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 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 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.

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 Lack of Immune Responses to Mycobacterium tuberculosis DosR Regulon Proteins following Mycobacterium bovis BCG Vaccination

2007 ◽  
Vol 75 (7) ◽  
pp. 3523-3530 ◽  
Author(s):  
May Young Lin ◽  
Annemieke Geluk ◽  
Steven G. Smith ◽  
Amanda L. Stewart ◽  
Annemieke H. Friggen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Mycobacterium Bovis ◽  
Protective Efficacy ◽  
Transcriptional Profiling ◽  
In Silico Analysis ◽  
Dna Encoding ◽  
Bcg Vaccination ◽  
Dosr Regulon

ABSTRACT Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), despite its variable protective efficacy. Relatively little is known about the immune response profiles following BCG vaccination in relation to protection against TB. Here we tested whether BCG vaccination results in immune responses to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens are targeted by the immune system during persistent Mycobacterium tuberculosis infection and have been associated with immunity against latent M. tuberculosis infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis showed at least 97% amino acid sequence homology, with 41 out of 48 genes being identical. Transcriptional profiling of 14 different BCG strains, under hypoxia and nitric oxide exposure in vitro, revealed a functional DosR regulon similar to that observed in M. tuberculosis. Next, we assessed human immune responses to a series of immunodominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency antigens. Since immune responses to TB latency antigens have been associated with control of latent M. tuberculosis infection, our findings support the development of vaccination strategies incorporating DosR regulon antigens to complement and improve the current BCG vaccine.

scholarly journals In Silico Identification and Biological Evaluation of Antimicrobial Peptides Based on Human Cathelicidin LL-37

2006 ◽  
Vol 50 (9) ◽  
pp. 2983-2989 ◽  
Author(s):  
Thorgerdur Sigurdardottir ◽  
Pia Andersson ◽  
Mina Davoudi ◽  
Martin Malmsten ◽  
Artur Schmidtchen ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Amino Acid ◽  
In Silico ◽  
In Silico Analysis ◽  
Biological Evaluation ◽  
Binding Activity ◽  
Multiple Organ ◽  
Peptide Antibiotics ◽  
Cultured Smooth Muscle Cells

ABSTRACT Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide LL-37 not only possesses a broad-spectrum antimicrobial activity but also binds and neutralizes LPS. However, the use of LL-37 in sepsis treatment is hampered by the fact that it is also cytotoxic. To find a less toxic analog of LL-37, we used in silico analysis to identify amphipathic helical regions of LL-37. A 21-amino-acid fragment (GKE) was synthesized, the biological actions of which were compared to those of two equally long peptides derived from the N and C termini of LL-37 as well as native LL-37. GKE displayed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Candida parapsilosis that was similar to or even stronger than LL-37. GKE, as well as the equally long control peptides, attracted granulocytes in a fashion similar to that of LL-37, while only GKE was as potent as LL-37 in inhibiting LPS-induced vascular nitric oxide production. GKE caused less hemolysis and apoptosis in human cultured smooth muscle cells than LL-37. In summary, we have identified an active domain of LL-37, GKE, which displays antimicrobial activity in vitro and LPS-binding activity similar to those of LL-37 but is less toxic. GKE therefore holds promise as a template for the development of peptide antibiotics for the treatment of sepsis.

scholarly journals Engineered Human Heavy-Chain Ferritin with Half-Life Extension and Tumor Targeting by PAS and RGDK Peptide Functionalization

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 521
Author(s):  
Shuang Yin ◽  
Yan Wang ◽  
Bingyang Zhang ◽  
Yiran Qu ◽  
Yongdong Liu ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Half Life ◽  
Tumor Targeting ◽  
Drug Carrier ◽  
Life Extension ◽  
Sprague Dawley ◽  
Functional Peptides ◽  
Targeting Peptide

Ferritin, one of the most investigated protein nanocages, is considered as a promising drug carrier because of its advantageous stability and safety. However, its short half-life and undesirable tumor targeting ability has limited its usage in tumor treatment. In this work, two types of functional peptides, half-life extension peptide PAS, and tumor targeting peptide RGDK (Arg-Gly-Asp-Lys), are inserted to human heavy-chain ferritin (HFn) at C-terminal through flexible linkers with two distinct enzyme cleavable sites. Structural characterizations show both HFn and engineered HFns can assemble into nanoparticles but with different apparent hydrodynamic volumes and molecular weights. RGDK peptide enhanced the internalization efficiency of HFn and showed a significant increase of growth inhibition against 4T1 cell line in vitro. Pharmacokinetic study in vivo demonstrates PAS peptides extended ferritin half-life about 4.9 times in Sprague Dawley rats. RGDK peptides greatly enhanced drug accumulation in the tumor site rather than in other organs in biodistribution analysis. Drug loaded PAS-RGDK functionalized HFns curbed tumor growth with significantly greater efficacies in comparison with drug loaded HFn.

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.

Degradation of IGF-I in the adult rat gastrointestinal tract is limited by a specific antiserum or the dietary protein casein

1995 ◽  
Vol 146 (2) ◽  
pp. 215-225 ◽  
Author(s):  
C J Xian ◽  
C A Shoubridge ◽  
L C Read
Keyword(s):  
Receptor Binding ◽  
Dietary Protein ◽  
Half Life ◽  
Structural Integrity ◽  
Binding Activity ◽  
Adult Rats ◽  
Adult Rat ◽  
Igf I

Abstract To investigate the potential of IGF-I peptides as therapeutics in the gut, the survival profiles of a bolus of 125I-labelled IGF-I (8·6 ng) in vivo in various ligated gut segments of fasted adult rats have been examined. The intactness of IGF-I tracer in the flushed luminal contents was estimated by trichloroacetic acid precipitation, antibody and receptor binding assays. It was found that IGF-I was degraded very rapidly in duodenum and ileum segments with a half-life (t1/2) of 2 min by all three methods. IGF-I was slightly more stable in the stomach (t1/2=8, 5 and 2·5 min by the above three methods), and considerably more stable in the colon (t1/2=38, 33 and 16 min as judged by the three methods). Rates of degradation in gut flushings in vitro were similar to the in vivo rates except for the colon, where IGF-I was proteolysed more rapidly in vivo. As a means of developing gut-stable and active forms of IGF-I, several approaches were examined for their effectiveness in prolonging IGF-I survival in the upper gut. It was found that the extension peptide on the analogue, LR3IGF-I did not protect IGF-I, nor did association with IGF-binding protein-3. However, an IGF-I antiserum was effective in prolonging IGF-I half-life in duodenum fluid by 28-fold. Charge interaction between IGF-I and heparin could also protect IGF-I in the stomach but not in duodenum flushings. Furthermore, casein (a non-specific dietary protein) and to a lesser extent, BSA and lactoferrin, were effective in preserving IGF-I structural integrity and receptor binding activity in both stomach and duodenum fluids. It can be concluded that IGF-I cannot be expected to retain bioactivity if delivered orally because of rapid proteolysis in the upper gut, but the use of IGF antibodies and casein could represent useful approaches for IGF-I protection in oral formulae. Journal of Endocrinology (1995) 146, 215–225

scholarly journals Amyloid aggregation of Streptococcus mutans Cnm influences its collagen-binding activity

2021 ◽  
Author(s):  
Nicholas de Mojana di Cologna ◽  
Sandip Samaddar ◽  
Carolina Valle ◽  
Jonathan A Vargas ◽  
Alejandro Aviles-Reyes ◽  
...  
Keyword(s):  
Quaternary Structure ◽  
Ex Vivo ◽  
In Silico Analysis ◽  
Binding Activity ◽  
Amyloid Aggregation ◽  
Binding Assays ◽  
Collagen Binding ◽  
Microtiter Plates

The glycosylated collagen- and laminin-binding surface adhesin Cnm is present in approximately 20% of S. mutans clinical isolates and is associated with systemic infections and increased caries risk. Other surface-associated collagen-binding proteins of S. mutans such as P1 and WapA have been demonstrated to form an amyloid quaternary structure with functional implications within biofilms. In silico analysis predicted that the b-sheet rich N-terminal collagen-binding domain (CBD) of Cnm has propensity for amyloid aggregation, whereas the threonine-rich C-terminal domain was predicted to be disorganized. In this study, thioflavin-T fluorescence and electron microscopy were used to show that Cnm forms amyloids either in its native glycosylated or recombinant non-glycosylated forms and that the CBD of Cnm is the main amyloidogenic unit of Cnm. We then performed a series of in vitro, ex vivo and in vivo assays to characterize the amylogenic properties of Cnm.  In addition, Congo red birefringence indicated that Cnm is a major amyloidogenic protein of S. mutans biofilms. Competitive binding assays using collagen-coated microtiter plates and dental roots, a substrate rich in collagen, revealed that Cnm monomers inhibit S. mutans binding to collagenous substrates whereas Cnm amyloid aggregates lose this property. Thus, while Cnm contributes to recognition and initial binding of S. mutans to collagen-rich surfaces, Cnm amyloid aggregation appears to represent a mechanism to modulate this activity in mature biofilms.

scholarly journals Il-1Β Primed Mesenchymal Stromal Cells Moderate Hemorrhagic Shock Induced Organ Injuries

2020 ◽  
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 BackgroundOrgan 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.ObjectiveAssess the effect of naive MSC (MSCn) or interleukin (IL)-1β primed (MSCp) treatment in a context of HS- induced organ injury.MethodsRats 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.ResultsPlasma 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-6 and IL-10) as well as CD80, 86 and PD-1/PDL-1 axis were decreased by MSCp on monocytes and T lymphocytes. In vitro, MSCp showed higher level of secreted immunomodulatory molecules than MSCn.ConclusionAn 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.

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