Search

Abstract Endothelial-mesenchymal transformation (EndoMT) is the process through which endothelial cells transform into mesenchymal cells, affecting their morphology, gene expression, and function. EndoMT is a potential risk factor for cardiovascular and cerebrovascular diseases, tumor metastasis, and fibrosis. Recent research has highlighted the role of exosomes, a mode of cellular communication, in the regulation of EndoMT. Exosomes from diseased tissues and microenvironments can promote EndoMT, increase endothelial permeability, and compromise the vascular barrier. Conversely, exosomes derived from stem cells or progenitor cells can inhibit the EndoMT process and preserve endothelial function. By modifying exosome membranes or contents, we can harness the advantages of exosomes as carriers, enhancing their targeting and ability to inhibit EndoMT. This review aims to systematically summarize the regulation of EndoMT by exosomes in different disease contexts and provide effective strategies for exosome-based EndoMT intervention.

Ferroptosis contributes to brain injury after germinal matrix hemorrhage (GMH). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, reduces oxidative stress in neurodegenerative diseases. In vitro, Deferiprone has been shown to upregulate FTMT. However, the effects of FTMT upregulation by Deferiprone on neuronal ferroptosis after GMH and its underlying mechanism has not been investigated. In our study, 389 Sprague-Dawley rat pups of postnatal day 7 were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. The brain expressions of FTMT, N-myc downstream-regulated gene-1 (NDGR1), Yes-associated protein (YAP), ferroptosis-related molecules including transferrin receptor (TFR) and acyl-CoA synthase long-chain family member 4 (ACSL4) were increased after GMH. FTMT agonist Deferiprone improved neurological deficits and hydrocephalus after GMH. Deferiprone or Adenovirus-FTMT enhanced YAP phosphorylation at the Ser127 site and attenuated ferroptosis, which was reversed by NDRG1 CRISPR Knockout. Iron overload induced neuronal ferroptosis and neurological deficits, which were improved by YAP CRISPR Knockout. Collectively, FTMT upregulation by Deferiprone reduced neuronal ferroptosis and neurological deficits via the NDRG1/YAP signaling pathway after GMH. Deferiprone may serve as a potential non-invasive treatment for GMH patients. [ABSTRACT FROM AUTHOR]

Gram-positive bacterial pneumonia is a significant cause of hospitalization and death. Shortage of a good experimental model and therapeutic targets hinders the cure of acute lung injury (ALI). This study has established a mouse model of ALI using Gram-positive bacteria Lactobacillus casie cell wall extracts (LCWE) and identified the key regulator NLRP3. We show that LCWE induces TNF, NF-κB signaling, and so on pathways. Similar to lipopolysaccharide (LPS), LCWE induces the infiltration of CD11b-positive cells and inflammation in lungs. LCWE also triggers inflammatory signaling through TLR2, different from LPS through TLR4. It suggests that cytokines amplify inflammation signaling relying on NLRP3 in LCWE-induced ALI. NLRP3 deletion disrupts inflammation, IL-1β cleavage, and the infiltration of neutrophils and macrophages in the injured lung. Our study highlights an animal ALI model for Gram-positive bacterial pneumonia and that NLRP3 is a key therapeutic target to prevent inflammation and lung damage in LCWE-induced ALI. NLRP3 drives inflammatory signaling and cleaved IL-1β in a mouse model of acute lung injury induced by Lactobacillus casei cell wall extracts, highlighting its role as a therapeutic target in Gram-positive bacterial pneumonia. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) poses a formidable challenge in stroke management, with limited therapeutic options, particularly in the realm of immune‐targeted interventions. Clinical trials targeting immune responses post‐ICH have encountered setbacks, potentially attributable to the substantial cellular heterogeneity and intricate intercellular networks within the brain. Here, we present a pioneering investigation utilizing single‐cell RNA sequencing and spatial transcriptome profiling at hyperacute (1 h), acute (24 h), and subacute (7 days) intervals post‐ICH, aimed at unraveling the dynamic immunological landscape and spatial distributions within the cerebral tissue. Our comprehensive analysis revealed distinct cell differentiation patterns among myeloid and lymphocyte populations, along with delineated spatial distributions across various brain regions. Notably, we identified a subset of lymphocytes characterized by the expression of Spp1 and Lyz2, termed macrophage‐associated lymphocytes, which exhibited close interactions with myeloid cells. Specifically, we observed prominent interactions between Lgmn+Macro‐T cells and microglia through the spp1–cd44 pathway during the acute phase post‐ICH in the choroid plexus. These findings represent a significant advancement in our understanding of immune cell dynamics at single‐cell resolution across distinct post‐ICH time points, thereby laying the groundwork for exploring critical temporal windows and informing the development of targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Backgroud: Glioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ. Methods: To explore the mechanisms underlying resistance, we developed two TMZ‐resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ‐resistant cell lines revealed that alterations in histone post‐translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi‐omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance. Results: We observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single‐cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy. Conclusions: The increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM. [ABSTRACT FROM AUTHOR]

Neutrophils and their production of neutrophil extracellular traps (NETs) significantly contribute to neuroinflammation and brain damage after intracerebral hemorrhage (ICH). Although Akebia saponin D (ASD) demonstrates strong anti‐inflammatory activities and blood–brain barrier permeability, its role in regulating NETs formation and neuroinflammation following ICH is uncharted. Our research focused on unraveling the influence of ASD on neuroinflammation mediated by NETs and the mechanisms involved. We found that increased levels of peripheral blood neutrophils post‐ICH are correlated with worse prognostic outcomes. Through network pharmacology, we identified ASD as a promising therapeutic target for ICH. ASD administration significantly improved neurobehavioral performance and decreased NETs production in neutrophils. Furthermore, ASD was shown to upregulate the membrane protein NTSR1 and activate the cAMP signaling pathway, confirmed through transcriptome sequencing, western blot, and immunofluorescence. Interestingly, the NTSR1 inhibitor SR48692 significantly nullified ASD's anti‐NETs effects and dampened cAMP pathway activation. Mechanistically, suppression of PKAc via H89 negated ASD's anti‐NETs effects but did not affect NTSR1. Our study suggests that ASD may reduce NETs formation and neuroinflammation, potentially involving the NTSR1/PKAc/PAD4 pathway post‐ICH, underlining the potential of ASD in mitigating neuroinflammation through its anti‐NETs properties. [ABSTRACT FROM AUTHOR]

Ferroptosis has been implicated in the pathogenesis of secondary brain injury following intracerebral hemorrhage (ICH), and regulating this process is considered a potential therapy for alleviating further brain injury. A previous study showed that CDGSH iron sulfur domain 2 (CISD2) can inhibit ferroptosis in cancer. Thus, we investigated the effects of CISD2 on ferroptosis and the mechanisms underlying its neuroprotective role in mice after ICH. CISD2 expression markedly increased after ICH. CISD2 over‐expression significantly decreased the number of Fluoro‐Jade C‐positive neurons and alleviated brain edema and neurobehavioral deficits at 24 h after ICH. In addition, CISD2 over‐expression up‐regulated the expression of p‐AKT, p‐mTOR, ferritin heavy chain 1, glutathione peroxidase 4, ferroportin, glutathione, and glutathione peroxidase activity, which are markers of ferroptosis. Additionally, CISD2 over‐expression down‐regulated the levels of malonaldehyde, iron content, acyl‐CoA synthetase long‐chain family member 4, transferrin receptor 1, and cyclooxygenase‐2 at 24 h after ICH. It also alleviated mitochondrial shrinkage and decreased the density of the mitochondrial membrane. Furthermore, CISD2 over‐expression increased the number of GPX4‐positive neurons following ICH induction. Conversely, knockdown of CISD2 aggravated neurobehavioral deficits, brain edema, and neuronal ferroptosis. Mechanistically, MK2206, an AKT inhibitor, suppressed p‐AKT and p‐mTOR and reversed the effects of CISD2 over‐expression on markers of neuronal ferroptosis and acute neurological outcome. Taken together, CISD2 over‐expression alleviated neuronal ferroptosis and improved neurological performance, which may be mediated through the AKT/mTOR pathway after ICH. Thus, CISD2 may be a potential target to mitigate brain injury via the anti‐ferroptosis effect after ICH. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Programmed cell death (PCD) is crucial for immunological balance, and includes necroptosis, pyroptosis, apoptosis, ferroptosis, and necrosis. However, the distinctions between these programmed cell death modalities after ICH remain to be further investigated. We used single-cell transcriptome (single-cell RNA sequencing) and spatial transcriptome (spatial RNA sequencing) techniques to investigate PCD-related gene expression trends in the rat brain following hemorrhagic stroke. Ferroptosis was the main PCD process after ICH, and primarily affected mature oligodendrocytes. Its onset occurred as early as 1 hour post-ICH, peaking at 24 hours post-ICH. Additionally, ferroptosis-related genes were distributed in the hippocampus and choroid plexus. We also elucidated a specific interaction between lipocalin-2 (LCN2)-positive microglia and oligodendrocytes that was mediated by the colony stimulating factor 1 (CSF1)/CSF1 receptor pathway, leading to ferroptosis induction in oligodendrocytes and subsequent neurological deficits. In conclusion, our study highlights ferroptosis as the primary PCD mechanism, emerging as early as 1 hour post-ICH. Early therapeutic intervention via the suppression of microglial LCN2 expression may alleviate ferroptosis-induced damage in oligodendrocytes and associated neurological deficits, thus offering a promising neuroprotective strategy following ICH., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)