Abstract Osteoarthritis (OA) can incapacitate the individual to perform their activities of daily living due to pain. This is an important public health issue that worsens worldwide and in Brazil, since the population goes through an aging process, and has caused increased public spending on the monitoring and maintenance of treatments that can last for years and still not be resolutive. Thus, the search for innovative and effective therapies that can reduce costs becomes necessary. In this context, the present study reports the first application of cell therapy with adipose-derived stem cells in the treatment of cases of OA that are refractory to the conservative treatment, performed in the Brazilian Unified Health System (Sistema Único de Saúde, SUS). The evaluation was performed with the application of the Visual Analog Scale (VAS), the Short Form Health Survey (SF-36) and the Western Ontario and McMaster Universities (WOMAC), specifics for OA evaluation, and also an analysis of the synovial fluid (inflammatory cytokines). The cell therapy improved the scores on the WOMAC, SF-36 and EVA, and reduced the inflammatory process. We observed a decrease of 0.73x in the TNF, of 0,71x in IL-1b, of 0,68x in IL-8, and of 0,70x in IL-10. For IL-6, an increase of 1,48x was observed. Therefore, this cell therapy can be considered promising in aiding the management of this disease, since it improved the patient's pain, decrease inflammatory markers, and enabled the return to activities of daily living, which resulted in an improvement in their quality of life. (OA pain Brazil process resolutive Thus necessary context adiposederived adipose derived Sistema Saúde SUS. SUS . SUS) VAS, VAS , (VAS) SF36 SF 36 (SF-36 WOMAC (WOMAC) cytokines. cytokines cytokines) SF-3 EVA 073x x 0 73x TNF 071x 71x IL1b, IL1b ILb IL 1b, 1b b IL-1b 068x 68x IL8, IL8 8, 8 IL-8 070x 70x IL10. IL10 10. 10 IL-10 IL6, IL6 6, 6 IL-6 148x 1 48x Therefore disease patients patient s markers life (VAS SF3 3 (SF-3 (WOMAC SF- IL- IL1 IL-1 (SF- (SF

Resumo A osteoartrite (OA) pode deixar o indivíduo incapacitado para realizar suas atividades da vida diária devido ao quadro álgico. Essa é uma importante questão de saúde pública que se agrava no mundo inteiro e no Brasil, uma vez que a população passa pelo processo de envelhecimento, e isso causa um aumento nos gastos públicos com o acompanhamento e manutenção dos tratamentos que podem perdurar por anos e mesmo assim não serem resolutivos. Assim, torna-se necessária a busca por terapias inovadoras e eficazes que possam reduzir esses custos. Nesse contexto, o presente estudo relata a primeira aplicação de terapia celular com células-tronco mesenquimais do tecido adiposo no tratamento de OA refratária ao tratamento conservador realizada no Sistema Único de Saúde (SUS). Na avaliação, foram usados os instrumentos Escala Visual Analógica (EVA), os questionários de qualidade de vida Short Form Health Survey (SF-36) e Western Ontario and McMaster Universities (WOMAC), específicos para avaliação da OA, e fez-se uma análise do líquido sinovial (citocinas inflamatórias). A terapia celular melhorou as pontuações no WOMAC, SF-36, e EVA, e reduziu o processo inflamatório. Observou-se redução de 0,73 × do TNF, de 0,71 × da IL-1b, de 0,68 × da IL-8, e de 0,70 × da IL-10. Já para a IL-6, observou-se aumento de 1,48 ×. Portanto, considera-se este tipo de terapia celular promissora no auxílio do manejo desta doença, pois melhorou o quadro álgico do paciente, reduziu os marcadores inflamatórios, e possibilitou o retorno às atividades da vida diária, o que resultou em uma melhora de sua qualidade de vida. (OA Brasil envelhecimento resolutivos Assim tornase torna custos contexto célulastronco células tronco SUS. SUS . (SUS) EVA , (EVA) SF36 SF 36 (SF-36 WOMAC (WOMAC) fezse fez citocinas inflamatórias. inflamatórias inflamatórias) SF36, 36, SF-36 inflamatório Observouse Observou 073 0 73 0,7 TNF 071 71 IL1b, IL1b ILb IL 1b, 1b b IL-1b 068 68 0,6 IL8, IL8 8, 8 IL-8 070 70 IL10. IL10 10. 10 IL-10 IL6, IL6 6, 6 IL-6 observouse observou 148 1 48 1,4 Portanto considerase considera doença paciente inflamatórios (SUS (EVA SF3 3 (SF-3 (WOMAC SF-3 07 7 0, 06 IL- IL1 IL-1 14 4 1, (SF- SF- (SF

Abstract Despite rapid advances in both the early detection and treatment of cancer, the mortality from this disease remains high, which justifies the development of new products that are more selective and effective and have fewer side effects. Accordingly, a novel ester was synthesized that contains two pharmacophores with important biological activities: (I) 4-aminoantipyrine, which has anti-inflammatory and antioxidant effects, and (II) the pharmacophore 1,4-dioxo-butenyl, which has cytotoxic activity. When administered alone, this compound is non-genotoxic, and it does not cause an increasing in splenic phagocytosis. Nevertheless, it can induce cell death. When administered in combination with commercial chemotherapeutic agents, such as doxorubicin, cisplatin, and cyclophosphamide, the ester shows antigenotoxic activity and decreases phagocytosis and reduces the potential to cause cell death. These results indicate that the compound should not be used in combination with chemotherapeutic agents that exert their effect through DNA damage, an important feature of antitumor drugs.

RESUMO Racional: Há diferentes opções de tratamento para a doença de Crohn, porém, em alguns casos, há a necessidade de outras abordagens terapêuticas, como o uso de células-tronco mesenquimais derivadas do tecido adiposo. Objetivo: Revisar sistematicamente a literatura para determinar as diferentes formas de administração das células-tronco mesenquimais derivadas do tecido adiposo em seres humanos com doença de Crohn refratária luminal e fistulizante perianal. Método: Buscaram-se artigos publicados entre 2008 e 2018 nas bases de dados PubMed e ScienceDirect, pelos descritores: Crohn’s disease, fistulizing Crohns disease, luminal Crohns disease e transplantation of mesenchymal stem cells ou mesenchymal stem cell ou stromal cells. Treze artigos foram selecionados. Resultados: Somente um trabalho se referiu à doença luminal. A quantidade de células administradas foi variável, obtendo-se principalmente do tecido adiposo subcutâneo por lipoaspiração. Destacou-se o transplante autólogo com a infusão exclusiva de células-tronco mesenquimais. Os procedimentos realizados no pré-transplante foram principalmente o de curetagem, colocação de setons e suturas com fio absorvível, e de exames e tratamento medicamentoso para a doença luminal. No transplante, ocorreu a injeção das células por todo o trajeto fistuloso, principalmente nas paredes do trato. Conclusão: Embora o uso de células-tronco mesenquimais seja promissor, o transplante na região luminal deve ser mais investigado. A injeção exclusiva de células-tronco mesenquimais é mais explorada quando comparada ao tratamento conjunto com outros produtos. A forma de preparo do trato fistuloso e o local de transplante envolvem cuidados médicos padronizados na maioria dos estudos.

ABSTRACT Background: Crohn’s disease is a pathological condition that has different options of treatment, but there are patients who need other therapeutic approach, such as the use of adipose-derived mesenchymal stem cells. Aim: Systematic literature review to determine the different ways of adipose-derived mesenchymal stem cells administration in humans with luminal refractory and perianal fistulizing Crohn’s disease. Methods: It was conducted a search for articles (from 2008 to 2018) on PubMed and ScienceDirect databases using the keywords Crohn’s disease, fistulizing Crohn’s disease, luminal Crohn’s disease and transplantation of mesenchymal stem cells or mesenchymal stem cells or stromal cells. Thirteen publications were selected for analysis. Results: Only one study referred to the luminal Crohn´s disease. The number of cells administered was variable, occurring mainly through subcutaneous adipose tissue by liposuction. It could be highlighted the autologous transplant with exclusive infusion of mesenchymal stem cells. The procedures involved in pre-transplant were mainly curettage, setons placement and stitching with absorbable suture, and conducting tests and drug treatment for luminal Crohn´s disease. During transplant, the injection of mesenchymal stem cells across the fistula path during the transplant was mainly on the intestinal tract wall. Conclusion: Although the use of mesenchymal stem cells is promising, the transplant on the luminal region should be more investigated. The injection of mesenchymal stem cells, exclusively, is more explored when compared to treatment with other products. The preparation of the fistulizing tract and the location of cell transplantation involve standardized health care in most studies.

Abstract The increased incidence of cancer and its high treatment costs have encouraged the search for new compounds to be used in adjuvant therapies for this disease. This study discloses the synthesis of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid (IR-01) and evaluates not only the action of this compound on genetic integrity, increase in splenic phagocytosis and induction of cell death but also its effects in combination with the commercial chemotherapeutic agents doxorubicin, cisplatin and cyclophosphamide. IR-01 was designed and synthesized based on two multifunctionalyzed structural fragments: 4-aminoantipyrine, an active dipyrone metabolite, described as an antioxidant and anti-inflammatory agent; and the pharmacophore fragment 1,4-dioxo-2-butenyl, a cytotoxic agent. The results indicated that IR-01 is an effective chemoprotector because it can prevent clastogenic and/or aneugenic damage, has good potential to prevent genomic damage, can increase splenic phagocytosis and lymphocyte frequency and induces cell death. However, its use as an adjuvant in combination with chemotherapy is discouraged since IR-01 interferes in the effectiveness of the tested chemotherapeutic agents. This is a pioneer study as it demonstrates the chemopreventive effects of IR-01, which may be associated with the higher antioxidant activity of the precursor structure of 4-aminoantipyrine over the effects of the 1,4-dioxo-2-butenyl fragment.

ABSTRACT The study evaluated the effects of brown flaxseed supplementation in natura on the prevention of DNA damage induced by 1,2-dimethylhydrazine (DMH) in vivo. The experimental groups were Negative and Positive Controls and the protocols of Pre-treatment, Simultaneous, Post-treatment, Pre+continuous in relation to the supplementation of brown flaxseed and administration with carcinogenic compound. The results showed that brown flaxseed supplementation does not cause genomic and genetic damage. In addition, brown flaxseed showed a chemopreventive food that reduced the damages assessed by the comet assay up to 94.07x and the damages assessed by the micronucleus assay up to 91.88x. Brown flaxseed supplementation also increased the frequency of monocytes and lymphocytes indicating immunological improvements. Thus, brown flaxseed supplementation is considered safe and reduces the frequency of DNA damage that can lead to tumors. Therefore, if these events are confirmed in humans, flaxseed will have reinforced its indication as a functional chemopreventive food in the prevention of cancer.

Abstract Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.

Abstract Acute renal failure (ARF) is an extremely important public health issue in need of novel therapies. The present study aimed to evaluate the capacity of mesenchymal stem cell (MSC) therapy to promote the improvement and recovery of renal function in a preclinical model. Wistar rats were used as the experimental model, and our results show that cisplatin (5mg/kg) can efficiently induce ARF, as measured by changes in biochemical (urea and creatinine) and histological parameters. MSC therapy performed 24h after the administration of chemotherapy resulted in normalized plasma urea and creatinine levels 30 and 45d after the onset of kidney disease. Furthermore, MSC therapy significantly reduced histological changes (intratubular cast formation in protein overload nephropathy and tubular hydropic degeneration) in this ARF model. Thus, considering that current therapies for ARF are merely palliative and that MSC therapy can promote the improvement and recovery of renal function in this model system, we suggest that innovative/alternative therapies involving MSCs should be considered for clinical studies in humans to treat ARF.

OBJETIVO: Determinar os efeitos do reparo nervoso término-lateral realizado apenas com cola de fibrina contendo fator de crescimento nervoso em ratos. MÉTODOS: Setenta e dois ratos Wistar foram distribuídos em seis grupos: A - não submetido à secção nervosa; B - secção do nervo fibular (sem reparo); Os outros grupos tiveram o nervo fibular seccionado e então reparado na superfície lateral do nervo tibial intacto, com diferentes procedimentos: C - RNTL com suturas; D - RNTL com suturas e FCN; E - RNTL apenas com CF; F - RNTL com CF contendo FCN. A função motora foi acompanhada e a massa do músculo tibial, o número e o diâmetro das fibras musculares e axônios regenerados foram medidos. RESULTADOS: Não houve diferença entre as variáveis avaliadas nos quatro grupos operados (p>0,05), os quais foram superiores ao grupo B (p<0,05), mas inferiores ao grupo A (p>0,05). CONCLUSÕES: O reparo nervoso término-lateral mostrou o mesmo padrão de recuperação, independente do tipo de reparo utilizado, evidenciando que a adição de fator de crescimento nervoso na cola de fibrina não foi suficiente para a potencialização dos resultados.

PURPOSE: To determine the effects of end-to-side nerve repair performed only with fibrin glue containing nerve growth in rats. METHODS: Seventy two Wistar rats were divided into six equal groups: group A was not submitted to nerve section; group B was submitted to nerve fibular section only. The others groups had the nerve fibular sectioned and then repaired in the lateral surface of an intact tibial nerve, with different procedures: group C: ETS with sutures; group D: ETS with sutures and NGF; group E: ETS with FG only; group F: ETS with FG containing NGF. The motor function was accompanied and the tibial muscle mass, the number and diameter of muscular fibers and regenerated axons were measured. RESULTS: All the analyzed variables did not show any differences among the four operated groups (p>0.05), which were statistically superior to group B (p<0.05), but inferior to group A (p>0.05). CONCLUSION: The end-to-side nerve repair presented the same recovery pattern, independent from the repair used, showing that the addition of nerve growth factor in fibrin glue was not enough for the results potentiating.

OBJETIVO: Estudar o reparo do defeito ósseo preenchido com enxerto ósseo autógeno ou matriz óssea bovina desvitalizada sob ação de antiinflamatórios em ratos. MÉTODOS: 240 ratos Wistar, distribuídos em dois grupos de 120 animais. Confeccionou-se defeito de 2 mm de diâmetro na diáfise femoral. Os animais do Grupo I tiveram o defeito ósseo preenchido com enxerto ósseo autógeno e os do Grupo II com matriz óssea bovina desvitalizada. Cada grupo foi redistribuído em quatro subgrupos segundo a administração intramuscular de antiinflamatório ou solução salina: A - diclofenaco de sódio; B - dexametasona; C - meloxicam; D - solução salina. Os períodos de avaliação foram de 7, 14 e 30 dias. A avaliação histológica constou da quantificação do processo inflamatório, osso neoformado, formação de colágeno e macrófagos. RESULTADOS: Os animais do Grupo I não mostraram diferença significante em relação à reação inflamatória. Observou-se aumento significante e progressivo da neoformação óssea nos Grupos I e II. Os animais que receberam meloxicam e enxerto autógeno mostraram menor aporte de colágeno aos 14 e 30 dias de observação. Os macrófagos apresentaram-se em maior quantidade no Grupo II que no Grupo I. Os animais tratados com dexametasona e solução salina não demonstraram diferença estatisticamente significante entre os Grupos I e II. CONCLUSÕES: O diclofenaco de sódio e o meloxicam retardam a reparação do enxerto ósseo. A dexametasona não interfere na reparação do enxerto ósseo.

PURPOSE: To study the repair of bone defect filled with autograft or bovine bone devitalized matrix in rats under anti-inflammatory action. METHODS: Two hundred and forty Wistar rats were distributed to two groups of 120 animals each. A 2mm-diameter defect was created in the femoral diaphysis. Animals of Group I had the bone defect filled with autograft and those of Group II, with bovine bone devitalized matrix. Animals of each group were redistributed to four subgroups according to the intramuscular administration of anti-inflammatory drug or saline solution: A - diclofenac sodium; B - dexamethasone; C - meloxicam; D - saline solution. Evaluation periods were 7, 14 and 30 days. Histological evaluation consisted of quantifying the inflammatory process, the bone neoformation, the collagen formation and the presence of macrophages. RESULTS: Animals of Group I did not show significant difference considering inflammatory reaction. Significant and progressive increase of bone neoformation was observed in both groups. The animals that received meloxicam and autograft showed less collagen formation at 14 and 30 days. The number of macrophages was higher in Group II than in Group I. The animals treated with dexamethasone and saline solution did not show statistically significant difference. CONCLUSIONS: Diclofenac sodium and meloxicam delayed bone graft repair and dexamethasone did not interfere in it.