behaviour and differentiation capacity of these cells. To reveal apoptotic pathways and to examine the distribution and the role of cell cycle-cell skeleton comparatively would necessitate tumour biology and stem cell biology to be assessed together in terms of oncogenesis and embryogenesis. The primary objectives of this study are to investigate the effects of flavopiridol, a cell cycle inhibitor, and geldanamycin, a heat shock protein inhibitor on mouse somatic, tumour and embryonic stem cells, by specifically focusing on alterations in cytoskeletal proteins, cell polarity and motility as well as cell cycle regulators. To meet these objectives, expression of several genes, cell cycle analysis and immunofluorescence staining of intracellular cytoskeletal molecules were performed in untreated and flavopiridol- or geldanamycin-treated cell lines. Cytotoxicity assays showed that SqCLCs are more sensitive to flavopiridol than MSFs and mESCs. Keratin-9 and keratin-2 expressions increased dramatically whereas cell cycle regulatory genes decreased significantly in the flavopiridol-treated MSFs. Flavopiridol-treated SqCLCs displayed a slight increase in several cell cytoskeleton regulatory genes as well as cell cycle regulatory genes. However, gene expression profiles of mESCs were not affected after flavopiridol treatment except the Cdc2a. Cytotoxic concentrations of geldanamycin were close to each other for all cell lines. Cdkn1a was the most increased gene in the geldanamycin-treated MSFs. However, expression levels of cell cytoskeleton-associated genes were increased dramatically in the geldanamycin-treated SqCLCs. Our results revealing differences in molecular mechanisms between embryogenesis and carcinogenesis may prove crucial in developing novel therapeutics that specifically target cancer cells.

Neuroprotective effects of chronic administration of levetiracetam in a rat model of diabetic neuropathy.

OBJECTIVE: Diabetic neuropathy (DNP) is a frequent and serious complication of diabetes mellitus (DM) that leads to progressive and length-dependent loss of peripheral nerve axons. The purpose of the present study is to assess the neuroprotective effects of levetiracetam (LEV) on DNP in a streptozotocin (STZ)-induced DM model in rats. METHODS: Adult Sprague-Dawley rats were administered with STZ (60mg/kg) to induce diabetes. DNP was confirmed by electromyography (EMG) and motor function test on 21st day following STZ injection. Study groups were assigned as follows; Group 1: Naïve control (n=8), Group 2: DM+1mL/kg saline (n=12), Group 3: DM+300mg/kg LEV (n=10), Group 4: DM+600mg/kg LEV (n=10). LEV was administered i.p. for 30 consecutive days. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and total anti-oxidant capacity), histological and immunohistochemical analysis of sciatic nerves (TUNEL assay, bax, caspase 3, caspase 8 and NGF) were performed to evaluate the efficacy of LEV. RESULTS: Treatment of diabetic rats with LEV significantly attenuated the inflammation and fibrosis in sciatic nerves and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves showed a considerable increase in bax, caspase 3 and caspase 8 and a decrease in NGF expression in saline-treated rats whereas LEV significantly suppressed apoptosis markers and prevented the reduction in NGF expression. Besides, LEV considerably reduced plasma lipid peroxides and increased total anti-oxidant capacity in diabetic rats. CONCLUSIONS: The results of the present study suggest that LEV may have therapeutic effects in DNP through modulation of anti-oxidant and anti-apoptotic pathways.

Levetiracetam ameliorates ovarian function in streptozotocin-induced diabetic rats.

Diabetes mellitus can adversely affect gonadal function. In the present study, we aimed to investigate the protective effects and mechanism of action of levetiracetam (LEV) on the ovaries in a streptozotocin (STZ)-induced diabetes model in rats. Twenty-one adult female rats were assigned to three groups as control, diabetes group treated with 1 mL/kg/d saline (STZ + SP) and diabetes group treated with 600 mg/kg/d LEV (STZ + LEV). Following 4 weeks treatment, blood samples were collected for biochemical analysis and ovariectomy was performed for histopathological examination. Plasma anti-Mullerian hormone (AMH), glutathione and total anti-oxidant capacity values were significantly lower whereas lipid peroxides and transforming growth factor-ß (TGF-ß) values were significantly higher in STZ + SP group compared to control. LEV treatment successfully decreased lipid peroxidation and TGF-ß levels, and also increased anti-oxidant parameters and AMH levels in diabetic rats. Saline-treated rats significantly displayed ovarian degeneration and decreased counts of follicles. However, treatment of diabetic rats with LEV effectively prevented the degenerative changes and follicle loss. Also, LEV suppressed ovarian nuclear factor-kappa B (NF-kB) immunoexpression in diabetic rats. Taken together, we propose that LEV can ameliorate the adverse effects of diabetes on ovarian function via decreasing NF-kB expression and oxidative stress and increasing anti-oxidant status in rats.

Effects of Resveratrol on Ovarian Morphology, Plasma Anti-Mullerian Hormone, IGF-1 Levels, and Oxidative Stress Parameters in a Rat Model of Polycystic Ovary Syndrome.

OBJECTIVE: To evaluate the effects of resveratrol in a rat model of polycystic ovarian syndrome (PCOS). STUDY DESIGN: After PCOS model was formed by subcutaneous dihydrotestosterone pellets, rats were randomly divided into 2 groups. The first group (n = 7) was treated with 1 mL/kg/d isotonic saline and the second group (n = 7) was treated with 10 mg/kg/d resveratrol. Seven rats were taken as controls without any medication. RESULTS: Our results showed (1) significant reduction in the number of antral follicle counts (P < .01); (2) significantly decreased plasma anti-Mullerian hormone and insulin-like growth factor 1 levels (P < .01 and P < .05, respectively); (3) significantly lower superoxide dismutase activity (P < .05); and (4) significantly increased glutathione peroxidase content (P < .01) following resveratrol treatment. CONCLUSION: Resveratrol appears to be effective in the treatment of PCOS due to its antioxidant properties. Future clinical studies with different dosages might provide useful implementations to our practice.

Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: an experimental rat model study.

The aim of our study is to investigate the effect of sunitinib on diabetes mellitus related-ovarian injury and fibrosis in rat models. An experimental diabetes mellitus model was created in 16 rats, and eight rats with normal blood glucose levels were included in control group (Group-1). The diabetic rats were divided into two groups:diabetic control group (water given) - Group-2 and sunitinib treatment group - Group-3. After four weeks, bilateral oophorectomy was performed and ovaries were examined histologically. The groups were compared by Student's t-test, analysis of variance (ANOVA) and Mann-Whitney's U-test. There was a significant increase in no-medication (water given) diabetic rat's ovary (Group-2) in terms of follicular degeneration, stromal degeneration, stromal fibrosis and NF-kappaB immune-expression compared with control group normal rats' ovary (Group-1) (p < 0.0001). Stromal degeneration (p = 0.04), stromal fibrosis (p = 0.01), follicular degeneration (p = 0.02), NF-kappaB immune-expression (p = 0.001) significantly decreased in sunitinib-treated diabetic rat's ovary (Group-3) when compared with no-medication (water given) diabetic rat's ovary (Group-2) (p < 0.05). When we used sunitinib in the treatment of diabetic rats, ovarian injury, fibrosis and NF-kappaB immunoexpression decreased significantly. The effects of sunitinib in rat models give hope to the improved treatment of premature ovarian failure due to diabetes mellitus in humans.

Exenatide improves ovarian and endometrial injury and preserves ovarian reserve in streptozocin induced diabetic rats.

We aimed to evaluate: (1) endometrial and ovarian tissue injury caused by the glucose toxicity in diabetic rat model and (2) the effect of GLP-1 analog (exenatide) on endometrial and ovarian diabetes induced injury with emphasizing the underlying mechanism. The study group composed of 24 female rats assigned randomly into 3 groups. Group 1 was the control group (n = 8) and received no treatment. Diabetes was induced by intraperitoneal injection of streptozocin for 16 rats which are further assigned randomly into 2 groups: 1 ml/kg intraperitoneal saline was given to Group-2 (diabetic non-treated control group, 8 rats) and 10 µg/kg/day of intraperitoneal exenatide was given to Group 3 (exenatide treated group, 8 rats) for four weeks. After four weeks, blood samples were collected and hysterectomy with bilateral oophorectomy was performed for histopathological examination. Diabetes caused endometrial and ovarian tissue injury in rats (p < 0.0001). Serum transforming growth factor beta (TGF-ß), malonylaldehyde (MDA), pentraxin-3 (PTX-3) levels were higher in diabetic rats (p < 0.0001), whereas antimullerian hormone (AMH) was lower (p < 0.001). Serum levels of these markers reflected that Diabetes induced injury in the reproductive tract occured via oxidative stress, fibrosis and severe inflammation. Diabetes diminished ovarian reserve. Exenatide treatment improved the histological degeneration and fibrosis in the endometrium and ovary with concomitant decrease in inflammatory and oxidative stress markers (p < 0.05). Exenatide also improved ovarian reserve (p < 0.05). Glucose toxicity occured severely in ovary and endometrium in DM. After exenatide treatment; ovarian and endometrial injury and fibrosis seems to decrease significantly. The effects of exenatide in rat models give hope to prevent the women with DM from premature ovarian failure and endometrial dysfunction.

Granulocyte-colony stimulating factor decreases the extent of ovarian damage caused by cisplatin in an experimental rat model.

OBJECTIVE: To investigate whether granulocyte-colony stimulating factor (G-CSF) can decrease the extent of ovarian follicle loss caused by cisplatin treatment. METHODS: Twenty-one adult female Sprague-Dawley rats were used. Fourteen rats were administered 2 mg/kg/day cisplatin by intraperitoneal injection twice per week for five weeks (total of 20 mg/kg). Half of the rats (n=7) were treated with 1 mL/kg/day physiological saline, and the other half (n=7) were treated with 100 µg/kg/day G-CSF. The remaining rats (n=7, control group) received no therapy. The animals were then euthanized, and both ovaries were obtained from all animals, fixed in 10% formalin, and stored at 4°C for paraffin sectioning. Blood samples were collected by cardiac puncture and stored at -30°C for hormone assays. RESULTS: All follicle counts (primordial, primary, secondary, and tertiary) and serum anti-Müllerian hormone levels were significantly increased in the cisplatin+G-CSF group compared to the cisplatin+physiological saline group. CONCLUSION: G-CSF was beneficial in decreasing the severity of follicle loss in an experimental rat model of cisplatin chemotherapy.

High-dose atorvastatin ameliorates the uterine microenvironment in streptozotocin-induced diabetic rats.

Abstract The aim of this study was to investigate whether atorvastatin can ameliorate the uterine microenvironment in diabetes mellitus. Six non-diabetic (control) and 12 diabetic mature female Sprague-Dawley albino rats were used in this study. Diabetes was induced by intraperitoneal injections of 60 mg/kg streptozotocin, and 10 mg/kg/day of oral atorvastatin was administered for 4 weeks via orogastric tubes. The animals were euthanized, and blood samples were collected via cardiac puncture for biochemical analysis. Bilateral hysterectomy was performed for the histopathologic examination. Endometrial gland degeneration and stromal fibrosis scores concomitant with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) immunoexpressions were analyzed. The endometrial gland degeneration scores, stromal fibrosis scores and VEGF immunoexpression was significantly lower, and the EGFR immunoexpression was significantly higher in the atorvastatin-treated diabetic rats when compared to the non-treated diabetic group, suggesting that atorvastatin ameliorates the uterine microenvironment in diabetes mellitus.