Testicular torsion (TT) is the most common urological emergency in children and young adults that can lead to infertility in many cases. The ischemia-reperfusion (IR) injury due to TT has been implicated in the pathogenesis of testicular damage. The main pathological mechanisms of contralateral injury after ipsilateral TT are not fully understood. In the presented study, we investigated the molecular and microscopic basis of ipsilateral and contralateral testicular injury following ipsilateral testicular torsion detorsion (T/D) and explored the possible protective role of vitamin D3. The biochemical analysis indicated that IR injury following T/D significantly decreased the activity of testicular glutathione peroxidase (GPx) enzyme, level of serum testosterone, serum inhibin B, and expression of testicular miRNA145, while increased the activity of testicular myeloperoxidase (MPO) enzyme, level of testicular malondialdehyde (MDA), level of serum antisperm-antibody (AsAb), and expression of ADAM-17. The histological and semen analysis revealed that torsion of the testis caused damages on different tissues in testis. Interestingly, administration of vitamin D3 prior to the IR injury reversed the deterioration effect of IR injury on the testicular tissues as indicated by biochemical and histological analysis which revealed normal appearance of the seminiferous tubules with an apparent decrease in collagen fiber deposition in both ipsilateral and contralateral testes. Our results revealed that the protective effect of vitamin D3 treatment could be attributed to target miRNA145 and ADAM17 protein. To further investigate these findings, we performed a detailed molecular modelling study in order to explore the binding affinity of vitamin D3 toward ADAM17 protein. Our results revealed that vitamin D3 has the ability to bind to the active site of ADAM17 protein via a set of hydrophobic and hydrophilic interactions with high docking score. In conclusion, this study highlights the protective pharmacological application of vitamin D3 to ameliorate the damages of testicular T/D on the testicular tissues via targeting miRNA145 and ADAM17 protein.

Smoking aggravates skin necrosis as a complication of random-pattern flap ischaemia. Sildenafil and nitroglycerin (NTG) are vasodilator agents that may affect skin flap survival. Fifty rats were subjected to a dorsal random-pattern flap operation and randomly divided into 5 groups. The control group received no treatment. The ischaemic group were administered local nicotine injections. The sildenafil group were administered oral sildenafil treatment in addition to the same intervention as the ischaemic group. The NTG group received topical NTG ointment application instead of sildenafil. The combined group were given both sildenafil and NTG treatments. After 7 days, all rats were sacrificed for flap assessment. Flap survival percentages at the 3 rd and 7 th days were significantly higher in the combined group than in the other study groups. Histologically, the ischaemic group exhibited dermal disorganization and inflammatory cell infiltration, which were improved in the 3 treated groups; however, the combined group presented the most relevant effect. The epidermal thickness showed a decrease in the ischaemic group (23.1 μm) that was significantly increased in the sildenafil (28.4 μm), NTG (28.8 μm) and combined (35.8 μm) groups. Immunohistochemically, the combined group exhibited a significant decrease in the apoptotic index and an increase in the proliferative index (2.3 and 56.9%, respectively) compared to those in the ischaemic (63.2 and 3%), sildenafil (41.7 and 28.1%) and NTG (39.3 and 30.4%) groups. Transmission electron microscopy (TEM) showed that the combined group displayed improvement in most of the ischaemic changes. Our analyses suggest that the combined use of sildenafil and NTG is more efficacious than using only one of these treatments for skin flap survival.Random skin flaps are widely used options for the reconstruction of large acquired or congenital skin defects 1 . Survival of these flaps is highly reliant on oxygen delivery to their tissues 2 . The main challenge is that the distal parts of the flap suffer from a reduced blood supply, which can trigger skin necrosis 3 . This reduction in the blood supply is mainly caused by anatomical or haemodynamic factors 4 . During vascular regeneration, ischaemia/reperfusion injury occurs, promoting oxidative stress and apoptosis 3 . Additionally, other factors, such as inadequate angiogenesis and inflammatory reactions, play roles in the pathogenesis of flap necrosis 5 .Skin flap ischaemic necrosis and increased incidence of infection can be aggravated by nicotine, which endangers the results of plastic skin reconstruction 6 . Smoking increases the risk of skin flap complications, which has been observed in clinical and experimental studies in both rats and hamsters 7 . Smokers have a higher risk of developing skin flap necrosis, namely, 13 times higher than that of non-smokers, which can result in flap loss or secondary contractures that negatively affect the aesthetic outcomes 6,8 . The potential mechanisms of this increased risk in smokers are highly...

Thiazole-substituted pyrazole is an important structural feature of many bioactive compounds, including antiviral, antitubercular, analgesic and anticancer agents. Herein we describe an efficient and facile approach for the synthesis of two series of 36 novel N-bridged pyrazole-1-phenylthiazoles. The antiproliferative activity of a set of representative compounds was evaluated in vitro against different human cancer cell lines. Among the identified compounds, compound 18 showed potent anticancer activity against the examined cancer cell lines. The in silico molecular docking study revealed that compound 18 possesses high binding affinity toward both SK1 and CDK2. Overall, these results indicate that compound 18 is a promising lead anticancer compound which may be exploited for development of antiproliferative drugs.

A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson’s disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.