Scientia Pharmaceutica — Open Access Journal

Treatment of certain central nervous system disorders, including different types of cerebral malignancies, is limited by traditional oral or systemic administrations of therapeutic drugs due to possible serious side effects and/or lack of the brain penetration and, therefore, the efficacy of the drugs is diminished. During the last decade, several new technologies were developed to overcome barrier properties of cerebral capillaries. This review gives a short overview of the structural elements and anatomical features of the blood–brain barrier. The various in vitro (static and dynamic), in vivo (microdialysis), and in situ (brain perfusion) blood–brain barrier models are also presented. The drug formulations and administration options to deliver molecules effectively to the central nervous system (CNS) are presented. Nanocarriers, nanoparticles (lipid, polymeric, magnetic, gold, and carbon based nanoparticles, dendrimers, etc.), viral and peptid vectors and shuttles, sonoporation and microbubbles are briefly shown. The modulation of receptors and efflux transporters in the cell membrane can also be an effective approach to enhance brain exposure to therapeutic compounds. Intranasal administration is a noninvasive delivery route to bypass the blood–brain barrier, while direct brain administration is an invasive mode to target the brain region with therapeutic drug concentrations locally. Nowadays, both technological and mechanistic tools are available to assist in overcoming the blood–brain barrier. With these techniques more effective and even safer drugs can be developed for the treatment of devastating brain disorders. Full article

Proteins play crucial roles in the transportation and distribution of therapeutic substances, including metal ions in living systems. Some metal ions can strongly associate, while others show low affinity towards proteins. Consequently, in the present work, the binding behaviors of Ca²⁺, Ba²⁺, Ag⁺, Ru³⁺, Cu²⁺ and Co²⁺ with bovine serum albumin (BSA) were screened. BSA and the metal ions were allowed to interact at physiological pH and their binding interactions were screened by using FT-IR spectroscopy. Spectra were collected by using hydrated films over a range of 4000–400 cm⁻¹. The interaction was demonstrated by a significant reduction in the spectral intensities of the amide I (C=O stretching) and amide II bands (C–N stretching coupled to NH bending) of the protein after complexation with metal ions. The binding interaction was further revealed by spectral shifting of the amide I band from 1651 cm⁻¹ (free BSA) to 1653, 1654, 1649, 1655, 1655, and 1654 cm⁻¹ for BSA–Ca²⁺, BSA–Ba²⁺, BSA–Ag⁺, BSA–Ru³⁺, BSA–Cu²⁺ and BSA–Co²⁺ complexes, respectively. The shifting of the amide I band was due to the interactions of metal ions with the O and N atoms of the ligand protein. Estimation of the secondary protein structure showed alteration in the protein conformation, characterized by a marked decrease (12.9–40.3%) in the α-helix accompanied by increased β-sheet and β-turn after interaction with the metal ions. The interaction results of this study were comparable with those reported in our previous investigation of metal ion–BSA interactions using affinity capillary electrophoresis (ACE), which has proven the accuracy of the FT-IR technique in the measurement of interactions between proteins and metal ions. Full article

Nigella sativa oil has been known to have potent anti-inflammatory activity. This research aimed to determine the anti-inflammation activity of Nigella sativa oil in a simple balm stick by topical application. The activity was checked using two methods: carrageenan-induced paw oedema and granuloma pouch on rats. The results showed that balm sticks which contained 10% Nigella sativa could overcome both acute and sub-acute inflammation showing by high oedema inhibition (60.64%), low leucocytes count (43.55% lower than control) as well as a notable TNF-α concentration (50% lower than control) on the inflamed area. In conclusion, topical application of a Nigella sativa balm stick was effective for both acute and sub-acute forms of inflammation. Full article

Berberis goudotii is an endemic Colombian plant found in the paramo ecosystem. It has been used in food preparation and as a medicinal plant for diverse treatments. Additionally, it is used as a mouthwash to strengthen the gums and combat throat irritations and periodontitis. The present research evaluated Berberis goudotii aerial parts extract and fractions antimicrobial activities. Ultrasonic-assisted extraction was used to attain total ethanol-water extract. Solid-liquid fractionation was used to obtain hexane fraction. The residue was dispersed in water and liquid-liquid fractionation was carried-out to acquire dichloromethane, butanol and water fractions. Preliminary phytochemical analysis was performed on total extract and phenol, polyphenol, flavonoid, and proanthocyanidin, while tannin content was quantified. Antimicrobial activity assessment was performed by agar diffusion method using disks and wells employing Ceftazidime as a positive control against Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus, Lactobacillus casei, Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum. Antimicrobial activity was determined as relative percentage inhibition (RPI), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Phenols (92.5 ± 7.7 mg GA/10 g), polyphenols (87.7 ± 8.1 mg PG/10 g) and tannins (44.1 ± 4.3 mg PG/10 g) were among the highest secondary metabolites observed. Total extract presented an MBC of 1.0 µg/µL against cariogenic bacteria (Streptococcus mutans and Streptococcus sobrinus) and 0.12 µg/µL against bacteria associated with periodontal disease (Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum). Butanol and hexane fractions showed antiperiodontal activity with MBC of 0.12 and 1.0 µg/µL, respectively. In conclusion, Berberis goudotii total extract demonstrated antimicrobial activity against cariogenic and periodontal microorganisms, on the other hand, hexane and butanol fractions displayed antiperiodontal activity. Full article

Usnic acid is known for its remarkable antimicrobial activity. The aim of this research was to formulate hydrogel of usnic acid and evaluate the antibacterial activity against Propionibacterium acne. Due to low solubility of usnic acid, solid dispersion was prepared using PVP K-30. In this study, intact usnic acid (UA) and usnic acid-solid dispersion (UA-SD) was formulated in hydrogel using several gelling agents: Aqupec HV-505, sodium alginate and HPMC K 100M. Concentration of each gelling agent was optimized for hydrogel base. All of hydrogel base showed homogenous gel, pH at range 5.37–6.33 and viscosity in range 259.07–10,759.00 cps. Hydrogel was prepared by dispersing 1% intact UA and 3% UA-SD in three different gelling agents. The hydrogel was evaluated for pH, viscosity, stability test for two months and microbiology test. The amount of usnic acid in hydrogel was determined by spectrophotometry UV-Vis. Hydrogel UA showed non-homogenous gel, while hydrogel usnic UA-SD was homogenous. The pH of all hydrogel was in range 5.5–6.4 and viscosity was 2,017.03–3,866.52 cps. All the hydrogel was stable and diameter inhibition of hydrogel was in a range 20–32 mm. The amount of usnic acid in hydrogel was in range 96.9–99.23%. In conclusion, hydrogel UA-SD is promising preparation in handling acne. Full article

(1) Background: Clitoria ternatea (butterfly pea), a plant species belonging to the Leguminosae (Fabaceae) family, is useful for medical treatments and has been used in folk medicines and to cure different diseases. The antioxidation ability of the total phenolic compounds of butterfly pea is useful for preserving flavor, and colour and for preventing vitamin destruction in processed foods. In this study, a butterfly pea flower fermentation solution was added to cosmetics as a whiting ingredient. (2) Methods: After the phenolics, flavonoids and ascorbic acid content of the butterfly pea flower extraction had been determined, lactic acid bacteria fermented the extraction. The whitening and moisturizing effect was assayed by SSC3 and NF333 analyzers. (3) Results: This study demonstrated that the butterfly pea flower fermentation solution has free radical scavenging ability, a reducing power in high concentrations, a moisturizing effect, and a whiting effect. (4) Conclusions: The results showed that the butterfly pea flower fermentation solution not only inhibits redness, itching, allergies, and irritation to the skin, but also has antioxidation properties and promotes moisture retention and whitening effects, and the results increase as the concentration increases. Therefore, butterfly bean flowers may be suitable as a raw material for natural beauty care products. Full article

The essential oil obtained from the leaves of Lippia alba (Mill.) N.E. Brown (Verbenaceae) has shown great pharmacological potential as an analgesic, antispasmodic, and antimicrobial agent. The aim of this study was to evaluate the modulatory effect of Lippia alba essential oil (LaEO I) on the activity of clinically used antimicrobial agents on Salmonella enterica serovar Typhi (Salmonella typhi) and Shigella dysenteriae biofilms. The Minimum Inhibitory Concentration of LaEO I (MIC_{LaEO I}) was determined by the microdilution method, and the effect of LaEO I on the activity of clinically used antimicrobials was assessed by the Checkboard method. The values obtained from MIC_{LaEO I} and ciprofloxacin were used to evaluate the effect of time of exposure on cell viability. LaEO I main components were geranial (34.2%), neral (25.9%), and myrcene (12.5%). The MIC_{LaEO I} was 1 mg/mL for both strains. LaEO I positively modulated the action of ciprofloxacin, cefepime, and ceftriaxone. After the first hour of treatment with MIC_{LaEO I}, the cell viability of the strains showed a 5 log10 CFU/mL reduction, and the LaEO I-CIP association was able to inhibit growth during the first 6 h of the test. Regarding the anti-biofilm activity, MIC_{LaEO I} was able to reduce the biofilm mass of Salmonella typhi by 61.2% and of Shigella dysenteriae by 38.9%. MIC_{LaEO I} was not able to eradicate the preformed biofilm; however, there was a reduction in the biofilm microbial viability. LaEO I has the potential to be used as an antimicrobial agent and interferes with biofilm formation; also, it is able to reduce cell viability in preformed biofilm and synergistically modulate the activity of ciprofloxacin. Full article

The aim of this study was to investigate the effect of adenosine in non-occluded or occluded femoral arteries (FA) that were isolated from healthy or diabetic Wistar rats. Determining the role of endothelium, and a transmembrane flow of potassium ions in adenosine actions were also of interest. Diabetes was experimentally induced by alloxan, while the vascular occlusion was performed for 45 min on randomly selected FA. Vascular tone changes were continuously recorded. Selected markers of endothelial dysfunction were measured in animal serum. Thus, adenosine produced a concentration-dependent relaxation of rat FA, which was endothelium-dependent, too, except in a group of diabetic animals. Moreover, serum asymmetric dimethylarginine (ADMA) levels were higher in diabetic animals, thus reflecting endothelial dysfunction (ED). Still, an occlusion of FA enhanced the relaxation effect of adenosine in endothelium-intact rings from diabetic animals. Oppositely, in the presence of high potassium concentration in the buffer, adenosine-induced relaxation was significantly reduced in all of the investigated groups/subgroups. These results suggest that in diabetic animals, an occlusion of FA most probably reversed adenosine-induced relaxation from endothelium-independent into an endothelium-dependent relaxation, thus indicating the possible protective mechanism against ischemic episodes of FA in the presence of diabetes. Full article

The analysis of our previous studies on the search for synthetic analgesics among N-R-amides of bicyclic hetaryl-3-carboxylic acids has been performed; on its basis N-hetaryl(aryl)-alkyl-4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamides have been selected as new study objects. The “one pot synthesis” of these compounds, which is simple to perform and at the same time highly effective, has been offered. The method consists in the initial reaction of 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid and N,N′-carbonyldiimidazole in anhydrous N,N-dimethylformamide with the subsequent amidation of imidazolide formed with hetarylalkyl- or benzylamines in the same solvent. The peculiarities of ¹H- and ¹³C-NMR spectra of the substances obtained, as well as their electrospray ionization liquid chromato-mass spectra are discussed. According to the results of the pharmacological tests carried out on the model of carrageenan inflammation it has been found that all without exception N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamides demonstrate the statistically significant analgesic and anti-inflammatory properties. Among the substances presented in this article analgesics and antiphlogistics, which increase the pain threshold and suppress the inflammatory response more effectively than Lornoxicam and Diclofenac in the same doses, have been identified. The molecular and crystal structures of a large group of the substances synthesized have been studied by X-ray diffraction analysis. Comparison of these data with the results of biological tests has revealed the fact of excellent correlation between the molecular conformations of N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamides recorded in the crystal and the potency of their analgesic effect. N-Thiophen-2-ylmethyl- and N-4-methoxybenzyl-amides of 4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid has shown a high analgesic and anti-inflammatory effect, therefore, they deserve more careful research. Full article

As the demand for healthy products targeted to prevent or ameliorate bowel disease and digestive disorders of the intestinal tract is increasing, this review describes non-starch polysaccharides, such as β-glucan, arabinoxylan, galactomannan, fructan, and heteropolysaccarides from mucilages, as useful sources for adequate and tailor-made products aimed for regulation of the colon and wellbeing effects on the gut microbiota. Their monosaccharide composition, structure, molecular dimensions, physicochemical characteristics and growth stimulation of lactobacilli and bifidobacteria in the gut microbiota is reported. Arabinoxylan from wheat and rye grains is discussed as an ingredient for gluten and lectin-free bread and baked goods. Galactomannans from legumes and their partially hydrolysed products are presented as sources for specific healthy products against bowel disease and digestive discomfort. Commercial fructan products obtained from inulin, fructan of agave, and fructooligosaccharides are discussed in detail as a selective substrate for fermentation by health-promoting bacteria in the colon, such as lactobacilli and bifidobacteria. Structurally different heteropolysaccharides from mucilages of traditional medicinal plants, such as seeds from psyllium, flax, chan, chia, and basil or cladodes from Opuntia spp., are discussed as useful sources of dietary fibre, with prebiotic characteristics and digestive regulation in the intestinal tract as well. Full article

The aim of this study was to increase the antibacterial spectrum of modified hen egg white lysozyme (HEWL) with thermal and chemical treatments against Gram-negative bacteria. The antibacterial activity of heat-denatured HEWL and chemical denatured HEWL against Gram-negative and Gram-positive bacteria was evaluated in 15 h of incubation tests. HEWL was denatured by heating at pH 6.0 and pH 7.0 and chemical denaturing was carried out for 1.0, 1.5, 2.0, and 4.0 h with DL-Dithiothreitol (DTT). HEWL modified by thermal and chemical treatments was characterized using the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) electrophoresis method. Heat-denatured HEWL lytic activity against Micrococcuslysodeikticus lessened with increasing temperature and time of incubation with the chemical agent (DTT). The loss of lytic activity in modified HEWL suggests that the mechanism of action of the antibacterial activity is not dependent on the lytic activity. Thermal and chemical treatments of HEWL enabled the production of oligoforms and increased antibacterial activity over a wider spectrum. Heat-denatured HEWL at pH 6.0 and chemically-denatured HEWL increased the HEWL antibacterial spectrum against Gram-negative bacteria (Escherichia coli ATCC 25922). HEWL at 120 °C and pH 6.0 (1.0 mg/mL) inhibited 78.20% of the growth of E. coli. HEWL/DTT treatment for 4.0 h (1.0 mg/mL) inhibited 68.75% of the growth E. coli. Heat-denatured HEWL at pH 6.0 and pH 7.0 and chemically-denatured HEWL (1.0, 1.5, 2.0, and 4.0 h with DTT) were active against Gram-positive bacteria (Staphylococcus carnosus CECT 4491T). Heat-denatured and chemical-denatured HEWL caused the death of the bacteria with the destruction of the cell wall. LIVE/DEAD assays of fluorescent dye stain of the membrane cell showed membrane perturbation of bacteria after incubation with modified HEWL. The cell wall destruction was viewed using electron microscopy. The results obtained in this study suggest that heat-denatured HEWL at pH 6.0 and chemical-denatured HEWL treatments increase the HEWL antibacterial activity against Gram-negative bacteria. Full article

Recently, thiazolidinone derivatives have been widely studied as antiparasitic agents. Previous investigations showed that fused 4-thiazolidinone derivatives (especially thiopyranothiazoles) retain pharmacological activity of their synthetic precursors—simple 5-ene-4-thiazolidinones. A series of isothiochromeno[4a,4-d][1,3] thiazoles was investigated in an in vitro assay towards bloodstream forms of Trypanosoma brucei brucei. All compounds inhibited parasite growth at concentrations in the micromolar range. The established low acute toxicity of this class of compounds along with a good trypanocidal profile indicates that isothiochromenothiazole derivatives may be promising for designing new antitrypanosomal drugs. Full article

NO donating iron nitrosyl complex with 2-aminothiophenyl ligand (2-AmPh complex) was studied for its ability to cause cell death and affect nuclear factor kappa B (NF-κB) signaling. The complex inhibited viability of HeLa cells and induced cell death that was accompanied by loss of mitochondrial membrane potential and characteristic for apoptosis phosphatidylserine externalization. At IC50, 2-AmPh caused decrease in nuclear content of NF-κB p65 polypeptide and mRNA expression of NF-κB target genes encoding interleukin-8 and anti-apoptotic protein BIRC3. mRNA levels of interleukin-6 and anti-apoptotic protein BIRC2 encoding genes were not affected. Our data demonstrate that NO donating iron nitrosyl complex 2-AmPh can inhibit tumor cell viability and induce apoptosis that is preceded by impairment of NF-κB function and suppression of a subset of NF-κB target genes. Full article

Mediterranean-native perennial plant Antirrhinum majus was scrutinized in this study for its antioxidant activity and its total phenolic content in order to test for the plant’s wound-healing capability. The traditional uses of this plant to treat gum scurvy, various tumors, ulcers, and hemorrhoids were the main idea behind this study. Leaves and flowers of the A. majus were extracted by maceration. Pilot qualitative phytochemical tests were made to check the presence of various secondary metabolites. Quantitatively, the flowers’ macerate indicated superlative results regarding antioxidant activity and total phenolic content. However, the in vivo wound-healing capability study was made using 30 Wistar strain albino rats. This innovative part of the study revealed that the healing power of the flowers’ extract ointment (5% w/w) was superior compared to the leaves’ extract (5% w/w) and the positive-control ointments (MEBO) (1.5% w/w) (p ≤ 0.001). This activity was assessed by visual examination, wound-length measurement, and estimation of hydroxyproline content. Antirrhinum majus is a promising plant to be considered for wound healing. However, further testing (including histological examination and high-performance liquid chromatography (HPLC) analysis) is necessary to understand more about its mechanisms of action. Full article

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. In an attempt to understand some potential mechanisms of persistence and oncogenicity of Hepatitis C virus (HCV)-related HCC, microfibrillar-associated protein 4 (MFAP4), fibrotic indices and oxidative status biomarkers were assessed in the sera of 50 patients with HCV-associated HCC, 25 patients with HCV-related liver cirrhosis and 15 healthy individuals. Serum oxidized Coenzyme Q10 (CoQ10) and malondialdehyde showed significant elevation in HCC patients compared to the control group (p < 0.001), as well as cirrhotic patients (p < 0.05 and p < 0.001, respectively), while serum glutathione content and superoxide dismutase activity were significantly decreased in HCC patients compared to the control group (p < 0.001). Serum MFAP4, aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4) and Forns index showed significant increase in HCC patients compared to the control group (p < 0.001), while only APRI and FIB-4 were significantly different between HCC and cirrhotic patients (p < 0.05), with a sensitivity of 86% and 92%, respectively, at cut off ≥0.7 for APRI and ≥1.57 for FIB-4. Therefore, increasing oxidative stress and fibrosis might mediate HCV induced cirrhosis and HCC. APRI and FIB-4 may be used as a simple non-expensive formula for the screening of HCC rather than MFAP4. Full article

Pharmacokinetic enhancers (boosters) are compounds used in combination with a primary therapeutic agent (drug) and are not used for their direct effects on the disease but because they enhance or restore the activity of the primary agent. Hence, in certain cases, they represent an indispensable escort for enzyme-labile drugs. Pharmacokinetic enhancers can exert their activity on different ways. In the most common case, they inhibit enzymes such as human cytochrome P450 enzymes in the liver or other organs and, thereby, block or reduce undesired metabolism and inactivation of the primary drug. In this review, an overview will be given on the therapeutically most important classes of pharmacokinetic enhancers like β-lactamase inhibitors, inhibitors of CYP (cytochrome P450) enzymes in HIV therapy and hepatitis C, boosters for fluoropyrimidine-type anticancer agents, compounds utilized for enabling therapy of Parkinson’s disease with levodopa, and others. Inhibitors of efflux pumps in both pathogenic bacteria and tumor cells will be addresses shortly. Full article

Bacterial resistance towards the existing class of antibacterial drugs continues to increase, posing a significant threat to the clinical usefulness of these drugs. These increasing and alarming rates of antibacterial resistance development and the decline in the number of new antibacterial drugs’ approval continue to serve as a major impetus for research into the discovery and development of new antibacterial agents. We synthesized a series of d-/l-alaninyl substituted triazolyl oxazolidinone derivatives and evaluated their antibacterial activity against selected standard Gram-positive and Gram-negative bacterial strains. Overall, the compounds showed moderate to strong antibacterial activity. Compounds 9d and 10d (d- and l-alaninyl derivatives bearing the 3,5-dinitrobenzoyl substituent), 10e (l-alaninyl derivative bearing the 5-nitrofurancarbonyl group) and 9f and 10f (d- and l-alaninyl derivatives bearing the 5-nitrothiophene carbonyl moiety) demonstrated antibacterial activity (MIC: 2 µg/mL) against Staphylococcusaureus, Staphylococcusepidermidis, Enterococcusfaecalis and Moraxellacatarrhalis standard bacterial strains. No significant differences were noticeable between the antibacterial activity of the d- and l-alaninyl derivatives as a result of the stereochemistry of the compounds. Full article

Conjugation of curcumin and gold with green chemistry is an approach to improve the effectiveness of curcumin as anti-fibrosis. In this work, curcumin and gold were conjugated to deliver curcumin to the liver. Curcumin-gold nanoparticles (cAuNPs) were prepared by varying curcumin pH and concentration. The successful of cAuNPs formation were identified by using UV-visible and FTIR spectrophotometers. The particle size and morphology were analyzed using particle size analyzer and cryo-TEM respectively. In vitro antioxidant assay was performed to determine the curcumin activity after conjugation. Physical and chemical stabilities of cAuNPs were studied for one month at 5 °C, 25 °C, and 40 °C. Furthermore, the cAuNPs activity to modulate early marker of fibrosis was tested on NIH/3T3 cells. The optimum condition for cAuNPs synthesis was by using 1.5 mM curcumin at pH 9.3. As compared to free curcumin, cAuNPs showed higher antioxidant activity and maintained the nanosize after stored for one month. In line with the antioxidant activity, cAuNPs 0.25–1 μg/mL reduced the collagen production by NIH/3T3 cells. More importantly, cAuNPs did not demonstrate any effect on the development of chicken embryo. Taken together, the attachment of gold to curcumin in the form of cAuNPs is promising for curcumin targeting to treat hepatic fibrosis. Full article