Etanercept Ameliorates Vascular, Endocrine, and Ovarian Changes in a Rat Model of DHEA-Induced Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disorder affecting women of reproductive age. This study examined the efficacy of etanercept (ETA), an anti-TNF-α drug, in alleviating endocrine, metabolic, and vascular dysfunction in a rat model of PCOS. Prepubertal female Wistar rats were divided into three groups: control, PCOS, and PCOS+ETA. The PCOS groups received dehydroepiandrosterone (DHEA) treatment, whereas the PCOS+ETA group received both DHEA and ETA. After 35 days, various biomarkers were evaluated, including systemic blood pressure, endothelial function, and eNOS and TNF-α expression levels in the thoracic aorta and ovaries. The PCOS group exhibited ovarian morphological changes, increased body weight, and hormonal imbalances, whereas the PCOS+ETA group showed restored levels of these parameters. Systemic blood pressure, urinary albumin levels, and protein excretion did not differ significantly differ among the groups. Endothelium-dependent relaxation, eNOS expression, TNF-α expression in the thoracic aorta, and TNF-α expression in the ovaries were restored to normal levels in the PCOS+ETA group. Furthermore, ovarian morphology was improved in the PCOS+ETA group. In conclusion, etanercept treatment shows promise in mitigating hormonal disturbances and vascular dysfunction in patients with PCOS, suggesting potential therapeutic advantages.

The anti-scar effect of tyrosine-kinase inhibitor nintedanib in experimental glaucoma filtration surgery in rabbits.

PURPOSE: To investigate the efficacy of nintedanib on preventing postoperative scar in formation following glaucoma filtering surgery (GFC) in rabbits in comparison with Mitomycin-C (MMC). DESIGN: Experimental Animal Study. METHODS: 24 New Zealand rabbits were divided randomly into 3 groups as Sham, Nindetanib and MMC(n = 8). Limbal-based trabeculectomy was performed on the right eyes of the rabbits. Left eyes that did'nt undergo surgery were included in the control group (n = 8). Following surgery, Intraocular pressures (IOP), postoperative complications and morphological changes in the bleb were evaluated. On the 28th day, eight eyes from each group were enucleated and histologically and immunohistochemically analyzed. Matrix metalloproteinase-2 (MMP-2), Transforming Growth Factor-1 (TGF-B1) and alpha-smooth muscle actin (a-SMA) were evaluated. RESULTS: It was observed that nintedanib has no side effects and reduces subconjunctival fibrosis. Postoperative IOP values in the Nindetanib group were lower than the other groups (p < 0.05). The longest bleb survival was observed in the Nintedanib group and the shortest in the Sham group (p < 0.001). Conjunctival vascularity and inflammation was reduced in the Nintedanib group compared to the Sham group (p < 0.05). The highest subconjunctival fibrosis was observed in the Sham group and the least in the Nintedanib group (p < 0.05). Although the fibrosis score was found lower in the Nintedanib group compared to the MMC(p > 0.05). α-SMA TGF-ß1, MMP-2 expressions were similar in Nintedanib and MMC groups (p > 0.05), however, it was observed that significantly decreased in both groups compared to Sham group (p < 0.05). CONCLUSION: It has been observed that Nindetanib suppress fibroblast proliferation Thus, It may be a drug that can prevent subconjunctival fibrosis in GFC.

Evaluation of nintedanib as a new postoperative antiscarring agent in experimental extraocular muscle surgery.

AIM: To investigate the efficacy of nintedanib on reducing postoperative inflammation, fibrosis and adhesion formation following extraocular muscle surgery in rabbits in comparison with triamcinolone acetonide (TA). METHODS: Reinsertion of superior rectus muscle in right eyes of 30 New Zealand white rabbits were performed. They were randomized to receive one of the following treatments: 0.9% normal saline, one of 1-, 5-, and 10 µmol doses of nintedanib subconjunctivally immediately after surgery and on postoperative day 1, 2, 3, 5, and 7, and TA immediately after surgery. As a control group, unoperated left eyes (n=6) were used. On the 28th day, six eyes from each group were enucleated and histopathologically and immunohistochemically analyzed to assess the postoperative inflammatory changes, fibrosis and adhesion. Transforming growth factor beta, matrix metalloproteinase-2 and alpha smooth muscle actin expressions were evaluated. RESULTS: Conjunctival and scleral inflammation in TA and nintedanib groups were significantly reduced compared to saline (sham) group. Conjunctival vascularity and rectus muscle fibrosis were significantly reduced in 10 µmol nintedanib group. Nintedanib groups were the most effective groups in reduction of perimuscular fibrosis. Neither three nintedanib groups nor TA group differed statistically from sham group with regard to adhesion. The expressions of transforming growth factor beta, alpha smooth muscle actin and matrix metalloproteinase-2 were reduced in nintedanib groups compared to saline group. CONCLUSION: Nintedanib appears to attenuate postoperative inflammation and fibrosis after extraocular muscle surgery. Nintedanib may be a safer and stronger alternative agent in extraocular muscle surgery when compared to steroids. Further investigation is needed to prove antiadhesive effect of nintedanib.

Comparative Analysis of Matrix-Regenerating Agent and Corneal Cross-Linking in an Experimental Alkali Burn Rabbit Model.

PURPOSE: This study aimed to investigate the clinical and histopathological effects of corneal cross-linking (CXL) and matrix-regenerating agent (RGTA) treatments after corneal alkali burn. MATERIALS AND METHODS: Twenty-four alkali-burned corneas from 24 rabbits were divided into three groups: control, CXL, and RGTA. All animals were investigated for epithelial healing, opacification, ulceration, and neovascularization at days 1, 7, 14, and 21 after the alkali burn. Corneas were excised and sent for histological examination on day 21. RESULTS: One animal each from the CXL and control groups exhibited moderate ulceration, while no ulceration was observed in the RGTA group. No significant difference was observed among the groups in corneal thickness or corneal opacity measurements at the final visit (p = .058 and p = .544, respectively). Both RGTA and CXL treatments were effective in terms of epithelial healing and neovascularization (p = .023 and p = .03, respectively). On histological examination, the CXL and RGTA groups were more effective in treating epithelial loss, stromal edema, corneal vascularization, and leukocytic infiltration than the control group (p < .05). The immunohistochemical staining scores of the CXL and RGTA groups for caspase-3, vascular endothelial growth factor, and matrix metalloproteinase-9 in the epithelium and stroma were significantly lower than those in the control group (p < .05). In the immunohistochemical examination for inducible nitric oxide synthase, epithelial staining scores were similar among the groups (p > .05). In contrast, the stromal staining scores of the CXL and RGTA groups were lower than those of the control group (p < .05). CONCLUSION: Both CXL and RGTA therapies were effective in reducing anatomical and histopathological complications after corneal alkali burn. Further investigation is needed to determine the optimal timing, duration, and dosage of these treatments.

Restorative effect of resveratrol on expression of endothelial and neuronal nitric oxide synthase in cavernous tissues of chronic unpredictable mild stress-exposed rats: an impact of inflammation.

We investigated the effect of resveratrol on endothelial and neuronal nitric oxide synthase (eNOS and nNOS) expression in the corpus cavernosum from chronic unpredictable mild stress (CUMS)-exposed rats in order to examine possible role of proinflammatory cytokines, which might play a role on erectile dysfunction (ED). Rats were randomly and equally divided into four groups such as control, control+resveratrol, CUMS and CUMS + resveratrol (20 mg/kg/day, i.p/8 weeks). Sucrose intake and forced swimming tests were used to evaluate depressive-like behaviors. nNOS, eNOS expressions, inflammatory markers, corticosterone and testosterone levels were analyzed either in blood samples and/or penile tissues. CUMS-exposed rats displayed depressive-like behaviors, reduced penile nNOS and eNOS expressions, and serum testosterone levels and enhanced serum and penile tissue levels of proinflammatory markers compared to controls. Resveratrol reversed depressive-like behaviors and suppressed serum and penile levels of proinflammatory markers, increased nNOS and eNOS expressions and testosterone levels in CUMS-exposed rats. Resveratrol exerted antidepressant-like effects and protected the development of CUMS-induced impairment of cavernosal eNOS and nNOS expressions associated with ED, which might be related to its anti-inflammatory action.

Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study.

BACKGROUND: PCOS is a reproductive hormonal abnormality and a metabolic disorder. It is frequently associated with insulin resistance, hyperandrogenism, chronic inflammation, and oxidative stress. We aim to investigate the potential therapeutic effects of combined therapy of resveratrol and metformin on polycystic ovaries via SIRT1 and AMPK activation. METHODS: Wistar albino rats were divided into control and experimental (PCOS) groups. DHEA-induced PCOS rats were given resveratrol (20 mg/kg/day), metformin (300 mg/kg/day) and combined therapy. At the end of the experiment, the body and ovarian weight of rats were measured and blood samples were analyzed for FSH, LH, testosterone, AMH, TNF-α and MDA levels. Histopathological evaluation of ovaries were carried out by light and electron microscopy. SIRT1 and AMPK immunreactivity and TUNEL assay were scored. Data were statistically analyzed by SPSS programme. RESULTS: Metformin and combined treatment groups reduced the body and ovary weights compared to the PCOS group. Serum testosterone levels were significantly higher in the PCOS group than in the control group and this was reduced when PCOS was treated with all but especially resveratrol. All the treatment groups decreased LH, LH/FSH, TNF-α and tissue AMH levels which were induced in the PCOS group, whereas metformin was unable to improve the increased MDA and plasma AMH levels. Treatment with resveratrol and/or metformin ameliorated the elevated number of secondary and atretic follicles and the decreased number of Graafian follicles in the PCOS group, which indicates the effect of the treatments on the maintenance of folliculogenesis. Light and electron microscopic findings supported the analysis of follicular count. Increased number of TUNEL (+) granulosa cells in the PCOS group were reduced significantly in the treatment groups. Resveratrol and metformin increased SIRT1 and AMPK immunreactivity, respectively, compared to the PCOS group. CONCLUSIONS: The results suggest that combined therapy of metformin and resveratrol may improve the weight gain, hormone profile and ovarian follicular cell architecture by inducing antioxidant and antiinflammatory systems via SIRT1 and AMPK activation in PCOS.

TNF-α antagonism with etanercept enhances penile NOS expression, cavernosal reactivity, and testosterone levels in aged rats.

Erectile dysfunction (ED) has been reported to be associated with inflammation. This study investigated the effects of tumor necrosis factor alpha (TNF-α) inhibitor etanercept on penile neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) expressions, testosterone concentrations, neurogenic and endothelium-dependent relaxations of corpus cavernosum (CC), and circulating and cavernosal levels of inflammatory markers in aged rats. Animals were separated into control, aged, and etanercept-treated aged groups. Aged rats displayed significantly increased serum and cavernosal TNF-α, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule (ICAM-1) levels, and decreased penile nNOS and eNOS expressions and serum testosterone levels compared with controls. In etanercept-treated aged group, NOS expressions were similar to that of the control group. The circulating and cavernosal concentrations of TNF-α, CRP, MCP-1, ICAM-1, and testosterone were also normalized by etanercept. Neurogenic and endothelium-dependent relaxant responses significantly decreased in aged rats and etanercept treatment markedly improved these relaxation responses. Our findings indicate that aging decreases penile NOS expression, neurogenic and endothelium-dependent relaxations of CC, and also suppresses serum testosterone levels by inducing inflammatory response that may contribute to the development of ED. TNF-α antagonism may be a novel strategy to treat aging-associated ED.