Foretinib, a c-MET receptor tyrosine kinase inhibitor, tackles multidrug resistance in cancer cells by inhibiting ABCB1 and ABCG2 transporters.

BACKGROUND: ABC transporter-mediated multidrug resistance (MDR) remains a major obstacle for cancer pharmacological treatment. Some tyrosine kinase inhibitors (TKIs) have been shown to reverse MDR. The present study was designed to evaluate for the first time whether foretinib, a multitargeted TKI, can circumvent ABCB1 and ABCG2-mediated MDR in treatment-resistant cancer models. METHODS: Accumulation of fluorescent substrates of ABCB1 and ABCG2 in ABCB1-overexpressing MES-SA/DX5 and ABCG2-overexpressing MCF-7/MX and their parenteral cells was evaluated by flow cytometry. The growth inhibitory activity of single and combination therapy of foretinib and chemotherapeutic drugs on MDR cells was examined by MTT assay. Analysis of combined interaction effects was performed using CalcuSyn software. RESULTS: It was firstly proved that foretinib increased the intracellular accumulation of rhodamine 123 and mitoxantrone in MES-SA/DX5 and MCF-7/MX cancer cells, with accumulation ratios of 12 and 2.2 at 25 µM concentration, respectively. However, it did not affect the accumulation of fluorescent substrates in the parental cells. Moreover, foretinib synergistically improved the cytotoxic effects of doxorubicin and mitoxantrone. The means of combination index (CI) values at fraction affected (Fa) values of 0.5, 0.75, and 0.9 were 0.64 ± 0.08 and 0.47 ± 0.09, in MES-SA/DX5 and MCF-7/MX cancer cells, respectively. In silico analysis also suggested that the drug-binding domain of ABCB1 and ABCG2 transporters could be considered as potential target for foretinib. CONCLUSION: Overall, our results suggest that foretinib can target MDR-linked ABCB1 and ABCG2 transporters in clinical cancer therapy.

Evaluation of the FDA-approved kinase inhibitors to uncover the potential repurposing candidates targeting ABC transporters in multidrug-resistant cancer cells: an in silico approach.

Multiple drug resistance (MDR) is characterized by the resistance of cancer cells to a broad spectrum of anticancer drugs. The main mechanism underlying the MDR phenotype is the overexpression of ATP-binding cassette (ABC) transporters by promoting active drug efflux from cancer cells. Some small-molecule protein kinase inhibitors have been found to overcome MDR by inhibiting ABC transporters as substrates or modulators. This study investigated the chemical activity of 58 FDA-approved anticancer kinase inhibitors against three multidrug resistance-related proteins. The studied proteins are ATP-Binding Cassette Sub-Family B Member 1 (ABCB1), ATP-Binding Cassette Subfamily C Member 1 (ABCC1), and ATP-binding cassette superfamily G member 2 (ABCG2). The drug-binding domain and ATP binding sites of the proteins were considered the kinase inhibitors' probable target. High-throughput virtual screening and molecular docking were employed to find the hit drugs, and the drugs with the highest binding affinity were further evaluated using the molecular dynamics (MD) simulation. The virtual screening revealed that several kinase inhibitors could be considered potential inhibitors of ABCB1, ABCC1, and ABCG2, among which larotrectinib, entrectinib, and infigratinib showed the highest binding affinity, respectively. Based on the obtained results from MD simulation, these drugs can form strong interactions with the essential residues of the target proteins. In silico investigation revealed that larotrectinib, entrectinib, and infigratinib can target the key residues of the studied proteins. Therefore, these approved kinase inhibitors could be considered potential therapies for MDR cancers by targeting these transporters.Communicated by Ramaswamy H. Sarma.

Novel quinazoline-1,2,3-triazole hybrids with anticancer and MET kinase targeting properties.

Oncogenic activation of receptor tyrosine kinases (RTKs) such as MET is associated with cancer initiation and progression. We designed and synthesized a new series of quinazoline derivatives bearing 1,2,3-triazole moiety as targeted anticancer agents. The MET inhibitory effect of synthesized compounds was assessed by homogeneous time-resolved fluorescence (HTRF) assay and western blot analysis. Sulforhodamine B assay was conducted to examine the antiproliferative effects of synthetic compounds against 6 cancer cell lines from different origins including MET-dependent AsPC-1, EBC-1 and MKN-45 cells and also Mia-Paca-2, HT-29 and K562 cells. The growth inhibitory effect of compounds in a three-dimensional spheroid culture was examined by acid phosphatase (APH) assay, while apoptosis induction was evaluated by Annexin V/propidium iodide method. Compound 8c bearing p-methyl benzyl moiety on the triazole ring exhibited the highest MET inhibitory capacity among tested agents that was further confirmed by western blot findings. Derivatives 8c and 8h exhibited considerable antiproliferative effects against all tested cell lines, with more inhibitory effects against MET-positive cells with IC50 values as low as 6.1 µM. These two agents also significantly suppressed cell growth in spheroid cultures and induced apoptosis in MET overexpressing AsPC-1 cells. Moreover, among a panel of 24 major oncogenic kinases, the PDGFRA kinase was identified as a target of 8c and 8h compounds. The docking study results of compounds 8c and 8h were in agreement with experimental findings. The results of the present study suggest that quinazoline derivatives bearing 1,2,3-triazole moiety may represent promising targeted anticancer agents.

Cytidine deaminase enzyme activity is a predictive biomarker in gemcitabine-treated cancer patients.

BACKGROUND: Gemcitabine is a chemotherapeutic agent, widely used for the treatment of many types of cancer. Cytidine deaminase (CDA) enzyme plays an important role in the metabolism of gemcitabine. This study aimed to assess the power of serum CDA residual activity in predicting drug efficacy and toxicity in gemcitabine-treated cancer patients. METHODS: This prospective observational study enrolled 63 patients with different types of malignancies who received gemcitabine chemotherapy between May 2019 and January 2022. Blood samples were obtained before the initiation of chemotherapy and serum CDA residual activity was determined using a modification of the Berthelot assay. The patients were followed up for at least 12 months up to 41 months. Overall survival was recorded and treatment-related toxicities were documented according to National Cancer Institute Common Terminology Criteria. RESULTS: Kaplan-Meier analysis showed that patients with a lower than median CDA value (≤ 8.06 U/mg protein) had a significantly longer survival compared to patients with higher CDA values (> 8.06 U/mg, P ˂ 0.005). Among several potentially involved factors, a significant association between CDA activity and overall survival was observed in univariate analysis (HR = 4.219, 95% CI 1.40-12.74, P = 0.011). On the other hand, the rate of anemia was significantly higher in low-CDA patients compared to high-CDA individuals (P < 0.05). CONCLUSION: These findings suggest that CDA activity could be a promising biomarker to predict survival and the occurrence of anemia in cancer patients treated with gemcitabine.

Novel spiroindoline quinazolinedione derivatives as anticancer agents and potential FLT3 kinase inhibitors.

Despite considerable recent progress in therapeutic strategies, cancer still remains one of the leading causes of death. Molecularly targeted therapies, in particular those focused on blocking receptor tyrosine kinases have produced promising outcomes in recent years. In this study, a new series of spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione derivatives (5a-5l) were synthesized and evaluated as potential kinase inhibitors with anticancereffects. The anti-proliferative activity was measured by MTT assay, while the cell cycle was studied using flow cytometry. Moreover, kinase inhibition profiles of the most promising compounds were assessed against a panel of 25 oncogenic kinases. Compounds 5f,5g,5i, and 5jshowed anti-proliferative effect against EBC-1, A549, and HT-29 solid tumor models in addition to leukemia cell line K562. In particular, compound 5f, bearing 4-methylphenyl pendant on the isatin ring displayed considerable potency with IC50 values of 2.4 to 13.4 µM against cancer cells. The most potent derivatives also altered the distribution of cells in different phases of cell cycle and increased the sub-G1 phase cells in K562 cells. Moreover, kinase inhibition assays identified FLT3 kinase was as the primary targetof these derivatives. Compound 5f at 25 µM concentration showed inhibitory activities of 55% and 62% against wild-type FLT3 and its mutant, D835Y, respectively. Finally, the docking and simulation studies revealed the important interactions of compound 5f with wild type and mutant FLT3. The results of this study showed that some novel spiroindoline quinazolinedione compounds could be potential candidates for further development as novel targeted anticancer agents.

Cation functional group effect on SO2 absorption in amino acid ionic liquids.

Introduction: The effect of the functional group of the cation on SO2 acidic gas absorption by some designed amino acid ionic liquids (AAILs) was studied. Methods: An isolated pair of glycinate anion and pristine imidazolium-based cation, as well as decorated cation functionalized by hydroxyl (OH), amine (NH2), carboxylic acid (COOH), methoxy (OCH3), and acetate (CH3COO) groups, were structurally optimized by density functional theory (DFT) using split-valence triple-zeta Pople basis set. Results and Discussion: The binding and Gibbs free energy (ΔGint) values of SO2 absorption show the AAIL functionalized by the COOH group is the most thermodynamically favorable green solvent and this functional group experiences the closest distance between anion and captured SO2 and vice versa in the case of cation … SO2 which may be the main reason for being the best absorbent; in addition, the highest net charge-transfer amount of SO2 is observed. Comparing the non-covalent interaction of the systems demonstrates that the strongest hydrogen bond between captured gas and anion, as well as π-hole, and van der Waals (vdW) interaction play critical roles in gas absorption; besides, the COOH functional group decreases the steric effect while the CH3COO functional group significantly increases steric effect after absorption that declines the hydrogen bond.

Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors.

The advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferative effect of the synthesized compounds was examined against EBC-1, A549, HT-29 and U-87MG cells by MTT assay. MET kinase inhibitory effect was tested by a Homogenous Time Resolved Fluorescence (HTRF) assay. The antiproliferative effect of compounds in a three-dimensional spheroid culture was studied by acid phosphatase (APH) assay, while apoptosis induction was examined by Hoechst 33258 staining. We found that compound CM9 bearing p-bromo benzyl pendant inhibited MET kinase activity at the concentrations of 10-50 µM (% Inhibition = 37.1-66.3%). Compound CM9 showed antiproliferative effect against cancer cells, in particular lung cancer cells with MET amplification (EBC-1) with an IC50 value of 8.6 µM. Moreover, this derivative inhibited cell growth in spheroid cultures in a dose-dependent manner and induced apoptosis in cancer cells. Assessment of inhibitory effect of CM9 against a panel of 18 different protein kinases demonstrated that this compound also inhibits ALK, AXL, FGFR1, FLT1 (VEGFR1) and FLT4 (VEGFR3) more than 50% at 25 µM. Finally, molecular docking and dynamics simulation corroborated the experimental findings and showed critical structural features for the interactions between CM9 and target kinases. The findings of this study present quinazolinone hydrazide triazole derivatives as kinase inhibitors with considerable anticancer effects.

In silico screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 as potential MDR reversal agents.

PURPOSE: Cancer is a significant public health problem and ranks as a leading cause of death globally. Multidrug resistance (MDR) affects the therapeutic potential of conventional chemotherapeutic agents in cancer chemotherapy. Receptor tyrosine kinases (RTKs) are enzymes whose aberrant activation contributes to the tumorigenesis of various types of cancers. The ability of several RTKs, such as c-Met, to reverse ABC transporters mediated MDR was shown before. We aimed to explore the ability of c-Met inhibitors to circumvent MDR in cancer by inhibiting the ABCB1 transporter using in silico studies. METHODS: Docking virtual screening of several potent and structurally diverse c-Met inhibitors were applied to find repurposed candidates to target the ATP binding sites and drug-substrate binding pockets of the ABCB1 transporter. The selected candidate was subjected to molecular dynamics simulations. RESULTS: Based on docking findings, among 19 clinical c-Met inhibitors, several drugs, particularly golvatinib, exerted the affinity to both ATP binding sites in the nucleotide-binding domains (NBDs) as well as the drug-substrate binding site in the transmembrane domains (TMDs). Moreover, several non-clinical c-Met inhibitors obtained from the ChEMBL database had strong interactions with TMDs and NBDs, among which CHEMBL1950194 and CHEMBL2385194 compounds showed the highest binding affinity, respectively. Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results. CONCLUSION: We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs.

Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all malignancies. PI3K/AKT/mTOR signaling pathway, a main downstream effector of KRAS is involved in the regulation of key hallmarks of cancer. We here report that whole-genome analyses demonstrate the frequent involvement of aberrant activations of PI3K/AKT/mTOR pathway components in PDAC patients and critically evaluate preclinical and clinical evidence on the application of PI3K/AKT/mTOR pathway targeting agents. Combinations of these agents with chemotherapeutics or other targeted therapies, including the modulators of cyclin-dependent kinases, receptor tyrosine kinases and RAF/MEK/ERK pathway are also examined. Although human genetic studies and preclinical pharmacological investigations have provided strong evidence on the role of PI3K/AKT/mTOR pathway in PDAC, clinical studies in general have not been as promising. Patient stratification seems to be the key missing point and with the advent of biomarker-guided clinical trials, targeting PI3K/AKT/mTOR pathway could provide valuable assets for treatment of pancreatic cancer patients.

Ultra selective and high-capacity dummy template molecular imprinted polymer to control quorum sensing and biofilm formation of Pseudomonas aeruginosa.

Here a highly selective molecular imprinting polymer was developed to attenuate biofilm formation of the multidrug-resistant pathogen Pseudomonas aeruginosa by disrupting the intermolecular signaling system. Firstly, a dummy template molecular imprinting polymer (MIP) was rationally designed through molecular modeling to capture 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal). This multifunctional signaling molecule interferes with the pathogenicity of P. aeruginosa as an auto-inducer. Then, the synthesized MIP and the non-imprinted polymer (NIP) as reference polymer were evaluated for their binding capacity and biofilm inhibition. The results indicated a significant difference in biofilm inhibition (∼56%) between imprinted (∼67%) and non-imprinted (∼11%) polymer, which is an impressive level, especially for the treatment of various surfaces affected by P. aeruginosa. These results open a new window in the special biological application of MIPs as a promising candidate to reduce concerns in clinical or industrial issues by preventing microbial infections.

Therapeutic potential of quinazoline derivatives for Alzheimer's disease: A comprehensive review.

Quinazolines are considered as a promising class of bioactive heterocyclic compounds with broad properties. Particularly, the quinazoline scaffold has an impressive role in the design and synthesis of new CNS-active drugs. The drug-like properties and pharmacological characteristics of quinazoline could lead to different drugs with various targets. Among CNS disorders, Alzheimer's disease (AD) is a progressive neurodegenerative disorder with memory loss, cognitive decline and language dysfunction. AD is a complex and multifactorial disease therefore, the need for finding multi-target drugs against this devastative disease is urgent. A literature survey revealed that quinazoline derivatives have diverse therapeutic potential for AD as modulators/inhibitors of ß-amyloid, tau protein, cholinesterases, monoamine oxidases, and phosphodiesterases as well as other protective effects. Thus, we describe here the most relevant and recent studies about anti-AD agents with quinazoline structure which can further aid the development and discovery of new anti-AD agents.

Molecular dynamic simulation studies of adsorption and diffusion behaviors of methanol and ethanol through ZSM-5 zeolite.

Due to the importance of synthesis gas's entire conversion to methanol, the separation of methanol from unconverted synthesis gas is an industrial challenge. In this work, the influence of temperature, guest molecules concentrations (methanol and ethanol), and acid site density (Si/Al) of zeolites on the diffusion of methanol and ethanol, pure and binary mixture (80% methanol and 20% ethanol) in silicalite-1 and HZSM-5 (Si/Al = 47 and 23) were studied by using of the COMPASS force-field molecular dynamics method. Also, the adsorption of pure methanol and ethanol and binary mixture through these zeolites has been studied by using the Grand Canonical Monte Carlo (GCMC) method. The calculated adsorption rate and isosteric heat of adsorption for ethanol are lower and higher than methanol, respectively. The results of the binary mixture show that HZSM-5 (Si/Al = 23) has the lowest adsorption selectivity and most diffusion selectivity. The calculated diffusion coefficients of methanol and ethanol guest molecules decreased with rising guest molecule concentration and Si/Al-ratios. The effect of both agents was investigated by analysis of mean square displacement (MSD) and RDF diagram.

Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met.

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5-25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC50 values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.

Combination of HGF/MET-targeting agents and other therapeutic strategies in cancer.

MET receptor has emerged as a druggable target across several human cancers. Agents targeting MET and its ligand hepatocyte growth factor (HGF) including small molecules such as crizotinib, tivantinib and cabozantinib or antibodies including rilotumumab and onartuzumab have proven their values in different tumors. Recently, capmatinib was approved for treatment of metastatic lung cancer with MET exon 14 skipping. In this review, we critically examine the current evidence on how HGF/MET combination therapies may take advantage of synergistic effects, overcome primary or acquired drug resistance, target tumor microenvironment, modulate drug metabolism or tackle pharmacokinetic issues. Preclinical and clinical studies on the combination of HGF/MET-targeted agents with conventional chemotherapeutics or molecularly targeted treatments (including EGFR, VEGFR, HER2, RAF/MEK, and PI3K/Akt targeting agents) and also the value of biomarkers are examined. Our deeper understanding of molecular mechanisms underlying successful pharmacological combinations is crucial to find the best personalized treatment regimens for cancer patients.

Antiproliferative effect, alteration of cancer cell cycle progression and potential MET kinase inhibition induced by 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives.

Cancer continues to be the second leading cause of death worldwide. Discovery of novel therapeutic agents has crucial importance for improvement of our medical management capabilities. Dysregulation of the MET receptor tyrosine kinase pathway plays an important role in cancer progression, making this receptor an attractive molecular target for anticancer drug discovery. In this study, twenty-seven 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives were synthesized and their cancer cell growth inhibitory activity was examined against MCF-7, HT-29 and MOLT-4 cells and also NIH/3T3 non-cancer cells by MTT assay. The antiproliferative effect of the most potent derivatives were tested against MET-dependent EBC-1 and MKN-45, lung and gastric cancer cell lines, respectively. MET kinase inhibition was measured by a Homogenous Time Resolved Fluorescence (HTRF) Assay. The influence of the test compounds on cell cycle was examined by RNase/PI flow cytometric assay. A number of compounds exhibited considerable antiproliferative effects against breast and colon cancer and leukemia cell lines, relatively sparing non-cancer cells. Some derivatives bearing benzothiazolyl carboxamide moiety at C5 position (15, 21, 23, 31, and 37) showed the highest activities with IC50 values as low as 10.9 µM. These compounds showed antiproliferative effects also against MET-amplified cells and dose-dependently inhibited MET kinase activity. They also induced G0/G1 cell cycle arrest at lower doses and apoptosis at higher doses. Molecular docking and dynamics simulation studies confirmed the interaction of compound 23 with the active site of the MET receptor. These findings demonstrate that 3,4-dihydropyrimidin-2(1H)-one analogues may represent promising targeted anticancer agents.

The effect of anion on aggregation of amino acid ionic liquid: Atomistic simulation.

Aggregation behavior of dodecyl betaine chloride [DB][Cl], as an amino acid ionic liquid, and dodecyl betaine N-acetyl glycinate [DB][AG], as a bio ionic liquid, in aqueous media was studied through molecular dynamics simulation. The aggregating was investigated by radial distribution function, coordination numbers, and hydrogen bond numbers. The results demonstrated the hydrogen bond between [DB]+ and [AG]- that leads to aggregation. The number of hydrogen bonds of [DB][AG] is greater than [DB][Cl] and causes a decrease in the gradient of the mean square displacement, thereby the diffusion coefficient of cation, anion, and water in [DB][AG]. The results point to a stable aggregation of [DB][AG] which is in agreement with the results of root mean square deviations. The aggregation number for [DB][AG] is 50 and 44 for [DB][Cl]. Computing the radius of gyration and geometrical radius shows that the aggregation size is 23.0 Å and 26.4 Å for [DB][AG] and [DB][Cl], respectively. It was also observed that the shape of the aggregates is quasi-spherical that points to a sub-diffusive regime.

Is the existence of a mutualistic relationship between Lobesia botrana and Botrytis cinerea well-founded?

Some studies have highlighted benefits for Lobesia botrana by adding Botrytis cinerea mycelium to an artificial larval diet and have suggested a mutualistic relationship between the two organisms on grapevine, hypothesizing that fungal sterols were the nutritional factor involved. Because the nutritional quality of an artificial diet should be similar to grapes to allow extrapolation of the results to the field conditions, in the current study L. botrana larval performance was compared when larvae were fed on grapes (berries) or two artificial diets either with or without enrichment with B. cinerea. Based on sterol analysis, the two artificial diets had high cholesterol content, but relative to berries showed comparable and low phytosterol contents, respectively (high- and low-phytosterol, HPh, and LPh). While larval fitness on the HPh diet was similar to berries, the LPh diet led to higher mortality and worse larval performance. The addition of the fungus compensated for the shortage in the LPh diet but did not improve the HPh diet. Supplementing the LPh diet with linoleic acid, which is supplied also from B. cinerea, partially improved larval performance. In a field experiment, females did not show any egg-laying preferences towards naturally botrytized bunches. The positive effect of B. cinerea on the moth's next generation that is reported in the literature could be a consequence of fungus developed inside berry tunnels bored by larvae. Therefore, based on our data and previous reports the existence of a mutualistic relationship between L. botrana and B. cinerea is not well-founded.

Does the addition of a heteropoly acid change the water percolation threshold of PFSA membranes?

A large system containing heteropoly acids (HPAs) and Nafion® 117 was simulated and studied to verify whether the additive particles affect the formation of the water percolating network or not. Two structures of HPA particles were considered as dopants, i.e. H9AlW6O24 and H3PW12O40. The SAXS simulation revealed that HPA particle addition to the membrane matrix leads to an increased order in the abundance and size of the hydrophilic region beside an expansion of the distance between the ionic domains. The morphological assessment shows that the hydrophilic phase domains in the HPA-doped Nafion® were spaced further apart than in the undoped membrane. These results show that adding HPA particles to the PFSA membrane reduces the so-called dead-pockets and makes the water channels more interconnected. For undoped Nafion®, the so-called percolating hydration level (λp) was 5.63. In other words, according to these results, approximately 8 wt% of water molecules are required to establish a spanning water network. The H9AlW6O24 and H3PW12O40 particles directly influence the morphology of water clusters and reduce by 10.12% and 17.41% the required hydration level to reach the percolation threshold, respectively.

Caffeic Acid Alkyl Amide Derivatives Ameliorate Oxidative Stress and Modulate ERK1/2 and AKT Signaling Pathways in a Rat Model of Diabetic Retinopathy.

The purpose of this study was to examine the neuroprotective effects of caffeic acid hexyl (CAF6) and dodecyl (CAF12) amide derivatives on the early stage of retinopathy in streptozotocin-induced diabetic rats. Animals were divided in five groups (n=8/group); one group consisted of non-diabetic rats as control, while the other four were diabetic animals either non-treated or treated with CAF6, CAF12 or resveratrol intravitreally for four weeks. Retinal superoxide dismutase (SOD) activity and 8-iso-prostaglandin F2α (iPF2α ) levels were evaluated by an ELISA assay. Phosphorylation of ERK1/2 and AKT was determined by immunoblotting in retinal homogenates. Retinal morphology was also examined using light microscopy. Treatment with CAF6 and CAF12 increased retinal SOD activity, while it decreased iPF2α levels in diabetic rats. Phosphorylation of ERK1/2 was increased, while AKT phosphorylation was decreased in diabetic rats compared to normal control and these alterations were significantly reversed in diabetic rats treated with CAF6 and CAF12. Furthermore, thickness of the whole retinal layer, outer nuclear layer, and ganglion cell count were decreased in diabetic rats compared to control and CAF6 and CAF12 treatments prevented these changes. CAF6 and CAF12 seem to be effective agents for treatment of diabetic retinopathy via attenuation of retinal oxidative stress and improvement of neuronal survival signaling.

Visual Outcomes of Adding Erythropoietin to Methylprednisolone for Treatment of Retrobulbar Optic Neuritis.

PURPOSE: To compare the short-term visual function results and safety of erythropoietin as an add-on to the standard corticosteroid therapy in retrobulbar optic neuritis (RON). METHODS: In this prospective pilot study, adult patients with isolated RON with less than 10 days of onset were enrolled. Patients were consecutively assigned to standard intravenous methylprednisolone treatment either in combination with intravenous erythropoietin (20,000 units/day for three days) (group-1) or intravenous methylprednisolone alone (group-2). Primary outcome measure was best-corrected visual acuity (BCVA), which was assessed up to 120 days from the day the treatment was begun. Systemic evaluations were performed during and after treatment. RESULTS: Sixty-two patients with RON (mean age = 26.6 ± 5.77 years; range = 18-40 years) were enrolled into the study (group-1, n = 35; group-2, n = 27). BCVA three months after the treatment was 0.19 ± 0.55 logMAR and 0.11 ± 0.32 logMAR in group-1 and group-2, respectively (95% CI: - 0.61 - 0.16; P = 0.62). Change in BCVA after three months was 2.84 ± 3.49 logMAR in group-1 and 2.46 ± 1.40 logMAR in group-2 (95% CI: - 0.93 - 1.91; P = 0.57). Pace of recovery was not significantly different between the groups. No complications were detected among patients. CONCLUSION: Intravenous erythropoietin as an add-on did not significantly improve the visual outcome in terms of visual acuity, visual field, and contrast sensitivity compared to traditional intravenous corticosteroid. This pilot study supports the safety profile of intravenous human recombinant erythropoietin, and it may help formulate future investigations with a larger sample size.