Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 186
Filter
1.
Molecules ; 26(21)2021 Oct 21.
Article in English | MEDLINE | ID: mdl-34770761

ABSTRACT

Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment able to trigger the immune response. Structural modification of MDP can lead to the preparation of analogs with improved immunostimulant properties, including desmuramyl peptides (DMPs). The aim of this work was to prepare the desmuramyl peptide (L-Ala-D-Glu)-containing adamantyl-triazole moiety and its mannosylated derivative in order to study their immunomodulatory activities in vivo. The adjuvant activity of the prepared compounds was evaluated in a murine model using ovalbumin as an antigen, and compared to the reference adjuvant ManAdDMP. The results showed that the introduction of the lipophilic adamantyl-triazole moiety at the C-terminus of L-Ala-D-Glu contributes to the immunostimulant activity of DMP, and that mannosylation of DMP modified with adamantyl-triazole causes the amplification of its immunostimulant activity.


Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/chemistry , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Chemistry Techniques, Synthetic , Drug Design , Triazoles/chemistry , Acetylmuramyl-Alanyl-Isoglutamine/chemical synthesis , Animals , Antibody Formation/drug effects , Dose-Response Relationship, Drug , Immunologic Factors/chemical synthesis , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Mice , Molecular Structure , Structure-Activity Relationship
2.
Carbohydr Polym ; 273: 118582, 2021 Dec 01.
Article in English | MEDLINE | ID: mdl-34560984

ABSTRACT

The large molecular weight and poor water solubility of ß-1,3-glucan impede its potential applications. In this study, the ß-1,3-glucan producing fungi and Trichoderma harzianum capable of secreting endo-ß-1,3-glucanase were co-cultivated to produce branched ß-1,3-glucan oligosaccharides (bOßGs) by fermentation with Sclerotium rolfsii and Schizophyllum commune. The highest bOßG yields from S. rolfsii in flasks were 4.53 and 9.94 g/L in a 7 L fermenter. Structural analysis proved that bOßG from S. rolfsii had a narrow degree of polymerization of 5-12, whereas bOßG from S. commune had a degree of polymerization of 5-15. Antioxidant tests showed that both bOßGs had remarkable DPPH radical scavenging activity and hydroxyl radical scavenging activity, and the activity of bOßG from S. commune was better than that of bOßG from S. rolfsii. In addition, bOßGs could promote the secretion of NO by mouse macrophages and increase the production of TNF-α, IL-1ß, and IL-6 in RAW264.7.


Subject(s)
Oligosaccharides/chemical synthesis , beta-Glucans/chemical synthesis , Animals , Basidiomycota/metabolism , Carbohydrate Conformation , Coculture Techniques , Fermentation , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/pharmacology , Hypocreales/metabolism , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Interleukin-6/metabolism , Mice , Nitric Oxide/metabolism , Oligosaccharides/pharmacology , Polymerization , RAW 264.7 Cells , Schizophyllum/metabolism , Transforming Growth Factor beta/metabolism , beta-Glucans/pharmacology
3.
J Mater Chem B ; 9(34): 6770-6801, 2021 09 14.
Article in English | MEDLINE | ID: mdl-34350452

ABSTRACT

Selenium is capable of forming a dynamic covalent bond with itself and other elements and can undergo metathesis and regeneration reactions under optimum conditions. Its dynamic nature endows selenium-containing polymers with striking sensitivity towards some environmental alterations. In the past decade, several selenium-containing polymers were synthesized and used for the preparation of oxidation-, reduction-, and radiation-responsive nanocarriers. Recently, thioredoxin reductase, sonication, and osmotic pressure triggered the cleavage of Se-Se bonds and swelling or disassembly of nanostructures. Moreover, some selenium-containing nanocarriers form oxidation products such as seleninic acids and acrylates with inherent anticancer activities. Thus, selenium-containing polymers hold promise for the fabrication of ultrasensitive and multifunctional nanocarriers of radiotherapeutic, chemotherapeutic, and immunotherapeutic significance. Herein, we discuss the most recent developments in selenium-containing polymeric micelles in light of their architecture, multiple stimuli-responsive properties, emerging immunomodulatory activities, and future perspectives in the delivery and controlled release of anticancer agents.


Subject(s)
Antineoplastic Agents/pharmacology , Biocompatible Materials/pharmacology , Drug Development , Immunologic Factors/pharmacology , Neoplasms/drug therapy , Polymers/pharmacology , Selenium/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biocompatible Materials/chemical synthesis , Biocompatible Materials/chemistry , Drug Carriers/chemistry , Drug Carriers/pharmacology , Drug Liberation , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/chemistry , Materials Testing , Micelles , Particle Size , Polymers/chemical synthesis , Polymers/chemistry , Selenium/chemistry
4.
J Med Chem ; 64(16): 11886-11903, 2021 08 26.
Article in English | MEDLINE | ID: mdl-34355886

ABSTRACT

The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.


Subject(s)
Cyclohexanols/therapeutic use , Graft vs Host Disease/drug therapy , Immunologic Factors/therapeutic use , Protein Kinase C-theta/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Animals , Caco-2 Cells , Cell Proliferation/drug effects , Cyclohexanols/chemical synthesis , Cyclohexanols/metabolism , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/metabolism , Lymphocyte Activation/drug effects , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Kinase C-delta/antagonists & inhibitors , Protein Kinase C-delta/metabolism , Protein Kinase C-theta/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effects
5.
J Med Chem ; 64(16): 12273-12285, 2021 08 26.
Article in English | MEDLINE | ID: mdl-34378936

ABSTRACT

Molecular glues and proteolysis targeting chimeras (PROTACs) are promising new therapeutic modalities. However, the lack of specificity for molecular glue- or PROTAC-mediated proteolysis in cancer cells versus normal cells raises potential toxicity concerns that will likely limit their clinical applications. Here, we developed a general strategy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate receptor α (FOLR1)-positive cancer cells. Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA, by incorporating a folate group as a caging and guiding element and validated its degradation effect on its neo-substrates in FOLR1-positive cancer cells in a FOLR1-dependent manner. We also developed a folate-caged pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048, which effectively degraded ALK fusion proteins in cancer cells, again in a FOLR1-dependent manner. This novel approach provides a generalizable platform for the targeted delivery of IMiD-based molecular glues and PROTACs to FOLR1-expressing cancer cells with the potential to ameliorate toxicity.


Subject(s)
Folic Acid/analogs & derivatives , Folic Acid/pharmacology , Immunologic Factors/pharmacology , Prodrugs/pharmacology , Proteolysis/drug effects , Thalidomide/analogs & derivatives , Adaptor Proteins, Signal Transducing/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Folate Receptor 1/metabolism , HEK293 Cells , Humans , Ikaros Transcription Factor/metabolism , Immunologic Factors/chemical synthesis , Oncogene Proteins, Fusion/metabolism , Prodrugs/chemical synthesis , Protein-Tyrosine Kinases/metabolism , Thalidomide/chemical synthesis , Thalidomide/pharmacology , Ubiquitin-Protein Ligases/metabolism
6.
Bioorg Med Chem Lett ; 50: 128320, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34400299

ABSTRACT

The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.


Subject(s)
Drug Discovery , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Receptors, CXCR/antagonists & inhibitors , Animals , Drug Delivery Systems , Drug Design , Immunologic Factors/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Signal Transduction , Structure-Activity Relationship
7.
J Med Chem ; 64(16): 12132-12151, 2021 08 26.
Article in English | MEDLINE | ID: mdl-34403254

ABSTRACT

Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure-activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.


Subject(s)
Antineoplastic Agents/therapeutic use , Coordination Complexes/therapeutic use , Immunologic Factors/therapeutic use , Maleimides/therapeutic use , Neoplasms/drug therapy , Prodrugs/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , Drug Screening Assays, Antitumor , Female , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Male , Maleimides/chemical synthesis , Maleimides/pharmacology , Mice, Inbred BALB C , Mice, SCID , Molecular Structure , Platinum/chemistry , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Structure-Activity Relationship , Succinimides/chemical synthesis , Succinimides/pharmacology , Succinimides/therapeutic use
8.
Carbohydr Polym ; 269: 118334, 2021 Oct 01.
Article in English | MEDLINE | ID: mdl-34294344

ABSTRACT

To explore the disease resistance mechanism of chitosan conjugates, chitosan-gentamicin conjugate (CS-GT) was synthesized and systematically characterized, the immune mechanism of CS-GT on Litopenaeus vannamei infected with Vibrio parahaemolyticus was further explored. The results showed that imine groups in CS-GT were effectively reduced. Dietary supplementation of CS-GT can significantly increase the survival rate, total hemocyte counts, the antioxidant and immune related enzyme activity levels of shrimps (P < 0.05), which are all dose-dependent under the experimental conditions. In addition, CS-GT can protect the hepatopancreas from invading bacteria and alleviate inflammation. Particularly, CS-GT promotes the expressions of legumain (LGMN), lysosomal acid lipase (LIPA) and Niemann-Pick type C2 (NPC2) up-regulated. It is speculated that CS-GT may stimulate the lysosome to phagocytose pathogens more effectively. In conclusions, shrimps fed with CS-GT can produce immune response via lysosome and greatly improve the disease resistance to Vibrio parahaemolyticus.


Subject(s)
Chitosan/analogs & derivatives , Chitosan/therapeutic use , Gentamicins/therapeutic use , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Penaeidae/drug effects , Animals , Apoptosis/drug effects , Chitosan/chemical synthesis , Cysteine Endopeptidases/metabolism , Dietary Supplements , Gentamicins/chemical synthesis , Hemocytes/metabolism , Hepatopancreas/drug effects , Hepatopancreas/microbiology , Hepatopancreas/pathology , Immunologic Factors/chemical synthesis , Penaeidae/immunology , Penaeidae/metabolism , Penaeidae/microbiology , Phagocytes/metabolism , Sterol Esterase/metabolism , Vesicular Transport Proteins/metabolism , Vibrio parahaemolyticus/pathogenicity
9.
Biomed Pharmacother ; 141: 111924, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34328093

ABSTRACT

Silk fibroin is a protein with intrinsic characteristics that make it a good candidate as a scaffold for tissue engineering. Recent works have enhanced its benefits by adding inorganic phases that interact with silk fibroin in different ways. A systematic review was performed in four databases to study the physicochemical and biological performance of silk fibroin nanocomposites. In the last decade, only 51 articles contained either in vitro cell culture models or in vivo tests. The analysis of such works resulted in their classification into the following scaffold types: particles, mats and textiles, films, hydrogels, sponge-like structures, and mixed conformations. From the physicochemical perspective, the inorganic phase imbued in silk fibroin nanocomposites resulted in better stability and mechanical performance. This review revealed that the inorganic phase may be associated with specific biological responses, such as neovascularisation, cell differentiation, cell proliferation, and antimicrobial and immunomodulatory activity. The study of nanocomposites as tissue engineering scaffolds is a highly active area mostly focused on bone and cartilage regeneration with promising results. Nonetheless, there are still many challenges related to their application in other tissues, a better understanding of the interaction between the inorganic and organic phases, and the associated biological response.


Subject(s)
Biocompatible Materials/chemical synthesis , Fibroins/chemical synthesis , Nanocomposites/chemistry , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Animals , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/chemical synthesis , Biocompatible Materials/administration & dosage , Cell Proliferation/drug effects , Cell Proliferation/physiology , Fibroins/administration & dosage , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/chemical synthesis , Nanocomposites/administration & dosage , Neovascularization, Physiologic/drug effects , Neovascularization, Physiologic/physiology
10.
Angew Chem Int Ed Engl ; 60(34): 18734-18741, 2021 08 16.
Article in English | MEDLINE | ID: mdl-34124819

ABSTRACT

The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (-)-vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity. The synthesis allows for a high degree of flexibility in modifying the macrocyclic framework, including the formation of all possible stereoisomers. In total, 18 analogues were prepared. Two analogues with minor structural modifications showed clearly enhanced cancer cell line selectivity and reduced toxicity. Moreover, these compounds possessed broad inhibitory activity against innate immunological pathways in human PBMCs, including the DNA-sensing cGAS-STING pathway. Initial mechanistic characterization suggests a surprising impairment of the STING-TBK1 interaction.


Subject(s)
Immunologic Factors/pharmacology , Membrane Proteins/antagonists & inhibitors , Nucleotidyltransferases/antagonists & inhibitors , DNA/drug effects , DNA/metabolism , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/chemistry , Lactones/chemical synthesis , Lactones/chemistry , Lactones/pharmacology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Membrane Proteins/metabolism , Molecular Conformation , Nucleotidyltransferases/metabolism
11.
Res Vet Sci ; 138: 69-78, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34111716

ABSTRACT

Astaxanthin (AST) is a red pigment of carotenoid and is considered a high-quality keto-carotenoid pigment with food, livestock, cosmetic, therapeutic and nutraceutical proposes. Astaxanthin exists naturally in fish, crustacean, algae, and birds that naturally exists, principally as fatty acid esters. Many investigations have exhibited the beneficial impacts of astaxanthin when utilized as a pharmaceutical agent in animal nutrition. Astaxanthin has a variety of considerable biological actions, such as being antihypertensive, an antioxidant, anti-obesity properties, and anti-carcinogenic. Astaxanthin has recently acquired popularity as a powerful immunomodulator to maintain the health status and well-being of both animals and humans. The use of astaxanthin is broadly utilized in medical sciences and the nutrition pf aquatic species; however, it presently has limited applications in broader animal nutrition. Understanding astaxanthin's structure, source, and mode of action in the body provides a conceptual base for its clinical application and could enhance the screening of compounds associated with the treatment of many diseases. This review article aims to clarify the important aspects of astaxanthin such as its synthesis, bioavailability, and therapeutics actions, with special interest in practical applications. Awareness of this benefits and production is expected to aid the livestock industry to develop nutritional strategies that ensure the protection of animal health.


Subject(s)
Animal Husbandry , Immunologic Factors , Livestock , Animals , Biological Availability , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacokinetics , Immunologic Factors/therapeutic use , Xanthophylls/chemical synthesis , Xanthophylls/pharmacokinetics , Xanthophylls/therapeutic use
12.
Int J Mol Sci ; 22(6)2021 Mar 23.
Article in English | MEDLINE | ID: mdl-33806904

ABSTRACT

This study was conducted to compare the effects of commercially available (C) and green synthesized (GS) Zinc oxide nanoparticles (ZnO-NPs) on immunological responses of common carp (Cyprinus carpio) skin mucus. GS ZnO-NPs were generated using Thymus pubescent and characterized by UV-vis diffuse reflectance spectroscopy (DRS), Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), scanning electron microscope (SEM), and energy-dispersive X-ray spectroscopy (EDX). Fish (n = 150) were randomly allocated into five groups in triplicate and received a waterborne concentration of 0% (control), 25%, and 50% of LC50 96 h of commercially available (C1 and C2) and green synthesized ZnO-NPs (GS1 and GS2) for 21 days. Results from XRD displayed ZnO-NPs with 58 nm in size and UV-vis DRS, EDX, and FT-IR analysis showed that some functional groups from plant extract bonded to the surface of NPs. The SEM images showed that ZnO-NPs have conical morphology. Acute toxicity study showed a higher dose of LC5096h for green synthesized ZnO-NPs (78.9 mg.L-1) compared to the commercial source (59.95 mg.L-1). The highest activity of lysozyme and alternative complement activity (ACH50) were found in control and GS1 groups. A significant decrease in alkaline phosphatase activity (ALP) was found in C1 and C2 groups compared to other treatments. Protease activity (P) was significantly decreased in the C2 group compared to the control and GS groups. Total immunoglobulin (total Ig) content was the highest in the control. In addition, total Ig in the GS1 group was higher than GS2. The exposure to ZnO-NPs lowered total protein content in all experimental groups when compared to control. Present findings revealed lower induced immunosuppressive effects by green synthesized ZnO-NPs on key parameters of fish skin mucus.


Subject(s)
Carps/physiology , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Metal Nanoparticles/chemistry , Mucus/metabolism , Skin/drug effects , Skin/metabolism , Zinc Oxide/chemistry , Animals , Chemistry Techniques, Synthetic , Green Chemistry Technology , Metal Nanoparticles/ultrastructure , Spectrum Analysis
13.
J Med Chem ; 64(7): 3794-3812, 2021 04 08.
Article in English | MEDLINE | ID: mdl-33769811

ABSTRACT

The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10b as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+ chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aß25-35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.


Subject(s)
Alzheimer Disease/drug therapy , Coumaric Acids/therapeutic use , Histone Deacetylase 6/antagonists & inhibitors , Immunologic Factors/therapeutic use , Neuroprotective Agents/therapeutic use , Tryptamines/therapeutic use , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Animals , Catalytic Domain , Cell Line, Transformed , Coumaric Acids/chemical synthesis , Coumaric Acids/metabolism , Histone Deacetylase 6/chemistry , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/metabolism , Histone Deacetylase Inhibitors/therapeutic use , Immunologic Factors/chemical synthesis , Immunologic Factors/metabolism , Male , Melatonin/analogs & derivatives , Melatonin/metabolism , Melatonin/therapeutic use , Mice , Molecular Docking Simulation , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/metabolism , Structure-Activity Relationship , Tryptamines/chemical synthesis , Tryptamines/metabolism
14.
Bioorg Chem ; 109: 104754, 2021 04.
Article in English | MEDLINE | ID: mdl-33677416

ABSTRACT

Tumor immunotherapy is currently subject of intense scientific and clinical developments. In previous decade, therapists used natural immune system from the human body to treat several diseases. Although tumor immune disease is a big challenge, combinatorial therapeutic strategy has been succeeded to show the clinical significance. In this context, we discuss the HDAC6 and tumor immune diseases relationship. Also, we summarized the current state of knowledge that based on the combination treatments of the HDAC6 inhibitors (HDAC6is) with antitumor immunomodulatory agents. We observed that, the combination therapies slow down the tumor immune diseases by blocking the aggresome and proteasome pathway. The combination therapy was able to reduce M2 macrophage and increasing PD-L1 blockade sensitivity. Most importantly, multiple combinations of HDAC6is with other agents may consider as potential strategies to treat tumor immune diseases, by reducing the side effects and improve efficacy for the future clinical development.


Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Immunologic Factors/pharmacology , Immunotherapy , Neoplasms/therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Histone Deacetylase 6/chemistry , Histone Deacetylase 6/immunology , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/chemistry , Molecular Structure , Neoplasms/immunology , Neoplasms/pathology
15.
Nanoscale Horiz ; 6(2): 156-167, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33400743

ABSTRACT

The high mortality associated with glioblastoma multiforme (GBM) is attributed to its invasive nature, hypoxic core, resistant cell subpopulations and a highly immunosuppressive tumor microenvironment (TME). To support adaptive immune function and establish a more robust antitumor immune response, we boosted the local innate immune compartment of GBM using an immunostimulatory mesoporous silica nanoparticle, termed immuno-MSN. The immuno-MSN was specifically designed for systemic and proficient delivery of a potent innate immune agonist to dysfunctional antigen-presenting cells (APCs) in the brain TME. The cargo of the immuno-MSN was cyclic diguanylate monophosphate (cdGMP), a Stimulator of Interferon Gene (STING) agonist. Studies showed the immuno-MSN promoted the uptake of STING agonist by APCs in vitro and the subsequent release of the pro-inflammatory cytokine interferon ß, 6-fold greater than free agonist. In an orthotopic GBM mouse model, systemically administered immuno-MSN particles were taken up by APCs in the near-perivascular regions of the brain tumor with striking efficiency. The immuno-MSNs facilitated the recruitment of dendritic cells and macrophages to the TME while sparing healthy brain tissue and peripheral organs, resulting in elevated circulating CD8+ T cell activity (2.5-fold) and delayed GBM tumor growth. We show that an engineered immunostimulatory nanoparticle can support pro-inflammatory innate immune function in GBM and subsequently augment current immunotherapeutic interventions and improve their therapeutic outcome.


Subject(s)
Brain Neoplasms/therapy , Cyclic GMP/analogs & derivatives , Glioblastoma/therapy , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Nanoparticles/therapeutic use , Animals , Antigen-Presenting Cells/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , CD8-Positive T-Lymphocytes/drug effects , Cyclic GMP/chemical synthesis , Cyclic GMP/therapeutic use , Dendritic Cells/drug effects , Female , Immunologic Factors/chemical synthesis , Immunotherapy/methods , Interferon Type I/metabolism , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Porosity , RAW 264.7 Cells , Silicon Dioxide/chemistry , Tumor Microenvironment/drug effects
16.
Eur J Med Chem ; 213: 113057, 2021 Mar 05.
Article in English | MEDLINE | ID: mdl-33303237

ABSTRACT

The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels - TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.


Subject(s)
Immunologic Factors/chemical synthesis , Indazoles/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridones/chemistry , Shock, Septic/drug therapy , Amino Acid Sequence , Animals , Cytokines/metabolism , Dose-Response Relationship, Drug , Drug Discovery , Endotoxins/metabolism , Eukaryotic Initiation Factor-4E/metabolism , Humans , Immunologic Factors/pharmacology , Mice , Molecular Docking Simulation , Protein Binding , Protein Kinase Inhibitors/pharmacology , Shock, Septic/chemically induced , Signal Transduction , Structure-Activity Relationship
18.
J Drug Target ; 29(4): 430-438, 2021 04.
Article in English | MEDLINE | ID: mdl-33183080

ABSTRACT

The ultimate goal of bacterial based cancer therapy is to achieve non-toxic penetration and colonisation of the tumour microenvironment. To overcome this efficacy-limiting toxicity of anticancer immunotherapy, we have tested a therapy comprised of systemic delivery of a vascular disrupting agent to induce intratumoral necrotic space, cannabidiol to temporarily inhibit angiogenesis and acute inflammation, and a strain of Salmonella Typhimurium that was engineered for non-toxic colonisation and expression of immunomodulators within the tumour microenvironment. This combination treatment strategy was administered to transgenic mice burdened with autochthonous mammary gland tumours and demonstrated a statistically significant 64% slower tumour growth and a 25% increase in mean survival time compared to control animals without treatment. These experiments were accomplished with minimal toxicity as measured by less than 7% weight loss and a return to normal weight gain within three days following intravenous administration of the bacteria. Thus, non-toxic, robust colonisation of the microenvironment was achieved to produce a significant antitumor effect.


Subject(s)
Bioengineering/methods , Breast Neoplasms/therapy , Disease Models, Animal , Immunologic Factors/administration & dosage , Immunologic Factors/biosynthesis , Salmonella typhimurium/metabolism , Animals , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Immunologic Factors/chemical synthesis , Mice , Mice, Inbred BALB C , Mice, Transgenic , Salmonella typhimurium/chemistry , Salmonella typhimurium/immunology , Survival Rate , Tumor Burden/drug effects , Tumor Burden/physiology , Tumor Microenvironment/drug effects , Tumor Microenvironment/physiology , Virulence/immunology , Xenograft Model Antitumor Assays/methods
19.
Proc Natl Acad Sci U S A ; 117(52): 32962-32969, 2020 12 29.
Article in English | MEDLINE | ID: mdl-33318219

ABSTRACT

Clinical investigations have shown that a nonimmunogenic "cold" tumor is usually accompanied by few immunopositive cells and more immunosuppressive cells in the tumor microenvironment (TME), which is still the bottleneck of immune activation. Here, a fluorine assembly nanocluster was explored to break the shackles of immunosuppression, reawaken the immune system, and turn the cold tumor "hot." Once under laser irradiation, FS@PMPt produces sufficient reactive oxygen species (ROS) to fracture the ROS-sensitive linker, thus releasing the cisplatin conjugated PMPt to penetrate into the tumors and kill the regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Meanwhile, ROS will induce potent immunogenic cell death (ICD) and further promote the accumulation of dendritic cells (DCs) and T cells, therefore not only increasing the infiltration of immunopositive cells from the outside but also reducing the immunosuppressive cells from the inside to break through the bottleneck of immune activation. The FS@PMPt nanocluster regulates the immune process in TME from negative to positive, from shallow to deep, to turn the cold tumor into a hot tumor and provoke a robust antitumor immune response.


Subject(s)
Antineoplastic Agents/chemical synthesis , Fluorine/chemistry , Immunologic Factors/chemical synthesis , Nanoconjugates/chemistry , Tumor Microenvironment/drug effects , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Dendrimers/chemistry , Dendritic Cells/drug effects , Dendritic Cells/immunology , Female , Immunologic Factors/pharmacology , Mice , Mice, Inbred BALB C , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/immunology , Platinum/chemistry , Reactive Oxygen Species/metabolism , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Tumor Microenvironment/immunology
20.
Bull Exp Biol Med ; 170(1): 154-157, 2020 Nov.
Article in English | MEDLINE | ID: mdl-33231794

ABSTRACT

We studied the effect of KE and AED peptides on the expression of sirtuin-1, sirtuin-6, collagen I, cytokines (IL-1, TGF-ß), and transcription factor NF-κB in human skin fibroblasts during their replicative aging. Immunocytochemical analysis and confocal microscopy showed that KE peptide reduces the synthesis of factors of the inflammatory response IL-1, NF-κB, and TGF-ß and stimulates the synthesis of sirtuin-6. KE peptide normalizes the immunological function of human skin fibroblasts during their aging. AED peptide activates the synthesis of sirtuin-1, sirtuin-6, and collagen I in human skin fibroblasts during their replicative aging, which attests to its geroprotective effect.


Subject(s)
Antioxidants/pharmacology , Fibroblasts/drug effects , Gene Expression Regulation/drug effects , Immunologic Factors/pharmacology , Oligopeptides/pharmacology , Antioxidants/chemical synthesis , Cellular Senescence/drug effects , Collagen Type I/genetics , Collagen Type I/immunology , Female , Fibroblasts/cytology , Fibroblasts/immunology , Humans , Immunologic Factors/chemical synthesis , Interleukin-1/genetics , Interleukin-1/immunology , NF-kappa B/genetics , NF-kappa B/immunology , Oligopeptides/chemical synthesis , Primary Cell Culture , Signal Transduction , Sirtuin 1/genetics , Sirtuin 1/immunology , Sirtuins/genetics , Sirtuins/immunology , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology
SELECTION OF CITATIONS
SEARCH DETAIL
...