-
Gut Microbes Dec 2023Intestinal microbes impact the health of the intestine and organs distal to the gut. is a human intestinal microbe that promotes normal gut transit, the...
Intestinal microbes impact the health of the intestine and organs distal to the gut. is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for -mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We find that facilitates oxytocin secretion from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion by is dependent on the gut hormone secretin, which is produced in enteroendocrine cells, while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated by . This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.
Topics: Humans; Animals; Mice; Secretin; Oxytocin; Gastrointestinal Microbiome; Gastrointestinal Hormones; Intestinal Mucosa; Limosilactobacillus reuteri
PubMed: 37698879
DOI: 10.1080/19490976.2023.2256043 -
Proceedings of the National Academy of... Jul 2023The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the...
The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the inner leaflet is composed of glycerophospholipids. This lipid asymmetry creates mechanical strength, lowers membrane permeability, and is necessary for virulence in many pathogens. Glycerophospholipids that mislocalize to the outer leaflet are removed by the Mla pathway, which consists of the outer membrane channel MlaA, the periplasmic lipid carrier MlaC, and the inner membrane transporter MlaBDEF. The opportunistic pathogen has two proteins of the MlaA family: PA2800 and PA3239. Here, we show that PA2800 is part of a canonical Mla pathway, while PA3239 functions with the putative lipase PA3238. While loss of either pathway individually has little to no effect on outer membrane integrity, loss of both pathways weakens the outer membrane permeability barrier and increases production of the secondary metabolite pyocyanin. We propose that mislocalized glycerophospholipids are removed from the outer leaflet by PA3239 (renamed MlaZ), transferred to PA3238 (renamed MlaY), and degraded. This pathway streamlines recycling of glycerophospholipid degradation products by removing glycerophospholipids from the outer leaflet prior to degradation.
Topics: Membrane Lipids; Pseudomonas aeruginosa; Biological Transport; Phospholipases; Bacterial Outer Membrane Proteins; Cell Membrane; Glycerophospholipids
PubMed: 37463202
DOI: 10.1073/pnas.2302546120 -
Biochimica Et Biophysica Acta.... Aug 2023Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Mitochondrial Membranes; Mitochondria; Endoplasmic Reticulum
PubMed: 37044239
DOI: 10.1016/j.bbadis.2023.166716 -
Heliyon Dec 2023CD47 is a 50 kDa five-spanning membrane receptor that plays a crucial role in multiple cellular processes, including myeloid cell activation, neutrophils... (Review)
Review
CD47 is a 50 kDa five-spanning membrane receptor that plays a crucial role in multiple cellular processes, including myeloid cell activation, neutrophils transmigration, vascular remodeling, leukocyte adhesion and -endothelial migration. Recent studies have revealed that CD47 is a highly expressed anti-phagocytic signal in several types of cancer, and therefore, blocking of CD47 has shown an effective therapeutic potential in cancer immunotherapy. In addition, CD47 has been found to be involved in a complex interplay with microglia and other types of cells, and increasing evidence indicates that CD47 can be targeted as part of immune modulatory strategies for non-neoplastic diseases as well. In this review, we focus on CD47 and its role in non-neoplastic diseases, including neurological disorders, atherosclerosis and autoimmune diseases. In addition, we discuss the major challenges and potential remedies associated with CD47-SIRPα-based immunotherapies.
PubMed: 38125492
DOI: 10.1016/j.heliyon.2023.e22905 -
Applied Microbiology and Biotechnology Mar 2024Extremotolerant and extremophilic fungi are an important part of microbial communities that thrive in extreme environments. Among them, the black yeasts are particularly... (Review)
Review
Extremotolerant and extremophilic fungi are an important part of microbial communities that thrive in extreme environments. Among them, the black yeasts are particularly adaptable. They use their melanized cell walls and versatile morphology, as well as a complex set of molecular adaptations, to survive in conditions that are lethal to most other species. In contrast to extremophilic bacteria and archaea, these fungi are typically extremotolerant rather than extremophilic and exhibit an unusually wide ecological amplitude. Some extremely halotolerant black yeasts can grow in near-saturated NaCl solutions, but can also grow on normal mycological media. They adapt to the low water activity caused by high salt concentrations by sensing their environment, balancing osmotic pressure by accumulating compatible solutes, removing toxic salt ions from the cell using membrane transporters, altering membrane composition and remodelling the highly melanized cell wall. As protection against extreme conditions, halotolerant black yeasts also develop different morphologies, from yeast-like to meristematic. Genomic studies of black yeasts have revealed a variety of reproductive strategies, from clonality to intense recombination and the formation of stable hybrids. Although a comprehensive understanding of the ecological role and molecular adaptations of halotolerant black yeasts remains elusive and the application of many experimental methods is challenging due to their slow growth and recalcitrant cell walls, much progress has been made in deciphering their halotolerance. Advances in molecular tools and genomics are once again accelerating the research of black yeasts, promising further insights into their survival strategies and the molecular basis of their adaptations. KEY POINTS: • Black yeasts show remarkable adaptability to environmental stress • Black yeasts are part of microbial communities in hypersaline environments • Halotolerant black yeasts utilise various molecular and morphological adaptations.
Topics: Ascomycota; Saccharomyces cerevisiae; Archaea; Cell Wall; Extreme Environments; Extremophiles
PubMed: 38441672
DOI: 10.1007/s00253-024-13052-2 -
Biochimica Et Biophysica Acta.... Aug 2023Membrane trafficking is essential to maintain the spatiotemporal control of protein and lipid distribution within membrane systems of eukaryotic cells. To achieve their... (Review)
Review
Membrane trafficking is essential to maintain the spatiotemporal control of protein and lipid distribution within membrane systems of eukaryotic cells. To achieve their functional destination proteins are sorted and transported into lipid carriers that construct the secretory and endocytic pathways. It is an emerging theme that lipid diversity might exist in part to ensure the homeostasis of these pathways. Sphingolipids, a chemical diverse type of lipids with special physicochemical characteristics have been implicated in the selective transport of proteins. In this review, we will discuss current knowledge about how sphingolipids modulate protein trafficking through the endomembrane systems to guarantee that proteins reach their functional destination and the proposed underlying mechanisms.
Topics: Sphingolipids; Biological Transport; Protein Transport; Membranes
PubMed: 37201864
DOI: 10.1016/j.bbalip.2023.159334 -
Frontiers in Pharmacology 2023Part of the broader glycosphingolipid family, gangliosides are composed of a ceramide bound to a sialic acid-containing glycan chain, and locate at the plasma membrane.... (Review)
Review
Part of the broader glycosphingolipid family, gangliosides are composed of a ceramide bound to a sialic acid-containing glycan chain, and locate at the plasma membrane. Gangliosides are produced through sequential steps of glycosylation and sialylation. This diversity of composition is reflected in differences in expression patterns and functions of the various gangliosides. Ganglioside GD2 designates different subspecies following a basic structure containing three carbohydrate residues and two sialic acids. GD2 expression, usually restrained to limited tissues, is frequently altered in various neuroectoderm-derived cancers. While GD2 is of evident interest, its glycolipid nature has rendered research challenging. Physiological GD2 expression has been linked to developmental processes. Passing this stage, varying levels of GD2, physiologically expressed mainly in the central nervous system, affect composition and formation of membrane microdomains involved in surface receptor signaling. Overexpressed in cancer, GD2 has been shown to enhance cell survival and invasion. Furthermore, binding of antibodies leads to immune-independent cell death mechanisms. In addition, GD2 contributes to T-cell dysfunction, and functions as an immune checkpoint. Given the cancer-associated functions, GD2 has been a source of interest for immunotherapy. As a potential biomarker, methods are being developed to quantify GD2 from patients' samples. In addition, various therapeutic strategies are tested. Based on initial success with antibodies, derivates such as bispecific antibodies and immunocytokines have been developed, engaging patient immune system. Cytotoxic effectors or payloads may be redirected based on anti-GD2 antibodies. Finally, vaccines can be used to mount an immune response in patients. We review here the pertinent biological information on GD2 which may be of use for optimizing current immunotherapeutic strategies.
PubMed: 37670947
DOI: 10.3389/fphar.2023.1249929 -
Journal of Nephrology Nov 2023Hydroxychloroquine is one of the oldest disease-modifying anti-rheumatic drugs in clinical use. The drug interferes with lysosomal activity and antigen presentation,... (Review)
Review
Hydroxychloroquine is one of the oldest disease-modifying anti-rheumatic drugs in clinical use. The drug interferes with lysosomal activity and antigen presentation, inhibits autophagy, and decreases transcription of pro-inflammatory cytokines. Owing to its immunomodulatory, anti-inflammatory, anti-thrombotic effect, hydroxychloroquine has been an integral part of therapy for systemic lupus erythematosus and lupus nephritis for several decades. The therapeutic versatility of hydroxychloroquine has led to repurposing it for other clinical conditions, with recent studies showing reduction in proteinuria in IgA nephropathy. Research is also underway to investigate the efficacy of hydroxychloroquine in primary membranous nephropathy, Alport's syndrome, systemic vasculitis, anti-GBM disease, acute kidney injury and for cardiovascular risk reduction in chronic kidney disease. Hydroxychloroquine is well-tolerated, inexpensive, and widely available and therefore, should its indications expand in the future, it would certainly be welcomed. However, clinicians should be aware of the risk of irreversible and progressive retinal toxicity and rarely, cardiomyopathy. Monitoring hydroxychloroquine levels in blood appears to be a promising tool to evaluate compliance, individualize the dose and reduce the risk of retinal toxicity, although this is not yet standard clinical practice. In this review, we discuss the existing knowledge regarding the mechanism of action of hydroxychloroquine, its utility in lupus nephritis and other kidney diseases, the main adverse effects and the evidence gaps that need to be addressed in future research. Created with Biorender.com. HCQ, hydroxychloroquine; GBM, glomerular basement membrane; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; TLR, toll-like receptor.
Topics: Humans; Hydroxychloroquine; Lupus Nephritis; Nephrology; Antirheumatic Agents; Lupus Erythematosus, Systemic
PubMed: 37530940
DOI: 10.1007/s40620-023-01733-6