Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-ß Activity.

Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-ß (TGF-ß) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-ß. In the current study, we examine the contribution of TGF-ß activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-ß expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFßRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-ß activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-ß.

Antifungal potency of Nigella sativa seeds extract against Rhizopus stolonifer and their effect of immunomodulatory against aflatoxin-fed mice.

The present study describes the antifungal potency of Nigella sativa seeds extract and the effect of immunomodulatory of N. sativa against aflatoxin- fed mice. Disc diffusion method was used for antifungal efficacy of aqueous extract of N. sativa. In animal experiments, lymphoid cell count, total and differential counts of PEC, the phagocytic activity of PEC and detection of the plaque-forming were determined. E-rosette-forming cells (RFC), T-cell mitogenesis assay cells, ALT and AST were detected. The aqueous extract of N. sativa (50%) exhibited high inhibition zone with most of isolates of R. stolonifera.The results indicated that treatment of mice by using N. sativa showed marked rise in the number of cells from thymus and PLN with dose 0.50 g and absolute number and comparative ratio of macrophages (P < 0.01) with the doses 0.40 and 0.50 g. There is gradually rise in the scavenger activity of PEC with the dose 0.50 g at 60 min. Serum level of ALT was markedly reduced with dose 0.50 g as compared with a control group. These results indicated that N. sativa is promising modifier of biological response.

Unveiling allelopathic dynamics and impacts of invasive Erigeron bonariensis and Bidens pilosa on plant communities and soil parameters.

Invasive alien species are becoming more and more prevalent worldwide, Erigeron bonariensis and Bidens pilosa are two invasive species of Asteraceae in Egypt. To mitigate their detrimental effects and understand their differences in invasiveness, we compared the allelopathic potentials of E. bonariensis and B. pilosa using leachates, decaying residues, and volatilization processes. Notably, the allelopathic variances in leachates were significant, influenced by plant types, concentrations, and response patterns of target plant traits, as indicated by EC50. The relative phytotoxicity of the invasive species decayed residues peaked between 20 and 25 days in the soil, with a positive correlation with concentrations and soil properties. The highest quantities of phenolic acids were chlorogenic acid and caffeic acid reaching (5.41 and 4.39 µg g-1) E. bonariensis and (4.53 and 4.46 µg g-1) B. pilosa, in leachates extracts respectively, while in the soil extract of decayed residues were coumaric acid and ferulic acid measuring (1.66 and 1.67 µg g-1) E. bonariensis and (1.47 and 1.57 µg g-1) B. pilosa, respectively. Using GC/MS analysis, the main volatile components in E. bonariensis were 1, 8 cineole (5.62%), and α-terpinene (5.43%) and iso-Caryophyllene (5.2%) which showed the greatest inhibitory effects. While B. pilosa main constituents were trans-sabinene (5.39%) and Camphene (5.11%), respectively. Finally, the high invasion level displayed from E. bonariensis (0.221) compared with B. pilosa (0.094) which correlated with the stronger allelopathic activities against plant species, and soil properties. Therefore, the allelopathic potentialities of these species are critically relevant to their invasion success.

Effect of Transcranial Direct Current Stimulation versus Virtual Reality on Gait for Children with Bilateral Spastic Cerebral Palsy: A Randomized Clinical Trial.

Impaired gait is a common sequela in bilateral spastic cerebral palsy. We compared the effects of two novel research interventions-transcranial direct current stimulation and virtual reality-on spatiotemporal and kinetic gait impairments in children with bilateral spastic CP. Forty participants were randomized to receive either transcranial direct current stimulation or virtual reality training. Both groups received standard-of-care gait therapy during the assigned intervention and for the subsequent 10 weeks afterward. Spatiotemporal and kinetic gait parameters were evaluated at three different times: (i) before starting the intervention, (ii) after two weeks of intervention, and (iii) 10 weeks after intervention completion. Both groups exhibited higher velocity and cadence, as well as longer stance time, step length, and stride length after intervention (p < 0.001). Only the transcranial direct current stimulation group exhibited increased maximum force and maximum peak pressure after intervention (p's ≤ 0.001), with continued improvements in spatiotemporal parameters at follow-up. The transcranial direct current stimulation group had higher gait velocities, stride length, and step length at follow-up compared to the virtual reality group (p ≤ 0.02). These findings suggest that transcranial direct current stimulation has a broader and longer-lasting effect on gait than virtual reality training for children with bilateral spastic cerebral palsy.

Priming of Citrullus lanatus var. Colocynthoides seeds in seaweed extract improved seed germination, plant growth and performance under salinity conditions.

Citrullus lanatus var. Colocynthoide "Gurum" is an unconventional crop that can be utilized as a new source of edible oil and has the ability to grow in a variety of harsh conditions. To mitigate the adverse effects of salinity on seed germination and plant performance of C. lanatus, seeds were primed in the aqueous extracts of the seaweed Ulva lactuca before planting under greenhouse conditions. The aqueous extract of U. lactuca at 8% w/v led to maximal seed germination percentage and seedling growth of C. lanatus. Moreover, U. lactuca extract counteracted the negative effects of salt stress on the plant by significantly increasing the activity of SOD, CAT, and POD. The bioactive components of U. lactuca, e.g. glycine betaine and phenolic compounds can account for such beneficial role of algal extract on C. lanatus. Thus, priming of C. lanatus seeds in U. lactuca extract with various concentrations of U. lactuca extract can be employed as an effective practice for successful seed germination, improved plant growth and enhanced salt resistance, probably as a result of increased antioxidant enzymes activity and photosynthetic pigments.

Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway.

Major depressive disorder (MDD) is a common, complex disease with poorly understood pathogenesis. Disruption of glucose metabolism is implicated in the pathogenesis of depression. AMP-activated protein kinase (AMPK) has been shown to regulate the activity of several kinases, including pAKT, p38MAPK, and mTOR, which are important signaling pathways in the treatment of depression. This study tested the hypothesis that rosiglitazone (RGZ) has an antidepressant impact on dexamethasone (DEXA)-induced depression by analyzing the function of the pAKT/p38MAPK/mTOR pathway and NGF through regulation of AMPK. MDD-like pathology was induced by subcutaneous administration of DEXA (20 mg/kg) for 21 days in all groups except in the normal control group, which received saline. To investigate the possible mechanism of RGZ, the protein expression of pAMPK, pAKT, p38MAPK, and 4EBP1 as well as the levels of hexokinase, pyruvate kinase, and NGF were assessed in prefrontal cortex and hippocampal samples. The activities of pAMPK and NGF increased after treatment with RGZ. The administration of RGZ also decreased the activity of mTOR as well as downregulating the downstream signaling pathways pAKT, p38MAPK, and 4EBP1. Here, we show that RGZ exerts a potent inhibitory effect on the pAKT/p38MAPK/mTOR/4EBP1 pathway and causes activation of NGF in brain cells. This study has provided sufficient evidence of the potential for RGZ to ameliorate DEXA-induced depression. A new insight has been introduced into the critical role of NGF activation in brain cells in depression. These results suggest that RGZ is a promising antidepressant for the treatment of MDD.

Effect of silver nanoparticles on tropane alkaloid production of transgenic hairy root cultures of Hyoscyamus muticus L. and their antimicrobial activity.

The utilization of nanotechnology and biotechnology for enhancing the synthesis of plant bioactive chemicals is becoming increasingly common. The hairy root culture technique can be used to increase secondary metabolites such as tropane alkaloids. Agrobacterium was used to induce hairy roots from various explants of Hyoscyamus muticus. The effect of nano-silver particles (AgNPs) at concentrations of 0, 25, 50, 100, and 200 mg/L on tropane alkaloids synthesis, particularly hyoscyamine and scopolamine, was studied in transgenic hairy root cultures. Different types of explants obtained from 10-day-old seedlings of H. muticus were inoculated with two strains of Agrobacterium rhizogenes (15,834 and A4). The antimicrobial activity of an ethanolic extract of AgNPs-induced hairy root cultures of H. muticus was tested. The frequency of hairy roots was higher in hypocotyl, root, leaf, and stem explants treated with A. rhizogenes strain A4 compared to those treated with strain 15,834. In transgenic hairy root cultures, AgNPs application at a concentration of 100 mg/L resulted in the highest total tropane alkaloid production, which exhibited broad-spectrum antimicrobial activity. The study demonstrated the potential of nano-silver as an elicitor for promoting the production of target alkaloids in Hyoscyamus muticus hairy root cultures, which exhibit high biological activity.

Does GastroPlus Support Similarity and Dissimilarity Factors of in vitro-in vivo Prediction in Biowaiver Studies? A Lower Strength Amlodipine As a Model Drug.

BACKGROUND: Many generic pharmaceutical products are currently available on the market place worldwide. Recently, there is a growing concern on the quality and efficacy of generic products. However, health care professionals such as physicians and pharmacists are in difficult situations to choose among alternatives. PURPOSE: The aim of this study is to assess the effectiveness of the in silico technique (Gastro Plus®) in the biowaiver study and whether similarity and dissimilarity factors (f 2 and f 1 respectively) are effective in this regard. METHOD: The concentration of amlodipine in the sample was calculated by comparing the absorbance of the sample with that of a previously prepared amlodipine standard solution using validated HPLC method. The dissolution profile for each product (brand and generics) was constructed. The similarity (f2) and dissimilarity (f 1) factors were calculated for the generic product according to equation 1 and 2. GastroPlus™ software (version 9.0, Simulations Plus Inc., Lancaster, CA, USA) was used to predict the absorption profiles of amlodipine from the generic product Amlovasc® and the reference Norvasc®. CONCLUSION: These results may provide a rationale for the interchangeability between the RLD and generic version based on in vitro release profiles in silico technique especially in a lower strength dose drug.

Heterogeneity in mechanisms influencing glucocorticoid sensitivity: the need for a systems biology approach to treatment of glucocorticoid-resistant inflammation.

Glucocorticoids (GCs) have impressive anti-inflammatory and immunosuppressive effects and show a diversity of actions across a variety of cell phenotypes. Implicit in efforts to optimize GCs as anti-inflammatory agents for any or all indications is the notion that the relevant mechanism(s) of action of GCs are fully elucidated. However, recent advances in understanding GC signalling mechanisms have revealed remarkable complexity and contextual dependence, calling into question whether the mechanisms of action are sufficiently well-described to embark on optimization. In the current review, we address evidence for differences in the mechanism of action in different cell types and contexts, and discuss contrasts in mechanisms of glucocorticoid insensitivity, with a focus on asthma and Chronic Obstructive Pulmonary Disease (COPD). Given this complexity, we consider the potential breadth of impact and selectivity of strategies directed to reversing the glucocorticoid insensitivity.

Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies.

Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of cisplatin as an anti-tumoral drug. Our study was conducted to evaluate the protective potential of acetyl-l-carnitine, DL-α-lipoic acid and silymarin against cisplatin-induced myocardial injury. Eighty male albino rats were divided into eight groups. The first four groups were treated with normal saline, acetyl-l-carnitine (500mg/kg, i.p.), DL-α-lipoic acid (100mg/kg, p.o.) and silymarin (100mg/kg, p.o.) respectively, for 10 successive days. The remaining groups were treated with the same doses of normal saline, acetyl-l-carnitine, DL-α-lipoic acid and silymarin, respectively, for 5 successive days before and after a single dose of cisplatin (10mg/kg, i.p.). Serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB) and plasma cardiac troponin I (cTnI) concentration were estimated. Malondialdehyde (MDA), reduced glutathione (GSH) contents, superoxide dismutase activity (SOD) and protein content in cardiac tissues were measured. Moreover, integrity of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) was also examined. Cisplatin-treated rats experienced a significant elevation of serum activities of LDH, CK, CK-MB and cTnI plasma concentration. These effects were accompanied by a significant increase in MDA level. On the other hand, a significant decrease in GSH content, SOD activity and total protein content was observed. In addition, both mtDNA and nDNA were heavily damaged. However, acetyl-l-carnitine, DL-α-lipoic acid and silymarin significantly attenuated the cisplatin-evoked disturbances in the above-mentioned parameters. In conclusion, the former drugs were proven to be potential candidates to ameliorate cisplatin-induced cardiotoxicity.