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Cell Feb 2024Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large...
Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.
Topics: Axons; Brain; Macrophages; Microglia; Morphogenesis
PubMed: 38309258
DOI: 10.1016/j.cell.2024.01.012 -
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 -
Frontiers in Chemistry 2023Despite the promising pharmacological activity and material properties of five-membered heterocyclic compounds containing phosphorus and nitrogen, synthetic examples of...
Despite the promising pharmacological activity and material properties of five-membered heterocyclic compounds containing phosphorus and nitrogen, synthetic examples of them have been rather limited due to the instability of phosphorus toward air and water. In this study, 1,3-benzoazaphosphol analogues were selected as target molecules, and various synthetic routes were examined to establish a fundamental technology for the introduction of phosphorus groups into aromatic rings and formation of five-membered rings containing phosphorus and nitrogen by cyclization. As a result, we found that 2-aminophenyl(phenyl)phosphine is an extremely promising synthetic intermediate with high stability and easy handling. Furthermore, 2-methyl-3-phenyl-2,3-dihydro-1-benzo[][1,3]azaphosphole and 3-phenyl-2,3-dihydro-1-benzo[][1,3]azaphosphole-2-thione as synthetically useful 1,3-benzoazaphosphol analogues were successfully synthesized by using 2-aminophenyl(phenyl)phosphine as a key intermediate.
PubMed: 37304686
DOI: 10.3389/fchem.2023.1174895 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2024Imidazolidine-4-thiones (ITOs) are cyclic, secondary amines that were considered as potential prebiotic organocatalysts for light-driven α-alkylations of aldehydes by...
Imidazolidine-4-thiones (ITOs) are cyclic, secondary amines that were considered as potential prebiotic organocatalysts for light-driven α-alkylations of aldehydes by bromoacetonitrile (BAN). Recent studies showed that the initially supplied ITOs represent the pre-catalyst because they undergo S-alkylation with BAN to give 4-(alkylthio)-3-imidazolines (TIMs). Given that the same reagent mix that undergoes light-driven α-alkylations is also effective in the dark, we synthesized ten ITO- or TIM-derived enamines of aldehydes and characterized their nucleophilic reactivities by kinetic studies in acetonitrile. The experimental second-order rate constants k for reactions of enamines with benzhydrylium ions (reference electrophiles) were evaluated by the Mayr-Patz equation, lg k (20 °C)=s (N+E). The determined nucleophilicities N (and s ) reveal the reactivity profiles of these enamines under prebiotically relevant conditions as well as their potential for use in organocatalytic synthesis.
PubMed: 37850416
DOI: 10.1002/chem.202302764 -
International Journal of Molecular... Aug 2023Psoriasis is a chronic autoimmune skin disease with a significant impact on quality of life and potential for severe comorbidities. Inflammation in the skin is induced...
Psoriasis is a chronic autoimmune skin disease with a significant impact on quality of life and potential for severe comorbidities. Inflammation in the skin is induced by immune cells that overexpress pro-inflammatory cytokines, with the Th17 cell playing a crucial role. NLRP3 inflammasome activation is associated with inflammatory diseases and abnormal T cell differentiation. 3H-1,2-dithiole-3-thione (D3T), isolated from cruciferous vegetables, has anti-inflammatory effects and inhibits Th17 differentiation. This study aimed to investigate how D3T reduces skin inflammation and modulates Th17 cell differentiation by inhibiting NLRP3 inflammasome activation. In an imiquimod-induced psoriasis mouse model, D3T treatment demonstrated significant reductions in ear thickness, skin redness, and scaling compared to a control group. Our study also observed decreased expression of ki-67, NLRP3 inflammasome, and cleaved caspase-1 in skin samples, reduced levels of IL-6 and IL-17A in serum samples, and inhibition of Th17 differentiation after D3T application. D3T could also inhibit the expression of NLRP3, caspase-1, and IL-1β in TNF-α stimulated HaCaT cells. The mechanical study also revealed that D3T could inhibit NLRP3 inflammasome activation by inhibiting the JNK pathway in HaCaT cells. These results indicate that targeting NLRP3 inflammasome activation is a promising strategy in the treatment of psoriasis.
Topics: Animals; Mice; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Quality of Life; Psoriasis; Caspase 1
PubMed: 37686332
DOI: 10.3390/ijms241713528 -
ACS Infectious Diseases Nov 2023The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and...
The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of () growth and survival. Structure-activity relationship studies led us to identify several potent analogs displaying low micromolar to nanomolar inhibitory activity, specifically against . The potent analogs demonstrated no cytotoxicity in mammalian cells at over 100 times the effective concentration required in and were bactericidal against during infection of macrophages. In the exploratory ADME investigations, we observed suboptimal ADME characteristics, which prompted us to identify potential metabolic liabilities for further optimization. Our preliminary investigations into the mechanism of action suggest that this series is not engaging the promiscuous targets that arise from many phenotypic screens. We selected for resistant mutants with the nanomolar potent nitro-containing compound and identified resistant isolates with mutations in genes required for coenzyme F biosynthesis and the nitroreductase Ddn. This suggests that the aromatic nitro-1,2,4-triazolyl pyridines are activated by F-dependent Ddn activity, similar to the nitro-containing TB drug pretomanid. We were able to circumvent the requirement for F-dependent Ddn activity using compounds that contained non-nitro groups, identifying a key feature to be modified to avoid this predominant resistance mechanism. These studies provide the foundation for the development of a new class of 1,2,4-triazole compounds for the treatment of tuberculosis.
Topics: Animals; Antitubercular Agents; Mammals; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 37788674
DOI: 10.1021/acsinfecdis.3c00341