scholarly journals Design and Immunological Evaluation of a Hybrid Peptide as a Potent TLR2 Agonist by Structure-Based Virtual Screening

2021 ◽  
Vol 9 ◽  
Author(s):  
Lulu Zhang ◽  
Xubiao Wei ◽  
Rijun Zhang ◽  
Paul E. Mozdziak ◽  
Dayong Si ◽  
...  
Keyword(s):  
Immune System ◽  
Organ Injury ◽  
Immunomodulatory Activity ◽  
Immunomodulatory Effects ◽  
T Lymphocyte Subsets ◽  
Immunomodulatory Agents ◽  
Tlr2 Agonist ◽  
Hybrid Peptides ◽  
Long Time

Immunity is a versatile defensive response that is involved in protecting against disease by identifying and destroying self and non-self harmful substances. As a state of temporary or permanent immune dysfunction, immunosuppression can make an organism more susceptible to infection, organ injury, and cancer due to damage to the immune system. It has taken a long time to develop new immunomodulatory agents to prevent and treat immunosuppressive diseases. In recent years, Toll-like receptor 2 (TLR2) agonists have been reported to have profound effects on the immune system, and they are regarded as potent immunomodulatory candidates. TP5 and LL-37, the potent immunomodulatory agents, have been reported to produce a robust innate immune response by binding to TLR2. However, their development has been weakened by several concerns, such as potential cytotoxicity, weak physiological stability and poor immunomodulatory activity. To overcome these challenges, hybridization has been proposed. Therefore, six hybrid peptides (LTPa, LTPb, LTPc, TPLa, TPLb, and TPLc) were designed by combining the full-length TP5 with a characteristic fragment of LL-37 that included LL-37 (13–36), LL-37 (17–29), and LL-37 (13–31). LTPa, the most potent TLR2 agonist, was simply and effectively screened by molecular docking and in vitro experiments. Furthermore, the immunomodulatory effects of LTPa were confirmed by a CTX-immunosuppressed murine model, which demonstrated that LTPa successfully inhibit immunosuppression, increased immune organ indices, enhanced DC maturation, regulated T lymphocyte subsets, and increased cytokine and Ig contents. Our study also revealed that the immunomodulatory effects of LTPa are associated with binding to TLR2, forming TLR2 clusters, and activating the NF-κB signaling pathway.

scholarly journals Targeting the TLR2 Receptor With a Novel Thymopentin-Derived Peptide Modulates Immune Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Xubiao Wei ◽  
Lulu Zhang ◽  
Rijun Zhang ◽  
Rujuan Wu ◽  
James N. Petitte ◽  
...  
Keyword(s):  
Immune Responses ◽  
Half Life ◽  
In Silico Analysis ◽  
Binding Activity ◽  
Organ Injury ◽  
Immunomodulatory Activity ◽  
T Lymphocyte Subsets ◽  
Hybrid Peptides ◽  
Functional Peptides

The innate and adaptive immune systems act in concert to protect us from infectious agents and other harmful substances. As a state of temporary or permanent immune dysfunction, immunosuppression can make an organism more susceptible to infection, organ injury, and cancer due to damage to the immune system. It takes a long time to develop new immunomodulatory agents to prevent and treat immunosuppressive diseases, with slow progress. Toll-like receptor 2 (TLR2) agonists have been reported as potential immunomodulatory candidates due to their effective activation of immune responses. It has been demonstrated that thymopentin (TP5) could modulate immunity by binding to the TLR2 receptor. However, the fairly short half-life of TP5 greatly reduces its pharmacological potential for immunosuppression therapy. Although peptide cathelicidin 2 (CATH2) has a long half-life, it shows poor immunomodulatory activity and severe cytotoxicity, which seriously hampers its clinical development. Peptide hybridization is an effective approach for the design and engineering of novel functional peptides because hybrid peptides combine the advantages and benefits of various native peptides. In this study, to overcome all these challenges faced by the parental peptides, six hybrid peptides (CaTP, CbTP, CcTP, TPCa, TPCb, and TPCc) were designed by combining the full-length TP5 with different active fragments of CATH2. CbTP, the most potent TLR2 agonist among the six hybrid peptides, was effectively screened through in silico analysis and in vitro experiments. The CbTP peptide exhibited lower cytotoxicity than either CATH2 or TP5. Furthermore, the immunomodulatory effects of CbTP were confirmed in a CTX-immunosuppressed mouse model, which showed that CbTP has increased immunopotentiating activity and physiological stability compared to the parental peptides. CbTP successfully inhibited immunosuppression and weight loss, increased immune organ indices, and improved CD4+/CD8+ T lymphocyte subsets. In addition, CbTP significantly increased the production of the cytokine TNF-α and IL-6, and the immunoglobulins IgA, IgM, and IgG. The immunoenhancing effects of CbTP were attributed to its TLR2-binding activity, promoting the formation of the TLR2 cluster, the activation of the TLR2 receptor, and thus activation of the downstream MyD88-NF-кB signaling pathway.

scholarly journals Development of a Highly Efficient Hybrid Peptide That Increases Immunomodulatory Activity Via the TLR4-Mediated Nuclear Factor-κB Signaling Pathway

2019 ◽  
Vol 20 (24) ◽  
pp. 6161
Author(s):  
Lulu Zhang ◽  
Xubiao Wei ◽  
Rijun Zhang ◽  
Matthew Koci ◽  
Dayong Si ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Immunosuppressive Agents ◽  
Immunomodulatory Activity ◽  
Hybrid Peptide ◽  
T Lymphocyte Subsets ◽  
Necrosis Factor Alpha ◽  
Hybrid Peptides ◽  
Macrophage Phagocytosis ◽  
Native Peptides

Immunity is a defensive response that fights disease by identifying and destroying harmful substances or microbiological toxins. Several factors, including work-related stress, pollution, and immunosuppressive agents, contribute to low immunity and poor health. Native peptides, a new class of immunoregulatory agents, have the potential for treating immunodeficiencies, malignancies, and infections. However, the potential cytotoxicity and low immunoregulatory activity and stability of native peptides have prevented their development. Therefore, we designed three hybrid peptides (LTAa, LTAb, and LTAc) by combining a characteristic fragment of LL-37 with an active Tα1 center that included Tα1 (17–24), Tα1 (20–25), and Tα1 (20–27). The best hybrid peptide (LTAa), according to molecule docking and in vitro experiments, had improved immunoregulatory activity and stability with minimal cytotoxicity. We investigated the immunoregulatory effects and mechanisms of LTAa using a cyclophosphamide-immunosuppressed murine model. LTAa effectively reversed immunosuppression by enhancing immune organ development, activating peritoneal macrophage phagocytosis, regulating T lymphocyte subsets, and increasing cytokine (tumor necrosis factor-alpha, interleukin-6, and interleukin-1β) and immunoglobulin (IgA, IgG, and IgM) contents. The immunomodulatory effects of LTAa may be associated with binding to the TLR4/MD-2 complex and activation of the NF-κB signaling pathway. Therefore, LTAa could be an effective therapeutic agent for improving immune function.

Effects of Pouteria cambodiana extracts on in vitro immunomodulatory activity of mouse immune system

Fitoterapia ◽  
2006 ◽  
Vol 77 (3) ◽  
pp. 189-193 ◽  
Author(s):  
Aranya Manosroi ◽  
Aurasorn Saraphanchotiwitthaya ◽  
Jiradej Manosroi
Keyword(s):  
Immune System ◽  
Immunomodulatory Activity

scholarly journals Antitumor and immunomodulatory activity of Inonotus obliquus

2017 ◽  
Vol 63 (2) ◽  
pp. 48-58 ◽  
Author(s):  
Justyna Staniszewska ◽  
Marcin Szymański ◽  
Ewa Ignatowicz
Keyword(s):  
Immune System ◽  
Tumor Cells ◽  
Good Alternative ◽  
Immunomodulatory Activity ◽  
Host Immune System ◽  
Protein Synthesis Inhibition ◽  
Inonotus Obliquus ◽  
Different Types

SummaryThe article presents the antitumor and immunomodulatory activity of compounds and extracts fromInonotus obliquus.Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention.In vitroexperiments have shown the inhibition of inflammation with the influence of action ofI. obliquusextracts; however,in vivoexperiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

scholarly journals Immunostimulants in respiratory diseases: focus on Pidotimod

2019 ◽  
Vol 14 ◽  
Author(s):  
Francesca Puggioni ◽  
Magna Alves-Correia ◽  
Manar-Farouk Mohamed ◽  
Niccolò Stomeo ◽  
Riccardo Mager ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Respiratory Diseases ◽  
Dendritic Cell Maturation ◽  
Immunomodulatory Activity ◽  
T Lymphocyte Subsets ◽  
T Lymphocyte Proliferation ◽  
Hla Dr ◽  
Airway Infections ◽  
Tract Infections

Usefulness of Pidotimod and its role as immunostimulant, has been discussed, we know, for several decades. Nevertheless, there is still much to know. Understanding its mechanisms and its potential usefulness in airway infections and its prevention, asthma both Th2 and non Th2 type, bronchiectasis, as adjuvant in vaccination and in allergen immunotherapy still remains to clearly unveil. The aim of this paper was to provide a useful updated review of the role of the main available immunostimulants, giving particular focus on Pidotimod use and its potentials utility in respiratory diseases. Pidotimod showed its usefulness in reducing need for antibiotics in airway infections, increasing the level of immunoglobulins (IgA, IgM, IgG) and T-lymphocyte subsets (CD3+, CD4+) endowed with immunomodulatory activity that affect both innate and adaptive immune responses. Higher expression of TLR2 and of HLA-DR molecules, induction of dendritic cell maturation and release of pro-inflammatory molecules, stimulation of T lymphocyte proliferation and differentiation toward a Th1 phenotype, as well as an increase of the phagocytosis have been demonstrated to be associated with Pidotimod in in vitro studies. All these activities are potentially useful for several respiratory conditions such as asthma, COPD, and recurrent respiratory tract infections.

scholarly journals Pairwise Interactions in Adjuvant Combinations Dictate Immune Responses and Inform Cancer Immunotherapy Design

2020 ◽  
Author(s):  
Surya Pandey ◽  
Adam Gruenbaum ◽  
Tamara Kanashova ◽  
Philipp Mertins ◽  
Philippe Cluzel ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Mouse Models ◽  
Protein Secretion ◽  
Immune Cells ◽  
Rational Design ◽  
Complex Mixtures ◽  
Immunomodulatory Agents ◽  
Pairwise Interactions

SUMMARYThe immune system makes decisions in response to complex combinations of microbial inputs. We do not understand the combinatorial logic that governs how the interplay between higher-order combinations of microbial or adjuvant signals shape immune responses, which hampers the rational design of vaccines and immunotherapies. Here, using in vitro coculture experiments and statistical analyses, we discover a general property for the combinatorial sensing of microbial signals, whereby the effects of triplet combinations of adjuvants on immune responses can be explained by the effects of single and pairwise stimulations. Mechanistically, we find that adjuvant singles and pairs dictate the information signaled by triplets in mouse and human DCs at the levels of transcription, chromatin and protein secretion. Furthermore, we exploit this simplifying property to develop and characterize cell-based immunotherapies using adjuvant combinations with anti-tumor properties in mouse models. We conclude that the processing of complex mixtures of microbial or adjuvant inputs by immune cells is governed by pairwise effects, which will inform the rationale combination of immunomodulatory agents such as adjuvants to manipulate immunity.

scholarly journals Immunomodulatory Effects and Mechanisms of Curcuma Species and Their Bioactive Compounds: A Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuandani ◽  
Ibrahim Jantan ◽  
Ade Sri Rohani ◽  
Imam Bagus Sumantri
Keyword(s):  
Clinical Trials ◽  
Bioactive Metabolites ◽  
Future Research ◽  
Immunomodulatory Effects ◽  
Research Strategies ◽  
Immunomodulatory Agents ◽  
Preclinical Pharmacokinetics ◽  
Underlying Mechanisms

Curcuma species (family: Zingiberaceae) are widely utilized in traditional medicine to treat diverse immune-related disorders. There have been many scientific studies on their immunomodulating effects to support their ethnopharmacological uses. In this review, the efficacy of six Curcuma species, namely, C. longa L., C. zanthorrhiza Roxb., C. mangga Valeton & Zijp, C. aeruginosa Roxb. C. zedoaria (Christm.) Roscoe, and C. amada Roxb., and their bioactive metabolites to modulate the immune system, their mechanistic effects, and their potential to be developed into effective and safe immunomodulatory agents are highlighted. Literature search has been carried out extensively to gather significant findings on immunomodulating activities of these plants. The immunomodulatory effects of Curcuma species were critically analyzed, and future research strategies and appropriate perspectives on the plants as source of new immunomodulators were discussed. Most of the pharmacological investigations to evaluate their immunomodulatory effects were in vivo and in vitro experiments on the crude extracts of the plants. The extracts were not chemically characterized or standardized. Of all the Curcuma species investigated, the immunomodulatory effects of C. longa were the most studied. Most of the bioactive metabolites responsible for the immunomodulating activities were not determined, and mechanistic studies to understand the underlying mechanisms were scanty. There are limited clinical studies to confirm their efficacy in human. Of all the bioactive metabolites, only curcumin is undergoing extensive clinical trials based on its anti-inflammatory properties and main use as an adjuvant for the treatment of cancer. More in-depth studies to understand the underlying mechanisms using experimental in vivo animal models of immune-related disorders and elaborate bioavailability, preclinical pharmacokinetics, and toxicity studies are required before clinical trials can be pursued for development into immunomodulatory agents.

scholarly journals IL-1β primed mesenchymal stromal cells moderate hemorrhagic shock-induced organ injuries

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Clotilde Aussel ◽  
Nathalie Baudry ◽  
Marion Grosbot ◽  
Cécile Caron ◽  
Eric Vicaut ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Kidney Injury ◽  
Organ Injury ◽  
Immunomodulatory Activity ◽  
In Vitro Characterization ◽  
Liver And Kidney

Abstract Background Organ damages following hemorrhagic shock (HS) have been partly attributed to an immunological dysfunction. The current challenge in the management of HS patients is to prevent organ injury-induced morbidity and mortality which currently has not etiological treatment available. Mesenchymal stromal cells (MSC) are used in clinical cell therapy for immunomodulation and tissue repair. In vitro priming is often used to improve the immunomodulation efficiency of MSC before administration. Objective Assess the effect of naive MSC (MSCn) or interleukin (IL)-1β primed (MSCp) treatment in a context of HS-induced organ injury. Methods Rats underwent fixed pressure HS and were treated with allogenic MSCn or MSCp. Liver and kidney injuries were evaluated 6h later by histological and biochemical analysis. Whole blood was collected to measure leukocytes phenotypes. Then, in vitro characterization of MSCn or MSCp was carried out. Results Plasma creatinine, blood urea nitrogen, and cystatin C were decrease by MSCp infusion as well as kidney injury molecule (KIM)-1 on histological kidney sections. Transaminases, GGT, and liver histology were normalized by MSCp. Systemic cytokines (IL-1α, IL-6, and IL-10) as well as CD80, 86, and PD-1/PDL-1 axis were decreased by MSCp on monocytes and granulocytes. In vitro, MSCp showed higher level of secreted immunomodulatory molecules than MSCn. Conclusion An early administration of MSCp moderates HS-induced kidney and liver injury. IL-1β priming improves MSC efficiency by promoting their immunomodulatory activity. These data provide proof of concept that MSCp could be a therapeutic tool to prevent the appearance of organs injury following HS.

scholarly journals Evaluation of immunomodulatory effects of lamotrigine in BALB/c mice

2017 ◽  
Vol 67 (4) ◽  
pp. 543-555 ◽  
Author(s):  
Eman Y. Abu-Rish ◽  
Shada Y. Elhayek ◽  
Yehia S. Mohamed ◽  
Islam Hamad ◽  
Yasser Bustanji
Keyword(s):  
Immune System ◽  
Delayed Type Hypersensitivity ◽  
Splenocyte Proliferation ◽  
Immunomodulatory Effects ◽  
Hemagglutination Titer ◽  
In Vitro Effects ◽  
Hematological Changes ◽  
In Vivo Effects

Abstract Modulation of the immune system has recently been shown to be involved in the pharmacological effects of old antiepileptic drugs and in the pathogenesis of epilepsy. Therefore, the most recent guidelines for immunotoxicological evaluation of drugs were consulted to investigate the immunomodulatory effects of lamotrigine, a newer antiepileptic drug, in BALB/c mice. These included the in vivo effects of lamotrigine on delayed-type hypersensitivity (DTH) response to sheep red blood cell (SRBC) antigens, hemagglutination titer assays and hematological changes. In vitro effects of lamotrigine on ConA-induced splenocyte proliferation and cytokine secretion were assessed. The results showed that lamotrigine treatment significantly increased the DTH response to SRBC in the mouse model of this study. This was accompanied by a significant increase in relative monocyte and neutrophil counts and in spleen cellularity. Lamotrigine significantly inhibited ConA-induced splenocyte proliferation in vitro and it significantly inhibited IL-2 and TNF-α secretion in ConA-stimulated splenocytes. In conclusion, the results demonstrated significant immunomodulatory effects of lamotrigine in BALB/c mice. These data could expand the understanding of lamotrigine-induced adverse reactions and its role in modulating the immune system in epilepsy.

Comparison of water- and alkali-extracted polysaccharides from Fuzhuan brick tea and their immunomodulatory effects in vitro and in vivo

2022 ◽  
Author(s):  
Yujiao Sun ◽  
Fan Wang ◽  
Yang Liu ◽  
Yuye An ◽  
Dawei Chang ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
Water Extraction ◽  
Immunomodulatory Activity ◽  
Immunomodulatory Effects ◽  
Effect Of Water ◽  
Assisted Extraction

In the present study, the purpose is to compare the effect of water extraction and alkali-assisted extraction on the structural characteristics and immunomodulatory activity of polysaccharides from Fuzhuan brick tea...

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