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Frontiers in Immunology 2023miRNAs are involved in various vital processes, including cell growth, development, apoptosis, cellular differentiation, and pathological cellular activities.... (Review)
Review
miRNAs are involved in various vital processes, including cell growth, development, apoptosis, cellular differentiation, and pathological cellular activities. Circulating miRNAs can be detected in various body fluids including serum, plasma, saliva, and urine. It is worth mentioning that miRNAs remain stable in the circulation in biological fluids and are released from membrane-bound vesicles called exosomes, which protect them from RNase activity. It has been shown that miRNAs regulate blood-brain barrier integrity by targeting both tight junction and adherens junction molecules and can also influence the expression of inflammatory cytokines. Some recent studies have examined the impact of certain commonly used drugs in Multiple Sclerosis on miRNA levels. In this review, we will focus on the recent findings on the role of miRNAs in multiple sclerosis, including their role in the cause of MS and molecular mechanisms of the disease, utilizing miRNAs as diagnostic and clinical biomarkers, using miRNAs as a therapeutic modality or target for Multiple Sclerosis and drug responses in patients, elucidating their importance as prognosticators of disease progression, and highlighting their potential as a future treatment for MS.
Topics: Humans; MicroRNAs; Blood-Brain Barrier; Multiple Sclerosis; Circulating MicroRNA; Body Fluids
PubMed: 38193092
DOI: 10.3389/fimmu.2023.1281567 -
The Journal of Cell Biology Dec 2023Notch receptors control tissue morphogenic processes that involve coordinated changes in cell architecture and gene expression, but how a single receptor can produce...
Notch receptors control tissue morphogenic processes that involve coordinated changes in cell architecture and gene expression, but how a single receptor can produce these diverse biological outputs is unclear. Here, we employ a 3D model of a human ductal epithelium to reveal tissue morphogenic defects result from loss of Notch1, but not Notch1 transcriptional signaling. Instead, defects in duct morphogenesis are driven by dysregulated epithelial cell architecture and mitogenic signaling which result from the loss of a transcription-independent, Notch1 cortical signaling mechanism that ultimately functions to stabilize adherens junctions and cortical actin. We identify that Notch1 localization and cortical signaling are tied to apical-basal cell restructuring and discover that a Notch1-FAM83H interaction underlies control of epithelial adherens junctions and cortical actin. Together, these results offer new insights into Notch1 signaling and regulation and advance a paradigm in which transcriptional and cell adhesive programs might be coordinated by a single receptor.
Topics: Humans; Actins; Adherens Junctions; Cell Adhesion; Cell Proliferation; Epithelial Cells; Proteins; Receptor, Notch1; Signal Transduction
PubMed: 37796194
DOI: 10.1083/jcb.202303013 -
Frontiers in Cellular and Infection... 2023disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected...
disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected zoonotic disease. induces E-cadherin (E-cad) endocytosis and cytoskeletal rearrangement during AJ disassembly, but the detailed mechanism remains unknown. Elucidation of AJ disassembly mechanisms will guide new approaches to developing vaccines and diagnostic methods. In this study, we combine proteomic and imaging analysis with chemical inhibition studies to demonstrate that disrupting the AJs of renal proximal tubule epithelial cells involves the degradation of two armadillo repeat-containing proteins, p0071 and p120-catenin, that stabilize E-cad at the plasma membrane. Combining proteasomal and lysosomal inhibitors substantially prevented p120-catenin degradation, and monolayer integrity destruction without preventing p0071 proteolysis. In contrast, the pan-caspase inhibitor Z-VAD-FMK inhibited p0071 proteolysis and displacement of both armadillo repeat-containing proteins from the cell-cell junctions. Our results show that induces p120-catenin and p0071 degradation, which mutually regulates E-cad stability by co-opting multiple cellular degradation pathways. This strategy may allow to disassemble AJs and disseminate through the body efficiently.
Topics: Delta Catenin; Adherens Junctions; Leptospira interrogans; Proteomics; Catenins
PubMed: 37795382
DOI: 10.3389/fcimb.2023.1228051 -
BioEssays : News and Reviews in... Sep 2023RAS GTPases play essential roles in normal development and are direct drivers of human cancers. Three decades of study have failed to wholly characterize pathways... (Review)
Review
RAS GTPases play essential roles in normal development and are direct drivers of human cancers. Three decades of study have failed to wholly characterize pathways stimulated by activated RAS, driven by engagement with 'effector' proteins that have RAS binding domains (RBDs). Bone fide effectors must bind directly to RAS GTPases in a nucleotide-dependent manner, and this interaction must impart a clear change in effector activity. Despite this, for most proteins currently deemed effectors there is little mechanistic understanding of how binding to the GTPase alters protein function. There has also been limited effort to comprehensively resolve the specificity of effector binding to the full array of RAS superfamily GTPase proteins. This review will summarize what is known about RAS-driven activation for an array of potential effector proteins, focusing on structural and mechanistic effects and highlighting how little is still known regarding this key paradigm of cellular signal transduction.
Topics: Humans; Signal Transduction; ras Proteins; Protein Binding; Proteins; Nucleotides
PubMed: 37401638
DOI: 10.1002/bies.202300088 -
Nature Communications Jul 2023Delivering cancer therapeutics to tumors necessitates their escape from the surrounding blood vessels. Tumor vasculatures are not always sufficiently leaky. Herein, we...
Delivering cancer therapeutics to tumors necessitates their escape from the surrounding blood vessels. Tumor vasculatures are not always sufficiently leaky. Herein, we engineer therapeutically competent leakage of therapeutics from tumor vasculature with gold nanoparticles capable of inducing endothelial leakiness (NanoEL). These NanoEL gold nanoparticles activated the loss of endothelial adherens junctions without any perceivable toxicity to the endothelial cells. Microscopically, through real time live animal intravital imaging, we show that NanoEL particles induced leakiness in the tumor vessels walls and improved infiltration into the interstitial space within the tumor. In both primary tumor and secondary micrometastases animal models, we show that pretreatment of tumor vasculature with NanoEL particles before therapeutics administration could completely regress the cancer. Engineering tumoral vasculature leakiness represents a new paradigm in our approach towards increasing tumoral accessibility of anti-cancer therapeutics instead of further increasing their anti-cancer lethality.
Topics: Animals; Endothelial Cells; Gold; Metal Nanoparticles; Nanoparticles; Endothelium; Neoplasms; Neoplasms, Vascular Tissue
PubMed: 37460554
DOI: 10.1038/s41467-023-40015-4 -
IScience Nov 2023Fucoxanthin is the most abundant marine carotenoid extracted from seaweed. Our previous study has shown that fucoxanthin inhibited oxidative stress after traumatic brain...
Fucoxanthin is the most abundant marine carotenoid extracted from seaweed. Our previous study has shown that fucoxanthin inhibited oxidative stress after traumatic brain injury (TBI). However, the effects of fucoxanthin on TBI-induced blood-brain barrier (BBB) destruction have not been well understood. In the present study, we found that fucoxanthin improved neurological dysfunction, reduced brain edema, attenuated cortical lesion volume, and decreased dendrites loss after TBI . Moreover, fucoxanthin suppressed BBB leakage, preserved tight junction (TJ) and adherens junction (AJ) proteins, and inhibited MMP-9 expression. Furthermore, fucoxanthin alleviated apoptosis and ferroptosis, and activated mitophagy in endothelial cells (ECs) after TBI. However, the protection of fucoxanthin on BBB was attenuated when mitophagy was inhibited. Importantly, fucoxanthin also provided protective effects in bEnd.3 cells after TBI. Taken together, our results suggested that fucoxanthin played a key role in the protection of BBB after TBI through mitophagy.
PubMed: 37965135
DOI: 10.1016/j.isci.2023.108270 -
Angiogenesis Aug 2023Angiogenesis, barriergenesis, and immune cell migration are all key physiological events that are dependent on the functional characteristics of the vascular... (Review)
Review
Angiogenesis, barriergenesis, and immune cell migration are all key physiological events that are dependent on the functional characteristics of the vascular endothelium. The protein family of Nectins and Nectin-like molecules (Necls) is a group of cell adhesion molecules that are widely expressed by different endothelial cell types. The family includes four Nectins (Nectin-1 to -4) and five Necls (Necl-1 to -5) that either interact with each other by forming homo- and heterotypical interactions or bind to ligands expressed within the immune system. Nectin and Necl proteins are mainly described to play a role in cancer immunology and in the development of the nervous system. However, Nectins and Necls are underestimated players in the formation of blood vessels, their barrier properties, and in guiding transendothelial migration of leukocytes. This review summarizes their role in supporting the endothelial barrier through their function in angiogenesis, cell-cell junction formation, and immune cell migration. In addition, this review provides a detailed overview of the expression patterns of Nectins and Necls in the vascular endothelium.
Topics: Nectins; Cell Adhesion Molecules; Cell Movement; Transendothelial and Transepithelial Migration; Cell Adhesion
PubMed: 36867287
DOI: 10.1007/s10456-023-09871-y -
Investigative Ophthalmology & Visual... Oct 2023Human corneal endothelial cells (hCECs) have been considered unable to regenerate in vivo, resulting in corneal decompensation after significant loss of hCECs....
PURPOSE
Human corneal endothelial cells (hCECs) have been considered unable to regenerate in vivo, resulting in corneal decompensation after significant loss of hCECs. adipose-derived mesenchymal stem cell (ASC)-derived exosomes can regenerate tissues and organs. In this study, we investigated whether ASC-derived exosomes could protect and regenerate CECs.
METHODS
We performed cell viability and cell-cycle analyses to evaluate the effect of ASC-derived exosomes on the regeneration capacity of cultured hCECs. Transforming growth factor-β (TGF-β) and hydrogen peroxide (H2O2) were used to induce biological stress in CECs. The effect of ASC-derived exosomes on CECs was investigated in vivo. ASC-derived exosomes were introduced into rat CECs using electroporation, and rat corneas were injured using cryoinjury. Next-generation sequencing analysis was performed to compare the differentially expressed microRNAs (miRNAs) between ASC-derived and hCEC-derived exosomes.
RESULTS
ASC-derived exosomes induced CEC proliferation and suppressed TGF-β- or H2O2-induced oxidative stress and senescence. ASC-derived exosomes protect hCECs against TGF-β- or H2O2-induced endothelial-mesenchymal transition and mitophagy. In an in vivo study, ASC-derived exosomes promoted wound healing of rat CECs and protected the corneal endothelium against cryoinjury-induced corneal endothelium damage. Next-generation sequencing analysis revealed differentially expressed miRNAs for ASC-derived and hCEC-derived exosomes. They are involved in lysine degradation, adherens junction, the TGF-β signaling pathway, the p53 signaling pathway, the Hippo signaling pathway, the forkhead box O (FoxO) signaling pathway, regulation of actin cytoskeleton, and RNA degradation based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.
CONCLUSIONS
ASC-derived exosomes promoted wound healing and regeneration of endothelial cells by inducing a shift in the cell cycle and suppressing senescence and autophagy.
Topics: Humans; Rats; Animals; Endothelium, Corneal; Endothelial Cells; Exosomes; Hydrogen Peroxide; Regeneration; MicroRNAs; Mesenchymal Stem Cells; Transforming Growth Factor beta
PubMed: 37850944
DOI: 10.1167/iovs.64.13.29 -
Nature Communications Oct 2023Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we...
Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we identify the requirement of the ubiquitin E3-ligase CHFR as a key mechanism of ubiquitylation-dependent degradation of VE-cadherin. CHFR was essential for disrupting the endothelium through control of the VE-cadherin protein expression at AJs. We observe augmented expression of VE-cadherin in endothelial cell (EC)-restricted Chfr knockout (Chfr) mice. We also observe abrogation of LPS-induced degradation of VE-cadherin in Chfr mice, suggesting the pathophysiological relevance of CHFR in regulating the endothelial junctional barrier in inflammation. Lung endothelial barrier breakdown, inflammatory neutrophil extravasation, and mortality induced by LPS were all suppressed in Chfr mice. We find that the transcription factor FoxO1 is a key upstream regulator of CHFR expression. These findings demonstrate the requisite role of the endothelial cell-expressed E3-ligase CHFR in regulating the expression of VE-cadherin, and thereby endothelial junctional barrier integrity.
Topics: Animals; Mice; Adherens Junctions; Ubiquitin; Ligases; Lipopolysaccharides; Cadherins; Endothelium; Ubiquitination; Endothelium, Vascular; Cells, Cultured
PubMed: 37852964
DOI: 10.1038/s41467-023-42225-2 -
Frontiers in Immunology 2023The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin...
INTRODUCTION
The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).
METHODS
Adult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.
RESULTS
Ionizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.
CONCLUSION
These data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.
Topics: Humans; Adult; Animals; Mice; Paneth Cells; alpha-Defensins; Dysbiosis; Endotoxemia; RNA, Ribosomal, 16S; Radiation Injuries; Cytokines; Inflammation
PubMed: 37638013
DOI: 10.3389/fimmu.2023.1174140