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Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases, including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer's disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders are not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways, including AMPK, insulin and glucose transporters, will be explored and the potential therapeutic effects of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Determination of the potential effect of metabolic syndrome (MetS) on erectile function in Egyptian men and description of the sociodemographic characteristics of these men. Materials and methods: A cohort of 615 patients presenting to urology department aged between 30 and 75 years were prospectively assessed and divided into two groups. Group I ( n  = 325) diagnosed with MetS and mean age of 56.07 ± 8.51 years. Group II ( n  = 290) subjects with no MetS and mean age 54.97 ± 8.14 years. Patients filled the IIEF questionnaire, medical, personal history, and BMI data were tabulated. Metabolic syndrome was determined when three or more of the five risk factors were present according to the NCEP. Results: In Group I (79.4%) of the patients had erectile dysfunction (ED). Of these, 20.3% had mild, 22.5% had moderate, and 36.6% had severe ED and 30% of patients without MetS had ED. Of these, 17.2% had mild, 5.9% had moderate, and 6.9% had severe ED ( p  < .001; odds ratio 5.549; 95% CI 3.101-9.928). Patients with metabolic syndrome had lower IIEF-EF domain scores. Logistic regression analysis revealed that DM, dyslipidemia, age, and HTN were the most important criteria for ED in the MetS group ( p  < .01). While in the group without MetS, DM, HTN, HDL, and age were the most important risk factors ( p  < .01), and TG and BMI were less important. Conclusions: MetS is a potential risk factor for ED in Egyptian men. Patients with MetS should be questioned about ED. The diabetic patients are most risky for ED.

In light of the most challenging public health crisis of modern history, COVID-19 mortality continues to rise at an alarming rate. Patients with co-morbidities such as hypertension, cardiovascular disease, and diabetes mellitus (DM) seem to be more prone to severe symptoms and appear to have a higher mortality rate. In this review, we elucidate suggested mechanisms underlying the increased susceptibility of patients with diabetes to infection with SARS-CoV-2 with a more severe COVID-19 disease. The worsened prognosis of COVID-19 patients with DM can be attributed to a facilitated viral uptake assisted by the host's receptor angiotensin-converting enzyme 2 (ACE2). It can also be associated with a higher basal level of pro-inflammatory cytokines present in patients with diabetes, which enables a hyperinflammatory "cytokine storm" in response to the virus. This review also suggests a link between elevated levels of IL-6 and AMPK/mTOR signaling pathway and their role in exacerbating diabetes-induced complications and insulin resistance. If further studied, these findings could help identify novel therapeutic intervention strategies for patients with diabetes comorbid with COVID-19.

Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is an adipocytokine with several intriguing properties. It was first identified as pre-B-cell colony-enhancing factor but turned out to possess enzymatic functions in nicotinamide adenine dinucleotide biosynthesis, with ubiquitous expression in skeletal muscles, liver, cardiomyocytes, and brain cells. Visfatin exists in an intracellular (iNAMPT) and extracellular (eNAMPT) form. Intracellularly, visfatin/iNAMPT plays a regulatory role in NAD + biosynthesis and thereby affects many NAD-dependent proteins such as sirtuins, PARPs, MARTs and CD38/157. Extracellularly, visfatin is associated with many hormone-like signaling pathways and activates some intracellular signaling cascades. Importantly, eNAMPT has been associated with several metabolic disorders including obesity and type 1 and 2 diabetes. In this review, a brief overview about visfatin is presented with special emphasis on its relevance to metabolic diseases. Visfatin/NAMPT appears to be a unique molecule with clinical significance with a prospective promising diagnostic, prognostic, and therapeutic applications in many cardiovasculo-metabolic disorders.

NETosis, a novel form of neutrophil-related cell death, acts as a major regulator of diabetes and diabetes-associated complications. In this review, we show that the extrusion of neutrophil extracellular traps, termed NETs, plays an important role in the pathogenesis of type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and diabetes-induced complications. In T1DM, β-cell death induces the sequestration of neutrophils in the pancreas and seems to be correlated with increased NETosis. In T2DM patients, products of NETs release are significantly elevated. Increased levels of dsDNA are correlated with the presence of cardiovascular disease and diabetic kidney disease, further supporting the role of NETosis in the pathogenesis of other diabetes-induced complications such as impaired wound healing and diabetic retinopathy. NETosis is induced by high glucose through incompletely understood mechanisms, but it also appears to be elevated in patients with diabetes who have tightly controlled glucose levels. We hypothesize that hyperglycemia worsens the already elevated baseline of NETosis in diabetic patients to further increase its detrimental effects.

Diabetic cardiomyopathy (DCM) is a constellation of symptoms consisting of ventricular dysfunction and cardiomyocyte disarray in the presence of diabetes. The exact cause of this type of cardiomyopathy is still unknown; however, several processes involving the mitochondria, such as lipid and glucose metabolism, reactive oxygen species (ROS) production, apoptosis, autophagy and mitochondrial biogenesis have been implicated. In addition, polyphenols have been shown to improve the progression of diabetes. In this review, we discuss some of the mechanisms by which polyphenols, particularly resveratrol, play a role in slowing the progression of DCM. The most important intermediates by which polyphenols exert their protective effect include Bcl-2, UCP2, SIRT-1, AMPK and JNK1. Bcl-2 acts to attenuate apoptosis, UCP2 decreases oxidative stress, SIRT-1 increases mitochondrial biogenesis and decreases oxidative stress, AMPK increases autophagy, and JNK1 decreases apoptosis and increases autophagy. Our dissection of these molecular players aims to provide potential therapeutic targets for the treatment of DCM.

Painless, needle-free, and continuous glucose monitoring sensors are needed to enhance the life quality of diabetic patients. To that extent, we propose a first-of-its-kind, highly sensitive, noninvasive continuous glycemic monitoring wearable multisensor system. The proposed sensors are validated on serum, animal tissues, and animal models of diabetes and in a clinical setting. The noninvasive measurement results during human trials reported high correlation (>0.9) between the system's physical parameters and blood glucose levels, without any time lag. The accurate real-time responses of the sensors are attributed to their unique vasculature anatomy-inspired tunable electromagnetic topologies. These wearable apparels wirelessly sense hypo- to hyperglycemic variations with high fidelity. These components are designed to simultaneously target multiple body locations, which opens the door for the development of a closed-loop artificial pancreas., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The intracellular molecular pathways involved in radiation-induced nephropathy are still poorly understood. Glomerular endothelial cells are key components of the structure and function of the glomerular filtration barrier but little is known about the mechanisms implicated in their injury and repair. The current study establishes the response of immortalized human glomerular endothelial cells (GEnC) to ionizing radiation (IR). We investigated the role of sphingolipids and the lipid-modifying enzyme sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in radiation-induced GEnC damage. After delivering a single dose of radiation, long and very-long-chain ceramide species, and the expression levels of SMPDL3b were elevated. In contrast, levels of ceramide-1-phosphate (C1P) dropped in a time-dependent manner although mRNA and protein levels of ceramide kinase (CERK) remained stable. Treatment with C1P or knocking down SMPDL3b partially restored cell survival and conferred radioprotection. We also report a novel role for the NADPH oxidase enzymes (NOXs), namely NOX1, and NOX-derived reactive oxygen species (ROS) in radiation-induced GEnC damage. Subjecting cultured endothelial cells to radiation was associated with increased NOX activity and superoxide anion generation. Silencing NOX1 using NOX1-specific siRNA mitigated radiation-induced oxidative stress and cellular injury. In addition, we report a novel connection between NOX and SMPDL3b. Treatment with the NOX inhibitor, GKT, decreased radiation-induced cellular injury and restored SMPDL3b basal levels of expression. Our findings indicate the importance of SMPDL3b as a potential therapeutic target in radiation-induced kidney damage., (© 2020 Federation of American Societies for Experimental Biology.)

Several theories were proposed to explain the pathophysiology of varicocele-related infertility seen in some patients. Our aim was to study the levels of angiotensin II in semen and angiotensin II type 2 receptor expression on spermatozoa in varicocele patients in relation to their fertility status and to evaluate the influence of varicocelectomy on their levels in infertile varicocele patients. Thirty fertile and 30 infertile varicocele patients and 30 healthy controls were subjected to measurement of reproductive hormones, semen analysis, measurement of seminal angiotensin II and evaluation of angiotensin II type 2 receptor expression on spermatozoa. Infertile varicocele patients underwent varicocelectomy and were re-evaluated for the same parameters after the operation. Sperm concentration, morphology, progressive motility, seminal angiotensin II and angiotensin II type 2 receptor expression were significantly lower in infertile varicocele patients compared with the other groups. Post-operative values showed significant increase in the studied parameters compared with the pre-operative values but not to other two groups. A significant positive correlation between angiotensin II type 2 receptor expression and progressive motility was detected in all studied groups. In conclusion, dysregulation of angiotensin II and angiotensin II type 2 receptor in varicocele patients may be involved in varicocele-related infertility., (© 2020 Blackwell Verlag GmbH.)

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach., (© 2019 by the American Diabetes Association.)

Diabetic kidney disease is one of the most serious complications of diabetes worldwide and is the leading cause of end-stage renal disease. While research has primarily focused on hyperglycemia as a key player in the pathophysiology of diabetic complications, recently, increasing evidence have underlined the role of adipose inflammation in modulating the development and/or progression of diabetic kidney disease. This review focuses on how adipose inflammation contribute to diabetic kidney disease. Furthermore, it discusses in detail the underlying mechanisms of adipose inflammation, including pro-inflammatory cytokines, oxidative stress, and AMPK/mTOR signaling pathway and critically describes their role in diabetic kidney disease. This in-depth understanding of adipose inflammation and its impact on diabetic kidney disease highlights the need for novel interventions in the treatment of diabetic complications., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Clinical studies showed that dextran sulfate sodium (DSS) alleviates stroke, diabetic retinopathy and hypercholesterolemia, yet its mechanism of action was unrevealed. This study show that DSS reduces hyperglycemia, plasma insulin and enhances glucose utilization by attenuating ROS production, suggesting a novel therapeutic use of DSS in diabetes and its complication., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Diabetic dysbiosis has been described as a novel key player in diabetes and diabetic complications. However, the cellular/molecular alterations associated with dysbiosis remain poorly characterized. For that, control, non-obese type 2 diabetic MKR mice and MKR mice treated with butyrate were used to delineate the epigenetic, cellular and molecular mechanisms by which dysbiosis associated with diabetes induces colon shortening and inflammation attesting to gastrointestinal disturbance. Our results show that dysbiosis is associated with T2DM and characterized by reduced Bacteroid fragilis population and butyrate-forming bacteria. The reduction of butyrate-forming bacteria and inadequate butyrate secretion result in alleviating HDAC3 inhibition and altering colon permeability. The observed changes are also associated with an increase in ROS production, a rise in NOX4 proteins, and a shift in the inflammatory markers, where IL-1β is increased and IL-10 and IL-17α are reduced. Treatment with butyrate restores the homeostatic levels of NOX4 and IL-1β. In summary, our data suggest that in T2DM, dysbiosis is associated with a reduction in butyrate content leading to increased HDAC3 activity. Butyrate treatment restores the homeostatic levels of the inflammatory markers and reduces ROS production known to mediate diabetes-induced colon disturbance. Taken together, our results suggest that butyrate could be a potential treatment to attenuate diabetic complications.

Purpose: The aim of this study was to evaluate the combined effect of corticotomy and Low-Level Laser Therapy(LLLT) on the rate of orthodontic tooth movement., Methods: A randomized split-mouth design for 16 female patients compared the rate of maxillary canine retraction using corticotomy combined with LLLT versus corticotomy only. The device used in the present study was an In-Ga-As semiconductor diode laser emitting at 940 nm (IR) with these parameters: 0.5 W/ cm 2 power density, 5 J/cm 2 Fluence, CW, 240 sec time irradiation, weekly for the first month and twice monthly for the next three months. Assessment of the rate of canine retraction was carried out via a series of dental models., Results: A non-significant statistical rate of canine retraction was achieved by LLLT combined to corticotomy compared with the corticotomy technique alone., Conclusion: Low-Level Laser Therapy combined to corticotomy could not achieve a higher rate of canine retraction compared to the golden standard corticotomy technique alone. No long-term adverse effects on the alveolar mucosa were detected following both techniques., (2019, Japan Medical Laser Laboratory.)

Cancer was recently annexed to diabetic complications. Furthermore, recent studies suggest that cancer can increase the risk of diabetes. Consequently, diabetes and cancer share many risk factors, but the cellular and molecular pathways correlating diabetes and colon and rectal cancer (CRC) remain far from understood. In this study, we assess the effect of hyperglycemia on cancer cell aggressiveness in human colon epithelial adenocarcinoma cells in vitro and in an experimental animal model of CRC. Our results show that Nox (NADPH oxidase enzyme) 4-induced reactive oxygen species (ROS) production is deregulated in both diabetes and CRC. This is paralleled by inactivation of the AMPK and activation of the mammalian target of rapamycin (mTOR) C1 signaling pathways, resulting in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulation, induction of DNA damage, and exacerbation of cancer cell aggressiveness, thus contributing to the genomic instability and predisposition to increased tumorigenesis in the diabetic milieu. Pharmacologic activation of AMPK, inhibition of mTORC1, or blockade of Nox4 reduce ROS production, restore the homeostatic signaling of 8-oxoguanine DNA glycosylase/8-oxodG, and lessen the progression of CRC malignancy in a diabetic milieu. Taken together, our results identify the AMPK/mTORC1/Nox4 signaling axis as a molecular switch correlating diabetes and CRC. Modulating this pathway may be a strategic target of therapeutic potential aimed at reversing or slowing the progression of CRC in patients with or without diabetes.-Mroueh, F. M., Noureldein, M., Zeidan, Y. H., Boutary, S., Irani, S. A. M., Eid, S., Haddad, M., Barakat, R., Harb, F., Costantine, J., Kanj, R., Sauleau, E.-A., Ouhtit, A., Azar, S. T., Eid, A. H., Eid, A. A. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer.

The onset of vascular impairment precedes that of diagnostic hyperglycemia in diabetic patients suggesting a vascular insult early in the course of metabolic dysfunction without a well-defined mechanism. Mounting evidence implicates adipose inflammation in the pathogenesis of insulin resistance and diabetes. It is not certain whether amelioration of adipose inflammation is sufficient to preclude vascular dysfunction in early stages of metabolic disease. Recent findings suggest that antidiabetic drugs, metformin, and pioglitazone, improve vascular function in prediabetic patients, without an indication if this protective effect is mediated by reduction of adipose inflammation. Here, we used a prediabetic rat model with delayed development of hyperglycemia to study the effect of metformin or pioglitazone on adipose inflammation and vascular function. At the end of the metabolic challenge, these rats were neither obese, hypertensive, nor hyperglycemic. However, they showed increased pressor responses to phenylephrine and augmented aortic and mesenteric contraction. Vascular tissues from prediabetic rats showed increased Rho-associated kinase activity causing enhanced calcium sensitization. An elevated level of reactive oxygen species was seen in aortic tissues together with increased Transforming growth factor β1 and Interleukin-1β expression. Although, no signs of systemic inflammation were detected, perivascular adipose inflammation was observed. Adipocyte hypertrophy, increased macrophage infiltration, and elevated Transforming growth factor β1 and Interleukin-1β mRNA levels were seen. Two-week treatment with metformin or pioglitazone or switching to normal chow ameliorated adipose inflammation and vascular dysfunction. Localized perivascular adipose inflammation is sufficient to trigger vascular dysfunction early in the course of diabetes. Interfering with this inflammatory process reverses this early abnormality., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There is a growing clinical demand for topical itraconazole (ITC) delivery systems because of the expanding potential of the drug for topical fungal and non-fungal applications. Lipid-based nanocarriers offer great promise in this respect. In the present study, a new topical ITC gel based on lipid nanocapsules (LNC) was developed. ITC-LNC were compared to ITC-loaded nanostructured lipid carriers (ITC-NLC) with more established benefits as topical vectors. Both nanocarriers showed high entrapment efficiency (EE > 98%). Compared to ITC-NLC, the ITC-LNC showed a significantly smaller particle size (∼50 vs 155 nm), narrower size distribution (0.09 vs 0.38), faster initial release rate under sink conditions and greater in vitro antifungal activity against Candida albicans (C. albicans) (inhibition zone 29.4 vs 26.4 mm). ITC-LNC and ITC-NLC-based gels significantly enhanced the dermal retention of ITC in excised human skin relative to a conventional ITC gel. Histopathological assessment of a 14-day treatment of induced cutaneous candidiasis in a rat model indicated efficacy of the gel preparations. Fungal elements developed in the superficial epidermal skin layer were cleared by the end of treatment. Equally important, no histopathological changes in the epidermal and dermal layers of rat skin were observed. Findings of this study verified efficacy of topical ITC in the treatment of superficial fungal infections as well as effectiveness of LNC as biomimetic nanocarrier for dermal drug delivery. Combining ITC and LNC would present a bioactive nanocarrier system with good potentials for fungal infections and other skin applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Objective determination of skin color has become an essential requirement in managing pigmentary disorders including vitiligo. The readings of available devices can be influenced by factors such as surrounding temperature, vasodilation/constriction, and skin surface properties. Our aim was to investigate the influence of hair color and length, skin stretching, incomplete contact of the device with the skin, and the pressure with which the device is applied to the test area on skin color determination., Materials and Methods: Dermacatch® was used to determine the influence of hair color and length in 30 vitiligo patients, and of wrinkles, incomplete contact of the device with the skin and pressure of the device on the test area in 30 healthy volunteers on melanin and erythema indices measured by the device., Results: Melanin index was significantly higher in lesions with black hair compared to lesions with white hair (P < 0.001) and the MI significantly decreased when the black hair was shaved (P < 0.001) and when the skin over the test area was stretched (P < 0.001). Incomplete contact of the device with the test area led to significantly higher MI (P < 0.001) and lower EI (P < 0.001). Meanwhile, high pressure induced by the device on the test area led to significantly lower MI (P < 0.001) and significantly higher EI (P < 0.001)., Conclusions: Factors influencing the readings of devices used for objective determination of skin color have to be taken consideration to ensure accuracy of the measurements done., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. It is depicted as the leading cause of end-stage renal disease. Oxidative stress plays a key role in hyperglycemia-induced DN. The preparation and characterization of novel mono-, di-, and trisubstituted-s-triazines endowed with uracil and/or thymine are described in this paper. The synthesis of the title compounds was realized through selective nucleophilic substitution reactions of cyanuric chloride with the corresponding hydrazide nucleobases. In this study, we assessed the effects of these derivatives on the progression of diabetic nephropathy. Our results show that trisubstituted-s-triazines endowed with acylhydrazides attenuate high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. Notably, these derivatives also display anti-oxidative properties. This suggests that the novel trisubstituted-s-triazine derivatives provide renal protection through a reactive oxygen species (ROS)-dependent mechanism. Our data provide evidence that these derivatives may serve as potential therapeutic candidates in the treatment of DN., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction and Aim: Children with neuropathic lower urinary tract dysfunction usually suffer from associated bowel dysfunction, urinary tract infection and vesicoureteral reflux. This work aimed to highlight the impact of bowel management on bladder dynamics., Patients and Methods: In the period from January 2011 to January 2013, 30 patients, 21 girls and 9 boys with neuropathic lower urinary tract dysfunction were studied. All suffered from urinary tract and bowel dysfunctions. All children were on urological treatment. They had their bowel managed by assurance and psychological support, dietary modification, retrograde or antegrade enemas and maintenance therapy. They were evaluated initially and on follow up by history, physical examination, ultrasound, urodynamics, Wexener score and bowel control chart., Results: Mean age was 8.3 ± 3.47 years (range from 4 to 18). There was a significant decrease in bowel dysfunction (Wexener score decreased from 12.67 ± 1.54 to 10.17 ± 1.76, p = 0.00), rectal diameter (decreased from 34.83 ± 5.91 to 27.90 ± 5.32 mm, p = 0.00), and frequency of UTI (p = 0.00). Detrusor leak point pressure decreased from 37.33 ± 24.95 to 30 ± 17.35 cmH2O, (p = 0.42). The cystometric capacity increased from 136.63 ± 45.69 to 155.17 ± 39.29 ml. (p = 0.001). Reflux and kidney function improved but was not statistically significant (p = 0.25 and p = 0.066 respectively)., Conclusion: Management of bowel dysfunction is of utmost importance in the treatment of children with neuropathic bladder dysfunction. It has a positive effect on lower urinary tract function and decreasing the incidence of complications. This is a LEVEL III prospective study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Ischemia-Reperfusion (I/R) injury is the tissue damage that results from re-oxygenation of ischemic tissues. There are many players that contribute to I/R injury. One of these factors is the family of microRNAs (miRNAs), which are currently being heavily studied. This review aims to critically summarize the latest papers that attributed roles of certain miRNAs in I/R injury, particularly in diabetic conditions and dissect their potential as novel pharmacologic targets in the treatment and management of diabetes., Methods: PubMed was searched for publications containing microRNA and I/R, in the absence or presence of diabetes. All papers that provided sufficient evidence linking miRNA with I/R, especially in the context of diabetes, were selected. Several miRNAs are found to be either pro-apoptotic, as in the case of miR-34a, miR-144, miR-155, and miR-200, or anti-apoptotic, as in the case of miR-210, miR-21, and miR-146a. Here, we further dissect the evidence that shows diverse cell-context dependent effects of these miRNAs, particularly in cardiomyocytes, endothelial, or leukocytes. We also provide insight into cases where the possibility of having two miRNAs working together to intensify a given response is noted., Conclusions: This review arrives at the conclusion that the utilization of miRNAs as translational agents or pharmaco-targets in treating I/R injury in diabetic patients is promising and becoming increasingly clearer., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Cardiovascular disease (CVD) continues to be the leading cause of death worldwide. The effect of estrogen on these diseases has been assessed in in vitro and in vivo models, as well as in observational studies. Collectively, these studies alluded to a cardiovasculo-protective effect of estrogen. However, comprehensive clinical investigation failed to produce concrete proof of a cardiovascular protective effect for hormone replacement therapy (HRT), let alone rule out potential harm. These seemingly paradoxical effects of estrogen were explained by the 'theory of timing and opportunity'. This theory states that the effect of estrogen, whether cardiovasculo-protective or pathological, significantly depends on the age of the individual when estrogen administration takes place. Here, we review the conflicting effects of estrogen on vascular smooth muscle cells, mainly proliferation and migration as two cellular capacities intimately related to physiology and pathophysiology of the cardiovascular system. Furthermore, we critically discuss the major parameters and signaling pathways that may account for the aforementioned paradoxical observations, as well as the key molecular players involved., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine A(CSA). In this study, we tested the hypothesis that administration of calcium channel blockers such as verapamil or nifedipine ameliorates renal CSA-induced renal dysfunction. Furthermore, our study investigates the roles of inflammatory, oxidative, and fibrotic pathways in CSA-induced renal dysfunction. Six groups of male rats ( n = 6/group) were used and received one of the following treatments for seven consecutive days: vehicle (Cremophor EL ip), CSA (25 mg·kg -1 ·day -1 ip), verapamil (2 mg·kg -1 ·day -1 ip), nifedipine (3 mg·kg -1 ·day -1 ip), CSA in the presence or absence of either verapamil, or nifedipine. Biochemical and histomorphometric analyses showed that rats treated with CSA exhibited clear signs of nephrotoxicity that included 1) proteinuria and elevations in serum creatinine and blood urea nitrogen, 2) mesangial expansion, 3) increases in glomerular and tubular type IV collagen expression, and 4) increases in the glomerulosclerosis and tubulointerstitial fibrosis indices. Although the single administration of nifedipine or verapamil had no significant effect on renal pathology, or its biochemical and physiological function, the concurrent use of either calcium channel blockers significantly and equipotently ameliorated the biochemical, morphological, and functional derangements caused by CSA. More importantly, we report that the oxidative (reactive oxygen species production, NADPH-oxidase activity, and dual oxidase 1/2 levels), fibrotic (transforming growth factor-β1 expression), and inflammatory (NF-κB expression) manifestations of renal toxicity induced by CSA were significantly reversed upon administration of nifedipine or verapamil. Together, these results highlight the efficacy of calcium channel-blocking agents in attenuating CSA-induced nephrotoxicity and predisposing biochemical and molecular machineries.

The gut microbiota plays a substantial role in regulating the host metabolic and immune functions. Dysbiosis, resulting from disruption of gut microbiota, predisposes many morbid pathologies like obesity and its associated comorbidities, diabetes and inflammatory conditions including some types of cancer. There are numerous proposed signaling pathways through which alterations in gut microbiota and its metabolites can disturb the host's normal physiological functions. Interestingly, many of these processes happen to be controlled by the mammalian target of rapamycin (mTOR). The mTOR pathway responds to environmental changes and regulates accordingly many intracellular processes such as transcription, translation, cell growth, cytoskeletal organization and autophagy. In this review, we aim to highlight the cross-talk between the gut microbiota and the mTOR pathway and discuss how this emerging field of research gives a beautiful insight into how the mentioned cross-talk impacts the body's homeostasis thus leading to undesirable complications including obesity, diabetes, colon and pancreatic cancer, immune system malfunctioning and ageing. Although there are a limited number of studies investigating the crosstalk between the gut microbiota and the mTOR pathway, the results obtained so far are enough to elucidate the key role of the mTOR signaling in microbiota-associated metabolic and immune regulations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Reactive oxygen species (ROS) modify proteins and lipids leading to deleterious outcomes. Thus, maintaining their homeostatic levels is vital. This study highlights the endogenous role of LXRs (LXRα and β) in the regulation of oxidative stress in peripheral nerves. We report that the genetic ablation of both LXR isoforms in mice (LXRdKO) provokes significant locomotor defects correlated with enhanced anion superoxide production, lipid oxidization and protein carbonylation in the sciatic nerves despite the activation of Nrf2-dependant antioxidant response. Interestingly, the reactive oxygen species scavenger N-acetylcysteine counteracts behavioral, electrophysical, ultrastructural and biochemical alterations in LXRdKO mice. Furthermore, Schwann cells in culture pretreated with LXR agonist, TO901317, exhibit improved defenses against oxidative stress generated by tert-butyl hydroperoxide, implying that LXRs play an important role in maintaining the redox homeostasis in the peripheral nervous system. Thus, LXR activation could be a promising strategy to protect from alteration of peripheral myelin resulting from a disturbance of redox homeostasis in Schwann cell.

Objective and Design: The aim of this study is to elucidate TGF-β1 signaling pathways involved in COX-2 protein induction and modulation of TAU protein phosphorylation in cultured podocytes., Materials, Treatment and Methods: In vitro cultured immortalized podocytes were stimulated with TGF-β1 in presence and absence of pharmacologic inhibitors for various signaling pathways and phosphatases. Then, COX-2 protein expression, as well as P38MAPK, AKT and TAU phosphorylation levels were evaluated by western blot analysis., Results: TGF-β1 induction of COX-2 protein levels was completely blocked by pharmacologic inhibitors of phosphatases, P38 MAPK, or NF-қB pathways. Time course experiments showed that TGF-β1 activated p38 MAPK after 5 min of stimulation. Interestingly, podocyte co-incubated with TGF-β1, high glucose and/or PGE2 showed strong increase in p38 MAPK and AKT phosphorylation as well as COX- 2 protein expression levels. Levels of phosphorylated AKT were further reduced and levels of phosphorylated p38 were increased when PGE2 was added to the culture media. Interestingly, selective phosphatases inhibitors completely abrogated PGE2-induced P38 MAPK and TAU phosphorylation. Also, inhibition of phosphatases reversed TGF-β1-induced COX-2 protein expression either alone or when incubated with high glucose or PGE2., Conclusion: These data suggest TGF-β1 mediates its effect in podocyte through novel signaling mechanisms including phosphatases and TAU protein phosphorylation.

Aims: Laughter has been used for centuries to alleviate pain in morbid conditions. It was not until 1976 that scientists thought about laughter as a form of therapy that can modulate hormonal and immunological parameters that affect the outcome of many serious diseases. Moreover, laughter therapy was shown to be beneficial in type 2 diabetes mellitus (T2DM) by delaying the onset of many diabetic complications. Laughter is also described to influence the cardiovascular and endothelial functions and thus may protect against diabetic cardiovascular complications. In this review, we outline the different biochemical, physiological and immunological mechanisms by which laughter may influence the overall state of wellbeing and enhance disease prognosis. We also focus on the biological link between laughter therapy and diabetic cardiovascular complications as well as the underlying mechanisms involved in T2DM., Methods: Reviewing all the essential databases for "laughter" and "type 2 diabetes mellitus"., Results: Although laughter therapy is still poorly investigated, recent studies show that laughter may retard the onset of diabetic complications, enhance cardiovascular functions and rectify homeostatic abnormalities associated with T2DM., Conclusions: Laughter therapy is effective in delaying diabetic complications and should be used as an adjuvant therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sphingolipids, long thought to be passive components of biological membranes with merely a structural role, have proved throughout the past decade to be major players in the pathogenesis of many human diseases. The study and characterization of several genetic disorders like Fabry's and Tay Sachs, where sphingolipid metabolism is disrupted, leading to a systemic array of clinical symptoms, have indeed helped elucidate and appreciate the importance of sphingolipids and their metabolites as active signaling molecules. In addition to being involved in dynamic cellular processes like apoptosis, senescence and differentiation, sphingolipids are implicated in critical physiological functions such as immune responses and pathophysiological conditions like inflammation and insulin resistance. Interestingly, the kidneys are among the most sensitive organ systems to sphingolipid alterations, rendering these molecules and the enzymes involved in their metabolism, promising therapeutic targets for numerous nephropathic complications that stand behind podocyte injury and renal failure., Competing Interests: The authors declare no conflict of interest.

The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days. Blood pressure (BP) was measured by tail-cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L-NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor, DIC), and preconstricted with phenylephrine. CSA (25mgkg -1 day -1 for 7days) increased BP and augmented carbachol renal vasodilations. The co-treatment with verapamil (2mgkg -1 day -1 ) or nifedipine (3mgkg -1 day -1 ) abolished CSA hypertension and conversely affected carbachol vasodilations (increases vs. decreases). Infusion of MSPPOH (epoxyeicosatrienoic acids, EETs, inhibitor) reduced carbachol vasodilations in kidneys of all rat groups, suggesting the importance of EETs in these responses. By contrast, 20-Hydroxyeicosatetraenoic Acid (20-HETE) inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared by CSA treatment, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. Renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs/20-HETE) were increased in CSA-treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20-HETE effects were reduced by either CCB. Overall, nifedipine and verapamil blunts CSA hypertension but variably affected concomitantly enhanced EDHF-dependent renal vasodilations and alterations in CYP2C/CYP4A signaling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Traumatic brain injury is a detrimental medical condition particularly when accompanied by diabetes. There are several comorbidities going along with diabetes including, but not limited to, kidney failure, obesity, coronary artery disease, peripheral vascular disease, hypertension, stroke, neuropathies and amputations. Unlike diabetes type 1, diabetes type 2 is more common in adults who simultaneously suffer from other comorbid conditions making them susceptible to repetitive fall incidents and sustaining head trauma. The resulting brain insult exacerbates current psychiatric disorders such as depression and anxiety, which, in turn, increases the risk of sustaining further brain traumas. The relationship between diabetes, traumatic brain injury and psychiatric health constitutes a triad forming a non-reversible vicious cycle. At the proteomic and psychiatric levels, cellular, molecular and behavioral alterations have been reported with the induction of non-traumatic brain injury in diabetic models such as stroke. However, research into traumatic brain injury has not been systematically investigated. Thus, in cases of diabetic neuropathy complicated with traumatic brain injury, utilizing fine structural and analytical techniques allows the identification of key biological markers that can then be used as innovative diagnostics as well as novel therapeutic targets in an attempt to treat diabetes and its sequelae especially those arising from repetitive mild brain trauma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Enzymes may offer great potentials in topical pharmaceutical applications provided that treatment conditions are controlled for efficacy and safety. In this study, the effect of alkaline protease produced by recombinant Bacillus subtilis cells on the ex-vivo permeability of rabbit ear skin was investigated under different conditions of enzyme activity (5-60 units) and exposure time (15-60min). Data for transepidermal water loss (TEWL) and permeation of a hydrophilic dye, rhodamine B (Rb), indicated biphasic activity-dependent and exposure time-dependent skin permeability. Maximum effects were obtained at 20 proteolytic units and 30min exposure. Findings proved consistent with histopathological changes indicating progressive stratum corneum (SC) loss and disruption of the dermo-epidermal junction at 20 units and up to 30min exposure time followed by dermal hyalinization at longer exposure. This was associated with progressive loss of skin hair. Applying the identified pretreatment conditions to transdermal delivery of vardenafil in a gel base across dorsal rat skin indicated a significant increase in plasma levels at 30 and 60min with minimal histopathological changes 5days post enzyme treatment. Accordingly, the recombinant B. subtilis alkaline protease offers promise as a pharmaceutical enzyme for transdermal drug delivery bioenhancement and dermatological applications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: Paraquat (PQT), a redox-active herbicide, is a free radical-producing molecule, causing damage particularly to the nervous system; thus, it is employed as an animal model for Parkinson's disease. However, its impact on peripheral nerve demyelination is still unknown. Our aim is to decipher the influence of PQT-induced reactive oxygen species (ROS) production on peripheral myelin., Results: We report that PQT provokes severe locomotor and sensory defects in mice. PQT elicited an oxidative stress in the nerve, resulting in an increase of lipid peroxidation and protein carbonylation, despite the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant defenses. We observed a dramatic disorganization of myelin sheaths in the sciatic nerves, dysregulation of myelin gene expression, and aggregation of myelin proteins, a hallmark of demyelination. PQT altered myelin gene expression via liver X receptor (LXR) signaling, a negative regulator of peripheral myelin gene expression through its dialog with the Wnt/β-catenin pathway. PQT prevented β-catenin binding on myelin gene promoters, resulting in the inhibition of Wnt/β-catenin-dependent myelin gene expression. Wnt pathway activation by LiCl dampened the deleterious effects of PQT. LiCl blocked PQT-induced oxidative stress and reduced Schwann cell death. LiCl+PQT-treated mice had normal sensorimotor behaviors and a usual nerve structure., Innovation: We reveal that PQT damages the sciatic nerve by generating an oxidative stress, dysregulating LXR and Wnt/β-catenin pathways. The activation of Wnt signaling by LiCl reduced the deleterious effects of PQT on the nerve., Conclusion: We demonstrate that PQT instigates peripheral nerve demyelinating neuropathies by enhancing ROS production and deregulating LXR and Wnt pathways. Stimulating Wnt pathway could be a therapeutic strategy for neuropathy treatment. Antioxid. Redox Signal. 27, 168-183.

Objectives: To define the learning curve of laparoendoscopic single-site surgery (LESS) of an experienced laparoscopist., Patients and Methods: Patients who had LESS, since its implementation in December 2009 until December 2014, were retrospectively analysed. Procedures were divided into groups of 10 and scored according to the European Scoring System for Laparoscopic Operations in Urology. Different LESS indications were done by one experienced laparoscopist. Technical feasibility, surgical safety, outcome, as well as the number of patients required to achieve professional competence were assessed., Results: In all, 179 patients were included, with mean (SD) age of 36.3 (17.5) years and 25.4% of the patients had had previous surgeries. Upper urinary tract procedures were done in 65.9% of patients and 54.7% of the procedures were extirpative. Both transperitoneal and retroperitoneal LESS were performed in 92.8% and 7.2% of the patients, respectively. The intraoperative and postoperative complication rates were 2.2% and 5.6% (Clavien-Dindo Grade II 3.9% and IIIa 1.7%), respectively. In all, 75% of intraoperative complications and all conversions were reported during the first 30 LESS procedures; despite the significantly higher difficulty score in the subsequent LESS procedures. One 5-mm extra port, conversion to conventional laparoscopy and open surgery was reported in 14%, 1.7%, and 1.1% of the cases, respectively. At mean (SD) follow-up of 39.7 (11.4) months, all the patients that underwent reconstructive LESS procedures but one were successful., Conclusion: In experienced hands, at least 30 LESS procedures are required to achieve professional competence. Although difficult, both conversion and complication rates of LESS are low in experienced hands.

Association of hepatitis C virus (HCV) with autoimmune phenomena and impaired semen parameters has been previously reported. The aim of this study was to investigate the influence of HCV infection on the development of antisperm antibodies (ASAs) in HCV-positive males. The study was conducted on 30 HCV-infected individuals and 30 healthy control subjects. In both patients and control groups, liver enzymes and reproductive hormones were measured; computer-assisted semen analysis (CASA) was performed; HCV-RNA in serum was measured and IgG and IgA ASAs in semen were determined. Free testosterone, sperm concentration, progressive and total motility were significantly lower in HCV patients than in the control group, whereas ASAs of the IgG and IgA classes were significantly higher in HCV patients. However, correlations between viral load and the examined semen parameters and ASAs were nonsignificant. In conclusion, HCV may be responsible for the increased ASAs detected in HCV patients in the present study, possibly providing another plausible explanation for the decreased sperm motility reported in HCV patients. These findings could be of value in fertility management of HCV patients., (© 2016 Blackwell Verlag GmbH.)

Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.

Aim: Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. We explored the hypothesis that mammalian target of rapamycin complex 2 (mTORC2) mediates podocyte injury in diabetes., Results: High glucose (HG)-induced podocyte injury reflected by alterations in the slit diaphragm protein podocin and podocyte depletion/apoptosis. This was paralleled by activation of the Rictor/mTORC2/Akt pathway. HG also increased the levels of Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using small interfering RNA (siRNA)-targeting Rictor in vitro decreased HG-induced Nox1 and Nox4, NADPH oxidase activity, restored podocin levels, and reduced podocyte depletion/apoptosis. Inhibition of mTORC2 had no effect on mammalian target of rapamycin complex 1 (mTORC1) activation, described by our group to be increased in diabetes, suggesting that the mTORC2 activation by HG could mediate podocyte injury independently of mTORC1. In isolated glomeruli of OVE26 mice, there was a similar activation of the Rictor/mTORC2/Akt signaling pathway with increase in Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using antisense oligonucleotides targeting Rictor restored podocin levels, reduced podocyte depletion/apoptosis, and attenuated glomerular injury and albuminuria., Innovation: Our data provide evidence for a novel function of mTORC2 in NADPH oxidase-derived reactive oxygen species generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes., Conclusion: mTORC2 and/or NADPH oxidase inhibition may represent a therapeutic modality for diabetic kidney disease. Antioxid. Redox Signal. 25, 703-719., Competing Interests: Author Disclosure Statement No competing financial interests exist.

Background: There is strong evidence for an autoimmune etiology of alopecia areata (AA). Interleukin-17A (IL-17A) is a Th17 proinflammatory cytokine that has been linked to the pathogeneses of diverse autoimmune and inflammatory diseases., Objectives: This study aimed to measure serum IL-17A in AA patients and to study associations between IL-17A levels and AA severity, duration, and age of onset, and patient gender and age., Methods: The study enrolled 39 AA patients and 37 healthy control subjects. Scalp involvement was assessed using the Severity of Alopecia Tool (SALT), and clinical disease severity was determined. Serum IL-17A was measured using ELISAs., Results: Serum IL-17A was significantly higher in AA patients than in control subjects (P < 0.001). Correlations between serum IL-17A and gender, disease duration, SALT score, and disease severity were non-significant. Serum IL-17A was significantly higher in patients aged ≤30 years than in patients aged >30 years (P = 0.045). Age and serum IL-17A were significantly negatively correlated in patients with AA (rs = -0.363, P = 0.023) but not in control subjects (rs = -0.294, P = 0.077). Patients with juvenile-onset AA had significantly higher IL-17A levels than those with maturity-onset disease (P = 0.034). There was a significant negative correlation between age at disease onset and serum IL-17A (rs = -0.349, P = 0.029)., Conclusions: It is possible that IL-17A plays a role in the pathogenesis of AA. Serum IL-17A may be influenced by patient age and age of onset of AA but does not seem to influence disease severity., (© 2015 The International Society of Dermatology.)

Objective: To investigate the effect of chronic daily administration of different doses of tadalafil on the structure of the seminiferous tubules and on spermatogenesis., Materials and Methods: Sixty adult male Wistar rats were included; they were divided into four groups: a control group (group I) and groups II, III, and IV that received daily tadalfil in doses of 0.45, 0.9, and 1.8 mg/kg for 12 weeks (equivalent to human doses of 5, 10, and 20 mg daily), respectively. The epididymis was processed for evaluation of sperm parameters, serum testosterone was measured, Johnsen score for rats was calculated, and testicular histopathological and ultrastructural examinations were performed., Results: Serum testosterone was significantly lower in group IV than in groups I and II. Moreover, posttreatment values in group IV were significantly lower than pretreatment values. A significant decline in sperm motility and morphology was detected in groups III and IV compared to groups I and II. Sperm count was significantly lower in group IV compared to the other groups. Johnsen score was significantly lower in groups III and IV compared to groups I and II and in group IV compared to group III. In addition, histopathological and ultrastructural degenerative changes in rat testes were detected; these changes were dose dependent and increased with increasing the dose of tadalafil., Conclusion: Chronic daily oral administration of tadalafil to male albino rats demonstrates a dose-dependent alteration to testicular histology and semen parameters. The influence of these changes on the actual fertility of these animals remains to be determined., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We report herein the synthesis of a novel series of carbocyclic acylhydrazone derivatives of uracil, thymine and cytosine from the corresponding nucleic bases and their biological activity to treat diabetic nephropathy. Intriguingly, five derivatives significantly reduced high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. The anti-oxidative effects displayed by these molecules suggest that their activity might involve a ROS-dependent mechanism., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Endometriosis is defined as endometriotic tissue growing outside the uterine cavity. It is a common gynecological disorder in women of reproductive age and is associated with chronic pelvic pain and infertility. Despite several studies and theories to explain its cause, the exact pathogenesis of endometriosis remains unclear. Retrograde menstruation is the most plausible theory, however, it is not exclusive. The disparity between the actual prevalence of retrograde menstruation and the prevalence of endometriosis suggests that other factors may determine the susceptibility to endometriosis development. Oxidative stress has been associated with endometriosis. This study aimed to explore the role of NADPH oxidase family in the production of reactive oxygen species (ROS) and to determine whether ROS induce the proliferation of endometriotic implants via mammalian target of rapamycin (mTOR) signaling. Anonymous endometriotic tissue samples were collected from women undergoing laparoscopy for endometriosis. The samples were stained with dihydroethidium and fluorescent images of the slides were taken to detect ROS production. After extraction of RNA from the samples and c-DNA generation, quantitative real-time PCR, protein extraction and Western blot were performed to study gene and protein expression of NADPH oxidase 1 (NOX 1), mTOR and fibronectin. The results showed an increase in ROS levels and NOX 1 gene and protein expression in the endometriotic tissues compared to the normal surrounding tissue control. Also, mTOR and fibronectin, gene expression was found to be increased. Up regulation of NOX at gene and protein level leads to increased production of ROS in the endometriotic tissue, which in turn causes proliferation of the ectopic tissue via alteration of the mTOR signaling pathway. Increased fibronectin gene expression points towards tissue injury in endometriosis as compared to the normal surrounding tissue. This manuscript adds a new insight into the pathogenesis of endometriosis and serves as a background for development of new treatments for the disease-associated pain and infertility.

Despite dramatic improvements in short-term mortality rates following myocardial infarction (MI), long-term survival for MI patients who progress to heart failure remains poor. MI occurs when the left ventricle (LV) is deprived of oxygen for a sufficient period of time to induce irreversible necrosis of the myocardium. The LV response to MI involves significant tissue, cellular, and molecular level modifications, as well as substantial hemodynamic changes that feedback negatively to amplify the response. Inflammation to remove necrotic myocytes and fibroblast activation to form a scar are key wound healing responses that are highly variable across individuals. Few biomarkers of early remodeling stages are currently clinically adopted. The discovery of underlying pathophysiological mechanisms and associated novel biomarkers has the potential of improving prognostic capability and therapeutic monitoring. Combining these biomarkers with other prominent ones could constitute a powerful diagnostic and prognostic tool that directly reflects the pathophysiological remodeling of the LV. Understanding temporal remodeling at the tissue, cellular, and molecular level and its link to a well-defined set of biomarkers at early stages post-MI is a prerequisite for improving personalized care and devising more successful therapeutic interventions. Here we summarize the integral mechanisms that occur during early cardiac remodeling in the post-MI setting and highlight the most prominent biomarkers for assessing disease progression.

Germ cell apoptosis has been proposed as one of the mechanisms by which varicocele can influence fertility. The aim of this study was to investigate the relationship between seminal tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels and male infertility in patients with varicocele. This study included 112 males: 30 fertile males with varicocele, 44 infertile males with varicocele and 38 healthy fertile control subjects without varicocele. Semen analysis was performed, and serum levels of reproductive hormones were measured. Seminal TRAIL levels in the infertile varicocele group were significantly higher than in the fertile varicocele and the control groups (P = 0.014). A significant negative correlation was found between seminal TRAIL and progressive (P < 0.001) and total motility scores (P < 0.001) in the infertile varicocele group. A significant negative correlation was also detected between seminal TRAIL levels and normal sperm morphology in the fertile varicocele (P = 0.007) and infertile varicocele patients (P = 0.047). Seminal TRAIL was significantly correlated with varicocele grade whether the patients were fertile (P = 0.001) or infertile (P = 0.035). Seminal TRAIL may thus have a potential role in varicocele-associated male infertility through its negative effect on sperm motility and morphology., (© 2014 Blackwell Verlag GmbH.)

Cyclooxygenases (COXs) are important membrane-bound heme containing enzymes important in platelet activation and inflammation. COX-1 is constitutively expressed in most cells whereas COX-2 is an inducible isoform highly expressed in inflammatory conditions. Studies have been carried out to evaluate thiazole derivatives as anti-inflammatory molecules. In this study, we investigated the in vitro and in vivo effects of two novel thiazole derivatives compound 1 (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl] acetamide) and compound 2 (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol) on prostaglandin E2 (PGE2) production and COX activity in inflammatory settings. Our results reveal a potent inhibition of both compound 1 (IC50 9.01±0.01µM) and 2 (IC50 11.65±6.20µM) (Mean±S.E.M.) on COX-2-dependent PGE2 production. We also determined whether COX-1 activity was inhibited. Using cells stably over-expressing COX-1 and human blood platelets, we showed that compound 1 is a specific inhibitor of COX-1 with IC50 (5.56×10(-8)±2.26×10(-8)µM), whereas compound 2 did not affect COX-1. Both compounds exhibit anti-inflammatory effect in the dorsal air pouch model of inflammation as shows by inhibition of PGE2 secretion. Modeling analysis of docking in the catalytic site of COX-1 or COX-2 further confirmed the difference in the effect of these two compounds. In conclusion, this study contributes to the design of new anti-inflammatory agents and to the understanding of cyclooxygenase inhibition by thiazole., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: Two distinguishable subclades of H5N1 (classic and variant strains) are cocirculating among the poultry populations in Egypt despite the intensive vaccination programs. A study to investigate the genetic relationship between avian influenza virus (AIV) isolates from backyard chickens in Sharkia (2009-2011), subclades, and commercially available vaccines was carried out., Methods: Forty-eight suspected AIV infected birds were clinically examined and used for virus isolation followed by reverse transcription-polymerase chain reaction. Four H5N1 virus isolates were sequenced and analyzed. The intravenous pathogenicity index (IVPI) of three AIV isolates was determined., Results: Thirty-four hemagglutinating viral agents (30 AIV subtype H5N1 and 4 Newcastle disease virus) were detected. Both the nucleotide and amino acid sequence identities of four H5N1 virus isolates (SHZA-0412/2009, SHZA-0801/2010, SHMK-1903/2010, and SHAH-1403/2011) were high--98.4-99.7% and 100%, respectively--indicative of their genetic homogeneity. The hemagglutinin cleavage site characterization revealed the presence of multiple basic amino acids (-PQRERRRKKR/GL-) of the highly pathogenic phenotype. These results were supported by IVPI in chickens of 2.69-2.90. The similarity of our isolates with H5N1 AIV vaccine strains (93.9-95.1%) was higher than that with H5N2 strains (77.8-91.9%). The divergence of four sequences with classic and variant lineages is 2-2.7% and 2.3-3%, respectively, with two amino acid substitutions (A249P and N251Y)., Conclusion: Genetic characterization and IVPI data of backyard H5N1 isolates are indicative of a highly pathogenic avian influenza virus with hemagglutinin cleavage site constancy and two amino acids substitutions with Egyptian classic and variant lineages, suggesting a beginning of antigenic drift., (Copyright © 2013. Published by Elsevier B.V.)

Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

Objectives: The present study examined the quality of obturation in root canals obturated by GuttaCore, a gutta-percha-based core-carrier system with a cross-linked thermoset gutta-percha carrier, by comparing the incidence of gaps and voids identified from similar canals obturated by cold lateral compaction or warm vertical compaction., Methods: Thirty single-rooted premolars with oval-shaped canals were shaped and cleaned, and obturated with one of the three obturation techniques (N=10): GuttaCore, warm vertical compaction or cold lateral compaction. Filled canals were scanned with micro-computed tomography (micro-CT); reconstructed images were analysed for the volumetric percentage of gaps and voids at three canal levels (0-4mm, 4-8mm and 8-12mm from working length). The roots were subsequently sectioned at the 4-mm, 8-mm and 12-mm levels for analyses of the percentage of interfacial gaps, and area percentage of interfacial and intracanal voids, using scanning electron microscopy (SEM) to examine negative replicas of root sections. Data were analysed with parametric or non-parametric statistical methods at α=0.05., Results: Both micro-CT and SEM data indicated that canals obturated with GuttaCore core-carriers had the lowest incidence of interfacial gaps and voids, although the results were not significantly different from canals obturated by warm vertical compaction. Both the GuttaCore and the warm vertical compaction groups, in turn, had significantly lower incidences of gaps and voids than the cold lateral compaction group., Conclusions: Because of the similarity in obturation quality between GuttaCore and warm vertical compaction, practitioners may find the GuttaCore core-carrier technique a valuable alternative for obturation of oval-shaped canals., Clinical Significance: The quality of obturation achieved by GuttaCore in single-rooted canals is not significantly different from that achieved by warm vertical compaction., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Tricalcium silicate cements have been successfully employed in the biomedical field as bioactive bone and dentin substitutes, with widely acclaimed osteoactive properties. This research analyzed the effects of different tricalcium silicate cement formulations on the temporal osteoactivity profile of human bone marrow-derived mesenchymal stem cells (hMW-MSCs). These cells were exposed to four commercially available tricalcium silicate cement formulations in osteogenic differentiation medium. After 1, 3, 7 and 10 days, quantitative real-time polymerase chain reaction and Western blotting were performed to detect expression of the target osteogenic markers ALP, RUNX2, OSX, OPN, MSX2 and OCN. After 3, 7, 14 and 21 days, alkaline phosphatase assay was performed to detect changes in intracellular enzyme level. An Alizarin Red S assay was performed after 28 days to detect extracellular matrix mineralization. In the presence of tricalcium silicate cements, target osteogenic markers were downregulated at the mRNA and protein levels at all time points. Intracellular alkaline phosphatase enzyme levels and extracellular mineralization of the experimental groups were not significantly different from the untreated control. Quantitative polymerase chain reaction results showed increases in downregulation of RUNX2, OSX, MSX2 and OCN with increasing time of exposure to the tricalcium silicate cements, while ALP showed peak downregulation at day 7. For Western blotting, OSX, OPN, MSX2 and OCN showed increased downregulation with increased exposure time to the tested cements. Alkaline phosphatase enzyme levels generally declined after day 7. Based on these results, it is concluded that tricalcium silicate cements do not induce osteogenic differentiation of hBM-MSCs in vitro., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

New obturation biomaterials have been introduced over the past decade to improve the seal of the root canal system. However, it is not clear whether they have really produced a three-dimensional impervious seal that is important for reducing diseases associated with root canal treatment. A review of the literature was performed to identify models that have been employed for evaluating the seal of the root canal system. In vitro and in vivo models are not totally adept at quantifying the seal of root canals obturated with classic materials. Thus, one has to resort to clinical outcomes to examine whether there are real benefits associated with the use of recently introduced materials for obturating root canals. However, there is no simple answer because endodontic treatment outcomes are influenced by a host of other predictors that are more likely to take precedence over the influence of obturation materials. From the perspective of clinical performance, classic root filling materials have stood the test of time. Because many of the recently introduced materials are so new, there is not enough evidence yet to support their ability to improve clinical performance. This emphasizes the need to translate anecdotal information into clinically relevant research data on new biomaterials., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: MTA Plus is a new calcium silicate cement with unknown cytotoxicity characteristics. The objectives of this study were to examine the effect of MTA Plus on the viability, apoptosis/necrosis profile, and oxidative stress levels of rat odontoblast-like cells., Methods: MDPC-23 cells were exposed to gray and white MTA Plus (GMTAP, WMTAP), gray and white ProRoot MTA (GMTA, WMTA) cements, or their eluents. The cells were evaluated for (1) cell viability by using XTT assay, (2) apoptosis/necrosis by using flow cytometry and confocal laser scanning microscopy, and (3) oxidative stress by measuring reactive oxygen species., Results: XTT assay showed that all test cements exhibited marked initial cytotoxicity that decreased with time. By the end of the third week, GMTAP and GMTA were comparable to untreated cells (negative control) in terms of cell viability, whereas WMTAP and WMTA were significantly lower than the untreated cells. Apoptosis/necrosis profiles of cells exposed to WMTAP and GMTAP were not significantly different from untreated cells, whereas cells exposed to WMTA and GMTA showed significantly less viable cells. All experimental groups exhibited reduction of intracellular reactive oxygen species formation compared with untreated cells, although cells exposed to WMTA were not significantly different from untreated cells., Conclusions: Both the gray and white versions of MTA Plus possess negligible in vitro cytotoxic risks that are time and dilution dependent. They enrich the spectrum of hydraulic calcium silicate cements currently available to clinicians for endodontic applications., (Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)