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The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response. Here, Chen et. al . characterize the relationship between the gut microbiota and plasma metabolite changes in the context of ST-elevation myocardial infarction (STEMI), unveiling a role of butyrate-producing bacteria and their ketogenesis in post-STEMI cardiac repair, a finding validated in nonhuman primate and mouse models. They show that butyrate supplementation reduces myocardial infarction severity in mice, underscoring the significance of butyrate-producing bacteria and beta-hydroxybutyrate in improving post-MI outcomes.

The discovery of Toll-like receptors (TLRs) and their role in dendritic cells earned the Nobel Prize for 2011 because TLRs profoundly enhanced our understanding of the immune system. Specifically, TLR3 is located within the endosomal compartments of dendritic cells and plays a crucial role in the immune response by acting as a pattern recognition receptor that detects both exogenous (viral) and endogenous (mammalian) double-stranded RNA. However, TLR3 activation is a double-edged sword in various immune-mediated diseases. On one hand, it can enhance anti-viral defenses and promote pathogen clearance, contributing to host protection. On the other hand, excessive or dysregulated TLR3 signaling can lead to chronic inflammation and tissue damage, exacerbating conditions such as autoimmune diseases, chronic viral infections, and cancer. In cancer, TLR3 expression has been linked to both favorable and poor prognoses, though the underlying mechanisms remain unclear. Recent clinical and preclinical advances have explored the use of TLR3 agonists in cancer immunotherapy, attempting to capitalize on their potential to enhance anti-tumor responses. The dual role of TLR3 highlights its complexity as a therapeutic target, necessitating careful modulation to maximize its protective effects while minimizing potential pathological consequences. In this review, we explore the intricate roles of TLR3 in immune responses across different disease contexts, including cancer, infections, autoimmune disorders, and allergies, highlighting both its protective and detrimental effects in these disorders, as well as progress in developing TLR3 agonists as part of the immunotherapy landscape.

Gut microbiota affect transplantation outcomes; however, the influence of immunosuppression and cell therapy on the gut microbiota in cardiovascular care remains unexplored. We investigated gut microbiota dynamics in a nonhuman primate (NHP) cardiac ischemia/reperfusion model while under immunosuppression and receiving cell therapy with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (EC) and cardiomyocytes (CM). Both immunosuppression and EC/CM co-treatment increased gut microbiota alpha diversity. Immunosuppression promoted anaerobes, such as Faecalibacterium , Streptococcus , Anaerovibrio and Dialister , and altered amino acid metabolism and nucleosides/nucleotides biosynthesis in host plasma. EC + CM cotreatment favors Phascolarctobacterium , Fusicatenibacter , Erysipelotrichaceae UCG-006 , Veillonella and Mailhella . Remarkably, gut microbiota of the EC/CM co-treatment group resembled that of the pre-injury group, and the NHPs exhibited a metabolic shift towards amino acid and fatty acid/lipid biosynthesis in plasma following cell therapy. The interplay between shift in microbial community and host homeostasis during treatment suggests gut microbiome modulation could improve cell therapy outcomes.

Extracellular vesicle (EV) secretion is an important mechanism used by cells to release biomolecules. A common necroptosis effector—mixed lineage kinase domain like (MLKL)—was recently found to participate in the biogenesis of small and large EVs independent of its function in necroptosis. The objective of the current study is to gain mechanistic insights into EV biogenesis during necroptosis. Assessing EV number by nanoparticle tracking analysis revealed an increased number of EVs released during necroptosis. To evaluate the nature of such vesicles, we performed a newly adapted, highly sensitive mass spectrometry‐based proteomics on EVs released by healthy or necroptotic cells. Compared to EVs released by healthy cells, EVs released during necroptosis contained a markedly higher number of unique proteins. Receptor interacting protein kinase‐3 (RIPK3) and MLKL were among the proteins enriched in EVs released during necroptosis. Further, mouse embryonic fibroblasts (MEFs) derived from mice deficient of Rab27a and Rab27b showed diminished basal EV release but responded to necroptosis with enhanced EV biogenesis as the wildtype MEFs. In contrast, necroptosis‐associated EVs were sensitive to Ca2+ depletion or lysosomal disruption. Neither treatment affected the RIPK3‐mediated MLKL phosphorylation. An unbiased screen using RIPK3 immunoprecipitation‐mass spectrometry on necroptotic EVs led to the identification of Rab11b in RIPK3 immune‐complexes. Our data suggests that necroptosis switches EV biogenesis from a Rab27a/b dependent mechanism to a lysosomal mediated mechanism.

Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.