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https://www.readbyqxmd.com/read/29452258/recent-findings-related-to-immune-responses-against-leptospirosis-and-novel-strategies-to-prevent-infection
#1
Frédérique Vernel-Pauillac, Catherine Werts
What are the new approaches and emerging ideas to prevent leptospirosis, a neglected bacterial re-emerging zoonotic disease? How do Leptospira interrogans escape the host defenses? We aim here to review and discuss the most recent literature that provides some answers to these questions, in particular data related to a better understanding of adaptive and innate immunity towards leptospires, and design of vaccines. This is an opinion paper, not a comprehensive review. We will try to highlight the new strategies and technologies boosting the search for drugs and vaccines...
February 13, 2018: Microbes and Infection
https://www.readbyqxmd.com/read/29422777/imiquimod-inhibits-growth-and-induces-differentiation-of-myeloid-leukemia-cell-lines
#2
Eva Villamón, Javier González-Fernández, Esperanza Such, José Vicente Cervera, Daniel Gozalbo, M Luisa Gil
Background: The antitumoral effects of different Toll-like receptor (TLRs) agonists is mediated by activating immune responses to suppress tumors growth, although TLR ligands may also have a direct effect on tumoral cells. Given that TLR signaling induces hematopoietic cell differentiations this may serve as a novel differentiation therapeutic approach for AML. Methods: We investigated the effects of agonists for the ten human TLRs on the proliferation, apoptosis, cell cycle and differentiation of ten different types of myeloid leukemia cell lines (HL-60, U-937, KG-1, KG-1a, K-562, Kasumi-1, EOL-1, NB4, MOLM-13 and HEL)...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/29415982/combination-therapy-with-proteasome-inhibitors-and-tlr-agonists-enhances-tumour-cell-death-and-il-1%C3%AE-production
#3
Anthony C Tang, Seyed M Rahavi, Shan-Yu Fung, Henry Y Lu, Hong Yang, Chinten J Lim, Gregor S Reid, Stuart E Turvey
Proteasome inhibitors have emerged as an effective therapy for the treatment of haematological malignancies; however, their efficacy can be limited by the development of tumour resistance mechanisms. Novel combination strategies including the addition of TLR adjuvants to increase cell death and augment immune responses may help enhance their effectiveness. Although generally thought to inhibit inflammatory responses and NF-κB activation, we found that under specific conditions proteasome inhibitors can promote inflammatory responses by mediating IL-1β maturation and secretion after TLR stimulation...
February 7, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29413846/tnip1-reduction-sensitizes-keratinocytes-to-post-receptor-signalling-following-exposure-to-tlr-agonists
#4
Swetha Rudraiah, Rambon Shamilov, Brian J Aneskievich
Cell level inflammatory signalling is a combination of initiation at cell membrane receptors and modulation by cytoplasmic regulatory proteins. For keratinocytes, the predominant cell type in the epidermis, this would include toll-like receptors (TLR) and cytoplasmic proteins that propagate or dampen post-receptor signalling. We previously reported that increased levels of tumor necrosis factor α induced protein 3-interacting protein 1 (TNIP1) in HaCaT keratinocytes leads to decreased expression of stress response and inflammation-associated genes...
February 5, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29398273/the-choice-of-linker-for-conjugating-r848-to-inactivated-influenza-virus-determines-the-stimulatory-capacity-for-innate-immune-cells
#5
Marlena M Westcott, Elene A Clemens, Beth C Holbrook, S Bruce King, Martha A Alexander-Miller
Inactivated influenza vaccines are not approved for use in infants less than 6 months of age due to poor immunogenicity in that population. While the live attenuated influenza vaccine has the potential to be more immunogenic, it is not an option for infants and other vulnerable populations, including the elderly and immunocompromised individuals due to safety concerns. In an effort to improve the immunogenicity of the inactivated vaccine for use in vulnerable populations, we have used an approach of chemically crosslinking the Toll-like receptor (TLR) 7/8 agonist R848 directly to virus particles...
February 2, 2018: Vaccine
https://www.readbyqxmd.com/read/29386357/eradication-of-spontaneous-malignancy-by-local-immunotherapy
#6
Idit Sagiv-Barfi, Debra K Czerwinski, Shoshana Levy, Israt S Alam, Aaron T Mayer, Sanjiv S Gambhir, Ronald Levy
It has recently become apparent that the immune system can cure cancer. In some of these strategies, the antigen targets are preidentified and therapies are custom-made against these targets. In others, antibodies are used to remove the brakes of the immune system, allowing preexisting T cells to attack cancer cells. We have used another noncustomized approach called in situ vaccination. Immunoenhancing agents are injected locally into one site of tumor, thereby triggering a T cell immune response locally that then attacks cancer throughout the body...
January 31, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29378134/tlr-agonist-conjugation-a-chemical-perspective
#7
Bob J Ignacio, Tyler Albin, Aaron P Esser-Kahn, Martijn Verdoes
Toll-like receptors (TLRs) are vital elements of the mammalian immune system that function by recognizing pathogen-associated molecular patterns (PAMPs), bridging innate and adaptive immunity. They have become a prominent therapeutic target for the treatment of infectious diseases, cancer, and allergies, with many TLR agonists currently in clinical trials or approved as immunostimulants. Numerous studies have shown that conjugation of TLR agonists to other molecules can beneficially influence their potency, toxicity, pharmacokinetics, or function...
January 29, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29374468/chronic-kidney-disease-alters-lipid-trafficking-and-inflammatory-responses-in-macrophages-effects-of-liver-x-receptor-agonism
#8
Ryohei Kaseda, Yohei Tsuchida, Hai-Chun Yang, Patricia G Yancey, Jianyong Zhong, Huan Tao, Aihua Bian, Agnes B Fogo, Mac Rae F Linton, Sergio Fazio, Talat Alp Ikizler, Valentina Kon
BACKGROUND: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. METHODS: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively)...
January 27, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29366653/discovery-of-selective-2-4-diaminoquinazoline-toll-like-receptor-7-tlr-7-agonists
#9
Serge Pieters, David McGowan, Florence Herschke, Frederik Pauwels, Bart Stoops, Stefaan Last, Werner Embrechts, Annick Scholliers, Wendy Mostmans, Kris Van Dijck, Bertrand Van Schoubroeck, Tine Thoné, Dorien De Pooter, Gregory Fanning, Mari Luz Rosauro, Mourad Daoubi Khamlichi, Ioannis Houpis, Eric Arnoult, Tim H M Jonckers, Pierre Raboisson
The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice.
January 16, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29364499/toll-like-receptors-and-radiation-protection
#10
Z Liu, X Lei, X Li, J-M Cai, F Gao, Y-Y Yang
Exposure to ionizing radiation (IR) causes severe injuries to the human body, and normal tissue toxicity also limits the further application of cancer radiotherapy. However, current clinically used radioprotective agents are difficult to produce satisfactory effects. Toll-Like receptor (TLR) is a kind of pattern recognition receptor (PRR) that has been extensively studied for radioprotection in recent years. Several TLR family members are closely related to radioprotection. In cultured cells, TLR2, TLR5 or TLR9 agonist was proved to inhibit radiation-induced apoptosis and increase cell survival...
January 2018: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29348267/toll-like-receptor-9-dependent-ampk%C3%AE-activation-occurs-via-tak1-and-contributes-to-rhoa-rock-signaling-and-actin-polymerization-in-vascular-smooth-muscle-cells
#11
Cameron G McCarthy, Camilla Ferreira Wenceslau, Safia Ogbi, Theodora Szasz, R Clinton Webb
Traditionally, Toll-like receptor (TLR)9 signals through a MyD88-dependent cascade that results in pro-inflammatory gene transcription. Recently it was reported that TLR9 also participates in a stress tolerance signaling cascade in non-immune cells. In this non-canonical pathway, TLR9 binds to and inhibits sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), modulating intracellular calcium handling, and subsequently resulting in the activation of 5'-AMP-activated protein kinase (AMPK)α. We have previously reported TLR9 causes increased contraction in isolated arteries; however, the mechanisms underlying this vascular dysfunction need to be further clarified...
January 18, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29345364/the-n-terminal-peptide-moiety-of-the-mycobacterium-tuberculosis-19-kda-lipoprotein-harbors-rp105-agonistic-properties
#12
Thomas E Schultz, Karl-Heinz Wiesmüller, Megan Lucas, Karen M Dobos, Alan G Baxter, Antje Blumenthal
Radioprotective 105 kDa (RP105, CD180) is a member of the Toll-like receptor (TLR) family that interacts with TLR2 and facilitates recognition of mature lipoproteins expressed by Mycobacterium tuberculosis and Mycobacterium bovis BCG. In this study, we used synthetic lipopeptide analogs of the M. tuberculosis 19 kDa lipoprotein to define structural characteristics that promote RP105-mediated host cell responses. A tripalmitoylated lipopeptide composed of the first 16 N-terminal amino acids of the M. tuberculosis 19 kDa lipoprotein induced RP105-dependent TNF and IL-6 production by macrophages...
January 9, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29344995/activation-of-human-cd141-and-cd1c-dendritic-cells-in-vivo-with-combined-tlr-3-and-tlr-7-8-ligation
#13
Frances E Pearson, Karshing Chang, Yoshihito Minoda, Ingrid M Leal Rojas, Oscar L Haigh, Ghazal Daraj, Kirsteen M Tullett, Kristen J Radford
Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141+ and CD1c+ myeloid and CD123+ plasmacytoid dendritic cells (DC) develop from human cord blood CD34+ cells in immunodeficient mice. CD141+ DC are the human equivalents of murine CD8+ /CD103+ DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte (CTL) responses, making them attractive targets to exploit for the development of new cancer immunotherapies...
January 18, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29330675/recognizing-conserved-non-canonical-localization-patterns-of-toll-like-receptors-in-tissues-and-across-species
#14
REVIEW
Glenn Hamonic, J Alex Pasternak, Heather L Wilson
Toll-like receptors (TLR) 1, 2, 4, 5 and 6 were originally characterized as exclusively expressed on the cell surface and TLR 3, 7, 8 and 9 were said to be localized to the endosomes. However, continued research in this area shows that TLR localization may be altered across cell-types, and in response to stimulation, age or disease. Mucosal surfaces must remain tolerant to the commensal flora and thus intracellular or basal lateral localization of TLRs at mucosal surfaces may be necessary to prevent induction of an inflammatory response to commensal flora while still allowing the possibility for the receptors to prime an immune response when a pathogen has crossed the epithelial barrier...
January 12, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29325699/co-delivery-of-tumor-antigen-and-dual-toll-like-receptor-ligands-into-dendritic-cell-by-silicon-microparticle-enables-efficient-immunotherapy-against-melanoma
#15
Motao Zhu, Xilai Ding, Ruifang Zhao, Xuewu Liu, Haifa Shen, Chunmei Cai, Mauro Ferrari, Helen Y Wang, Rong-Fu Wang
Despite the importance and promise of cancer vaccines for broader prevention and treatment of cancer, limited clinical responses are observed, suggesting that key rational designs are required for inducing potent immune responses against cancer. Here we report a mesoporous silicon vector (MSV) as a multi-functional microparticle for formulating an efficient cancer vaccine composed of B16 melanoma derived-tyrosinase related protein 2 (TRP2) peptide and dual toll-like receptor (TLR) agonists. We demonstrated that MSV microparticles protected the peptide from rapid degradation for prolonged antigen presentation to immune cells...
January 8, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29301276/rosiglitazone-as-a-modulator-of-tlr4-and-tlr3-signaling-pathways-in-rat-primary-neurons-and-astrocytes
#16
Dmitry V Chistyakov, Nadezda V Azbukina, Alexandr V Lopachev, Ksenia N Kulichenkova, Alina A Astakhova, Marina G Sergeeva
An antidiabetic drug of the thiazolidinedione class, rosiglitazone (RG) demonstrates anti-inflammatory properties in various brain pathologies. The mechanism of RG action in brain cells is not fully known. To unravel mechanisms of RG modulation of toll-like receptor (TLR) signaling pathways, we compare primary rat neuron and astrocyte cultures stimulated with the TLR4 agonist lipopolysaccharide (LPS) and the TLR3 agonist poly I:C (PIC). Both TLR agonists induced tumor necrosis factor (TNFα) release in astrocytes, but not in neurons...
January 2, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29281743/hdac6-controls-innate-immune-and-autophagy-responses-to-tlr-mediated-signalling-by-the-intracellular-bacteria-listeria-monocytogenes
#17
Olga Moreno-Gonzalo, Marta Ramírez-Huesca, Noelia Blas-Rus, Danay Cibrián, María Laura Saíz, Inmaculada Jorge, Emilio Camafeita, Jesús Vázquez, Francisco Sánchez-Madrid
Recent evidence on HDAC6 function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Our data show that Hdac6-/- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6+/+ cells, correlating with weaker induction of IFN-related genes, pro-inflammatory cytokines and nitrite production after bacterial infection...
December 27, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29261777/self-extracellular-rna-acts-in-synergy-with-exogenous-danger-signals-to-promote-inflammation
#18
Frederik Noll, Jonas Behnke, Silke Leiting, Kerstin Troidl, Gustavo Teixeira Alves, Holger Müller-Redetzky, Klaus T Preissner, Silvia Fischer
Self-extracellular RNA (eRNA), released from stressed or injured cells upon various pathological situations such as ischemia-reperfusion-injury, has been shown to act as an alarmin by inducing procoagulatory and proinflammatory responses. In particular, M1-polarization of macrophages by eRNA resulted in the expression and release of a variety of cytokines, including tumor necrosis factor (TNF)-α or interleukin-6 (IL-6). The present study now investigates in which way self-eRNA may influence the response of macrophages towards various Toll-like receptor (TLR)-agonists...
2017: PloS One
https://www.readbyqxmd.com/read/29258247/targeting-nrf2-for-improved-skin-barrier-function-and-photoprotection-focus-on-the-achiote-derived-apocarotenoid-bixin
#19
REVIEW
Montserrat Rojo de la Vega, Andrea Krajisnik, Donna D Zhang, Georg T Wondrak
The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as 'annatto') originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times...
December 18, 2017: Nutrients
https://www.readbyqxmd.com/read/29248267/a-combined-carrier-adjuvant-system-of-peptide-nanofibers-and-toll-like-receptor-agonists-potentiates-robust-cd8-t-cell-responses
#20
Jai S Rudra, Brianne N Banasik, Gregg N Milligan
Improving CD8+ T cell responses activated by subunit vaccination is crucial for improving vaccine efficacy and safety. Here we report a carrier-adjuvant system composed of self-assembling peptide nanofibers presenting an immunodominant antigen from herpes simplex virus (HSV) and toll-like receptor (TLR) agonists that induces robust effector and memory CD8+ T cell responses in mice. The effector function of vaccine-induced CD8+ T cells was influenced by the type of TLR agonist. The use of CpG (TLR9 agonist) resulted in significantly greater specific in vivo cytotoxicity and trended towards more cells producing both IFN-γ and TNF-α compared to gardiquimod (TLR7 agonist)...
December 13, 2017: Vaccine
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