Lipoplexes' Structure, Preparation, and Role in Managing Different Diseases.

Lipid-based vectors are becoming promising alternatives to traditional therapies over the last 2 decades specially for managing life-threatening diseases like cancer. Cationic lipids are the most prevalent non-viral vectors utilized in gene delivery. The increasing number of clinical trials about lipoplex-based gene therapy demonstrates their potential as well-established technology that can provide robust gene transfection. In this regard, this review will summarize this important point. These vectors however have a modest transfection efficiency. This limitation can be partly addressed by using functional lipids that provide a plethora of options for investigating nucleic acid-lipid interactions as well as in vitro and in vivo nucleic acid delivery for biomedical applications. Despite their lower gene transfer efficiency, lipid-based vectors such as lipoplexes have several advantages over viral ones: they are less toxic and immunogenic, can be targeted, and are simple to produce on a large scale. Researchers are actively investigating the parameters that are essential for an effective lipoplex delivery method. These include factors that influence the structure, stability, internalization, and transfection of the lipoplex. Thorough understanding of the design principles will enable synthesis of customized lipoplex formulations for life-saving therapy.

Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N-(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies.

In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt to improve their biological availability and antiviral activity. Next, both cytotoxicity and anti-SARS-CoV-2 activities of the examined compounds loaded EMLs (F3a-g) were assessed in Vero E6 cells via MTT assay to calculate the CC50 and inhibitory concentration 50 (IC50) values. The most potent 3e-loaded EMLs (F3e) elicited a selectivity index of 18 with an IC50 value of 0.73 µg/mL. Moreover, F3e was selected for further elucidation of a possible mode of action where the results showed that it exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition. Besides, molecular docking and MD simulations towards the SARS-CoV-2 Mpro were performed. Finally, a structure-activity relationship (SAR) study focussed on studying the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide in addition to compound contraction on SARS-CoV-2 activity.HighlightsEmulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g).The most potent 3e-loaded EMLs (F3e) showed an IC50 value of 0.73 µg/mL against SARS-CoV-2.F3e exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition.Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA calculations were performed.Structure-activity relationship (SAR) study was discussed to study the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide on the anti-SARS-CoV-2 activity.

Design and synthesis of new trimethoxylphenyl-linked combretastatin analogues loaded on diamond nanoparticles as a panel for ameliorated solubility and antiproliferative activity.

A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of ß-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit ß-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound 6 was loaded on PEG-PCL modified diamond nanoparticles (PEG-PCL-NDs) and F4 was picked as the optimum formula. F4 exhibited enhanced solubility and release over the drug suspension. In the comparative cytotoxic activity, PEG-PCL modified F4 was capable of diminishing the IC50 by around 2.89 times for nude F4, while by 3.48 times relative to non-formulated compound 6.

Three Rings Schiff Base Ester Liquid Crystals: Experimental and Computational Approaches of Mesogenic Core Orientation Effect, Heterocycle Impact.

Three rings 2-hydroxypyridine liquid crystalline compounds have been prepared and fully characterized. The mesomorphic behavior of the prepared compounds has been investigated in terms of differential scanning calorimetry (DSC) and polarized optical microscopy (POM). Moreover, a comparative study between the prepared compounds and previously reported analogs has been discussed in terms of the orientation and position of the mesogenic core, in addition to the direction of the terminal alkyl chains. Furthermore, a detailed computational approach has been studied to illustrate the effect of geometrical and dimensional parameters on the type of the enhanced texture and the mesomorphic range and stability. The results of the DFT study revealed that the orientation of the mesogen could affect the mesomorphic behavior and this has been attributed in terms of the degree of the polarizability of the linking groups. This result has been confirmed by calculation of the net dipole moment and the molecular electrostatic potential that show how the mesogen orientation and position could impact the molecular charge separation. Finally, the effect of the pyridyl group has been also investigated in terms of the calculated aromaticity index and the π-π stacking.

Magnetic NiFe2 O4 Nanoparticles Prepared via Non-Aqueous Microwave-Assisted Synthesis for Application in Electrocatalytic Water Oxidation.

Phase-pure spinel-type magnetic nickel ferrite (NiFe2 O4 ) nanocrystals in the size range of 4 to 11 nm were successfully synthesized by a fast and energy-saving microwave-assisted approach. Size and accessible surface areas can be tuned precisely by the reaction parameters. Our results highlight the correlation between size, degree of inversion, and magnetic characteristics of NiFe2 O4 nanoparticles, which enables fine-tuning of these parameters for a particular application without changing the elemental composition. Moreover, the application potential of the synthesized powders for the electrocatalytic oxygen evolution reaction in alkaline media was demonstrated, showing that a low degree of inversion is beneficial for the overall performance. The most active sample reaches an overpotential of 380 mV for water oxidation at 10 mA cm-2 and 38.8 mA cm-2 at 1.7 V vs. RHE, combined with a low Tafel slope of 63 mV dec-1 .

Optimizing the Cosensitization Effect of SQ02 Dye on BP-2 Dye-Sensitized Solar Cells: A Computational Quantum Chemical Study.

Cosensitization of the semiconducting electrode in dye-sensitized solar cells (DSCs), with two or more light-harvesting dyes, is a chemical fabrication method that aims to achieve a panchromatic absorption spectrum emulating that of the solar emission spectrum. In this paper, SQ02 and BP-2 cosensitizers have been investigated, as isolated monomers/dimer and adsorbed monomers/dimer on the TiO2 (101) anatase surface, by employing density functional theory (DFT) and time-dependent DFT calculations. Computed results showed that the dominant electron injection pathway is direct injection from each dye into the conduction band of TiO2. The almost complete spectral overlap between the simulated absorption spectrum of BP-2 and fluorescence emissions of SQ02 implies that excitation energy transfer occurs between cosensitizers via the trivial reabsorption mechanism. However, the results showed very limited unidirectional intermolecular charge transfer (CT) from SQ02 dye to BP-2 dye (0.04 |e-|). Therefore, this study also presents a stepwise molecular engineering of BP-2 dye, aiming at optimizing the cosensitization functionality. First, 14 redesigned dye candidates are reported to identify dyes with photophysical properties matching the requirements for efficient DSCs. Second, the four most promising dyes are shortlisted for testing as cosensitizers with the SQ02 dye. The molecular design factors of cosensitization that need validation are chemical compatibility, availability of CT between cosensitizers, and complementarity of the absorption spectra. This screening suggests the judicious choice of the modeled difluorenyl amine donor-based dye (BP-D4) as a very promising cosensitizer. In particular, the SQ02/BP-D4 dimer showed 10 times larger (0.53 |e-|) unidirectional CT than that of SQ02/BP-2 dimer, in addition to the maximum increased electron population of acceptor moieties upon photoexcitation.

Natural history and mechanisms of COPD.

The natural history of COPD is complex, and the disease is best understood as a syndrome resulting from numerous interacting factors throughout the life cycle with smoking being the strongest inciting feature. Unfortunately, diagnosis is often delayed with several longitudinal cohort studies shedding light on the long 'preclinical' period of COPD. It is now accepted that individuals presenting with different COPD phenotypes may experience varying natural history of their disease. This includes its inception, early stages and progression to established disease. Several scenarios regarding lung function course are possible, but it may conceptually be helpful to distinguish between individuals with normal maximally attained lung function in their early adulthood who thereafter experience faster than normal FEV1 decline, and those who may achieve a lower than normal maximally attained lung function. This may be the main mechanism behind COPD in the latter group, as the decline in FEV1 during their adult life may be normal or only slightly faster than normal. Regardless of the FEV1 trajectory, continuous smoking is strongly associated with disease progression, development of structural lung disease and poor prognosis. In developing countries, factors such as exposure to biomass and sequelae after tuberculosis may lead to a more airway-centred COPD phenotype than seen in smokers. Mechanistically, COPD is characterized by a combination of structural and inflammatory changes. It is unlikely that all patients share the same individual or combined mechanisms given the heterogeneity of resultant phenotypes. Lung explants, bronchial biopsies and other tissue studies have revealed important features. At the small airway level, progression of COPD is clinically imperceptible, and the pathological course of the disease is poorly described. Asthmatic features can further add confusion. However, the small airway epithelium is likely to represent a key focus of the disease, combining impaired subepithelial crosstalk and structural/inflammatory changes. Insufficient resolution of inflammatory processes may facilitate these changes. Pathologically, epithelial metaplasia, inversion of the goblet to ciliated cell ratio, enlargement of the submucosal glands and neutrophil and CD8-T-cell infiltration can be detected. Evidence of type 2 inflammation is gaining interest in the light of new therapeutic agents. Alarmin biology is a promising area that may permit control of inflammation and partial reversal of structural changes in COPD. Here, we review the latest work describing the development and progression of COPD with a focus on lung function trajectories, exacerbations and survival. We also review mechanisms focusing on epithelial changes associated with COPD and lack of resolution characterizing the underlying inflammatory processes.

Anti-COVID-19 activity of some benzofused 1,2,3-triazolesulfonamide hybrids using in silico and in vitro analyses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic fatal infection with no known treatment. The severity of the disease and the fast viral mutations forced the scientific community to search for potential solution. Here in the present manuscript, some benzofused1,2,3triazolesulfonamide hybrids were synthesized and evaluated for their anti- SARS-CoV-2 activity using in silico prediction then the most potent compounds were assessed using in-Vitro analysis. The in-Silico study was assessed against RNA dependent RNA polymerase, Spike protein S1, Main protease (3CLpro) and 2'-O-methyltransferase (nsp16). It was found that 4b and 4c showed high binding scores against RNA dependent RNA polymerase reached -8.40 and -8.75 â€‹kcal/mol, respectively compared to the approved antiviral (remdesivir -6.77 â€‹kcal/mol). Upon testing the binding score with SARS-CoV-2 Spike protein it was revealed that 4c exhibited the highest score (-7.22 â€‹kcal/mol) compared to the reference antibacterial drug Ceftazidime (-6.36 â€‹kcal/mol). Surprisingly, the two compounds 4b and 4c showed the highest binding scores against SARS-CoV-2 3CLpro (-8.75, -8.48 â€‹kcal/mol, respectively) and nsp16 (- 8.84 and - 8.89 â€‹kcal/mol, respectively) displaying many types of interaction with all the enzymes binding sites. The derivatives 4b and 4c were examined in vitro for their potential anti-SARS-CoV-2 and it was revealed that 4c was the most promising compound with IC50 reached 758.8108 â€‹mM and complete (100%) inhibition of the binding of SARS-CoV-2 virus to human ACE2 can be accomplished by using 0.01 â€‹mg.

Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation.

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2-5.6-fold) and suppressed cyclin D expression (0.8-0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.

Synthesis and Computational Characterization of Organic UV-Dyes for Cosensitization of Transparent Dye-Sensitized Solar Cells.

The fabrication of colorless and see-through dye-sensitized solar cells (DSCs) requires the photosensitizers to have little or no absorption in the visible light region of the solar spectrum. However, a trade-off between transparency and power conversion efficiency (PCE) has to be tackled, since most transparent DSCs are showing low PCE when compared to colorful and opaque DSCs. One strategy to increase PCE is applying two cosensitizers with selective conversion of the UV and NIR radiation, therefore, the non-visible part only is absorbed. In this study, we report synthesis of novel five UV-selective absorbers, based on diimide and Schiff bases incorporating carboxyl and pyridyl anchoring groups. A systematic computational investigation using density functional theory (DFT) and time-dependent DFT approaches was employed to evaluate their prospect of application in transparent DSCs. Experimental UV/Vis absorption spectra showed that all dyes exhibit an absorption band covering the mid/near-UV region of solar spectrum, with a bathochromic shift and a hyperchromic shifts for Py-1 dye. Computational results showed that the studied dyes satisfied the basic photophysical and energetics requirements of operating DSC as well as the stability and thermodynamical spontaneity of adsorption onto surface of TiO2. However, results revealed outperformance of the thienothiophene core-containing Py-1 UV-dye, owing to its advantageous structural attributes, improved conjugation, intense emission, large Stokes shift and maximum charge transferred to the anchor. Chemical compatibility of Py-1 dye was then theoretically investigated as a potential cosensitizer of a reference VG20-C2 NIR-dye. By the judicious selection of pyridyl anchor-based UV-absorber (Py-1) and carboxyl anchor-based NIR-absorber (VG20), the advantage of the optical complementarity and selectivity of different TiO2-adsorption-site (Lewis- and Bronsted-acidic) can be achieved. An improved overall PCE is estimated accordingly.

Combretastatin A-4 disodium phosphate and low dose gamma irradiation suppress hepatocellular carcinoma by downregulating ROCK1 and VEGF gene expression.

Hepatocellular carcinoma (HCC) is a tough opponent. HCC contributes to 14.8% of all cancer mortality in Egypt. There are many choices for management of HCC; however tumor relapse has been reported in animal and clinical studies. This study was conducted to investigate the impact of low dose γ-irradiation (LDR) and combretastatin A-4 disodium phosphate (CA-4DP) on HCC recurrence. HCC was induced in male Wistar albino rats by oral administration of N-nitrosodiethylamine (NDEA) for 17 weeks. We evaluated the expression of the endothelial cell marker (CD31) by immunostaining. Expression of Rho Associated Coiled-Coil Containing Protein Kinase 1(ROCK1) and Vascular endothelial growth factor (VEGF) expression was assessed by real-time PCR after (6, 24 and 48 h). Our results showed that expression of CD31 and gene expression of ROCK1 and VEGF was significantly repressed at all-time intervals by combination therapy ofLDR and CA-4DP as compared with untreated NDEA/HCC group and NDEA/HCC groups treated with either LDR or CA-4DP alone, (P < 0.05). Our study demonstrated the additive effect of LDR in combination with CA-4DP in suppression of HCC.

Adefovir dipivoxil loaded proliposomal powders with improved hepatoprotective activity: formulation, optimization, pharmacokinetic, and biodistribution studies.

The present study aimed to prepare proliposomal formulae for improving the oral bioavailability of adefovir dipivoxil (AD), a nucleoside reverse transcriptase inhibitor effective against hepatitis B virus (HBV). The prepared proliposomal formulae were characterized for entrapment efficiency (E.E.%), vesicle size and in vitro drug release after reconstitution to conventional liposomes. The optimized formula (F9) with a maximum desirability value of 0.858 was selected having E.E.% of 71 ± 3.3% with an average vesicle size of 164.6 ± 5 nm. Moreover, the crystallization of AD within the optimized formula investigated via powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) confirmed the presence of the drug in an amorphous state within the lipid vesicles with enhanced stability over a storage period of 12 months. Thioacetamide-induced liver damage in rats evidenced by elevated liver enzymes was significantly improved after treatment with the optimum formula. Pharmacokinetic and biodistribution studies of formula F9 showed a higher accumulation of AD in the liver with enhanced bioavailability compared to AD suspension which highlights its potential advantage for an effective treatment of chronic HBV. Hence, proliposomal drug delivery is considered as a better choice for the oral delivery of AD.

Cyano-Bridged Trimetallic Coordination Polymer Nanoparticles and Their Thermal Decomposition into Nanoporous Spinel Ferromagnetic Oxides.

The synthesis of a novel family of cyano-bridged trimetallic coordination polymers (CPs) with various compositions and shapes has been reported by changing the compositional ratios of Fe, Co, and Ni species in the reaction system. In order to efficiently control the nucleation rate and the crystal growth, trisodium citrate dihydrate plays an important role as a chelating agent. After the obtained cyano-bridged trimetallic CPs undergo thermal treatment in air at three different temperatures (250, 350, and 450 °C), nanoporous spinel metal oxides are successfully obtained. Interestingly, the obtained nanoporous metal oxides are composed of small crstalline grains, and the grains are oriented in the same direction, realizing pseudo-single crystals with nanopores. The resultant nanoporous spinel oxides feature interesting magnetic properties. Cyano-bridged multimetallic CPs with various sizes and shapes can provide a pathway toward functional nanoporous metal oxides that are not attainable from simple cyano-bridged CPs containing single metal ions.

Hydrogels Containing Prussian Blue Nanoparticles Toward Removal of Radioactive Cesium Ions.

Recent reports have demonstrated the practical application of Prussian blue (PB) nanoparticles toward environmental clean-up of radionuclide 173Cs. Herein, we prepared a large amount of PB nanoparticles by mixing both iron(III) chloride and sodium ferrocyanide hydrate as starting precursors. The obtained PB nanoparticles show a high surface area (440 m2. g-1) and consequently an excellent uptake ability of Cs ions from aqueous solutions. The uptake ability of Cs ions into poly(N-isopropylacrylamide (PNIPA) hydrogel is drastically increased up to 156.7 m2. g-1 after incorporating our PB nanoparticles, compared to 30.2 m2 . g-1 after using commercially available PB. Thus, our PB-containing PNIPA hydrogel can be considered as an excellent candidate for the removal of Cs ions from aqueous solutions, which will be useful for the remediation of the nuclear waste.

Self-Construction from 2D to 3D: One-Pot Layer-by-Layer Assembly of Graphene Oxide Sheets Held Together by Coordination Polymers.

Deposition of Ni-based cyanide bridged coordination polymer (NiCNNi) flakes onto the surfaces of graphene oxide (GO) sheets, which allows precise control of the resulting lamellar nanoarchitecture by in situ crystallization, is reported. GO sheets are utilized as nucleation sites that promote the optimized crystal growth of NiCNNi flakes. The NiCNNi-coated GO sheets then self-assemble and are stabilized as ordered lamellar nanomaterials. Regulated thermal treatment under nitrogen results in a Ni3 C-GO composite with a similar morphology to the starting material, and the Ni3 C-GO composite exhibits outstanding electrocatalytic activity and excellent durability for the oxygen reduction reaction.

Controlled synthesis of nanoporous nickel oxide with two-dimensional shapes through thermal decomposition of metal-cyanide hybrid coordination polymers.

The urgent need for nanoporous metal oxides with highly crystallized frameworks is motivating scientists to try to discover new preparation methods, because of their wide use in practical applications. Recent work has demonstrated that two-dimensional (2D) cyanide-bridged coordination polymers (CPs) are promising materials and appropriate for this purpose (Angew. Chem. Int. Ed.- 2013, 52, 1235). After calcination, 2D CPs can be transformed into nanoporous metal oxides with a highly accessible surface area. Here, this strategy is adopted in order to form 2D nanoporous nickel oxide (NiO) with tunable porosity and crystallinity, using trisodium citrate dihydrate as a controlling agent. The presence of trisodium citrate dihydrate plays a key role in the formation of 2D nanoflakes by controlling the nucleation rate and the crystal growth. The size of the nanoflakes gradually increases by augmenting the amount of trisodium citrate dihydrate in the reaction. After heating the as-prepared CPs in air at different temperatures, nanoporous NiO can be obtained. During this thermal treatment, organic units (carbon and nitrogen) are completely removed and only the metal content remains to take part in the formation of nanoporous NiO. In the case of large-sized 2D CP nanoflakes, the original 2D flake-shapes are almost retained, even after thermal treatment at low temperature, but they are completely destroyed at high temperature because of further crystallization in the framework. Nanoporous NiO with high surface area shows significant efficiency and interesting results for supercapacitor application.

Single-crystal-like nanoporous spinel oxides: a strategy for synthesis of nanoporous metal oxides utilizing metal-cyanide hybrid coordination polymers.

Development of a new method to synthesize nanoporous metal oxides with highly crystallized frameworks is of great interest because of their wide use in practical applications. Here we demonstrate a thermal decomposition of metal-cyanide hybrid coordination polymers (CPs) to prepare nanoporous metal oxides. During the thermal treatment, the organic units (carbon and nitrogen) are completely removed, and only metal contents are retained to prepare nanoporous metal oxides. The original nanocube shapes are well-retained even after the thermal treatment. When both Fe and Co atoms are contained in the precursors, nanoporous Fe-Co oxide with a highly oriented crystalline framework is obtained. On the other hand, when nanoporous Co oxide and Fe oxide are obtained from Co- and Fe-contacting precursors, their frameworks are amorphous and/or poorly crystallized. Single-crystal-like nanoporous Fe-Co oxide shows a stable magnetic property at room temperature compared to poly-crystalline metal oxides. We further extend this concept to prepare nanoporous metal oxides with hollow interiors. Core-shell heterostructures consisting of different metal-cyanide hybrid CPs are prepared first. Then the cores are dissolved by chemical etching using a hydrochloric acid solution (i.e., the cores are used as sacrificial templates), leading to the formation of hollow interiors in the nanocubes. These hollow nanocubes are also successfully converted to nanoporous metal oxides with hollow interiors by thermal treatment. The present approach is entirely different from the surfactant-templating approaches that traditionally have been utilized for the preparation of mesoporous metal oxides. We believe the present work proves a new way to synthesize nanoporous metal oxides with controlled crystalline frameworks and architectures.

Isolation of Enterococcus faecium NM113, Enterococcus faecium NM213 and Lactobacillus casei NM512 as novel probiotics with immunomodulatory properties.

Probiotics, defined as living bacteria that are beneficial for human health, mainly function through their immunomodulatory abilities. Hence, these microorganisms have proven successful for treating diseases resulting from immune deregulation. The aim of this study was to find novel candidates to improve on and complement current probiotic treatment strategies. Of 60 lactic acid bacterial strains that were isolated from fecal samples of healthy, full-term, breast-fed infants, three were chosen because of their ability to activate human immune cells. These candidates were then tested with regard to immunomodulatory properties, antimicrobial effects on pathogens, required pharmacological properties and their safety profiles. To identify the immunomodulatory structures of the selected isolates, activation of specific innate immune receptors was studied. The three candidates for probiotic treatment were assigned Enterococcus faecium NM113, Enterococcus faecium NM213 and Lactobacillus casei NM512. Compared with the established allergy-protective strain Lactococcus lactis G121, these isolates induced release of similar amounts of IL-12, a potent inducer of T helper 1 cells. In addition, all three neonatal isolates had antimicrobial activity against pathogens. Analysis of pharmacological suitability showed high tolerance of low pH, bile salts and pancreatic enzymes. In terms of safe application in humans, the isolates were sensitive to three antibiotics (chloramphenicol, tetracycline and erythromycin). In addition, the Enterococcus isolates were free from the four major virulence genes (cylA, agg, efaAfs and ccf). Moreover, the isolates strongly activated Toll-like receptor 2, which suggests lipopeptides as their active immunomodulatory structure. Thus, three novel bacterial strains with great potential as probiotic candidates and promising immunomodulatory properties have here been identified and characterized.

Potential role of serum copeptin among smoker T2DM patients with emphasis to ACE I/D gene polymorphism predicting DN.

Diabetic nephropathy represents one of the main long-term complications in T2DM patients. Cigarette smoking represents one of modifiable renal risk factors to kidney damage due to lead (Pb) exposure in these patients. Our goal is to investigate serum copeptin and Kidney injury molecule-1 (KIM-1) and urinary lead (UPb) in type 2 diabetes mellitus (T2DM) patients even smokers and non-smokers groups and compared to corresponding health controls and assess its associations with Angiotensin-Converting enzyme Insertion/Deletion polymorphism [ACE (I/D)] polymorphism in diabetic nephropathy progression in those patients. In present study, 106 T2DM patients and 102 healthy control individuals were enrolled. Serum glucose, copeptin, KIM-1, total cholesterol (TChol), triglycerides (TG), estimated glomerular filtration rate (eGFR) and UPb levels and ACE (I/D) polymorphisms were assessed in both groups. Results mentioned to significant variations in all parameters compared to in T2DM group compared to control group. Serum copeptin and UPb demonstrated significant difference in diabetic smokers (DS) and diabetic non-smokers (DNS) groups while KIM-1 exhibited significant change between DNS and healthy control non-smokers (CNS) groups. Positive relation was recorded between serum glucose and KIM-1 while negative one was found between serum copeptin and TChol. D allele was associated with significant variation in most parameters in T2DM, especially insertion/deletion (ID) polymorphism. ROC curve analysis (AUC) for serum copeptin was 0.8, p < 0.044 and for Kim-1 was 0.54, p = 0.13 while for uPb was 0.71, p < 0.033. Serum copeptin and UPb might be a prognostic biomarker for renal function decline in smoker T2DM patients while KIM-1 was potent marker in non-smoker T2DM with association with D allele of ACE I/D gene polymorphism.

Sildenafil Use and Cigarette Smoking Associated with Intracerebral Hemorrhage: A Rare Case Report.

Background: Intracerebral hemorrhage (ICH) is a serious condition characterized by bleeding within the brain tissue. Although the use of sildenafil, a vasodilator agent for erectile dysfunction, has been associated with rare cases of ICH, the combination of sildenafil usage and smoking as risk factors for ICH has not yet been reported. This case report describes the occurrence of ICH in a patient with a history of both sildenafil usage and heavy smoking. Case Presentation: A 53-year-old male, with a history of smoking and regular sildenafil use, was brought to the emergency department due to loss of consciousness with right-side weakness, he initially experienced with nausea, vomiting and dizziness after taking sildenafil 100mg tablet once. The Glasgow Coma Score (GCS) was 10 with side hemiparesis. Non-contrast CT revealed left thalamic acute hemorrhage with ventricular extension. Furthermore, a head CT angiography ruled out any vascular anomalies after that the patient was admitted to the intensive care unit (ICU) for conservative management. After three days on clinical and neurological improvement, the patient was transferred to the inpatient ward for further management, monitoring and physiotherapy. On day 6, the patient was discharged and planned for flow up. Conclusion: This rare case highlights the need for further research and awareness regarding the potential risks associated with the combination of sildenafil and heavy smoking. Healthcare professionals should carefully evaluate the individual risk factors of patients, educate them about potential complications, and consider alternative treatments if necessary. Additionally, patients should be encouraged to quit smoking and adopt a healthy lifestyle to minimize the risk of cerebrovascular events.