Anti-inflammatory properties of menthol and menthone in schistosoma mansoni infection

Schistosomiasis is a parasitic disease caused by several species of trematode worms and it is believed that more than 261 million people are affected worldwide. New drug development has become essential because there is a risk of the parasite becoming resistant to Praziquantel, the only drug available for this infection. This study evaluated parasitological, immunological and histological parameters in mice infected with Schistosoma mansoni and treated with an herbal commercial medicine. This drug consists of menthol (30-55%) and menthone (14-32%). A 60 day treatment regimen with the herbal medicine decreased the number of S. mansoni eggs in the feces, liver, and intestine and reduced the number of hepatic granulomas. We observed a reduction of 84% in blood eosinophilia and a decrease in the IL-4 and IL-10 blood levels after treatment. Therefore, we propose that schistosomiasis treatment with this herbal medicine for 60 days has an immunomodulatory and anti-inflammatory action in this animal model for schistosomiasis thus contributing to the decrease in physio pathological effects caused by S. mansoni infection7COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESnão te

A Comparative Proteomic Analysis of Praziquantel-Susceptible and Praziquantel-Resistant Schistosoma mansoni Reveals Distinct Response Between Male and Female Animals

Funding Information: We acknowledge the Mass Spectrometry Laboratory at Brazilian Biosciences National Laboratory, CNPEM, Campinas, Brazil for their support with the mass spectrometry analysis. The authors would like to thank Professor Ana Tomás from IBMC and GABBA program (Porto, Portugal), for very helpful suggestions that improved greatly this paper. Funding Information: This work was initially supported by Fundação para a Ciência e a Tecnologia de Portugal (FCT) by grant PEst-OE/SAU/UI0074/2014. AP-A was initially funded by Graduate Program in Areas of Basic and Applied Biology (GABBA) from the Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto and FCT (SFRH/BD/51697/2011) meanwhile received the António Coutinho Science Award (11/BI-PD/20) by the Instituto Gulbenkian de Ciência (IGC) of the Fundação Calouste Gulbenkian, and Fundação Familia Merk and Câmara Municipal de Oeiras, and nowadays is funded by the German Federal Ministry of Education and Research (BMBF), the West African Science Service Centre on Climate Change and Adapted Land Use (WASCAL) through WASCAL Graduate Studies Programme in Climate Change and Marine Sciences at the Institute for Enginneering and Marine Sciences, Atlantic Technical University, Cabo Verde. The Brazilian agencies that were involved in this project are Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq Proc. Nrs 400168/2013-8, and 375781/2013-7 that funded AA, and Fundação de Amparo a Pesquisa no Estado de São Paulo – FAPESP Proc. Nrs 2009/54040-8, 2009/16598-7, and 2008/04050-4 that funded infrastructure to EC. Project FAPESP 2014/07331-5 funded infrastructure to FA. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 1742613 and 88882.317690/2019-01, as a fellowship to CG and Finance Code 001 as a fellowship to TM. AA is now being funded by Fundação para a Ciência e Tecnologia (FCT) of Portugal PTDC/CVT-CVT/28798/2017. Fundação para a Ciência e Tecnologia (FCT) of Portugal provided funds to GHTM (UID/Multi/04413/2020) funded PF, ABA, and SB. Publisher Copyright: Copyright © 2021 Pinto-Almeida, Mendes, Ferreira, Abecasis, Belo, Anibal, Allegretti, Galinaro, Carrilho and Afonso.Schistosomiasis is a chronic neglected tropical disease saddling millions of people in the world, mainly children living in poor rural areas. Praziquantel (PZQ) is currently the only drug used for the treatment and control of this disease. However, the extensive use of this drug has brought concern about the emergence of PZQ-resistance/tolerance by Schistosoma mansoni. Studies of Schistosoma spp. genome, transcriptome, and proteome are crucial to better understand this situation. In this in vitro study, we compare the proteomes of a S. mansoni variant strain stably resistant to PZQ and isogenic to its fully susceptible parental counterpart, identifying proteins from male and female adult parasites of PZQ-resistant and PZQ-susceptible strains, exposed and not exposed to PZQ. A total of 60 Schistosoma spp. proteins were identified, some of which present or absent in either strain, which may putatively be involved in the PZQ-resistance phenomenon. These proteins were present in adult parasites not exposed to PZQ, but some of them disappeared when these adult parasites were exposed to the drug. Understanding the development of PZQ-resistance in S. mansoni is crucial to prolong the efficacy of the current drug and develop markers for monitoring the potential emergence of drug resistance.publishersversionpublishe

Anthelmintic Activity In Vivo of Epiisopiloturine against Juvenile and Adult Worms of Schistosoma mansoni

Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported

Epiisopilosine alkaloid has activity against Schistosoma mansoni in mice without acute toxicity

Schistosomiasis is a disease caused by parasites of the genus Schistosoma, currently affecting more than 200 million people. Among the various species of this parasite that infect humans, S. mansoni is the most common. Pharmacological treatment is limited to the use of a single drug, praziquantel (PZQ), despite reports of parasite resistance and low efficacy. It is therefore necessary to investigate new potential schistosomicidal compounds. In this study, we tested the efficacy of epiisopilosine (EPIIS) in a murine model of schistosomiasis. A single dose of EPIIS (100 or 400 mg/kg) administered orally to mice infected with adult S. mansoni resulted in reduced worm burden and egg production. The treatment with the lower dose of EPIIS (100 mg/kg) significantly reduced total worm burden by 60.61% (P < 0.001), as well as decreasing hepatosplenomegaly and egg excretion. Scanning electron microscopy revealed morphological changes in the worm tegument after treatment. Despite good activity of EPIIS in adult S. mansoni, oral treatment with single dose of EPIIS 100 mg/kg had only moderate effects in mice infected with juvenile S. mansoni. In addition, we performed cytotoxicity and toxicological studies with EPIIS and found no in vitro cytotoxicity (in HaCaT, and NIH-3T3 cells) at a concentration of 512 μg/mL. We also performed in silico analysis of toxicological properties and showed that EPIIS had low predicted toxicity. To confirm this, we investigated systemic acute toxicity in vivo by orally administering a 2000 mg/kg dose to Swiss mice. Treated mice showed no significant changes in hematological, biochemical, or histological parameters compared to non-treated animals. Epiisopilosine showed potential as a schistosomicidal drug: it did not cause acute toxicity and it displayed an acceptable safety profile in the animal model

In vitro schistosomicidal activity of tamoxifen and its effectiveness in a murine model of schistosomiasis at a single dose

Schistosomiasis is a neglected tropical disease affecting 220 million people worldwide. Praziquantel has proven to be effective against this parasitic disease, though there are increasing concerns regarding tolerance/resistance that calls for new drugs. Repurposing already existing and well-known drugs has been a desirable approach since it reduces time, costs, and ethical concerns. The anti-cancer drug tamoxifen (TAM) has been used worldwide for several decades to treat and prevent breast cancer. Previous reports stated that TAM affects Schistosoma hormonal physiology; however, no controlled schistosomicidal in vivo assays have been conducted. In this work, we evaluated the effect of TAM on female and male Schistosoma mansoni morphology, motility, and egg production. We further assessed worm survival and egg production in S. mansoni-infected mice. TAM induced morphological alterations in male and female parasites, as well as in eggs in vitro. Furthermore, in our in vivo experiments, one single dose of intraperitoneal TAM citrate reduced the total worm burden by 73% and led to a decrease in the amount of eggs in feces and low percentages of immature eggs in the small intestine wall. Eggs obtained from TAM citrate-treated mice were reduced in size and presented hyper-vacuolated structures. Our results suggest that TAM may be repurposed as a therapeutic alternative against S. mansoni infections118516251631FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo16/07137-0; 14/21129-

Occurrence of Microcerella halli (Engel) (Diptera, Sarcophagidae) in snake carrion in southeastern Brazil

The occurrence of 27 second-instar larvae of the flesh fly Microcerella halli (Engel, 1931) (Diptera, Sarcophagidae) in a carcass of a snake usually called as Urutu, Bothrops alternatus (Duméril, Bibron & Duméril, 1854) (Serpentes, Viperidae, Crotalinae) is reported. The snake was kept in captivity in a snake farm in Morungaba, São Paulo state, Brazil. Descriptions of reptile carcass colonization by insects and general biological data of this flesh fly are scarce and this necrophagic behavior is described for the first time in literature

Ocorrência de Microcerella halli (Engel) (Diptera, Sarcophagidae) em uma Carcaça de Cobra no Sudeste Brasileiro

The occurrence of 27 second-instar larvae of the flesh fly Microcerella halli (Engel, 1931) (Diptera, Sarcophagidae) in a carcass of a snake usually called as Urutu, Bothrops alternatus (Duméril, Bibron & Duméril, 1854) (Serpentes, Viperidae, Crotalinae) is reported. The snake was kept in captivity in a snake farm in Morungaba, São Paulo state, Brazil. Descriptions of reptile carcass colonization by insects and general biological data of this flesh fly are scarce and this necrophagic behavior is described for the first time in literature.A ocorrência de 27 larvas de segundo estádio do sarcofagídeo Microcerella halli (Engel, 1931) (Diptera, Sarcophagidae) em uma carcaça de urutu Bothrops alternatus (Duméril, Bibron & Duméril, 1854) (Serpentes, Viperidae, Crotalinae) é relatada. A cobra era mantida em cativeiro em um serpentário no município de Morungaba, estado de São Paulo, Brasil. Descrições de colonização de carcaças de répteis por insetos e dados gerais da biologia deste sarcofagídeo são escassos, e este comportamento necrófago é descrito pela primeira vez na literatura.31832

Efeito do praziquantel incorporado a lipossomas nos diferentes estágios de desenvolvimento dos ovos de Schistosoma mansoni

Mansonian schistosomiasis is caused by an intravascular digenetic trematode Schistosoma mansoni. Praziquantel (PZQ) and oxamniquine (OXA) are the drugs of choice for the treatment of this disease. However, both drugs are subject to some limitations in their action and cases of tolerance and resistance have been reported. Moreover, tolerance and resistance cases have been reported. For this reason, there is an urgent need for research on new alternatives aimed at improving the action of existing drugs, such as the incorporation of these drugs into liposomes. In this study, the efficiency of action of liposome- encapsulated praziquantel (lip.PZQ) on oviposition by S. mansoni, strain BH, was assessed in Mus musculus mices (SPF Swiss mice). Four PZQ and lip.PZQ doses (47; 60; 250 e 300mg/kg) were tested. Some mice were treated 30 days post-infection and others after 45 days. The oogram analyses showed that the most effective lip.PZQ treatment was 300mg/kg dose given on the 45th day post infection, which reduced the number of S. mansoni eggs per gram of tissue.A esquistossomose mansônica é causada pelo trematódeo digenético intravascular Schistosoma mansoni. Para o tratamento dessa enfermidade o praziquantel (PZQ) e a oxamniquina (OXA) são os fármacos escolhidos. No entanto, esses fármacos apresentam limitações quanto à ação e casos de resistência ou tolerância já foram relatados. Por esse motivo, são necessários os estudos de novas alternativas que visam melhorar os fármacos já existentes, como a incorporação desses em lipossomas. Este estudo verificou a ação do praziquantel incorporado a lipossomas (lip.PZQ) sobre os ovos de S. mansoni, linhagem BH em camundongos Mus musculus (Swiss- SPF). Para tanto, foram testadas quatro doses de PZQ e lip.PZQ (47; 60; 250 e 300mg/kg) sendo que parte dos camundongos foi tratada após 30 dias de infecção e outra após 45 dias. A análise do oograma mostrou que a dose lip.PZQ 300mg/kg administrada no 45º dia de infecção foi mais eficaz, pois reduziu a oviposição pelas fêmeas de S. mansoni

Nanostructured lipid carriers as a strategy to improve the in vitro schistosomiasis activity of Praziquantel

Praziquantel (PZQ) is a pyrazinoisoquinoline anthelmintic that was discovered in 1972 by Bayer Germany. Currently, due to its efficacy, PZQ is the drug of choice against all species of Schistosoma. Although widely used, PZQ exhibits low and erratic bioavailability because of its poor water solubility. Nanostructured lipid carriers (NLC), second-generation solid lipid nanoparticles, were developed in the 1990s to improve the bioavailability of poorly water soluble drugs. The aim of this study was to investigate nanostructured lipid carriers as a strategy to improve the efficacy of PZQ in S. mansoni treatment. We prepared NLC2 and NLC4 by adding seventy percent glycerol monostearate (GMS) as the solid lipid, 30% oleic acid (OA) as the liquid lipid and two surfactant systems containing either soybean phosphatidylcholine/poloxamer (PC/P-407) or phosphatidylcholine/Tween 60 (PC/T60), respectively. The carriers were characterized by nuclear magnetic resonance, differential scanning calorimetry, thermogravimetric analysis and Fourier transform-infrared spectroscopy. The safety profile was evaluated using red cell hemolysis and in vitro cytotoxicity assays. The results showed that the encapsulation of PZQ in NLC2 or NLC4 improved the safety profile of the drug. Treatment efficacy was evaluated on the S. mansoni BH strain. PZQ-NLC2 and PZQ-NLC4 demonstrated an improved efficacy in comparison with free PZQ. The results showed that the intestinal transport of free PZQ and PZQ-NLC2 was similar. However, we observed that the concentration of PZQ absorbed was smaller when PZQ was loaded in NLC4. The difference between the amounts of absorbed PZQ could indicate that the presence of T60 in the nanoparticles (NLC4) increased the rigid lipid matrix, prolonging release of the drug. Both systems showed considerable in vitro activity against S. mansoni, suggesting that these systems may be a promising platform for the administration of PZQ for treating schistosomiasis.Fil: Kolenyak Santos, Fernanda. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Garnero, Claudia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: De Oliveira, Rosimeire N.. Universidade Estadual de Campinas; BrasilFil: De Souza, Ana L. R.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Chorilli, Marlus. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Allegretti, Silmara M.. Universidade Estadual de Campinas; BrasilFil: Longhi, Marcela Raquel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chaud, Marco V.. Universidade de Sorocaba; BrasilFil: Gremião, Maria P.D.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasi