sábado, 6 de abril de 2019
Patent-pending probiotic could disrupt Crohn's disease biofilms
Probiotic found to help weaken stubborn microbial biofilm communities in the gut that can worsen symptoms
Date: April 3, 2019 Source: Case Western Reserve University Summary: Probiotics typically aim to rebalance bacteria populations in the gut, but new research suggests they may also help break apart stubborn biofilms. Biofilms are living microbial communities -- they provide a haven for microbes and are often resistant to antibiotics. A new study describes a specific probiotic mix that could help patients with gastrointestinal diseases avoid harmful biofilms that can worsen their symptoms.
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sexta-feira, 5 de abril de 2019
Compound that kills drug-resistant fungi is isolated from ant microbiota
Date: April 4, 2019 Source: Fundação de Amparo à Pesquisa do Estado de São PauloSummary:A project conducted by researchers in Brazil and the US investigated bacteria living in symbiosis with insects as a source for novel drugs.
Fungus-growing ants of the genus Cyphomyrmex. A project conducted by researchers in Brazil and the US investigated bacteria living in symbiosis with insects as a source for novel drugs.
Credit: Weilan Melo, Taise Fukuda & Camila Pereira
Antimicrobial and antifungal resistance, which describe the ability of bacteria and other pathogens to resist the effects of drugs to which they were once sensitive, is a major public health problem worldwide. A study published recently in the journal Nature Communications suggests that the solution may come from the tiny bodies of insects, or more accurately, from the microbiota that they host.
This innovative hypothesis was first proposed by Brazilian and US researchers as part of a collaborative project begun in 2014 with support from FAPESP and the US National Institutes of Health (NIH).
The idea was to isolate bacteria that live in symbiosis with leafcutting ants of the genus Atta and to look for natural compounds with the potential to yield new drugs.
By pursuing this strategy, a research group led by Monica Tallarico Pupo, Professor of Medicinal Chemistry at the University of São Paulo's Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP), and Jon Clardy, Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School in the US, discovered cyphomycin, which, when tested in vitro and in vivo, was shown to be capable of killing fungi that cause diseases in humans and are resistant to currently available drugs.
"It was an exciting discovery because it confirmed our hypothesis that the insect microbiota is a promising source for the isolation of compounds with antibacterial and antifungal activity. Of course, it's too soon to know whether cyphomycin will become a drug, but we've made sufficient progress to apply for a patent," Pupo told Agência FAPESP.
Many antibiotics, she added, originate from compounds produced by bacteria found in soil. Most of these bacteria belong to the genus Streptomyces. The researchers decided to investigate this same group of filamentous bacteria in insect bodies. Their hypothesis was that if the bacteria help insects defend against pathogens, they might play the same role in humans.
"Soil was thoroughly explored at the time the first antibiotics were discovered and produced," Pupo said. "We wanted to find a new ecological niche. We set out to confirm whether evolutionary pressure made the bacteria hosted by insects even more effective against pathogens."
Broad sample
Specimens were collected by collaborators from the US, Costa Rica and Panama. In addition to leafcutting ants of the tribe Attini, butterflies, wasps, bees and moths were included, for a total of 1,400 insects.
"In Brazil, more than 300 ant colonies were collected in the Cerrado [Brazilian savanna], Atlantic Rainforest and Amazon biomes. Cyphomycin was isolated in one specimen of the genus Cyphomyrmex collected on the University of São Paulo's Ribeirão Preto campus," Pupo said.
After the insects were collected, the bacteria found in their bodies were isolated, purified in the laboratory, and tested in vitro against microorganisms that act as pathogens in humans. The species that proved most effective against these pathogens were selected for metabolomic analysis -- to characterize the metabolites they produce and identify the most active of these -- and for phylogenetic studies, in which gene sequencing indicated to what extent the insect-associated bacteria resembled the strains of Streptomyces that live in soil.
"We combined chemometrics and liquid chromatography coupled with mass spectrometry to profile the compounds produced by the insect microbiota. The aim was to identify the Streptomyces strains that produce a distinctive chemistry -- in other words, to find compounds quite different from those synthesized by soil bacteria. In this way, we increased the likelihood of finding a genuinely innovative molecule," Pupo explained.
The compounds shown to be most effective by these rigorous methods were tested again, in vitro and in mice, against pathogens resistant to the drugs used in clinical practice.
According to Pupo, cyphomycin was not effective against bacteria but proved capable of combating infection by Aspergillus fumigatus, the fungus most frequently found in hospital-acquired infections and the cause of aspergillosis, a disease with an attributable mortality as high as 85% even after antifungal treatment.
When administered to laboratory animals, cyphomycin also combated infection by Candida glabrata and C. auris, fungi that cause candidiasis in humans and are resistant to existing drugs.
"Cyphomycin wasn't the first compound with antimicrobial action identified in our project, but no others displayed this level of activity," Pupo said.
The part of the study that developed the chemical profile of the bacterial compounds was performed during the PhD research of Humberto Enrique Ortega Dominguez with FAPESP's support and supervision by Pupo at FCFRP-USP. During a postdoctoral research internship at the University of Wisconsin-Madison in the US, with supervision by Tim Bugni and a scholarship from FAPESP, Dominguez focused on metabolomic studies and isolated cyphomycin, finalizing its structural determination after his return to Brazil. The trials with mice were conducted by David Andes and his group at UW-Madison.
Weilan Gomes da Paixão Melo, a postdoctoral researcher with a scholarship from FAPESP, participated in insect collection and in microbiota isolation and identification. She also performed phylogenetic studies during a research internship in Cameron Currie's laboratory at UW-Madison.
Story Source:
Materials provided by Fundação de Amparo à Pesquisa do Estado de São Paulo. Note: Content may be edited for style and length.
Journal Reference:
Marc G. Chevrette, Caitlin M. Carlson, Humberto E. Ortega, Chris Thomas, Gene E. Ananiev, Kenneth J. Barns, Adam J. Book, Julian Cagnazzo, Camila Carlos, Will Flanigan, Kirk J. Grubbs, Heidi A. Horn, F. Michael Hoffmann, Jonathan L. Klassen, Jennifer J. Knack, Gina R. Lewin, Bradon R. McDonald, Laura Muller, Weilan G. P. Melo, Adrián A. Pinto-Tomás, Amber Schmitz, Evelyn Wendt-Pienkowski, Scott Wildman, Miao Zhao, Fan Zhang, Tim S. Bugni, David R. Andes, Monica T. Pupo, Cameron R. Currie. The antimicrobial potential of Streptomyces from insect microbiomes. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-08438-0
Cite This Page:
Fundação de Amparo à Pesquisa do Estado de São Paulo. "Compound that kills drug-resistant fungi is isolated from ant microbiota." ScienceDaily. ScienceDaily, 4 April 2019. <www.sciencedaily.com/releases/2019/04/190404214756.htm>.
quinta-feira, 4 de abril de 2019
quarta-feira, 3 de abril de 2019
Tackling challenge of antifungal resistance
Better understanding of antifungal drug resistance
Date: April 3, 2019 Source: Swansea University
Summary:
Ground-breaking work is helping develop a better understanding of the growing threat posed by antifungal drug resistance. Invasive aspergillosis is a devastating disease caused by breathing in small airborne spores of the fungus Aspergillus fumigatus and it is a condition where drug resistance has been encountered. They have just released a paper revealing how they have been able to identify a previously uncharacterized genetic mutation in clinical isolates that leads to resistance.
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Vitamin B12 is identified as the inhibitor of a key enzyme in hereditary Parkinson's disease
Date: April 4, 2019 Source: University of the Basque Country Summary: Parkinson's is the most common, chronic neurodegenerative movement disorder affecting 1% of the global population over seventy years of age. Right now, there is no cure for this disease and the available treatments focus on addressing its symptoms but not its progression.
Parkinson's is the most common, chronic neurodegenerative movement disorder affecting 1% of the global population over seventy years of age. Right now, there is no cure for this disease and the available treatments focus on addressing its symptoms but not its progression.
Although most cases of Parkinson's are sporadic, the inheritable variants of the disease are mainly associated with mutations of the gene that encodes the LRRK2 enzyme. In 2004 an international research team, in which researchers from the Basque Country participated, established the link between one of the mutations in this enzyme and patients diagnosed with the disease.
So the LRRK2 enzyme, which is also known internationally by the name "dardarina," the Basque word that means tremor, has become one of the most attractive therapeutic targets for developing new drugs to combat inheritable Parkinson's. Neurotoxicity, or the pathogenic effects as a whole associated with LRRK2, is mainly due to the fact that pathogenic mutations increase the kinase activity of this enzyme, which has prompted an international race to develop inhibitors. Right now, specific, powerful inhibitors of the kinase activity of LRRK2 do in fact exist. Yet many of them cause undesirable side effects or produce very unclear clinical results.
This research conducted by Iban Ubarretxena, the Ikerbasque researcher and director of the Biofisika Institute (mixed centre of the CSIC-Spanish National Research Council and the UPV/EHU-University of the Basque Country) at the UPV/EHU's Science Park (Leioa-Erandio Area), together with an international research team, has revealed that AdoCbl, one of the active forms of vitamin B12, acts as an inhibitor of the kinase activity of LRRK2 in cultured cells and brain tissue. It also significantly prevents the neurotoxicity of the LRRK2 variants associated with Parkinson's in cultured cells of primary rodents, as well as in various genetically modified models used to study this disease. The results of the research have been published in the journal Cell Research.
So according to the study, vitamin B12 has turned out to be a new class of modulator of the kinase activity of LRRK2, which, as Iban Ubarretxena pointed out, "constitutes a huge step forward because it is a neuroprotective vitamin in animal models and has a mechanism unlike that of currently existing inhibitors. So it could be used as a basis to develop new therapies to combat hereditary Parkinson's associated with pathogenic variants of the LRRK2 enzyme."
Story Source:
Materials provided by University of the Basque Country. Note: Content may be edited for style and length.
Journal Reference:
Adam Schaffner, Xianting Li, Yacob Gomez-Llorente, Emmanouela Leandrou, Anna Memou, Nicolina Clemente, Chen Yao, Farinaz Afsari, Lianteng Zhi, Nina Pan, Keita Morohashi, Xiaoluan Hua, Ming-Ming Zhou, Chunyu Wang, Hui Zhang, Shu G. Chen, Christopher J. Elliott, Hardy Rideout, Iban Ubarretxena-Belandia, Zhenyu Yue. Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection. Cell Research, 2019; 29 (4): 313 DOI: 10.1038/s41422-019-0153-8
Cite This Page:
University of the Basque Country. "Vitamin B12 is identified as the inhibitor of a key enzyme in hereditary Parkinson's disease." ScienceDaily. ScienceDaily, 4 April 2019. <www.sciencedaily.com/releases/2019/04/190404124818.htm>.
terça-feira, 2 de abril de 2019
Poll: Pets help older adults cope with health issues, get active and connect with others
For some, time commitment, cost and allergies stand in the way of pet ownership
Date: April 3, 2019 Source: Michigan Medicine - University of Michigan
Summary:
Pets help older adults cope with mental and physical health issues, according to a new national poll. But pets can also bring concerns, and some people may even put their animals' needs ahead of their own health, the poll finds. Three-quarters of pet owners aged 50 to 80 say their animals reduce their stress and give them a sense of purpose. But 18 percent also said having one puts a strain on their budget.
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Human history through tree rings: Trees in Amazonia reveal pre-colonial human disturbance
New study shows that tropical trees act as a living record of past human activity in the Amazon
Date: April 3, 2019 Source: Max Planck Institute for the Science of Human History
Summary:
The Brazil nut tree (Bertholletia excelsa) is well known around the world today and has been an important part of human subsistence strategies in the Amazon forest from at least the Early Holocene. These trees can live for hundreds of years and are managed today by humans for their valuable, energy-filled nuts. Patterns in the establishment and growth of living Brazil nut trees in Central Amazonia reflect over 400 years of changes in human occupation, politics, and socioeconomic activities in the region.
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Ready, steady, go: Steps in plant immune receptor activation
Date: April 4, 2019 Source: Max Planck Institute for Plant Breeding Research Summary: Two landmark studies provide unprecedented structural insight into how plant immune receptors are primed -- and then activated -- to provide plants with resistance against microbial pathogens.
Although separated by more than one billion years of evolution, plants and animals have hit upon similar immune strategies to protect themselves against pathogens. One important mechanism is defined by cytoplasmic receptors called NLRs that, in plants, recognize so-called effectors, molecules that invading microorganisms secrete into the plant's cells. These recognition events can either involve direct recognition of effectors by NLRs or indirect recognition, in which the NLRs act as 'guards' that monitor additional host proteins or 'guardees' that are modified by effectors. Host recognition of effectors, whether direct or indirect, results in cell death to confine microbes to the site of infection. However, until now, a detailed understanding of the mechanisms of action of plant NLRs has been lacking, and much of our understanding of how these molecules function in plants has been based on comparison with animal counterparts.
In two new studies published in the journal Science, Jijie Chai who is affiliated with Tsinghua University in Beijing as well as the University of Cologne and the Max Planck Institute for Plant Breeding Research together with the groups of Hong-Wei Zhang and Jian-Min Zhou at Tsinghua University and the Chinese Academy of Sciences in Beijing have now pieced together the sequence of molecular events that convert inactive NLR molecules into active complexes that provide disease resistance.
The authors focused their attentions on a protein called ZAR1, an ancient plant molecule that is likely to be of broad importance since it interacts with multiple 'guardees' to recognize unrelated bacterial effectors.
Using cryo-electron microscopy, Chai and co-authors observed that in the absence of bacterial effectors, ZAR1, together with the plant protein RKS1, is maintained in a latent state through interactions involving multiple domains of the ZAR1 protein. Upon infection, a bacterial effector modifies the plant 'guardee' PBL2, which then activates RKS1 resulting in huge conformational changes that first allow plants to swap ADP for ATP and then result in the assembly of a pentameric, wheel-like structure that the authors term the 'ZAR1 resistosome'.
One striking feature of this structure is its similarity with animal NLR proteins, which, once activated, also assemble into wheel-like structures that act as signaling platforms for cell death execution and immune signaling. However, one important difference between the structures offers a tantalizing clue as to how ZAR1 induces cell death. The authors could identify a highly ordered funnel-like structure in ZAR1 that tethers the resistosome to the plasma membrane and is required for cell death and disease resistance. The authors speculate that ZAR1 may form a pore in the plasma membrane and in this way perturb cellular function leading to immune signaling and cell death.
Other plant NLRs also assemble into complexes that associate with the plasma membrane and it is thus highly likely that Chai's findings have important general implications for understanding plant immunity. MPIPZ director Paul Schulze-Lefert, who was not involved in the studies, is in no doubt about the importance of the new studies: "This will become textbook knowledge."
Story Source:
Materials provided by Max Planck Institute for Plant Breeding Research. Note: Content may be edited for style and length.
Journal References:
Jizong Wang, Jia Wang, Meijuan Hu, Shan Wu, Jinfeng Qi, Guoxun Wang, Zhifu Han, Yijun Qi, Ning Gao, Hong-Wei Wang, Jian-Min Zhou, Jijie Chai. Ligand-triggered allosteric ADP release primes a plant NLR complex. Science, 2019; 364 (6435): eaav5868 DOI: 10.1126/science.aav5868
Jizong Wang, Meijuan Hu, Jia Wang, Jinfeng Qi, Zhifu Han, Guoxun Wang, Yijun Qi, Hong-Wei Wang, Jian-Min Zhou, Jijie Chai. Reconstitution and structure of a plant NLR resistosome conferring immunity. Science, 2019; 364 (6435): eaav5870 DOI: 10.1126/science.aav5870
Cite This Page:
Max Planck Institute for Plant Breeding Research. "Ready, steady, go: Steps in plant immune receptor activation." ScienceDaily. ScienceDaily, 4 April 2019. <www.sciencedaily.com/releases/2019/04/190404143742.htm>.