Antinociception induced by artemisinin nanocapsule in a model of postoperative pain via spinal TLR4 inhibition.

Artemisinin (ART) was initially described for the control of inflammation and pain. However, the mechanisms involved with its antinociceptive effect are still poorly understood. Thus, this present study aimed to investigate the effect of ART in both free and nanocapsulated form on postoperative pain, as well as the participation of the spinal Toll-like receptor 4 (TLR4) in this process. Postoperative pain was induced using the skin/muscle incision retraction (SMIR) model in male Swiss mice. After 3 and 28 days of SMIR, the animals received an intrathecal injection of free or nanocapsulated ART, and the nociceptive threshold was evaluated by von Frey filament test. To evaluate the involvement of the microglia, astrocytes, and TLR4, minocycline (a microglia inhibitor), fluorocitrate (an astrocyte inhibitor), and Lipopolysaccharide Rhodobacter sphaeroides (LPS-RS), a TLR4 antagonist, were intrathecally injected on the third day of SMIR. The levels of spinal TLR4 protein and proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1ß) were quantified by western blot and enzyme-linked immunosorbent assay, respectively. The results showed that free ART reduced postoperative pain (P < 0.001, F5,30 = 7.49, 16.66% for 1000 ng dose; and P < 0.01, F5,30 = 7.49, 14.58% for 500 ng dose) on the 3rd day of SMIR; while the ART nanocapsule had this effect on both the third (P < 0.001; F5,30 = 4.94; 43.75, 39.58 and 72.91% for the 250, 500 and 1000 ng doses, respectively) and 28th (P < 0.05; F5,30 = 7.71; 29.16 and 33.33% for the 500 and 1000 ng doses, respectively) day. The ART nanocapsule had a more potent and longer antinociceptive effect than free ART or morphine. Postoperative pain was also reduced by minocycline and LPS-RS. The ART nanocapsule also reduced the increased levels of TLR4, TNF-α, and IL-1ß induced by SMIR. These data suggest that the ART nanocapsule has a potent analgesic effect on postoperative pain at the spinal level, and this response involves the inhibition of TLR4 and the proinflammatory cytokines TNF-α and IL-1ß.

Plant-based active photoprotectants for sunscreens.

Excessive exposure to the sun's radiation is the major exogenous mediator of skin damage, which accelerates skin ageing and increases the risk of developing skin cancer. Compounds with photoprotectant activity are extremely useful for decreasing the effect of ultraviolet (UV) radiation on the skin; however, numerous sun filters, especially organic sunscreens, are allergenic. Therefore, the development of formulations containing plant extracts, which may be potentially safer, is extensively being explored. Plant-based cosmetics are commonly used to avoid skin ageing because they contain antioxidant agents that minimize free radical activity, and numerous studies have investigated the skin-protectant effects of related plant species. In addition to their antioxidant properties, plant-based cosmetics protect the skin against solar radiation because they contain polyphenols such as flavonoids and carotenoids. Therefore, this study aims to present a review of plant species commonly used in sunscreens to protect the skin against damage due to sunlight exposure.

Pterodon pubescens oil: characterisation, certification of origin and quality control via mass spectrometry fingerprinting analysis.

INTRODUCTION: The oil obtained from Pterodon pubescens (Leguminosae) seeds are known to display anti-cancer, anti-dermatogenic and anti-nociceptive activitiy. Phytochemical studies have demonstrated that its main constituents are diterpenoids with voucapan skeletons. Considering the potential biological activities of the oil, rapid and efficient methods for assessing its quality would facilitate certification and quality control. OBJECTIVE: To develop a direct mass spectrometric fingerprinting method for the P. pubescens seed oil that would focus on the major diterpenoids constituents, enabling quality control, origin certification and recognition of marker species in commercially available products. METHOD: Two techniques were used: (i) direct infusion electrospray ionisation (ESI) mass spectrometry after solvent extraction and dilution and (ii) ambient desorption/ionisation via easy ambient sonic-spray ionisation, EASI(+)-MS, performed directly on the seed surface or at a paper surface imprinted with the oil. RESULTS: From a combination of ESI-MS, HRESI-MS and ESI-MS/MS data, 12 diterpenes were characterised, and typical profiles were obtained for the oil extract or the crude oil via both ESI-MS and EASI-MS. These techniques require no or very simple sample preparation protocols and the whole analytical processes with spectra acquisition take just a few minutes. CONCLUSION: Both techniques, but particularly EASI-MS, provide simple, fast and efficient MS fingerprinting methodologies to characterise the P. pubescens oil with typical (di)terpene profiles being applicable to quality control and certification of authenticity and origin.

Artemisinin-type drugs for the treatment of hematological malignancies.

Qinghaosu, known as artemisinin (ARS), has been for over two millennia, one of the most common herbs prescribed in traditional Chinese medicine (TCM). ARS was developed as an antimalarial drug and currently belongs to the established standard treatments of malaria as a combination therapy worldwide. In addition to the antimalarial bioactivity of ARS, anticancer activities have been shown both in vitro and in vivo. Like other natural products, ARS acts in a multi-specific manner also against hematological malignancies. The chemical structure of ARS is a sesquiterpene lactone, which contains an endoperoxide bridge essential for activity. The main mechanism of action of ARS and its derivatives (artesunate, dihydroartemisinin, artemether) toward leukemia, multiple myeloma, and lymphoma cells comprises oxidative stress response, inhibition of proliferation, induction of various types of cell death as apoptosis, autophagy, ferroptosis, inhibition of angiogenesis, and signal transducers, as NF-κB, MYC, amongst others. Therefore, new pharmaceutically active compounds, dimers, trimers, and hybrid molecules, could enhance the existing therapeutic alternatives in combating hematologic malignancies. Owing to the high potency and good tolerance without side effects of ARS-type drugs, combination therapies with standard chemotherapies could be applied in the future after further clinical trials in hematological malignancies.

The atomic approach to the Anderson model for the finite U case: application to a quantum dot.

In the present work we apply the atomic approach to the single-impurity Anderson model (SIAM). A general formulation of this approach, that can be applied both to the impurity and to the lattice Anderson Hamiltonian, was developed in a previous work (Foglio et al 2009 arxiv: 0903.0139v2 [cond-mat.str-el]). The method starts from the cumulant expansion of the periodic Anderson model, employing the hybridization as a perturbation. The atomic Anderson limit is analytically solved and its sixteen eigenenergies and eigenstates are obtained. This atomic Anderson solution, which we call the AAS, has all the fundamental excitations that generate the Kondo effect, and in the atomic approach is employed as a 'seed' to generate the approximate solutions for finite U. The width of the conduction band is reduced to zero in the AAS, and we choose its position such that the Friedel sum rule is satisfied, close to the chemical potential mu. We perform a complete study of the density of states of the SIAM over the whole relevant range of parameters: the empty dot, intermediate valence, Kondo and magnetic regimes. In the Kondo regime we obtain a density of states that characterizes well the structure of the Kondo peak. To show the usefulness of the method we have calculated the conductance of a quantum dot, side-coupled to a conduction band.

Liposomes incorporating essential oil of Brazilian cherry (Eugenia uniflora L.): characterization of aqueous dispersions and lyophilized formulations.

Multilamellar liposomes incorporating essential oil of Brazilian cherry (Eugenia uniflora L.) leaves were produced by dry film hydration. Gas chromatography demonstrated the compounds found in the essential oil were effectively incorporated in the aqueous dispersions of liposomes. Differential scanning calorimetry analyses revealed the incorporation of the essential oil did not cause phase separation in the membrane structure; the gel-liquid crystalline transition temperature (main transition) remained the same despite the higher heterogeneity indicated by the transition peak broadening. Different cryoprotectors (sucrose and trehalose) were added to the liposomal formulations to be tested in their ability to protect the liposomal structure during the lyophilization. The morphological aspect of the lyophilized powders analysed by scanning electron microscopy showed significant differences among the samples with and without cryoprotectors. Fourier-transform infrared spectroscopy indicated the cryoprotectors interacted effectively with the polar heads of phospholipids in the bilayer. In terms of water absorption, trehalose was identified as a much more effective protector agent against it than sucrose. The cryoprotectors showed different degrees of effectiveness of preservation of the liposomal structure when the rehydration assays of lyophilized liposomes were carried out, as particle size measurements indicated a moderate process of fusion when the formulations with sucrose were rehydrated.

Flexible, dense and porous chitosan and alginate membranes containing the standardized extract of Arrabidaea chica Verlot for the treatment of skin lesions.

The combination of chitosan (C) with alginate (A) has been explored for the production of dressings due to the positive results on wound healing. CA films can show a dense or porous flexible structure, with characteristics tunable for different applications. Porosity and flexibility can be achieved, respectively, by the addition of surfactants such as Kolliphor® P188 (P) and silicone-based compounds as Silpuran® 2130 A/B (S). Furthermore, composite matrices of these polysaccharides have potential applications as devices for releasing bioactive compounds to skin lesions. The purpose of this study was to evaluate the physicochemical and biological characteristics of flexible dense and porous CA membranes incorporating the standardized extract of Arrabidaea chica Verlot (A. chica), and also to analyze the release mechanism of the extract from different membrane formulations. The results show that the inclusion of P in the formulation allows obtaining porous matrices, promotes greater homogeneity of the mixture of the silicone gel with the suspension of polysaccharides, and increases the swelling of the polymer matrix. All formulations presented high stability, reaching a maximum mass loss of 18% after seven days. The formulations with S showed the best performance in terms of flexibility and strain at break. The presence of A. chica standardized extract did not affect negatively the characteristics of the membranes. Incorporation efficiencies of the bioactive compound above 87% were achieved, and the addition of P and S to the membrane formulation changed the release of the A. chica extract kinetics. In addition, the developed formulations did not significantly affect Vero cells proliferation.

In vitro degradation of linamarin by microorganisms isolated from cassava wastewater treatment lagoons.

This study aimed at isolating and characterizing of microorganisms able to use linamarin as sole carbon source. Thirty one microbial strains were isolated from manipueira, a liquid effluent of cassava processing factories. Among these strains, Bacillus licheniformis (isolate 2_2) and Rhodotorulla glutinis (isolate L1) were able to degrade 71% and 95% of added linamarin, respectively, within 7 days, showing high biodegradation activity and great potential for detoxification of cassava processing wastewaters.

A high-resolution linkage map for the Z chromosome in chicken reveals hot spots for recombination.

A comprehensive linkage map for chicken chromosome Z was constructed as the result of a large-scale screening of single nucleotide polymorphisms (SNPs). A total of 308 SNPs were assigned to Z based on the genotype distribution among 182 birds representing several populations. A linkage map comprising 210 markers and spanning 200.9 cM was established by analyzing a small Red junglefowl/White Leghorn intercross. There was excellent agreement between the linkage map for Z and a recently released assembly of the chicken genome (May 2006). Almost all SNPs assigned to chromosome Z in the present study are on Z in the new genome assembly. The remaining 12 loci are all found on unassigned contigs that can now be assigned to Z. The average recombination rate was estimated at 2.7 cM/Mb but there was a very uneven distribution of recombination events with both cold and hot spots of recombination. The existence of one of the major hot spots of recombination, located around position 39.4 Mb, was supported by the observed pattern of linkage disequilibrium. Thirteen markers from unassigned contigs were shown to be located on chromosome W. Three of these contigs included genes that have homologues on chromosome Z. The preliminary assignment of three more genes to the gene-poor W chromosome may be important for studies on the mechanism of sex determination and dosage compensation in birds.

The role of short-range magnetic correlations in the gap opening of topological Kondo insulators.

In this article we investigate the effects of short-range anti-ferromagnetic correlations on the gap opening of topological Kondo insulators. We add a Heisenberg term to the periodic Anderson model at the limit of strong correlations in order to allow a small degree of hopping of the localized electrons between neighboring sites of the lattice. This new model is adequate for studying topological Kondo insulators, whose paradigmatic material is the compound [Formula: see text]. The main finding of the article is that the short-range antiferromagnetic correlations, present in some Kondo insulators, contribute decisively to the opening of the Kondo gap in their density of states. These correlations are produced by the interaction between moments on the neighboring sites of the lattice. For simplicity, we solve the problem on a two dimensional square lattice. The starting point of the model is the [Formula: see text] ions orbitals, with [Formula: see text] multiplet in the presence of spin-orbit coupling. We present results for the Kondo and for the antiferromagnetic correlation functions. We calculate the phase diagram of the model, and as we vary the [Formula: see text] level position from the empty regime to the Kondo regime, the system develops metallic and topological Kondo insulator phases. The band structure calculated shows that the model describes a strong topological insulator.

Derivatives of furanditerpenes from Pterodon genus: Pharmacological studies disclose their potential as chronic pain relief in mice.

Pterodon genus fruits are commercially available at the Brazilian medicinal market used in folk medicine due to their anti-inflammatory, analgesic, and anti-rheumatic effects. Previous studies demonstrated that furanditerpenes possessing vouacapan skeleton, isolated from Pterodon genus, possess expressive antinociceptive activities, with promising moiety for the development of new analgesic products. The antinociceptive properties of compounds 6α,7ß-6α-hidroxivouacapan-7ß-17ß-lactone (HVL) and 6α-oxovouacapan-7ß-17ß-lactone (OVL), semi-synthetic analogues of furanditerpenes previously reported as analgesic agents were evaluated on animal experimental models (Spindola et al., 2010, 2011). The chemical-induced pain methods used in the present work, demonstrated for the first time that both compounds HVL and OVL have potential as important templates for the development of chronic pain control drugs. The main findings of this work were that both compounds were: effective in the writhing test; reduced paw edema in the carrageenan test; effective in the inflammatory phase of the formalin test corroborating their activity against inflammatory pain conditions; effective on reducing pain through the stimulation of vanilloid receptors sensible to capsaicin (an important pathway for chronic pain maintenance); reduced the pain stimulus caused by PGE2 injection (a pathway involved in chronic pain hypersensitivity); effective on decreasing mechanical allodynia in the CFA-model, demonstrating their potential use against chronic pain disorders.

Pharmacological activities investigation of crude extracts and fractions from Qualea grandiflora Mart.

This study investigates pharmacological activities of crude hydroalcoholic extract and fractions of Qualea grandiflora Mart. leaves employing different experimental models using mice. The treatment with crude hydroalcoholic extract (EH) in a dose of 500 mg/kg, i.p. caused: signs of central nervous system depressant action in the Hippocratic screening test, confirmed by the potentiation of sodium pentobarbital sleeping time. Increasing in the latency time of hot plate assay that indicate an analgesic effect; significantly delaying of the onset of clonic PTZ convulsions, increasing in the time for death, suppressing of the tonic PTZ convulsion, and decreasing of severity and number of convulsions. The median lethal dose of EH was 1.321 mg/kg. The convulsions induced by PTZ, ethyl ether fraction (300 mg/kg, i.p.) was more active in increasing the latency time for first convulsion, moreover, the hexane fraction, at the same dose, was more active in increasing the time for death and/or avoiding the death. Both did not cause disturbance in motor coordination at the dose of 500 mg/kg, assessed by rotarod test. These results suggest that the crude extract of leaves of Qualea grandiflora Mart. has a central nervous system depressant action, an analgesic effect and behave as a potential anticonvulsant.

Effects of Arctium lappa on Cadmium-Induced Damage to the Testis and Epididymis of Adult Wistar Rats.

The protective role of Arctium lappa (AL) on the testes of rats acutely exposed to cadmium (Cd) was tested. The rats were randomly divided into a control group (C-group) and three major experimental groups, which were further subdivided into minor groups (n = 6) according to the experimental period (7 or 56 days). The C-group was subdivided into C-7 and C-56 [receiving a single saline solution, intraperitoneal (i.p.), on the first day]; the AL-group, AL-7, and AL-56, received AL extract (300 mg/kg/daily); the Cd group, Cd-7 and Cd-56, received a single i.p. dose of CdCl2 (1.2 mg/kg body weight (BW)) on the first day; the CdAL group, CdAL-7 and CdAL-56, received the same Cd dose, followed by AL extract. Water or AL extract was administered daily by gavage. After either 7 or 56 days, the testis and accessory glands were removed after whole-body perfusion. Exposure to Cd and CdAL decreased the weight of the testis and epididymis, the gonadosomatic index, seminiferous tubular (ST) diameter, and ST volumetric proportion, and increased the volumetric proportion of interstitium after 56 days. In the epididymis caput, the tubular volumetric proportion decreased along with an increase of interstitial volumetric proportion and epithelium height after 56 days. The alterations observed were less severe only after 7 days. A progressive testicular damage resulted mainly in tubules lined only by Sertoli cells. The sperm number and cell debris decreased in the epididymis. We demonstrated that the testicular damage induced by single acute i.p. exposure to Cd occurred despite the daily oral intake of AL extract.

Molecular docking studies on interaction of diverse retinol structures with human alcohol dehydrogenases predict a broad role in retinoid ligand synthesis.

Some members of the human alcohol dehydrogenase (ADH) family possess retinol dehydrogenase activity and may thus function in production of the active nuclear receptor ligand retinoic acid. Many diverse natural forms of retinol exist including all-trans-retinol (vitamin A(1)), 9-cis-retinol, 3,4-didehydroretinol (vitamin A(2)), 4-oxo-retinol, and 4-hydroxy-retinol as well as their respective carboxylic acid derivatives which are active ligands for retinoid receptors. This raises the question of whether ADHs can accommodate all these different retinols and thus participate in the activation of several retinoid ligands. The crystal structures of human ADH1B and ADH4 provide the opportunity to examine their active sites for potential binding to many diverse retinol structures using molecular docking algorithms. The criteria used to score successful docking included achievement of distances of 1.9-2.4 A between the catalytic zinc and the hydroxyl oxygen of retinol and 3.2-3.6 A between C-4 of the coenzyme NAD and C-15 of retinol. These distances are sufficient to enable hydride transfer during the oxidation of an alcohol to an aldehyde. By these criteria, all-trans-retinol, 4-oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and ADH4. However, 9-cis-retinol and 3,4-didehydroretinol, which have more restrictive conformations, were successfully docked to only ADH4 which possesses a wider active site than ADH1B and more easily accommodates the C-19 methyl group. Furthermore, docking of all retinols was more favorable in the active site of ADH4 rather than ADH1B as measured by force field and contact scores. These findings suggest that ADH1B has a limited capacity to metabolize retinols, but that ADH4 is well suited to function in the metabolism of many diverse retinols and is predicted to participate in the synthesis of the active ligands all-trans-retinoic acid, 9-cis-retinoic acid, 3, 4-didehydroretinoic acid, 4-oxo-retinoic acid, and 4-hydroxy-retinoic acid.

Phenolic compounds of Hibiscus sabdariffa and influence of organic residues on its antioxidant and antitumoral properties.

The aim of this study was to evaluate the phenolic and flavonoids contents and the antioxidant and antitumoral activity of leaf and calyx methanolic extracts from Hibiscus sabdariffa (roselle) cultivated with poultry litter and organosuper® under three modes of application. The total phenolic content in the each extract was determined using the Folin-Ciocalteu reagent and for aluminium chloride flavonoids. The antioxidant parameters were analyzed using a 2, 2-diphenyl-1-picrylhydrazyl (DPPH.) free radical scavenging assay. An antitumor colorimetric assay using sulforhodamine B. The highest contents of phenolic and flavonoids were observed in leaf extracts (389.98 and 104.52 mg g-1, respectively) and calyx extracts (474.09 and 148.35 mg g-1, respectively) from plants cultivated with organosuper®, although these values did not differ significantly from those observed for the other treatments. The average IC50 of leaves (43.48 µg mL-1) and calyces (37.15 µg mL-1) demonstrated that both have substances that may contribute to free radical scavenging action. The methanol extract from calyces showed significant selective activity against a leukemia line (K-562), with IC50 values of 0.12 mg mL-1 (organosuper®) and 1.16 mg mL-1 (poultry litter), with concentration-dependent, cytotoxic and cytocidal effects.

In vitro biological screening of the anticholinesterase and antiproliferative activities of medicinal plants belonging to Annonaceae.

The aim of this research was to investigate the antiproliferative and anticholinesterase activities of 11 extracts from 5 Annonaceae species in vitro. Antiproliferative activity was assessed using 10 human cancer cell lines. Thin-layer chromatography and a microplate assay were used to screen the extracts for acetylcholinesterase (AchE) inhibitors using Ellman's reagent. The chemical compositions of the active extracts were investigated using high performance liquid chromatography. Eleven extracts obtained from five Annonaceae plant species were active and were particularly effective against the UA251, NCI-470 lung, HT-29, NCI/ADR, and K-562 cell lines with growth inhibition (GI50) values of 0.04-0.06, 0.02-0.50, 0.01-0.12, 0.10-0.27, and 0.02-0.04 µg/mL, respectively. In addition, the Annona crassiflora and A. coriacea seed extracts were the most active among the tested extracts and the most effective against the tumor cell lines, with GI50 values below 8.90 µg/mL. The A. cacans extract displayed the lowest activity. Based on the microplate assay, the percent AchE inhibition of the extracts ranged from 12 to 52%, and the A. coriacea seed extract resulted in the greatest inhibition (52%). Caffeic acid, sinapic acid, and rutin were present at higher concentrations in the A. crassiflora seed samples. The A. coriacea seeds contained ferulic and sinapic acid. Overall, the results indicated that A. crassiflora and A. coriacea extracts have antiproliferative and anticholinesterase properties, which opens up new possibilities for alternative pharmacotherapy drugs.

Evaluation of the antiedematogenic activity of artemetin isolated from Cordia curassavica DC.

The species Cordia curassavica (Boraginaceae), known popularly as "erva baleeira", is used in folk medicine for the treatment of several inflammatory processes and as a healing agent. The objective of the present study was to evaluate the antiedematogenic activity of crude dichloromethane extracts of Cordia curassavica and of the artemetin-enriched fraction. The crude extract and artemetin fraction were tested in the model of carrageenin-induced paw edema in male Swiss mice (25-30 g). The crude dichloromethane extract (300 and 1000 mg/kg, po, N = 6) showed significant antiedematogenic activity, reducing the edema by 42, 57 and 45% and 46, 62 and 69%, 3, 4 and 5 h after carrageenin administration, respectively. Indomethacin (10 mg/kg, po, N = 6) reduced the edema by 45 and 48%, after 4 and 5 h, but the artemetin-enriched fraction (30, 100 and 300 mg/kg, po, N = 6) had no activity. The dichloromethane extract (300 and 1000 mg/kg, po, N = 6) also showed antinociceptive activity by reducing acetic acid-induced writhing in mice from 37.1 +/- 2.28 (control) to 17.3 +/- 1.34 and 13.2 +/- 1.44, respectively, but had no activity in the hot-plate test.

Antiulcerogenic activity of crude hydroalcoholic extract of Rosmarinus officinalis L.

Rosmarinus officinalis L. crude hydroalcoholic (70%) extract was evaluated for antiulcerogenic activity employing different experimental models. The crude hydroalcoholic extract (CHE) decreased the ulcerative lesion index produced by indomethacin, ethanol and reserpine in rats. No antisecretory activity was observed on pyloric ligation model. The previous administration of L-NAME, a NO-synthase inhibitor, did not reduce the antiulcerogenic activity of CHE in ethanol induced ulcer model, suggesting that the pharmacological mechanism has no relationship with nitric oxide (NO). Whereas when the animal groups were treated with indomethacin, using the same experimental model, CHE did not reduce the antiulcerogenic activity, suggesting that the pharmacological mechanism has no relationship with prostaglandins. The previous treatment with N-ethymaleimide, a thiol blocker, including mucosal nonprotein sulfhydryl groups, reduced the anitulcerogenic activity of CHE on ethanol induced ulcer model. This result suggests that the crude hydroalcoholic extract of R. officinalis L. has active substances that increase the mucosal nonprotein sulfhydryl groups content. In another hypothesis, the pharmacological mechanism could be attributed to the activity of antioxidant compounds found in the crude hydroalcoholic extract which can react with N-ethylmaleimide.