Amazonian plant natural products:perspectives for discovery of new antimalarial drug leads

Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cause severe manifestations and death; hence there is a need for P. vivax-directed research. Plants used in traditional medicine, namely Artemisia annua and Cinchona spp. are the sources of the antimalarial natural products artemisinin and quinine, respectively. Based on these compounds, semi-synthetic artemisinin-derivatives and synthetic quinoline antimalarials have been developed and are the most important drugs in the current therapeutic arsenal for combating malaria. In the Amazon region, where P. vivax predominates, there is a local tradition of using plant-derived preparations to treat malaria. Here, we review the current P. falciparum and P. vivax drug-sensitivity assays, focusing on challenges and perspectives of drug discovery for P. vivax, including tests against hypnozoites. We also present the latest findings of our group and others on the antiplasmodial and antimalarial chemical components from Amazonian plants that may be potential drug leads against malaria

TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria

Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the effect of Toll-like receptors (TLRs) activation on placental malaria (PM) development by using the Plasmodium berghei NK65(GFP) infection model. We observed that activation of the innate immune system by parasites leads to PM due to local inflammation. We identified TLR4 activation as the main pathway involved in the inflammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-inflammatory responses, which resulted in an improved pregnancy outcome. Additionally, a similar result was obtained when infected pregnant mice were treated with IAXO-101, a TLR4/CD14 blocker. Together, this study illustrates the importance of TLR4 signalling for the generation of the severe inflammatory response involved in PM pathogenesis. Therefore, our results implicate that TLR4 blockage could be a potential candidate for therapeutic interventions to reduce malaria-induced pathology both in the mother and the fetus.Fundação de Amparo a Pesquisa do Estado de São Paulo - FAPESPCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESConselho Nacional de Desenvolvimento Científico e Tecnológico - CNPqUniv Fed São Paulo, Dept Ciencias Biol, Diadema, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Parasitol, São Paulo, BrazilHosp Israelita Albert Einstein, São Paulo, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolvimento, São Paulo, BrazilUniv Estadual Campinas, Dept Genet Evolucao & Bioagentes, Inst Biol, Campinas, SP, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Imunol, São Paulo, BrazilUniv São Paulo, Dept Analises Clin & Toxicol, Fac Ciencias Farmaceut, São Paulo, BrazilUniv Fed São Paulo, Dept Ciencias Biol, Diadema, BrazilFAPESP: 2009/53889-0FAPESP: 2014/09964-5FAPESP: 2014/20451-0FAPESP: 2012/16525-2FAPESP: 2011/17880-8FAPESP: 2013/16417-8FAPESP: 2011/19048-8FAPESP: 2013/00981-1FAPESP: 2015/06106-0]CAPES: AUX-PE-PNPD 2751/2010CNPq: 475771/2009-5Web of Scienc

Vaccines Containing Attenuated Strains, Method For Forming Attenuated Strains, Vaccine Vectors And Use Thereof For The Treatment Of Salmonellosis

Vacinas Compreendendo Linhagens Atenuadas, Processo de Construção de Linhagens Atenuadas, Vetores Vacinais e seu Uso no Tratamento da Salmonelose. A presente invenção revela uma nova alternativa para a prevenção de salmonelose, a partir de mutantes capazes de promover imunização do hospedeiro. Em especial tais mutantes são nulos para os genes himA e himD de IHF e foram testados quanto a atenuação da virulência e capacidade de desencadear resposta imune efetiva e protetora contra a salmonelose, em especial a salmonelose murina. Logo, a presente invenção está destinada a um processo de produção desta linhagem de mutantes atenuados, capazes de promover imunização, a vetores vacinais e vacinas para o tratamento de salmonelose e a seu uso no combate a tal infecção.BRPI0902944 (A2)A61K39/112A61P1/00C12N15/31BR2009PI02944A61K39/112A61P1/00C12N15/3

Uso De Violaceìna, Na Forma Livre Ou Encapsulada Em Sistemas Poliméricos Como Antimalárico

USO DA VIOLACEÍNA, NA FORMA LIVRE OU ENCAPSULADA EM SISTEMAS POLIMÉRICOS COMO ANTIMALÁRICO CAMPO DA INVENÇÃO. A presente invenção se refere ao uso da violaceína extraída da Chromobacteriurn violaceum e de suas formulações, em sistemas poliméricos biodegradáveis nano- e microparticulados, para manufatura de medicamentos para aplicação na área da saúde humana diretamente no tratamento de infecções maláricas já estabelecidas. A atividade antimalárica descoberta foi constatada, in vivo, em modelo de infecção experimental utilizando camundongos isogênicos infectados com formas sangüíneas de Plasmodium chabaudi e, in vitro, contra estágios sangüíneos de Plasmodium falciparum, principal causador da malária em humanos. FUNDAMENTOS DA INVENÇÃO. A malária continua sendo a principal doença parasitária do mundo, causando morbidade e mortalidade nas regiões tropicais e subtropicais em mais de 100 países. Estima-se que esta doença coloque em risco 2,4 bilhões de pessoas, principalmente aquelas expostas à infecção por Plasmodium falciparum e P. vivax, responsáveis por cerca de 100-300 e de 70-80 milhões dos casos anuais respectivamente (WHO, WHO Wkly. Epidem. Rec. 22, 161 (1997); Mendis e col., Am. J. Trop. Med. Hyg. 64, 97 (2001)). No Brasil, foram registrados cerca de 500.000 casos de malária, principalmente na região amazônica, sendo 76,4% registrados.BRPI0506399 (A)A61P33/06A61K9/22A61K31/404BR2005PI06399A61P33/06A61K9/22A61K31/40

ComposiÇÃo FarmacÊutica Contendo Condroitin Sulfato Fucosilado (fuccs) Para Tratamento E PrevenÇÃo Do Desenvolvimento Da MalÁria Cerebral E Gestacional E Seu Uso

COMPOSIÇAO FARMACÊUTICA CONTENDO CONDROITIN SULFATO FUCOSILADO (FucCS) PARA TRATAMENTO E PREVENÇÃO DO DESENVOLVIMENTO DA MALÁRIA CEREBRAL E GESTACIONAL E SEU USO. A presente invenção se refere ao uso do composto químico condroitin sulfato fucosilado (FucCS) extraído do pepino do mar Ludwigothurea grisea, como principal componente para elaboração de medicamentos com aplicação como terapia complementar eiou prevenindo as formas graves da malária (malária cerebral e gestacional), atuando na inibição do processo de citoadesão parasitária em receptores endoteliais e no processo inflamatório associado a doença. Mais precisamente, a presente invenção está baseada nas propriedades anti-adesivas descritas para diversos glicoconjugados sulfatados, principalmente contra P. falciparum, e nas propriedades antiinflamatõrias do FucCS.BRPI1001787 (A2)A61K35/616A61K31/737A61P33/06BR2010PI01787A61K35/616A61K31/737A61P33/0

Publisher Correction: TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria

Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the effect of Toll-like receptors (TLRs) activation on placental malaria (PM) development by using the Plasmodium berghei NK65(GFP) infection model. We observed that activation of the innate immune system by parasites leads to PM due to local inflammation. We identified TLR4 activation as the main pathway involved in the inflammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-inflammatory responses, which resulted in an improved pregnancy outcome. Additionally, a similar result was obtained when infected pregnant mice were treated with IAXO-101, a TLR4/CD14 blocker. Together, this study illustrates the importance of TLR4 signalling for the generation of the severe inflammatory response involved in PM pathogenesis. Therefore, our results implicate that TLR4 blockage could be a potential candidate for therapeutic interventions to reduce malaria-induced pathology both in the mother and the fetus.Fundação de Amparo a Pesquisa do Estado de São Paulo - FAPESPCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESConselho Nacional de Desenvolvimento Científico e Tecnológico - CNPqUniv Fed São Paulo, Dept Ciencias Biol, Diadema, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Parasitol, São Paulo, BrazilHosp Israelita Albert Einstein, São Paulo, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolvimento, São Paulo, BrazilUniv Estadual Campinas, Dept Genet Evolucao & Bioagentes, Inst Biol, Campinas, SP, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Imunol, São Paulo, BrazilUniv São Paulo, Dept Analises Clin & Toxicol, Fac Ciencias Farmaceut, São Paulo, BrazilUniv Fed São Paulo, Dept Ciencias Biol, Diadema, BrazilFAPESP: 2009/53889-0FAPESP: 2014/09964-5FAPESP: 2014/20451-0FAPESP: 2012/16525-2FAPESP: 2011/17880-8FAPESP: 2013/16417-8FAPESP: 2011/19048-8FAPESP: 2013/00981-1FAPESP: 2015/06106-0]CAPES: AUX-PE-PNPD 2751/2010CNPq: 475771/2009-5Web of Scienc

TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria (vol 7, 2017)

Malaria-associate pregnancy has a signifcant impact on infant morbidity and mortality. The detrimental efects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the efect of Toll-like receptors (TLRs) activation on placental malaria (PM) development by using the Plasmodium berghei NK65GFP infection model. We observed that activation of the innate immune system by parasites leads to PM due to local infammation. We identifed TLR4 activation as the main pathway involved in the infammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-infammatory responses, which resulted in an improved pregnancy outcome. Additionally, a similar result was obtained when infected pregnant mice were treated with IAXO-101, a TLR4/CD14 blocker. Together, this study illustrates the importance of TLR4 signalling for the generation of the severe infammatory response involved in PM pathogenesis. Therefore, our results implicate that TLR4 blockage could be a potential candidate for therapeutic interventions to reduce malaria-induced pathology both in the mother and the fetus.Univ Fed Sao Paulo, Dept Ciencias Biol, Diadema, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Sao Paulo, BrazilHosp Israelita Albert Einstein, Sao Paulo, BrazilUniv Sao Paulo, Dept Biol Celular & Desenvolvimento, Sao Paulo, BrazilUniv Estadual Campinas, Inst Biol, Dept Genet Evolucao & Bioagentes, Campinas, SP, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Sao Paulo, BrazilUniv Sao aulo, Fac Ciencias Farmaceut, Dept Anal Clin & Toxicol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Ciencias Biol, Diadema, BrazilWeb of Scienc

Efficient detection of Zika virus RNA in patients' blood from the 2016 outbreak in Campinas, Brazil

Abstract Infection with Zika virus (ZIKV), a mosquito-borne flavivirus has been casually linked with increased congenital microcephaly in Brazil from 2015 through 2016. Sensitive and specific diagnosis of patients with Zika fever (ZIKF) remains critical for patient management. We developed a ZIKV NS5 qRT-PCR assay by combining primers described by Balm et al. and a new Taqman probe. The assay was evaluated and compared with another assay described by Lanciotti et al. (ZIKV 1107) using 51 blood and 42 urine samples from 54 suspected ZIKV patients. ZIKV NS5 performed better in terms of sensitivity with more samples detected as ZIKV-positive (n = 37) than ZIKV 1107 (n = 34) for urine, and ZIKV-positive (n = 29) than ZIKV 1107 (n = 26) for blood. Both assays displayed good overall agreement for urine (κappa = 0.770) and blood (κappa = 0.825) samples. Improved availability of validated diagnostic tests, such ZIKV NS5 qRT-PCR, will be critical to ensure adequate and accurate ZIKV diagnosis