Nanostructured Systems in Advanced Drug Targeting for the Cancer Treatment: Recent Patents.

BACKGROUND: Cancer is one of the leading causes of death in the world and it is necessary to develop new strategies for its treatment because most therapies have limited access to many types of tumors, as well as low therapeutic efficacy and high toxicity. OBJECTIVE: The present research aims to identify recent patents of drug delivery nanostructured systems that may have application in improving cancer treatment. METHODS: Recent patents regarding the drug delivery nanostructured systems for cancer treatment were obtained from the patent databases of the six main patent offices of the world: United States Patent and Trademark Office, European Patent Office, World Intellectual Property Organization, Japan Patent Office, State Intellectual Property Office of China and Korean Intellectual Property Office. RESULTS: A total of 1710 patent documents from 1998 to 2017 including "drug delivery nanostructured systems for cancer treatment" were retrieved. The top five countries in patent share were USA, China, South Korea, Canada and Germany. The universities and enterprises of USA had the highest amount of patents followed by institutions from China. CONCLUSION: There is a strong tendency for the development of new nanostructured systems for the release of drugs; particularly, in recent years, the development of nanoparticles has focused on nanodiscs, gold nanoparticles and immunoliposomes.

Human apolipoprotein A-I Gly26Arg stimulation of inflammatory responses via NF-kB activation: Potential roles in amyloidosis?

The cascade of molecular events leading to Human apolipoprotein A-I (apoA-I) amyloidosis is not completely understood, not even the pathways that determine clinical manifestations associated to systemic protein deposition in organs such as liver, kidney and heart. About twenty natural variants of apoA-I were described as inducing amyloidosis, but the mechanisms driving their aggregation and deposition are still unclear. We previously identified that the mutant Gly26Arg but not Lys107-0 induced the release of cytokines and reactive oxygen species from cultured RAW 264.7 murine macrophages, suggesting that part of the pathogenic pathway could elicit of an inflammatory signal. In this work we gained deep insight into this mechanism and determined that Gly26Arg induced a specific pro-inflammatory cascade involving activation of NF-κB and its translocation into the nucleus. These findings suggest that some but not all apoA-I natural variants might promote a pro-oxidant microenvironment which could in turn result in oxidative processing of the variants into a misfolded conformation.

Influence of Dimerization of Apocynin on Its Effects in Experimental Colitis.

Apocynin has been widely used as an inhibitor of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) system and shows promise as an anti-inflammatory drug. Diapocynin, the dimeric product generated by the oxidation of apocynin in the presence of myeloperoxidase (MPO), is supposed to be its active form. In this study, diapocynin has been chemically synthesized and its activity on several inflammatory mediators in LPS-stimulated RAW 264.7 macrophages and its anti-inflammatory effect on ulcerative colitis induced by dextran sodium sulfate (DSS) in mice analyzed. We found that diapocynin showed higher inhibitory activity than apocynin. The dimer reduced ROS production, TNF-α, IL-6, and IL-1ß levels and inhibited iNOS and COX-2 expression as well as decreased NO and PGE2 production induced in LPS-stimulated RAW 264.7 cells. The anti-inflammatory molecular mechanism of diapocynin was associated with the suppression of NF-κB activation. However, these results were not paralleled by in vivo studies. Oral administration of apocynin and diapocynin (100 mg/kg) three times a week exhibited similar protections against experimental inflammatory bowel disease induced by DSS; therefore, apocynin should not be considered a prodrug. However, it should be taken into account that the dimer is more potent because its dose (0.3 mmol/kg) is half that of apocynin.

Prolonged Release of Bioactive Model Proteins from Anionic Microgels Fabricated with a New Microemulsion Approach.

PURPOSE: Therapeutic proteins have become an integral part of health care. However, their controlled delivery remains a challenge. Protein function depends on a delicate three dimensional structure, which can be damaged during the fabrication of controlled release systems. This study presents a microgel-based controlled release system capable of high loading efficiencies, prolonged release and retention of protein function. METHODS: A new DMSO/Pluronic microemulsion served as a reaction template for the crosslinking of poly(acrylic acid) and oligo (ethylene glycol) to form microgels. Poly(acylic acid) molecular weights and microgel crosslinking densities were altered to make a series of microgels. Microgel capacity to capture and retain proteins of different sizes and isoelectric points, to control their release rate (over ~30 days) and to maintain the biofunctionality of the released proteins were evaluated. RESULTS: Microgels of different sizes and morphologies were synthesized. Loading efficiencies of 100% were achieved with lysozyme in all formulations. The loading efficiency of all other proteins was formulation dependent. Release of lysozyme was achieved for up to 30 days and the released lysozyme retained over 90% of its activity. CONCLUSIONS: High loading efficiencies and prolonged release of different proteins was achieved. Furthermore, lysozyme's functionality remained uncompromised after encapsulation and release. This work begins to lay the foundation for a broad platform for the delivery of therapeutic proteins.

Modulation of Cox-1, 5-, 12- and 15-Lox by popular herbal remedies used in southern Italy against psoriasis and other skin diseases.

Acanthus mollis (Acanthaceae), Achillea ligustica, Artemisia arborescens and Inula viscosa (Asteraceae) are used in Southern Italy against psoriasis and other skin diseases that occur with an imbalanced production of eicosanoids. We here assessed their in vitro effects upon 5-, 12-, 15-LOX and COX-1 enzymes as well as NFκB activation in intact cells as their possible therapeutic targets. All methanol crude extracts inhibited both 5-LOX and COX-1 activities under 200 µg/mL, without significant effects on the 12-LOX pathway or any relevant in vitro free radical scavenging activity. NFκB activation was prevented by all extracts but A. mollis. Interestingly, A. ligustica, A. arborescens and A. mollis increased the biosynthesis of 15(S)-HETE, an anti-inflammatory eicosanoid. A. ligustica (IC50 =49.5 µg/mL) was superior to Silybum marianum (IC50 =147.8 µg/mL), which we used as antipsoriatic herbal medicine of reference. Its n-hexane, dichloromethane and ethyl acetate fractions had also inhibitory effects on the LTB4 biosynthesis (IC50 s=9.6, 20.3 and 68 µg/mL, respectively) evidencing that the apolar extracts of A. ligustica are promising active herbal ingredients for future phytotherapeutical products targeting psoriasis.

Dietary oleanolic acid mediates circadian clock gene expression in liver independently of diet and animal model but requires apolipoprotein A1.

Oleanolic acid is a triterpene widely distributed throughout the plant kingdom and present in virgin olive oil at a concentration of 57 mg/kg. To test the hypotheses that its long-term administration could modify hepatic gene expression in several animal models and that this could be influenced by the presence of APOA1-containing high-density lipoproteins (HDLs), diets including 0.01% oleanolic acid were provided to Apoe- and Apoa1-deficient mice and F344 rats. Hepatic transcriptome was analyzed in Apoe-deficient mice fed long-term semipurified Western diets differing in the oleanolic acid content. Gene expression changes, confirmed by reverse transcriptase quantitative polymerase chain reaction, were sought for their implication in hepatic steatosis. To establish the effect of oleanolic acid independently of diet and animal model, male rats were fed chow diet with or without oleanolic acid, and to test the influence of HDL, Apoa1-deficient mice consuming the latter diet were used. In Apoe-deficient mice, oleanolic acid intake increased hepatic area occupied by lipid droplets with no change in oxidative stress. Bmal1 and the other core component of the circadian clock, Clock, together with Elovl3, Tubb2a and Cldn1 expressions, were significantly increased, while Amy2a5, Usp2, Per3 and Thrsp were significantly decreased in mice receiving the compound. Bmal1 and Cldn1 expressions were positively associated with lipid droplets. Increased Clock and Bmal1 expressions were also observed in rats, but not in Apoa1-deficient mice. The core liver clock components Clock-Bmal1 are a target of oleanolic acid in two animal models independently of the diets provided, and this compound requires APOA1-HDL for its hepatic action.

Modulation of COX, LOX and NFκB activities by Xanthium spinosum L. root extract and ziniolide.

Xanthium spinosum L. (Asteraceae) is a medicinal weed distributed worldwide. Many of its diverse ethnopharmacological uses - namely diarrhoea, inflammation, liver disorders, snake bite and fever - are linked - at least in part - to an uncontrolled release of arachidonic acid metabolites. The crude extract of X. spinosum roots from Jordanian origin dose-dependently inhibited the 5-LOX (IC50 is approximately equal to 10 µg/mL), COX-1(IC50 is approximately equal to 50 µg/mL), and 12-LOX (IC50 is approximately equal to 170 µg/mL) enzymatic pathways in intact pro-inflammatory cells. A direct activity at the level of PLA2 is not probable, but the extract induced the synthesis of the anti-inflammatory eicosanoid 15(S)-HETE, which may in turn inhibit this enzyme. 5-LOX bioguided fractionation of the crude extract led to the isolation of ziniolide, a known 12,8-guaianolide sesquiterpene lactone, from the hydro-alcoholic fraction of the n-hexane extract (IC50=69 µM). Both the plant extract and ziniolide are in vitro inhibitors of the phorbol-induced NFκB activation, a key regulator of the arachidonic pathway.

Hip labral cyst caused by psoas impingement.

Hip labral impingement can cause labral tears and secondary paralabral cyst formation. Femoroacetabular impingement is the main cause of labral impingement, but other conditions such as iliopsoas tendon impingement are described. There is no description of labral cyst resulting from psoas impingement treated arthroscopically in the literature. We present the case of a young sportsman with groin pain caused by psoas impingement with a labral tear and secondary paralabral cyst who was treated arthroscopically by cyst debridement, psoas tenotomy, and labral repair.

Poluição intra e extradomiciliar: [revisão] / Indoor and outdoor pollution: [review]

Objetivo: Abordar alguns aspectos da poluição do ar e sua influênciasobre a saúde dos indivíduos, dando maior ênfase aos efeitos sobre oaparelho respiratório.Fontes de dados: Artigos originais, revisões e consensos indexadosnos bancos de dados PubMed, Medline e SciELO nos últimos 30 anos,assim como a linha de pesquisa desenvolvida pelos autores no LaboratórioMultidisciplinar da Universidade Federal do Rio de Janeiro para aelaboração de suas Teses de Doutorado.Síntese dos dados: Crescentes evidências demonstram que aexposição a certos poluentes aéreos pode aumentar a resposta a alérgenos,fazendo com que indivíduos com doenças respiratórias (asmae/ou rinite) sejam especialmente susceptíveis ao impacto dos poluentesintra ou extradomiciliares.Comentários: O conhecimento dos mecanismos através dos quaisa poluição agrava os sintomas da rinite e da asma e sua provável relaçãocom o aumento da prevalência dessas doenças é fundamental naimplementação de medidas apropriadas de prevenção.

Objective: To discuss some aspects of the air pollution and theinfluence on the population’s health, giving more emphasis on therespiratory tract effects.Sources: Original articles, reviews and consensus indexed inPubMed, MEDLINE and SciELO databases in the last 30 years. In addition,the results of the research that was developed by the authors in theMultidisciplinary Laboratory of the Federal University of Rio de Janeirofor the development of their PhD thesis.Results: Growing evidences show that the air pollutants exposurecan increase the reaction to allergens, making individuals with respiratorydiseases (asthma and/or rhinitis) more susceptible to the impact ofindoor or outdoor pollution.Comments: Knowledge of the mechanisms through them thepollution get worse the symptoms of rhinitis and asthma and the probablerelation with the increased prevalence of these diseases is fundamentalfor appropriate prevent measures implementation.

Interaction of dicaffeoylquinic derivatives with peroxynitrite and other reactive nitrogen species.

Plant phenolic antioxidants, among them catechins and hydroxycinnamoyl conjugates, constitute a well defined class of inhibitors of reactive nitrogen species (RNS). To gain deeper insight in this field, we examined the effects of 3,5-di-O-caffeoylquinic acid (DCA), its methyl ester (DCE) and epigallocatechin gallate (EGCG) in nitrative and oxidative processes. These compounds were found to be strong inhibitors of the nitration of tyrosine residues induced by ONOO- in bovine seroalbumin, with their IC50 values (10-40 microM) notably decreasing in the presence of bicarbonate. When studied on the intracellular protein tyrosine nitration induced by ONOO- in cultured murine fibroblasts as well as that induced by phorbol ester (PMA) in nitrite-supplemented human neutrophils, all three phenolics were also effective (100% and over 75% inhibition for fibroblasts and neutrophils, respectively, at 25 microM). This ability seems to be due to a direct interaction with ONOO- or with the species generated by leukocytes. The possible interference with the production of NO was also studied: both DCA and EGCG inhibited nitrite production in LPS-stimulated macrophages by 24% and 40%, respectively, and the expression of nitric oxide synthase-2 (NOS-2), as well. DCA and EGCG reduced by 52% and 59%, respectively, the NF-kappaB transcriptional activity. In contrast, DCE did not show any effect. The assayed phenolics exert varying degrees of protection against the chemical modifications induced by RNS depending not only on the hydroxyl pattern, but also on the presence of bicarbonate.

Constituents of Oxandra cf. xylopioides with anti-inflammatory activity.

A new triterpenoid (1) derived from 24-methylcycloartanol was isolated from the leaves of Oxandra cf. xylopioides. An unusual structure of the new compound was assigned as 1, for which the name berenjenol is proposed, on the basis of the spectroscopic data of the natural product and of its derivatives 2 and 3. The leaves also afforded the known monoterpene isoespintanol (4). Compounds 1 and 4 significantly reduced the paw edema induced by carrageenan by 64% and 43%, at 3 h, respectively. Moreover, 4 reduced IL-1 beta production by 72% at 100 microM and reduced IL-1 beta mRNA synthesis.

Deep venous thrombosis prophylaxis practice and treatment strategies among plastic surgeons: survey results.

BACKGROUND: Deep vein thrombosis is a known serious complication of surgical procedures and a significant cause of morbidity and mortality. Plastic surgeons' management of the risk of deep vein thrombosis and current information regarding deep vein thrombosis incidence rates are limited. A survey was designed and mailed to plastic surgeons to collect data on the patterns of practice with regard to deep vein thrombosis in patients undergoing plastic surgery procedures. METHODS: A comprehensive self-administered, anonymous survey was mailed to 1557 plastic surgeons in March of 2003. RESULTS: A total of 334 completed responses were available for analysis. Subsets of surgeons do not use any deep vein thrombosis prophylaxis: 16.4 percent who perform face lifts; 21.3 percent who perform liposuction; and 8.7 percent who perform a combined abdominoplasty-liposuction procedure. Only 48.7 percent of surgeons performing face lifts, 43.7 percent of surgeons performing liposuction, and 60.8 percent performing a combined procedure use deep vein thrombosis prophylaxis all the time. CONCLUSIONS: These results demonstrate a need for educational efforts and guidelines to direct clinical practice in line with evidence-based data concerning plastic surgery procedures and deep vein thrombosis. Plastic surgeons should be aware of the potential and real risks of deep vein thrombosis and procedures for prevention and treatment to reduce morbidity and mortality associated with deep vein thrombosis in all plastic surgery patients.

Protein tyrosine nitration induced by heme/hydrogen peroxide: inhibitory effect of hydroxycinnamoyl conjugates.

The present study was designed to optimize the experimental conditions that govern the heme-catalyzed nitration of protein tyrosine residues by nitrite, and, within this framework, to study the effects of 3,5-dicaffeoylquinic acid and its methyl ester, both of which have been previously reported to be antioxidants and inhibitors of leukocyte functions. Although the presence of hydrogen peroxide is essential in cell-free systems, an excess of this compound was found to be detrimental, so much so that an increase in hemin concentration actually resulted in an inverse effect on the reaction, depending on the levels of fixed hydrogen peroxide. Unlike previous reports on nitrite-induced albumin tyrosine nitration, the optimal pH here was found to be 7.0. The two caffeoyl conjugates tested were found to be effective inhibitors of protein nitration, with IC50 values ranging from 20 - 30 microM, regardless of the presence of bicarbonate. For the inhibition of myeloperoxidase-catalyzed protein nitration by human polymorphonuclear leukocytes stimulated by phorbol ester, the potencies obtained were up to two times higher. This is the first time that caffeoylquinic esters have been reported as inhibitors of heme-based protein nitration.

Enhancing patient outcomes in aesthetic and reconstructive breast surgery using triple antibiotic breast irrigation: six-year prospective clinical study.

BACKGROUND: Capsular contracture remains one of the most commonly reported complications in aesthetic and reconstructive breast patients. Previous in vitro studies from the authors' laboratory have recommended a new triple antibiotic povidone-iodine irrigation (2000) and subsequently a triple antibiotic non-povidone-iodine-containing irrigant (2001) to optimize broad-spectrum coverage of various bacteria implicated in capsular contracture; however, the clinical efficacy of these in vitro studies remains unproven. The purpose of this study was to determine the clinical efficacy for the previously reported triple antibiotic breast irrigation. The cost-effectiveness of universal application of irrigation solutions in breast prosthesis surgery was analyzed as well. METHODS: Patients undergoing aesthetic and reconstructive breast implant procedures were treated with a standardized operative technique, including the use of triple antibiotic breast irrigation by a single surgeon. Capsular contracture was assessed using a simplified Baker scale and graded by two independent caregivers to maximize objectivity and consistency. Additional complications were also recorded, including reoperation. Patient charges for antibiotic irrigation and reoperation for contracture were determined and compared. RESULTS: A total of 335 patients operated on since 1997 were evaluated prospectively. They ranged in age from 18 to 86 years, and the mean follow-up was 14 months (range, 6 to 75 months). The rate of grade III/IV capsular contracture in the study groups was 1.8 percent for patients undergoing primary breast augmentation. Patients undergoing augmentation-mastopexy had a grade III/IV contracture rate of 0 percent. Breast reconstruction patients had a 9.5 percent rate of grade III/IV contracture. CONCLUSIONS: Triple antibiotic breast irrigation is clinically associated with a low incidence of capsular contracture compared with other published reports, and its clinical efficacy supports previously published in vitro studies. Application of triple antibiotic irrigation is recommended for all aesthetic and reconstructive breast procedures and is cost effective.

Neck rejuvenation revisited.

PURPOSE: Restoration of the aesthetic neck contour is an integral component of facial rejuvenation. Multiple deformities of the neck and chin complex can make treatment of the cervical region daunting. An algorithmic approach to neck rejuvenation based on individual anatomic and clinical analysis is prudent. The authors created a simplified anatomic approach to the most common cervical deformities encountered in the patient seeking facial rejuvenation. METHODS: Retrospective analysis of the senior author's (R.J.R.) technique evolution over the last 15 years was performed. The operative techniques used in neck rejuvenation were evaluated and the long-term postoperative results were reviewed. RESULTS: Recurrent patterns of cervical deformity are present in patients presenting for facial rejuvenation. These patterns can be classified into categories based on specific anatomic deformities. CONCLUSIONS: Facial rejuvenation requires appropriate identification of deformity to effect the desired changes. Cervical deformities are classified into clinically useful categories based on careful preoperative analysis. A thorough understanding of the anatomic bases for the deformities allows the surgeon to choose the appropriate treatments to achieve consistent and reliable results.

Enhancing patient outcomes in aesthetic and reconstructive breast surgery using triple antibiotic breast irrigation: six-year prospective clinical study.

BACKGROUND: Capsular contracture remains one of the most commonly reported complications in aesthetic and reconstructive breast patients. Previous in vitro studies from the authors' laboratory have recommended a new triple antibiotic povidone-iodine irrigation (2000) and subsequently a triple antibiotic non-povidone-iodine-containing irrigant (2001) to optimize broad-spectrum coverage of various bacteria implicated in capsular contracture; however, the clinical efficacy of these in vitro studies remains unproven. The purpose of this study was to determine the clinical efficacy for the previously reported triple antibiotic breast irrigation. The cost-effectiveness of universal application of irrigation solutions in breast prosthesis surgery was analyzed as well. METHODS: Patients undergoing aesthetic and reconstructive breast implant procedures were treated with a standardized operative technique, including the use of triple antibiotic breast irrigation by a single surgeon. Capsular contracture was assessed using a simplified Baker scale and graded by two independent caregivers to maximize objectivity and consistency. Additional complications were also recorded, including reoperation. Patient charges for antibiotic irrigation and reoperation for contracture were determined and compared. RESULTS: A total of 335 patients operated on since 1997 were evaluated prospectively. They ranged in age from 18 to 86 years, and the mean follow-up was 14 months (range, 6 to 75 months). The rate of grade III/IV capsular contracture in the study groups was 1.8 percent for patients undergoing primary breast augmentation. Patients undergoing augmentation-mastopexy had a grade III/IV contracture rate of 0 percent. Breast reconstruction patients had a 9.5 percent rate of grade III/IV contracture. CONCLUSIONS: Triple antibiotic breast irrigation is clinically associated with a low incidence of capsular contracture compared with other published reports, and its clinical efficacy supports previously published in vitro studies. Application of triple antibiotic irrigation is recommended for all aesthetic and reconstructive breast procedures and is cost effective.

A asma em crianças brasileiras é problema de saúde pública? / Is asthma in Brazilian children a public health problem?

A asma é uma das doenças de maior importância da infância. Comparações internacionais de sua prevalência têm sido inviabilizadas pela diferença dos métodos empregados na sua avaliação. O "International Study of Asthma and Allergies in Childhood" (ISAAC) foi desenvolvido para possibilitar comparações, nacionais e internacionais, de prevalência e gravidade da asma empregando-se um questionário escrito padronizado. Objetivos: Apresentar dados nacionais relativos à prevalência de asma e de sintomas relacionados obtidos aplicando-se o questionário escrito padrão do ISAAC em várias cidades brasileiras (Belém, Recife, Salvador, Brasília, Cuiabá, Itabira, Uberlândia, Montes Claros, Campos Gerais, Duque de Caxias, Seropédica, Ribeirão Preto, São Paulo, Curitiba e Porto Alegre). Material e Métodos: Os dados foram obtidos por vários investigadores, de acordo com as recomendações do protocolo ISAAC. O estudo avaliou 23.457 escolares, com idades entre seis e sete anos e, 40.111 adolescentes com idades entre 13 e 14 anos. Resultados: A prevalência de "sibilos no último ano" foi significantemente maior do que a de "diagnóstico médico de asma", tanto no grupo de escolares (10,1 per cent e 25,7 per cent respectivamente) quanto no de adolescentes (14,3 per cent e 21,4 per cent, respectivamente). Conclusões: A asma é subdiagnosticada se os pacientes forem identificados apenas pelo diagnóstico médico de asma.

Progressive tension sutures to prevent seroma formation after latissimus dorsi harvest.

The latissimus dorsi muscle flap is a versatile flap used in a variety of reconstructive procedures. The major complication reported with its use is donor-site seroma, reported to occur in 20 to 79 percent of cases. A retrospective review of 47 patients undergoing latissimus dorsi muscle harvest from April of 1998 through May of 2002 was performed. Progressive tension sutures were used during donor-site closure in 22 patients from March of 2000 through May of 2002. This group was compared with historical controls from April of 1998 through March of 2000 (n = 23) who underwent latissimus dorsi harvest without use of the technique. Seven of 23 controls (30 percent) developed seromas at the donor site, compared with 0 of 22 (Fisher's exact text, p = 0.0092). The authors conclude that use of progressive tension sutures placed at the time of donor-site closure is an effective method to reduce or eliminate the most common complication associated with latissimus dorsi harvest. Technique recommendations are reviewed.