Biology subjects

Reis, S.

Publications and source records attributed to Reis, S..

4 recordsLinked to original sources

bioRxiv2024

Nucleic Acid Aptamers Protect Against Lead (Pb(II)) Toxicity

Lead (Pb(II)) is a pervasive heavy metal toxin with many well-established negative effects on human health. Lead toxicity arises from cumulative, repeated environmental exposures. Thus, prophylactic strategies to protect against the bioaccumulation of lead could reduce lead-associated human pathologies. Here we show that DNA and RNA aptamers protect C. elegans from toxic phenotypes caused by lead. Reproductive toxicity, as measured by brood size assays, is prevented by co-feeding of animals with DNA or RNA aptamers. Similarly, lead-induced behavioral anomalies are also normalized by aptamer feeding. Further, cultured human HEK293 and primary murine osteoblasts are protected from lead toxicity by transfection with DNA aptamers. The osteogenic development, which is decreased by lead exposure, is maintained by prior transfection of lead-binding DNA aptamers. Aptamers may be an effective strategy for the protection of human health in the face of increasing environmental toxicants. SYNOPSISLead remains a pervasive environmental contaminant with significant human health implications. This study investigates an entirely novel intervention for the problem of lead toxicity, using nucleic acid aptamers.

pharmacology and toxicology↗

bioRxiv2023

Cholesterol Dysregulation Drives Seed-Dependent Tau Aggregation in Patient Stem Cell-Derived Models of Tauopathy

Tauopathies are a class of neurodegenerative diseases characterized by the progressive misfolding and accumulation of pathological tau protein in focal regions of the brain, leading to insidious neurodegeneration. Abnormalities in cholesterol metabolism and homeostasis have also been implicated in various neurodegenerative diseases. However, the connection between cholesterol dysregulation and tau pathology remains largely unknown. To model and measure the impact of cholesterol dysregulation on tau, we utilized a combination of in vitro and ex vivo tau aggregation assays using an engineered tau biosensor cell line and human induced pluripotent stem cell (iPSC)-derived neuronal cultures from an individual harboring an autosomal dominant P301L tau mutation and from a healthy control. We demonstrate that excess cholesterol esters lead to an increased rate of tau aggregation in vitro and an increase in seed-dependent insoluble tau aggregates detected in the biosensor line. We observed a strong correlation between cholesterol ester concentration and the presence of high-molecular-weight, oligomeric tau species. Importantly, in tauopathy patient iPSC-derived neurons harboring a P301L tau mutation with endogenous forms of misfolded tau, we show that acute dysregulation of cholesterol homeostasis through acute exposure to human plasma-purified cholesterol esters formed by the linkage of fatty acids to the hydroxyl group of cholesterol leads to the rapid accumulation of phosphorylated tau. Conversely, treatment with the same cholesterol esters pool did not lead to subsequent accumulation of phosphorylated tau in control iPSC-derived neurons. Finally, treatment with a heterobifunctional, small-molecule degrader designed to selectively engage and catalyze the ubiquitination and proteasomal degradation of aberrant tau species prevented cholesterol ester-induced aggregation of tau in the biosensor cell line in a Cereblon E3 ligase-dependent manner. Degrader treatment also restored the resiliency of tauopathy patient-derived neurons towards cholesterol ester-induced tau aggregation phenotypes. Taken together, our study supports a key role of cholesterol dysregulation in tau aggregation. Moreover, it provides further pre-clinical validation of the therapeutic strategy of targeted protein degradation with heterobifunctional tau degraders for blocking tau seeding.

neuroscience↗

bioRxiv2022

Indigenous peoples in eastern Brazil: insights from 19th century genomes and metagenomes

Although Brazil was inhabited by more than 3,000 Indigenous populations prior to European colonization, todays Indigenous peoples represent less than 1% of Brazils census population. Some of the decimated communities belonged to the so-called "Botocudos" from central-eastern Brazil. These peoples are thought to represent a case of long-standing genetic continuity bearing a strong craniometric resemblance to that of the oldest Indigenous Americans ("Paleoamericans"). Yet, little is known about their origins and genetic relationship to other Native Americans, as only two "Botocudo" genomes have been sequenced so far and those were surprisingly of Polynesian ancestry. To deepen our knowledge on the genomic history of pre-contact Indigenous Americans and the pathogens they were exposed to, we carbon-dated and sequenced 24 ancient Brazilians (including 22 "Botocudos") whose remains were hosted at the National Museum of Rio de Janeiro and recovered prior to the tragic 2018 fire. The resulting genomes depth of coverage ranged from 0.001x to 24x. Their genetic ancestry was found to be Indigenous American without gene flow from external populations such as Europeans, Africans or Polynesians. Unlike Mesoamericans, the "Botocudos" and Amazonians do not seem to have experienced a population expansion once in the Americas. Moreover, remarkably, their genomes exhibit amongst the lowest levels of heterozygosity worldwide and long runs of homozygosity, which could be explained by unique social practices or a very small effective size. Finally, whole genomes of likely ancient pathogens were recovered, including lineages of Human parvovirus B19 that were possibly introduced after the European contact. Significance statementTo better understand the genetic relationship among Indigenous populations in Brazil, we sequenced the genomes of 24 ancient individuals (22 of which labelled as "Botocudos", a term used to describe hunter-gatherer tribes) whose remains were hosted at the Museu Nacional of Rio de Janeiro prior to the tragic fire that consumed it in 2018. Unlike two previously published "Botocudo" genomes, the 22 "Botocudos" from this study have Indigenous American-related ancestry without any Polynesian-related ancestry, and they are similarly related to several Native Brazilian populations. Finally, unlike Eurasian hunter-gatherers, the "Botocudos" exhibit among the lowest heterozygosity and longest runs of homozygosity worldwide - compatible with a very small effective size and suggesting a unique social structure among hunter-gatherers in the Americas.

genomics↗

bioRxiv2021

Targeting activated macrophages intracellular milieu to augment anti-inflammatory drug potency

We present pH-responsive phosphorylcholine polymersomes ability to target activated macrophages via scavenger receptors, enter them via endocytosis, and escape from early endosomes enabling the intra-cellular drug delivery. Using an arthritis experimental model and the gold standard disease modifying anti-rheumatic drug, methotrexate, we prove that polymersomes augments therapeutic efficacy, while minimizing the off-target effect. First, we demonstrate the selective accumulation of polymersomes within the inflamed synovial tissues and cells, including macrophages. Second, we show the beneficial therapeutic effect of methotrexate loaded polymersomes in preventing both joint inflammation and further damage. Hence, we prove the therapeutic potential of polymersomes in enhancing the complete prevention of arthritis progression, which makes it a promising nanotherapy for arthritis treatment as well as other inflammatory disorders. TeaserWe show that the effective targeting and delivery of drugs to the main inflammation actors, the macrophages, enhances arthritis therapy.

immunology↗