The novel coronavirus SARS-CoV-2 causes COVID-19, a highly pathogenic viral infection threatening millions. The majority of the individuals infected are asymptomatic or mildly symptomatic showing ...typical clinical signs of common cold. However, approximately 20% of the patients can progress to acute respiratory distress syndrome (ARDS), evolving to death in about 5% of cases. Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for virus entry into host target cells. The upregulation of ACE2 in patients with comorbidities may represent a propensity for increased viral load and spreading of infection to extrapulmonary tissues. This systemic infection is associated with higher neutrophil to lymphocyte ratio in infected tissues and high levels of pro-inflammatory cytokines leading to an extensive microthrombus formation with multiorgan failure. Herein we investigated whether SARS-CoV-2 can stimulate extracellular neutrophils traps (NETs) in a process called NETosis. We demonstrated for the first time that SARS-CoV-2 in fact is able to activate NETosis in human neutrophils. Our findings indicated that this process is associated with increased levels of intracellular Reactive Oxygen Species (ROS) in neutrophils. The ROS-NET pathway plays a role in thrombosis formation and our study suggest the importance of this target for therapy approaches against disease.
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Mucormycosis is considered concerning invasive fungal infections due to its high mortality rates, difficult diagnosis and limited treatment approaches. Mucorales species are highly resistant to many ...antifungal agents and the search for alternatives is an urgent need. In the present study, a library with 400 compounds called the Pandemic Response Box
was used and four compounds were identified: alexidine and three non-commercial molecules. These compounds showed anti-biofilm activity, as well as alterations in fungal morphology and cell wall and plasma membrane structure. They also induced oxidative stress and mitochondrial membrane depolarization. In silico analysis revealed promising pharmacological parameters. These results suggest that these four compounds are potent candidates to be considered in future studies for the development of new approaches to treat mucormycosis.
Scedosporium and Lomentospora species are opportunistic filamentous fungi that cause localized and disseminated infections in immunocompetent and immunocompromised patients. These species are ...considered resistant fungi due to their low susceptibility to most current antifungal agents used in healthcare settings. The search for new compounds that could work as promising candidate antifungal drugs is an increasing field of interest. In this context, in the present study we screened the Pandemic Response Box® library (Medicines for Malaria Venture MMV, Switzerland) to identify compounds with antifungal activity against Scedosporium and Lomentospora species. An initial screening of the drugs from this collection at 5 μM was performed using a clinical Scedosporium aurantiacum isolate according to the EUCAST protocol. Compounds with activity against this fungus were also tested against four other species (S. boydii¸ S. dehoogii, S. apiospermum and L. prolificans) at concentrations ranging from 0.078 to 10 μM. Seven compounds inhibited more than 80% of S. aurantiacum growth, three of them (alexidine, amorolfine and olorofim) were selected due to their differences in mechanism of action, especially when compared to drugs from the azole class. These compounds were more active against biofilm formation than against preformed biofilm in Scedosporium and Lomentospora species, except alexidine, which was able to decrease preformed biofilm about 50%. Analysis of the potential synergism of these compounds with voriconazole and caspofungin was performed by the checkerboard method for S. aurantiacum. The analysis by Bliss methodology revealed synergistic effects among selected drugs with caspofungin. When these drugs were combined with voriconazole, only alexidine and amorolfine showed a synergistic effect, whereas olorofim showed an antagonistic effect. Scanning electron microscopy revealed that alexidine induces morphology alterations in S. aurantiacum biofilm grown on a catheter surface. Reactive oxygen species production, mitochondrial activity and surface components were analyzed by fluorescent probes when S. aurantiacum was treated with selected drugs and revealed that some cell parameters are altered by these compounds. In conclusion, alexidine, amorolfine and olorofim were identified as promising compounds to be studied against scedosporiosis and lomentosporiosis.
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Visceral leishmaniasis is a neglected disease caused by
protozoa parasites transmitted by infected sand fly vectors. This disease represents the second in mortality among tropical infections and is ...associated to a profound immunosuppression state of the host. The hallmark of this infection-induced host immunodeviation is the characteristic high levels of the regulatory interleukin-10 (IL-10) cytokine. In the present study, we investigated the role of B-1 cells in the maintenance of splenic IL-10 levels that could interfere with resistance to parasite infection. Using an experimental murine infection model with
we demonstrated an improved resistance of B-1 deficient BALB/XID mice to infection. BALB/XID mice developed a reduced splenomegaly with diminished splenic parasite burden and lower levels of IL-10 secretion of purified splenocytes at 30 days post-infection, as compared to BALB/c wild-type control mice. Interestingly, we found that resident peritoneal macrophages isolated from BALB/XID mice were more effective to control the parasite load in comparison to cells isolated from BALB/c wild-type mice. Our findings point to a role of B-1 cells in the host susceptibility to visceral leishmaniasis.
Leishmania infantum is responsible for visceral leishmaniasis, the most severe form of the disease. The treatments currently used are pentavalent antimonials and amphotericin B, but they present ...serious side effects and resistant species that already exist. Therefore, it is necessary to find new compounds to avoid those acute problems. In vitro, this study evaluated the effects of fifteen digoxin derivative compounds on promastigotes and two of these compounds on amastigotes of L. infantum. We also assess the impact of these compounds on mitochondrial metabolism. The results showed that two of the fifteen compounds tested showed a high anti-Leishmania effect. Compounds 3 and 15 showed no toxicity across the cell lines RAW 264.7. Compound 15 inhibited macrophage infection and reduced the number of amastigotes. The two compounds showed a reduction in oxygen consumption by promastigotes. In this way, compounds 3 and 15 appear to be promising anti-leishmanial. Therefore, we checked both compounds in vivo also evaluating the toxicity by measuring ALT, AST, urea, and creatinine. Our results may contribute in the future to the development and application of new anti-Leishmania drugs.
Introdução: Com a pandemia da Covid-19, muitos procedimentos médicos sofreram alterações significativas devido à realocação de recursos para os pacientes contaminados pelo Sars-Cov-2. A logística de ...transplantes foi diretamente afetada, com repercussões importantes para o paciente na fila de espera para um novo órgão. Objetivo: Esta revisão busca analisar o impacto da pandemia da Covid-19 na logística de disponibilidade de órgãos sólidos e volume de transplantes. Métodos: Foi realizada uma busca integrativa de artigos com os descritores “Covid OR Sars-Cov-2”, “COVID-19”, “Transplant”, “Donor”, “Waiting list”, “Organ donation” no PubMed e Web of Science. Só foram considerados artigos sobre transplante de pâncreas, coração, fígado, rim e intestino, e que abordassem um dos seguintes tópicos: disponibilidade de doadores, volume e tempo na lista de espera, mortalidade dos pacientes em espera, volume de transplantes realizados. Resultados: Dos 68 artigos encontrados, 49 deles eram multicêntricos. Dentre todos os 68, 29 fizeram alguma colocação em relação ao volume de doador, 42 em relação ao volume de transplante, 18 em relação à mortalidade na fila de transplante, 15 em relação ao volume da lista de espera e quatro em relação ao tempo na lista de espera. Com tais dados, de forma geral, foi possível observar diminuição do volume de doadores e do volume de transplantes, redução de adições à lista de espera, e aumento tanto no tempo de espera para transplantes, quanto na mortalidade do paciente que aguardava pelo transplante. Conclusão: A pandemia da SARS-CoV-2 prejudicou diretamente a logística dos transplantes de órgãos sólidos de forma global. Os motivos que levaram a tal fato estão relacionados à diminuição dos leitos de UTI, contaminação do doador pelo vírus, e protocolos rigorosos para prevenção de transmissibilidade do vírus.
The increase in the prevalence and severity of fungal infections and the resistance to available antifungals highlights the imperative need for novel therapeutics and the search for new targets. ...High-content screening of libraries containing hundreds of compounds is a powerful strategy for searching for new drug candidates. In this study, we screened the Pandemic Response Box library (Medicines for Malaria Venture) of 400 diverse molecules against the Sporothrix pathogenic species. The initial screen identified twenty-four candidates that inhibited the growth of Sporothrix brasiliensis by more than 80%. Some of these compounds are known to display antifungal activity, including olorofim (MMV1782354), a new antifungal drug. Olorofim inhibited and killed the yeasts of S. brasiliensis, S. schenckii, and S. globosa at concentrations lower than itraconazole, and it also showed antibiofilm activity. According to the results obtained by fluorimetry, electron microscopy, and particle characterization analyses, we observed that olorofim induced profound alterations on the cell surface and cell cycle arrest in S. brasiliensis yeasts. We also verified that these morphophysiological alterations impaired their ability to adhere to keratinocytes in vitro. Our results indicate that olorofim is a promising new antifungal against sporotrichosis agents.
Scedosporium and Lomentospora species are opportunistic filamentous fungi that cause localized and disseminated infections in immunocompetent and immunocompromised patients. These species are ...considered resistant fungi due to their low susceptibility to most current antifungal agents used in healthcare settings. The search for new compounds that could work as promising candidate antifungal drugs is an increasing field of interest. In this context, in the present study we screened the Pandemic Response Box.sup.® library (Medicines for Malaria Venture MMV, Switzerland) to identify compounds with antifungal activity against Scedosporium and Lomentospora species. An initial screening of the drugs from this collection at 5 muM was performed using a clinical Scedosporium aurantiacum isolate according to the EUCAST protocol. Compounds with activity against this fungus were also tested against four other species (S. boydii¸ S. dehoogii, S. apiospermum and L. prolificans) at concentrations ranging from 0.078 to 10 muM. Seven compounds inhibited more than 80% of S. aurantiacum growth, three of them (alexidine, amorolfine and olorofim) were selected due to their differences in mechanism of action, especially when compared to drugs from the azole class. These compounds were more active against biofilm formation than against preformed biofilm in Scedosporium and Lomentospora species, except alexidine, which was able to decrease preformed biofilm about 50%. Analysis of the potential synergism of these compounds with voriconazole and caspofungin was performed by the checkerboard method for S. aurantiacum. The analysis by Bliss methodology revealed synergistic effects among selected drugs with caspofungin. When these drugs were combined with voriconazole, only alexidine and amorolfine showed a synergistic effect, whereas olorofim showed an antagonistic effect. Scanning electron microscopy revealed that alexidine induces morphology alterations in S. aurantiacum biofilm grown on a catheter surface. Reactive oxygen species production, mitochondrial activity and surface components were analyzed by fluorescent probes when S. aurantiacum was treated with selected drugs and revealed that some cell parameters are altered by these compounds. In conclusion, alexidine, amorolfine and olorofim were identified as promising compounds to be studied against scedosporiosis and lomentosporiosis.
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Introduction: With the Covid-19 pandemic, many medical procedures underwent significant changes due to the reallocation of resources to patients infected with Sars-Cov-2. The logistics of transplants ...were directly affected, with important repercussions for the patient on the waiting list for a new organ. Objective: This review seeks to analyze the impact of the Covid-19 pandemic on the logistics of solid organ availability and volume of transplants. Methods: An integrative search of articles with the descriptors “Covid ORSars-Cov-2”, “COVID-19”, “Transplant”, “Donor”, “Waiting list”, and “Organ donation” in PubMed and Web of Science was performed. Only articles on pancreas, heart, liver, kidney and intestine transplantation that addressed one of the following topics were considered: availability of donors, volume and time on the waiting list, mortality of patients on the waiting list, and volume of transplants performed. Results: Of the 68 articles found, 49 of them were multicentric. Among all 68, 29 made a statement concerning donor volume, 42 concerning transplant volume, 18 about mortality on the transplant waiting list, 15 concerning the volume on the waiting list, and 4 regarding time on the waiting list. Thus, with such data, in general, it was possible to observe a decrease in the volume of donors and the volume of transplants, besides a reduction in addition to the waiting list and an increase both in the waiting time for transplantation and in the mortality of the patients waiting for the transplant. Conclusion: The SARS-CoV-2 pandemic has directly influenced the logistics of solid organ transplants globally. The reasons that led to this fact are related to the decrease in the availability of ICU beds, contamination of the donor by the virus, and strict protocols to prevent the transmission of the virus.
Scedosporium and Lomentospora species are opportunistic filamentous fungi that cause localized and disseminated infections in immunocompetent and immunocompromised patients. These species are ...considered resistant fungi due to their low susceptibility to most current antifungal agents used in healthcare settings. The search for new compounds that could work as promising candidate antifungal drugs is an increasing field of interest. In this context, in the present study we screened the Pandemic Response Box® library (Medicines for Malaria Venture MMV, Switzerland) to identify compounds with antifungal activity against Scedosporium and Lomentospora species. An initial screening of the drugs from this collection at 5 μM was performed using a clinical Scedosporium aurantiacum isolate according to the EUCAST protocol. Compounds with activity against this fungus were also tested against four other species (S. boydii¸ S. dehoogii, S. apiospermum and L. prolificans) at concentrations ranging from 0.078 to 10 μM. Seven compounds inhibited more than 80% of S. aurantiacum growth, three of them (alexidine, amorolfine and olorofim) were selected due to their differences in mechanism of action, especially when compared to drugs from the azole class. These compounds were more active against biofilm formation than against preformed biofilm in Scedosporium and Lomentospora species, except alexidine, which was able to decrease preformed biofilm about 50%. Analysis of the potential synergism of these compounds with voriconazole and caspofungin was performed by the checkerboard method for S. aurantiacum. The analysis by Bliss methodology revealed synergistic effects among selected drugs with caspofungin. When these drugs were combined with voriconazole, only alexidine and amorolfine showed a synergistic effect, whereas olorofim showed an antagonistic effect. Scanning electron microscopy revealed that alexidine induces morphology alterations in S. aurantiacum biofilm grown on a catheter surface. Reactive oxygen species production, mitochondrial activity and surface components were analyzed by fluorescent probes when S. aurantiacum was treated with selected drugs and revealed that some cell parameters are altered by these compounds. In conclusion, alexidine, amorolfine and olorofim were identified as promising compounds to be studied against scedosporiosis and lomentosporiosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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