A novel source of biologically active compounds - The leaves of Serbian herbaceous peonies.

In order to gain further insight into how various extraction techniques (maceration, microwave-, and ultrasound-assisted extractions) affect the chemical profile and biological activities of leaf extracts from Paeonia tenuifolia L., Paeonia peregrina Mill., and Paeonia officinalis L., this research was performed. The targeted chemical characterization of the extracts was achieved using the Ultra-High-Performance-Liquid-Chromatography-Linear-Trap-Mass-Spectrometry OrbiTrap instrumental technique, while Fourier Transform Infrared Spectroscopy was conducted to investigate the structural properties of the examined leaf extracts. According to the results, the species P. officinalis, Bozurna locality as the origin of the plant material, and microwave-assisted extraction produced the maximum polyphenol yield, (491.9 ± 2.7 mg gallic acid equivalent (GAE)/mL). The ethanolic extracts exhibited moderate antioxidant activity as evaluated by DPPH (2,2-diphenyl-1-picrylhydrazyl) and phosphomolybdenum tests. With MIC values of 0.125 mg/mL, the leaf extracts produced by ultrasound-assisted extraction and maceration (Deliblato sands and Bogovo gumno) had the best antibacterial activity against Pseudomonas aeruginosa and Salmonella Typhimurium. Ultrasound-assisted extraction has proven to produce the most effective antimicrobial agents. Inhibitory potential towards glucosidase, amylase, cholinesterases, and tyrosinase was evaluated in enzyme inhibition assays and molecular docking simulations. Results show that leaves of P. tenuifolia L. obtained by ultrasound-assisted extraction had the highest acetylcholinesterase and butyrylcholinesterase inhibitory activity. Namely, the complexity of the polyphenol structures, the extraction method, the used locality, and the different mechanisms of the reactions between bioactives from leaf extracts and other components (free radicals, microorganisms, and enzymes) are the main factors that influence the results of the antioxidant tests, as well as the antibacterial and enzyme-inhibitory activities of the extracts. Hydroxymethyl-phenyl pentosyl-hexoside and acetyl-hydroxyphenyl-hexoside were the first time identified in the leaf extract of the Paeonia species. Due to their proven biological activities and the confirmed existence of bioactive compounds, leaf extracts may find use in foodstuffs, functional foods, and pharmaceutical products.

Paeonia peregrina Mill Petals as a New Source of Biologically Active Compounds: Chemical Characterization and Skin Regeneration Effects of the Extracts.

Paeonia peregrina Mill. is a perennial herbaceous plant species, known for the medicinal value of all of its plant parts, although the chemical composition of the petals is unknown. This study aimed to determine the chemical fingerprint of the petals and also establish the optimal extraction parameters, extraction medium, and extraction method for petals collected from different localities in Serbia. The optimization was performed in order to acquire extracts that are rich in the contents of total polyphenol content (TPC) and total flavonoid content (TFC), and also exhibit strong antioxidant activity. In addition, the influence of the extracts on several human skin pathogens was evaluated, as well as their ability to aid wound closure and act as anti-inflammatory agents. Both the extraction medium and the applied technique significantly influenced the skin-beneficial biological activities, while methanol proved to be a more favorable extraction medium. In conclusion, the extraction conditions that yielded the extract with the richest phenolic content with satisfactory biological potential varied between the assays, while the most promising locality in Serbia for the collection of P. peregrina petals was Pancevo (South Banat).

Monoamine oxidase A and organic cation transporter 3 coordinate intracellular ß1AR signaling to calibrate cardiac contractile function.

We have recently identified a pool of intracellular ß1 adrenergic receptors (ß1ARs) at the sarcoplasmic reticulum (SR) crucial for cardiac function. Here, we aim to characterize the integrative control of intracellular catecholamine for subcellular ß1AR signaling and cardiac function. Using anchored Förster resonance energy transfer (FRET) biosensors and transgenic mice, we determined the regulation of compartmentalized ß1AR-PKA signaling at the SR and plasma membrane (PM) microdomains by organic cation transporter 3 (OCT3) and monoamine oxidase A (MAO-A), two critical modulators of catecholamine uptake and homeostasis. Additionally, we examined local PKA substrate phosphorylation and excitation-contraction coupling in cardiomyocyte. Cardiac-specific deletion of MAO-A (MAO-A-CKO) elevates catecholamines and cAMP levels in the myocardium, baseline cardiac function, and adrenergic responses. Both MAO-A deletion and inhibitor (MAOi) selectively enhance the local ß1AR-PKA activity at the SR but not PM, and augment phosphorylation of phospholamban, Ca2+ cycling, and myocyte contractile response. Overexpression of MAO-A suppresses the SR-ß1AR-PKA activity and PKA phosphorylation. However, deletion or inhibition of OCT3 by corticosterone prevents the effects induced by MAOi and MAO-A deletion in cardiomyocytes. Deletion or inhibition of OCT3 also negates the effects of MAOi and MAO-A deficiency in cardiac function and adrenergic responses in vivo. Our data show that MAO-A and OCT3 act in concert to fine-tune the intracellular SR-ß1AR-PKA signaling and cardiac fight-or-flight response. We reveal a drug contraindication between anti-inflammatory corticosterone and anti-depressant MAOi in modulating adrenergic regulation in the heart, providing novel perspectives of these drugs with cardiac implications.

Liposomal Bilayer as a Carrier of Rosa canina L. Seed Oil: Physicochemical Characterization, Stability, and Biological Potential.

Rosa canina L. seeds are rich in bioactive components that can add value to the various formulations. The focus of the study was the development of liposomes for R. canina oil to protect its sensitive compounds and prolong their shelf-life. Oil-loaded liposomes were characterized via the determination of the particle size, polydispersity index (PDI), zeta potential, conductivity, mobility, density, surface tension, viscosity, and stability. Raman and FT-IR spectroscopy were employed to investigate the chemical composition of the non-treated and UV-treated samples, and the presence of different interactions. Antioxidant and antimicrobial activities were examined as well. The liposome size was 970.4 ± 37.4 nm, the PDI 0.438 ± 0.038, the zeta potential -32.9 ± 0.8 mV, the conductivity 0.068 ± 0.002 mS/cm, the mobility -2.58 ± 0.06 µmcm/Vs, the density 0.974 ± 0.004 g/cm3, the surface tension 17.2 ± 1.4 mN/m, and the viscosity 13.5 ± 0.2 mPa•s. The Raman and FT-IR spectra showed the presence of lipids, fatty acids, polyphenols, and carotenoids. It was approved that the oil compounds were distributed inside the phospholipid bilayer and were combined with the membrane interface of the bilayer. The UV irradiation did not cause any chemical changes. However, neither the pure oil nor the oil-loaded liposomes showed any antimicrobial potential, while the antioxidant capacity of the oil-loaded liposomes was significantly low. The sizes of the liposomes did not change significantly during 60 days of storage. Due to the proven stability of the oil-loaded liposomes, as well as the liposome's ability to protect the sensitive oil compounds, their potential application in the pharmaceutical and cosmetic formulations could be investigated with a focus on the skin regeneration effects.

Hyperinsulinemia promotes heterologous desensitization of ß2 adrenergic receptor in airway smooth muscle in obesity.

ß-Adrenergic receptor (ß-AR) agonists are the most common clinical bronchodilators for asthma. Obesity influences asthma severity and may impair response to ß-AR agonists. Previous studies show that in obese mice, hyperinsulinemia plays a crucial role in ß-AR desensitization in the heart. We therefore investigated whether insulin promotes ß-AR desensitization in airway smooth muscle (ASM) and compromises airway relaxation responsiveness to ß-AR agonists. We found that human ASM cells and mouse airway tissues exposed to insulin exhibit impaired ß2 AR-induced cAMP accumulation and airway relaxation. This impaired relaxation is associated with insulin-induced phosphorylation and expression of phosphodiesterase 4D (PDE4D) through transactivation of a G protein-coupled receptor kinase 2 (GRK2)-dependent ß2 AR-Gi -ERK1/2 cascade. Both acute and chronic pharmacological inhibition of PDE4 effectively reversed impaired ß2 AR-mediated ASM relaxation in an obesity mouse model induced by a high fat diet. Collectively, these findings reveal that cross talk between insulin and ß2 AR signaling promotes ASM ß2 AR desensitization in obesity through upregulation of PDE4D phosphorylation and expression. Our results identify a novel pathway of asthma pathogenesis in patients with obesity/metabolic syndrome, in which the GRK2-mediated signaling can be a potential therapeutic modality to prevent or treat ß2 AR desensitization in ASM. Moreover, PDE4 inhibitors may be used as efficacious therapeutic agents for asthma in obese and diabetic subjects.

Freeze vs. Spray Drying for Dry Wild Thyme (Thymus serpyllum L.) Extract Formulations: The Impact of Gelatin as a Coating Material.

Freeze drying was compared with spray drying regarding feasibility to process wild thyme drugs in order to obtain dry formulations at laboratory scale starting from liquid extracts produced by different extraction methods: maceration and heat-, ultrasound-, and microwave-assisted extractions. Higher total powder yield (based on the dry weight prior to extraction) was achieved by freeze than spray drying and lower loss of total polyphenol content (TPC) and total flavonoid content (TFC) due to the drying process. Gelatin as a coating agent (5% w/w) provided better TPC recovery by 70% in case of lyophilization and higher total powder yield in case of spray drying by diminishing material deposition on the wall of the drying chamber. The resulting gelatin-free and gelatin-containing powders carried polyphenols in amount ~190 and 53-75 mg gallic acid equivalents GAE/g of powder, respectively. Microwave-assisted extract formulation was distinguished from the others by a higher content of polyphenols, proteins and sugars, higher bulk density and lower solubility. The type of the drying process mainly affected the position of the gelatin-derived -OH and amide bands in FTIR spectra. Spray-dried formulations compared to freeze-dried expressed higher thermal stability as confirmed by differential scanning calorimetry analysis and a higher diffusion coefficient; the last feature can be associated with the lower specific surface area of irregularly shaped freeze-dried particles (151-223 µm) compared to small microspheres (~8 µm) in spray-dried powder.

Whether the Support Region of Three-Bit Uniform Quantizer Has a Strong Impact on Post-Training Quantization for MNIST Dataset?

Driven by the need for the compression of weights in neural networks (NNs), which is especially beneficial for edge devices with a constrained resource, and by the need to utilize the simplest possible quantization model, in this paper, we study the performance of three-bit post-training uniform quantization. The goal is to put various choices of the key parameter of the quantizer in question (support region threshold) in one place and provide a detailed overview of this choice's impact on the performance of post-training quantization for the MNIST dataset. Specifically, we analyze whether it is possible to preserve the accuracy of the two NN models (MLP and CNN) to a great extent with the very simple three-bit uniform quantizer, regardless of the choice of the key parameter. Moreover, our goal is to answer the question of whether it is of the utmost importance in post-training three-bit uniform quantization, as it is in quantization, to determine the optimal support region threshold value of the quantizer to achieve some predefined accuracy of the quantized neural network (QNN). The results show that the choice of the support region threshold value of the three-bit uniform quantizer does not have such a strong impact on the accuracy of the QNNs, which is not the case with two-bit uniform post-training quantization, when applied in MLP for the same classification task. Accordingly, one can anticipate that due to this special property, the post-training quantization model in question can be greatly exploited.

Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high-fat diet.

The aim of this study was to investigate whether the presence of endogenous estradiol alters the effects of a high-fat (HF) diet on activity/expression of the cardiac Na+/K+-ATPase, via PI3K/IRS and RhoA/ROCK signalling cascades in female rats. For this study, female Wistar rats (8 weeks old, 150-200 g) were fed a standard diet or a HF diet (balanced diet for laboratory rats enriched with 42% fat) for 10 weeks. The results show that rats fed a HF diet exhibited a decrease in phosphorylation of the α1 subunit of Na+/K+-ATPase by 30% (p < 0.05), expression of total α1 subunit of Na+/K+-ATPase by 31% (p < 0.05), and association of IRS1 with p85 subunit of PI3K by 42% (p < 0.05), while the levels of cardiac RhoA and ROCK2 were significantly increased by 84% (p < 0.01) and 62% (p < 0.05), respectively. Our results suggest that a HF diet alters cardiac Na+/K+-ATPase expression via molecular mechanisms involving RhoA/ROCK and IRS-1/PI3K signalling in female rats.

A high fat diet induces sex-specific differences in hepatic lipid metabolism and nitrite/nitrate in rats.

Men and women differ substantially with regard to the severity of insulin resistance (IR) but the underlying mechanism(s) of how this occurs is poorly characterized. We investigated whether a high fat (HF) diet resulted in sex-specific differences in nitrite/nitrate production and lipid metabolism and whether these variances may contribute to altered obesity-induced IR. Male and female Wistar rats were fed a standard laboratory diet or a HF diet for 10 weeks. The level of plasma nitrite/nitrate, as well as free fatty acid (FFA), in both plasma and liver lysates were assessed. The levels of inducible nitric oxide (NO) synthase (iNOS), p65 subunit of NFκB, total and phosphorylated forms of Akt, mTOR and PDK-1 in lysates, and the levels of glucose transporter 2 (Glut-2) and fatty acid translocase/cluster of differentiation 36 (FAT/CD36) in plasma membrane fractions of liver were assessed. HF-fed male rats exhibited a significant increase in plasma nitrite/nitrate, and hepatic FFA and FAT/CD36 levels compared with controls. They also displayed a relative decrease in iNOS and Glut-2 levels in the liver. Phosphorylation of Akt (at Ser(473) and Thr(308)), mTOR and PDK-1 was also reduced. HF-fed female rats exhibited increased levels of NFκB-p65 in liver compared with controls, while levels of Glut-2, FAT/CD36 and Akt phosphorylation at Thr(308) and PDK-1 were decreased. Our results reveal that altered lipid and glucose metabolism in obesity, lead to altered iNOS expression and nitrite/nitrate production. It is likely that this mechanism contributes to sex-specific differences in the development of IR.

Interrelatedness between C-reactive protein and oxidized low-density lipoprotein.

C-reactive protein (CRP) is a marker of inflammation. Atherosclerosis is now recognized as inflammatory disease, and it seems that CRP directly contributes to atherogenesis. Oxidation of low-density lipoprotein (LDL) molecule increases the uptake of lipid products by macrophages leading to cholesterol accumulation and subsequent foam cell formation. The elevated levels of high sensitivity CRP (hsCRP) and oxidized LDL (OxLDL) in the blood were found to be associated with cardiovascular diseases (CVD). In this review, we highlighted the evidence that CRP and OxLDL are involved in interrelated (patho) physiological pathways. The findings on association between hsCRP and OxLDL in the clinical setting will be also summarized.

Thrombin stimulates VSMC proliferation through an EGFR-dependent pathway: involvement of MMP-2.

In this study, the role of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK1/2), heparin-binding EGF-like growth factor (HB-EGF), general metalloproteinases, matrix metalloproteinases-2 (MMP-2) in mediating the mitogenic action of thrombin in rat vascular smooth muscle cells (VSMC) was investigated. The incubation of rat VSMC with thrombin (1 U/ml) for 5 min resulted in significant (p < 0.001) increase of ERK1/2 phosphorylation by 8.7 ± 0.9-fold, EGFR phosphorylation by 8.5 ± 1.3-fold (p < 0.001) and DNA synthesis by 3.6 ± 0.4-fold (p < 0.001). Separate 30-min pretreatments with EGFR tyrosine kinase irreversible inhibitor, 10 µM PD169540 (PD), and 20 µM anti-HB-EGF antibody significantly reduced thrombin-stimulated EGFR and ERK1/2 phosphorylation by 81, 72 % and by 48 and 61 %, respectively. Furthermore, the same pretreatments with PD or anti-HB-EGF antibody reduced thrombin-induced VSMC proliferation by 44 and 45 %, respectively. In addition, 30-min pretreatments with 10 µM specific MMP-2 inhibitor significantly reduced thrombin-stimulated phosphorylation of both EGFR and ERK1/2 by 25 %. Moreover, the same pretreatment with MMP-2 inhibitor reduced thrombin-induced VSMC proliferation by 45 %. These results show that the thrombin-induced DNA synthesis correlates with the level of ERK1/2 activation rather than EGFR activation. These results further suggest that thrombin acts through EGFR and ERK 1/2 signaling pathways involving MMP-2 to upregulate proliferation of VSMC.

Vaccinium myrtillus L. Leaf Waste as a Source of Biologically Potent Compounds: Optimization of Polyphenol Extractions, Chemical Profile, and Biological Properties of the Extracts.

The aims of the present research include (1) optimization of extraction from Vaccinium myrtillus leaf waste via investigation of plant material:medium ratio, extraction medium, and extraction period, employing extractions at room and high temperatures, or using ultrasound and microwaves (M, HAE, UAE, and MAE, respectively), (2) physicochemical characterization, and (3) investigation of extract biological potential. The statistical analysis revealed that optimal levels of parameters for the greatest polyphenolic yield were a proportion of 1:30 g/mL, ethyl alcohol 50% (v/v) during 2 min of microwave irradiation. By LC-MS analysis, 29 phenolic components were detected; HAE showed the highest richness of almost all determined polyphenols, while chlorogenic acid and quercetin 3-O-glucuronide were dominant. All extracts showed a high inhibition of Staphylococcus aureus growth. The effect of different parameters on extracts' antioxidant capacity depended on the used tests. The extracts also showed a stimulative influence on keratinocyte viability and anti-inflammatory activity (proven in cell-based ELISA and erythrocyte stabilization assays). The extraction procedure significantly affected the extraction yield (MAE ≥ maceration ≥ UAE ≥ HAE), whereas conductivity, density, surface tension, and viscosity varied in a narrow range. The presented research provides evidence on the optimal extraction conditions and technique, chemical composition, and antioxidant, antimicrobial, anti-inflammatory, and keratinocyte viability properties of bilberry extracts for potential applications in pharmacy and cosmetics.

Liposome Encapsulation Enhances the Antidiabetic Efficacy of Silibinin.

Silibinin has considerable therapeutic potential for the treatment of diabetes through anti-inflammatory, antioxidant, and immunomodulatory properties. However, the therapeutic application of silibinin is quite limited due to its poor bioavailability. In the present study, an attempt was made to improve the antidiabetic efficacy of silibinin by its encapsulation in liposomal vesicles. The liposomes with a high encapsulation efficiency of silibinin (96%) and a zeta potential of -26.2 ± 0.6 mV were developed and studied using nicotinamide/streptozotocin-induced diabetic rats. Administration of silibinin-loaded liposomes to diabetic rats lowered glucose levels, increased insulin levels, and improved pancreatic islet architecture. The anti-inflammatory effect of silibinin-loaded liposomes was demonstrated by a decrease in serum C-reactive protein (CRP) levels and a reduced deposition of collagen fibers in the islets of diabetic rats. Furthermore, silibinin-loaded liposomes were more efficient in lowering glucose, alanine transaminase, triglyceride, and creatinine levels in diabetic rats than pure silibinin. In addition, silibinin-loaded liposomes had a significantly better effect on beta-cell mass and Glut2 glucose receptor distribution in diabetic islets than pure silibinin. The present results clearly show that liposome encapsulation of silibinin enhances its antidiabetic efficacy, which may contribute to the therapeutic benefit of silibinin in the treatment of diabetes and its complications.

Liposomal Encapsulation of Ascorbyl Palmitate: Influence on Skin Performance.

L-ascorbic acid represents one of the most potent antioxidant, photoprotective, anti-aging, and anti-pigmentation cosmeceutical agents, with a good safety profile. However, the main challenge is the formulation of stable topical formulation products, which would optimize the penetrability of L-ascorbic acid through the skin. The aim of our research was to evaluate the performance of ascorbyl palmitate on the skin, incorporated in creams and emulgels (2%) as carriers, as well as to determine the impact of its incorporation into liposomes on the penetration profile of this ingredient. Tape stripping was used to study the penetration of ascorbyl palmitate into the stratum corneum. In addition, the sensory and textural properties of the formulations were determined. The liposomal formulations exhibited a better penetration profile (p < 0.05) of the active substance compared to the non-liposomal counterpart, leading to a 1.3-fold and 1.2 fold-increase in the total amount of penetrated ascorbyl palmitate in the stratum corneum for the emulgel and cream, respectively. Encapsulation of ascorbyl palmitate into liposomes led to an increase in the adhesiveness and density of the prepared cream and emulgel samples. The best spreadability and absorption during application were detected in liposomal samples. The obtained results confirmed that liposomal encapsulation of ascorbyl palmitate improved dermal penetration for both the cream and emulgel formulations.

Multifunctional Pomegranate Peel Microparticles with Health-Promoting Effects for the Sustainable Development of Novel Nutraceuticals and Pharmaceuticals.

Recovering the bioactive components from pomegranate peel (PP) in the fruit-processing industry has attracted great attention in terms of minimizing the waste burden, as well as providing a new source of a multitude of functional compounds. The present study aimed to develop a feasible microencapsulation process of PP extract by using pectin and a pectin/2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) blend as coating materials. Microsized powders obtained by a spray drying technique were examined in terms of technological characteristics, exhibiting high powder yield and desirable moisture content, flowability, and cohesive properties. Assuming that the interactions with the used biopolymers occur on the surface hydrophobic domain, their presence significantly improved the thermal stability of the microencapsulated powders up to 200 °C. The health-promoting effects of PP have been associated with its high content in ellagitannins, particularly punicalagin. The obtained PP powders exhibited strong antioxidant and hypoglycemic potential, while an antimicrobial assay revealed their potent activity against Gram-positive bacteria. Additionally, an in vitro release study suggested that the used biopolymers can modify the release of target bioactive compounds, thus establishing a basis for developing an oral-controlled release system. Altogether, biowaste valorization from PP by the production of effective multifunctional microsized powders represents a sustainable way to obtain novel nutraceuticals and/or pharmaceuticals.

Phytochemical Analysis, Biological Activities, and Molecular Docking Studies of Root Extracts from Paeonia Species in Serbia.

Without being aware of their chemical composition, many cultures have used herbaceous peony roots for medicinal purposes. Modern phytopreparations intended for use in human therapy require specific knowledge about the chemistry of peony roots and their biological activities. In this study, ethanol-water extracts were prepared by maceration and microwave- and ultrasound-assisted extractions (MAE and UAE, respectively) in order to obtain bioactive molecules from the roots of Paeonia tenuifolia L., Paeonia peregrina Mill., and Paeonia officinalis L. wild growing in Serbia. Chemical characterization; polyphenol and flavonoid content; antioxidant, multianti-enzymatic, and antibacterial activities of extracts; and in vitro gastrointestinal digestion (GID) of hot water extracts were performed. The strongest anti-cholinesterase activity was observed in PT extracts. The highest anti-ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical potential was observed in PP extracts, whereas against DPPH (2,2-diphenyl-1-picrylhydrazyl radicals), the best results were achieved with PO extracts. Regarding antibacterial activity, extracts were strongly potent against Bacillus cereus. A molecular docking simulation was conducted to gather insights into the binding affinity and interactions of polyphenols and other Paeonia-specific molecules in the active sites of tested enzymes. In vitro GID of Paeonia teas showed a different recovery and behavior of the individual bioactives, with an increased recovery of methyl gallate and digallate and a decreased recovery of paeoniflorin and its derivatives. PT (Gulenovci) and PP (Pirot) extracts obtained by UAE and M were more efficient in the majority of the bioactivity assays. This study represents an initial step toward the possible application of Paeonia root extracts in pharmacy, medicine, and food technologies.

Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). ß-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac ß-adrenoceptors (ßARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local ßAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different ßAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by ß1AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca2+) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced ß1AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the ß1AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with ß1AR were observed. Stimulating ß1AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament ß1AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

Rosehip Extract-Loaded Liposomes for Potential Skin Application: Physicochemical Properties of Non- and UV-Irradiated Liposomes.

In the present study, rosehip (Rosa canina L.) extract was successfully encapsulated in phospholipid liposomes using a single-step procedure named the proliposome method. Part of the obtained liposomes was subjected to UV irradiation and non-treated (native) and UV-irradiated liposomes were further characterized in terms of encapsulation efficiency, chemical composition (HPLC analysis), antioxidant capacity, particle size, PDI, zeta potential, conductivity, mobility, and antioxidant capacity. Raman spectroscopy as well as DSC analysis were applied to evaluate the influence of UV irradiation on the physicochemical properties of liposomes. The encapsulation efficiency of extract-loaded liposomes was higher than 90%; the average size was 251.5 nm; the zeta potential was -22.4 mV; and the conductivity was found to be 0.007 mS/cm. UV irradiation did not cause a change in the mentioned parameters. In addition, irradiation did not affect the antioxidant potential of the liposome-extract system. Raman spectroscopy indicated that the extract was completely covered by the lipid membrane during liposome entrapment, and the peroxidation process was minimized by the presence of rosehip extract in liposomes. These results may guide the potential application of rosehip extract-loaded liposomes in the food, pharmaceutical, or cosmetic industries, particularly when liposomal sterilization is needed.

Derivatives of L-Ascorbic Acid in Emulgel: Development and Comprehensive Evaluation of the Topical Delivery System.

The dual controlled release of emulgels makes them efficient drug delivery systems of increasing interest. The framework of this study was to incorporate selected L-ascorbic acid derivatives into emulgels. From the formulated emulgels, the release profiles of actives were evaluated considering their different polarities and concentrations, and consequently their effectiveness on the skin via a long-term in vivo study that lasted for 30 days was determined. Skin effects were assessed by measuring the electrical capacitance of the stratum corneum (EC), trans-epidermal water loss (TEWL), melanin index (MI) and skin pH. In addition, the sensory and textural properties of emulgel formulations were compared with each other. The changes in the rate of the release of the L-ascorbic acid derivatives were monitored using the Franz diffusion cells. The obtained data were statistically significant, and indicated an increase in the degree of hydration of the skin and skin whitening potential, while no significant changes in TEWL and pH values were detected. The consistency, firmness and stickiness of the emulgels were estimated by volunteers applying the established sensory evaluation protocol. In addition, it was revealed that the difference in hydrophilic/lipophilic properties of L-ascorbic acid derivatives influenced their release profiles without changing their textural characteristics. Therefore, this study highlighted emulgels as L-ascorbic acid suitable carrier systems and one of the promising candidates as novel drug delivery systems.