Therapeutic concentrations of antidepressants inhibit pancreatic beta-cell function via mitochondrial complex inhibition

Diabetes mellitus risk is increased by prolonged usage of antidepressants (ADs). Although various mechanisms are suggested for their diabetogenic potential, whether a direct effect of ADs on pancreatic β-cells is involved is unclear. We examined this idea for 3 ADs: paroxetine, clomipramine and, with particular emphasis, fluoxetine, on insulin secretion, mitochondrial function, cellular bioenergetics, KATP channel activity, and caspase activity in murine and human cell-line models of pancreatic β-cells. Metabolic assays showed that these ADs decreased the redox, oxidative respiration, and energetic potential of β-cells in a time and concentration dependent manner, even at a concentration of 100 nM, well within the therapeutic window. These effects were related to inhibition of mitochondrial complex I and III. Consistent with impaired mitochondrial function, lactate output was increased and insulin secretion decreased. Neither fluoxetine, antimycin nor rotenone could reactivate KATP channel activity blocked by glucose unlike the mitochondrial uncoupler, FCCP. Chronic, but not acute, AD increased oxidative stress and activated caspases, 3, 8, and 9. A close agreement was found for the rates of oxidative respiration, lactate output and modulation of KATP channel activity in MIN6 cells with those of primary murine cells; data that supports MIN6 as a valid model to study beta-cell bioenergetics. To conclude, paroxetine, clomipramine and fluoxetine were all cytotoxic at therapeutic concentrations on pancreatic beta-cells; an action suggested to arise by inhibition of mitochondrial bioenergetics, oxidative stress and induction of apoptosis. These actions help explain the diabetogenic potential of these ADs in humans

Delineating groundwater and subsurface structures by using 2D resistivity, gravity and 3D magnetic data interpretation around Cairo–Belbies Desert road, Egypt

AbstractGeophysical tools such as magnetic, gravity and electric resistivity have been used to delineate subsurface structures, groundwater aquifer around Cairo–Belbies Desert road. A dipole–dipole section was measured at the central part of the study area with 2100m length and electrode spacing 50m for greater penetration depth. The results of the inverse resistivity data indicate that the study area includes two groundwater aquifers at different depths. The shallow aquifer water is near the surface and the deep aquifer lies at depth of about 115m and exhibits low resistivity values ranging from 20 to 100ohmm.One hundred and fifty-two gravity stations were measured using Autograv gravimeter (CG3), different gravity corrections (drift, elevation and latitude corrections) were applied. The corrected data represented by Bouguer anomaly map were filtered into regional and residual gravity anomaly maps. The residual gravity map indicates that the area is dissected by many faults with NW-SE, N-S, E-W and NE-SW trends.One hundred and fifty-three ground magnetic measurements are collected using two Proton magnetometers (Envimag). The corrected magnetic data are represented by total magnetic intensity map that was reduced to the magnetic pole. 3D magnetic modeling was applied to detect the depth of basaltic sheet and basement complex. The results indicated that the elevation of upper surface of basalt is ranging from 148 to −153m and the elevation of lower surface of basalt is ranging from 148 to 269m

Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies

Being one of the highly effective drugs in treatment of Alzheimer’s disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, −8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels

Heavy metals assessment in Egyptian smokers with lung cancer

Background Smoking and heavy metals are major risk factors and have an important role in development of lung cancer. Purpose The purpose of this study was to investigate the relationship between development of lung cancer and the synergistic effect of smoking and heavy metals in Egyptian smokers. Patients and methods A total of 41 participants enrolled in this study and were subdivided into three groups: smokers with lung cancer (n=11), nonsmokers with lung cancer (n=15), and apparently healthy smokers (n=15). The diagnosis and types of lung cancer based on pathological examination of biopsies taken either by computed tomography-guided, ultrasound-guided, fiberoptic bronchoscopy (FOB), and blind or thoracoscopic pleural biopsy. Serum levels of five heavy metals (zinc, lead, nickel, manganese, chromium) were assayed using inductive plasma spectrometry. Results Squamous cell carcinoma represents the major type of lung cancer (72.7%) among group of smokers with lung cancer; however, adenocarcinoma either primary or metastatic represents the major type (93.4%) among the nonsmoker group, and all investigated heavy metals in this study (zinc, lead, nickel, manganese, chromium) express significantly higher mean value of their serum levels (P=0.005, 0.005, 0.006, <0.001, and 0.007, respectively) in case of squamous cell carcinoma compared with adenocarcinoma. There is no impact of the degree of severity of smoking on serum levels of all investigated heavy metals. Conclusion Squamous cell carcinoma has been strongly associated with higher serum levels of all investigated heavy metals. There is no association between degree of severity of smoking and serum levels of all investigated heavy metals

Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, <i>ex vivo</i>, bio-distribution and <i>in vivo</i> pharmacokinetic studies

<p>Being one of the highly effective drugs in treatment of Alzheimer’s disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, −8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and <i>in vitro</i> release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the <i>in vivo</i> pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels.</p

Wave Front-Guided Photorefractive Keratectomy Using a High-Resolution Aberrometer After Corneal Collagen Cross-Linking in Keratoconus

Purpose: To evaluate the clinical outcomes of wave front–guided (WFG) photorefractive keratectomy (PRK) using a high-definition aberrometer in corneas with keratoconus at least 1 year after corneal collagen cross-linking (CXL). Methods: Prospective uncontrolled interventional case series study including a total of 34 consecutive eyes of 25 patients with keratoconus previously treated with CXL. All cases underwent WFG PRK using the VISX STAR S4 IR excimer laser and the iDesign system. All eyes had keratoconus grade I or II according to the Amsler–Krumeich classification. Visual, refractive, and ocular aberrometric outcomes were evaluated during a 12-month follow-up. Astigmatic changes were analyzed with the Alpins vector method. Results: A significant improvement was observed in the uncorrected and corrected distance visual acuities (P < 0.001). The mean efficacy and safety indices at 12 months postoperatively were 1.58 ± 1.11 and 1.96 ± 1.52, respectively. Manifest sphere and cylinder were reduced significantly (P < 0.001), with 76.5% of the eyes having a spherical equivalent within ±1.00 D at 12 months postoperatively. The mean difference vector and magnitude of error were 1.06 ± 0.92 and 0.43 ± 0.86 D, respectively. Some corneal irregularity indices were reduced significantly with surgery (P ≤ 0.005) as well as the level of ocular higher order aberrations, primary coma, and trefoil (P < 0.001). Conclusions: Sequential WFG PRK using the iDesign system and the STAR S4 IR excimer laser after CXL is an effective option to correct the spherocylindrical error and to minimize the level of higher order aberrations in mild and moderate keratoconus if the maximum intended ablation depth does not exceed 15% of the minimal corneal thickness

Pre and postharvest characteristics of Dahlia pinnata var. pinnata, cav. As affected by SiO2 and CaCO3 nanoparticles under two different planting dates

Agriculture faces many challenges because of climate changes. The nutrients present in nano-sized form improve plant productivity, especially when used at the appropriate planting time. Field experiments were conducted as a factorial experiment for evaluating two planting dates (20th September and 20th October), foliar application with nanoparticles (NPs) including silica nanoparticles (SiO2-NPs) at 1.5 and 3 mM, calcium carbonate nanoparticles (CaCO3-NPs) at 5 and 10 mM and distilled water (control) on pre- and post-harvest characteristics of Dahlia pinnata var. pinnata Cav. The results indicate that the interactions during the late planting time (20th October) and exogenous applications of SiO2-NPs at 1.5 mM or CaCO3-NPs at 10 mM have improved plant growth including plant height, stem diameter, fresh and dry weights of plant, leaf area, inflorescence diameter, inflorescence stalk length, branches number, tuber numbers, inflorescences number on the plant, and the vase life. At the same time, insignificant differences appeared in the interaction during the planting dates and SiO2 or CaCO3 -NPs concentrations on inflorescence stalk diameter, total soluble solids, membrane stability index, maximum increase in fresh weight (FW), and Si and Ca contents. In addition, all exogenous applications of NPs at the late planting time promoted the plant growth characteristics like lignin %, cellulose %, inflorescence water content, change in FW, and total water uptake. Moreover, the controls through the two planting dates recorded the maximum change in water uptake and water loss values. In short, it can be recommended to use SiO2-NPs at 1.5 mM or CaCO3-NPs at 10 mM as a foliar application at the late planting time (20th October) for obtaining the optimum quantitative and qualitative parameters of D. pinnata

The Anti-Rheumatic Drug, Leflunomide, Induces Nephrotoxicity in Mice via Upregulation of TGFβ-Mediated p53/Smad2/3 Signaling

Recent studies indicated renal toxicity and interstitial nephritis in patients receiving leflunomide (LEFN), but the exact mechanism is still unknown. The transforming growth factor β (TGFβ)/p53/Smad2/3 pathway crucially mediates renal fibrosis. We aimed to assess the nephrotoxic effect of LEFN in mice and the possible role of TGFβ-stimulated p53/SMAD2/3 signaling. The study design involved distributing sixty male albino mice into four groups: (i) vehicle-treated mice, (ii) LEFN (2.5 mg/kg), (iii) LEFN (5 mg/kg), and (iv) LEFN (10 mg/kg). The drug was given orally every 48 h and continued for 8 weeks. Blood samples were then taken from mice for the determination of kidney function parameters. Right kidneys were used for histopathologic staining and immunohistochemistry, whereas left kidneys were frozen and used for Western blot analysis of the target proteins, p-p53 and Smad2/3. Results indicated that chronic administration of LEFN in mice resulted in a four- and nine-fold increase in serum urea and creatinine levels, respectively. Kidney specimens stained with hematoxylin and eosin or periodic acid–Schiff showed significant histopathological manifestations, such as cellular irregularity, interstitial congestion, and moderate lymphocytic inflammatory infiltrate in mice treated with LEFN. Western blotting indicated upregulation of the p-p53/Smad2/3 proteins. LEFN, especially in the highest dose (10 mg/kg), produced prominent nephrotoxicity in mice. This toxicity is mediated through stimulating fibrotic changes through TGFβ-stimulated p53/Smad2/3 signaling and induction of glomerular and tubular apoptosis. An improved understanding of LEFN-induced nephrotoxicity would have great implications in the prediction, prevention, and management of leflunomide-treated rheumatic patients, and may warrant further clinical studies for following up these toxidromes

Betanin improves motor function and alleviates experimental Parkinsonism via downregulation of TLR4/MyD88/NF-κB pathway: Molecular docking and biological investigations

Parkinson’s disease (PD) is a progressive neuroinflammatory and degenerative disease. In this study, we investigated the neuroprotective action of betanin in the rotenone-induced Parkinson-like mice model. Twenty-eight adult male Swiss albino mice were divided into four groups: Vehicle, Rotenone, Rotenone + Betanin 50 mg/kg, and Rotenone + Betanin 100 mg/kg. Parkinsonism was induced by subcutaneous injection of 9 doses of rotenone (1 mg/kg/48 h) plus betanin at 50 and 100 mg/kg/48 h in rotenone + betanin groups for twenty days. Motor dysfunction was assessed after the end of the therapeutic period using the pole, rotarod, open-field, grid, and cylinder tests. Malondialdehyde, reduced glutathione (GSH), Toll-like receptor 4 (TLR4), myeloid differentiation primary response-88 (MyD88), nuclear factor kappa- B (NF-κB), neuronal degeneration in the striatum were evaluated. In addition, we assessed the immunohistochemical densities of tyrosine hydroxylase (TH) in Str and in substantia nigra compacta (SNpc). Our results showed that rotenone remarkably decreased (results of tests), increased decreased TH density with a significant increase in MDA, TLR4, MyD88, NF-κB, and a decrease in GSH (p < 0.05). Treatment with betanin significantly results of tests), increased TH density. Furthermore, betanin significantly downregulated malondialdehyde and improved GSH. Additionally, the expression of TLR4, MyD88, and NF-κB was significantly alleviated. Betanin’s powerful antioxidative and anti-inflammatory properties can be related to its neuroprotective potential as well as its ability to delay or prevent neurodegeneration in PD