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https://www.readbyqxmd.com/read/29741098/monophosphoryl-lipid-a-prevents-impairment-of-medullary-thick-ascending-limb-hco-3-absorption-and-improves-plasma-hco-3-concentration-in-septic-mice
#1
Bruns A Watts, Thampi George, Edward R Sherwood, David W Good
Metabolic acidosis is the most common acid-base disorder in septic patients and is associated with increased mortality. Previously we demonstrated that sepsis induced by cecal ligation and puncture (CLP) impairs HCO3 - absorption in the MTAL by: 1) decreasing the intrinsic HCO3 - absorptive capacity, and 2) enhancing inhibition of HCO3 - absorption by LPS through upregulation of TLR4 signaling. Both effects depend on ERK activation. Monophosphoryl lipid A (MPLA) is a detoxified TLR4 agonist that enhances innate antimicrobial immunity and improves survival following sepsis...
May 9, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29728623/specific-features-of-human-monocytes-activation-by-monophosphoryl-lipid-a
#2
Ryme Chentouh, Catherine Fitting, Jean-Marc Cavaillon
We deciphered the mechanisms of production of pro- and anti-inflammatory cytokines by adherent human blood mononuclear cells (PBMC) activated by lipopolysaccharide (LPS) or monophosphoryl lipid A (MPLA). Both LPS and MPLA induced tumor necrosis factor (TNF) production proved to be dependent on the production of interleukin-1β (IL-1β). Of note, MPLA induced IL-1β release in human adherent PBMCs whereas MPLA was previously reported to not induce this cytokine in murine cells. Both LPS and MPLA stimulatory effects were inhibited by Toll-like receptor-4 (TLR4) antagonists...
May 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29702142/dual-tlr-agonist-nanodiscs-as-a-strong-adjuvant-system-for-vaccines-and-immunotherapy
#3
Rui Kuai, Xiaoqi Sun, Wenmin Yuan, Lukasz J Ochyl, Yao Xu, Alireza Hassani Najafabadi, Lindsay Scheetz, Min-Zhi Yu, Ishina Balwani, Anna Schwendeman, James J Moon
Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in vivo in a manner that is effective, facile, and amenable for clinical translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides...
April 24, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29686054/the-tlr4-agonist-monophosphoryl-lipid-a-drives-broad-resistance-to-infection-via-dynamic-reprogramming-of-macrophage-metabolism
#4
Benjamin A Fensterheim, Jamey D Young, Liming Luan, Ruby R Kleinbard, Cody L Stothers, Naeem K Patil, Allison G McAtee-Pereira, Yin Guo, Irina Trenary, Antonio Hernandez, Jessica B Fults, David L Williams, Edward R Sherwood, Julia K Bohannon
Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with Staphylococcus aureus and Candida albicans that was associated with augmented microbial clearance and organ protection...
April 23, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29682589/parenterally-administered-norovirus-gii-4-virus-like-particle-vaccine-formulated-with-aluminum-hydroxide-or-monophosphoryl-lipid-a-adjuvants-induces-systemic-but-not-mucosal-immune-responses-in-mice
#5
Suvi Heinimäki, Maria Malm, Timo Vesikari, Vesna Blazevic
Norovirus (NoV) is a main cause of acute gastroenteritis across all ages worldwide. NoV vaccine candidates currently in clinical trials are based on noninfectious highly immunogenic virus-like particles (VLPs) delivered intramuscularly (IM). Since NoV is an enteric pathogen, it is likely that mucosal immunity has a significant role in protection from infection in the intestine. Due to the fact that IM delivery of NoV VLPs does not generate mucosal immunity, we investigated whether NoV genotype GII.4 VLPs coadministered with aluminum hydroxide (Al(OH)3 ) or monophosphoryl lipid A (MPLA) would induce mucosal antibodies in mice...
2018: Journal of Immunology Research
https://www.readbyqxmd.com/read/29678225/synergistic-effect-of-co-stimulation-of-membrane-and-endosomal-tlrs-on-chicken-innate-immune-responses
#6
Sungwon Kim, Pete Kaiser, Dominika Borowska, Lonneke Vervelde
Toll-like receptor (TLR) ligands (TLR-Ls) are critical activators of immunity and are successfully being developed as vaccine adjuvants in both mammals and birds. In this study, we investigated the synergistic effect of co-stimulation of membrane and endosomal TLRs on the innate immune responses using chicken bone marrow-derived macrophages (BMMs), and studied the effect of age on the induction of innate responses. BMMs from 1 and 4-week-old birds were stimulated with Pam3Cys-SK4 (PCSK; TLR2), synthetic monophosphoryl lipid A (MPLA), Di[3-deoxy-d-manno-octulosonyl]-lipid A ammonium salt (KLA; TLR4), Gardiquimod, Resiquimod (R848; TLR7), CpG class B and C (TLR21)...
May 2018: Veterinary Immunology and Immunopathology
https://www.readbyqxmd.com/read/29673285/tlr-agonist-combinations-that-stimulate-th-type-i-polarizing-responses-from-human-neonates
#7
Naveen Surendran, Andrea Simmons, Michael E Pichichero
Each year millions of neonates die due to vaccine preventable infectious diseases. Our study seeks to develop novel neonatal vaccines and improve immunogenicity of early childhood vaccines by incorporating TLR agonist-adjuvant combinations that overcome the inherent neonatal Th2 bias and stimulate Th1 polarizing response from neonatal APCs. We systematically stimulated cord blood mononuclear cells with single and multiple combinations of TLR agonists and measured levels of IL-12p70, IFN-γ, IFN-α, IL-10, IL-13, TNF-α, IL-6 and IL-1β from cell culture supernatants...
January 1, 2018: Innate Immunity
https://www.readbyqxmd.com/read/29535714/formulation-in-dda-mpla-tdb-liposome-enhances-the-immunogenicity-and-protective-efficacy-of-a-dna-vaccine-against-mycobacterium-tuberculosis-infection
#8
Maopeng Tian, Zijie Zhou, Songwei Tan, Xionglin Fan, Longmeng Li, Nadeem Ullah
Despite the vaccine Mycobacterium bovis Bacillus Calmette-Guérin is used worldwide, tuberculosis (TB) remains the first killer among infectious diseases. An effective vaccine is urgently required. DNA vaccine has shown prophylactic as well as therapeutic effects against TB, while its weak immunogenicity hinders the application. As a strong inducer of Th1-biased immune response, DMT, consisting of dimethyldioctadecylammonium (DDA) and two pattern recognition receptor agonists monophosphoryl lipid A and trehalose 6,6'-dibehenate (TDB), was a newly developed liposomal adjuvant...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29468926/development-and-characterization-of-hbsag-loaded-eudragit-nanoparticles-for-effective-colonic-immunization
#9
Kantrol Kumar Sahu, Ravi Shankar Pandey
The present study was undertaken with an aim to investigate the potential of targeting colonic mucosa following oral vaccine delivery to generate prophylactic humoral and mucosal immune response. In present study, response surface methodology (RSM) using the central composite design (CCD) was applied for optimization of process and composition to get uniform, stable reproducible eudragit nanoparticles suitable for targeting to colon. The optimized formulation had the composition of 173 μg HBsAg, 250 mg polymers concentration (4:1 combination of Eudragit S-100 and L-100) and 2% w/v Polyvinyl alcohol (PVA) along with adjuvant Monophosphoryl lipid A (MPLA)...
March 20, 2018: Pharmaceutical Development and Technology
https://www.readbyqxmd.com/read/29454622/development-of-adjuvanted-solid-fat-nanoemulsions-for-pulmonary-hepatitis-b-vaccination
#10
Sunita Minz, Ravi Shankar Pandey
Pulmonary vaccination is one of the most promising routes for immunization owing to its noninvasive nature and induction of strong mucosal immunity and systemic response. In the present study, recombinant hepatitis B surface antigen loaded solid fat nanoemulsions (SFNs) as carrier system and monophosphoryl lipid A as an adjuvant-carrier system was prepared and evaluated as multiadjuvanted vaccine system for deep pulmonary vaccination. Deposition and clearance from the deep lung of rats were determined by gamma scintigraphy...
February 15, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29432824/immune-response-to-antigen-adsorbed-to-aluminum-hydroxide-particles-effects-of-co-adsorption-of-alf-or-alfq-adjuvant-to-the-aluminum-antigen-complex
#11
Zoltan Beck, Oscar B Torres, Gary R Matyas, David E Lanar, Carl R Alving
Aluminum salts have been used as vaccine adjuvants for >50 years, and they are currently present in at least 146 licensed vaccines worldwide. In this study we examined whether adsorption of Army Liposome Formulation (ALF) to an aluminum salt that already has an antigen adsorbed to it might result in improved immune potency of the aluminum-adsorbed antigen. ALF is composed of a family of anionic liposome-based adjuvants, in which the liposomes contain synthetic phospholipids having dimyristoyl fatty acyl groups, cholesterol and monophosphoryl lipid A (MPLA)...
April 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29377154/a-novel-glycocluster-molecule-prevents-timothy-induced-allergic-airway-inflammation-in-mice
#12
M Lehto, H Wolff, R Leino, H Alenius, J Savolainen
BACKGROUND: Allergen-specific immunotherapy (SIT) effectively alleviates type I allergic diseases characterized by T helper (Th)2-type immunity. Our recent studies have shown that a synthetic trivalent glycocluster, triacedimannose (TADM), suppresses the Th2-type allergic inflammation. The aim of this study was to compare TADM with two well-known adjuvants, unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG) and monophosphoryl lipid A (MPLA) in a grass allergen-induced chronic allergic inflammation model in mice...
January 26, 2018: Allergy
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
#13
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...
February 28, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29302041/analysis-of-cytokine-immune-response-profile-in-response-to-inflammatory-stimuli-in-mice-with-genetic-defects-in-fetal-and-adult-hemoglobin-chain-expression
#14
Ismat Khatri, Christian Alexander, Klaus Brandenburg, Zhiqi Chen, Adrian Heini, Didier Heumann, Jean-Pierre Mach, Vienna Mazzoli, Ernst Rietschel, Alexey Tersikh, Artur Ulmer, Kai Yu, Ulrich Zähringer, Reginald Gorczynski
Injections of a crude fetal sheep liver extract (FSLE) containing fetal hemoglobin, MPLA, and glutathione (GSSH) reversed cytokine changes in aged mice. To investigate the role of fetal hemoglobin we derived mice with homzygous deletions for either of the two major βchains, Hgbβma KO or Hgbβmi KO. Hgbβmi is the most prominent fetal Hgbβ chain, with Hgbβma more prominent in adult mice. Mice lacking another fetal Hgb chain, HgbεKO, died in utero. CHO cells transfected with cloned Hgb chains were used to produce proteins for preparation of rabbit heteroantibodes...
January 4, 2018: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29278302/monophosphoryl-lipid-a-adjuvanted-virosomes-with-ni-chelating-lipids-for-attachment-of-conserved-viral-proteins-as-cross-protective-influenza-vaccine
#15
Wei Dong, Yoshita Bhide, Sonny Marsman, Marijke Holtrop, Tjarko Meijerhof, Jacqueline de Vries-Idema, Aalzen de Haan, Anke Huckriede
Induction of CD8+ cytotoxic T cells (CTLs) to conserved internal influenza antigens, such as nucleoprotein (NP), is a promising strategy for the development of cross-protective influenza vaccines. However, influenza NP protein alone cannot induce CTL immunity due to its low capacity to activate antigen-presenting cells (APCs) and get access to the MHC class I antigen processing pathway. To facilitate the generation of NP-specific CTL immunity the authors develop a novel influenza vaccine consisting of virosomes with the Toll-like receptor 4 (TLR4) ligand monophosphoryl lipid A (MPLA) and the metal-ion-chelating lipid DOGS-NTA-Ni incorporated in the membrane...
December 26, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/29243216/lipid-a-adjuvanted-chylomicron-mimicking-solid-fat-nanoemulsions-for-immunization-against-hepatitis-b
#16
Sunita Minz, Ravi Shankar Pandey
Traditional parenteral recombinant hepatitis B virus (HBV) vaccines have effectively reduced the disease burden despite being able to induce seroprotective antibody titers in 5-10% vaccinated individuals (non-responders). Moreover, an estimated 340 million chronic HBV cases are in need of treatment. Development of safe, stable, and more effective hepatitis B vaccine formulation would address these challenges. Recombinant hepatitis B surface antigen (rHBsAg) entrapped solid fat nanoemulsions (SFNs) containing monophosphoryl lipid A (MPLA) that was prepared and optimized by quality by design (QbD) using response surface methodology (RSM), i...
December 14, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/29190754/encryption-of-agonistic-motifs-for-tlr4-into-artificial-antigens-augmented-the-maturation-of-antigen-presenting-cells
#17
Masaki Ito, Kazumi Hayashi, Tamiko Minamisawa, Sadamu Homma, Shigeo Koido, Kiyotaka Shiba
Adjuvants are indispensable for achieving a sufficient immune response from vaccinations. From a functional viewpoint, adjuvants are classified into two categories: "physical adjuvants" increase the efficacy of antigen presentation by antigen-presenting cells (APC) and "signal adjuvants" induce the maturation of APC. Our previous study has demonstrated that a physical adjuvant can be encrypted into proteinous antigens by creating artificial proteins from combinatorial assemblages of epitope peptides and those peptide sequences having propensities to form certain protein structures (motif programming)...
2017: PloS One
https://www.readbyqxmd.com/read/29179132/rational-incorporation-of-molecular-adjuvants-into-a-hybrid-nanoparticle-based-nicotine-vaccine-for-immunotherapy-against-nicotine-addiction
#18
Zongmin Zhao, Brian Harris, Yun Hu, Theresa Harmon, Paul R Pentel, Marion Ehrich, Chenming Zhang
Current clinically-tested nicotine vaccines have yet shown enhanced smoking cessation efficacy due to their low immunogenicity. Achieving a sufficiently high immunogenicity is a necessity for establishing a clinically-viable nicotine vaccine. This study aims to facilitate the immunogenicity of a hybrid nanoparticle-based nicotine vaccine by rationally incorporating toll-like receptor (TLR)-based adjuvants, including monophosphoryl lipid A (MPLA), Resiquimod (R848), CpG oligodeoxynucleotide 1826 (CpG ODN 1826), and their combinations...
February 2018: Biomaterials
https://www.readbyqxmd.com/read/29156775/monophosphoryl-lipid-a-attenuates-radiation-injury-through-tlr4-activation
#19
Jiaming Guo, Yuanyuan Chen, Xiao Lei, Yang Xu, Zhe Liu, Jianming Cai, Fu Gao, Yanyong Yang
Ionizing radiation causes severe damage to human body, and normal tissue toxicity in cancer radiotherapy also limits its further application. It is urgently required to develop safe and effective radioprotector. Our previous study has shown that toll like receptor 4 (TLR4) was dispensable for basal radiation resistance. However, severe toxicity of its traditional agonist lipopolysaccharide limits the clinical application. In present study, we demonstrated that monophosphoryl lipid A (MPLA), a potent TLR4 agonist with low toxicity, effectively attenuated radiation injury on in vitro and in vivo ...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29112822/synthesis-and-immunological-comparison-of-differently-linked-lipoarabinomannan-oligosaccharide-monophosphoryl-lipid-a-conjugates-as-antituberculosis-vaccines
#20
Lizhen Wang, Shaojie Feng, Subo Wang, Hui Li, Zhongwu Guo, Guofeng Gu
A monophosphoryl lipid A (MPLA) derivative having the 6'-OH group substituted with an NH2 group was synthesized and coupled with the upstream terminal tetrasaccharide of mycobacterial lipoarabinomannan (LAM) via an amide bond to create a novel type of MPLA-based fully synthetic glycoconjugate vaccine. The same tetrasaccharide was also coupled with MPLA at the 1-O-position. Immunological activities of the two synthetic conjugates were evaluated in mice and compared. Both afforded robust overall and IgG antibody responses, but intraperitoneal injection elicited responses significantly stronger than those from subcutaneous injection...
December 1, 2017: Journal of Organic Chemistry
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