Montelukast Influence on Lung in Experimental Diabetes.

Background and Objectives: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. Materials and Methods: The study was conducted on four groups of six adult male Wistar rats. Diabetes was produced by administration of streptozotocin 65 mg/kg ip. in a single dose. Before the administration of streptozotocin, after 72 h, and after 8 weeks, the serum values of glucose, SOD, MDA, and total antioxidant capacity (TAS) were determined. After 8 weeks, the animals were anesthetized and sacrificed, and the lungs were harvested and examined by optical microscopy. Pulmonary fibrosis, the extent of lung lesions, and the lung wet-weight/dry-weight ratio were evaluated. Results: The obtained results showed that MK significantly reduced pulmonary fibrosis (3.34 ± 0.41 in the STZ group vs. 1.73 ± 0.24 in the STZ+MK group p < 0.01) and lung lesion scores and also decreased the lung wet-weight/dry-weight (W/D) ratio. SOD and TAS values increased significantly when MK was administered to animals with diabetes (77.2 ± 11 U/mL in the STZ group vs. 95.7 ± 13.3 U/mL in the STZ+MK group, p < 0.05, and 25.52 ± 2.09 Trolox units in the STZ group vs. 33.29 ± 1.64 Trolox units in the STZ+MK group, respectively, p < 0.01), and MDA values decreased. MK administered alone did not significantly alter any of these parameters in normal animals. Conclusions: The obtained data showed that by blocking the action of peptide leukotrienes on cysLT1 receptors, montelukast significantly reduced the lung lesions caused by diabetes. The involvement of these leukotrienes in the pathogenesis of fibrosis and other lung diabetic lesions was also demonstrated.

Montelukast influence on kidney in experimental induced diabetes mellitus.

Leukotrienes are important icosanoids group involved in a lot of normal and pathological states. Montelukast (MK) is a selective cysteinyl leukotriene receptor (Cys LT1) antagonist. Purpose. The purpose of the study is to observe the influence of MK on renal damage caused by experimental diabetes in rats. The experiment was carried out on four groups of adult male Wistar rats. Lot I was a witness and received 1.5ml of physiological saline ip. in unique dose on the first day of the experiment. Lots II and III have been caused experimental diabetes by streptozotocin (STZ) administration of 60mg/kg ip. in the unique dose. Lot III also received MK daily 10mg/kg/day daily 8weeks.Lot IV received only MK 10mg/kg/day daily 8 weeks. After eight weeks all animals were anesthetized and were sacrificed. The following pathological modifications were observed: tubular injury, glomerular hypertrophy and lesions, leukocytes infiltration. Obtained data showed that MK has significantly reduced the intensity of glomerular lesions (score 3.50+/-0.21 in STZ lot vs. 2.50+/-0.17 in STZ+MK lot p<0.01) and tubular damages. Renal interstitial leukocyte infiltration in animals with diabetes has been also reduced by MK. MK has a partially protective action against the lesions produced by experimental diabetes.

The Involvement of Smooth Muscle, Striated Muscle, and the Myocardium in Scleroderma: A Review.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by heterogeneous changes involving numerous organs and systems. The currently available data indicate that muscle injury (both smooth and striated muscles) is widespread and leads to significant morbidity, either directly or indirectly. From the consequences of smooth muscle involvement in the tunica media of blood vessels or at the level of the digestive tract, to skeletal myopathy (which may be interpreted strictly in the context of SSc, or as an overlap with idiopathic inflammatory myopathies), muscular injury in scleroderma translates to a number of notable clinical manifestations. Heart involvement in SSc is heterogenous depending on the definition used in the various studies. The majority of SSc patients experience a silent form of cardiac disease. The present review summarizes certain important features of myocardial, as well as smooth and skeletal muscle involvement in SSc. Further research is needed to fully describe and understand the pathogenic pathways and the implications of muscle involvement in scleroderma.

Skin Dialogues in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic skin disorder associated with significant quality-of-life impairment and increased risk for allergic and non-allergic comorbidities. The aim of this review is to elucidate the connection between AD and most common comorbidities, as this requires a holistic and multidisciplinary approach. Advances in understanding these associations could lead to the development of highly effective and targeted treatments.

Aqueous Humor Cytokines in Non-Proliferative Diabetic Retinopathy.

Background and Objectives: Cytokines are cell-signaling proteins whose identification may serve as inflammatory markers or early indicators for progressive disease. The aim of our study was to quantify several cytokines in aqueous humor (AH) and their correlations with biochemical parameters in diabetic eyes with non-proliferative diabetic retinopathy (NPDR). Materials and Methods: A total of 62 eyes from 62 patients were included in the study: 37 eyes from nondiabetic patients (group 1), 13 diabetic eyes with no retinopathy changes (group 2) and 12 diabetic eyes with early and moderate NPDR (group 3). AH samples were collected during uneventful cataract surgery. The cytokines IL-1ß, IL-6, IL-8, IL-10, IL-12, IP-10, MCP-1, TNF-α and VEGF were quantified using multiplex bead-based immunoassay. Due to unreliable results, IL-1ß, TNF-α, IL-10 and IL-12 were excluded. Concentrations were compared between groups. Biochemical parameters (fasting blood sugar, glycated hemoglobin, C-reactive protein) and the duration of diabetes were recorded. Results: VEGF levels were significantly different between groups (p = 0.001), while levels of IL-6, IL-8, IP-10 and MCP-1 were comparable across all groups (p > 0.05). IL-6 concentration correlated with VEGF in group 1 (rho = 0.651, p = 0.003) and group 3 (rho = 0.857, p = 0.007); no correlation could be proved between IL-6, IL-8, IP-10, MCP-1 or VEGF and biochemical parameters. Duration of diabetes was not correlated with the cytokine levels in groups 2 and 3. The receiver operating characteristic (ROC) curve revealed that VEGF concentrations could discriminate early and moderate NPDR from diabetes, with an area under the curve (AUC) of 0.897 (p = 0.001, 95% CI = 0.74−1.0). Conclusions: Diabetes mellitus induces significant intraocular changes in the VEGF expression in diabetic patients vs. normal subjects, even before proliferative complications appear. VEGF was increasingly expressed once the diabetes progressed from no retinopathy to early or moderate retinopathy.

Choroidal Assessment in Patients with Type 2 Diabetes Mellitus and Non-Proliferative Diabetic Retinopathy by Swept-Source Ocular Coherence Tomography and Image Binarization.

Background and Objectives: The aim of this study was to evaluate choroidal structure and vascularity indices in patients with non-proliferative diabetic retinopathy (NPDR). Materials and Methods: Sixty-three eyes from sixty-three patients were evaluated: 21 from healthy subjects, 20 with diabetes mellitus (DM) and no diabetic retinopathy (DR), and 22 with DM and non-proliferative diabetic retinopathy without diabetic macular edema (DME). Each patient underwent ocular examination, macular swept-source ocular coherence tomography (SS-OCT) imaging, glycemic control, and systemic high blood pressure (HBP) evaluation. Subfoveal choroidal thickness (SF-CT) was manually assessed on a line scan. Line scan OCT images were exported to ImageJ program. The areas under a 1.5, 3 and 6 mm horizontal line centered on the fovea were assessed by converting the OCT images to binary images, and total choroidal area (TCA), luminal area (LA), stromal area (SA), LA:SA ratio, and choroidal vascularity index (CVI) were evaluated. SF-CT and choroidal parameters were compared between groups, and correlations with ocular and systemic factors were analyzed. Results: SF-CT, TCA, LA, and SA were similar between groups. CVIs were significantly different between groups for all three studied areas (CVI-1.5: 66.21% vs. 66.06% vs. 63.74%, p = 0.003; CVI-3: 65.88% vs. 66.46% vs. 63.79%, p = 0.008; CVI-6: 64.79% vs. 65.40% vs. 63.61%, p = 0.032). NPDR patients had significantly lower CVIs compared to DM patients (p < 0.05). No association of choroidal parameters with glycemic control, DM duration and HBP was found significant (p < 0.05). Conclusions: Choroidal assessment by SS-OCT and image binarization in healthy subjects, subjects with DM without DR, and subjects with DM and NPDR indicated that CVI changes were identifiable and significant in early DR. The lack of association with ocular and systemic factors suggest that CVIs are reliable assessment parameters of choroidal vascular structure.

Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms.

Kaposi's sarcoma is a rare disease with four known variants: classic, epidemic, endemic and iatrogenic (transplant-related), all caused by an oncogenic virus named Human Herpes Virus 8. The viral infection in itself, along with the oncogenic properties of HHV8 and with immune system dysfunction, forms the grounds on which Kaposi's Sarcoma may develop. Infection with HHV8 occurs through saliva via close contacts, blood, blood products, solid organ donation and, rarely, vertical transmission. Chronic inflammation and oncogenesis are promoted by a mix of viral genes that directly promote cell survival and transformation or interfere with the regular cell cycle and cell signaling (of particular note: LANA-1, v-IL6, vBCL-2, vIAP, vIRF3, vGPCR, gB, K1, K8.1, K15). The most common development sites for Kaposi's sarcoma are the skin, mucocutaneous zones, lymph nodes and visceral organs, but it can also rarely appear in the musculoskeletal system, urinary system, endocrine organs, heart or eye. Histopathologically, spindle cell proliferation with slit-like vascular spaces, plasma cell and lymphocyte infiltrate are characteristic. The clinical presentation is heterogenic depending on the variant; some patients have indolent disease and others have aggressive disease. The treatment options include highly active antiretroviral therapy, surgery, radiation therapy, chemotherapy, and immunotherapy. A literature search was carried out using the MEDLINE/PubMed, SCOPUS and Google Scholar databases with a combination of keywords with the aim to provide critical, concise, and comprehensive insights into advances in the pathogenic mechanism of Kaposi's sarcoma.

Idazoxan and Efaroxan Potentiate the Endurance Performances and the Antioxidant Activity of Ephedrine in Rats.

Background and objectives: The connections between the imidazoline system and multiple other neurotransmitter systems in the brain (adrenergic, dopaminergic, serotoninergic, glutamatergic, opioid) indicate the complexity of the mechanisms underlying motor activity and behavior. The aim of the present research was to investigate the effects of the combination of ephedrine (EPD) and imidazoline antagonists idazoxan (IDZ) and efaroxan (EFR) on the endurance performance in the treadmill test in rats. Materials and Methods: We used Wistar rats distributed as follows: Group 1 (Control) receiving distilled water 0.3 mL/100 g body weight; Group 2 (EPD) receiving 20 mg/kg ephedrine; Group 3 (EPD + IDZ) receiving 20 mg/kg ephedrine + 3 mg/kg idazoxan; Group 4 (EPD + EFR) receiving 20 mg/kg ephedrine + 1 mg/kg efaroxan. An additional group (C) of animals receiving 0.3 mL/100 g body weight distilled water (but not subjected) to effort was used. Endurance capacity was evaluated using a treadmill running PanLAB assay. The evaluation of the substances' influence on oxidative stress was performed by spectrophotometric determination of superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity. Results: Treatment with EPD-IDZ and EPD-EFR were correlated with a longer distance traveled on the belt and with a decrease in the necessary electric shocks to motivate the animal to continue running in the forced locomotion test. Additionally, an increase in the activity of antioxidant enzymes was found. Conclusions: Idazoxan and efaroxan potentiated the physical effort-related effects of ephedrine with regard to endurance capacity and antioxidant activity in rats.

Posterior choroidal boundary morphology and segmentation errors influence on choroidal thickness assessment in diabetic patients - a swept-source OCT study.

Objective: to evaluate the choroidal morphology and choroidal thickness (CT) in normal and diabetic subjects and to compare the differences between automated segmentation (AS) and manual segmentation (MS) of the choroid. Methods: in this observational cross-sectional study we included 48 eyes: 24 normal eyes (group 1), 9 eyes with DM without diabetic retinopathy (DR) (group 2) and 15 eyes with DM and DR (group 3). Swept-source OCT line scans images were analyzed for the presence of the suprachoroidal layer (SCL), choroidal morphology and the CT was measured manually subfoveal and at 750 µ both nasal and temporal to the fovea after AS and MS. SCL was not included in the CT evaluation. CT values were compared between the groups and between the three points of evaluation. Results: SCL was visualized in 21 eyes (43.8%). In diabetic patients, SCL was visible in 11 (45.83%) cases and in nondiabetic patients, in 10 eyes (41.66%). There was a good AS of Bruch's membrane, which was not further corrected manually. There were statistically significant differences between AS and MS at the level of CSJ for all three locations in all three groups (P ≤ 0.01). After MS, the choroid was statistically significantly thicker. Group 2 and group 3 showed a higher CT thickness. There were no statistically significant differences in the CT between groups in all three locations. Conclusions: Defining posterior choroidal boundary and the applied segmentation method can result in differences in CT measurements. Diabetic patients have altered CT and choroidal morphology. Abbreviations: CT = choroidal thickness, AS = automated segmentation, MS = manual segmentation, CSJ = choroidoscleral junction, SCL = suprachoroidal layer, SCS = suprachoroidal space, DM = diabetes mellitus, DR = diabetic retinopathy, RPE = retinal pigmented epithelium, BM = Buch's membrane.

Inactivity and Skeletal Muscle Metabolism: A Vicious Cycle in Old Age.

Aging is an inevitable and gradually progressive process affecting all organs and systems. The musculoskeletal system makes no exception, elderly exhibit an increased risk of sarcopenia (low muscle mass),dynapenia (declining muscle strength), and subsequent disability. Whereas in recent years the subject of skeletal muscle metabolic decline in the elderly has been gathering interest amongst researchers, as well as medical professionals, there are many challenges yet to be solved in order to counteract the effects of aging on muscle function efficiently. Noteworthy, it has been shown that aging individuals exhibit a decline in skeletal muscle metabolism, a phenomenon which may be linked to a number of predisposing (risk) factors such as telomere attrition, epigenetic changes, mitochondrial dysfunction, sedentary behavior (leading to body composition alterations), age-related low-grade systemic inflammation (inflammaging), hormonal imbalance, as well as a hypoproteic diet (unable to counterbalance the repercussions of the age-related increase in skeletal muscle catabolism). The present review aims to discuss the relationship between old age and muscle wasting in an effort to highlight the modifications in skeletal muscle metabolism associated with aging and physical activity.

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy.

Cannabis has been used in pain management since 2900 BC. In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs. Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed. In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography-mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed. In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.