Pharmacokinetics,hepatic disposition,and heart tissue distribution of 14 compounds in rat after oral administration of Qi-Li-Qiang-Xin capsule via ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry

In the present study, a specific and sensitive approach using ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry was developed and validated for the quantitative analysis of 14 constituents in rat plasma, liver, and heart. The method was fully validated and successfully applied to pharmacokinetic, hepatic disposition, and heart tissue distribution studies of 14 compounds after the oral administration of Qi-Li-Qiang-Xin capsule. Ginsenoside Rb1, alisol A, astragaloside IV, and periplocymarin were found to be highly exposed in rat plasma, while toxic components such as hypaconitine, mesaconitine, and periplocin had low circulation levels in vivo. Moreover, sinapine thiocyanate, neoline, formononetin, calycosin, and alisol A exhibited significant liver first-pass effects. Notably, high levels of alisol A, periplocymarin, benzoylmesaconine, and benzoylhypaconine were observed in the heart. Based on high exposure and appropriate pharmacokinetic features in the systemic plasma and heart, astragaloside IV, ginsenoside Rb1, periplocymarin, benzoylmesaconine, benzoylhypaconine, and alisol A can be considered as the main potentially effective components. Ultimately, the results provide relevant information for discovery of effective substances, as well as further anti-heart failure action mechanism investigations of Qi-Li-Qiang-Xin capsule.     

Solvent free synthesis,characterization, DFT,cyclic voltammetry and biological assay of Cu(II), Hg(II) and UO2(II) – Schiff base complexes

A series of metal ion complexes was prepared in solid state from Cu(II), Hg(II) and UO₂(II) ions with 3-oxo-3-(2-(2-oxoindolin-3-ylidene)hydrazineyl)-N-phenylpropanamide (H₃L) ligand through solvent free synthesis methodology. The chemical formulae of the new compounds were estimated according to variable spectral and analytical investigations. The ligand exhibited a neutral or mononegative tetradentate mode of coordination towards the central ions inside the octahedral arrangement that proposed for the three complexes. The DFT/B3LYP method was applied under different basis sets (6-31G*or SDD) to optimize the structures of new compounds except the UO₂(II) complex. The computational data were investigated to verify the binding mode that suggested spectrally. Moreover, studies in solution regarding Cu(II) ion via cyclic voltammetry were performed in absence or presence of H₃L, to realize the significant effect of complex formation on the electrochemical manners of copper. The shifts in the potential peaks accompanied by the changes in the values of parameters correspond to kinetic and thermodynamic. Also, the solvation and kinetic characteristics for the cathodic and anodic potential of Cu(II) ion in absence or presence of H₃L at different scan rates, were estimated. Finally, the ligand and copper ion exhibited high affinity towards complexation in solution. Furthermore, the activity of the new compounds towards inhibiting microbes was studied against Staphylococcus aureus (G+) and Escherichia coli (G-) bacteria as well as Candida albicans (fungus) by determining the inhibition zone diameter. Also, both the antioxidant and cytotoxic activity of the isolated compounds were evaluated. Commonly, a remarkable antimicrobial and anticancer activity was appeared with UO₂(II) complex and the ligand. While, the antioxidant activity of all compounds appeared lower.     

Phytochemical profiling,in vitro biological activities,and in-silico molecular docking studies of Typha domingensis

A comparative study between methanolic extract and n-hexane fraction of Typha domingensis (Typhaceae) was conducted for the evaluation of phytochemical potential, in vitro biological activities, and in-silico molecular docking studies. The phytochemical composition was estimated by total phenolic and total flavonoid contents, and by GC–MS analysis. Several biological activities were performed such as antioxidant assays (ABTS, FRAP, DPPH, & CUPRAC), enzyme inhibition activity (Tyrosinase, Acetylcholinesterase & Butyrylcholinesterase), thrombolytic activity, and antimicrobial activity (antibacterial & antiviral) to evaluate the medicinal importance of Typha domingensis. The results of the comparative study showed that methanolic extract has more total phenolic and total flavonoid contents (95.72 ± 5.76 mg GAE/g, 131.66 ± 7.92 mg QE/g, respectively) as compared to n-hexane fraction which confirms its maximum antioxidant potential (ABTS 114.31 ± 8.17, FRAP 116.84 ± 3.01, DPPH 283.54 ± 7.3 & CUPRAC 284.16 ± 6.5 mg TE/g). In the case of in vitro enzyme inhibition study and thrombolytic activity, better results were observed for methanolic extract. Almost similar antimicrobial patterns were observed for both methanolic extract and n-hexane fraction of Typha domingensis. The major bioactive phytochemicals identified by GC–MS were further analyzed for in-silico molecular docking studies to determine the binding affinity between ligands and the enzymes. The docking study indicated that most of the bioactive compounds showed a better binding affinity with enzymes as compared to the standard compounds (kojic acid & galantamine). The results of this study recommended that Typha domingensis has promising pharmaceutical importance and it should be further analyzed for the isolation of bioactive phytochemicals which may be useful for the treatment of several diseases.     

Localized surface plasmon resonance properties and biomedical applications of copper selenide nanomaterials

Nanomaterials with localized surface plasmon resonance (LSPR) locating in the near-infrared region have broad application prospects in the field of biomedicine. However, the biggest problem that limits the biomedical application of such nanomaterials lies in two aspects: First, the potential long-term in vivo toxicity caused by the metabolism of many nanomaterials with LSPR effect; Second, most of current nanomaterials with LSPR effect are difficult to achieve LSPR wavelength tunability in the near-infrared region to adapt to different biomedical applications. Copper selenide nanomaterials are composed of selenium and copper, which are necessary nutrient elements for human life. Because of the active and flexible chemical properties of selenium and copper, copper selenide nanomaterials can not only be effectively degraded and utilized in human body, but also be endowed with various physicochemical properties by chemical modification or doping. Recently, copper selenide nanomaterials have shown unique properties such as LSPR in the near-infrared region, making them attractive for near-infrared thermal ablation, photoacoustic imaging, disease marker detection, multimode imaging, and so on. Currently, to the best of our knowledge, there is no review on the LSPR properties of copper selenide nanomaterials and its biomedical applications. This review first discusses the relationship between the physicochemical properties and the LSPR of copper selenide nanomaterials and then summarizes the latest progress in the application of copper selenide nanomaterials in biological detection, diagnosis, and treatment of diseases. In addition, the advantages, and prospects of copper selenide nanomaterials in biomedicine are also highlighted.     

Evaluation of PEGylated fibrin as a three-dimensional biodegradable scaffold for ovarian tissue engineering

The most challenging task of creating a bioengineered ovary to restore fertility in cancer patients is choosing an appropriate biomaterial to encapsulate isolated preantral follicles and ovarian cells. In this study, as a biocompatible and biodegradable biomaterial containing fibrin-like bioactivity and manageable physical properties, PEGylated fibrin aims to encapsulate isolated ovarian stromal cells as a first step of creating an engineered ovarian tissue. For this purpose, human ovarian stromal cells were isolated from frozen-thawed ovarian tissue and cultured in the PEGylated fibrin hydrogels (PEG:Fib), which were fabricated by combining two different molar ratios of PEG:Fib (10:1 and 5:1) and two thrombin concentrations. The samples were analyzed at days 0 and 5 of in vitro for cell density, proliferation (Ki67), and apoptosis (caspase-3). Moreover, LIVE/DEAD and PrestoBlue assays assessed cell viability and proliferation on days 1, 3, and 5. The effect of PEGylation on the biodegradation behavior of fibrin was evaluated by measuring the remaining mass ratio of non-modified fibrin, PEG:Fib 10:1, and PEG:Fib 5:1 hydrogels after 1, 2, 3, 5, 8, 11, and 15 days. The results showed that PEGylated fibrin hydrogels enhanced scaffold stability and supported cell viability and proliferation. In addition, PEG:Fib 5:1 T50 indicated a significantly higher cell density dynamic and non-significantly lower expression of caspase-3 on day 5. Besides, uniformity of cell distribution inside the hydrogel and a tendency to a high rate of Ki67-positive cells was observed in PEG:Fib 10:1 T50 hydrogels. In conclusion, this study reveals the positive effects of PEGylated fibrin hydrogels on isolated human ovarian stromal cells. Based on such promising findings, we believe that this matrix should be tested to encapsulate isolated human ovarian follicles.     

Keratin Scaffolds Containing Casomorphin Stimulate Macrophage Infiltration and Accelerate Full-Thickness Cutaneous Wound Healing in Diabetic Mice

Impaired wound healing is a major medical challenge, especially in diabetics. Over the centuries, the main goal of tissue engineering and regenerative medicine has been to invent biomaterials that accelerate the wound healing process. In this context, keratin-derived biomaterial is a promising candidate due to its biocompatibility and biodegradability. In this study, we evaluated an insoluble fraction of keratin containing casomorphin as a wound dressing in a full-thickness surgical skin wound model in mice (n = 20) with iatrogenically induced diabetes. Casomorphin, an opioid peptide with analgesic properties, was incorporated into keratin and shown to be slowly released from the dressing. An in vitro study showed that keratin-casomorphin dressing is biocompatible, non-toxic, and supports cell growth. In vivo experiments demonstrated that keratin-casomorphin dressing significantly (p < 0.05) accelerates the whole process of skin wound healing to the its final stage. Wounds covered with keratin-casomorphin dressing underwent reepithelization faster, ending up with a thicker epidermis than control wounds, as confirmed by histopathological and immunohistochemical examinations. This investigated dressing stimulated macrophages infiltration, which favors tissue remodeling and regeneration, unlike in the control wounds in which neutrophils predominated. Additionally, in dressed wounds, the number of microhemorrhages was significantly decreased (p < 0.05) as compared with control wounds. The dressing was naturally incorporated into regenerating tissue during the wound healing process. Applied keratin dressing favored reconstruction of more regular skin structure and assured better cosmetic outcome in terms of scar formation and appearance. Our results have shown that insoluble keratin wound dressing containing casomorphin supports skin wound healing in diabetic mice.     

Exploration of carbonic anhydrase inhibition of bioactive metabolites from Pistacia integerrima by molecular docking and first-principles investigations

Bioassay guided fractionation of Pistacia integerrima crude methanolic extract gave Pistacide-A (1) and Pistacide-B (2), along with ten known phytochemicals (3–12). Biochemical analysis of crude plant extract, in-vitro and in-silico carbonic anhydrase inhibitory potential of newly isolated compounds Pistacide-A (1) and Pistacide-B (2) were performed. The cytotoxicity of extract in methanol, ethylacetate and n-butanol against Artemia salina brine-shrimp was 34.98 g/ml, 160.81 g/ml, and 135.77 g/ml, respectively. The significant antimicrobial activity was exhibited by crude, ethyl acetate, and n-butanol fractions. Compounds 1 (IC₅₀ = 6.51 ± 0.42 mM) and 2 (IC₅₀ = 2.85 ± 0.09 mM) showed good carbonic anhydrase inhibition compared with standard zonisamide drug (IC₅₀ = 1.87 ± 0.003 mM). In addition, we have also clarified the electronic properties, absorption wavelengths, molecular electrostatic potential and Hirshfeld analysis by first-principles studies. The coherent intra-molecular charge transfer was seen from occupied to unoccupied molecular orbitals. The absorption wavelengths calculated at time dependent B3LYP/6-31G** level in methanol provided excellent accord with the experimental evidence. Molecular docking score revealed that Pistacide-B would be an efficient drug than its other counterpart that is rational to the experimental data.     

Investigation of Parameters Influencing Tubular-Shaped Chitosan-Hydroxyapatite Layer Electrodeposition

Tubular-shaped layer electrodeposition from chitosan-hydroxyapatite colloidal solutions has found application in the field of regeneration or replacement of cylindrical tissues and organs, especially peripheral nerve tissue regeneration. Nevertheless, the quantitative and qualitative characterisation of this phenomenon has not been described. In this work, the colloidal systems are subjected to the action of an electric current initiated at different voltages. Parameters of the electrodeposition process (i.e., total charge exchanged, gas volume, and deposit thickness) are monitored over time. Deposit structures are investigated by scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR). The value of voltage influences structural characteristics but not thickness of deposit for the process lasting at least 20 min. The calculated number of exchanged electrons for studied conditions suggests that the mechanism of deposit formation is governed not only by water electrolysis but also interactions between formed hydroxide ions and calcium ions coordinated by chitosan chains.     

Two Ecdysteroids Isolated from Micropropagated Lychnis flos-cuculi and the Biological Activity of Plant Material

Genetically uniform plant material, derived from Lychnis flos-cuculi propagated in vitro, was used for the isolation of 20-hydroxyecdysone and polypodine B and subjected to an evaluation of the antifungal and antiamoebic activity. The activity of 80% aqueous methanolic extracts, their fractions, and isolated ecdysteroids were studied against pathogenic Acanthamoeba castellani. Additionally, a Microtox^® acute toxicity assay was performed. It was found that an 80% methanolic fraction of root extract exerts the most potent amoebicidal activity at IC₅₀ of 0.06 mg/mL at the 3rd day of treatment. Both ecdysteroids show comparable activity at IC₅₀ of 0.07 mg/mL. The acute toxicity of 80% fractions at similar concentrations is significantly higher than that of 40% fractions. Crude extracts exhibited moderate antifungal activity, with a minimum inhibitory concentration (MIC) within the range of 1.25–2.5 mg/mL. To the best of our knowledge, the present report is the first to show the biological activity of L. flos-cuculi in terms of the antifungal and antiamoebic activities and acute toxicity. It is also the first isolation of the main ecdysteroids from L. flos-cuculi micropropagated, ecdysteroid-rich plant material.     

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors,Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A_2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.