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1.
Nutrients ; 14(3)2022 Feb 04.
Article in English | MEDLINE | ID: mdl-35277026

ABSTRACT

It is unclear whether gestational diabetes mellitus (GDM) alters breast milk composition. We prospectively examined associations of GDM status with concentrations of six potentially bioactive elements (glucose, insulin, C-reactive protein (CRP), interleukin-6 (IL-6), leptin, and adiponectin) in human milk. These were measured at both 1 and 3 months postpartum in 189 fully breastfeeding women. Mixed-effects linear regression assessed GDM status-related differences in these milk bioactives, adjusting for demographics, maternal factors, and diet. At 1 and 3 months postpartum, milk CRP was higher (1.46 ± 0.31 ng/mL; p < 0.001 and 1.69 ± 0.31 ng/mL; p < 0.001) in women with GDM than in women without GDM, whereas milk glucose (-5.23 ± 2.22 mg/dL; p = 0.02 and -5.70 ± 2.22; p = 0.01) and milk insulin (-0.38 ± 0.17 µIU/mL; p = 0.03 and -0.53 ± 0.17; p = 0.003) were lower in women with GDM. These significant associations remained similar after additional adjustment for maternal weight status and its changes. No difference was found for milk IL-6, leptin, and adiponectin. There was no evidence of association between these milk bioactive compounds and 1 h non-fasting oral glucose challenge serum glucose in the women without GDM. This prospective study provides evidence that potentially bioactive elements of human milk composition are altered in women with GDM.


Subject(s)
Cytokines , Diabetes, Gestational , Hormones , Milk, Human , Breast Feeding , Cytokines/chemistry , Female , Glucose Tolerance Test , Hormones/chemistry , Humans , Milk, Human/chemistry , Pregnancy , Prospective Studies , United States
2.
Mikrochim Acta ; 189(2): 74, 2022 01 26.
Article in English | MEDLINE | ID: mdl-35080669

ABSTRACT

Severe infections can cause a dysregulated response leading to organ dysfunction known as sepsis. Sepsis can be lethal if not identified and treated right away. This requires measuring biomarkers and pathogens rapidly at the different points where sepsis care is provided. Current commercial approaches for sepsis diagnosis are not fast, sensitive, and/or specific enough for meeting this medical challenge. In this article, we review recent advances in the development of diagnostic tools for sepsis management based on micro- and nanostructured materials. We start with a brief introduction to the most popular biomarkers for sepsis diagnosis (lactate, procalcitonin, cytokines, C-reactive protein, and other emerging protein and non-protein biomarkers including miRNAs and cell-based assays) and methods for detecting bacteremia. We then highlight the role of nano- and microstructured materials in developing biosensors for detecting them taking into consideration the particular needs of every point of sepsis care (e.g., ultrafast detection of multiple protein biomarkers for diagnosing in triage, emergency room, ward, and intensive care unit; quantitative detection to de-escalate treatment; ultrasensitive and culture-independent detection of blood pathogens for personalized antimicrobial therapies; robust, portable, and web-connected biomarker tests outside the hospital). We conclude with an overview of the most utilized nano- and microstructured materials used thus far for solving issues related to sepsis diagnosis and point to new challenges for future development.


Subject(s)
Bacteria/isolation & purification , Nanotechnology , Sepsis/blood , Sepsis/microbiology , Biomarkers/blood , Biosensing Techniques/instrumentation , Cytokines/blood , Cytokines/chemistry , Humans , Sepsis/diagnosis
3.
J Med Chem ; 65(1): 876-884, 2022 01 13.
Article in English | MEDLINE | ID: mdl-34981929

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic, a global health threat, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 papain-like cysteine protease (PLpro) was recognized as a promising drug target because of multiple functions in virus maturation and antiviral immune responses. Inhibitor GRL0617 occupied the interferon-stimulated gene 15 (ISG15) C-terminus-binding pocket and showed an effective antiviral inhibition. Here, we described a novel peptide-drug conjugate (PDC), in which GRL0617 was linked to a sulfonium-tethered peptide derived from PLpro-specific substrate LRGG. The EM-C and EC-M PDCs showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 µM, respectively. EC-M could covalently label PLpro active site C111 and display anti-ISGylation activities in cellular assays. The results represent the first attempt to design PDCs composed of stabilized peptide inhibitors and GRL0617 to inhibit PLpro. These novel PDCs provide promising opportunities for antiviral drug design.


Subject(s)
Aniline Compounds/chemistry , Antiviral Agents/metabolism , Benzamides/chemistry , Coronavirus Papain-Like Proteases/metabolism , Drug Design , Naphthalenes/chemistry , Peptides/chemistry , SARS-CoV-2/enzymology , Aniline Compounds/metabolism , Aniline Compounds/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzamides/metabolism , Benzamides/pharmacology , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cell Line , Cell Survival/drug effects , Coronavirus Papain-Like Proteases/chemistry , Cytokines/chemistry , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Naphthalenes/metabolism , Naphthalenes/pharmacology , SARS-CoV-2/isolation & purification , Ubiquitins/chemistry
4.
Nature ; 600(7887): 153-157, 2021 12.
Article in English | MEDLINE | ID: mdl-34819673

ABSTRACT

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system1,2. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies3. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma4-7. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain8,9. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands10-14 to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.


Subject(s)
Anaplastic Lymphoma Kinase/chemistry , Anaplastic Lymphoma Kinase/metabolism , Anaplastic Lymphoma Kinase/ultrastructure , Binding Sites , Cell Membrane/chemistry , Cell Membrane/metabolism , Cryoelectron Microscopy , Crystallography, X-Ray , Cytokines/chemistry , Cytokines/metabolism , Cytokines/ultrastructure , Enzyme Activation , Humans , Ligands , Models, Molecular , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Multiprotein Complexes/ultrastructure , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Protein Domains , Protein Multimerization
5.
Biochemistry ; 60(48): 3714-3727, 2021 12 07.
Article in English | MEDLINE | ID: mdl-34788017

ABSTRACT

The 3'-5', 3'-5' cyclic dinucleotides (3'3'CDNs) are bacterial second messengers that can also bind to the stimulator of interferon genes (STING) adaptor protein in vertebrates and activate the host innate immunity. Here, we profiled the substrate specificity of four bacterial dinucleotide synthases from Vibrio cholerae (DncV), Bacillus thuringiensis (btDisA), Escherichia coli (dgcZ), and Thermotoga maritima (tDGC) using a library of 33 nucleoside-5'-triphosphate analogues and then employed these enzymes to synthesize 24 3'3'CDNs. The STING affinity of CDNs was evaluated in cell-based and biochemical assays, and their ability to induce cytokines was determined by employing human peripheral blood mononuclear cells. Interestingly, the prepared heterodimeric 3'3'CDNs bound to the STING much better than their homodimeric counterparts and showed similar or better potency than bacterial 3'3'CDNs. We also rationalized the experimental findings by in-depth STING-CDN structure-activity correlations by dissecting computed interaction free energies into a set of well-defined and intuitive terms. To this aim, we employed state-of-the-art methods of computational chemistry, such as quantum mechanics/molecular mechanics (QM/MM) calculations, and complemented the computed results with the {STING:3'3'c-di-ara-AMP} X-ray crystallographic structure. QM/MM identified three outliers (mostly homodimers) for which we have no clear explanation of their impaired binding with respect to their heterodimeric counterparts, whereas the R2 = 0.7 correlation between the computed ΔG'int_rel and experimental ΔTm's for the remaining ligands has been very encouraging.


Subject(s)
Immunity, Innate/genetics , Membrane Proteins/ultrastructure , Nucleotides/biosynthesis , Structure-Activity Relationship , Bacillus thuringiensis/enzymology , Bacillus thuringiensis/ultrastructure , Crystallography, X-Ray , Cytokines/chemistry , Cytokines/genetics , Escherichia coli/enzymology , Escherichia coli/ultrastructure , Humans , Leukocytes, Mononuclear/chemistry , Leukocytes, Mononuclear/enzymology , Membrane Proteins/chemistry , Membrane Proteins/genetics , Nucleotides/chemistry , Nucleotides/genetics , Quantum Theory , Substrate Specificity , Thermotoga maritima/enzymology , Thermotoga maritima/ultrastructure , Vibrio cholerae/enzymology , Vibrio cholerae/ultrastructure
6.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: mdl-34681871

ABSTRACT

Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as "cytokine storm", which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation. Peptides from the N-terminal fragment of Tag7 bind only to TREM-1, while peptides from the C-terminal fragment interact solely with TNFR1. Selected peptides are capable of inhibiting the production of proinflammatory cytokines both in peripheral blood mononuclear cells (PBMCs) from healthy donors and in vivo in the mouse model of acute lung injury (ALI) by diffuse alveolar damage (DAD). Treatment with peptides significantly decreases the infiltration of mononuclear cells to lungs in animals with DAD. Our findings suggest that Tag7-derived peptides might be beneficial in terms of the therapy or prevention of acute lung injury, e.g., for treating COVID-19 patients with severe pulmonary lesions.


Subject(s)
Acute Lung Injury/pathology , Cytokines/chemistry , Peptides/metabolism , Receptors, Tumor Necrosis Factor, Type I/metabolism , Triggering Receptor Expressed on Myeloid Cells-1/metabolism , Acute Lung Injury/metabolism , Animals , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism , Lung/pathology , Lymphocyte Activation/drug effects , Male , Mice , Mice, Inbred ICR , Peptides/chemistry , Peptides/pharmacology , Protein Binding , Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors , Triggering Receptor Expressed on Myeloid Cells-1/antagonists & inhibitors
7.
J Interferon Cytokine Res ; 41(10): 355-359, 2021 10.
Article in English | MEDLINE | ID: mdl-34672799
8.
Nature ; 600(7887): 143-147, 2021 12.
Article in English | MEDLINE | ID: mdl-34646012

ABSTRACT

Anaplastic lymphoma kinase (ALK)1 and the related leukocyte tyrosine kinase (LTK)2 are recently deorphanized receptor tyrosine kinases3. Together with their activating cytokines, ALKAL1 and ALKAL24-6 (also called FAM150A and FAM150B or AUGß and AUGα, respectively), they are involved in neural development7, cancer7-9 and autoimmune diseases10. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain11, consistent with a metabolic role for Drosophila ALK12. Despite such functional pleiotropy and growing therapeutic relevance13,14, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases.


Subject(s)
Anaplastic Lymphoma Kinase/chemistry , Anaplastic Lymphoma Kinase/metabolism , Cytokines/chemistry , Cytokines/metabolism , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Anaplastic Lymphoma Kinase/classification , Anaplastic Lymphoma Kinase/genetics , Binding Sites , Enzyme Activation , Epidermal Growth Factor/chemistry , Glycine , HEK293 Cells , Humans , Models, Molecular , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Mutation , Protein Binding , Protein Domains , Protein Multimerization , Substrate Specificity
9.
Int J Mol Sci ; 22(17)2021 Aug 26.
Article in English | MEDLINE | ID: mdl-34502130

ABSTRACT

Bifidobacteria are some of the major agents that shaped the immune system of many members of the animal kingdom during their evolution. Over recent years, the question of concrete mechanisms underlying the immunomodulatory properties of bifidobacteria has been addressed in both animal and human studies. A possible candidate for this role has been discovered recently. The PFNA cluster, consisting of five core genes, pkb2, fn3, aaa-atp, duf58, tgm, has been found in all gut-dwelling autochthonous bifidobacterial species of humans. The sensory region of the species-specific serine-threonine protein kinase (PKB2), the transmembrane region of the microbial transglutaminase (TGM), and the type-III fibronectin domain-containing protein (FN3) encoded by the I gene imply that the PFNA cluster might be implicated in the interaction between bacteria and the host immune system. Moreover, the FN3 protein encoded by one of the genes making up the PFNA cluster, contains domains and motifs of cytokine receptors capable of selectively binding TNF-α. The PFNA cluster could play an important role for sensing signals of the immune system. Among the practical implications of this finding is the creation of anti-inflammatory drugs aimed at alleviating cytokine storms, one of the dire consequences resulting from SARS-CoV-2 infection.


Subject(s)
Bacterial Proteins/genetics , Bifidobacterium/physiology , COVID-19/therapy , /genetics , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , COVID-19/immunology , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Cytokines/chemistry , Cytokines/metabolism , Humans , Immune System , Operon/genetics , /metabolism , SARS-CoV-2/isolation & purification
10.
Front Immunol ; 12: 722411, 2021.
Article in English | MEDLINE | ID: mdl-34497612

ABSTRACT

Nonviral systems, such as lipid nanoparticles, have emerged as reliable methods to enable nucleic acid intracellular delivery. The use of cationic lipids in various formulations of lipid nanoparticles enables the formation of complexes with nucleic acid cargo and facilitates their uptake by target cells. However, due to their small size and highly charged nature, these nanocarrier systems can interact in vivo with antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. As this might prove to be a safety concern for developing therapies based on lipid nanocarriers, we sought to understand how they could affect the physiology of APCs. In the present study, we investigate the cellular and metabolic response of primary macrophages or DCs exposed to the neutral or cationic variant of the same lipid nanoparticle formulation. We demonstrate that macrophages are the cells affected most significantly and that the cationic nanocarrier has a substantial impact on their physiology, depending on the positive surface charge. Our study provides a first model explaining the impact of charged lipid materials on immune cells and demonstrates that the primary adverse effects observed can be prevented by fine-tuning the load of nucleic acid cargo. Finally, we bring rationale to calibrate the nucleic acid load of cationic lipid nanocarriers depending on whether immunostimulation is desirable with the intended therapeutic application, for instance, gene delivery or messenger RNA vaccines.


Subject(s)
Cations/chemistry , Gene Transfer Techniques , Lipids/chemistry , Liposomes/chemistry , Nanoparticles/chemistry , Nucleic Acids/administration & dosage , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Cell Line , Cell Survival , Chemical Phenomena , Cytokines/chemistry , Drug Carriers , Lipopolysaccharides/chemistry , Mice , Mitochondria/metabolism , Reactive Oxygen Species
11.
Biochem Soc Trans ; 49(5): 1963-1973, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34495310

ABSTRACT

Many growth factors and cytokines are produced as larger precursors, containing pro-domains, that require proteolytic processing to release the bioactive ligand. These pro-domains can be significantly larger than the mature domains and can play an active role in the regulation of the ligands. Mining the UniProt database, we identified almost one hundred human growth factors and cytokines with pro-domains. These are spread across several unrelated protein families and vary in both their size and composition. The precise role of each pro-domain varies significantly between the protein families. Typically they are critical for controlling bioactivity and protein localisation, and they facilitate diverse mechanisms of activation. Significant gaps in our understanding remain for pro-domain function - particularly their fate once the bioactive ligand has been released. Here we provide an overview of pro-domain roles in human growth factors and cytokines, their processing, regulation and activation, localisation as well as therapeutic potential.


Subject(s)
Cytokines/chemistry , Cytokines/metabolism , Intercellular Signaling Peptides and Proteins/chemistry , Intercellular Signaling Peptides and Proteins/metabolism , Protein Precursors/chemistry , Protein Precursors/metabolism , Signal Transduction/physiology , Animals , Biomarkers , Cytokines/therapeutic use , Drug Discovery , Humans , Intercellular Signaling Peptides and Proteins/therapeutic use , Ligands , Protein Domains , Protein Precursors/therapeutic use , Proteolysis
12.
Adv Mater ; 33(42): e2102489, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34431569

ABSTRACT

Precision surface engineering is key to advanced biomaterials. A new platform of PEGylated styrene-maleic acid copolymers for adsorptive surface biofunctionalization is reported. Balanced amphiphilicity renders the copolymers water-soluble but strongly affine for surfaces. Fine-tuning of their molecular architecture provides control over adsorptive anchorage onto specific materials-which is why they are referred to as "anchor polymers" (APs)-and over structural characteristics of the adsorbed layers. Conjugatable with an array of bioactives-including cytokine-complexing glycosaminoglycans, cell-adhesion-mediating peptides and antimicrobials-APs can be applied to customize materials for demanding biotechnologies in uniquely versatile, simple, and robust ways. Moreover, homo- and heterodisplacement of adsorbed APs provide unprecedented means of in situ alteration and renewal of the functionalized surfaces. The related options are exemplified with proof-of-concept experiments of controlled bacterial adhesion, human umbilical vein endothelial cell, and induced pluripotent cell growth on AP-functionalized surfaces.


Subject(s)
Biocompatible Materials/chemistry , Polymers/chemistry , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Biocompatible Materials/pharmacology , Cell Adhesion/drug effects , Cytokines/chemistry , Glycosaminoglycans/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Maleates/chemistry , Oligopeptides/chemistry , Polyethylene Glycols/chemistry , Polymers/pharmacology , Styrene/chemistry , Surface Properties
13.
Adv Mater ; 33(33): e2101228, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34240485

ABSTRACT

Supplement-free induction of cellular differentiation and polarization solely through the topography of materials is an auspicious strategy but has so far significantly lagged behind the efficiency and intensity of media-supplementation-based protocols. Consistent with the idea that 3D structural motifs in the extracellular matrix possess immunomodulatory capacity as part of the natural healing process, it is found in this study that human-monocyte-derived macrophages show a strong M2a-like prohealing polarization when cultured on type I rat-tail collagen fibers but not on collagen I films. Therefore, it is hypothesized that highly aligned nanofibrils also of synthetic polymers, if packed into larger bundles in 3D topographical biomimetic similarity to native collagen I, would induce a localized macrophage polarization. For the automated fabrication of such bundles in a 3D printing manner, the strategy of "melt electrofibrillation" is pioneered by the integration of flow-directed polymer phase separation into melt electrowriting and subsequent selective dissolution of the matrix polymer postprocessing. This process yields nanofiber bundles with a remarkable structural similarity to native collagen I fibers, particularly for medical-grade poly(ε-caprolactone). These biomimetic fibrillar structures indeed induce a pronounced elongation of human-monocyte-derived macrophages and unprecedentedly trigger their M2-like polarization similar in efficacy as interleukin-4 treatment.


Subject(s)
Biomimetic Materials/chemistry , Collagen/chemistry , Cytokines/chemistry , Polyesters/chemistry , Tissue Scaffolds/chemistry , Animals , Biomimetic Materials/metabolism , Cell Culture Techniques , Cell Differentiation , Cell Line , Collagen/metabolism , Cytokines/genetics , Cytokines/metabolism , Extracellular Matrix/drug effects , Humans , Immunomodulation , Macrophages/cytology , /metabolism , Nanofibers/chemistry , Polyvinyls/chemistry , Printing, Three-Dimensional , Rats , Tissue Engineering
14.
Int Immunopharmacol ; 99: 107930, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34229178

ABSTRACT

Therapeutic strategies used to attenuate inflammation and to increase recovery of neurons after a stroke include microglia anti-inflammatory (M2) polarization and repression of proinflammatory (M1). Extracts isolated from Vaccina variola-inoculated rabbit skin, for example analgecine (AGC), have been used as a therapy for patients experiencing lower back pain associated with degenerative diseases of the spine for about twenty years. In the study presented here, neuroprotective effect associated with AGC was analyzed as well as the anti-inflammatory mechanism linked to AGC in terms of attenuating microglia-mediated neuronal damage. Rats were intravenously injected with AGC after middle cerebral artery occlusion (MCAO), which showed to suppress neuronal loss and reduce neurological deficits. In addition, AGC inhibited pro-inflammatory cytokine release and increased anti-inflammatory cytokines. Furthermore, this study revealed that treatment with AGC supported microglia transition from M1 to M2 in both oxygen-glucose deprivation/reperfusion (OGD/R) and LPS/IFN-γ induced microglia cells, as well as indirectly inhibited LPS/IFN-γ-induced neuronal damage through the modulation of microglial polarization. It is also important to note that AGC inhibited NF-κB p65 phosphorylation through repressing TLR4/Myd88/TRAF6 signaling pathway. In addition, we found that TLR4 inhibition by AGC depended on Myd88. Altogether, this work supports that AGC inhibits M1 microglial polarization and promotes anti-inflammation independently and dependently on TLR4/MyD88. Since it is shown to have neuroprotective effects in this study, AGC has great potential to be used in the clinic to reduce inflammation and aid in recovery after stroke.


Subject(s)
Infarction, Middle Cerebral Artery/drug therapy , Microglia/chemistry , Myeloid Differentiation Factor 88/metabolism , Toll-Like Receptor 4/metabolism , Animals , Brain Ischemia/metabolism , Cytokines/chemistry , Humans , I-kappa B Proteins/metabolism , Ischemic Stroke/metabolism , Male , NF-kappa B/metabolism , Neurons/metabolism , Neuroprotective Agents , Rabbits , Rats , Rats, Sprague-Dawley , Signal Transduction , Stroke/metabolism , Toll-Like Receptors , Transcription Factor RelA/metabolism
15.
Sci Rep ; 11(1): 12889, 2021 06 18.
Article in English | MEDLINE | ID: mdl-34145348

ABSTRACT

Intelectins are ancient carbohydrate binding proteins, spanning chordate evolution and implicated in multiple human diseases. Previous GWAS have linked SNPs in ITLN1 (also known as omentin) with susceptibility to Crohn's disease (CD); however, analysis of possible functional significance of SNPs at this locus is lacking. Using the Ensembl database, pairwise linkage disequilibrium (LD) analyses indicated that several disease-associated SNPs at the ITLN1 locus, including SNPs in CD244 and Ly9, were in LD. The alleles comprising the risk haplotype are the major alleles in European (67%), but minor alleles in African superpopulations. Neither ITLN1 mRNA nor protein abundance in intestinal tissue, which we confirm as goblet-cell derived, was altered in the CD samples overall nor when samples were analyzed according to genotype. Moreover, the missense variant V109D does not influence ITLN1 glycan binding to the glycan ß-D-galactofuranose or protein-protein oligomerization. Taken together, our data are an important step in defining the role(s) of the CD-risk haplotype by determining that risk is unlikely to be due to changes in ITLN1 carbohydrate recognition, protein oligomerization, or expression levels in intestinal mucosa. Our findings suggest that the relationship between the genomic data and disease arises from changes in CD244 or Ly9 biology, differences in ITLN1 expression in other tissues, or an alteration in ITLN1 interaction with other proteins.


Subject(s)
Cytokines/genetics , Gastrointestinal Tract/metabolism , Gene Expression Regulation , Genetic Variation , Lectins/genetics , Alleles , Crohn Disease/genetics , Cytokines/chemistry , Disease Susceptibility , GPI-Linked Proteins/chemistry , GPI-Linked Proteins/genetics , Genetic Loci , Humans , Lectins/chemistry , Organ Specificity/genetics
16.
J Phys Chem Lett ; 12(23): 5608-5615, 2021 Jun 17.
Article in English | MEDLINE | ID: mdl-34110168

ABSTRACT

Papain-like protease (PLpro) from SARS-CoV-2 plays essential roles in the replication cycle of the virus. In particular, it preferentially interacts with and cleaves human interferon-stimulated gene 15 (hISG15) to suppress the innate immune response of the host. We used small-angle X-ray and neutron scattering combined with computational techniques to study the mechanism of interaction of SARS-CoV-2 PLpro with hISG15. We showed that hISG15 undergoes a transition from an extended to a compact state after binding to PLpro, a conformation that has not been previously observed in complexes of SARS-CoV-2 PLpro with ISG15 from other species. Furthermore, computational analysis showed significant conformational flexibility in the ISG15 N-terminal domain, suggesting that it is weakly bound to PLpro and supports a binding mechanism that is dominated by the C-terminal ISG15 domain. This study fundamentally improves our understanding of the SARS-CoV-2 deISGylation complex that will help guide development of COVID-19 therapeutics targeting this complex.


Subject(s)
Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Cytokines/chemistry , Cytokines/metabolism , Interferons/metabolism , SARS-CoV-2/metabolism , Ubiquitins/chemistry , Ubiquitins/metabolism , Coronavirus Papain-Like Proteases/genetics , Cytokines/genetics , Humans , Neutron Diffraction , Protein Conformation , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Scattering, Small Angle , Ubiquitins/genetics , X-Ray Diffraction
17.
Adv Mater ; 33(30): e2101190, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34096117

ABSTRACT

The growing enthusiasm for cancer immunotherapies and adoptive cell therapies has prompted increasing interest in biomaterials development mimicking natural antigen-presenting cells (APCs) for T-cell expansion. In contrast to conventional bottom-up approaches aimed at layering synthetic substrates with T-cell activation cues, transformation of live dendritic cells (DCs) into artificial APCs (aAPCs) is demonstrated herein using a facile and minimally disruptive hydrogelation technique. Through direct intracellular permeation of poly(ethylene glycol) diacrylate (PEG-DA) hydrogel monomer and UV-activated radical polymerization, intracellular hydrogelation is rapidly accomplished on DCs with minimal influence on cellular morphology and surface antigen display, yielding highly robust and modular cell-gel hybrid constructs amenable to peptide antigen exchange, storable by freezing and lyophilization, and functionalizable with cytokine-releasing carriers for T-cell modulation. The DC-derived aAPCs are shown to induce prolonged T-cell expansion and improve anticancer efficacy of adoptive T-cell therapy in mice compared to nonexpanded control T cells, and the gelation technique is further demonstrated to stabilize primary DCs derived from human donors. The work presents a versatile approach for generating a new class of cell-mimicking biomaterials and opens new venues for immunological interrogation and immunoengineering.


Subject(s)
Antigens/chemistry , Biocompatible Materials/chemistry , Biomimetic Materials/chemistry , Dendritic Cells/chemistry , Hydrogels/chemistry , Polyethylene Glycols/chemistry , Animals , Cell Membrane Permeability , Cell Proliferation , Cytokines/chemistry , Humans , Immunotherapy , Immunotherapy, Adoptive , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Neoplasms, Experimental , T-Lymphocytes , Ultraviolet Rays
18.
Innate Immun ; 27(4): 313-323, 2021 05.
Article in English | MEDLINE | ID: mdl-34013820

ABSTRACT

Trichinella spiralis represents an effective treatment for autoimmune and inflammatory diseases. The effects of recombinant T. spiralis (TS) 53-kDa protein (rTsP53) on acute lung injury (ALI) remain unclear. Here, mice were divided randomly into a control group, LPS group, and rTsP53 + LPS group. ALI was induced in BALB/c mice by LPS (10 mg/kg) injected via the tail vein. rTsP53 (200 µl; 0.4 µg/µl) was injected subcutaneously three times at an interval of 5 d before inducing ALI in the rTsP53+LPS group. Lung pathological score, the ratio and markers of classic activated macrophages (M1) and alternatively activated macrophages (M2), cytokine profiles in alveolar lavage fluid, and pyroptosis protein expression in lung tissue were investigated. RTsP53 decreased lung pathological score. Furthermore, rTsP53 suppressed inflammation by increasing IL-4, IL-10, and IL-13. There was an increase in alveolar M2 macrophage numbers, with an increase in CD206 and arginase-1-positive cells and a decrease in alveolar M1 markers such as CD197 and iNOS. In addition, the polarization of M2 macrophages induced by rTsP53 treatment could alleviate ALI by suppressing lung pyroptosis. RTsP53 was identified as a potential agent for treating LPS-induced ALI via alleviating lung pyroptosis by promoting M2 macrophage polarization.


Subject(s)
Acute Lung Injury/drug therapy , Macrophages/drug effects , Protective Agents/pharmacology , Pyroptosis/drug effects , Trichinella spiralis/chemistry , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Bronchoalveolar Lavage Fluid , Cell Count , Cell Polarity/drug effects , Cytokines/chemistry , Interleukins/antagonists & inhibitors , Lipopolysaccharides , Macrophage Activation/drug effects , Male , Mice , Mice, Inbred BALB C , Nitric Oxide Synthase Type II/metabolism , Recombinant Proteins/pharmacology
19.
Adv Mater ; 33(20): e2100012, 2021 May.
Article in English | MEDLINE | ID: mdl-33837596

ABSTRACT

The COVID-19 pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great impact on the global economy and people's daily life. In the clinic, most patients with COVID-19 show none or mild symptoms, while approximately 20% of them develop severe pneumonia, multiple organ failure, or septic shock due to infection-induced cytokine release syndrome (the so-called "cytokine storm"). Neutralizing antibodies targeting inflammatory cytokines may potentially curb immunopathology caused by COVID-19; however, the complexity of cytokine interactions and the multiplicity of cytokine targets make attenuating the cytokine storm challenging. Nonspecific in vivo biodistribution and dose-limiting side effects further limit the broad application of those free antibodies. Recent advances in biomaterials and nanotechnology have offered many promising opportunities for infectious and inflammatory diseases. Here, potential mechanisms of COVID-19 cytokine storm are first discussed, and relevant therapeutic strategies and ongoing clinical trials are then reviewed. Furthermore, recent research involving emerging biomaterials for improving antibody-based and broad-spectrum cytokine neutralization is summarized. It is anticipated that this work will provide insights on the development of novel therapeutics toward efficacious management of COVID-19 cytokine storm and other inflammatory diseases.


Subject(s)
Biocompatible Materials/chemistry , COVID-19/pathology , Cytokine Release Syndrome/therapy , Cytokines/chemistry , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/immunology , Biocompatible Materials/metabolism , COVID-19/complications , COVID-19/virology , Cytokine Release Syndrome/etiology , Cytokines/immunology , Cytokines/metabolism , Extracellular Vesicles/chemistry , Humans , Nanoparticles/chemistry , Polymers/chemistry , SARS-CoV-2/isolation & purification
20.
J Ethnopharmacol ; 281: 114026, 2021 Dec 05.
Article in English | MEDLINE | ID: mdl-33727111

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodis rhizoma in Chinese Pharmacopoeia are Atractylodes lancea (Thunb.) DC and Atractylodes chinensis (DC.) Koidz. Atractylodes koreana (Nakai) Kitam has not been included in Chinese Pharmacopoeia, however, in the 'dictionary of traditional Chinese medicine', Atractylodes koreana (Nakai) Kitam is often used as Atractylodis rhizoma in the north of China. According to 'Chinese traditional medicine resources', Atractylodes koreana (Nakai) Kitam has the function of drying dampness and strengthening the spleen, dispelling wind and eliminating dampness. AIM OF THIS STUDY: The study was to explore the effect and mechanism of Atractylodes koreana (Nakai) Kitam on rheumatoid arthritis(RA) through intestinal flora and its metabolites(short chain fatty acids). MATERIALS AND METHODS: 36 male SD rats were randomly divided into 6 groups. The Freund's complete adjuvant method was used to reproduce RA model. The contents of inflammatory factors in the plasma of rats were monitored by ELISA method. The pathological changes of synovium were observed. 16SrDNA high-throughput sequence method was used to study the composition and structure of intestinal microflora in each group of rats. Gas Chromatography and Mass Spectrum(GC-MS) method was used to determine the content of short chain fatty acids(SCFAs) in colon of rats of each group. RESULTS: After oral administration of Atractylodes koreana (Nakai) Kitam, the synovial infiltration and vascular proliferation in RA rats were alleviated, the level of TNF - α, IL-1, IL-1 ß, IL-2, IL-6, hs-CRP in the plasma of RA rats were declined. RA could cause the disturbance of intestinal flora and SCFAs, Atractylodes koreana (Nakai) Kitam could regulate 8 genera of intestinal flora and improve the disorder of SCFAs. CONCLUSIONS: Atractylodes koreana (Nakai) Kitam has a therapeutic effect on RA, the therapeutic mechanism may be related to down-regulating inflammatory factors and improving the imbalance of intestinal flora and SCFAs.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Atractylodes/chemistry , Intestines/microbiology , Phytotherapy , Plant Extracts/therapeutic use , Rhizome/chemistry , Administration, Oral , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/therapeutic use , Cytokines/chemistry , Cytokines/therapeutic use , DNA/genetics , DNA/metabolism , Down-Regulation , Gastrointestinal Microbiome/drug effects , Gene Expression Regulation/drug effects , Inflammation/drug therapy , Male , Methotrexate/pharmacology , Plant Extracts/chemistry , RNA, Ribosomal, 16S/genetics , RNA, Ribosomal, 16S/metabolism , Rats , Rats, Sprague-Dawley , Synovial Membrane/drug effects , Synovial Membrane/pathology
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