The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [³⁵S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study. Full article

KD025 (SLx-2119), the first specific Rho-associated protein kinase 2 (ROCK2) inhibitor, is a potential new drug candidate currently undergoing several phase 2 clinical trials for psoriasis, idiopathic pulmonary fibrosis, chronic graft-versus-host disease, and systemic sclerosis. In this study, a bio-analytical method was developed and fully validated for the quantification of KD025 in rat plasma and for application in pharmacokinetic studies. KD025 and GSK429286A (the internal standard) in rat plasma samples were analyzed by high-performance liquid chromatography-tandem mass spectrometry with m/z transition values of 453.10 → 366.10 and 433.00 → 178.00, respectively. The method was fully validated according to the United State Food and Drug Administration guidelines in terms of selectivity, linearity, accuracy, precision, sensitivity, matrix effects, extraction recovery, and stability. The method enabled the quantification of KD025 levels in rat plasma following oral administration of 5 mg/kg KD025 and intravenous administration of 2 mg/kg KD025 to rats, respectively. Our findings suggest that the developed method is practical and reliable for pharmacokinetic studies of KD025 in preclinical animals. Full article

Two novel symmetrical bis-azobenzene red dyes ending with electron-withdrawing or donor groups were synthesized. Both chromophores display good solubility, excellent chemical, and thermal stability. The two dyes are fluorescent in solution and in the solid-state. The spectroscopic properties of the neat crystalline solids were compared with those of doped blends of different amorphous matrixes. Blends of non-conductive and of emissive and conductive host polymers were formed to evaluate the potential of the azo dyes as pigments and as fluorophores. Both in absorbance and emission, the doped thin layers have CIE coordinates in the spectral region from yellow to red. The fluorescence quantum yield measured for the brightest emissive blend reaches 57%, a remarkable performance for a steadily fluorescent azo dye. A DFT approach was employed to examine the frontier orbitals of the two dyes. Full article

Establishing the metabolism pathway of the drug undergoing the hepatic biotransformation pathway is one of the most important aspects in the preclinical discovery process since the presence of toxic or reactive metabolites may result in drug withdrawal from the market. In this study, we present the structural elucidation of six, not described yet, metabolites of an antipsychotic molecule: molindone. The elucidation of metabolites was supported with a novel photocatalytical approach with the use of WO₃ and WS₂ assisted photochemical reactions. An UHPLC-ESI-Q-TOF combined system was used for the registration of all obtained metabolite profiles as well as to record the high resolution fragmentation spectra of the observed transformation products. As a reference in the in vitro metabolism simulation method, the incubation with human liver microsomes was used. Chemometric comparison of the obtained profiles pointed out the use of the WO₃ approach as being more convenient in the field of drug metabolism studies. Moreover, the photocatalysis was used in the direction of the main drug metabolite synthesis in order to further isolation and characterization. Full article

Drought stress is becoming more prevalent with global warming, and has been shown to have large effects on gluten proteins linked to wheat bread making quality. Likewise, low temperature stress can detrimentally affect proteins in wheat. This study was done to determine the differential abundance of high molecular weight (HMW) glutenin proteins in a drought and low temperature stressed high quality hard red spring wheat cultivar (PAN3478), against a control. The treatments were applied in the greenhouse at the soft dough stage. HMW glutenin proteins were extracted from the flour, and were separated by using two-dimensional gel electrophoresis. Protein spots that had p values lower than 0.05 and fold values equal to or greater than 1.2 were considered to be significantly differentially abundant. These proteins were further analyzed by using tandem mass spectrometry. There was a 1.3 to 1.8 fold change in 17 protein spots due to the cold treatment. The drought treatment caused a 1.3 to 3.8 fold change in 19 protein spots. These spots matched either HMW or low molecular weight (LMW) glutenin subunits. In the latter case, the C subunits of LMW glutenins were notably found to be up-regulated under both stress conditions. All the proteins that have been identified can directly influence dough characteristics. Data are available via ProteomeXchange with the identifier PXD017578. Full article

The aim of the present study was to determine the antioxidant and antimicrobial properties in freeze-dried extracts of rose fruits (Rosa rugosa) obtained using various extraction techniques and to determine the effect of a selected extract on bacterial survival in model fluids imitating protein food. Ethanolic extracts from rose fruits showed higher antioxidant activity compared to other tested extracts. The rose fruits aqueous extract showed the highest inhibitory activity against most of the 10 bacterial strains tested. From the group of Gram-positive bacteria, the Bacillus cereus strain proved to be the most sensitive to the action of the rose extract. From the Gram-negative bacteria: Escherichia coli and Klebsiella pneumoniae were the most sensitive. The reduction in the number of bacterial cells in matrices imitating protein food depended on the concentration of the aqueous extract used. However, at none of the concentrations used was a complete inhibition of bacterial growth observed. We have confirmed that the traditional extraction and freeze-drying of rose fruits is still suitable for the food industry due to obtaining extracts with good antibacterial and antioxidant properties and the use of bio-solvents, such as water or ethanol, which are easily available in high purity and completely biodegradable. Full article

The present review presents an overview of antitumor pyrazoles of natural or bioinspired origins. Pyrazole compounds are relatively rare in nature, the first ones having been reported in 1966 and being essentially used as somniferous drugs. Cytotoxic pyrazoles of natural sources were first isolated in 1969, and a few others have been reported since then, most of them in the last decade. This paper presents a perspective on the current knowledge on antitumor natural pyrazoles, organized into two sections. The first focuses on the three known families of cytotoxic pyrazoles that were directly isolated from plants, for which the knowledge of the medicinal properties is in its infancy. The second section describes pyrazole derivatives of natural products, discussing their structure–activity relationships. Full article

Halogenidoantimonate(III) monohydrates of the (C₄H₁₂N₂)[SbX₅]·H₂O (X = Cl, 1 or Br, 2) formula, crystallizing in the same monoclinic space group of P2₁/n, are isostructural, with an isostructurality index close to 99%. The single crystal X-ray diffraction data do not show any indication of phase transition in cooling these crystals from room temperature to 85 K. Both hybrid crystals are built up from [SbX₆]^3– octahedra that are joined together by a common edge forming isolated bioctahedral [Sb₂X₁₀]^4– units, piperazine-1,4-diium (C₄H₁₂N₂)²⁺ cations and water of crystallization molecules. These structural components are joined together by related but somewhat different O/N/C–H···X and N–H···O hydrogen bonded systems. The evolution of structural parameters, notably the secondary Sb–X bonds along with the associated X/Sb–Sb/X–X/Sb angles and O/N/C–H···X hydrogen bonds, as a function of ligand exchange and temperature, along with their influence on the irregularity of [SbX₆]^3– octahedra, was determined. The comparison of packing features and hydrogen bond parameters, additionally supported by the Hirshfeld surface analysis and data retrieved from the Cambridge Structural Database, demonstrates the hierarchy and importance of hydrogen bond interactions that influence the irregularity of single [SbX₆]^3– units. Full article

Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using [¹¹C]carfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids. Full article

In our natural products screening program for mosquitoes, we tested essential oils extracted from different plant parts of Magnolia grandiflora L. for their insecticidal and biting deterrent activities against Aedes aegypti. Biting deterrence of seeds essential oil with biting deterrence index value of 0.89 was similar to N,N-diethyl-3-methylbenzamide (DEET). All the other oils were active above the solvent control but the activity was significantly lower than DEET. Based on GC-MS analysis, three pure compounds that were only present in the essential oil of seed were further investigated to identify the compounds responsible for biting deterrent activity. 1-Decanol with PNB value of 0.8 was similar to DEET (PNB = 0.8), whereas 1-octanol with PNB value of 0.64 showed biting deterrence lower than 1-decanol and DEET. The activity of 1-heptanol with PNB value of 0.36 was similar to the negative control. Since 1-decanol, which was 3.3% of the seed essential oil, showed biting deterrence similar to DEET as a pure compound, this compound might be responsible for the activity of this oil. In in vitro A & K bioassay, 1-decanol with MED value of 6.25 showed higher repellency than DEET (MED = 12.5). Essential oils of immature and mature fruit showed high toxicity whereas leaf, flower, and seeds essential oils gave only 20%, 0%, and 50% mortality, respectively, at the highest dose of 125 ppm. 1-Decanol with LC₅₀ of 4.8 ppm was the most toxic compound. Full article

This study aimed to assess the physicochemical, nutritional and sensory properties of gluten-free breads containing isolated coffee cascara dietary fiber (ICCDF) as a food ingredient. ICCDF was obtained by aqueous extraction. The oil and water holding capacity and the nutritional profile of the novel ingredient were determined. Its safety was certificated by analysis of ochratoxin A, caffeine and gluten. Gluten-free bread formulations were prepared enriching a commercial bakery premix in rice protein (8%) and ICCDF (3% and 4.5%). Nutritional profile of the novel gluten-free breads (dietary fiber, protein, amino acids, lipids, fatty acid profile and resistant starch), as well as bread volume, crumb density, moisture, firmness, elasticity and color intensity were determined. A sensory quantitative descriptive analysis of the breads was conducted using eight trained panelists. New breads showed significantly higher (p < 0.05) content of dietary fiber and protein than the control bread. The addition of ICCDF allowed increasing dough yield, a less crumb firmness and a higher crumb elasticity. The nutrition claims “source of protein and high in dietary fiber” were assigned to the new formulations. In conclusion, a certificated gluten-free bread with improved nutritional and physicochemical properties and good sensorial profile was obtained. Full article

Encapsulated fat-soluble powders containing vitamin A (VA) and E (VE) were prepared as a feasible additive for extruded feed products. The effect of the encapsulating agents (Capsul-CAP^®, sodium caseinate-SC) in combination with Tween 80 (TW) as an emulsifier and maltodextrin (MD) as a wall material on the physicochemical properties of emulsions and powders was evaluated. First, nanoemulsions containing MD:CAP:TW:VA/VE and MD:SC:TW:VA/VE were prepared and characterized. Then, powders were obtained by means of spray-drying and analyzed in terms of the product yield, encapsulation efficiency, moisture content, porosity, surface morphology, chemical structure, and thermal properties and thermo-oxidative/thermal stability. Results showed that although nanoemulsions were obtained for all the compositions, homogeneous microcapsules were found after the drying process. High product yield and encapsulation efficiency were obtained, and the presence of the vitamins was corroborated. The characteristics of the powders were mainly influenced by the encapsulating agent used and also by the type of vitamin. In general, the microcapsules remained thermally stable up to 170 °C and, therefore, the proposed encapsulation systems for vitamins A and E were suitable for the preparation of additives for the feed manufacturing through the extrusion process. Full article

Sustainable production of secondary metabolites in medicinal plants by artificial culturing on the industrial scale has gained worldwide importance. Engineered nanoparticles (ENPs) play a pivotal role in the elicitation of compounds of medicinal value. This investigation explores the influence of ZnO and CuO ENPs on in vitro roots formation, non-enzymatic antioxidant activities, and production of steviol glycosides (SGs) in regenerants of Candyleaf, Stevia rebaudiana. ENPs were applied in 0, 2, 20, 200, and 2000 mg/L of concentration in the MS medium containing plant shoots. The percentage of rooting induced was 91% and 94% by applying ZnO ENPs (2 mg/L) and CuO ENPs (20 mg/L), respectively. Moreover, at 2 mg/L of ZnO and 20 mg/L of CuO ENPs, the high performance liquid chromatography studies determined the significantly greatest content of SGs; rebaudioside A (4.42 and 4.44) and stevioside (1.28 and 1.96). Phytochemical studies including total flavonoid content, total phenolic content, and 2,2-diphenyl-1-picryl hydrazyl-free radical scavenging activity were calculated highest by the regenerants grown in 2 mg/L of ZnO and 20 mg/L of CuO ENPs dosage. Both ZnO and CuO ENPs at 200 mg/L and 2000 mg/L of concentration induced adverse effects on plant biomass, antioxidant activities, and SGs content up to 1.22 and 1.77 for rebaudioside A and 0.21 and 0.25 for stevioside. Hence, the biochemical and morphophysiological responses of Candyleaf were elicited as a defense against ZnO and CuO ENPs applied under threshold limit. This artificial biotechnological technique holds great promise for continued production of natural antioxidants on commercial scale and our study has further strengthened this impact. Full article