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Redox Biology Jun 2021There has been a recent surge of interest in the unique low molecular weight dietary thiol/thione, ergothioneine. This compound can accumulate at high levels in the body...
There has been a recent surge of interest in the unique low molecular weight dietary thiol/thione, ergothioneine. This compound can accumulate at high levels in the body from diet and may play important physiological roles in human health and development, and possibly in prevention and treatment of disease. Blood levels of ergothioneine decline with age and onset of various diseases. Here we highlight recent advances in our knowledge of ergothioneine.
Topics: Antioxidants; Diet; Ergothioneine; Humans
PubMed: 33558182
DOI: 10.1016/j.redox.2021.101868 -
Science (New York, N.Y.) Oct 2018Cross-talk between the nervous and immune systems has been well described in the context of adult physiology and disease. Recent advances in our understanding of immune... (Review)
Review
Cross-talk between the nervous and immune systems has been well described in the context of adult physiology and disease. Recent advances in our understanding of immune cell ontogeny have revealed a notable interplay between neurons and microglia during the prenatal and postnatal emergence of functional circuits. This Review focuses on the brain, where the early symbiotic relationship between microglia and neuronal cells critically regulates wiring, contributes to sex-specific differences in neural circuits, and relays crucial information from the periphery, including signals derived from the microbiota. These observations underscore the importance of studying neurodevelopment as part of a broader framework that considers nervous system interactions with microglia in a whole-body context.
Topics: Animals; Apoptosis; Brain; Cell Communication; Mice; Microbiota; Microglia; Neurons
PubMed: 30309946
DOI: 10.1126/science.aat0474 -
Cell Death & Disease Feb 2019The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and... (Review)
Review
The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome has been implicated in a wide range of diseases, including Alzheimer's disease, Prion diseases, type 2 diabetes, and some infectious diseases. It has been found that a variety of stimuli including danger-associated molecular patterns (DAMPs, such as silica and uric acid crystals) and pathogen-associated molecular patterns (PAMPs) can activate NLRP3 inflammasome, but the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Understanding the mechanisms of NLRP3 activation will enable the development of its specific inhibitors to treat NLRP3-related diseases. In this review, we summarize current understanding of the regulatory mechanisms of NLRP3 inflammasome activation as well as inhibitors that specifically and directly target NLRP3.
Topics: Animals; Calcium Signaling; Diterpenes, Kaurane; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Indenes; Inflammasomes; Lysosomes; Metals, Alkali; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Nitriles; Protein Processing, Post-Translational; Reactive Oxygen Species; Sulfonamides; Sulfones; Thiazolidines; Thiones; ortho-Aminobenzoates
PubMed: 30755589
DOI: 10.1038/s41419-019-1413-8 -
Cell Jan 2018Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial...
Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.
Topics: Animals; Brain; Cell Differentiation; Cells, Cultured; Chromatin Assembly and Disassembly; Female; Germ-Free Life; Humans; Male; Mice; Mice, Inbred C57BL; Microbiota; Microglia; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors; Transcriptome
PubMed: 29275859
DOI: 10.1016/j.cell.2017.11.042 -
IUCrData Oct 2021The title compound, CHNS, was obtained by the reduction of 2-mercapto-pyrazine (during its crystallization with 2-mercapto-pyrazine and isonicotinic acid -oxide in...
The title compound, CHNS, was obtained by the reduction of 2-mercapto-pyrazine (during its crystallization with 2-mercapto-pyrazine and isonicotinic acid -oxide in ethanol solution. It crystallizes in the monoclinic space group P. In the crystal, the mol-ecules are linked by N-H⋯N and C-H⋯S hydrogen bonds.
PubMed: 36340983
DOI: 10.1107/S2414314621011020 -
Journal of Extracellular Vesicles Mar 2021Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC)...
Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC) and associated with their poor prognosis. However, its underlying mechanisms remain elusive. Here, we developed an ESCC-induced cachexia mouse model using human xenograft ESCC cell lines and found that ESCC-derived extracellular vesicles (EVs) containing prolyl 4-hydroxylase subunit beta (P4HB) induced apoptosis of skeletal muscle cells. We further identified that P4HB promoted apoptotic response through activating ubiquitin-dependent proteolytic pathway and regulated the stability of phosphoglycerate dehydrogenase (PHGDH) and subsequent antiapoptotic protein Bcl-2. Additionally, we proved that the P4HB inhibitor, CCF642, not only rescued apoptosis of muscle cells in vitro, but also prevented body weight loss and muscle wasting in ESCC-induced cachexia mouse model. Overall, these findings demonstrate a novel pathway for ESCC-induced muscle wasting and advocate for the development of P4HB as a potential intervention target for cachexia in patients with ESCC.
Topics: Animals; Apoptosis; Cell Line, Tumor; Disease Models, Animal; Drug Delivery Systems; Esophageal Squamous Cell Carcinoma; Extracellular Vesicles; Humans; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscular Atrophy; Phosphoglycerate Dehydrogenase; Procollagen-Proline Dioxygenase; Protein Disulfide-Isomerases; Thiazolidines; Thiones
PubMed: 33732415
DOI: 10.1002/jev2.12060 -
IUCrData Jun 2023The study of the oxidation of various proteins necessitates scrutiny of the amino acid sequence. Since me-thio-nine (Met) and tyrosine (Tyr) are easily oxidized,...
The study of the oxidation of various proteins necessitates scrutiny of the amino acid sequence. Since me-thio-nine (Met) and tyrosine (Tyr) are easily oxidized, peptides that contain these amino acids are frequently studied using a variety of oxidation methods, including, but not limited to, pulse radiolysis, electrochemical oxidation, and laser flash photolysis. To date, the oxidation of the Met-Tyr dipeptide is not fully understood. Several investigators have proposed a mechanism of intra-molecular electron transfer between the sulfide radical of Met and the Tyr residue. Our elucidation of the structure and absolute configuration of l-Met-l-Tyr monohydrate, CHNOS·HO (systematic name: (2)-2-{[(2)-2-amino-4-methyl-sulfanyl-butano-yl]amino}-3-(4-hy-droxy-phen-yl)propanoic acid monohydrate) is presented herein and provides information about the zwitterionic nature of the dipeptide. We suspect that the zwitterionic state of the dipeptide and its inter-action within the solvent medium may play a major role in the oxidation of the dipeptide. In the crystal, all the potential donor atoms inter-act strong N-H⋯O, C-H⋯O, O-H⋯S, and O-H⋯O hydrogen bonds.
PubMed: 37936870
DOI: 10.1107/S2414314623005515 -
The Journal of Experimental Medicine Nov 2017The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome...
The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.
Topics: Adult; Animals; Cell Line, Tumor; Cryopyrin-Associated Periodic Syndromes; Diabetes Mellitus, Type 2; Disease Models, Animal; HEK293 Cells; Humans; Immunoblotting; Inflammasomes; Inflammation; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein; Small Molecule Libraries; Thiazolidines; Thiones
PubMed: 29021150
DOI: 10.1084/jem.20171419