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Cell Metabolism Sep 2019Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using...
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interferon-gamma; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Microglia; Oxidative Phosphorylation; Phagocytosis; Recombinant Proteins; TOR Serine-Threonine Kinases
PubMed: 31257151
DOI: 10.1016/j.cmet.2019.06.005 -
Cell Mar 2023Suppressing sensory arousal is critical for sleep, with deeper sleep requiring stronger sensory suppression. The mechanisms that enable sleeping animals to largely...
Suppressing sensory arousal is critical for sleep, with deeper sleep requiring stronger sensory suppression. The mechanisms that enable sleeping animals to largely ignore their surroundings are not well understood. We show that the responsiveness of sleeping flies and mice to mechanical vibrations is better suppressed when the diet is protein rich. In flies, we describe a signaling pathway through which information about ingested proteins is conveyed from the gut to the brain to help suppress arousability. Higher protein concentration in the gut leads to increased activity of enteroendocrine cells that release the peptide CCHa1. CCHa1 signals to a small group of dopamine neurons in the brain to modulate their activity; the dopaminergic activity regulates the behavioral responsiveness of animals to vibrations. The CCHa1 pathway and dietary proteins do not influence responsiveness to all sensory inputs, showing that during sleep, different information streams can be gated through independent mechanisms.
Topics: Animals; Mice; Arousal; Biological Transport; Brain; Peptides; Sleep; Intestines
PubMed: 36958331
DOI: 10.1016/j.cell.2023.02.022 -
Journal of Controlled Release :... Oct 2020Exosomes are natural nanovesicles excreted by many cells for intercellular communication and for transfer of materials including proteins, nucleic acids and even... (Review)
Review
Exosomes are natural nanovesicles excreted by many cells for intercellular communication and for transfer of materials including proteins, nucleic acids and even synthetic therapeutic agents. Surface modification of exosomes imparts additional functionality to the exosomes to enable site specific drug delivery and in vivo imaging and tracking and is an emerging area in drug delivery research. The present review focuses upon these modifications on the exosomal surface, the chemistry involved and their impact on targeted drug delivery for the treatment of brain, breast, lung, liver, colon tumors and, heart diseases and for understanding their in vivo fate including their uptake mechanisms, pharmacokinetics and biodistribution. The specific exosomal membrane proteins such as tetraspanins (CD63, CD81, CD9), lactadherin (LA), lysosome associated membrane protein-2b (Lamp-2b) and, glycosyl-phosphatidyl-inositol (GPI) involved in functionalization of exosome surface have also been discussed along with different strategies of surface modification like genetic engineering, covalent modification (click chemistry and metabolic engineering of parent cells of exosomes) and non-covalent modification (multivalent electrostatic interactions, ligand-receptor interaction, hydrophobic interaction, aptamer based modification and modification by anchoring CP05 peptide) along with optical (fluorescent and bioluminescent) and radioactive isotope labelling techniques of exosomes for imaging purpose.
Topics: Drug Delivery Systems; Exosomes; Peptides; Proteins; Tissue Distribution
PubMed: 32730952
DOI: 10.1016/j.jconrel.2020.07.042 -
Theranostics 2020Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting... (Review)
Review
Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.
Topics: Animals; Humans; Drug Delivery Systems; Peptides; Proteins; Proteolysis; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 32929339
DOI: 10.7150/thno.46985 -
Nutrients Jun 2020Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white... (Review)
Review
The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review.
Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body's response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.
Topics: Adipokines; Adipose Tissue; Animals; Appetite Regulation; Body Composition; Bone and Bones; Energy Metabolism; Exercise; Humans; Lipid Metabolism; Liver; Metabolic Networks and Pathways; Muscle, Skeletal; Obesity; Peptide Hormones; Peptides; Weight Loss
PubMed: 32604889
DOI: 10.3390/nu12061899 -
Angewandte Chemie (International Ed. in... Sep 2023Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte...
Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte growth factor (HGF) receptor, known as MET, plays an important role in tissue regeneration. Here we show the development of ubiquitin (Ub)-based protein ligand multimers, referred to as U-bodies, which act as surrogate agonists for MET and are derived from MET-binding macrocyclic peptides. Monomeric Ub constructs (U-body) were first generated by genetic implantation of a macrocyclic peptide pharmacophore into a structural loop of Ub (lasso-grafting) and subsequent optimization of its flanking spacer sequences via mRNA display. Such U-body constructs exhibit potent binding affinity to MET, thermal stability, and proteolytic stability. The U-body constructs also partially/fully inhibited or enhanced HGF-induced MET-phosphorylation. Their multimerization to dimeric, tetrameric, and octameric U-bodies linked by an appropriate peptide linker yielded potent MET activation activity and downstream cell proliferation-promoting activity. This work suggests that lasso-grafting of macrocycles to Ub is an effective approach to devising protein-based artificial RTK agonists and it can be useful in the development of a new class of biologics for various therapeutic applications.
Topics: Hepatocyte Growth Factor; Ubiquitin; Protein Binding; Proto-Oncogene Proteins c-met; Phosphorylation; Peptides
PubMed: 37450419
DOI: 10.1002/anie.202307157 -
Chemical Reviews Mar 2020Subtiligase-catalyzed peptide ligation is a powerful approach for site-specific protein bioconjugation, synthesis and semisynthesis of proteins and peptides, and... (Review)
Review
Subtiligase-catalyzed peptide ligation is a powerful approach for site-specific protein bioconjugation, synthesis and semisynthesis of proteins and peptides, and chemoproteomic analysis of cellular N termini. Here, we provide a comprehensive review of the subtiligase technology, including its development, applications, and impacts on protein science. We highlight key advantages and limitations of the tool and compare it to other peptide ligase enzymes. Finally, we provide a perspective on future applications and challenges and how they may be addressed.
Topics: Biocatalysis; Peptide Synthases; Peptides; Subtilisins
PubMed: 31663725
DOI: 10.1021/acs.chemrev.9b00372 -
Topics in Current Chemistry (Cham) Oct 2020Enzyme, which exists widely in organisms, has high specificity and high catalytic efficiency for its substrates. The absence, the reduced activity, or the overexpression... (Review)
Review
Enzyme, which exists widely in organisms, has high specificity and high catalytic efficiency for its substrates. The absence, the reduced activity, or the overexpression of enzyme are closely related to the occurrence and development of diseases. Therefore, enzyme is often used as markers for disease detection and treatment. To detect enzyme activity and track drug release, aggregation-induced emission (AIE) bioprobes have been developed because of their excellent photostability and high signal-to-noise ratio (SNR). Among them, peptide-based AIE bioprobes with great biocompatibility and specificity are favored by an increasing number of researchers. Enzymatic hydrolysis of peptide can cause aggregation of AIE molecules and drug release. In this review, enzyme-responsive peptide-based AIE bioprobes used for biomedical application are summarized according to the three aggregation strategies triggered by various reaction between peptide and enzyme, including enzyme-triggered precipitate, enzyme-catalyzed coupling, and enzyme-instructed self-assembly. By giving some representative examples, we discuss how each aggregation strategy detects enzyme activity and treats the diseases under imaging guidance. Finally, we comment on the current problems and future prospects of enzyme-responsive peptide-based AIE bioprobes.
Topics: Biocatalysis; Biosensing Techniques; Chymases; Peptides
PubMed: 33026529
DOI: 10.1007/s41061-020-00311-9 -
Natural Product Reports Sep 2020Covering1993 up to May 2020 Linaridins, defined as linear, dehydrated (arid) peptides, are a small but growing family of natural products belonging to the ribosomally... (Review)
Review
Covering1993 up to May 2020 Linaridins, defined as linear, dehydrated (arid) peptides, are a small but growing family of natural products belonging to the ribosomally synthesized and post-translationally modified peptide (RiPP) superfamily. To date, only a few members of the linaridin family have been characterized; however, in silico analysis has shown that this family of RiPPs is widespread in nature with high structural diversity. Unlike the case of most of the dehydroamino acid-containing RiPPs, such as lanthipeptides and thiopeptides, in which dehydroamino acids are produced by lanthipeptide dehydratase-like enzymes, in linaridins, dehydroamino acids are produced by a distinct set of enzymes with still unknown biochemistry. In this Highlight we have discussed the structural features, classification, biosynthesis, engineering, and widespread occurrence of linaridins and highlighted several intriguing issues in the maturation of this RiPP family.
Topics: Bioengineering; Biological Products; Peptide Biosynthesis; Peptides; Protein Processing, Post-Translational; Terminology as Topic
PubMed: 32484193
DOI: 10.1039/c9np00074g -
Chemical Society Reviews Jun 2020The art of transforming peptides into drug leads is still a dynamic and fertile field in medicinal chemistry and drug discovery. Peptidomimetics can respond to peptide... (Review)
Review
The art of transforming peptides into drug leads is still a dynamic and fertile field in medicinal chemistry and drug discovery. Peptidomimetics can respond to peptide limitations by displaying higher metabolic stability, good bioavailability and enhanced receptor affinity and selectivity. Various synthetic strategies have been developed over the years in order to modulate the conformational flexibility and the peptide character of peptidomimetic compounds. This tutorial review aims to outline useful tools towards peptidomimetic design, spanning from local modifications, global restrictions and the use of secondary structure mimetics. Selected successful examples of each approach are presented to document the relevance of peptidomimetics in drug discovery.
Topics: Coordination Complexes; Drug Evaluation, Preclinical; Drug Stability; Humans; Models, Molecular; Peptides; Peptidomimetics; Protein Binding; Protein Structure, Secondary; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 32255135
DOI: 10.1039/d0cs00102c