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Despite the success of antiretroviral therapy in suppressing plasma viremia in people living with human immunodeficiency virus type-1 (HIV-1), persistent viral RNA expression in tissue reservoirs is observed and can contribute to HIV-1-induced immunopathology and comorbidities. Infection of long-lived innate immune cells, such as tissue-resident macrophages and microglia may contribute to persistent viral RNA production and chronic inflammation. We recently reported that de novo cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) in macrophages and microglia leads to MDA5 and MAVS-dependent innate immune sensing and induction of type I IFN responses, demonstrating that HIV icRNA is a pathogen-associated molecular pattern (PAMP). In this report, we show that cytoplasmic expression of HIV-1 icRNA also induces NLRP1 inflammasome activation and IL-1β secretion in macrophages and microglia in an RLR- and endosomal TLR-independent manner. Infection of both macrophages and microglia with either replication-competent or single-cycle HIV-1 induced IL-1β secretion, which was attenuated when cytoplasmic expression of viral icRNA was prevented. While IL-1β secretion was blocked by treatment with caspase-1 inhibitors or knockdown of NLRP1 or caspase-1 expression in HIV-infected macrophages, overexpression of NLRP1 significantly enhanced IL-1β secretion in an HIV-icRNA-dependent manner. Immunoprecipitation analysis revealed interaction of HIV-1 icRNA, but not multiply-spliced HIV-1 RNA, with NLRP1, suggesting that HIV-1 icRNA sensing by NLRP1 is sufficient to trigger inflammasome activation. Together, these findings reveal a pathway of NLRP1 inflammasome activation induced by de novo expressed HIV icRNA in HIV-infected myeloid cells.

Particulate matters such as diesel exhaust particles induce oxidative stress in cells and thereby have a negative impact on health. The aim of this study was to test whether the membrane-permeable, anti-inflammatory metabolite 4-Octyl Itaconate can counteract the oxidative stress induced by diesel exhaust particles and to analyze the downstream-regulated pathways both in human nasal epithelial cells and PBMCs. Human nasal epithelial cells were cultured from nasal swabs, and the response of the cells to diesel exhaust particles either alone or in combination with 4-Octyl Itaconatee was investigated using RNA sequencing, qPCR, and cytokine measurement. The presence of reactive oxygen species in the cells was analyzed using CellROX staining and flow cytometric DCFDA assay. Diesel exhaust particles caused an upregulation of CYP1A1 in nasal epithelial cells. The administration of 4-Octyl Itaconate reduced the reactive oxygen species and increased the expression of antioxidant genes regulated by the transcription factor NRF2, which was also confirmed in PBMCs. IL-6 secretion from NEC was elevated by diesel exhaust particles and reduced when 4-Octyl Itaconate was administered. 4-Octyl Itaconate can reduce the diesel-exhaust-particle-induced oxidative damage by the activation of NRF2-regulated antioxidative pathways.

Advancing research in oncology highlights the inverse correlation between antibiotic treatment and the positive outcomes of immune checkpoint inhibitor (ICI) administration, confirming once more the importance of microbiota and microbiota-derived compounds as complementary tools for treating cancer. Among the immune checkpoints, the CD200 cell surface glycoprotein has gained attention for its role in promoting self-tolerance and potentially facilitating tumor growth through interaction with the CD200R1 receptor. We developed a robust AlphaLISA-based screening to identify human gut microbiota-derived proteins that may interact with CD200R1 and screened a library of 10,966 gut bacterial proteins. The antitumor activity of BOC1 was investigated in vitro by cytokine analysis, mixed lymphocyte reactions, and myeloid-derived suppressor cell (MDSC)–T-cell suppression assay. AlphaFold modeling was used to predict potential interaction points between BOC1 and CD200R1. We successfully identified BOC1, a protein from the Bacteroides genus, showing better affinity than the natural ligand, CD200, toward the CD200R1 receptor. BOC1 induces cytokine secretion by monocyte-derived dendritic cells (MoDCs) and enhances CD8 + /CD4 + T-cell populations and IFNγ production, highlighting its potent immunostimulatory properties. BOC1 also negatively impacts the differentiation of MDSCs, maintaining an immature monocytic profile (high CD14 and HLA-DR expression) and restoring T-cell proliferation even at low (10 nM) concentration. Mutation of amino acids within the N-terminal region of BOC1 reduces binding to CD200R1, supporting the importance of this region for a possible interaction with CD200R1. The immunostimulatory properties of BOC1 observed in vitro are compatible with an ICI-like behavior of this bacterial protein. Given that neither the CD200 protein nor the anti-CD200 antibody is able to compete with BOC1 for binding to CD200R1, and as supported by AlphaFold modeling predictions, CD200 and BOC1 might target different regions of CD200R1.

Chronic myeloid leukemia (CML) is a clonal malignancy propelled by the BCR::ABL1 fusion gene originating from the Philadelphia chromosome. This gene activates ABL tyrosine kinase, which enhances the survival of leukemic cells. Although tyrosine kinase inhibitors (TKIs) have significantly advanced the treatment of CML, resistance to these inhibitors presents a substantial hurdle. Consequently, novel therapeutic strategies targeting resistance mechanisms independent of BCR::ABL1 are urgently needed. This study investigated the potential impact of combining WEE1 inhibitors, particularly MK‐1775, with vitamin K2 (VK2) in treating CML. To analyze differentially expressed and spliced transcripts in CML, we examined mRNA profiles from peripheral blood mononuclear cells of five patients with CML (during chronic and blast phases) and five healthy controls. The samples were analyzed using deep sequencing. Differential expression analyses were performed using RaNA‐Seq and Heatmapper, the latter of which was designed for complex data set visualizations. WEE1 controls the G2/M checkpoint to prevent early mitosis, and blocking it increases the cytotoxicity of agents that damage deoxyribonucleic acid, especially in cancers lacking p53. VK2, a micronutrient, exerts anticancer effects against various malignancies. Gene expression studies have indicated that PKMYT1 expression is elevated in CML but not WEE1 cells. MK‐1775 successfully halted the growth of both standard and TKI‐resistant CML cell lines by triggering apoptosis via caspase 3/7 activation. VK2 reduced the viability of CML cells and increased cytotoxicity. A combined regimen of MK‐1775 and VK2 markedly decreased colony growth, disrupted mitochondrial membrane potential, and increased death in CML cells, including those resistant to TKIs. The results suggest that a combination of MK‐1775 and VK2 represents a potentially effective treatment strategy for CML, especially in drug‐resistant cases.

Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination, and therefore is of interest as a therapeutic in demyelinating diseases such as multiple sclerosis (MS). Here, we test whether metformin has a similar effect in human stem cell derived-OPCs. We assess how well human monoculture, organoid and chimera model culture systems simulate in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increases myelin proteins and/or sheaths in all models even when human cells remain fetal-like. In the chimera model, metformin leads to increased mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase of mitochondrial function/metabolism transcripts. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also express similar transcripts. Metformin’s brain effect is thus not cell-specific, alters metabolism in part through mitochondrial changes and leads to more myelin production. This bodes well for clinical trials testing metformin for neuroprotection. Subject terms: Oligodendrocyte, Multiple sclerosis, Multiple sclerosis, Regeneration and repair in the nervous system

Renal failure due to drug nephrotoxicity or disease is frequently observed in patients. The development of in vitro models able to recapitulate kidney biology offers new possibilities to study drug toxicity or model diseases. Induced pluripotent stem cell–derived kidney organoids already show promise, but several drawbacks must be overcome to maintain them in culture, among which is the presence of non-renal cell populations such as cartilage. We modified the culture protocol and maintained kidney organoids in medium containing FGF9 for 1 additional week compared to the control protocol (Takasato). In comparison to the control, the FGF9-treated kidney organoids had reduced cartilage at day 7 + 25 and diminished chondrocyte marker expression. Importantly, the renal structures assessed by immunofluorescence were unaffected by the FGF9 treatment. This reduction of cartilage produces a higher quality kidney organoid that can be maintained longer in culture to improve their maturation for further in vivo work. Subject terms: Pluripotent stem cells, Stem-cell differentiation, Kidney