Can drug-bearing liposomes penetrate intact skin?

Using liposomes to deliver drugs to and through human skin is controversial, as their function varies with type and composition. Thus they may act as drug carriers controlling release of the medicinal agent. Alternatively, they may provide a localized depot in the skin so minimizing systemic effects or can be used for targeting delivery to skin appendages (hair follicles and sweat glands). Liposomes may also enhance transdermal drug delivery, increasing systemic drug concentrations. With such a multiplicity of functions, it is not surprising that mechanisms of liposomal delivery of therapeutic agents to and through the skin are unclear. Accordingly, this article provides an overview of the modes and mechanisms of action of different vesicles as drug delivery vectors in human skin. Our conclusion is that vesicles, depending on the composition and method of preparation, can vary with respect to size, lamellarity, charge, membrane fluidity or elasticity and drug entrapment. This variability allows for multiple functions ranging from local to transdermal effects. Application to dissimilar skins (animal or human) via diverse protocols may reveal different mechanisms of action with possible vesicle skin penetration reaching different depths, from surface assimilation to (rarely) the viable tissue and subsequent systemic absorption.

Prebiotics and lipid metabolism

Prebiotics are defined as nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or the activity of one or a limited number of bacteria (bifidobacteria, lactobacilli) in the colon. Dietary fructans are nutritionally interesting oligosaccharides that strictly conform to the definition of prebiotics and (in view of experimental studies in animals and of less numerous studies in humans) exhibit interesting serum or hepatic lipid lowering properties. Other nondigestible/fermentable nutrients, which also modulate intestinal flora activity, exhibit cholesterol or triglyceride lowering effects. Are changes in intestinal bacterial flora composition or fermentation activity responsible for those effects? What is the future of prebiotics in the nutritional control of lipidaemia and cardiovascular disease risk in humans? Those questions only receive partial response in the present review because studies of the systemic effects of prebiotics are still in their infancy, and require fundamental research devoted to elucidating the biochemical and physiological events that allow prebiotics to exert systemic effects on lipid metabolism.

Apples and cardiovascular health: is the gut microbiota a core consideration?

There is now considerable scientific evidence that a diet rich in fruits and vegetables can improve human health and protect against chronic diseases. However, it is not clear whether different fruits and vegetables have distinct beneficial effects. Apples are among the most frequently consumed fruits and a rich source of polyphenols and fiber. A major proportion of the bioactive components in apples, including the high molecular weight polyphenols, escape absorption in the upper gastrointestinal tract and reach the large intestine relatively intact. There, they can be converted by the colonic microbiota to bioavailable and biologically active compounds with systemic effects, in addition to modulating microbial composition. Epidemiological studies have identified associations between frequent apple consumption and reduced risk of chronic diseases such as cardiovascular disease. Human and animal intervention studies demonstrate beneficial effects on lipid metabolism, vascular function and inflammation but only a few studies have attempted to link these mechanistically with the gut microbiota. This review will focus on the reciprocal interaction between apple components and the gut microbiota, the potential link to cardiovascular health and the possible mechanisms of action.

Tityus discrepans scorpion venom activates platelets through GPVI and a novel Src-dependent signaling pathway

In humans and other mammals, Tityus discrepans (Td) scorpion envenomation produces a variety of systemic effects including respiratory distress, a generalized inflammatory reaction, modulation of blood pressure, fibrin formation, and platelet activation. For many of these effects, the venom components and underlying mechanisms are not known. In the present study, we demonstrate that Td venom (TdV) stimulates integrin αIIbβ3-dependent aggregation of washed human and mouse platelets downstream of Src kinase activation. The pattern of increase in tyrosine phosphorylation induced by TdV in human platelets is similar to that induced by the collagen receptor GPVI, and includes FcR γ-chain, Syk, and PLC γ 2. Confirmation of GPVI activation by TdV was achieved by expression of human GPVI in chicken DT40 B cells and use of a reporter assay. To our surprise, TdV was able to activate mouse platelets deficient in the GPVI-FcR γ-chain complex through a pathway that was also dependent on Src kinases. TdV therefore activates platelets through GPVI and a second, as yet unidentified Src kinase-dependent pathway.

O judiciário e a governança democrática dos recursos hídricos na região metropolitana: uma abordagem a partir do caso Matanza-Riachuelo

A previsão constitucional de competência concorrente dos entes políticos para a promoção de políticas públicas nas regiões metropolitanas abre caminho para que no caso de omissão dos poderes legislativos e executivos a questão seja judicializada. O Judiciário, como guardião dos direitos fundamentais e dos princípios democráticos, tem legitimidade para impor a cooperação entre os entes políticos a fim de que seja prestado um serviço publico eficiente e igualitário para todos os cidadãos. Essa atuação, contudo, está limitada aos princípios constitucionais e à vontade popular, além da existência de capacidade institucional e atenção aos efeitos sistêmicos. É apresentado o caso Matanza Riachuelo, em que o Judiciário condenou os entes políticos a promoverem, entre outras medidas, um plano estratégico comum. Ao final, apresenta-se uma visão crítica da atuação do Judiciário na execução desse julgado.

Mucoadhesive drug delivery systems

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Analysis of Bothrops jararacussu venomous gland transcriptome focusing on structural and functional aspects: I - gene expression profile of highly expressed phospholipases A(2)

Snake venom glands are a rich source of bioactive molecules such as peptides, proteins and enzymes that show important pharmacological activity leading to in local and systemic effects as pain, edema, bleeding and muscle necrosis. Most studies on pharmacologically active peptides and proteins from snake venoms have been concerned with isolation and structure elucidation through methods of classical biochemistry. As an attempt to examine the transcripts expressed in the venom gland of Bothrops jararacussu and to unveil the toxicological and pharmacological potential of its products at the molecular level, we generated 549 expressed sequence tags (ESTs) from a directional cDNA library. Sequences obtained from single-pass sequencing of randomly selected cDNA clones could be identified by similarities searches on existing databases, resulting in 197 sequences with significant similarity to phospholipase A(2) (PLA(2)), of which 83.2% were Lys49-PLA(2) homologs (BOJU-1), 0.1% were basic Asp49-PLA(2)s (BOJU-II) and 0.6% were acidic Asp49-PLA(2)s (BOJU-III). Adjoining this very abundant class of proteins we found 88 transcripts codifying for putative sequences of metalloproteases, which after clustering and assembling resulted in three full-length sequences: BOJUMET-I, BOJUMET-II and BOJUMET-III; as well as 25 transcripts related to C-type lectin like protein including a full-length cDNA of a putative galactose binding C-type lectin and a cluster of eight serine-proteases transcripts including a full-length cDNA of a putative serine protease. Among the full-length sequenced clones we identified a nerve growth factor (Bj-NGF) with 92% identity with a human NGF (NGHUBM) and an acidic phospholipase A2 (BthA-I-PLA(2)) displaying 85-93% identity with other snake venom toxins. Genetic distance among PLA(2)s from Bothrops species were evaluated by phylogenetic analysis. Furthermore, analysis of full-length putative Lys49-PLA(2) through molecular modeling showed conserved structural domains, allowing the characterization of those proteins as group II PLA(2)s. The constructed cDNA library provides molecular clones harboring sequences that can be used to probe directly the genetic material from gland venom of other snake species. Expression of complete cDNAs or their modified derivatives will be useful for elucidation of the structure-function relationships of these toxins and peptides of biotechnological interest. (C) 2004 Elsevier SAS. All rights reserved.

Insect Venom Peptides

The insects of the order Hymenoptera ( bees, wasps, and ants) are classified in two groups, based on their life history: social and solitary. The venoms of the social Hymenoptera evolved to be used as defensive tools to protect the colonies of these insects from the attacks of predators. Generally they do not cause lethal effects but cause mainly inflammatory and/or immunological reactions in the victims of their stings. However, sometimes it is also possible to observe the occurrence of systemic effects like respiratory and/or kidney failure. Meanwhile, the venoms of solitary Hymenoptera evolved mainly to cause paralysis of the preys in order to permit egg laying on/within the prey's body; thus, some components of these venoms cause permanent/transient paralysis in the preys, while other components seem to act preventing infections of the food and future progenies. The peptide components of venoms from Hymenoptera are spread over the molar mass range of 1400 to 7000 da and together comprise up to 70% of the weight of freeze-dried venoms. Most of these toxins are linear polycationic amphipatic peptides with a high content of alpha-helices in their secondary structures. These peptides generally account for cell lysis, hemolysis, antibiosis, and sometimes promote the delivery of cellular activators/mediators through interaction with the G-protein receptor, and perhaps some of them are even immunogenic components. In addition to these peptides, the Hymenopteran venoms also may contain a few neurotoxins that target Na+ and/or Ca+2 channels or even the nicotinic ACh receptor. This review summarizes current knowledge of the biologically active Hymenoptera venoms.

SMase II, a new sphingomyelinase D from Loxosceles laeta venom gland: Molecular cloning, expression, function and structural analysis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Glucose metabolism in rats submitted to skeletal muscle denervation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Efeitos da administração epidural de amitraz, xilazina ou dimetil sulfóxido em vacas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Measuring fluoride concentration in mineral waters in the Araraquara region, Brazil

It has been shown that people of all ages can benefit from the topical and systemic effects of water fluoridation. However, the increase in consumption of bottled water, either to substitute for or supplement consumption of water from public sources, has implications for safe fluoride supplementation. Taking that into consideration, in 1995 we analyzed the fluoride content in 31 commercial brands of mineral water in the region of Araraquara, state of Sao Paulo, Brazil. Fluoride concentration as determined by our analysis was compared to the concentration of fluoride specified on each label. Only 25% of the products studied listed the fluoride concentration on their labels. In addition, among 31 mineral water brands, 26 listed the date when the chemical analysis to determine chemical composition had been performed. Of these, 20 had not been put through the annual chemical analysis determined by Brazilian law. Based on these results, if the mineral waters tested had been the only source of drinking water, fluoride supplementation would have been necessary in 69% of the samples analyzed. In the case of children up to 6 years of age who use products containing fluoride, such as topical gels, mouthwashes or toothpastes, supplementation should be recommended only if commercially bottled water is the only source of water used, not only for drinking but for cooking as well.

Manifestações sistêmicas na doença pulmonar obstrutiva crônica

Chronic obstructive pulmonary disease is progressive and is characterized by abnormal inflammation of the lungs in response to inhalation of noxious particles or toxic gases, especially cigarette smoke. Although this infirmity primarily affects the lungs, diverse extrapulmonary manifestations have been described. The likely mechanisms involved in the local and systemic inflammation seen in this disease include an increase in the number of inflammatory cells (resulting in abnormal production of inflammatory cytokines) and an imbalance between the formation of reactive oxygen species and antioxidant capacity (leading to oxidative stress). Weakened physical condition secondary to airflow limitation can also lead to the development of altered muscle function. Chronic obstructive pulmonary disease presents diverse systemic effects including nutritional depletion and musculoskeletal dysfunction (causing a reduction in exercise tolerance), as well as other effects related to the comorbidities generally observed in these patients. These manifestations have been correlated with survival and overall health status in chronic obstructive pulmonary disease patients. In view of these facts, the aim of this review was to discuss findings in the literature related to the systemic manifestations of chronic obstructive pulmonary disease, emphasizing the role played by systemic inflammation and evaluating various therapeutic strategies.

Ensaios biológicos para avaliação de segurança de produtos cosméticos

Despite efforts to the contrary, some cosmetic products can cause undesirable side effects in the users. These may often be due to individual factors or inappropriate use of the product. Thus, biological assays to assess the safety of a new cosmetic must precede its being placed on the market. Historically, these tests have always been carried out in vivo, in animals, since such tests can be used to evaluate many of the potential risks, such as irritation, allergy or systemic effects; but, recently, some research centers have been adopting in vitro alternatives, in order to replace the animal tests. This review emphasizes the need to employ biological assays to test the safety of cosmetic products, and reviews the main in vivo and in vitro tests used, focusing on the need to develop and use alternatives to the in vivo assays of product safety, so as to offer the consumers the maximum safety with the least possible risk, while ensuring the best conditions of use of the product.

Structure of a novel class II phospholipase D: Catalytic cleft is modified by a disulphide bridge

Phospholipases D (PLDs) are principally responsible for the local and systemic effects of Loxosceles envenomation including dermonecrosis and hemolysis. Despite their clinical relevance in loxoscelism, to date, only the SMase I from Loxosceles laeta, a class I member, has been structurally characterized. The crystal structure of a class II member from Loxosceles intermedia venom has been determined at 1.7. Å resolution. Structural comparison to the class I member showed that the presence of an additional disulphide bridge which links the catalytic loop to the flexible loop significantly changes the volume and shape of the catalytic cleft. An examination of the crystal structures of PLD homologues in the presence of low molecular weight compounds at their active sites suggests the existence of a ligand-dependent rotamer conformation of the highly conserved residue Trp230 (equivalent to Trp192 in the glycerophosphodiester phosphodiesterase from Thermus thermophofilus, PDB code: 1VD6) indicating its role in substrate binding in both enzymes. Sequence and structural analyses suggest that the reduced sphingomyelinase activity observed in some class IIb PLDs is probably due to point mutations which lead to a different substrate preference. © 2011 Elsevier Inc.