Differential effects of antiepileptic drugs on human bone cells

Antiepileptic drugs (AED) have been associated to in vivo deleterious consequences in bone tissue. The present work aimed to characterize the cellular and molecular effects of five different AED on human osteoclastogenesis and osteblastogenesis. It was observed that the different drugs had the ability to differentially modulate both processes, in a way dependent on the identity and dose of the AED. Shortly, valproic acid stimulated either osteoclastogenesis and osteoblastogenesis, whereas carbamazepine, gabapentin, and lamotrigine revealed an opposite behavior; topiramate elicited a decrease of osteoclast development and an increase in osteoblast differentiation. This is the first report describing the direct effects of different AED on human primary bone cells, which is a very important issue, because these drugs are usually consumed in long-term therapeutics, with acknowledged in vivo effects in bone tissue.info:eu-repo/semantics/publishedVersio

Antiproliferative Organic Salts Derived from Betulinic Acid: Disclosure of an Ionic Liquid Selective Against Lung and Liver Cancer Cells

In the last few years, we have been witnessing an increasing interest in ionic liquids (ILs) and organic salts, given their potential applications in biological and pharmaceutical sciences. We report the synthesis and in vitro evaluation of novel organic salts combining betulinate, known for its anticancer properties, with antimalarial drugs, primaquine, chloroquine, and mepacrine, and also with the trihexyltetradecylphosphonium ([P6,6,6,14]) cation. The salts were screened for their in vitro activity against tumor lines HepG2 (liver), MG63 (osteosarcoma), T47D (breast), A459 (lung), and RKO (colon), and also on normal human fibroblasts. All betulinates prepared displayed antiproliferative properties, with the trihexyltetradecylphosphonium betulinate standing out for its higher selectivity. This unprecedented disclosure of a betulinic acid (BA)-derived IL with selective antitumor activity constitutes a relevant first step toward development of novel anticancer therapies based on BA-derived IL.info:eu-repo/semantics/publishedVersio

A Novel Approach for Bisphosphonates: Ionic Liquids and Organic Salts from Zoledronic Acid

Novel ionic liquids and organic salts based on mono- or dianionic zoledronate and protonated superbases, choline and n-alkylmethylimidazolium cations, were prepared and characterized by spectroscopic and thermal analyses. Most of the prepared salts display amorphous structures and very high solubility in water and saline solutions, especially the dianionic salts. Among the zoledronate-based ionic compounds, those containing choline [Ch] and methoxyethylmethylimidazolium [C3 OMIM] cations appear to have significant cytotoxicity against human osteosarcoma cells (MG63) and low toxicity toward healthy skin fibroblast cells. Because osteosarcoma is a bone pathology characterized by an increase in bone turnover rate, the results presented herein may be a promising starting point for the development of new ionic pharmaceutical drugs against osteosarcoma.info:eu-repo/semantics/publishedVersio

Epidemiological profile of patients on the waiting list for renal transplantation

Objective: To identify and describe the profile of patients placed on a single waiting list for renal transplantation in the state of Sao Paulo. Methods: Cross-sectional epidemiological study of quantitative approach to identify and describe the profile of patients placed on a single waiting list for renal transplantation. In the period from 2009 to 2015, a survey was conducted in the databases of the Notification, Collection and Distribution Center of Organs of the Single Technical Registry, and the following characteristics were established as variables: clinical, demographic and information related to the convocation result. The sample included 12,415 patients undergoing hemodialysis who were simultaneously registered for renal transplantation. The Chi-Square and Student's t-test were used for descriptive statistical analysis and the Kaplan-Meier estimate was used for significance. Results: A total of 12,415 patients were included, mean age was 50 years, male gender (59.6%), white color (63.1%), blood type O (48.9%), metropolitan region of Sao Paulo (73.82%), unspecified diagnosis (34.5%), did not undergo transplantation (77.2%), and without clinical conditions to perform the transplant (99.8%). Conclusion: Knowing the profile of patients with chronic kidney disease on the single waiting list allows the development of new health care strategies for reducing mainly morbidity and mortality rates. There is lack in meeting the care demands and high rates of refusal.Objetivo: Identificar e descrever o perfil dos pacientes inscritos em lista única de espera para a realização do transplante renal no estado de São Paulo. Métodos: Estudo epidemiológico transversal com abordagem quantitativa para identificar e descrever o perfil dos pacientes inscritos em fila única de espera para o transplante renal. Realizou-se levantamento nas bases de dados da Central de Notificação, Captação e Distribuição de Órgãos do Cadastro Técnico Único, estabelecendo-se como variáveis as características clínicas, demográficas e relativas ao desfecho de convocação no período de período de 2009 a 2015. A amostra foi composta por 12.415 pacientes que realizavam hemodiálise e paralelo ao tratamento encontravam-se inscritos para a realização do transplante renal. Para análise estatística descritiva, utilizou-se os testes Qui-Quadrado, t de Student e para significância Kaplan-Meier. Resultados: Foram incluídos 12.415 pacientes, identificou-se média de idade de 50 anos, sexo masculino (59,6%), cor branca (63,1%), tipo sanguíneo O (48,9%), região metropolitana de São Paulo (73,82%), diagnóstico não especificado (34,5%), não realizaram transplante (77,2%) e sem condições clínicas de realizar o transplante (99,8%). Conclusão: Conhecer o perfil dos pacientes com doença renal crônica que aguardam em lista única nos permite traçar novas estratégias de cuidados em saúde para redução principalmente das taxas de morbidade e mortalidade. Nota-se carência de atendimento da demanda e altos índices de recusa.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Univ Fed Sao Paulo, Escola Paulista Enfermagem, Sao Paulo, SP, BrazilSecretaria Saude Estado Sao Paulo, Cent Estadual Transplantes, Sao Paulo, SP, BrazilSecretaria Saude Estado Sao Paulo, Sistema Estadual Transplantes, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Enfermagem, Sao Paulo, SP, BrazilWeb of Scienc

Antitumor Activity of Ionic Liquids Based on Ampicillin

Significant antiproliferative effects against various tumor cell lines were observed with novel ampicillin salts as ionic liquids. The combination of anionic ampicillin with appropriate ammonium, imidazolium, phosphonium, and pyridinium cations yielded active pharmaceutical ingredient ionic liquids (API-ILs) that show potent antiproliferative activities against five different human cancer cell lines: T47D (breast), PC3 (prostate), HepG2 (liver), MG63 (osteosarcoma), and RKO (colon). Some API-ILs showed IC50 values between 5 and 42 nm, activities that stand in dramatic contrast to the negligible cytotoxic activity level shown by the ampicillin sodium salt. Moreover, very low cytotoxicity against two primary cell lines—skin (SF) and gingival fibroblasts (GF)—indicates that the majority of these API-ILs are nontoxic to normal human cell lines. The most promising combination of antitumor activity and low toxicity toward healthy cells was observed for the 1-hydroxyethyl-3-methylimidazolium–ampicillin pair ([C2OHMIM][Amp]), making this the most suitable lead API-IL for future studies.info:eu-repo/semantics/publishedVersio

α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy; a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that acts by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo

α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy; a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that acts by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo

Paradoxical Increase in TAG and DAG Content Parallel the Insulin Sensitizing Effect of Unilateral DGAT1 Overexpression in Rat Skeletal Muscle

BACKGROUND: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle. CONCLUSIONS/SIGNIFICANCE: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling

Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has antiinflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-c and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, fo