Stability of caffeic acid phenethyl amide (CAPA) in rat plasma

A validated C₁₈ reverse‐phase HPLC method with UV detection at 320 nm was developed and used for the stability evaluation of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) in rat plasma. CAPA is the amide derivative of CAPE, a naturally occurring polyphenolic compound that has been found to be active in a variety of biological pathways. CAPA has been shown to protect endothelial cells against hydrogen peroxide‐induced oxidative stress to a similar degree to CAPE. CAPE has been reported to be rapidly hydrolyzed in rat plasma via esterase enzymes. CAPA is expected to display a longer half‐life than CAPE by avoiding hydrolysis via plasma esterases. The stability of CAPA and CAPE in rat plasma was investigated at three temperatures. The half‐lives for CAPA were found to be 41.5, 10 and 0.82 h at 25, 37 and 60 °C, respectively. The half‐lives for CAPE were found to be 1.95, 0.35 and 0.13 h at 4, 25 and 37 °C, respectively. The energy of activation was found to be 22.1 kcal/mol for CAPA and 14.1 kcal/mol for CAPE. A more stable compound could potentially extend the beneficial effects of CAPE. Copyright © 2011 John Wiley & Sons, Ltd.     

A Novel Synthetic Precursor of Styryl Sulfone Neuroprotective Agents Inhibits Neuroinflammatory Responses and Oxidative Stress Damage through the P38 Signaling Pathway in the Cell and Animal Model of Parkinson’s Disease

A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson’s disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP⁺)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.     

明胶/胶原改性的研究进展

明胶/胶原因其优良的理化性质和生物学性能而在生物材料、食品包装等方面得到了广泛的应用,但其热稳定性差、机械强度低、水汽阻隔性能差等缺点限制了它的应用,因此在很多应用场合需要对明胶/胶原进行交联改性处理。本文主要综述了近年来国内外对明胶/胶原进行共混和化学交联改性以及物理改性的研究进展,并对其作用效果进行了分析。     

Ultra high performance liquid chromatography-quadrupole-time of flight analysis for the identification and the determination of resveratrol and its metabolites in mouse plasma

Resveratrol is a polyphenol that has numerous interesting biological properties, but, per os, it is quickly metabolized. Some of its metabolites are more concentrated than resveratrol, may have greater biological activities, and may act as a kind of store for resveratrol. Thus, to understand the biological impact of resveratrol on a physiological system, it is crucial to simultaneously analyze resveratrol and its metabolites in plasma. This study presents an analytical method based on UHPLC-Q-TOF mass spectrometry for the quantification of resveratrol and of its most common hydrophilic metabolites. The use of ¹³C- and D-labeled standards specific to each molecule led to a linear calibration curve on a larger concentration range than described previously. The use of high resolution mass spectrometry in the full scan mode enabled simultaneous identification and quantification of some hydrophilic metabolites not previously described in mice. In addition, UHPLC separation, allowing run times lower than 10 min, can be used in studies that requiring analysis of many samples.     

The Influence of Polysaccharides/TiO2 on the Model Membranes of Dipalmitoylphosphatidylglycerol and Bacterial Lipids

The aim of the study was to determine the bactericidal properties of popular medical, pharmaceutical, and cosmetic ingredients, namely chitosan (Ch), hyaluronic acid (HA), and titanium dioxide (TiO₂). The characteristics presented in this paper are based on the Langmuir monolayer studies of the model biological membranes formed on subphases with these compounds or their mixtures. To prepare the Langmuir film, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) phospholipid, which is the component of most bacterial membranes, as well as biological material-lipids isolated from bacteria Escherichia coli and Staphylococcus aureus were used. The analysis of the surface pressure-mean molecular area (π-A) isotherms, compression modulus as a function of surface pressure, C_S⁻¹ = f(π), relative surface pressure as a function of time, π/π₀ = f(t), hysteresis loops, as well as structure visualized using a Brewster angle microscope (BAM) shows clearly that Ch, HA, and TiO₂ have antibacterial properties. Ch and TiO₂ mostly affect S. aureus monolayer structure during compression. They can enhance the permeability of biological membranes leading to the bacteria cell death. In turn, HA has a greater impact on the thickness of E. coli film.     

Chemistry and Bioactivity of Microsorum scolopendria (Polypodiaceae): Antioxidant Effects on an Epithelial Damage Model

Microsorum scolopendia (MS), which grows on the Chilean island of Rapa Nui, is a medicinal fern used to treat several diseases. Despite being widely used, this fern has not been deeply investigated. The aim of this study was to perform a characterization of the polyphenolic and flavonoid identity, radical scavenging, antimicrobial, and anti-inflammatory properties of MS rhizome and leaf extracts (RAE and HAE). The compound identity was analyzed through the reversed-phase high-performance liquid chromatography (RP-HPLC) method coupled with mass spectrometry. The radical scavenging and anti-inflammatory activities were evaluated for DPPH, ORAC, ROS formation, and COX inhibition activity assay. The antimicrobial properties were evaluated using an infection model on Human Dermal Fibroblast adult (HDFa) cell lines incubated with Staphylococcus aureus and Staphylococcus epidermidis. The most abundant compounds were phenolic acids between 46% to 57% in rhizome and leaf extracts, respectively; followed by flavonoids such as protocatechic acid 4-O-glucoside, cirsimaritin, and isoxanthohumol, among others. MS extract inhibited and disaggregated the biofilm bacterial formed and showed an anti-inflammatory selective property against COX-2 enzyme. RAE generated a 64% reduction of ROS formation in the presence of S. aureus and 87.35% less ROS in the presence of S. epidermidis on HDFa cells. MS has great therapeutic potential and possesses several biological properties that should be evaluated.     

Metalloporphyrin Metal–Organic Frameworks: Eminent Synthetic Strategies and Recent Practical Exploitations

The emergence of metal–organic frameworks (MOFs) in recent years has stimulated the interest of scientists working in this area as one of the most applicable archetypes of three-dimensional structures that can be used as promising materials in several applications including but not limited to (photo-)catalysis, sensing, separation, adsorption, biological and electrochemical efficiencies and so on. Not only do MOFs have their own specific versatile structures, tunable cavities, and remarkably high surface areas, but they also present many alternative procedures to overcome emerging obstacles. Since the discovery of such highly effective materials, they have been employed for multiple uses; additionally, the efforts towards the synthesis of MOFs with specific properties based on planned (template) synthesis have led to the construction of several promising types of MOFs possessing large biological or bioinspired ligands. Specifically, metalloporphyrin-based MOFs have been created where the porphyrin moieties are either incorporated as struts within the framework to form porphyrinic MOFs or encapsulated inside the cavities to construct porphyrin@MOFs which can combine the peerless properties of porphyrins and porous MOFs simultaneously. In this context, the main aim of this review was to highlight their structure, characteristics, and some of their prominent present-day applications.     

Poly(ethylene oxide)-block-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone) diblock copolymer nanocarriers for enhanced solubilization of caffeic acid phenethyl ester

We report novel micellar carriers, comprising pendant cinnamyl moieties in the core-forming block, designed to increase the solubilization of caffeic acid phenethyl ester (CAPE) in aqueous media. Amphiphilic poly(ethylene oxide)-block-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone) (PEO-b-P(CyCL-co-CL) diblock copolymers were synthesized by ring-opening copolymerization of α-propargyl-ε-caprolactone and ε-caprolactone from a monofunctional PEO macroinitiator and subsequent attachment of cinnamyl groups via click reaction. In addition, a linear PEO-b-PCL diblock copolymer was synthesized and used in this study for comparison. Next, nanosized micelles from PEO-b-P(CyCL-co-CL) and PEO-b-PCL were formed via the solvent evaporation method and then loaded with CAPE. Dynamic and electrophoretic light scattering, and transmission electron microscopy were used to characterize both blank and loaded carriers. The potential of the micelles comprising pendant cinnamyl group to solubilize CAPE in water was evaluated in a comparative fashion to that of nonmodified PEO-b-PCL diblock copolymer.     

Microalgae as a Potential Functional Ingredient: Evaluation of the Phytochemical Profile,Antioxidant Activity and In-Vitro Enzymatic Inhibitory Effect of Different Species

The functional food market has been in a state of constant expansion due to the increasing awareness of the impact of the diet on human health. In the search for new natural resources that could act as a functional ingredient for the food industry, microalgae represent a promising alternative, considering their high nutritional value and biosynthesis of numerous bioactive compounds with reported biological properties. In the present work, the phytochemical profile, antioxidant activity, and enzymatic inhibitory effect aiming at different metabolic disorders (Alzheimer’s disease, Type 2 diabetes, and obesity) were evaluated for the species Porphyridium purpureum, Chlorella vulgaris, Arthorspira platensis, and Nannochloropsis oculata. All the species presented bioactive diversity and important antioxidant activity, demonstrating the potential to be used as functional ingredients. Particularly, P. purpureum and N. oculata exhibited higher carotenoid and polyphenol content, which was reflected in their superior biological effects. Moreover, the species P. purpureum exhibited remarkable enzymatic inhibition for all the analyses.     

Development and validation of an LCMS method to determine the pharmacokinetic profiles of caffeic acid phenethyl amide and caffeic acid phenethyl ester in male Sprague–Dawley rats

A validated LCMS method was developed for the quantitative determination of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) from rat plasma. Separation was achieved using a reverse‐phase C₁₂ HPLC column (150 × 2.00 mm, 4 µm) with gradient elution running water (A) and acetonitrile (B). Mass spectrometry was performed with electrospray ionization in negative mode. This method was used to determine the pharmacokinetic profiles of CAPA and CAPE in male Sprague–Dawley rats following intravenous bolus administration of 5, 10 and 20 mg/kg of CAPA and 20 mg/kg of CAPE. The pharmacokinetic analysis suggests the lack of dose proportionality in the dose range of 5–20 mg/kg of CAPA. Total clearance values for CAPA ranged from 45 to 156 mL/min and decreased with increasing dose of CAPA. The volume of distribution for CAPA ranged from 17,750 to 52,420 mL, decreasing with increasing dose. The elimination half‐life for CAPA ranged from 243.1 to 295.8 min and no statistically significant differences were observed between dose groups in the range of 5–20 mg/kg (p > 0.05). The elimination half‐life for CAPE was found to be 92.26 min. Copyright © 2013 John Wiley & Sons, Ltd.     

Quantitative analysis of caffeic acid phenethyl ester in crude propolis by liquid chromatography-electrospray ionization mass spectrometry

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have antimitogenic, anticarcinogenic, antinflammatory, and immunomodulatory properties. The paper describes a rapid and simple liquid chromatography-electrospray ionisation mass spectrometry method for qualitative and quantitative determination of CAPE. The chromatographic separation was performed with a Luna RP-C18 column using a water-acetonitrile linear gradient. The method was linear over a 0.125-80 ng/mL range (LOD = 62.5 pg/mL). The method was applied for the quantitation of caffeic acid phenethyl ester in crude propolis samples, which were analysed directly after extraction with ethyl acetate solution.     

Alleviation of Ulcerative Colitis Potentially through th1/th2 Cytokine Balance by a Mixture of Rg3-enriched Korean Red Ginseng Extract and Persicaria tinctoria

Ginseng is a vastly used herbal supplement in Southeast Asian countries. Red ginseng extract enriched with Rg3 (Rg3-RGE) is a formula that has been extensively studied owing to its various biological properties. Persicaria tinctoria (PT), belonging to the Polygonaceae family, has also been reported for its anti-inflammatory properties. Ulcerative colitis (UC) is inflammation of the large intestine, particularly in the colon. This disease is increasingly common and has high probability of relapse. We investigated, separately and in combination, the effects of Rg3-RGE and PT using murine exemplary of UC induced by DSS (Dextran Sulfate Sodium). For in vitro and in vivo experiments, nitric oxide assay, qRT-Polymerase Chain Reaction (PCR), Western blot, ulcerative colitis introduced by DSS, Enzyme Linked Immunosorbent Assay (ELISA), and flow cytometry analysis were performed. The results obtained demonstrate that treatment with Rg3-RGE + PT showed synergism to suppress inflammation (in vitro) in RAW 264.7 cells via mitogen-activated protein kinase and nuclear factor κB pathways. Moreover, in C57BL/6 mice, this mixture exhibits strong anti-inflammatory effects in restoring colon length, histopathological damage, pro-inflammatory mediators, and cytokines amount, and decreasing levels of NLRP3 inflammasome (in vivo). Our results recommend that this mixture can be used for the prevention of UC as a prophylactic/therapeutic supplement.     

Stability of caffeic acid phenethyl ester and its fluorinated derivative in rat plasma

The stability of caffeic acid phenethyl ester (CAPE) and its fluorinated derivative (FCAPE) in rat plasma and conditions preventing their degradation are reported. Reverse-phase high-pressure liquid chromatography (HPLC) using taxifolin as an internal standard was applied for the quantitative determination of CAPE and FCAPE in rat plasma extracted with ethyl acetate. The assay was validated over a linear range of 0.25-10 microg/mL plasma (r(2) > 0.9990, n = 3). No endogenous interferences were observed in the chromatographic region of interest. The limits of quantification and detection were set at 0.25 and 0.1 microg/mL, respectively. The precision ranged from 0.7 to 13.7% for CAPE, and from 0.4 to 10.4% for FCAPE. Accuracy ranged from -2.8 to 12.4% for CAPE and from -0.6 to 6.8% for FCAPE. The stability was conducted at 4, 25 and 37 degrees C. First-order kinetics was observed for the degradation of CAPE and FCAPE. The energies of activation of CAPE and FCAPE were found to be 17.9 and 20.1 kcal/mol, respectively. Addition of 0.4% of sodium chloride and pH adjustment to 6 prevented their degradation in rat plasma for 24 h and at least one month at -20 degrees C. This study provides useful information for the future pharmacokinetic study of CAPE and FCAPE in rat.     

Vibrational study of caffeic acid phenethyl ester,a potential anticancer agent,by infrared,Raman, and NMR spectroscopy

The structural and vibrational properties of caffeic acid phenethyl ester (CAPE) were studied using infrared and Raman spectroscopy in the solid phase and multidimensional nuclear magnetic resonance (NMR) spectroscopy in solution. The theoretical structures of the compound and of its dimer in the gas phase and in DMSO solution by using density functional theory (DFT) were studied. The harmonic vibrational frequencies for the optimized geometry of CAPE and its dimeric species were calculated at the B3LYP level of theory using the 6–31G* basis set. These data allow a complete assignment of the vibration modes of the FTIR and Raman spectra in the solid state using the scaled quantum mechanical force field (SQMFF) methodology. The vibrational analysis for the dimer was performed taking into account the correlation diagram by means of the factor group analysis in accordance with the experimental structure determined by X-ray diffraction. The presence of the dimer of CAPE is supported by the IR bands at 1654, 1635, 1563, 1533, 1300, 1107, 1050, 738 cm⁻¹ and the Raman bands at 1684, 1681, 1634, 1112, 1050, 928, 873, 850, 740, 445, 371 and 141 cm⁻¹. The calculated ¹H and ¹³C chemicals shifts are consistent with the corresponding experimental NMR spectra of the compound in solution. In addition, a natural bond orbital (NBO) study revealed the characteristics of the electronic delocalization of the stable structure, while the corresponding topological properties of the electronic charge density were analyzed by employing Bader's atoms in the molecules theory (AIM).     

An integrated microfluidics for assessing the anti-aging effect of caffeic acid phenethylester in Caenorhabditis elegans

Aging is a fundamental and fascinating process. Anti-aging research tried to find the mysteries about the human lifespan. To investigate the longevity-extending role of caffeic acid phenethylester (CAPE) and reveal the possible regulation mechanism, the long-term cultivation under well-defined environments, real-time monitoring, and live imaging is highly desired. In this paper, a well-designed microfluidic device was proposed to analyze the anti-aging effect of CAPE in Caenorhabditis elegans. With the combined use of multiple functional units, including micro-pillar, worm responder, a branching network of distribution channels, and microchambers, the longitudinal measurements of the exact number of worms throughout the whole lifespans is possible. Meanwhile, the brief cooling function of temperature-controllable system can achieve temporary and repeated immobilization of nematodes for fluorescence imaging. Our research data showed that CAPE can increase the survival of worms under normal and stress condition, including heat stress and paraquat-induced oxidative stress. The further studies revealed the anti-aging mechanism of CAPE. This proposed strategy and device would be a useful platform to facilitate future anti-aging studies and the finding of new lead compounds.     

Cytotoxic Assessment of 3,3-Dichloro-β-Lactams Prepared through Microwave-Assisted Benzylic C-H Activation from Benzyl-Tethered Trichloroacetamides Catalyzed by RuCl2(PPh3)3

Natural and synthetic β-lactam derivatives constitute an interesting class of compounds due to their diverse biological activity. Mostly used as antibiotics, they were also found to have antitubercular, anticancer and antidiabetic activities, among others. In this investigation, six new 3,3-dichloro-β-lactams prepared in a previous work were evaluated for their hemolytic and cytotoxic properties. The results showed that the proposed compounds have non-hemolytic properties and exhibited an interesting cytotoxic activity toward squamous cell carcinoma (A431 cell line), which was highly dependent on the structure and concentration of these β-lactams. Among the molecules tested, 2b was the most cytotoxic, with the lowest IC₅₀ values (30–47 µg/mL) and a promising selectivity against the tumor cells compared with non-tumoral cells.     

Bioactive Diarylpentanoids: Insights into the Biological Effects beyond Antitumor Activity and Structure–Activity Relationships

Diarylpentanoids, a class of natural products and their synthetic analogs which are structurally related to chalcones, have gained increasing attention due to their wide array of biological activities, including antitumor, anti-infective, antioxidant, anti-inflammatory, antidiabetic, anti-hyperuricemic, and neuroprotective properties. Previously, we reviewed diarylpentanoids with promising antitumor activity. However, in view of the wide range of biological activities described for this class of compounds, the purpose of this review is to provide a more detailed overview of the synthetic bioactive diarylpentanoids that have been described over the last two decades, beyond simply their antitumor effects. A total of 745 compounds were found, highlighting the main synthetic methodologies used in their synthesis as well as the structure–activity relationship studies and structural features for all activities reported. Collectively, this review highlights the diarylpentanoid scaffold as a promising starting point for the development of new therapeutic agents.     

Strategies for Improving Bioavailability,Bioactivity, and Physical-Chemical Behavior of Curcumin

Curcumin (CCM) is one of the most frequently explored plant compounds with various biological actions such as antibacterial, antiviral, antifungal, antineoplastic, and antioxidant/anti-inflammatory properties. The laboratory data and clinical trials have demonstrated that the bioavailability and bioactivity of curcumin are influenced by the feature of the curcumin molecular complex types. Curcumin has a high capacity to form molecular complexes with proteins (such as whey proteins, bovine serum albumin, β-lactoglobulin), carbohydrates, lipids, and natural compounds (e.g., resveratrol, piperine, quercetin). These complexes increase the bioactivity and bioavailability of curcumin. The current review provides these derivatization strategies for curcumin in terms of biological and physico-chemical aspects with a strong focus on different type of proteins, characterization methods, and thermodynamic features of protein–curcumin complexes, and with the aim of evaluating the best performances. The current literature review offers, taking into consideration various biological effects of the CCM, a whole approach for CCM-biomolecules interactions such as CCM-proteins, CCM-nanomaterials, and CCM-natural compounds regarding molecular strategies to improve the bioactivity as well as the bioavailability of curcumin in biological systems.     

Production of α-Tocopherol–Chitosan Nanoparticles by Membrane Emulsification

α-tocopherol (α-T) has the highest biological activity with respect to the other components of vitamin E; however, conventional formulations of tocopherol often fail to provide satisfactory bioavailability due to its hydrophobic characteristics. In this work, α-tocopherol-loaded nanoparticles based on chitosan were produced by membrane emulsification (ME). A new derivative was obtained by the cross-linking reaction between α-T and chitosan (CH) to preserve its biological activity. ME was selected as a method for nanoparticle production because it is recognized as an innovative and sustainable technology for its uniform-particle production with tuned sizes and high encapsulation efficiency (EE%), and its ability to preserve the functional properties of bioactive ingredients operating in mild conditions. The reaction intermediates and the final product were characterized by ¹HNMR, Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC), while the morphological and dimensional properties of the nanoparticles were analyzed using electronic scanning microscopy (SEM) and dynamic light scattering (DLS). The results demonstrated that ME has high potential for the development of α-tocopherol-loaded nanoparticles with a high degree of uniformity (PDI lower than 0.2), an EE of almost 100% and good mechanical strength, resulting in good candidates for the production of functional nanostructured materials for drug delivery. In addition, the chemical bonding between chitosan and α-tocopherol allowed the preservation of the antioxidant properties of the bioactive molecule, as demonstrated by an enhanced antioxidant property and evaluated through in vitro tests, with respect to the starting materials.     

Mushroom-Derived Bioactive Molecules as Immunotherapeutic Agents: A Review

Mushrooms with enhanced medicinal properties focus on finding such compounds that could modulate the human body’s immune systems. Mushrooms have antimicrobial, antidiabetic, antiviral, hepatoprotective, antitumor, and immunomodulatory properties due to the presence of various bioactive components. β-glucans are the major constituent of the mushroom cell wall and play a significant role in their biological activity. This review described the techniques used in the extraction of the active ingredients from the mushroom. We highlighted the structure of the bioactive polysaccharides present in the mushrooms. Therapeutic applications of different mushrooms were also described. It is interesting to note that mushrooms have the potential sources of many bioactive products that can regulate immunity. Thus, the development of functional medicinal food based on the mushroom is vital for human welfare.