The impact of mild hypercholesterolemia on injury repair in the rat patellar tendon

Hypercholesterolemia is associated with tendon pathology and injury prevalence. Lipids can accumulate in the tendon's extracellular spaces, which may disrupt its hierarchical structure and the tenocytes physicochemical environment. We hypothesized that the tendon's ability to repair after injury would be attenuated with elevated cholesterol levels, leading to inferior mechanical properties. Fifty wild‐type (sSD) and 50 apolipoprotein E knock‐out rats (ApoE−/− ) were given a unilateral patellar tendon (PT) injury at 12 weeks old; the uninjured limb served as a control. Animals were euthanized at 3‐, 14,‐ or 42‐days postinjury and PT healing was investigated. ApoE−/− serum cholesterol was double that of SD rats (mean: 2.12 vs. 0.99 mg/mL, p < 0.001) and cholesterol level was related to the expression of several genes after injury; notably rats with higher cholesterol demonstrated a blunted inflammatory response. There was little physical evidence of tendon lipid content or differences in injury repair between groups, therefore we were not surprised that tendon mechanical or material properties did not differ between strains. The young age and the mild phenotype of our ApoE−/− rats might explain these findings. Hydroxyproline content was positively related to total blood cholesterol, but this result did not translate to observable biomechanical differences, perhaps due to the narrow range of cholesterol levels observed. Tendon inflammatory and healing activity is modulated at the mRNA level even with a mild hypercholesterolemia. These important initial impacts need to be investigated as they may contribute to the known consequences of cholesterol on tendons in humans

The importance of CDC27 in cancer: molecular pathology and clinical aspects

Background: CDC27 is one of the core components of Anaphase Promoting complex/cyclosome. The main role of this protein is defined at cellular division to control cell cycle transitions. Here we review the molecular aspects that may affect CDC27 regulation from cell cycle and mitosis to cancer pathogenesis and prognosis. Main text: It has been suggested that CDC27 may play either like a tumor suppressor gene or oncogene in different neoplasms. Divergent variations in CDC27 DNA sequence and alterations in transcription of CDC27 have been detected in different solid tumors and hematological malignancies. Elevated CDC27 expression level may increase cell proliferation, invasiveness and metastasis in some malignancies. It has been proposed that CDC27 upregulation may increase stemness in cancer stem cells. On the other hand, downregulation of CDC27 may increase the cancer cell survival, decrease radiosensitivity and increase chemoresistancy. In addition, CDC27 downregulation may stimulate efferocytosis and improve tumor microenvironment. Conclusion: CDC27 dysregulation, either increased or decreased activity, may aggravate neoplasms. CDC27 may be suggested as a prognostic biomarker in different malignancies. © 2021, The Author(s)

Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?

The drugs cyclosporine A (CsA) and tacrolimus (FK506) revolutionized organ transplantation. Both compounds are still widely used in the clinic as well as for basic research, even though they have dramatic side effects and modulate other pathways than calcineurin-NFATc, too. To answer the major open question - whether the adverse side effects are secondary to the actions of the drugs on the calcineurin-NFATc pathway - alternative inhibitors were developed. Ideal inhibitors should discriminate between the inhibition of (i) calcineurin and peptidyl-prolyl cis-trans isomerases (PPIases; the matchmaker proteins of CsA and FK506), (ii) calcineurin and the other Ser/Thr protein phosphatases, and (iii) NFATc and other transcription factors. In this review we summarize the current knowledge about novel inhibitors, synthesized or identified in the last decades, and focus on their mode of action, specificity, and biological effects

Oxidative discolouration in whole-head and cut lettuce: biochemical and environmental influences on a complex phenotype and potential breeding strategies to improve shelf-life

Lettuce discolouration is a key post-harvest trait. The major enzyme controlling oxidative discolouration has long been considered to be polyphenol oxidase (PPO) however, levels of PPO and subsequent development of discolouration symptoms have not always correlated. The predominance of a latent state of the enzyme in plant tissues combined with substrate activation and contemporaneous suicide inactivation mechanisms are considered as potential explanations for this phenomenon. Leaf tissue physical properties have been associated with subsequent discolouration and these may be influenced by variation in nutrient availability, especially excess nitrogen and head maturity at harvest. Mild calcium and irrigation stress has also been associated with a reduction in subsequent discolouration, although excess irrigation has been linked to increased discolouration potentially through leaf physical properties. These environmental factors, including high temperature and UV light intensities, often have impacts on levels of phenolic compounds linking the environmental responses to the biochemistry of the PPO pathway. Breeding strategies targeting the PALand PPOpathway biochemistry and environmental response genes are discussed as a more cost-effective method of mitigating oxidative discolouration then either modified atmosphere packaging or post-harvest treatments, although current understanding of the biochemistry means that such programs are likely to be limited in nature and it is likely that they will need to be deployed alongside other methods for the foreseeable future

Neuroprotective effect of ethanol and Modafinil on focal cerebral ischemia in rats

Ethanol is known as an effective agent against cerebral lesions after ischemia. Modafinil is a stimulant of the central nervous system (CNS) with antioxidant properties. We assessed the neuroprotective effect of modafinil in combination with ethanol after focal cerebral ischemia. Male wistar rats weighing 280�300 g were divided into nine groups (n = 12 each group): The groups consisted of the MCAO (middle cerebral artery occlusion) group (i.e. ischemia without treatment); the vehicle group(Dimethylsulfoxide); the modafinil group including three subgroups which pretreated with Modafinil (10, 30, 100 mg/kg), respectively, for seven days prior to the induction of MCAO; the ethanol group which received 1.5g/kg ethanol at the time of reperfusion; and modafinil+ethanol group which was divided into three subgroups that received three doses of modanifil (10, 30,100 mg/kg), respectively, for seven days prior to MCAO as well as ethanol at the time of reperfusion. Transient cerebral ischemia was induced by 60-min intraluminal occlusion of the right middle cerebral artery. Edema, infarct volume, glial scar formation (gliosis) and apoptosis were analyzed. The ethanol alone treatment (with a less significant effect), modafinil (in a dose-dependent way), and the combination of modafinil and ethanol significantly decreased the brain infarct volume, edema, apoptosis, and gliosis (P � 0.05). Additionally, modafinil+ethanol mediated the restoration of aerobic metabolism and hyper-glycolysis suppress, thereby resulting in an increase in pyruvate dehydrogenase and a decrease in lactate dehydrogenase activity, respectively, which ultimately reduced oxidative reperfusion injury. These results demonstrate that pretreatment with modafinil (100 mg/kg) and modafinil+ethanol(1.5 g/kg) may prevent ischemic brain injuries. © 2019, Springer Science+Business Media, LLC, part of Springer Nature

Oxytocinergic system mediates the proconvulsant effects of sildenafil: The role of calcineurin

Sildenafil is a phosphodiesterase type 5 inhibitor used to treat male erectile dysfunction and pulmonary hypertension. A potential side effect of sildenafil is a noticeable decrease in seizure threshold. Oxytocin (OXT) secretion and the subsequent cAMP-responsive element-binding (CREB) phosphorylation are involved in proconvulsant effects of sildenafil in experimental models. The aim of the present study was to investigate the potential role of OXT receptors and their downstream calcineurin (CN)/inducible nitric oxide synthase (iNOS) pathways in proconvulsant effects of sildenafil. The pentylenetetrazole (PTZ)-induced seizure was used as a standard convulsion model in this study. Cortical CN activity, hippocampal nitrite levels, and proinflammatory cytokine content were measured. Our results indicated that following PTZ administration, sildenafil significantly increased CN activity at 40 mg/kg, respectively, in the control group. The combination of sildenafil and OXT receptor antagonist, atosiban (10 μg/kg, i.c.v) 30 min before sildenafil administration significantly reduced the CN activity. Also, the subeffective dose of CN inhibitor cyclosporine (5 mg/kg) 30 min before the administration of effective dose of sildenafil (40 mg/kg) reversed proconvulsant actions of sildenafil. This effect was iNOS-dependent because pretreatment of a low dose of aminoguanidine (20 mg/kg) 15 min before the administration of a low dose of cyclosporine (1 mg/kg) reversed the proconvulsant action of sildenafil (40 mg/kg). Finally, sildenafil induced the elevation of tumor necrosis factor alpha (TNF-α) and the nitrite level was blocked by the administration of cyclosporine in PTZ-treated mice. Collectively, our data provide insights into the role of OXT receptor/CN/iNOS pathway in the proconvulsant aspect of sildenafil. © 202

Seroprevalance Determination of Cytomegalovirus Infection in Women in Their Reproductive Age Referred to Shahid Mofateh Clinic of Yasuj, Iran, in 2013

Background & Aim: According to the maternal health, and the fact that cytomegalovirus infection is associated with abortion and the incidence of fetal malformations, the aim of this study was to determine the seroprevalance of cytomegalovirus infection of women in the reproductive age. Methods: The present cross-sectional study was conducted on women of childbearing referred to Yasuj Mofatteh clinic in 2013. Ninety-four eligible women (married women aged 17 to 45 years) were selected by random-stratified sampling. After completing the questionnaire which included demographic and clinical characteristics, blood samples were collected and IgG & IgM antibodies titers against CMV were measured by ELISA. The collected data was analyzed by SPSS and statistical tests and independent T-test & chi-square. Results: 98.9% of the participants (93 eligible women) were positive for anti-CMV IgG antibody, whereas the IgM antibody in only one patient (1.1 %) was border line. Also no significant association was observed between the IgG and IgM antibodies and clinical manifestations with demographic variables. Moreover, the titer of IgG and IgM antibodies and clinical manifestations associated with demographic variables was not significant (p>0.05). Conclusion: The results indicated that exposure to cytomegalovirus in women at childbearing age was significant in Yasuj and need serious care in order to prevent complications and congenital malformation felt in this group

A novel resource allocation model based on the modularity concept for resiliency enhancement in electric distribution networks

Paying attention to the modularity feature of electric distribution systems improves their performance against severe events and makes an outstanding opportunity for resiliency enhancement. In this paper, a novel framework based on the modularity concept is proposed in which, by deploying smart grid technologies and forming efficient modules, effective and robust energy in distribution systems is provided. Optimal placement of distributed generation (DG) resources, load control options, switching devices, and tie lines are simultaneously incorporated in the proposed linear allocation model. To consider electrical and topological characteristics in the independent functioning of the formed modules, a path-based method is employed. The effectiveness and computability of the proposed algorithm are examined by performing several simulations on two modified 37-bus and 84-bus test systems. The results demonstrate that the developed modular structure, by subdividing the system into several independent parts, creates more flexibility for the recovery process and facilitates the self-healing capabilities

Induction of Apoptosis by Miltefosine in Iranian Strain of Leishmania infantum Promastigotes

"nBackground: Miltefosine is a new drug of choice for the treatment of visceral leishmaniasis. Numerous experi­mental studies have shown miltefosine is effective on Leishmania donovani, however, effectiveness of miltefos­ine in treatment of L. infantum is not fully understood. The aims of the present study were to evaluate cytotoxic effects of miltefosine on Iranian strain of L. infantum, and to determine its 50% inhibitory concentration (IC50) as well as lethal dose. "nMethods: Anti-L. infantum activity of miltefosine was studied by treatment of cultured promastigotes with vari­ous concentration of miltefosine. MTT assay was used to determine L. infantum viability and the results were expressed as IC50. Annexin-V FLUOS staining was performed to study apoptotic properties of this drug by us­ing FACS flow cytometry."nResults: Miltefosine led to dose-dependent death of L. infantum with features compatible with apoptosis includ­ing cell shrinkage, DNA laddering, and externalization of phosphatidylserine with preservation of integrity of plasma membrane. The 100% effect was achieved at 22 µM and IC50 after 48 hours of incubation was 7 μM."nConclusion: Miltefosine exerts cytotoxic effect on Iranian strain of L. infantum via an apoptosis-related mechanism