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Diploma project proposalStudent name: Retyunskiy VladimirStudent number: L003160102Supervisor: Dr. Zhao YeTitleEvaluation of the anti-inflammation effect of alloferon based on skin injury modelPurposeThe purpose of this research is to discover and assess anti-inflammatory effect of the alloferons family, elicited based on skin injury model, thereby examining its potential as an anti-inflammatory compound.ReviewStructure of alloferonAlloferon, a representative of tridecapeptide class of linear peptide protein compounds, has been an object of research of numerous recent studies. The distinctive distribution of amino acids in alloferons follows the general formula of X1-HIS-GLY-X2-HIS-GLY-VAL-X3, where X1 section either absent or responsible for at least 1 amino acid in sequence, X2 section is responsible for either at least one amino acid in sequence or a peptide bond, X3 section either absent or responsible for at least one amino acid in sequence.The original isolation of the compound, having the structure of HIS-GLY-VAL-SER-GLY-HIS-GLY-GLN-HIS-GLY-VAL-HIS-GLY (Alloferon-1), was conducted with the use of blow fly Calliphora vicina (Diptera), an insect, known for its medicinal use. The maggots of the species were preliminary infected with bacteria and in prospect alloferon was isolated from the hemolymph of maggots. According to Sergei Chernish, purified acid extract of Calliphora Vicina, obtained from hemolymph (Vickers et al), was used to isolate two peptide structures consisting of 13 and 12 amino acids respectively that were further classified as alloferon-1 and alloferon-2 (GLY-VAL-SER-GLY-HIS-GLY-GLN-HIS-GLY-VAL-HIS-GLY). Belonging to anti-cancer Peptides (ACPs) and anti-microbial peptides (AMPs), alloferon possesses the common properties of both classes, including the molecular weight of approximately 1265 Da, net charge 4 and pH=7.4. According to Kuczer M., similarities between alloferon (H-HIS-GLY-VAL-SER-GLY-HIS-GLY-GLN-HIS-GLY-VAL-HIS-GLY-OH) and Sarcophaga peregrina antifungal protein9, precursors of influenza virus B haemagglutinin as well as bovine prion protein I and II were found regarding amino acid order. According to Chernysh S. et al., alloferon showcased antinociceptive activity in rats and antiviral, antitumoral and anti-inflammatory activities in experiments, conducted on mice. Alloferon-1 and alloferon-2 demonstrated the upregulation of natural cytotoxicity in mouse spleen lymphocytes. The research of antiviral effects of alloferon analogues demonstrated that the structural segment of alloferon responsive for exhibition of antiviral activity in-vitro is the first aromatic ring in peptide chain, moreover, the considerable activity was displayed by the analogue without the N-terminal dipeptide HIS-GLY. Anti-inflammatory effect of alloferonThe mechanism of the anti-inflammatory effect of alloferon is linked to the regulation of cytokine production by immune cells. In recent papers, to investigate the ability of alloferon to act against inflammation process the colitis C57BL/6 mice were treated with 3% dextran sulfate sodium. The Disease Activity Index (DAI) of the species, comprising daily activity, body weight, food and water consumption and the quality of stool, was monitored and used as a primary factor for groups comparison. The obtained data displayed the colitis reduction in the alloferon treated group against the control group according to the DAI. Phosphorylation of IκB and TNF-α-induced degradation of in Colo205 colon cancer cells underwent reduction influenced by alloferon. According to Yejin Kim, UVB-exposed inflamed Human Keratinocyte cell line HaCaT was used to determine anti-inflammatory properties of alloferon in-vitro. In the experiment, common pro-inflammatory cytokine in colitis IL-6 had its plasma level downregulated under the effect of alloferon. The research found that synthesis of IL-1α, IL-1β, IL-6 and IL-18, pro-inflammatory cytokines induced by UVB, also monitored by ELISA and RT-PCR, sustained downregulation on protein and mRNA levels, which was stimulated in presence of alloferon. The results were taken into consideration to denote the anti-inflammatory activity of alloferon as well as its impairing impact on DSS-induced colitis. Moreover, from transcription and translation control, the suppressive effects of alloferon on cytokine gene expression were also considered. In addition, through inhibition of antioxidant proteins, IkB-α and by NF-KB signaling pathway activation, alloferon invigorates immune cells. The intensification of NK-activation receptors functioning, as well as the activity of NK cells are also improved by alloferon. The expression ability of INF-γ, TNF-α and granule exocytosis in NK cells stimulated by alloferon either, thus improving the effectiveness against cancer cells. NF-KB signalling pathway activation and immune cells stimulation by alloferonTo invert immune system oppression, caused by tumor cells, NK cells activate interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). According to the papers (Chernysh S. et al, Xiong, G. et al., Huang Y. S.) the mechanism of cancer treatment is based on NK cells activation in the tumor cells, not on the direct cancer cells destruction. With the activation of NK cells, the expression degree of NKG2D, which is an activating receptor, get to the upregulation state, while the degree of CD94 expression, an inhibitory receptor, is upregulated during the suppression of NK cells. Also, biological factors IFN-γ and TNF-α are responsible for the elimination of tumor cells and activation of other lymphocytes. Therefore, the release of IFN-γ and TNF-α during NK cells activation is substantially escalated. According to Yi Huang et al., the levels of IFN-γ and TNF-α in the mices peripheral blood were explored by utilizing ELISA. The data displayed the increment of concentration of the biological factors in the alloferon-1 containing group against the control group. Lymphokine-activated killer (LAK) cell is the most widely used in immunotherapy type of white blood cells. Stimulated by specific cytokines, LAK cells demonstrate high levels of cytotoxicity against cancer. To upregulate the cytotoxicity of NK cells, cytokines IL-2, -12, -15, -18 and -21 are considered to be used. NK cells have a crucial role in the formation of adaptive immune response through their cytokine production capacities, while also eliminating autologous immune cells, thus supressing autoimmune processes. NK cells are the primary cells to affect the areas suffering from inflammation processes by the reason of being components of innate immune system, thus becoming potential sites for the targeted drug treatment. Alloferons anti-tumoral activity is bansed on enhancement of the cytotoxicity of NK cells by the increase of perfoin/granzyme formation. Through activation of NK cells, alloferon-1 induces the release of a significant amount of IFN-γ and TNF-α factors.The detailed research on anti-inflammatory effect of alloferon may clarify the potential of the compound for the usage as a narrowly targeted anti-inflammatory drug. The study should give a specific view on alloferons side effects to define the limitations of its application. Procedures1. LocationThe research is going to be conducted in the laboratory of Biochemistry department of Nanjing University of Technology, Nanjing.2. Resources1) Kowalik-Jankowska, T., Biega, L., Kuczer, M. Konopinska, D. Mononuclear copper(II) complexes of alloferons 1 and 2: a combined potentiometric and spectroscopic studies.2) Kuczer, M., Majewska, A. Zahorska, R. New alloferon analogues: synthesis and antiviral properties.3) Kuczer, M. et al. Studies of insect peptides alloferon,Any-GS and their analogues. Synthesis and antiherpes activity.4) Huang, Y. S. Enzyme responsiveness enhances the specificity and effectiveness of nanoparticles for the treatment of B16F10 melanoma.5) Bae, S. et al. The effect of alloferon on the enhancement of NK cell cytotoxicity against cancer via the up-regulation of perforin/granzyme B secretion.6) Kim, Y. et al. The anti-inflammatory effect of alloferon on UVB-induced skin inflammation through the down-regulation of pro-inflammatory cytokines.3. Study timeline
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