Design, syntheses, theoretical calculations, MM-GBSA, potential anti-cancer and enzyme activities of novel Schiff base compounds.

In this study, new Schiff base compounds (SB-F-OH, SB-Cl-OH and SB-Br-OH) were derived from chalcone-derived amine compounds containing halogen groups and 4-hydroxybenzaldehyde. Also, their phthalonitrile compounds (SB-F-CN, SB-Cl-CN and SB-Br-CN) have been synthesized. The structures of these compounds were elucidated by NMR, FT-IR and Mass spectroscopic methods. The quantum chemical parameters were calculated at B3LYP/6-31++g(d,p), HF/6-31++g(d,p) and M062X/6-31++g(d,p) levels. As the biological application of the synthesized compounds, (i) their inhibition properties of the synthesized compounds on Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) metabolic enzymes were investigated, and their potential anticancer activities against neuroblastoma (NB; SH-SY5Y) and healthy fibroblast (NIH-3T3) cell lines were determined by in vitro assays. All compounds showed inhibition at nanomolar level with the Ki values in the range of 97.86 ± 30.51-516.82 ± 31.42 nM for AChE, 33.21 ± 4.45-78.50 ± 8.91 nM for BChE, respectively. It has been determined that all tested compounds have a remarkable cytotoxic effect against SH-SY5Y, and IC50 values were significantly lower than NIH-3T3 cells. The lowest IC50 value was observed in SB-Cl-OH (7.48 ± 0.86 µM) and SB-Cl-CN (7.31 ± 0.69 µM). The molecular docking of the molecules was also investigated using crystal structure of AChE enzyme protein (PDB ID: 4M0E), crystal structure of BChE protein (PDB ID: 6R6V) and SH-SY5Y cancer protein (PDB ID: 2F3F, 3PBL and 5WIV). The ADME properties of the compounds were investigated. MM/GBSA method is calculated binding free energy. Afterwards, ADME/T analysis was performed to examine the some properties of the molecules.Communicated by Ramaswamy H. Sarma.

Chemical Profile and Cytotoxicity Evaluation of Aerial Parts of Marrubium vulgare L. From Different Locations in Turkey.

Marrubium vulgare L. (Lamiaceae) is used for respiratory and gastrointestinal system disorders in folk medicine. According to European Pharmacopoeia criteria, standardization of the plant is defined by its marrubiin content. In present study, phenolics, marrubiin and essential oil compositions of M. vulgare from different locations in Turkey were analyzed quantitatively by UPLC, GC and GC/MS. Besides, their cytotoxic potentials were evaluated. In the samples, forsythoside B (77-400 mg/100 g dw), arenarioside (forsythoside F) (0-241 mg/100 g dw), verbascoside (acteoside) (171-416 mg/100 g dw) and apigenin-7-O-glucoside (0-17 mg/100 g dw) were determined in different ranges. Marrubiin contents (0.58-1.46 %) of some samples were two times higher than European Pharmacopoeia standards (0.7 %). ß-Caryophyllene (7.24-20.34 %), (Z)-ß-farnesene (1.58-34.85 %), germacrene D (9.8-13.37 %), bicyclogermacrene (1.71-8.63 %) and ß-bisabolene (0-16.68 %) were detected as major compounds in essential oils. The sample from the west of Aegean Region showed cytotoxicity against human neuroblastoma (SH-SY5Y) cell lines (IC50 : 59.80 µg/mL) although it has no effect on non-cancerous NIH-3T3cell lines. This is the first report on phenolic profiles of M. vulgare populations from Turkey. Their potential as marrubiin source for pharmaceutical industry should be considered.

Design, synthesis, and biological activity studies on benzimidazole derivatives targeting myeloperoxidase.

Myeloperoxidase (MPO) plays a key role in human antimicrobial system by oxidizing vital molecules of microorganisms in phagolysosomes through produced hypochlorous acid (HOCl). However, MPO can be released outside the phagocyte and produces reactive intermediates leading to tissue damage. MPO, as a local mediator of tissue damage, has been associated with inflammatory diseases such as renal injury, multiple sclerosis, cardiovascular and neurodegenerative diseases. Therefore, the enzyme currently draws attention as a potential therapeutic target. In this study, isomeric 1,3-dihydro-2H-benzo[d]imidazole-2-thione derivatives having amide, hydrazide and hydroxamic acid groups either on nitrogen or on sulphur atom were designed and their inhibitory activity was determined on chlorination and peroxidation cycles of MPO. Among the compounds, 2-(2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)acetohydrazide(C19) was found as the most active inhibitor on both cycles.

Comparative Evaluation of Polyphenol Contents and Biological Activities of Five Cistus L. Species Native to Turkey.

In this study phytochemical compounds and antioxidant capacity, cytotoxic, antimicrobial and anti-biofilm activities of hydroethanolic extracts of five Cistus species (C. creticus L., C. laurifolius L., C. monspeliensis L., C. parviflorus Lam. and C. salviifolius L.) distributed in Turkey were investigated. (+)-catechin, epigallocatechin gallate, quercetin-3-O-rutinoside, quercetin-3-O-glucoside, kaempferol-3-O-glucoside, luteolin were detected in different amounts. Strongest antioxidant capacities were observed with C. creticus, and C. parvifolius (0.476 and 0.452, respectively). Minimum inhibitory concentrations (MIC) of the extracts were determined between 32 and 128 µg/mL against different bacteria and Candida strains. C. monspeliensis and C. laurifolius extracts were inhibited the biofilm production levels of three Gram-negative bacteria (E. coli, S. enterica, P. aeruginosa), two Gram-positive bacteria (S. aureus, B. subtilis) and three Candida strains (C. albicans, C. parapsilosis, C. krusei). C. creticus extract showed strongest cytotoxic activity against human breast adenocarcinoma (MCF-7) and prostate cell lines (PC-3) (IC50 : 14.04±2.78 µg/mL and 34.04±2.74 µg/mL, respectively) among all plants tested.

Probiotic kefir consumption improves serum apolipoprotein A1 levels in metabolic syndrome patients: a randomized controlled clinical trial.

Metabolic syndrome has become a major health hazard of the modern world. Studies investigating the effects of traditional fermented foods on metabolic syndrome are limited. We hypothesized that regular kefir consumption could improve the anthropometrical measurements, glycemic control, lipid profile, blood pressure, and inflammatory status in patients with metabolic syndrome. Sixty-two participants were randomly assigned to receive either 180 mL/d probiotic kefir or unfermented milk for 12 weeks. Dietary intake, anthropometrical measurements, biochemical status, and blood pressure were assessed at baseline and the end of weeks 4, 8, and 12. Serum apolipoprotein A1 concentration increased by 3.4% in the kefir group, whereas it decreased by 2.4% in the milk group in 12 weeks (P = .03). A subgroup analysis for participants with low-density lipoprotein cholesterol (LDL-C) levels >130 mg/dL showed that serum LDL-C and apolipoprotein B concentrations (7.6% and 5.4%, respectively) significantly decreased with kefir consumption compared with the baseline values at the 12th week (P < .05), but not compared with milk consumption (P > .05). Both milk and kefir consumption was associated with lower systolic and diastolic blood pressure compared with the baseline (P < .05). The 12-weeks of kefir administration also decreased serum tumor necrosis factor-α, interleukin 6, interleukin 10, interferon-gamma, and homocysteine concentrations significantly (P < .05). In conclusion, regular dairy consumption as part of a well-balanced diet can provide favorable effects in the management of metabolic syndrome, and probiotic kefir may deserve a special interest among dairy products. This trial was registered at clinicaltrials.gov (NCT03966846).

Production of wheat germ oil containing multilayer hydrogel dressing.

A composite wound dressing has been developed by combining different layers consisting of polymers and textiles. Wheat germ oil (WGO) loaded hydrogels have successfully formed on textile nonwovens by cross-linking sodium alginate (SA) with poly(ethylene glycol) diglycidyl ether (PEGDGE). Following freeze-drying, textile-hydrogel composites have been examined according to their physical properties, pH, fluid handling capacity, water vapour permeability, morphology, chemical structure, and cytotoxicity. Hydrogels containing WGO swelled less than pristine hydrogels. Samples with 1% WGO and no WGO showed swelling of 5.9 and 10.5 g/g after 8 h. WGO inclusion resulted in reduced, but more stable fluid handling properties, with more uniform pore distribution (100-200 µm). Moreover, the proliferation of NIH/3T3 cells significantly improved with 1% WGO contained hydrogels. Also, commercial self-adhesive dressings that secure the hydrogels to the wound area were investigated regarding transfer properties. The proposed product demonstrated 8.05 cm3/cm2/s and 541.37 g/m2/day air and water vapour permeability.

Dexamethasone loaded PLGA nanoparticles for potential local treatment of oral precancerous lesions.

The aim of this study was to develop dexamethasone loaded nanoparticles for the local treatment of oral precancerous lesions. Dexamethasone loaded nanoparticles were prepared using the emulsification/solvent evaporation method. The prepared nanoparticles were characterized for pH, particle size, polydispersity index, zeta potential, morphology, encapsulation efficiency and drug loading. Furthermore, in vitro drug release, stability, ex vivo drug diffusion, and cell culture studies were undertaken. The particle size, polydispersity index, zeta potential, and encapsulation efficiency were found to be approximately 200 nm, 0.2, -10 mV, and 95%, respectively. Atomic Force Microscopy results showed that the formulated nanoparticles had uniform and spherical shape. In vitro release studies demonstrated 80% release of dexamethasone from nanoparticles; the nanoparticles were stable for 6 months. The ex vivo studies revealed no drug diffusion into the receptor media phase which suggests a possible local effect. Cytotoxicity studies showed that nanoparticles were non-cytotoxic against the HK-2 and NIH-3T3 cell lines. Findings of this study suggest that dexamethasone loaded PLGA nanoparticles are promising and can be further investigated as potential treatment of oral precancerous lesions.

Propolis loaded liposomes: evaluation of antimicrobial and antioxidant activities.

Propolis, a natural bee product, has both antimicrobial/antifungal and antioxidant characteristics. Active substances having antimicrobial and antifungal effects are used to avoid infections, which develop during long treatment process of chronic wounds. Antioxidant substances protect wound areas against the effect of free radicals and accelerate the healing process. For this purpose, propolis was used to develop topical liposome formulations for wound treatment. Characterization studies (particle size distribution, polydispersity index, Zeta Potential, morphology pH, loading capacity, encapsulation efficiency, in-vitro release behaviour) as well as stability studies were performed. Then in-vitro antioxidant (free radical scavenging capacity and trolox equivalent antioxidant capacity) and antimicrobial/antifungal activities of formulations have been evaluated. The particle size of formulations was found within the range of 300-750 nm depending on the concentration of lipid and water phase in the formulation. The Zeta Potential and pH values of optimum formulation were -23.0 ± 0.666 and 6.34, respectively. Loading capacity and encapsulation efficiency were 66.535 ± 2.705% and 57.321 ± 2.448%. At the end of 8 h, 48.16% of propolis was released and the formulations were found stable during 3 months at +4 °C. Drug loaded liposome formulations significantly scavenged the ABTS+ radical in a dose-dependent manner of propolis when compared with unloaded liposome formulations (p < 0.05). The minimum inhibitory concentration (MIC) values of liposomes ranged from 512 to 128 µg/mL for bacteria and 256 to 128 µg/mL for fungi. Overall results showed that effective and innovative alternative was developed for topical application in wound treatment with propolis loaded liposomal formulations having antioxidant and antimicrobial effects.

Effects of Regular Kefir Consumption on Gut Microbiota in Patients with Metabolic Syndrome: A Parallel-Group, Randomized, Controlled Study.

Several health-promoting effects of kefir have been suggested, however, there is limited evidence for its potential effect on gut microbiota in metabolic syndrome This study aimed to investigate the effects of regular kefir consumption on gut microbiota composition, and their relation with the components of metabolic syndrome. In a parallel-group, randomized, controlled clinical trial setting, patients with metabolic syndrome were randomized to receive 180 mL/day kefir (n = 12) or unfermented milk (n = 10) for 12 weeks. Anthropometrical measurements, blood samples, blood pressure measurements, and fecal samples were taken at the beginning and end of the study. Fasting insulin, HOMA-IR, TNF-α, IFN-γ, and systolic and diastolic blood pressure showed a significant decrease by the intervention of kefir (p ≤ 0.05, for each). However, no significant difference was obtained between the kefir and unfermented milk groups (p > 0.05 for each). Gut microbiota analysis showed that regular kefir consumption resulted in a significant increase only in the relative abundance of Actinobacteria (p = 0.023). No significant change in the relative abundance of Bacteroidetes, Proteobacteria or Verrucomicrobia by kefir consumption was obtained. Furthermore, the changes in the relative abundance of sub-phylum bacterial populations did not differ significantly between the groups (p > 0.05, for each). Kefir supplementation had favorable effects on some of the metabolic syndrome parameters, however, further investigation is needed to understand its effect on gut microbiota composition.

Antioxidant properties evaluation of topical astaxanthin formulations as anti-aging products.

BACKGROUND: The reactive oxygen species lead to skin aging via oxidative damage that are induced by UV radiation. Therefore, topical formulations which have antioxidant effect could reduce aging level. Astaxanthin is an antioxidant substance. AIMS: The aim of this study was to investigate antioxidant activity and cytotoxicity potential of the astaxanthin-loaded gel formulations. METHODS: Astaxanthin-loaded oleoresin and algae extract were used as natural active materials. The lipogel and hydrogel of these natural materials were prepared as anti-aging formulations. The formulations were characterized via parameters such as, pH, rheological analysis, mechanical properties, and stability. And also in vitro release experiments of the formulations were carried out. The antioxidant activity and cytotoxicity test were performed. RESULTS: The results of characterization studies confirmed the formulations suitable for topical application. After 24 hours, 99 µg, 88.3 µg, 403 µg, and 234.8 µg of astaxanthin released through oleoresin lipogel, oleoresin hydrogel, algae extract lipogel, and algae extract hydrogel, respectively. It was found by the cytotoxicity tests that astaxanthin is more proliferative in lipogel formulations compared to hydrogel formulations. And finally, the highest antioxidant activity was found in the algae extract hydrogel and algae extract lipogel formulation, respectively (P < .05). CONCLUSIONS: Topical formulations of astaxanthin-loaded oleoresin and algae extract were prepared successfully. At the same time, according to antioxidant activity and release studies, algae extract loaded could be suggested as topical anti-aging formulations.

Synthesis, biological evaluations and molecular modelling studies of novel indolin-2-ones designing as FGFR inhibitors.

A series of novel 3,5-disubstituted indolin-2-ones were designed and synthesized as selective FGFR inhibitors. In the design process of 3,5-disubstituted indolin-2-ones for FGFRs, molecular docking studies were performed to generate and optimize novel compounds which have FGFR inhibitory potency, theoretically. In vitro enzyme inhibitory and selectivity profiles of the synthesized compounds, and their cytotoxicity against NIH-3T3 cells were evaluated. According to enzyme inhibition assay, compound A1 (FGFR1-4; IC50 = 19.82; 5.95; 1419; 37150 nM), compound A5 (FGFR1-4; IC50 = 1890; Nd; 6.50; 18590 nM) and compound A13 (FGFR1-4; IC50 = 6.99; 1022; 17090; 8993 nM) have displayed best inhibitory potency against FGFR2, FGFR3 and FGFR1, respectively. The studied compounds have displayed low affinity to FGFR4 in comparison with other isoforms. Molecular docking study data were used to determine the binding orientations of the synthesized compounds inside FGFRs in accordance with enzyme inhibition assay data. Molecular dynamics simulations and free energy calculations were performed to determine stability, binding modes and dynamics behaviors of compound A1, A5 and A13 inside FGFR-2, FGFR-3 and FGFR-1, respectively. The compounds bearing aromatic groups at the C5 position of indolin-2-one could be lead compounds for the development of more effective and selective FGFR1-3 inhibitors.

Synthesis, biological evaluation, and docking studies of some 5-chloro-2(3H)-benzoxazolone Mannich bases derivatives as cholinesterase inhibitors.

A series of N-substituted-5-chloro-2(3H)-benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC50 = 7.53 ± 0.17 µM), while compound 11 was found to be the most active compound against BuChE (IC50 = 17.50 ± 0.29 µM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC50 = 1.04 ± 0.04 mM) than Trolox (IC50 = 1.50 ± 0.05 mM).

Dual-Prevention for UV-Induced Skin Damage: Incorporation of Melatonin-Loaded Elastic Niosomes into Octyl Methoxycinnamate Pickering Emulsions.

Incorporation of antioxidants into sunscreens is a logical approach, yet co-delivery of them with UV filters is a challenge. Here, we purposed a combination therapy, in which the chemical UV filter, octyl methoxycinnamate, was accumulated on upper skin while the antioxidant, melatonin, can penetrate deeper layers to show its effects. Melatonin-loaded elastic niosomes and octyl methoxycinnamate Pickering emulsion were prepared separately. Lyophilized elastic niosomes were dispersed into the Pickering emulsion to prepare the proposed combination formulation. The characterization studies of the formulations revealed that elastic niosomes can be prepared with tunable nanometer sizes, whereas Pickering emulsions can encapsulate the UV filter in micrometer-sized droplets. Melatonin-loaded elastic niosomes prepared with Tween80/Span80 mixture were 146 nm with a PI of 0.438, and 58.42% entrapment efficiency was achieved. The mean diameter size of the combination formulation was 27.8 µm. Ex vivo permeation studies revealed that 7.40% of octyl methoxycinnamate and 58% of melatonin were permeated through the rat skin while 27.6% octyl methoxycinnamate and 37% of melatonin accumulated in the skin after 24 h. Cell culture studies with real-time cell analyzer showed that the proposed formulation consist of melatonin-loaded elastic niosomes and octyl methoxycinnamate Pickering emulsion had no negative effect on the cell proliferation and viability. According to α,α-diphenyl-ß-picrylhydrazyl free radical scavenging method, the proposed formulation showed as high antioxidant activity as melatonin itself. It is concluded that the proposed formulation would be a promising dual therapy for UV-induced skin damage with co-delivery strategy.