scholarly journals Nucleotides and AHCC Enhance Th1 Responses In Vitro in Leishmania-Stimulated/Infected Murine Cells

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3918
Author(s):  
María Auxiliadora Dea-Ayuela ◽  
Sergi Segarra ◽  
Dolores R. Serrano ◽  
Francisco Bolás-Fernández
Keyword(s):  
Immune Response ◽  
Lymphocyte Proliferation ◽  
No Production ◽  
Canine Leishmaniosis ◽  
Beneficial Effects ◽  
Dietary Nucleotides ◽  
Tnf Α ◽  
Cellular Immune

A stronger Th1 (cellular) immune response in canine leishmaniosis (CanL) leads to a better prognosis. Dietary nucleotides plus AHCC® have shown beneficial effects in dogs with clinical leishmaniosis and in clinically healthy Leishmania-infected dogs. The potential leishmanicidal activity of nucleotides and AHCC was assessed by quantifying nitric oxide (NO) production and replication of parasites. Their effects on lymphocyte proliferation were studied with and without soluble Leishmania infantum antigen (SLA) stimulation. Cytokine level variations were assessed using naïve and L. infantum-infected macrophages/lymphocytes cocultures. Promastigotes and amastigotes proliferation and NO macrophage production were not directly affected. Lymphocyte proliferation was significantly enhanced by nucleotides, AHCC, and their combinations only after SLA stimulation. Nucleotides and AHCC significantly increased the production of IL-1β, IL-2, IL-5, IL-9, IL-10, and IL-12 by naïve immune cells. In naïve and L. infantum-infected macrophage/lymphocyte cocultures, nucleotides with or without AHCC led to significant increases in IFN-γ and TNF-α. Given that these cytokines are involved in the effective Th1 immune response against Leishmania parasites, these mechanisms of action could explain the previously reported in vivo clinical efficacy of such combination and further support the use of nucleotides with or without AHCC in the management of CanL patients.

scholarly journals Therapeutic Effect of Camel Milk and Its Exosomes on MCF7 Cells In Vitro and In Vivo

2018 ◽  
Vol 17 (4) ◽  
pp. 1235-1246 ◽  
Author(s):  
Abdelnaser A. Badawy ◽  
Mohammed A. El-Magd ◽  
Sana A. AlSadrah
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Immune Response ◽  
Local Injection ◽  
Camel Milk ◽  
Anticancer Effect ◽  
Mcf7 Cells ◽  
Beneficial Effects

Background/Objectives: In the Middle East, people consume camel milk regularly as it is believed to improve immunity against diseases and decrease the risk for cancer. Recently, it was noted that most of the beneficial effects of milk come from their nanoparticles, especially exosomes. Herein, we evaluated the anticancer potential of camel milk and its exosomes on MCF7 breast cancer cells (in vitro and in vivo) and investigated the possible underlying molecular mechanism of action. Methods/Results: Administration of camel milk (orally) and its exosomes (orally and by local injection) decreased breast tumor progression as evident by ( a) higher apoptosis (indicated by higher DNA fragmentation, caspase-3 activity, Bax gene expression, and lower Bcl2 gene expression), ( b) remarkable inhibition of oxidative stress (decrease in MDA levels and iNOS gene expression); ( c) induction of antioxidant status (increased activities of SOD, CAT, and GPX), ( d) notable reduction in expression of inflammation-( IL1b, NFκB), angiogenesis-( VEGF) and metastasis-( MMP9, ICAM1) related genes; and ( e) higher immune response (high number of CD+4, CD+8, NK1.1 T cells in spleen). Conclusions: Overall, administration of camel milk–derived exosomes showed better anticancer effect, but less immune response, than treatment by camel milk. Moreover, local injection of exosomes led to better improvement than oral administration. These findings suggest that camel milk and its exosomes have anticancer effect possibly through induction of apoptosis and inhibition of oxidative stress, inflammation, angiogenesis and metastasis in the tumor microenvironment. Thus, camel milk and its exosomes could be used as an anticancer agent for cancer treatment.

scholarly journals Phylloseptin-1 is Leishmanicidal for Amastigotes of Leishmania amazonensis Inside Infected Macrophages

2020 ◽  
Vol 17 (13) ◽  
pp. 4856
Author(s):  
Selma A. S. Kückelhaus ◽  
Daniela Sant’Ana de Aquino ◽  
Tatiana K. Borges ◽  
Daniel C. Moreira ◽  
Luciana de Magalhães Leite ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Leishmania Amazonensis ◽  
In Vivo Studies ◽  
Public Health Issue ◽  
Neglected Diseases ◽  
No Production ◽  
Tnf Α ◽  
Production Of Hydrogen

Leishmania protozoans are the causal agents of neglected diseases that represent an important public health issue worldwide. The growing occurrence of drug-resistant strains of Leishmania and severe side effects of available treatments represent an important challenge for the leishmaniases treatment. We have previously reported the leishmanicidal activity of phylloseptin-1 (PSN-1), a peptide found in the skin secretion of Phyllomedusa azurea (=Pithecopus azureus), against Leishmania amazonensis promastigotes. However, its impact on the amastigote form of L. amazonensis and its impact on infected macrophages are unknown. In this work, we evaluated the effects of PSN-1 on amastigotes of L. amazonensis inside macrophages infected in vitro. We assessed the production of hydrogen peroxide and nitric oxide, as well as the levels of inflammatory and immunomodulatory markers (TGF-β, TNF-α and IL-12), in infected and non-infected macrophages treated with PSN-1. Treatment with PSN-1 decreased the number of infected cells and the number of ingested amastigotes per cell when compared with the untreated cells. At 32 µM (64 µg/mL), PSN-1 reduced hydrogen peroxide levels in both infected and uninfected macrophages, whereas it had little effect on NO production or TGF-β release. The effect of PSN-1 on IL-12 and TNF-α secretion depended on its concentration, but, in general, their levels tended to increase as PSN-1 concentration increased. Further in vitro and in vivo studies are needed to clarify the mechanisms of action of PSN-1 and its interaction with the immune system aiming to develop pharmacological applications.

scholarly journals A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 6043-6051 ◽  
Author(s):  
Michelle Elvington ◽  
Yuxiang Huang ◽  
B. Paul Morgan ◽  
Fei Qiao ◽  
Nico van Rooijen ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cell ◽  
Complement Activation ◽  
Metastatic Cancer ◽  
Protein Targets ◽  
Complement Inhibitors ◽  
Activation Products ◽  
Cellular Immune

Abstract Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer.

Design, Synthesis, Pharmacological Evaluation and Vascular Effects of Delphinidin Analogues

2019 ◽  
Vol 24 (46) ◽  
pp. 5580-5589 ◽  
Author(s):  
Samuel Legeay ◽  
Kien Trân ◽  
Yannick Abatuci ◽  
Hélène Justiniano ◽  
Claire Lugnier ◽  
...  
Keyword(s):  
Chemical Properties ◽  
Estrogen Receptor Α ◽  
Polyphenolic Compounds ◽  
Strong Increase ◽  
No Production ◽  
Vascular Effects ◽  
Oh Groups ◽  
Beneficial Effects

Background: Among polyphenolic compounds suggested to prevent cardiovascular diseases (CVDs) and to explain the “French paradox”, the anthocyanidin delphinidin (Dp) has been reported to support at least partly the vascular beneficial effects of dietary polyphenolic compounds including those from fruits and related products as red wine. It has also been highlighted that Dp interacts directly with the active site of estrogen receptor α (ERα), leading to activation of endothelial NO synthase (eNOS) pathway thus contributing to the prevention of endothelial dysfunction in mice aorta. However, anthocyanidins have very low bioavailability and despite a well described in vitro efficacy, the very high hydrophilicity and physicochemical instability of Dp might explain the lack of in vivo reported effects. Objective: The aim of this study was to identify new Dp analogues with increased lipophilicity and vasorelaxation potential by a chemical modulation of its structure and to characterize the signaling pathway notably in relation with ERα signaling and nitric oxide (NO) production. Method: OCH3-substituted delphinidin analogues were obtained through the coupling of the corresponding acetophenones with substituted benzaldehydes. Prediction of resorption of the flavylium derivatives was performed with the calculated logP and induction of vasorelaxation was performed by myography on WT and ERαKO mice thoracic aorta rings and compared to Dp. NO production was evaluated in vitro on human primary endothelial cells. Results: Eight Dp analogues were synthesized including four new flavylium derivatives. Two compounds (9 and 11) showed a strong increase of vasorelaxation potential and a theoretically increased bioavailability compared to Dp. Interestingly, 9 and 11 induced increased O2 - or NO endothelial production respectively and revealed a novel NO-dependent ERα-independent relaxation compared to Dp. We suggested that this mechanism may be at least in part supported by the inhibition of vascular cyclic nucleotide phosphodiesterase (PDEs). Conclusion: The current study demonstrated that pharmacomodulation of the Dp backbone by replacement of OH groups by OCH3 groups of the A and B rings led to the identification and characterization of two compounds (9 and 11) with enhanced physio-chemical properties that could be associated to higher permeability capability and pharmacological activity for the prevention of CVDs compared to Dp.

Characterization of MSC Potential To Treat GVHD Using Molecular Markers Linked to MSC-Mediated Immunosuppression In Vitro.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4322-4322 ◽  
Author(s):  
Diane Carter ◽  
Alicia Tyrell ◽  
Simon Bubnic ◽  
Michelle Marcelino ◽  
Keren Kedzierski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Enzyme Activity ◽  
Lymphocyte Proliferation ◽  
Tryptophan Depletion ◽  
Solid Organ ◽  
Adult Bone Marrow ◽  
Tnf Α ◽  
Adult Bone

Abstract Mesenchymal stem cells (MSCs) are rare progenitor cells present in adult bone marrow that have the capacity to differentiate into a variety of tissue types, including bone, cartilage and fat. The biological activities of MSCs suggest a number of potential clinical applications, where each particular application is related to a specific MSC activity mediated by a different mechanism. Osiris Therapeutics has developed a technology for isolation and expansion of hMSCs from adult bone marrow for clinical use. Data from pre-clinical and clinical studies suggest that the ability of MSCs to migrate to inflammatory sites, modulate immune response, down-regulate inflammation, and accelerate tissue repair in the local environment may have therapeutic effects. Therefore in developing therapeutic applications, the MSCs should be verified to display one or more of above-mentioned functions, calling for the need to develop predictive functional assays. Modulation of the immune response is an apparent in vivo therapeutic property of the MSC necessary for successful Graft versus Host Disease (GVHD) treatment. Based on previous knowledge regarding mechanisms underlying MSC-mediated immunosuppressive effects, several markers for developing an MSC potency assay have been proposed. In the present study a relationship between selected markers and hMSC-mediated immunosuppression was investigated in vitro. Results show that co-culture of hMSCs with anti-CD3/CD28-activated peripheral blood mononuclear cells (hPBMCs) caused inhibition of lymphocyte proliferation. The hMSC effect on lymphocyte proliferation is dose-dependent, causing > 50% inhibition at approximately 1:10–1:25 MSC: T-lymphocyte ratio. Supernatants of parallel co-cultures taken on days 1, 3, and 5 were analyzed for prostaglandin 2 (PGE2), tumor necrosis factor-α (TNF-α), and tryptophan. The results showed increased levels of PGE2, decreased levels of TNF-α and increased depletion of tryptophan related to indoleamine 2,3-dioxygenase (IDO) enzyme activity, associated with increasing number of MSCs in each well. The quantity of PGE2 on day 1 and the level of tryptophan on day 5 in the MSC-PBMC co-culture supernatants correlated to the level of inhibition of proliferation, with the PGE2 range from approximately 11,000 to 22,000 pg/mL and 50% tryptophan depletion resulting in a 50% inhibition of the lymphocyte proliferation point. Further studies demonstrated that the addition of TNF-α to MSCs induced PGE2 secretion at a level which was similar to that detected in the co-culture studies of MSCs-PBMC. Thus, a strong correlation between inducible PGE2 secretion/IDO enzyme activity and the inhibition of lymphocyte proliferation by hMSCs in vitro indicates key molecules responsible for hMSC functional activity related to the immunological responses involved with diseases such as GVHD, solid organ transplantation and autoimmune diseases.

scholarly journals Protective Immunity Elicited by a Divalent DNA Vaccine Encoding Both the L7/L12 and Omp16 Genes of Brucella abortus in BALB/c Mice

2006 ◽  
Vol 74 (5) ◽  
pp. 2734-2741 ◽  
Author(s):  
Deyan Luo ◽  
Bing Ni ◽  
Peng Li ◽  
Wei Shi ◽  
Songle Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Vaccine ◽  
Brucella Abortus ◽  
Protective Efficacy ◽  
Virulent Strain ◽  
T Helper 1 ◽  
Genetic Vaccine ◽  
Cellular Immune

ABSTRACT This study was designed to evaluate the immunogenicity and the protective efficacy of a divalent fusion DNA vaccine encoding both the Brucella abortus L7/L12 protein (ribosomal protein) and Omp16 protein (outer membrane lipoprotein), designated pcDNA3.1-L7/L12-Omp16. Intramuscular injection of this divalent DNA vaccine into BALB/c mice elicited markedly both humoral and cellular immune responses. The specific antibodies exhibited a dominance of immunoglobulin G2a (IgG2a) over IgG1. In addition, the dual-gene DNA vaccine elicited a strong T-cell proliferative response and induced a large amount of gamma interferon-producing T cells upon restimulation in vitro with recombinant fusion protein L7/L12-Omp16, suggesting the induction of a typical T-helper-1-dominated immune response in vivo. This divalent DNA vaccine could also induce a significant level of protection against challenge with the virulent strain B. abortus 544 in BALB/c mice. Furthermore, the protection level induced by the divalent DNA vaccine was significantly higher than that induced by the univalent DNA vaccines pcDNA3.1-L7/L12 or pcDNA3.1-Omp16. Taken together, the results of this study verify for the first time that the Omp16 gene can be a candidate target for a DNA vaccine against brucellosis. Additionally, a divalent genetic vaccine based on the L7/L12 and Omp16 genes can elicit a stronger cellular immune response and better immunoprotection than the relevant univalent vaccines can.

scholarly journals Anti-Arthritic and Anti-Inflammatory Potential of Spondias mangifera Extract Fractions: An In Silico, In Vitro and In Vivo Approach

Plants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 825
Author(s):  
Mohammad Khalid ◽  
Mohammed H. Alqarni ◽  
Ambreen Shoaib ◽  
Muhammad Arif ◽  
Ahmed I. Foudah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Arthritis Score ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

The fruits of Spondias mangifera (S. mangifera) have traditionally been used for the management of rheumatism in the northeast region of India. The present study explores the probable anti-arthritis and anti-inflammatory potential of S. mangifera fruit extract’s ethanolic fraction (EtoH-F). To support this study, we first approached the parameters in silico by means of the active constituents of the plant (beta amyrin, beta sitosterol, oleonolic acid and co-crystallised ligands, i.e., SPD-304) via molecular docking on COX-1, COX-2 and TNF-α. Thereafter, the absorption, distribution, metabolism, excretion and toxicity properties were also determined, and finally experimental activity was performed in vitro and in vivo. The in vitro activities of the plant extract fractions were evaluated by means of parameters like 1,1-Diphenyl-2- picrylhydrazyl (DPPH), free radical-reducing potential, albumin denaturation, and protease inhibitory activity. The in vivo activity was evaluated using parameters like COX, TNF-α and IL-6 inhibition assay and arthritis score in Freund Adjuvant (CFA) models at a dose of 400 mg/kg b.w. per day of different fractions (hexane, chloroform, alcoholic). The molecular docking assay was performed on COX-1, COX-2 and TNF-α. The results of in vitro studies showed concentration-dependent reduction in albumin denaturation, protease inhibitors and scavenging activity at 500 µg/mL. Administration of the S. mangifera alcoholic fraction at the abovementioned dose resulted in a significant reduction (p < 0.01) in arthritis score, paw diameters, TNF-α, IL-6 as compared to diseased animals. The docking results showed that residues show a critical binding affinity with TNF-α and act as the TNF-α antagonist. The alcoholic fraction of S. mangifera extract possesses beneficial effects on rheumatoid arthritis as well as anti-inflammatory potential, and can further can be used as a possible agent for novel target-based therapies for the management of arthritis.

scholarly journals Eucommia ulmoides Leaf Polysaccharide in Conjugation with Ovalbumin Act as Delivery System Can Improve Immune Response

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1384
Author(s):  
Haibo Feng ◽  
Jie Yang ◽  
Hui Zhi ◽  
Xin Hu ◽  
Yan Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Delivery System ◽  
Physicochemical Characteristics ◽  
Cellular Immune Responses ◽  
Ethylcarbodiimide Hydrochloride ◽  
Ifn Γ ◽  
Cellular Immune

In this investigation, to maximize the desired immunoenhancement effects of PsEUL and stimulate an efficient humoral and cellular immune response against an antigen, PsEUL and the model antigen ovalbumin (OVA) were coupled using the N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) reaction to yield a novel delivery system (PsEUL-OVA). The physicochemical characteristics and immune regulation effects of this new system were investigated. We found the yield of this EDC method to be 46.25%. In vitro, PsEUL-OVA (200 μg mL−1) could enhance macrophage proliferation and increase their phagocytic efficiency. In vivo, PsEUL-OVA could significantly increase the levels of OVA-specific antibody (IgG, IgG1, IgG2a, and IgG2b) titers and cytokine (IL-2, IL-4, IL-6, IFN-γ) levels. Additionally, it could activate T lymphocytes and facilitate the maturation of dendritic cells (DCs). These findings collectively suggested that PsEUL-OVA induced humoral and cellular immune responses by promoting the phagocytic activity of macrophages and DCs. Taken together, these results revealed that PsEUL-OVA had the potential to improve immune responses and provide a promising theoretical basis for the design of a novel delivery system.

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