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Chemokines belong to the family of cytokines with chemoattractant properties that regulate chemotaxis and leukocyte migration, as well as the induction of angiogenesis and maintenance of hemostasis. Curcumin, the major component of the Curcuma longa rhizome, has various pharmacological actions, including anti-inflammatory, immune-regulatory, anti-oxidative, and lipid-modifying properties. Chemokines and chemokine receptors are influenced/modulated by curcumin. Thus, the current review focuses on the molecular mechanisms associated with curcumin's effects on chemoattractant cytokines, as well as putting into context the many studies that have reported curcumin-mediated regulatory effects on inflammatory conditions in the organs/systems of the body (e.g., the central nervous system, liver, and cardiovascular system). Curcumin's effects on viral and bacterial infections, cancer, and adverse pregnancy outcomes are also reviewed.
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Curcumina , Curcumina/farmacologia , Curcumina/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Fígado , Citocinas , Quimiocinas , CurcumaRESUMO
BACKGROUND: Peptide-based immunotherapy (PIT) was introduced as an attractive approach in allergen-specific immunotherapy (AIT). However, PIT clinical trials have shown variable results, and immune response to peptides is not precisely predictable. On the other hand, induction of antigen-specific tolerance may be augmented when allergens are combined with the regulatory T cell epitope (Tregitope). This study aimed to evaluate the therapeutic administration of a plasmid DNA encoding Tregitope and ovalbumin (OVA) immunodominant epitope in the murine model of allergy. METHODS: Following the induction of allergic rhinitis by ovalbumin, vaccinated group received three doses of recombinant plasmid containing Signal peptide-Tregitope-OVA T cell epitope. After the final OVA challenge, clinical symptoms, histopathological changes, OVA-specific IgE level, and cytokine secretion pattern of spleen cells were examined. RESULTS: Our data are showing that AIT with the recombinant DNA vaccine significantly suppressed airway inflammation; reduced eosinophilic infiltration in the nasal mucosa; decreased expression level of IL-4 and IL-17 in spleen cells, while IFN-γ, IL-10, and TGF-ß expression were increased. Moreover, OVA-specific IgE levels were also decreased. CONCLUSION: These results suggest that Tregitope-immunodominant T cell epitope fusion can act as a safe and effective approach in DNA-based allergen-specific immunotherapy.
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Hipersensibilidade , Epitopos Imunodominantes , Alérgenos , Animais , Citocinas , Dessensibilização Imunológica , Modelos Animais de Doenças , Epitopos de Linfócito T , Epitopos Imunodominantes/uso terapêutico , Imunoglobulina E/genética , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Peptídeos , Plasmídeos/genéticaRESUMO
BACKGROUND & OBJECTIVES: Tumor cells have various effects and dominance over other healthy cells. Cancer cells alter the cell program in healthy cells by secreting exosomes containing microRNAs involved in epithelial-mesenchymal transition (EMT). They can migrate to distant organs and establish a pre-metastatic niche. The purpose of this study was to determine the expression of miRNA-21-5p and miRNA-10b-5p, both of which are involved in EMT, in breast cancer-derived exosomes of various grades in order to identify new biomarkers involved in breast cancer progression. METHODS: In this study, a blood sample was taken from 60 patients with grades I, II, or III breast cancer, as well as twenty healthy individuals as a control group. The exosomes were then purified from serum samples, and their relative expression of miRNA-21-5p and miRNA-10b-5p was determined using the real-time PCR method. RESULTS: miRNA-21-5p expression was significantly increased in patients with breast cancer grades I, II, and III compared to the control group (p < 0.01), (p < 0.0001) and (p < 0.0001), respectively, as was miRNA-10b-5p expression in patients with breast cancer grades I, II, and III compared to the control group (p < 0.0001), (p < 0.0001) and (p < 0.0001), respectively. CONCLUSION: Our results show that both microRNAs increase as cells lose their differentiation and become more invasive, which is evidence of cancer progression. Hence, both microRNAs may have the potential to be used alone or in combination with other biomarkers for the diagnosis and prognosis of breast cancer.
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Neoplasias da Mama , Exossomos , MicroRNAs , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Exossomos/genética , Exossomos/metabolismo , Feminino , Humanos , MicroRNAs/sangue , Gradação de TumoresRESUMO
The present study conducted a placebo-controlled clinical trial to evaluate the impact of nano-curcumin on the inflammatory cytokines in mild-to-moderate hospitalized COVID-19 patients. A total of 60 COVID-19 patients were randomly divided into nano-curcumin and control groups, and then they received 240 mg/day nano-curcumin for 7 days. The clinical manifestation and laboratory parameters in patients were recorded on days 0 and seven. Also, SYBR Green real-time PCR and ELISA techniques were implicated in assessing the mRNA expression of IFN-γ, IL-1ß, IL-6, MCP-1, and TNF-α and the serum levels of IL-1ß, IL-6, and TNF-α inflammatory mediators, respectively. Although the clinical manifestations and laboratory parameters improved via the nano-curcumin treatment, the mRNA expression of IFN-γ (p = 0.006) and TNF-α (p = 0.04) were significantly reduced. Besides, a considerable difference was observed between the nano-curcumin and control groups in the expression of IFN-γ (p = 0.001), IL-1ß (p = 0.0002), and IL-6 (p = 0.008). In addition, there was a significant difference between the nano-curcumin and control groups in the serum levels of IL-1ß (p = 0.042). The evidence demonstrated that nano-curcumin could be implicated as a complementary medication to act as an antiinflammatory agent and inhibit inflammatory complications.
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Anti-Inflamatórios , COVID-19 , Curcumina , Anti-Inflamatórios/uso terapêutico , Curcumina/uso terapêutico , Citocinas , Humanos , SARS-CoV-2RESUMO
Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T-cell activation via direct cell-cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) help maintain immunological tolerance through the induction of T-cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC-derived exosomes on the induction of mouse tolDCs, murine adipose-derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick-TC kits. BM-derived DCs (BMDCs) were prepared and cocultured with MSCs-derived exosomes (100 µg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS; 0.1µg/ml) at Day 8 for 24 hr. The study groups were divided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester-labeled BALB/C-derived splenocytes p. Interleukin-6 (IL-6), IL-10, and transforming growth factor-ß (TGF-ß) release were measured by enzyme-linked immunosorbent assay. MSC-derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC-derived exosomes decrease IL-6 release but augment IL-10 and TGF-ß release (p ≤ .05). Lymphocyte proliferation was decreased (p ≤ .05) in the presence of DCs treated with MSC-derived exosomes. CMSC-derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC-induced immune responses.
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Células Dendríticas/imunologia , Exossomos/imunologia , Tolerância Imunológica/imunologia , Células-Tronco Mesenquimais/imunologia , Animais , Biomarcadores/metabolismo , Comunicação Celular/imunologia , Proliferação de Células/fisiologia , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Exossomos/metabolismo , Feminino , Imunidade/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Scorpion venoms identified as agents with anti-tumor and anti-angiogenic features. Tumor microenvironment (TME) plays a pivotal role in the process of tumorigenesis, tumor development, and polarization of M2 phenotype tumor associated macrophages (TAMs). M2 polarized cells are associated with tumor growth, invasion, and metastasis. The fractionation process was performed by gel filtration chromatography on a Sephadex G50 column. To elucidate whether scorpion venom can alter macrophage polarization, we treated interleukin (IL)-4-polarized M2 cells with isolated fractions from Mesobuthus eupeus. Next, we evaluated the cytokine production and specific markers expression for M2 and M1 phenotype using enzyme linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR), respectively. The phagocytic capacity of macrophages was also assessed. In addition, the migration assay and MTT analysis were performed to investigate the effects of reprogrammed macrophages on the CT-26 colon cancer cells. The results indicated that F1 fraction of venom significantly upregulated the levels and expression of M1-associated cytokines and markers, including tumor necrosis factor-alpha (TNF-α) (p < 0.001), IL-1 (p < 0.01), interferon regulatory factor 5 (IRF5) (p < 0.0001), induced nitric oxide synthase (iNOS) (p < 0.0001), and CD86 (p < 0.0001), and downregulated M2-related markers, including transforming growth factor-beta (TGF-ß) (p < 0.05), IL-10 (p < 0.05), Fizz1 (p < 0.0001), arginase-1 (Arg-1) (p < 0.0001), and CD206 (p < 0.001). The macrophage phagocytic capacity was enhanced after treatment with F1 fraction (p < 0.01). Moreover, incubation of CT-26 cell line with conditioned media of F1-treated macrophages suppressed migration (p < 0.0001) and proliferation (p < 0.01) of tumor cells. In conclusion, our findings demonstrated the potential of Mesobuthus eupeus venom in M2-to-M1 macrophage polarization as a promising therapeutic approach against proliferation and metastasis of colon cancer cells.
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Animais Peçonhentos , Citocinas , Venenos de Escorpião , Animais , Venenos de Escorpião/farmacologia , Camundongos , Linhagem Celular Tumoral , Citocinas/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias do Colo/imunologia , Antineoplásicos/farmacologia , Escorpiões , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Movimento Celular/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Humanos , FenótipoRESUMO
Dendritic cells (DCs), professional antigen-presenting cells that process and deliver antigens using MHC II/I molecules, can be enhanced in numerous ways. Exosomes derived from heat-shocked tumor cells (HS-TEXs) contain high amounts of heat-shock proteins (HSPs). HSPs, as chaperons, can induce DC maturation. This study aimed to investigate whether HS-TEXs can promote DC maturation. To generate DC, bone marrow-derived cells were treated with Interleukin-4 and GM-CSF. Exosomes were isolated from heat-treated CT-26 cells. The expression level of HSP in exosomes was checked by western blot and the increase in the expression of this protein was observed. Then, HS-TEXs were co-cultured with iDCs to determine DC maturity, and then DCs were co-cultured with lymphocytes to determine DC activity. Our results showed that DCs treated with HS-TEXs express high levels of molecules involved in DC maturation and function including MHCII, CD40, CD83, and CD86. HS-TEXs caused phenotypic and functional maturation of DCs. In addition, flow cytometric results reflected a higher proliferative response of lymphocytes in the iDC / Tex + HSP group. HS-TEXs could be used as a strategy to improve DC maturation and activation.
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Exossomos , Células Dendríticas , Medula Óssea , Linfócitos T , Técnicas de Cocultura , Diferenciação CelularRESUMO
BACKGROUND: Allergen-specific sublingual immunotherapy (SLIT) was considered an interesting needle-free alternative for subcutaneous immunotherapy (SCIT). Mesenchymal stem cell (MSC)-derived exosomes were introduced as potent nanoscale delivery systems with immunomodulatory potentials. The current study investigated the therapeutic efficacy of SLIT using ovalbumin (OVA)-enriched MSC-derived exosomes formulation in a murine model of allergic asthma. MATERIAL AND METHODS: MSCs were harvested from mice adipose tissues. Then, exosomes were isolated, and OVA-loaded exosomes were prepared. Following sensitization, Balb/c mice received therapeutic formulation (10 µg/dose OVA-containing MSC-derived exosomes) twice a week for two months. Serum OVA-specific IgE levels as well as IFN-γ, IL-4, and TGF-ß secretions by cultured splenocytes were measured by ELISA. Also, lung tissue underwent histopathologic analysis, and the numbers of inflammatory cells and eosinophils in nasopharyngeal lavage fluid (NALF) were examined. RESULTS: SLIT using OVA-enriched exosomes significantly reduced IgE levels and IL-4 production, while the secretion of IFN-γ and TGF-ß were significantly elevated. Also, a decrease was observed in the numbers of total cells and eosinophils in the NALF, and lower levels of perivascular and peribronchiolar inflammation and cellular infiltrations were observed in the lung tissue. CONCLUSION: SLIT using OVA-loaded exosomes improved immunomodulatory responses and efficiently alleviated allergic inflammation.
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Exossomos , Células-Tronco Mesenquimais , Imunoterapia Sublingual , Animais , Camundongos , Alérgenos , Interleucina-4 , Imunoglobulina E , Fator de Crescimento Transformador beta , Imunidade , Inflamação , Camundongos Endogâmicos BALB C , Ovalbumina , Modelos Animais de Doenças , CitocinasRESUMO
Background: Exosomes are nanoscale vesicles widely used as drug delivery systems. Mesenchymal stem cell (MSC)-derived exosomes have shown immunomodulatory potential. This study optimized loading OVA into the mice adipose tissue-derived MSC-isolated exosomes to prepare the OVA-MSC-exosome complex for allergen-specific immunotherapy. Methods: MSCs were harvested from mice adipose tissue and characterized by flow cytometry and evaluating differentiation potential. The exosomes were isolated and characterized via Dynamic Light Scattering, Scanning Electron Microscopy, and flow cytometry. Different concentrations of ovalbumin were incubated with MSC-exosome in various durations to optimize a more suitable protocol. BCA and HPLC analysis were used to quantify, and DLS was applied to qualify the prepared formulation of the OVA-exosome complex. Results: The harvested MSCs and isolated exosomes were characterized. Analysis of the OVA-exosome complex revealed that OVA in primary 500 µg/ml concentration and incubation for 6 h results in higher efficacy. Conclusions: Loading OVA into MSC-derived exosomes was successfully optimized and could be administrated for allergen-specific immunotherapy in the animal model.
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Background : Colorectal cancer, a solid tumor with a high prevalence, contributes significantly to annual mortality rates. Various factors, including blood groups, may influence cancer risk. Multiple studies have suggested a potential connection between ABO and Rh blood groups and colorectal cancer risk. This study aims to investigate the role of ABO and Rh blood groups as risk factors in colorectal cancer patients. Materials and Methods: We conducted a retrospective study involving 71 colorectal cancer patients diagnosed between 2018 and 2020 in Khuzestan province, Iran, with known ABO blood types. Large-scale data from 29,922 blood donors in Khuzestan served as the healthy population control. The study analyzed the distribution of ABO blood groups among the blood donors. Results : Our findings revealed that the distribution of blood groups among colorectal cancer patients was as follows: O (31.0%), A (29.6%), B (29.6%), and AB (9.8%). However, our analysis did not establish a significant association between colorectal cancer risk and ABO antigens (P-value = 0.636) or Rh blood group (P = 0.198). Additionally, no significant differences in ABO blood types were observed concerning gender (P = 0.802), cancer type (P = 0.338), or tumor type (P = 0.207) among colorectal cancer patients. Conclusion : This study does not support a significant correlation between ABO and Rh blood groups and the risk of colorectal cancer, nor does it find associations with cancer type or tumor type.
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Background: Breast cancer and cervix cancer are the prevalent and deadly types of solid tumors around the world. According to the importance of cancer, it is necessary to understand predisposing factors that affect cancer risk. In this regard, previous studies suggest that blood types particularly ABO and Rh-Hr Blood-Group System could play roles in the risk and different features of cancers. In the present study, we aimed to evaluate the potential of ABO and Rh blood groups as risk factors for breast cancer and cervix cancer. Materials and Methods: A retrospective study included 109 and 14 patients diagnosed with breast cancer and cervix cancer, respectively with known ABO and Rh blood types, between 2018 and 2020 in Khuzestan province, Iran. For compression of ABO blood groups distribution between the cancer patients group and the healthy population, we used data from a large-scale study that report the distribution of ABO blood groups in 29,922 blood donors in Khuzestan province. Results: Based on obtained results the most frequent blood group is O followed by B, A, and AB in breast cancer and followed by A, B, and AB in cervix cancer. Results showed no significant association between ABO and Rh and the risk of breast and cervix cancer. Moreover, there is no relationship between blood types and clinic pathological features of breast cancer. Conclusion: Based on our data, ABO and in this regard, previous studies suggest that blood types particularly ABO and Rh-Hr Blood-Group System could play roles in the risk and different features of cancers. In the present study, we aimed to evaluate the potential of ABO and Rh blood groups as risk factors for breast cancer and cervix cancer do have not any association with the risk of breast and cervix cancer and their characteristics.
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AIM: This study evaluated the immunomodulatory and delivery potential of adipose tissue-isolated MSC-derived exosomes as a prophylactic regimen through a sublingual route in the ovalbumin (OVA)-induced allergic asthma murine model. MATERIAL AND METHODS: Balb/c mice received 10 µg/dose of OVA-enriched MSC-derived exosomes as a prophylactic regimen in six doses during three weeks, and then OVA sensitization was conducted through intraperitoneal and aerosol administration of allergen. The total cells and eosinophils counted in nasal lavage fluid (NALF) and lung tissues were assessed for histopathological analysis. In addition, the secretion of IFN-γ, IL-4, and TGF-ß by spleen cells and serum OVA-specific IgE levels were measured via ELISA. RESULTS: Significant reduction in the IgE levels and IL-4 production, along with elevated TGF-ß levels, were observed. Also, limited cellular infiltrations and perivascular and peribronchiolar inflammation in the lung tissues and normal total numbers of cells and eosinophils in the NALF were reported. CONCLUSION: Prophylactic regimen using OVA-enriched MSC-derived exosomes modulated immune responses and inhibited allergic OVA sensitization.
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Exossomos , Camundongos , Animais , Ovalbumina , Interleucina-4 , Líquido da Lavagem Broncoalveolar , Aerossóis e Gotículas Respiratórios , Imunoglobulina E , Fator de Crescimento Transformador beta , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças , CitocinasRESUMO
Increasing the efficacy of allergen-specific intranasal immunotherapy (INIT) has recently been the main goal of several studies to establish this route as a safe delivery method through mucosal pathways. In this case, the present study evaluated the potential of INIT using ovalbumin (OVA)-loaded mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo-OVA) in an allergic asthma mouse model. Together with control groups, sensitized Balb/c mice underwent intranasal immunotherapy with Exo-OVA (10 µg OVA per dose) for three consecutive weeks. Serum-specific immunoglobulin E (IgE) levels, transforming growth factor-beta (TGF-ß), interleukin (IL)-4, and interferon-gamma (IFN-γ) production by cultured spleen cells, lung histopathologic analysis, and nasopharyngeal lavage fluid cellular examinations were then conducted. The results showed that INIT using Exo-OVA significantly increased IFN-γ and TGF-ß secretion, while allergen-specific IgE and IL-4 production were dramatically decreased compared to the control group receiving phosphate-buffered saline. In addition, the eosinophil and total cell counts in the nasopharyngeal lavage fluid were reduced, and inflammatory conditions and cell accumulation in lung tissue were ameliorated. In conclusion, the Exo-OVA improved the INIT efficacy compared to free OVA. Therefore, this formulation could be introduced as an effective approach for immunomodulatory purposes with a shorter treatment duration and reduced side effects.
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Exossomos , Animais , Camundongos , Dessensibilização Imunológica , Ovalbumina , Imunoglobulina E , Fator de Crescimento Transformador beta , AlérgenosRESUMO
Allergen-specific Immunotherapy (AIT) is the main therapeutic strategy to control and treat allergic disorders. Intranasal Immunotherapy (INIT) was introduced as a needle-free, noninvasive, and efficient approach among various routes of allergen administration. Since direct exposure of nasal mucosa to allergen extracts could induce local and systemic reactions, recent studies focus on establishing novel formulations using various delivery systems and adjuvants to improve INIT efficacy. This review categorizes and describes natural and synthetic micro/nanoparticles such as chitosan, PLGA, liposome, exosome, and nano-emulation droplets used as delivery systems or immunomodulatory and immune-regulatory agents. Also, multiple microbial agents, including probiotics, mycobacterial and viral components, TLR ligands, and biologic agents, i.e., antibody fragments, recombinant cytokines, vitamin A, and pulsed dendritic cells (DCs), are other platforms that are discussed. In addition, future perspectives and proposed strategies to help INIT were provided.
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Dessensibilização Imunológica , Hipersensibilidade , Humanos , Alérgenos , Adjuvantes Imunológicos/uso terapêutico , Adjuvantes Imunológicos/farmacologia , Hipersensibilidade/tratamento farmacológico , Administração Intranasal , Imunoterapia , Adjuvantes FarmacêuticosRESUMO
Nowadays, various strategies are considered to prime Dendritic cells (DCs) with tumor antigens. The tumor cell-derived exosomes are recognized as one of the most efficient strategies for achieving this purpose. In this regard, MicroRNA 155 (miR-155) is employed as one of the most prominent miRNAs, which play substantial roles in DCs maturation and IL-12 production. This study investigates the tumor growth suppression and antitumor effects of DCs primed with miR-155-enriched exosome on the BALB/c murine model of colorectal cancer induced by CT-26 cell lines. Therefore, a holistic framework is proposed for the analysis procedure. In the first stage, miRNA-155 was electroporated into texosomes. In the second stage, bonemarrow-derived DCs were treated with miRNA-155 enriched texosomes. Then, antitumor properties of manipulated DC have been evaluated in the BALB/c mice model of colorectal cancer. After DC immunotherapy, several features have been assessed for each animal, including survival, body weight, tumor volume/size, histopathology, and serum cytokine levels. Also, flow cytometric evaluation has been performed for the spleen and the tumor tissue T-cell subsets. The findings demonstrated that the primed DCs could significantly increase IL-12p70 and IFN-γ in serum and accelerate the differentiation, proliferation, and cytotoxicity effects on the Th and CTL cells. Also, the treatment also increased the infiltration of Th and CTL cells into the tumor microenvironment while decreasing Tregs. This situation causes tumor growth control, and survival improvement. Therefore, DC immunotherapywith miR-155-enriched texosomes can be employed as a the desired approach for inducing antitumor immune responses, controlling tumor growth, and improving survival in mice with colorectal cancer. However, it is essential to perform more investigations to confirm the clinical application of this approach in humans and other types of tumors.
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Neoplasias Colorretais/terapia , Células Dendríticas/imunologia , Exossomos , Imunoterapia , MicroRNAs , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Metástase Linfática/imunologia , Metástase Linfática/patologia , Metástase Linfática/terapia , Camundongos Endogâmicos BALB C , Baço/citologia , Baço/imunologia , Carga TumoralRESUMO
Aim: This study aimed to investigate the effects of natural adjuvants (G2 and PC) to activate natural killer cells in colorectal cancer. Background: Natural killer (NK) cells are an element of the innate immune system that can recognize and kill cancer cells and provide hope for cancer therapy. One of the current methods in cancer immunotherapy is NK cell therapy. Immunotherapy with NK cells has been limited because of the low number and cytotoxicity level of NK cells. Natural adjuvants such as PC and G2 may stimulate the immune system. It seems that these adjuvants could increase cytotoxic NK cells. Methods: Twelve patients with colorectal cancer and six healthy individuals qualified for inclusion in this study. Peripheral blood mononuclear cells (PBMCs) from each patient with two distinctive concentrations (105and 5×104 cells/well) were treated with Interleukin2 (IL2), PC, and G2 adjuvant separately. The NK cell's surface markers, including CD16, CD56, and NKG2D, were evaluated by flow cytometry. The cytotoxicity effect of treated PBMCs as effector cells against NK sensitive cell line (K562) was assessed using the LDH assay method. Results: The results revealed a significant increase in the level of CD16+NKG2D+ NK cells in PBMCs treated with the G2 group compared with the control group in CRC PBMC (p<0.001) as well as the normal PBMC group (p < 0.01). In addition, the results indicated a significant increase in the level of CD56+NKG2D+ cells in the PBMC treated with PC (p < 0.05) and G2 (p < 0.001) groups compared with the PBMC group. The cytotoxicity result of PBMC from CRC patients in 10:1 ratio of the effector: target showed that the cells' cytotoxicity in the PBMCs treated with PC (p<0.01) and G2 (p<0.05) was significantly higher than the untreated PBMC. Conclusion: According to the result of this study, it can be stated that the PC and G2 adjuvants could be candidates for inducing cytotoxic natural killer cells.
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Tumor cells modulate immune responses by secreting exosomes. Tumor exosomes can affect the metabolism of immune cells and increase immune inhibitory molecules such as programmed cell death protein 1 (PD-1). PD-1 inhibits the glycolysis pathway in immune cells. We investigated the role of tumor exosomes in how metabolic changes occur through the PD1-GLUT1-HK2 metabolic axisin peripheral blood mononuclear cells (PBMCs). The MDA-MB-231 cell line was cultured, serum samples from breast cancer patients were collected, and exosomes purified from serum samples and the MDA-MB-231 cell line. PBMCs were treated with purified exosomes for 72 h and, the expression of PD1-GLUT1-HK2 genes was measured by real-time PCR. Our study results showed relative expression of the HK2 gene in both groups treated with MDA-MB-231 cell line exosomes and serum exosomes of breast cancer patients was significantly increased compared to the control group (p < 0.0001). Also, the relative expression of the PD1 gene and GLUT1 gene showed a significant increase compared to the control group only in the group treated with MDA-MB-231 cell line exosomes (p < 0.0001). Therefore, Breast cancer exosomes increased the expression of key genes in the glycolysis pathway, increasing the glycolysis pathway in PBMCs. Increased expression of PD-1 could not prevent the expression of critical genes in the glycolysis pathway as in previous studies.
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Neoplasias da Mama , Exossomos , Regulação Neoplásica da Expressão Gênica/imunologia , Transportador de Glucose Tipo 1 , Hexoquinase , Leucócitos Mononucleares , Proteínas de Neoplasias , Receptor de Morte Celular Programada 1 , Transdução de Sinais/imunologia , Adulto , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Exossomos/imunologia , Exossomos/metabolismo , Feminino , Transportador de Glucose Tipo 1/imunologia , Transportador de Glucose Tipo 1/metabolismo , Hexoquinase/imunologia , Hexoquinase/metabolismo , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismoRESUMO
OBJECTIVE: Seminal plasma (SP) contains large numbers of sub-cellular structures called extracellular vesicles (EV) which have been postulated to have immunological functions due to their bioactive contents including proteins and small non-coding RNAs. Although the response of endometrial cells to seminal EV (SEV) is recently being elucidated, the impact of these signaling vesicles on stroma-immune crosstalk is still unknown. Herein, we aimed to investigate the effect of conditioned medium (CM) derived from SEV-exposed endometrial stromal cells (eSC) on cytokine secretion by macrophages. STUDY DESIGN: SEV were isolated from SP samples of healthy donors and characterized by common methods needed for EV characterization, including size determination by dynamic light scattering (DLS), transmission electron microscopy (TEM), and western blot analysis of EV markers. Endometrial biopsies were obtained from healthy individuals and eSC were isolated and characterized. EV internalization assay was performed by labeling the SEV with PKH67 green fluorescent dye. Then, the eSC were exposed to SEV and the CM was collected. Finally, the CM from SEV-exposed eSC was added to the macrophage culture and the level of inflammatory (interleukin (IL)-1α and IL-6) and anti-inflammatory (IL-10) cytokines were measured in the culture supernatant of macrophages. RESULTS: The results demonstrated that the CM derived from SEV-exposed eSC induce IL-1α and IL-6 secretion by the macrophages, while the secretion of IL-10 was reduced. CONCLUSION: Our results support the idea that the stroma-immune interaction is affected by SEV. This effect may be a part of immunoregulatory function of SP inside upper female genital tract and have an obvious impact during peri-implantation period.
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Vesículas Extracelulares , Células Estromais , Meios de Cultivo Condicionados , Endométrio , Feminino , Humanos , MacrófagosRESUMO
In this study, we evaluated the effects of nanofiber and film polymers with doxycycline for treating a wound in a diabetic rat model. 108 male rats were divided into six groups, the control group, the diabetic control, and the groups were diabetic rats receiving different wound dressing. At the 3rd, 7th, and 14th days, macroscopic/histologic imaging and tissue sampling were performed. Tissues were analyzed for IL-1ß, TNF-α, IL-10, TIMP-1, and MMP-2 by using ELISA. Dressings of chitosan, polyvinyl alcohol, and doxycycline increased the rate of wound closure, the volume of collagen, dermal, and epidermis. In addition, it increased the number of fibroblasts and basal cell epidermis cells, vascular length, and decreased the number of neutrophil cells. Inflammatory cytokines and MMP-2 were decreased, and anti-inflammatory IL-10 and TIMP-1 were increased. It was ultimately attained that the combination of chitosan/ polyvinyl alcohol /doxycycline could be a useful dressing for the healing of diabetic wounds.
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INTRODUCTION: Albeit early stage gastrointestinal (GI) carcinomas have a good prognosis if treated with surgery, diagnosis is often confirmed at a late stage and efficacious drugs are lacking. Recent progress in immune-based therapies has focused on dendritic cells (DCs), aiming to elicit tumor-specific responses by inducing immunological memory. Our previous microarray study indicated that a biomarker, termed lymphocyte antigen-6E (LY6E), is commonly overexpressed in two potentially lethal GI cancers: those of colon and stomach. In this study, we examined the antigenic potency of LY6E in stimulating DCs. METHODS: Following isolation, differentiation, and maturation of mononuclear cells, DCs were pulsed with LY6E peptide, a protein related to major histocompatibility complex (MHC) class I/II. Subsequently, DCs were co-cultured with mouse splenocytes to assess antigen-specific T-cell proliferation. Elucidated cytotoxic T-lymphocyte responses were assessed using subcutaneous colorectal murine tumor models. RESULTS: Our in vitro results suggest that DCs loaded with LY6E peptide antigen are capable of stimulating and inducing proliferation of murine T-cells. Furthermore, our in vivo results demonstrate that LY6E peptide has a substantial impact on provoking immune responses against induced colon cancer in mice. DISCUSSION: In conclusion, based on the overexpression of LY6E in colorectal, gastric, and pancreatic cancers, the role of this peptide should be further investigated with a goal of developing new therapies for these challenging diseases.