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Kamboj K, Pariki A, Singhal M, Lal A, Naik S, Kumar V, Yadav AK, Jha V. Effect of cholecalciferol on immune and vascular function in non-diabetic chronic kidney disease. Front Immunol 2025; 16:1555304. [PMID: 40342405 PMCID: PMC12058780 DOI: 10.3389/fimmu.2025.1555304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025] Open
Abstract
Background and aims Vitamin D deficiency, widely prevalent in patients with chronic kidney disease (CKD) could play a role in the pathogenesis of cardiovascular disease (CVD) by causing alterations in endothelial and immune function. We investigated the change in immune and vascular functions following vitamin D supplementation in non-diabetic subjects with stage 3-4 CKD and vitamin D deficiency. Methods In this single-arm study, non-diabetic CKD subjects aged 18-75 years, eGFR 15-60 ml/min/1.73m2, and serum 25-hydroxyvitamin D3 levels <20 ng/ml were enrolled. Enrolled subjects received a directly observed oral dose of 300,000 IU cholecalciferol at baseline and 8 weeks. Outcome assessments, including immunological, vascular, endothelial, inflammatory, and biochemical parameters, were measured at baseline and 16 weeks. Results In total, 62 subjects were studied. The mean age was 44 ± 12 years with 58% men. TH1 cells decreased from 17% (9%, 27%) to 11% (6%, 16%) (p=0.002) and TH2 cells increased from 9% (5%, 16%) to 16% (10%, 27%) (p=0.001) after cholecalciferol treatment. A significant increase in mRNA expression of vitamin D-responsive genes (cathelicidin, IL-10, VDR, and CYP27B1) was observed. The levels of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-23, and IL-6) decreased whereas anti-inflammatory cytokines (IL-4, IL-10, and IL-13) showed an increase. Cholecalciferol treatment improved flow-mediated dilatation (FMD): 8.2% (6.2%, 12.1%) at baseline to 14.1% (10.0%, 20.1%) at 16 weeks (p<0.001). Conclusions This study confirms that cholecalciferol supplementation influenced immune function as it favored the TH2/TH1 phenotype, favorably affected the levels of inflammatory markers and mRNA expression of vitamin D responsive genes, and improved vascular function in CKD. Clinical Trial Registration https://www.ctri.nic.in, identifier CTRI/2019/10/021494.
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Affiliation(s)
- Kajal Kamboj
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Aruna Pariki
- Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Manphool Singhal
- Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anupam Lal
- Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sachin Naik
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vivek Kumar
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashok Kumar Yadav
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vivekanand Jha
- George Institute for Global Health, New Delhi, India
- School of Public Health, Imperial College, London, United Kingdom
- Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India
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Kamboj K, Kumar V, Yadav AK. In Vitro Study of Vitamin D Effects on Immune, Endothelial, and Vascular Smooth Muscle Cells in Chronic Kidney Disease. Int J Mol Sci 2025; 26:3967. [PMID: 40362207 PMCID: PMC12071356 DOI: 10.3390/ijms26093967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/11/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Vitamin D has been shown to improve immunity as well as vascular function. We investigated the effect of cholecalciferol on T-cell phenotype in cultured peripheral blood mononuclear cells (PBMCs) from twenty vitamin D-deficient, non-diabetic chronic kidney disease (CKD) subjects. We also studied vitamin D effects on endothelial and vascular function markers in human aortic endothelial cells (HAECs) and in human aortic smooth muscle cells (HASMCs), respectively. We studied endothelial nitric oxide synthase (eNOS), mitogen-activated protein kinase 38 (p38 Map kinase), protein kinase B (Akt), and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) in HAECs and α-smooth muscle actin (α-SMA), smooth muscle calponin (SM-Calponin), smooth muscle myosin heavy chain (SM-MHC), and calcium-sensing receptor (CaSR) in HASMCs. Vitamin D receptors (VDRs) and CYP27B1 were studied in both cell types. In cultured PBMCs isolated from CKD subjects, the percentage of T helper 1(TH1) cells significantly decreased while that of T helper 2 (TH2) cells increased after cholecalciferol treatment. No significant change in intracellular and surface markers of T helper 17 (TH17) and T regulatory (Treg) cells was observed. In vitro treatment of HASMCs and HAECs with cholecalciferol led to significant and favorable alterations in mRNA expression of markers of vascular smooth muscle cells, i.e., α-SMA, SM-Calponin, and SM-MHC. Regarding endothelial cell markers, mRNA encoding eNOS, p38 Map kinase, protein kinase B (Akt), NADPH oxidase, VDR, and CYP27B1 were also significantly changed. Finally, the expression levels of the following proteins were notably altered: NADPH oxidase and protein kinase B (Akt) (in HAECs); SM-MHC and SM-Calponin (in HASMCs). In vitro treatment of PBMCs with cholecalciferol led to a favorable change in T-cell population, decreasing TH1 and increasing TH2 cell percentage, along with beneficial alterations in mRNA expression of HASMCs and HAECs' cell markers. This study provides evidence that cholecalciferol can influence immune and vascular function in CKD.
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MESH Headings
- Humans
- Renal Insufficiency, Chronic/immunology
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Renal Insufficiency, Chronic/drug therapy
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/pathology
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Vitamin D/pharmacology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Nitric Oxide Synthase Type III/metabolism
- Male
- Middle Aged
- Receptors, Calcitriol/metabolism
- Receptors, Calcitriol/genetics
- Cells, Cultured
- Cholecalciferol/pharmacology
- Female
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- p38 Mitogen-Activated Protein Kinases/metabolism
- Adult
- NADPH Oxidases/metabolism
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Affiliation(s)
- Kajal Kamboj
- Departments of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India; (K.K.); (V.K.)
| | - Vivek Kumar
- Departments of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India; (K.K.); (V.K.)
| | - Ashok Kumar Yadav
- Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
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Shalaby R, Nawawy ME, Selim K, Bahaa S, Refai SE, Maksoud AE, Sayed ME, Essawy A, Elshaer A, ElShaer M, Kamel MM, Gamil Y. The role of vitamin D in amelioration of oral lichen planus and its effect on salivary and tissue IFN-γ level: a randomized clinical trial. BMC Oral Health 2024; 24:813. [PMID: 39020381 PMCID: PMC11256592 DOI: 10.1186/s12903-024-04239-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/09/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Oral lichen planus (OLP) is a common, prevalent, immune-mediated, inflammatory disease affecting both the skin and oral mucosa and is considered one of the potentially malignant diseases. Since OLP is regarded as an immunologically mediated disease, some studies suggest the use of vitamin D (VD) for its management as it exhibits immune-modulatory, anti-inflammatory, and antimicrobial properties, as well as anti-proliferative, pro-differentiative, and anti-angiogenic effects. VD has demonstrated a suppressive effect on TH1 pro-inflammatory cytokines, including IFN-γ while augmenting the secretion of anti-inflammatory cytokines. At the same time, VD deficiency is a prevalent public issue. Therefore, the present study aimed to investigate the role of VD as an adjunct to steroids in the management of VD-deficient OLP patients as well as its inhibitory effect on IFN-γ through measurement of salivary and tissue IFN-γ levels in OLP patients. METHODS A total of 40 patients with ulcerative or erythematous OLP, diagnosed according to the World Health Organization's (WHO) modified criteria for OLP, were randomly allocated into one of the two study groups to receive either systemic steroids in addition to VD supplements (Group A) or systemic steroids only (Group B). Blood samples were collected for the measurement of serum VD level (SVDL) using the enzyme-linked immunosorbent assay (ELISA) to involve only patients with VD deficiency or insufficiency (≤ 30 ng/ml). Clinical evaluation of the lesion involved objective signs and subjective symptoms. Also, changes in salivary and tissue INF-γ levels (in pg/mL and pg/mg, respectively) were determined using the ELISA technique. All parameters were measured at baseline and after 4 weeks of treatment. The clinical pharmacy team devised a checklist to record all team interventions. The interventions were categorized into six domains, including drug interactions and/or adverse reactions, medication dose issues, drug selection issues, support with medication history, patient-related concerns, and suggestions for dental medication. RESULTS After one month of treatment, a significantly greater number of patients in group A showed complete pain relief and resolution of clinical lesions, as well as a greater number of patients showing a reduction in the clinical severity of lesions than in group B (P = 0.005). Also, there was a statistically significant reduction in average VAS pain scores and clinical scores in group A compared to group B after 1 month of treatment (P = 0.001 and 0.002, respectively). Furthermore, there was a statistically significant greater reduction in salivary and tissue IFN-γ levels in group A than in group B (P ≤ 0.001 and 0.029, respectively) after 1 month of treatment. CONCLUSION Current evidence suggests a significant preventive and therapeutic role for VD as an adjunct to standard therapies indicated for OLP lesions. These protective and therapeutic functions are achieved through the suppressive effect of VD on pro-inflammatory cytokines, particularly IFN-γ. Also, salivary IFN-γ appears to be a valuable prognostic marker for monitoring the progression of OLP. In addition, the inter-professional collaboration between dentists and clinical pharmacists helped to deliver complete, patient-centered primary care and ensured the quality of the medications included in patient kits, thus improving patient treatment and management. Nevertheless, further studies with larger sample sizes, longer follow-ups, and standardized designs may still be needed.
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Affiliation(s)
- Rania Shalaby
- Oral Medicine, Diagnosis, and Periodontology, Faculty of Dentistry, Fayoum University, Fayoum, Egypt.
| | - Marwa El Nawawy
- Oral Medicine, Diagnosis, and Periodontology, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Khaled Selim
- Oral Medicine, Diagnosis, and Periodontology, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Samah Bahaa
- Oral Medicine, Diagnosis, and Periodontology, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Sahar El Refai
- Oral Pathology, College of Dentistry, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | | | - Mahitab El Sayed
- Clinical Pharmacy Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Aya Essawy
- Clinical Pharmacy Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Asmaa Elshaer
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed ElShaer
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Moataz Maher Kamel
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Yasmine Gamil
- Department of Oral Medicine, Diagnosis, and Periodontology, Faculty of Oral and Dental Surgery, Modern University for Technology and Information, MTI University, Cairo, Egypt
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Lin N, Chi H, Guo Q, Liu Z, Ni L. Notch Signaling Inhibition Alleviates Allergies Caused by Antarctic Krill Tropomyosin through Improving Th1/Th2 Imbalance and Modulating Gut Microbiota. Foods 2024; 13:1144. [PMID: 38672818 PMCID: PMC11048830 DOI: 10.3390/foods13081144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/19/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024] Open
Abstract
Antarctic krill tropomyosin (AkTM) has been shown in mice to cause IgE-mediated food allergy. The objective of this work was to investigate the role of Notch signaling in AkTM-sensitized mice, as well as to determine the changes in gut microbiota composition and short-chain fatty acids (SCFAs) in the allergic mice. An AkTM-induced food allergy mouse model was built and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was used as an γ-secretase inhibitor to inhibit the activation of Notch signaling. Food allergy indices, some key transcription factors, histologic alterations in the small intestine, and changes in gut microbiota composition were examined. The results showed that DAPT inhibited Notch signaling, which reduced AkTM-specific IgE, suppressed mast cell degranulation, decreased IL-4 but increased IFN-γ production, and alleviated allergic symptoms. Quantitative real-time PCR and Western blotting analyses revealed that expressions of Hes-1, Gata3, and IL-4 were down-regulated after DAPT treatment, accompanied by increases in T-bet and IFN-γ, indicating that Notch signaling was active in AkTM-sensitized mice and blocking it could reverse the Th1/Th2 imbalance. Expressions of key transcription factors revealed that Notch signaling could promote Th2 cell differentiation in sensitized mice. Furthermore, 16S rRNA sequencing results revealed that AkTM could alter the diversity and composition of gut microbiota in mice, leading to increases in inflammation-inducing bacteria such as Enterococcus and Escherichia-Shigella. Correlation analysis indicated that reduced SCFA concentrations in AkTM-allergic mice may be related to decreases in certain SCFA-producing bacteria, such as Clostridia_UCG-014. The changes in gut microbiota and SCFAs could be partially restored by DAPT treatment. Our findings showed that inhibiting Notch signaling could alleviate AkTM-induced food allergy by correcting Th1/Th2 imbalance and modulating the gut microbiota.
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Affiliation(s)
- Na Lin
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
| | - Hai Chi
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
- College of Food Science and Engineering, Dalian Ocean University, Dalian 116023, China
| | - Quanyou Guo
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
| | - Zhidong Liu
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
| | - Ling Ni
- East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; (N.L.); (Q.G.); (L.N.)
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Macchione M, Yoshizaki K, Frias DP, Maier K, Smelan J, Prado CM, Mauad T. Fragrances as a trigger of immune responses in different environments. Toxicol In Vitro 2024; 96:105769. [PMID: 38142785 DOI: 10.1016/j.tiv.2023.105769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 12/18/2023] [Indexed: 12/26/2023]
Abstract
Fragrances can cause allergic skin reactions, expressed as allergic contact dermatitis and reactions in the respiratory tract that range from acute temporary upper airway irritation to obstructive lung disease. These adverse health effects may result from the stimulation of a specific (adaptive) immune response. Th1 cells, which essentially produce interleukin-2 (IL-2) and interferon-γ (IFN-γ), play a key role in allergic contact dermatitis and also on allergic sensitization to common allergens (e.g., nickel and fragrance). It has been shown that fragrance allergy leads to Th2/Th22 production of IL-4, IL-5 and IL-13, controlling the development of IgE and mediating hypersensitivity reactions in the lung, such as asthma. Cytokines released during immune response modulate the expression of cytochrome P450 (CYPs) proteins, which can result in alterations of the pharmacological effects of substances in inflammatory diseases. The mechanisms linking environment and immunity are still not completely understood but it is known that aryl hydrocarbon receptor (AhR) is a sensor with conserved ligand-activated transcription factor, highly expressed in cells that controls complex transcriptional programs which are ligand and cell type specific, with CYPs as targeted genes. This review focuses on these important aspects of immune responses of the skin and respiratory tract cells, describing some in vitro models applied to evaluate the mechanisms involved in fragrance-induced allergy.
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Affiliation(s)
- M Macchione
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil.
| | - K Yoshizaki
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - D P Frias
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - K Maier
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - J Smelan
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - C M Prado
- Federal University of Sao Paulo, Santos, Brazil
| | - T Mauad
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
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Li C, Yu J, Wang Y, Li X, Li Y, An M, Ni W, Liu K, Hu S. Efficacy of H 2O 2 inactivated bovine virus diarrhoea virus (BVDV) type 1 vaccine in mice. BMC Vet Res 2024; 20:43. [PMID: 38308297 PMCID: PMC10837870 DOI: 10.1186/s12917-024-03897-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 01/23/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Bovine viral diarrhea (BVD) is an acute febrile infectious disease caused by the bovine viral diarrhea virus (BVDV), which has brought huge economic losses to the world's cattle industry. At present, commercial inactivated BVDV vaccines may cause some adverse reactions during use. This study aims to develop a safer and more efficient inactivated BVDV vaccine. METHODS Here, we described the generation and preclinical efficacy of a hydrogen peroxide (H2O2) inactivated BVDV type 1 vaccine in mice, and administered it separately with commercial vaccine (formaldehyde inactivated) in mice to study its efficacy. RESULTS The BVDV type 1 IgG, IFN- γ, IL-4 and neutralizing antibody in the serum of the H2O2 inactivated vaccine group can be maintained in mice for 70 days. The IgG level reached its maximum value of 0.67 on the 42nd day, significantly higher than the commercial formaldehyde inactivated BVDV type 1 vaccine. IFN- γ and IL-4 reached their maximum values on the 28th day after immunization, at 123.16 pg/ml and 143.80 pg/ml, respectively, slightly higher than commercial vaccines, but the effect was not significant. At the same time the BVDV-1 neutralizing antibody titer reached a maximum of 12 Nu on the 42nd day post vaccination. CONCLUSIONS The H2O2 inactivated BVDV vaccine has good safety and immunogenicity, which provides a potential solution for the further development of an efficient and safe BVDV vaccine.
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Affiliation(s)
- Cunyuan Li
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China
| | - Jinming Yu
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China
| | - Yue Wang
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China
| | - Xiaoyue Li
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China
| | - Yaxin Li
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China
| | - Mingxuan An
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China
| | - Wei Ni
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China.
| | - Kaiping Liu
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China
| | - Shengwei Hu
- College of Life Sciences, Shihezi University, Shihezi, 832003, Xinjiang, China.
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Arita K, Tao H, Crowe P, Thacher S, Otake S, Kobayashi K, Ebihara S, Okamoto Y, Katsuda Y, Yamaguchi T, Matsushita M. Pharmacological Properties of JTE-151; A Novel Orally Available RORγ Antagonist That Suppresses Th17 Cell-Related Responses in Vitro and in Vivo. Biol Pharm Bull 2024; 47:2050-2057. [PMID: 39675971 DOI: 10.1248/bpb.b24-00490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Retinoid-related orphan receptor-γ (RORγ) is a nuclear receptor that plays important roles in the development and activation of T helper type-17 (Th17) cells. In this study, we characterized the pharmacological profile of JTE-151 ((4S)-6-[(2-chloro-4-methylphenyl)amino]-4-{4-cyclopropyl-5-[cis-3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3yl}-6-oxohexanoic acid), which is a novel RORγ antagonist identified by our group. JTE-151 dissociated co-activator peptide from the human RORγ-ligand binding domain (LBD) and recruited co-repressor peptide into human RORγ-LBD, and potently inhibited the transcriptional activity of RORγ of human, mouse and rat. JTE-151 also demonstrated high selectivity against other receptors in nuclear receptor family. JTE-151 suppressed the differentiation of mouse naïve CD4+ T cells into Th17 cells without affecting the differentiation of those cells into other CD4+ T cell subsets in vitro. In addition, JTE-151 inhibited the production of interleukin-17 (IL-17) but not interferon-γ (IFN-γ) and IL-4 from activated human helper T cells in vitro. Furthermore, treatment with JTE-151 suppressed the production of IL-17 in antigen-sensitized mice and ameliorated the severity of arthritis in mice with collagen-induced arthritis regardless of treatment start date. Based on these results, we reasoned that JTE-151 could serve as a novel therapeutic compound for various autoimmune diseases linked to Th17 cells, such as psoriasis and rheumatoid arthritis.
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Affiliation(s)
- Kojo Arita
- Central Pharmaceutical Research Institute, Japan Tobacco Inc
| | | | | | | | - Sho Otake
- Central Pharmaceutical Research Institute, Japan Tobacco Inc
| | | | - Shin Ebihara
- Central Pharmaceutical Research Institute, Japan Tobacco Inc
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Zhang QQ, Zhang WJ, Chang S. HDAC6 inhibition: a significant potential regulator and therapeutic option to translate into clinical practice in renal transplantation. Front Immunol 2023; 14:1168848. [PMID: 37545520 PMCID: PMC10401441 DOI: 10.3389/fimmu.2023.1168848] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/30/2023] [Indexed: 08/08/2023] Open
Abstract
Histone deacetylase 6 (HDAC6), an almost exclusively cytoplasmic enzyme, plays an essential role in many biological processes and exerts its deacetylation-dependent/independent effects on a variety of target molecules, which has contributed to the flourishing growth of relatively isoform-specific enzyme inhibitors. Renal transplantation (RT) is one of the alternatively preferred treatments and the most cost-effective treatment approaches for the great majority of patients with end-stage renal disease (ESRD). HDAC6 expression and activity have recently been shown to be increased in kidney disease in a number of studies. To date, a substantial amount of validated studies has identified HDAC6 as a pivotal modulator of innate and adaptive immunity, and HDAC6 inhibitors (HDAC6i) are being developed and investigated for use in arrays of immune-related diseases, making HDAC6i a promising therapeutic candidate for the management of a variety of renal diseases. Based on accumulating evidence, HDAC6i markedly open up new avenues for therapeutic intervention to protect against oxidative stress-induced damage, tip the balance in favor of the generation of tolerance-related immune cells, and attenuate fibrosis by inhibiting multiple activations of cell profibrotic signaling pathways. Taken together, we have a point of view that targeting HDAC6 may be a novel approach for the therapeutic strategy of RT-related complications, including consequences of ischemia-reperfusion injury, induction of immune tolerance in transplantation, equilibrium of rejection, and improvement of chronic renal graft interstitial fibrosis after transplantation in patients. Herein, we will elaborate on the unique function of HDAC6, which focuses on therapeutical mechanism of action related to immunological events with a general account of the tantalizing potential to the clinic.
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Affiliation(s)
- Qian-qian Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Wei-jie Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Sheng Chang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Zhao L, Wang Y, Jaganathan A, Sun Y, Ma N, Li N, Han X, Sun X, Yi H, Fu S, Han F, Li X, Xiao K, Walsh MJ, Zeng L, Zhou M, Cheung KL. BRD4-PRC2 represses transcription of T-helper 2-specific negative regulators during T-cell differentiation. EMBO J 2023; 42:e111473. [PMID: 36719036 PMCID: PMC10015369 DOI: 10.15252/embj.2022111473] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 12/26/2022] [Accepted: 01/11/2023] [Indexed: 02/01/2023] Open
Abstract
BRD4 is a well-recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type-specific manner has remained elusive. In this study, we report that BRD4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of the T-helper 2 (Th2)-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 during lineage-specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 binds to the lysine-acetylated-EED subunit of the PRC2 complex via its second bromodomain (BD2) to facilitate histone H3 lysine 27 trimethylation (H3K27me3) at target gene loci and thereby transcriptional repression. We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 promotes its ubiquitination-directed protein degradation. BRD4-mediated repression of Foxp3 and Fbxw7 in turn promotes BRD4- and Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5, and Il13. Chemical inhibition of the BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and thus transcriptional downregulation of Il4, Il5, and Il13, resulting in inhibition of Th2 cell lineage differentiation. Our study presents a previously unappreciated mechanism of BRD4's role in orchestrating a Th2-specific transcriptional program that coordinates gene repression and activation, and safeguards cell lineage differentiation.
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Affiliation(s)
- Li Zhao
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Yiqi Wang
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Anbalagan Jaganathan
- Department of Pharmacological SciencesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Yifei Sun
- Department of Pharmacological SciencesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Ning Ma
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Ning Li
- The Institute of Genetics and Cytology, Northeast Normal UniversityChangchunChina
| | - Xinye Han
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Xueying Sun
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Huanfa Yi
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Shibo Fu
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Fangbin Han
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Xue Li
- Department of ChemistryMichigan State UniversityEast LansingMIUSA
| | - Kunhong Xiao
- Center for Proteomics & Artificial Intelligence and Center for Clinical Mass SpectrometryAllegheny Health Network Cancer InstitutePittsburghPAUSA
- Department of Pharmacology and Chemical Biology, School of MedicineUniversity of PittsburghPittsburghPAUSA
| | - Martin J Walsh
- Department of Pharmacological SciencesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Lei Zeng
- Institute of Epigenetic Medicine, First Hospital of Jilin UniversityChangchunChina
| | - Ming‐Ming Zhou
- Department of Pharmacological SciencesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Ka Lung Cheung
- Department of Pharmacological SciencesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
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10
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Lee JH, Kim HS, Jang SW, Lee GR. Histone deacetylase 6 plays an important role in TGF-β-induced murine Treg cell differentiation by regulating cell proliferation. Sci Rep 2022; 12:22550. [PMID: 36581745 PMCID: PMC9800578 DOI: 10.1038/s41598-022-27230-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 12/28/2022] [Indexed: 12/30/2022] Open
Abstract
Regulatory T (Treg) cells maintain immune homeostasis by preventing abnormal or excessive immune responses. Histone deacetylase 6 (HDAC6) regulates expression of Foxp3, and thus, Treg cell differentiation; however, its role in Treg cell differentiation is unclear and somewhat controversial. Here, we investigated the role of HDAC6 in TGF-β-induced murine Treg cells. HDAC6 expression was higher in Treg cells than in other T helper cell subsets. Pharmacological inhibitors of HDAC6 selectively inhibited Treg cell differentiation and suppressive function. A specific HDAC6 inhibitor induced changes in global gene expression by Treg cells. Of these changes, genes related to cell division were prominently affected. In summary, HDAC6 plays an important role in TGF-β-induced murine Treg cell differentiation by regulating cell proliferation.
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Affiliation(s)
- Ji Hyeon Lee
- grid.263736.50000 0001 0286 5954Department of Life Science, Sogang University, 35 Baekbeom-Ro, Mapo-Gu, Seoul, 04107 Korea
| | - Hyeong Su Kim
- grid.263736.50000 0001 0286 5954Department of Life Science, Sogang University, 35 Baekbeom-Ro, Mapo-Gu, Seoul, 04107 Korea
| | - Sung Woong Jang
- grid.263736.50000 0001 0286 5954Department of Life Science, Sogang University, 35 Baekbeom-Ro, Mapo-Gu, Seoul, 04107 Korea
| | - Gap Ryol Lee
- grid.263736.50000 0001 0286 5954Department of Life Science, Sogang University, 35 Baekbeom-Ro, Mapo-Gu, Seoul, 04107 Korea
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11
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Shi X, Zhao L, Niu L, Yan Y, Chen Q, Jin Y, Li X. Oral Intervention of Narirutin Ameliorates the Allergic Response of Ovalbumin Allergy. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:13313-13326. [PMID: 36217946 DOI: 10.1021/acs.jafc.2c05383] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
A new intervention was investigated for the induction of oral tolerance (OT) of OVA using narirutin by in vivo and in vitro experiments combined with network pharmacology and structural analysis of molecular docking. Narirutin (and its metabolism naringenin) has effects on OT by affecting B cell function, DCs, and T cell response by prediction. It was verified that narirutin could affect B cell function of secreting antibodies, thereby reducing the ability of DCs to absorb antigens by affecting GATA3, CCR7, STAT5, and MHCII expression and regulating T cell response by suppressing Th2 and improving Treg cells in vivo. Molecular docking showed that steric hindrance effects may be the reason for weaker binding energy with targets of narirutin. However, this does not mean that it has no bioactivity, for it can inhibit mast cell degranulation. This finding is interesting because it offers the possibility of using natural compounds to promote oral tolerance.
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Affiliation(s)
- Xiaolei Shi
- College of Food Science and Engineering, Jilin University, Changchun130012, P. R. China
| | - Lina Zhao
- College of Food Science and Engineering, Jilin University, Changchun130012, P. R. China
| | - Liyan Niu
- College of Food Science and Engineering, Jilin University, Changchun130012, P. R. China
| | - Yixuan Yan
- College of Food Science and Engineering, Jilin University, Changchun130012, P. R. China
| | - Qiushi Chen
- College of Food Science and Engineering, Jilin University, Changchun130012, P. R. China
| | - Yongri Jin
- College of Chemistry, Jilin University, Changchun130012, P. R. China
| | - Xuwen Li
- College of Chemistry, Jilin University, Changchun130012, P. R. China
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12
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Li HM, Tang F, Huang Q, Pan HF, Zhang TP. Investigation on Probable Association Between IL-13, IL-13RA1, and IL-13RA2 Genes Polymorphism and Pulmonary Tuberculosis. J Inflamm Res 2022; 15:4527-4536. [PMID: 35966004 PMCID: PMC9373994 DOI: 10.2147/jir.s374714] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/30/2022] [Indexed: 11/23/2022] Open
Abstract
Objective Our study aimed to explore the association of IL-13, IL-13RA1, and IL-13RA2 genes polymorphisms with PTB susceptibility and its clinical features. Methods Nine SNPs were genotyped by improved multiple ligase detection reaction (iMLDR) in 476 PTB patients and 473 controls. The association between these SNPs and PTB risk was analyzed using SPSS software and haplotype analysis was assessed using SHEsis software. Results The IL-13RA1 rs2495636 GA genotype frequency in PTB patients was significantly decreased, and IL-13RA2 rs5946039 A allele was related to the lower risk of PTB. In IL-13 gene, rs20541 variant was found to be associated with PTB risk under recessive mode. Moreover, IL-13RA1 rs141573089 C allele was significantly lower in PTB presenting with fever, drug resistance, and CC genotype was decreased in PTB presenting with leukopenia. IL-13RA1 rs2495636 polymorphism was associated with drug resistance, pulmonary infection, and IL-13RA2 rs3795175, rs638376 polymorphisms were related to drug resistance in PTB patients. Conclusion IL-13 rs20541, IL-13RA1 rs2495636, IL-13RA2 rs5946039 polymorphisms might be contributed to the genetic background of PTB in Chinese population.
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Affiliation(s)
- Hong-Miao Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, People's Republic of China
| | - Fei Tang
- Department of Interventional Pulmonology and Endoscopic Diagnosis and Treatment Center, Anhui Chest Hospital, Hefei, People's Republic of China
| | - Qian Huang
- Department of Public Health, Medical Department, Qinghai University, Xining, People's Republic of China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, People's Republic of China
| | - Tian-Ping Zhang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People's Republic of China
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13
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Mahadik R, Kiptoo P, Tolbert T, Siahaan TJ. Immune Modulation by Antigenic Peptides and Antigenic Peptide Conjugates for Treatment of Multiple Sclerosis. MEDICAL RESEARCH ARCHIVES 2022; 10:10.18103/mra.v10i5.2804. [PMID: 36381196 PMCID: PMC9648198 DOI: 10.18103/mra.v10i5.2804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The immune system defends our body by fighting infection from pathogens utilizing both the innate and adaptive immune responses. The innate immune response is generated rapidly as the first line of defense. It is followed by the adaptive immune response that selectively targets infected cells. The adaptive immune response is generated more slowly, but selectively, by targeting a wide range of foreign particles (i.e., viruses or bacteria) or molecules that enter the body, known as antigens. Autoimmune diseases are the results of immune system glitches, where the body's adaptive system recognizes self-antigens as foreign. Thus, the host immune system attacks the self-tissues or organs with a high level of inflammation and causes debilitation in patients. Many current treatments for autoimmune diseases (i.e., multiple sclerosis (MS), rheumatoid arthritis (RA)) have been effective but lead to adverse side effects due to general immune system suppression, which makes patients vulnerable to opportunistic infections. To counter these negative effects, many different avenues of antigen specific treatments are being developed to selectively target the autoreactive immune cells for a specific self-antigen or set of self-antigens while not compromising the general immune system. These approaches include soluble antigenic peptides, bifunctional peptide inhibitors (BPI) including IDAC and Fc-BPI, polymer conjugates, and peptide-drug conjugates. Here, various antigen-specific methods of potential treatments, their efficacy, and limitations will be discussed along with the potential mechanisms of action.
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Affiliation(s)
- Rucha Mahadik
- Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, 2093 Constant Avenue, Lawrence, KS 66047
| | | | - Tom Tolbert
- Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, 2093 Constant Avenue, Lawrence, KS 66047
| | - Teruna J Siahaan
- Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, 2093 Constant Avenue, Lawrence, KS 66047
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14
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Wang A, Wang L, Fu Q, Shi Z, Chen X, Zhang X, Xu W, Wang T, Yu X, Zhang S, Gao Y, Li W, Hu S. Yiqi Jiedu herbal decoction attenuates the 2 Gy 60Co γ ray induced spleen injury by inhibiting apoptosis and modulating the immune balance. JOURNAL OF ETHNOPHARMACOLOGY 2022; 286:114925. [PMID: 34933086 DOI: 10.1016/j.jep.2021.114925] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/08/2021] [Accepted: 12/14/2021] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Irradiation-induced immunosuppression often occurs during radiotherapy in patients, which would increase the risk of opportunistic infections. Many Chinese herbal prescriptions or natural extracts have recently attracted increased radiation protection and therapy attention due to their low toxicity. AIM OF THE STUDY The present study aimed to investigate the protective effects of Yiqi Jiedu (YQJD) decoction on spleen injury induced by 2 Gy 60Co γ ray in mice. MATERIALS AND METHODS A total of 180 Balb/c mice were randomly divided into five groups: blank control (Ctrl), model (IR), positive drug (IRA), low-dose YQJD decoction (IRL), and high-dose YQJD decoction (IRH). After a ten-day intervention, mice were exposed to a single dose of total body irradiation (2 Gy) and sacrificed on the 1st, 3rd, and 7th day after irradiation. The indicators include general observations and body weight, changes in peripheral hemogram, index and histopathology examination of the spleen, distribution of lymphocyte subsets, cytokine levels, and apoptosis in the spleen. RESULTS In comparison to the Ctrl group, the body weight, spleen index, peripheral blood cell, and splenocyte quantities decreased significantly after exposure, accompanied by a notable increase of apoptosis in spleen cells. Moreover, ionizing radiation also broke the balance of CD4+/CD8+, Th1/Th2, and Th17/Treg, triggering immune imbalance and immunosuppression. The above injuries occurred on the 1st day after exposure, worsened on the 3rd, and were relieved on the 7th day. However, the pretreatment of YQJD decoction increased the spleen index, improved the spleen structure, and inhibited radiation-induced apoptosis after exposure. Additionally, YQJD decoction has shown its ability to promote immunological balance recovery following exposure by regulating CD4+/CD8+, Th1/Th2, and Th17/Treg ratios, which may minimize the risk of infection. In addition, the high-dose of YQJD decoction showed a better protective effect than the low-dose group. CONCLUSION The protective effects of YQJD decoction on 2 Gy 60Coγray induced spleen injury were confirmed in this study. This mechanism may be related to inhibiting apoptosis and modulating immune balance. This exploration might provide new insights into the use of Chinese herbs on radioprotection of the immune system.
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Affiliation(s)
- An Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; Beijing Engineering Research Center of Radiographic Techniques and Equipment, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China.
| | - Lei Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Qian Fu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Zhongyu Shi
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Xiaoying Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Xiaomeng Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Wenhui Xu
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Tieshan Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Xue Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Shujing Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Yushan Gao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Wei Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Sumin Hu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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15
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The Immune Underpinnings of Barrett's-Associated Adenocarcinogenesis: a Retrial of Nefarious Immunologic Co-Conspirators. Cell Mol Gastroenterol Hepatol 2022; 13:1297-1315. [PMID: 35123116 PMCID: PMC8933845 DOI: 10.1016/j.jcmgh.2022.01.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 12/10/2022]
Abstract
There is no doubt that chronic gastroesophageal reflux disease increases the risk of esophageal adenocarcinoma (EAC) by several fold (odds ratio, 6.4; 95% CI, 4.6-9.1), and some relationships between reflux disease-mediated inflammation and oncogenic processes have been explored; however, the precise interconnections between the immune response and genomic instabilities underlying these pathologic processes only now are emerging. Furthermore, the precise cell of origin of the precancerous stages associated with EAC development, Barrett's esophagus, be it cardia resident or embryonic remnant, may shape our interpretation of the likely immune drivers. This review integrates the current collective knowledge of the immunology underlying EAC development and outlines a framework connecting proinflammatory pathways, such as those mediated by interleukin 1β, tumor necrosis factor α, leukemia inhibitory factor, interleukin 6, signal transduction and activator of transcription 3, nuclear factor-κB, cyclooxygenase-2, and transforming growth factor β, with oncogenic pathways in the gastroesophageal reflux disease-Barrett's esophagus-EAC cancer sequence. Further defining these immune and molecular railroads may show a map of the routes taken by gastroesophageal cells on their journey toward EAC tumor phylogeny. The selective pressures applied by this immune-induced journey likely impact the phenotype and genotype of the resulting oncogenic destination and further exploration of lesser-defined immune drivers may be useful in future individualized therapies or enhanced selective application of recent immune-driven therapeutics.
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Mirlekar B. Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy. SAGE Open Med 2022; 10:20503121211069012. [PMID: 35096390 PMCID: PMC8793114 DOI: 10.1177/20503121211069012] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/07/2021] [Indexed: 12/23/2022] Open
Abstract
Cytokines play a critical role in regulating host immune response toward cancer and determining the overall fate of tumorigenesis. The tumor microenvironment is dominated mainly by immune-suppressive cytokines that control effector antitumor immunity and promote survival and the proliferation of cancer cells, which ultimately leads to enhanced tumor growth. In addition to tumor cells, the heterogeneous immune cells present within the tumor milieu are the significant source of immune-suppressive cytokines. These cytokines are classified into a broad range; however, in most tumor types, the interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 are consistently reported as immune-suppressive cytokines that help tumor growth and metastasis. The most emerging concern in cancer treatment is hijacking and restraining the activity of antitumor immune cells in the tumor niche due to a highly immune-suppressive environment. This review summarizes the role and precise functions of interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 in modulating tumor immune contexture and its implication in developing effective immune-therapeutic approaches. CONCISE CONCLUSION Recent effort geared toward developing novel immune-therapeutic approaches faces significant challenges due to sustained mutations in tumor cells and a highly immune-suppressive microenvironment present within the tumor milieu. The cytokines play a crucial role in developing an immune-suppressive environment that ultimately dictates the fate of tumorigenesis. This review critically covers the novel aspects of predominant immune-suppressive cytokines such as interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 in dictating the fate of tumorigenesis and how targeting these cytokines can help the development of better immune-therapeutic drug regimens for the treatment of cancer.
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Affiliation(s)
- Bhalchandra Mirlekar
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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17
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Immunomodulatory Activity of Extracellular Vesicles of Kimchi-Derived Lactic Acid Bacteria ( Leuconostoc mesenteroides, Latilactobacillus curvatus, and Lactiplantibacillus plantarum). Foods 2022; 11:foods11030313. [PMID: 35159463 PMCID: PMC8834128 DOI: 10.3390/foods11030313] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/21/2022] [Accepted: 01/21/2022] [Indexed: 12/12/2022] Open
Abstract
Lactic acid bacteria present in Kimchi, such as Leuconostoc mesenteroides (Lm), Latilactobacillus curvatus (Lc), and Lactiplantibacillus plantarum (Lp) produce extracellular vesicles (ECVs) that modulate immune responses. The ECVs of probiotic Kimchi bacteria are abbreviated as LmV, LcV, and LpV. Treatment of macrophages (RAW264.7) with ECVs (LmV, LcV, and LpV) increased the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin-6 (IL-6). Immunostimulatory effects exerted on the RAW264.7 cells were stronger after treatments with LmV and LcV than with LpV. Treatment of mice with LcV (1 mg/kg, orally) induced splenocyte proliferation and subsequent production of both NO and cytokines (INF-γ, TNF-α, IL-4, and IL-10). Furthermore, pre-treatment of macrophages and microglial cells with ECVs prior to LPS stimulation significantly attenuated the production of NO and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Therefore, ECVs (LmV, LcV, and LpV) prevent inflammatory responses in the LPS-stimulated microglial cells by blocking the extracellular signal-regulated kinase (Erk) and p38 signaling pathways. These results showed that LmV, LcV, and LpV from Kimchi probiotic bacteria safely exert immunomodulatory effects.
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18
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Zhou Y, Zhang P, Zheng X, Ye C, Li M, Bian P, Fan C, Zhang Y. miR-155 regulates pro- and anti-inflammatory cytokine expression in human monocytes during chronic hepatitis C virus infection. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1618. [PMID: 34926662 PMCID: PMC8640902 DOI: 10.21037/atm-21-2620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/27/2021] [Indexed: 12/15/2022]
Abstract
Background Hepatitis C virus (HCV) dysregulates innate and adaptive immune responses while monocytes (M) play a crucial role in linking innate and adaptive immunity to control viral infection. A transcription factor T-bet is upregulated to dampen M functions via the c-Jun N-terminal kinase (JNK) pathway, followed by enhanced Tim-3 expression in chronic HCV infection. However, the molecular mechanisms that control the expression in M are yet unknown. miR-155 has been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression, but the influences of miR-155 on these regulators and effectors still need to be studied. Methods Forty HCV-infected patients and 40 healthy subjects (HS) were recruited, THP-1 cells (human acute monocyte leukemia cell line) were cultured with HCV-infected Huh 7.5 cells. The expression levels of miR-155 and JNK1/JNK2/JNK3 were measured by real-time RT-PCR. IL-10/IL-12 was detected by flow cytometry. THP-1 cells were transfected with mimics-155 and negative control, SOCS1, p-STAT1, p65, p-smad, p-p38, and p-JNK were measured by Western blot. TNF-α levels were measured by ELISA. Student’s t-test was used in statistics. Results The study showed that miR-155 was upregulated in CD14+ M in HCV-infected patients compared to healthy subjects (P<0.05). Moreover, the upregulation of miR-155 in CD14+ M from HCV-infected patients induced TNF-α production and JNK gene expression, which, in turn, led to T-bet upregulation. Also, miR-155 upregulation in CD14+ M of HCV-infected patients increased the IL-12 and decreased the IL-10 production. Conclusions The obtained results indicated that miR-155 upregulation in M during HCV infection enhances the activation of TNF-α and JNK pathways, promotes the expression of transcription factor T-bet, and triggers pro- and anti-inflammatory mediators. Together, these data reveal new information regarding the mechanisms of chronic HCV infection.
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Affiliation(s)
- Yun Zhou
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Peixin Zhang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xuyang Zheng
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Chuantao Ye
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Mengyuan Li
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Peiyu Bian
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Chao Fan
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Ying Zhang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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19
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Redondo N, Navarro D, Aguado JM, Fernández-Ruiz M. Human genetic polymorphisms and risk of viral infection after solid organ transplantation. Transplant Rev (Orlando) 2021; 36:100669. [PMID: 34688126 DOI: 10.1016/j.trre.2021.100669] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 12/16/2022]
Abstract
The immune system plays a key role in the host defense against viral pathogens. A signaling cascade is activated upon infection involving a variety of molecules such as pattern-recognition receptors (PRRs), interleukins or antiviral interferons. Long-term immunosuppression after solid organ transplantation (SOT) mainly abrogates adaptive T-cell-mediated responses, thus highlighting the relative contribution of innate immunity. Single-nucleotide polymorphisms (SNPs) within genes coding for PRRs or soluble mediators have been associated with differential susceptibility to viral infections among SOT recipients. A protective effect against cytomegalovirus (CMV) infection or disease has been attributed to certain SNPs in TLR9 or IFNL3 genes, whereas the opposite effect has been attributed to genetic polymorphisms in TLR2, MBL2, DC-SIGN, IL10 or IFNG. The presence of SNPs in other molecules not directly involved in innate or adaptive immune responses such as aquaporins or pregnane X appear to modulate the risk of CMV or BK polyomavirus infection, respectively. Little information is available on the genetic determinants of the post-transplant susceptibility to herpesviruses causing clinical infection (herpes simplex virus or varicella zoster virus) or the replication kinetics of components of the human blood virome used as immune surrogates (Torque teno virus). The present review critically summarizes the current knowledge on how SNP genotyping would be useful to stratify SOT recipients according to the individual risk of viral infection and proposes next research steps. Genetic susceptibility testing may improve personalized medicine and contribute to minimize the risk of viral infection after SOT.
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Affiliation(s)
- Natalia Redondo
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain.
| | - David Navarro
- Department of Microbiology, Hospital Clínico Universitario, Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; Department of Microbiology, School of Medicine, Universidad de Valencia, Valencia, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
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20
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Ishizaka A, Koga M, Mizutani T, Parbie PK, Prawisuda D, Yusa N, Sedohara A, Kikuchi T, Ikeuchi K, Adachi E, Koibuchi T, Furukawa Y, Tojo A, Imoto S, Suzuki Y, Tsutsumi T, Kiyono H, Matano T, Yotsuyanagi H. Unique Gut Microbiome in HIV Patients on Antiretroviral Therapy (ART) Suggests Association with Chronic Inflammation. Microbiol Spectr 2021; 9:e0070821. [PMID: 34378948 PMCID: PMC8552706 DOI: 10.1128/spectrum.00708-21] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation is a hallmark of human immunodeficiency virus (HIV) infection and a risk factor for the development and progression of age-related comorbidities. Although HIV-associated gut dysbiosis has been suggested to be involved in sustained chronic inflammation, there remains a limited understanding of the association between gut dysbiosis and chronic inflammation during HIV infection. Here, we investigated compositional changes in the gut microbiome and its role in chronic inflammation in patients infected with HIV. We observed that the gut microbiomes of patients with low CD4 counts had reduced alpha diversity compared to those in uninfected controls. Following CD4 recovery, alpha diversity was restored, but intergroup dissimilarity of bacterial composition remained unchanged between patients and uninfected controls. Patients with HIV had higher abundance of the classes Negativicutes, Bacilli, and Coriobacteriia, as well as depletion of the class Clostridia. These relative abundances positively correlated with inflammatory cytokines and negatively correlated with anti-inflammatory cytokines. We found that gut dysbiosis accompanying HIV infection was characterized by a depletion of obligate anaerobic Clostridia and enrichment of facultative anaerobic bacteria, reflecting increased intestinal oxygen levels and intestinal permeability. Furthermore, it is likely that HIV-associated dysbiosis shifts the immunological balance toward inflammatory Th1 responses and encourages proinflammatory cytokine production. Our results suggest that gut dysbiosis contributes to sustaining chronic inflammation in patients with HIV infection despite effective antiretroviral therapy and that correcting gut dysbiosis will be effective in improving long-term outcomes in patients. IMPORTANCE Chronic inflammation is a hallmark of HIV infection and is associated with the development and progression of age-related comorbidities. Although the gastrointestinal tract is a major site of HIV replication and CD4+ T-cell depletion, the role of HIV-associated imbalance of gut microbiome in chronic inflammation is unclear. Here, we aimed to understand the causal relationship between abnormalities in the gut microbiome and chronic inflammation in patients with HIV. Our results suggest HIV-associated gut dysbiosis presents a more aerobic environment than that of healthy individuals, despite prolonged viral suppression. This dysbiosis likely results from a sustained increase in intestinal permeability, which supports sustained bacterial translocation in HIV patients, despite effective therapy. Additionally, we observed that several bacterial taxa enriched in HIV patients were associated with increased expression of inflammatory cytokines. Collectively, these results suggest that gut dysbiosis plays an important role in chronic inflammation in HIV patients.
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Affiliation(s)
- Aya Ishizaka
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Research and Development Center for Mucosal Vaccines, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Taketoshi Mizutani
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- International Research and Development Center for Mucosal Vaccines, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Prince Kofi Parbie
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Diki Prawisuda
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Nozomi Yusa
- Department of Applied Genomics, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Ayako Sedohara
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tadashi Kikuchi
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Ikeuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomohiko Koibuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoichi Furukawa
- Department of Applied Genomics, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Laboratory Medicine, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiya Imoto
- Division of Health Medical Data Science, Health Intelligence Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Kiyono
- International Research and Development Center for Mucosal Vaccines, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tetsuro Matano
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- Department of AIDS Vaccine Development, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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21
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Anderluh M, Berti F, Bzducha‐Wróbel A, Chiodo F, Colombo C, Compostella F, Durlik K, Ferhati X, Holmdahl R, Jovanovic D, Kaca W, Lay L, Marinovic‐Cincovic M, Marradi M, Ozil M, Polito L, Reina‐Martin JJ, Reis CA, Sackstein R, Silipo A, Švajger U, Vaněk O, Yamamoto F, Richichi B, van Vliet SJ. Emerging glyco-based strategies to steer immune responses. FEBS J 2021; 288:4746-4772. [PMID: 33752265 PMCID: PMC8453523 DOI: 10.1111/febs.15830] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/12/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
Glycan structures are common posttranslational modifications of proteins, which serve multiple important structural roles (for instance in protein folding), but also are crucial participants in cell-cell communications and in the regulation of immune responses. Through the interaction with glycan-binding receptors, glycans are able to affect the activation status of antigen-presenting cells, leading either to induction of pro-inflammatory responses or to suppression of immunity and instigation of immune tolerance. This unique feature of glycans has attracted the interest and spurred collaborations of glyco-chemists and glyco-immunologists to develop glycan-based tools as potential therapeutic approaches in the fight against diseases such as cancer and autoimmune conditions. In this review, we highlight emerging advances in this field, and in particular, we discuss on how glycan-modified conjugates or glycoengineered cells can be employed as targeting devices to direct tumor antigens to lectin receptors on antigen-presenting cells, like dendritic cells. In addition, we address how glycan-based nanoparticles can act as delivery platforms to enhance immune responses. Finally, we discuss some of the latest developments in glycan-based therapies, including chimeric antigen receptor (CAR)-T cells to achieve targeting of tumor-associated glycan-specific epitopes, as well as the use of glycan moieties to suppress ongoing immune responses, especially in the context of autoimmunity.
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Affiliation(s)
- Marko Anderluh
- Chair of Pharmaceutical ChemistryFaculty of PharmacyUniversity of LjubljanaSlovenia
| | | | - Anna Bzducha‐Wróbel
- Department of Biotechnology and Food MicrobiologyWarsaw University of Life Sciences‐SGGWPoland
| | - Fabrizio Chiodo
- Department of Molecular Cell Biology and ImmunologyCancer Center AmsterdamAmsterdam Infection and Immunity InstituteAmsterdam UMCVrije Universiteit AmsterdamNetherlands
| | - Cinzia Colombo
- Department of Chemistry and CRC Materiali Polimerici (LaMPo)University of MilanItaly
| | - Federica Compostella
- Department of Medical Biotechnology and Translational MedicineUniversity of MilanItaly
| | - Katarzyna Durlik
- Department of Microbiology and ParasitologyJan Kochanowski UniversityKielcePoland
| | - Xhenti Ferhati
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Rikard Holmdahl
- Division of Medical Inflammation ResearchDepartment of Medical Biochemistry and BiophysicsKarolinska InstituteStockholmSweden
| | - Dragana Jovanovic
- Vinča Institute of Nuclear Sciences ‐ National Institute of the Republic of SerbiaUniversity of BelgradeSerbia
| | - Wieslaw Kaca
- Department of Microbiology and ParasitologyJan Kochanowski UniversityKielcePoland
| | - Luigi Lay
- Department of Chemistry and CRC Materiali Polimerici (LaMPo)University of MilanItaly
| | - Milena Marinovic‐Cincovic
- Vinča Institute of Nuclear Sciences ‐ National Institute of the Republic of SerbiaUniversity of BelgradeSerbia
| | - Marco Marradi
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Musa Ozil
- Department of ChemistryFaculty of Arts and SciencesRecep Tayyip Erdogan University RizeTurkey
| | | | | | - Celso A. Reis
- I3S – Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortugal
- IPATIMUP‐Institute of Molecular Pathology and ImmunologyInstituto de Ciências Biomédicas Abel SalazarUniversity of PortoPortugal
| | - Robert Sackstein
- Department of Translational Medicinethe Translational Glycobiology InstituteHerbert Wertheim College of MedicineFlorida International UniversityMiamiFLUSA
| | - Alba Silipo
- Department of Chemical SciencesUniversity of Naples Federico IIComplesso Universitario Monte Sant’AngeloNapoliItaly
| | - Urban Švajger
- Blood Transfusion Center of SloveniaLjubljanaSlovenia
| | - Ondřej Vaněk
- Department of BiochemistryFaculty of ScienceCharles UniversityPragueCzech Republic
| | - Fumiichiro Yamamoto
- Immunohematology & Glycobiology LaboratoryJosep Carreras Leukaemia Research InstituteBadalonaSpain
| | - Barbara Richichi
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Sandra J. van Vliet
- Department of Molecular Cell Biology and ImmunologyCancer Center AmsterdamAmsterdam Infection and Immunity InstituteAmsterdam UMCVrije Universiteit AmsterdamNetherlands
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22
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Wei LY, Jiang AQ, Jiang R, Duan SY, Xu X, Su ZDZ, Xu J. Protective effects of recombinant 53-kDa protein of Trichinella spiralis on acute lung injury in mice via alleviating lung pyroptosis by promoting M2 macrophage polarization. Innate Immun 2021; 27:313-323. [PMID: 34013820 PMCID: PMC8186157 DOI: 10.1177/17534259211013397] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Trichinella spiralis represents an effective treatment for autoimmune and inflammatory diseases. The effects of recombinant T. spiralis (TS) 53-kDa protein (rTsP53) on acute lung injury (ALI) remain unclear. Here, mice were divided randomly into a control group, LPS group, and rTsP53 + LPS group. ALI was induced in BALB/c mice by LPS (10 mg/kg) injected via the tail vein. rTsP53 (200 µl; 0.4 μg/μl) was injected subcutaneously three times at an interval of 5 d before inducing ALI in the rTsP53+LPS group. Lung pathological score, the ratio and markers of classic activated macrophages (M1) and alternatively activated macrophages (M2), cytokine profiles in alveolar lavage fluid, and pyroptosis protein expression in lung tissue were investigated. RTsP53 decreased lung pathological score. Furthermore, rTsP53 suppressed inflammation by increasing IL-4, IL-10, and IL-13. There was an increase in alveolar M2 macrophage numbers, with an increase in CD206 and arginase-1-positive cells and a decrease in alveolar M1 markers such as CD197 and iNOS. In addition, the polarization of M2 macrophages induced by rTsP53 treatment could alleviate ALI by suppressing lung pyroptosis. RTsP53 was identified as a potential agent for treating LPS-induced ALI via alleviating lung pyroptosis by promoting M2 macrophage polarization.
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Affiliation(s)
- Ling-Yu Wei
- Emergency Department, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080, Guangzhou, China
| | - An-Qi Jiang
- Emergency Department, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080, Guangzhou, China
| | - Ren Jiang
- Emergency Department, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080, Guangzhou, China
| | - Si-Ying Duan
- Emergency Department, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080, Guangzhou, China
| | - Xue Xu
- Emergency Department, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080, Guangzhou, China
| | - Ze-da-Zhong Su
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, China
| | - Jia Xu
- Emergency Department, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080, Guangzhou, China
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23
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Abstract
The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.
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24
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Dang C, Lu Y, Chen X, Li Q. Baricitinib Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating the Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathway. Front Immunol 2021; 12:650708. [PMID: 33927721 PMCID: PMC8076548 DOI: 10.3389/fimmu.2021.650708] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/22/2021] [Indexed: 02/05/2023] Open
Abstract
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and a CD4+ T cell-mediated autoimmune disease. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is recognized as the major mechanism that regulates the differentiation and function of T helper (Th) 1 and Th17 cells, which are recognized as pivotal effector cells responsible for the development of EAE. We used baricitinib, a JAK 1/2 inhibitor, to investigate the therapeutic efficacy of inhibiting the JAK/STAT pathway in EAE mice. Our results showed that baricitinib significantly delayed the onset time, decreased the severity of clinical symptoms, shortened the duration of EAE, and alleviated demyelination and immune cell infiltration in the spinal cord. In addition, baricitinib treatment downregulated the proportion of interferon-γ+CD4+ Th1 and interleukin-17+CD4+ Th17 cells, decreased the levels of retinoic acid-related orphan receptor γ t and T-bet mRNA, inhibited lymphocyte proliferation, and decreased the expression of proinflammatory cytokines and chemokines in the spleen of mice with EAE. Furthermore, our results showed the role of baricitinib in suppressing the phosphorylation of STATs 1, 3, and 4 in the spleen of EAE mice. Therefore, our study demonstrates that baricitinib could potentially alleviate inflammation in mice with EAE and may be a promising candidate for treating MS.
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Affiliation(s)
- Chun Dang
- West China Medical Publishers, West China Hospital, Sichuan University, Chengdu, China
| | - Yaoheng Lu
- Department of General Surgery, Chengdu Integrated Traditional Chinese Medicine & Western Medicine Hospital, Chengdu, China
- Department of General Surgery, Chengdu University of Traditional Chinese Medicine Affiliated Traditional Chinese Medicine & Western Hospital, Chengdu, China
| | - Xingyu Chen
- Department of General Surgery, Chengdu Integrated Traditional Chinese Medicine & Western Medicine Hospital, Chengdu, China
| | - Qian Li
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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25
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Hirawat R, Saifi MA, Godugu C. Targeting inflammatory cytokine storm to fight against COVID-19 associated severe complications. Life Sci 2021; 267:118923. [PMID: 33358906 PMCID: PMC7831473 DOI: 10.1016/j.lfs.2020.118923] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 12/09/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023]
Abstract
Such testing and trying time probably never seen before in the human history. The novel coronavirus disease abbreviated as COVID-19 is the ongoing health crisis which entered into human life in late December 2019. The ease of transmission between humans and the undetectability in early stage makes COVID-19 frightening and unprecedented. The disease is characterised by pneumonia progressing to breathing difficulty, acute respiratory distress syndrome (ARDS) and multi-organ failure. Clinical studies suggest excessive release of inflammatory mediators leads to cytokine storm, a phenomenon which appears to be potentially life-threatening in COVID-19. Across the globe, when the world authorities are grappling to contain the virus, our review provides a glimpse on structure, pathophysiology of the virus and further sheds light on various clinical complications associated with the disease in order to open up/raise new horizons to explore various possible theoretical targets for COVID-19. The review also portrays a question and debates: Can targeting cytokine storm can be a feasible approach to combat COVID-19?
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Affiliation(s)
- Rishabh Hirawat
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
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26
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Immunogenicity and protective efficacy of enterotoxigenic Escherichia coli (ETEC) total RNA against ETEC challenge in a mouse model. Sci Rep 2020; 10:20530. [PMID: 33239756 PMCID: PMC7689534 DOI: 10.1038/s41598-020-77551-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 11/09/2020] [Indexed: 11/15/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC), an essential cause of post-weaning diarrhea (PWD) in piglets, leads to significant economic losses to the pig industry. The present study aims to identify the role of ETEC total RNA in eliciting immune responses to protect animals against ETEC infection. The results showed that the total RNA isolated from pig-derived ETEC K88ac strain effectively stimulated the IL-1β secretion of porcine intestinal epithelial cells (IPEC-J2). The mouse model immunized with ETEC total RNA via intramuscular injection (IM) or oral route (OR) was used to evaluate the protective efficiency of the ETEC total RNA. The results suggested that 70 μg ETEC total RNA administered by either route significantly promoted the production of the serum IL-1β and K88ac specific immunoglobulins (IgG, IgM, and IgA). Besides, the ETEC RNA administration augmented strong mucosal immunity by elevating K88ac specific IgA level in the intestinal fluid. Intramuscularly administered RNA induced a Th1/Th2 shift toward a Th2 response, while the orally administered RNA did not. The ETEC total RNA efficiently protected the animals against the ETEC challenge either by itself or as an adjuvant. The histology characterization of the small intestines also suggested the ETEC RNA administration protected the small intestinal structure against the ETEC infection. Particularly of note was that the immunity level and protective efficacy caused by ETEC RNA were dose-dependent. These findings will help understand the role of bacterial RNA in eliciting immune responses, and benefit the development of RNA-based vaccines or adjuvants.
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27
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Wei Y, Han B, Dai W, Guo S, Zhang C, Zhao L, Gao Y, Jiang Y, Kong X. Exposure to ozone impacted Th1/Th2 imbalance of CD 4+ T cells and apoptosis of ASMCs underlying asthmatic progression by activating lncRNA PVT1-miR-15a-5p/miR-29c-3p signaling. Aging (Albany NY) 2020; 12:25229-25255. [PMID: 33223504 PMCID: PMC7803560 DOI: 10.18632/aging.104124] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023]
Abstract
This investigation attempted to elucidate whether lncRNA PVT1-led miRNA axes participated in aggravating ozone-triggered asthma progression. One hundred and sixty-eight BALB/c mice were evenly divided into saline+air group, ovalbumin+air group, saline+ozone group and ovalbumin+ozone group. Correlations were evaluated between PVT1 expression and airway smooth muscle function/inflammatory cytokine release among the mice models. Furthermore, pcDNA3.1-PVT1 and si-PVT1 were, respectively, transfected into CD4+T cells and airway smooth muscle cells (ASMCs), and activities of the cells were observed. Ultimately, a cohort of asthma patients was recruited to estimate the diagnostic performance of PVT1. It was demonstrated that mice of ovalbumin+ozone group were associated with higher PVT1 expression, thicker trachea/airway smooth muscle and smaller ratio of Th1/Th2-like cytokines than mice of ovalbumin+air group and saline+ozone group (P<0.05). Moreover, pcDNA3.1-PVT1 significantly brought down Th1/Th2 ratio in CD4+ T cells by depressing miR-15a-5p expression and activating PI3K-Akt-mTOR signaling (P<0.05). The PVT1 also facilitated ASMC proliferation by sponging miR-29c-3p and motivating PI3K-Akt-mTOR signaling (P<0.05). Additionally, PVT1 seemed promising in diagnosis of asthma, with favorable sensitivity (i.e. 0.844) and specificity (i.e. 0.978). Conclusively, lncRNA PVT1-miR-15a-5p/miR-29c-3p-PI3K-Akt-mTOR axis was implicated in ozone-induced asthma development by promoting ASMC proliferation and Th1/Th2 imbalance.
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Affiliation(s)
- Yangyang Wei
- Department of Respiratory and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Baofen Han
- Department of Respiratory and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Wenjuan Dai
- Department of Respiratory and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Shufang Guo
- Department of Respiratory and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Caiping Zhang
- Department of Respiratory and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Lixuan Zhao
- Department of Medicine, Shanxi Medical University, Taiyuan 030001, China
| | - Yan Gao
- Department of Medicine, Shanxi Medical University, Taiyuan 030001, China
| | - Yi Jiang
- Department of Respiratory and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Xiaomei Kong
- Department of Respiratory and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
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Cerboni S, Gehrmann U, Preite S, Mitra S. Cytokine-regulated Th17 plasticity in human health and diseases. Immunology 2020; 163:3-18. [PMID: 33064842 DOI: 10.1111/imm.13280] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/30/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Upon activation, naïve CD4+ T helper (Th) cells differentiate into distinct Th effector cell lineages depending on the local cytokine environment. However, these polarized Th cells can also adapt their function and phenotype depending on the changing cytokine environment, demonstrating functional plasticity. Here, Th17 cells, which play a critical role in host protection from extracellular pathogens and in autoimmune disorders, are of particular interest. While being able to shift phenotype within their lineage, Th17 cells can also acquire characteristics of Th1, Th2, T follicular helper (Tfh) or regulatory T cells. Th17 cell identity is determined by a spectrum of extracellular signals, including cytokines, which are critical orchestrators of cellular immune responses. Cytokine induces changes in epigenetic, transcriptional, translational and metabolomic parameters. How these signals are integrated to determine Th17 plasticity is not well defined, yet this is a crucial point of investigation as it represents a potential target to treat autoimmune and inflammatory diseases. The goal of this review was to discuss how cytokines regulate intracellular networks, focusing on the regulation of lineage-specific transcription factors, chromatin remodelling and metabolism, to control human Th17 cell plasticity. We discuss the importance of Th17 plasticity in autoimmunity and cancer and present current strategies and challenges in targeting pathogenic Th17 cells with cytokine-based approaches, considering human genetic variants associated with altered Th17 differentiation. Finally, we discuss how modulating Th17 plasticity rather than targeting the Th17 lineage as a whole might preserve its essential immune function while purging its adverse effects.
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Affiliation(s)
- Silvia Cerboni
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ulf Gehrmann
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Silvia Preite
- Bioscience, In vivo, Research and Early Development, Respiratory & Immunology (R&I, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Suman Mitra
- CNRS, INSERM, CHU Lille, Institut pour la Recherche contre le Cancer de Lille, UMR9020 - UMR-S 1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, Lille, France
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29
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Kousha A, Mahdavi Gorabi A, Forouzesh M, Hosseini M, Alexander M, Imani D, Razi B, Mousavi MJ, Aslani S, Mikaeili H. Interleukin 4 gene polymorphism (-589C/T) and the risk of asthma: a meta-analysis and met-regression based on 55 studies. BMC Immunol 2020; 21:55. [PMID: 33087044 PMCID: PMC7579954 DOI: 10.1186/s12865-020-00384-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 10/08/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Numerous investigations have previously evaluated the association of interleukin (IL) 4 gene polymorphisms and the risk of asthma, conferring inconsistent results. To resolve the incongruent outcomes yielded from different single studies, we conducted the most up-to-date meta-analysis of IL4 gene -589C/T (rs2243250) polymorphism and susceptibility to asthma. METHODS A systematic literature search was performed in ISI web of science, Scopus, Medline/PubMed databases prior to September 2020, and the pooled odds ratio (OR) and their corresponding 95% CI were calculated to determine the association strength. RESULTS Literature search led to retrieving of 49 publications (55 case-control studies) containing 9572 cases and 9881 controls. It was revealed that IL4 gene -589C/T polymorphism increased the risk of asthma across all genetic models, including dominant model (OR = 1.22), recessive model (OR = 1.17), allelic model (OR = 1.21), and TT vs. CC model (OR = 1.34), but not the CT vs. TT model. The subgroup analysis by age indicated that IL4 gene -589C/T polymorphism was significantly associated with asthma risk in both pediatrics and adults. Additionally, the subgroup analysis by ethnicity revealed significant association in Asian, American, and Europeans. Finally, subgroup analysis by East Asian and non-East Asian populations indicated significant associations. CONCLUSIONS The current meta-analysis revealed that IL4 gene -589C/T polymorphism was a susceptibility risk in both pediatrics and adults in the whole and different ethnic groups.
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Affiliation(s)
- Ahmad Kousha
- Department of Health Education and Health Promotion, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Forouzesh
- Legal medicine Research Center, Legal Medicine organization, Tehran, Iran
| | - Mojgan Hosseini
- Department of Science, Islamshahr Branch, Islamic Azad University, Islamshahr, Tehran, Iran.
| | | | - Danyal Imani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahman Razi
- Department of Hematology and Blood Banking, School of Medicine, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Javad Mousavi
- Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Haleh Mikaeili
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical sciences, Tabriz, Iran.
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30
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Saha B, Bhattacharjee S, Sarkar A, Bhor R, Pai K, Bodhale N. Conundrums in leishmaniasis. Cytokine 2020; 145:155304. [PMID: 33004260 DOI: 10.1016/j.cyto.2020.155304] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 11/19/2022]
Abstract
Parasites of the genus Leishmania cause the disease leishmaniasis. As the sandfly vector transfers the promastigotes into the skin of the human host, the infection is either cured or exacerbated. In the process, there emerge several unsolved paradoxes of leishmaniasis. Chronologically, as the infections starts in skin, the role of the salivary proteins in supporting the infection or the host response to these proteins influencing the induction of immunological memory becomes a conundrum. As the parasite invokes inflammation, the infiltrating neutrophils may act as "Trojan Horse" to transfer parasites to macrophages that, along with dendritic cells, carry the parasite to lymphoid organs to start visceralization. As the visceralized infection becomes chronic, the acutely enhanced monocytopoiesis takes a downturn while neutropenia and thrombocytopenia ensue with concomitant rise in splenic colony-forming-units. These responses are accompanied by splenic and hepatic granulomas, polyclonal activation of B cells and deviation of T cell responses. The granuloma formation is both a containment process and a form of immunopathogenesis. The heterogeneity in neutrophils and macrophages contribute to both cure and progression of the disease. The differentiation of T-helper subsets presents another paradox of visceral leishmaniasis, as the counteractive T cell subsets influence the curing or non-curing outcome. Once the parasites are killed by chemotherapy, in some patients the cured visceral disease recurs as a cutaneous manifestation post-kala azar dermal leishmaniasis (PKDL). As no experimental model exists, the natural history of PKDL remains almost a black box at the end of the visceral disease.
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Affiliation(s)
- Baibaswata Saha
- Centre of Advanced Study, Department of Zoology, Savitribai Phule Pune University, Pune 411007, India
| | - Surajit Bhattacharjee
- Department of Molecular Biology and Bioinformatics, Tripura Central University, Agartala, India
| | - Arup Sarkar
- Trident Academy of Creative Technology, Bhubaneshwar, Odisha 751024, India
| | - Renuka Bhor
- Centre of Advanced Study, Department of Zoology, Savitribai Phule Pune University, Pune 411007, India
| | - Kalpana Pai
- Centre of Advanced Study, Department of Zoology, Savitribai Phule Pune University, Pune 411007, India
| | - Neelam Bodhale
- Jagadis Bose National Science Talent Search, 1300 Rajdanga Road, Kolkata 700107, India; National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
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31
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ROY PRITIKUMAR, ROY AMITKUMAR, KHAILOV EVGENIIN, AL BASIR FAHAD, GRIGORIEVA ELLINAV. A MODEL OF THE OPTIMAL IMMUNOTHERAPY OF PSORIASIS BY INTRODUCING IL-10 AND IL-22 INHIBITORS. J BIOL SYST 2020; 28:609-639. [DOI: 10.1142/s0218339020500084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Psoriasis is a chronic skin disease in which the process of hyper-proliferation (excessive division) of skin cells starts. Externally, psoriasis appears as red papules, on the surface of which there are scales of white–gray color. There is substantial evidence that T-helper cells take vital accountability for creating the hyper-proliferation of keratinocytes (skin cells), which causes itching of skin patches. In this paper, we propose a mathematical model describing the concentrations of T-helper and keratinocyte cell populations to predict cellular behaviors for psoriasis regulation under normal or anomalous immune circumstances. Local and global asymptotic stabilities of the model equilibria are investigated. Additionally, by introducing two scalar bounded controls into the model, the effect of combined immunotherapy using IL-10 and IL-22 inhibitors is analyzed. The optimal control problem of minimizing the cost of immune therapy and simultaneous optimizing the effect of this therapy on T-helper cells and keratinocytes proliferation is formulated and solved by applying the Pontryagin maximum principle. Within the restrictions of the proposed model, the obtained analytical and numerical outcomes suggest that the optimal strategy of injecting IL-10 and IL-22 inhibitors can be effective for psoriasis treatment.
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Affiliation(s)
- PRITI KUMAR ROY
- Centre for Mathematical Biology and Ecology, Department of Mathematics, Jadavpur University, Kolkata 700032, India
| | - AMIT KUMAR ROY
- Centre for Mathematical Biology and Ecology, Department of Mathematics, Jadavpur University, Kolkata 700032, India
| | - EVGENII N. KHAILOV
- Faculty of Computational Mathematics and Cybernetics, Lomonosov Moscow State University, Moscow 119992, Russia
| | - FAHAD AL BASIR
- Department of Mathematics, Asansol Girls College, Asansol-4, West Bengal 713304, India
| | - ELLINA V. GRIGORIEVA
- Department of Mathematics and Computer Sciences, Texas Woman’s University, Denton, TX 76204, USA
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32
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Fan Y, Shayahati B, Tewari R, Boehning D, Akimzhanov AM. Regulation of T cell receptor signaling by protein acyltransferase DHHC21. Mol Biol Rep 2020; 47:6471-6478. [PMID: 32789573 DOI: 10.1007/s11033-020-05691-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/26/2020] [Indexed: 12/11/2022]
Abstract
S-acylation reversible-post-translational lipidation of cysteine residues-is emerging as an important regulatory mechanism in T cell signaling. Dynamic S-acylation is critical for protein recruitment into the T cell receptor complex and initiation of the subsequent signaling cascade. However, the enzymatic control of protein S-acylation in T cells remains poorly understood. Here, we report a previously uncharacterized role of DHHC21, a member of the mammalian family of DHHC protein acyltransferases, in regulation of the T cell receptor pathway. We found that loss of DHHC21 prevented S-acylation of key T cell signaling proteins, resulting in disruption of the early signaling events and suppressed expression of T cell activation markers. Furthermore, downregulation of DHHC21 prevented activation and differentiation of naïve T cells into effector subtypes. Together, our study provides the first direct evidence that DHHC protein acyltransferases can play an essential role in regulation of T cell-mediated immunity.
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Affiliation(s)
- Ying Fan
- Department of Biochemistry and Molecular Biology, University of Texas-McGovern Medical School, 6431 Fannin Street, Suite 6.200, Houston, TX, 77030, USA
- Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ, 08103, USA
| | - Bieerkehazhi Shayahati
- Department of Biochemistry and Molecular Biology, University of Texas-McGovern Medical School, 6431 Fannin Street, Suite 6.200, Houston, TX, 77030, USA
| | - Ritika Tewari
- Department of Biochemistry and Molecular Biology, University of Texas-McGovern Medical School, 6431 Fannin Street, Suite 6.200, Houston, TX, 77030, USA
| | - Darren Boehning
- Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ, 08103, USA
| | - Askar M Akimzhanov
- Department of Biochemistry and Molecular Biology, University of Texas-McGovern Medical School, 6431 Fannin Street, Suite 6.200, Houston, TX, 77030, USA.
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33
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Assar S, Nosratabadi R, Khorramdel Azad H, Masoumi J, Mohamadi M, Hassanshahi G. A Review of Immunomodulatory Effects of Fluoroquinolones. Immunol Invest 2020; 50:1007-1026. [PMID: 32746743 DOI: 10.1080/08820139.2020.1797778] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Past researches indicate that some types of antibiotics, apart from their antimicrobial effects, have some other important effects which indirectly are exerted by modulating and regulating the immune system's mediators. Among the compounds with antimicrobial effects, fluoroquinolones (FQs) are known as synthetic antibiotics, which exhibit the property of decomposing of DNA and prevent bacterial growth by inactivating the enzymes involved in DNA twisting, including topoisomerase II (DNA gyrase) and IV. Interestingly, immune responses are indirectly modulated by FQs through suppressing pro-inflammatory cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), and super-inducing IL-2, which tend to increase both the growth and activity of T and B lymphocytes. In addition, they affect the development of immune responses by influencing of expression of other cytokines and mediators. This study aims to review past research on the immunomodulatory effects of FQs on the expression of cytokines, especially IL-2 and to discuss controversial investigations.
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Affiliation(s)
- Shokrollah Assar
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Microbiology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Reza Nosratabadi
- Department of Immunology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hossein Khorramdel Azad
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Javad Masoumi
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mahshad Mohamadi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Gholamhossein Hassanshahi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Campos ACP, Kikuchi DS, Paschoa AFN, Kuroki MA, Fonoff ET, Hamani C, Pagano RL, Hernandes MS. Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson's Disease Rat Model. Cell Mol Neurobiol 2020; 40:939-954. [PMID: 31939008 PMCID: PMC7295825 DOI: 10.1007/s10571-019-00784-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 12/31/2019] [Indexed: 12/13/2022]
Abstract
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson's disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN-DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.
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Affiliation(s)
| | | | | | - Mayra Akemi Kuroki
- Division of Neuroscience, Hospital Sírio-Libanês, São Paulo, SP, 01308-060, Brazil
| | - Erich Talamoni Fonoff
- Division of Neurosurgery, Department of Neurology, University of São Paulo Medical School, São Paulo, 01246-903, Brazil
| | - Clement Hamani
- Sunnybrook Health Research Institute, Harquail Centre for Neuromodulation, Toronto, ON, M4N 3M5, Canada
| | - Rosana Lima Pagano
- Division of Neuroscience, Hospital Sírio-Libanês, São Paulo, SP, 01308-060, Brazil.
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SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev 2020; 54:62-75. [PMID: 32513566 PMCID: PMC7265853 DOI: 10.1016/j.cytogfr.2020.06.001] [Citation(s) in RCA: 770] [Impact Index Per Article: 154.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 05/19/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023]
Abstract
A wide range of cytokines are involved in the development of COVID-19 disease. Some of these biomolecules are related to the progression and even to the prognosis of the infection. Findings on the role of cytokine storm associated with SARS-CoV-2 infection can be useful in order to manage this highly virulent disease. COVID-19 disease, caused by infection with SARS-CoV-2, is related to a series of physiopathological mechanisms that mobilize a wide variety of biomolecules, mainly immunological in nature. In the most severe cases, the prognosis can be markedly worsened by the hyperproduction of mainly proinflammatory cytokines, such as IL-1, IL-6, IL-12, IFN-γ, and TNF-α, preferentially targeting lung tissue. This study reviews published data on alterations in the expression of different cytokines in patients with COVID-19 who require admission to an intensive care unit. Data on the implication of cytokines in this disease and their effect on outcomes will support the design of more effective approaches to the management of COVID-19.
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Physcion-Matured Dendritic Cells Induce the Differentiation of Th1 Cells. Int J Mol Sci 2020; 21:ijms21051753. [PMID: 32143368 PMCID: PMC7084398 DOI: 10.3390/ijms21051753] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/20/2020] [Accepted: 03/03/2020] [Indexed: 12/12/2022] Open
Abstract
In addition to their use as colorants, anthraquinone derivatives have numerous medical applications, for example, as antibacterial and antiinflammatory agents. We confirmed that physcion (an anthraquinone derivative) induces TNF-alpha production by macrophages and increased the expressions of surface molecules (CD40, CD80, and CD86) and major histocompatibility complex (MHC) II. Based on these results, we hypothesized that physcion might induce the maturation of dendritic cells (DCs) to antigen-presenting cells (APCs), and decided to conduct in vitro experiments using bone-marrow-derived DCs (BMDCs). Physcion was not toxic to DCs and increased the expression of surface molecules (e.g., CD40, CD80, CD86, and MHC II) and the production of cytokines (e.g., IL-12p70, IL-1beta, IL-6, and TNF-alpha), but not of IL-10. To confirm that DCs matured by physcion induce T-cell-immune responses, naive CD4+ T cells were treated with physcion-treated DCs or their supernatants. Physcion induced the maturation of DCs, which promoted the polarization of Th1 cells. Our results show physcion-induced DC maturation via TLR4, and that mature DCs promote the differentiation of Th1 cells without affecting the differentiation of Th2 cells. These findings show that physcion has potential use as a treatment for inflammatory diseases associated with Th1/Th2 cell imbalance.
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37
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Servaas NH, Spierings J, Pandit A, van Laar JM. The role of innate immune cells in systemic sclerosis in the context of autologous hematopoietic stem cell transplantation. Clin Exp Immunol 2020; 201:34-39. [PMID: 31990046 PMCID: PMC7290088 DOI: 10.1111/cei.13419] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2020] [Indexed: 12/30/2022] Open
Abstract
Systemic sclerosis (SSc) is a complex, heterogeneous autoimmune connective tissue disease. Autologous hematopoietic stem‐cell transplantation (AHSCT) has emerged as a valuable treatment option for rapidly progressive diffuse cutaneous SSc (dcSSc) patients, and thus far is the only treatment that has been shown to have a long‐term clinical benefit. AHSCT is thought to reintroduce immune homeostasis through elimination of pathogenic self‐reactive immune cells and reconstitution of a new, tolerant immune system. However, the mechanism of action underlying this reset to tolerance remains largely unknown. In this study we review the immune mechanisms underlying AHSCT for SSc, with a focus on the role of the innate immune cells, including monocytes and natural killer (NK) cells, in restoring immune balance after AHSCT.
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Affiliation(s)
- N H Servaas
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - J Spierings
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - A Pandit
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - J M van Laar
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
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38
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Clarke EC, Bradfute SB. The use of mice lacking type I or both type I and type II interferon responses in research on hemorrhagic fever viruses. Part 1: Potential effects on adaptive immunity and response to vaccination. Antiviral Res 2020; 174:104703. [DOI: 10.1016/j.antiviral.2019.104703] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/10/2019] [Accepted: 12/20/2019] [Indexed: 12/25/2022]
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Abstract
AbstractImmunotherapy, especially immune checkpoint inhibitors, is becoming a promising treatment for hepatocellular carcinoma (HCC). However, the response rate remains limited due to the heterogeneity of HCC samples. Molecular subtypes of HCC vary in genomic background, clinical features, and prognosis. This study aims to compare the immune profiles between HCC subtypes and find subtype-specific immune characteristics that might contribute to the prognosis and potential of immunotherapy. The immune profiles consist of immune-related genes, cytolytic
activity, immune pathways, and tumor-infiltrating lymphocytes. HCC-c1 samples showed an overall higher activation level of immune genes and pathways, and this pattern was consistent in validation sets. We associated the difference in immune profiles with the activation level of cancer hallmarks and genomic mutations. There was a negative correlation between most of the metabolism pathway
and immune-related pathways in HCC samples. CTNNB1/WNT signaling pathway mutation, one of the common mutations in HCC, appears to be associated with the expression of immune genes as well. These results reveal the difference of immune profiles between HCC subtypes and possible reasons and influence, which may also deepen our understanding of the carcinogenesis process.
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40
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Zheng ZY, Yu XL, Dai TY, Yin LM, Zhao YN, Xu M, Zhuang HF, Chong BH, Gao RL. Panaxdiol Saponins Component Promotes Hematopoiesis and Modulates T Lymphocyte Dysregulation in Aplastic Anemia Model Mice. Chin J Integr Med 2019; 25:902-910. [PMID: 31802424 DOI: 10.1007/s11655-019-3049-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To investigate the potential efficacy of panaxadiol saponins component (PDS-C) in the treatment of aplastic anemia (AA) model mice. METHODS Totally 70 mice were divided into 7 groups as follows: normal, model, low-, medium-, high-dose PDS-C (20, 40, 80 mg/kg, namely L-, M-, H-PDS-C), cyclosporine (40 mg/kg), and andriol (25 mg/kg) groups, respectively. An immune-mediated AA mouse model was established in BALB/c mice by exposing to 5.0 Gy total body irradiation at 1.0 Gy/min, and injecting with lymphocytes from DBA mice. On day 4 after establishment of AA model, all drugs were intragastrically administered daily for 15 days, respectively, while the mice in the normal and model groups were administered with saline solution. After treatment, the peripheral blood counts, bone marrow pathological examination, colony forming assay of bone marrow culture, T lymphocyte subpopulation analysis, as well as T-bet, GATA-3 and FoxP3 proteins were detected by flow cytometry and Western blot. RESULTS The peripheral blood of white blood cell (WBC), platelet, neutrophil counts and hemoglobin (Hb) concentration were significantly decreased in the model group compared with the normal group (all P<0.01). In response to 3 dose PDS-C treatment, the WBC, platelet, neutrophil counts were significantly increased at a dose-dependent manner compared with the model group (all P<0.01). The myelosuppression status of AA was significantly reduced in M-, H-PDS-C groups, and hematopoietic cell quantity of bone marrow was more abundant than the model group. The colony numbers of myeloid, erythroid and megakaryocytic progenitor cells in the model group were less than those of the normal mice in bone marrow culture, while, PDS-C therapy enhanced proliferation of hematopoietic progenitor cells by significantly increasing colony numbers (all P<0.01). Furthermore, PDS-C therapy increased peripheral blood CD3+ and CD3+CD4+ cells and reduced CD3+CD8+ cells (P<0.05 or P<0.01). Meanwhile, PDS-C treatment at medium- and high doses groups also increased CD4+CD25+FoxP3+ cells, downregulated T-bet protein expression, and upregulated GATA-3 and FoxP3 protein expressions in spleen cells (P<0.05). CONCLUSION PDS-C possesses dual activities, promoting proliferation hematopoietic progenitor cells and modulating T lymphocyte immune functions in the treatment of AA model mice.
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Affiliation(s)
- Zhi-Yin Zheng
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Xiao-Ling Yu
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Tie-Ying Dai
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Li-Ming Yin
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Yan-Na Zhao
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Min Xu
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Hai-Feng Zhuang
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Beng Hock Chong
- Department of Hematology, St George Hospital, St George Clinical School, University of New South Wales, Kogarah, NSW, 2217, Australia
| | - Rui-Lan Gao
- Institution of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China.
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Preparation of Chicken Anemia Virus (CAV) Virus-Like Particles and Chicken Interleukin-12 for Vaccine Development Using a Baculovirus Expression System. Pathogens 2019; 8:pathogens8040262. [PMID: 31771230 PMCID: PMC6963176 DOI: 10.3390/pathogens8040262] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/13/2019] [Accepted: 11/20/2019] [Indexed: 01/24/2023] Open
Abstract
Chicken infectious anemia (CIA) is a poultry disease that causes huge economic losses in the poultry industry worldwide. Commercially available CIA vaccines are derived from wild-type chicken anemia viruses (CAVs) by serial passage in cells or chicken embryos. However, these vaccinal viruses are not completely attenuated; therefore, they can be transmitted vertically and horizontally, and may induce clinical symptoms in young birds. In this study, we sought to eliminate these issues by developing a subunit vaccine exploiting the CAV structural proteins, engineering recombinant baculovirus-infected Spodoptera frugiperda (Sf9) cells that contained both the viral protein 1 (VP1) and VP2 of CAV. Moreover, we produced single-chain chicken interleukin-12 (chIL-12) in the same system, to serve as an adjuvant. The recombinant VP1 was recognized by chicken anti-CAV polyclonal antibodies in Western blotting and immunofluorescence assays, and the bioactivity of the recombinant chIL-12 was confirmed by stimulating interferon-γ (IFN-γ) secretion in chicken splenocytes. Furthermore, the ability of the recombinant VP1 to generate self-assembling virus-like particles (VLPs) was confirmed by transmission electron microscopy. Specific pathogen-free (SPF) chickens inoculated with VLPs and co-administered the recombinant chIL-12 induced high CAV-specific antibodies and cell-mediated immunity. Taken together, the VLPs produced by the baculovirus expression system have the potential to be a safe and effective CIA vaccine. Finally, we demonstrated the utility of recombinant chIL-12 as an adjuvant for poultry vaccine development.
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Bertani L, Antonioli L, Fornai M, Tapete G, Baiano Svizzero G, Marchi S, Blandizzi C, Costa F. Evaluation of cytokine levels as putative biomarkers to predict the pharmacological response to biologic therapy in inflammatory bowel diseases. MINERVA GASTROENTERO 2019; 65:298-308. [PMID: 31646851 DOI: 10.23736/s1121-421x.19.02621-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cytokines play a central role in the pathogenesis of inflammatory bowel diseases. For this reason, the vast majority of biological therapies are aimed to block pro-inflammatory cytokines or their receptors. Although these drugs have modified the course of the disease due to their efficacy, a high rate of non-response or loss of response over time is still an important issue for clinicians. In this perspective, many studies have been conducted in recent years to individuate a reliable biomarker of therapeutic response. In this review, we discuss the role of cytokines involved in the pathogenesis and in the therapy of inflammatory bowel diseases, and their putative use as pharmacological biomarkers of therapy responsiveness.
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Affiliation(s)
- Lorenzo Bertani
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy -
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gherardo Tapete
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy
| | - Giovanni Baiano Svizzero
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy
| | - Santino Marchi
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy
| | - Corrado Blandizzi
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Costa
- Unit of Inflammatory Bowel Diseases, Department of General Surgery and Gastroenterology, Pisa University Hospital, Pisa, Italy
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43
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França FL, Honorio-França AC, Honorio MS, Silva FHD, Fujimori M, França EL, Araújo FGDS. Dental implant surfaces treated with phosphoric acid can modulate cytokine production by blood MN cells. Braz Oral Res 2019; 33:e040. [PMID: 31508724 DOI: 10.1590/1807-3107bor-2019.vol33.0040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 04/09/2019] [Indexed: 11/22/2022] Open
Abstract
The study characterizes dental implant surfaces treated with phosphoric acid to assess the effects of acid treatment on blood cells and correlate them with cytokine levels. The implant surfaces examined were divided into untreated metal surface (US; n = 50), metal surface treated with phosphoric acid (ATS; n = 50) and cement surface (CS; n = 50) groups. The samples were characterized by scanning electron microscopy (SEM) and rheometry. The implants were incubated with human blood mononuclear cells for 24 h, with surface rinsing in the ATS treatment. Cell viability was determined by colorimetric methods and cytokines in the culture supernatant were quantified using flow cytometry. In the ATS group, the surface porosity and contact surface were increased and plaques were observed on the surface. The blood flow and viscosity curves were similar among the treatments, and the high cell viability rates indicate the biocompatibility of the materials used. An increase in the levels of IL-2, IL-4, IL-6, IL-10 and TNF-α was observed in the ATS and CS groups. There were positive correlations between IL-10 and IL-2 levels and between IL-10 and IL-4 levels in the culture supernatant of the ATS group. The results suggest that implant surface treatment with phosphoric acid activates the production of inflammatory cytokines. The increased cytokine levels can modulate the immune response, thereby improving biofunctional processes and promoting the success of dental implants.
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Affiliation(s)
- Fernando Luzía França
- Program of Materials Engineering, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | | | - Mariana Silva Honorio
- Institute of Biological and Health Science, Universidade Federal de Mato Grosso, Barra do Garças, MT, Brazil
| | - Fabiana Helen da Silva
- Institute of Biological and Health Science, Universidade Federal de Mato Grosso, Barra do Garças, MT, Brazil
| | - Mahmi Fujimori
- Institute of Biological and Health Science, Universidade Federal de Mato Grosso, Barra do Garças, MT, Brazil
| | - Eduardo Luzía França
- Institute of Biological and Health Science, Universidade Federal de Mato Grosso, Barra do Garças, MT, Brazil
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Markel D, Bou-Akl T, Rossi M, Pizzimenti NM, Wu B, Ren WP. Response profiles of circulating leukocytes and metal ions in patients with a modular dual-mobility hip implant. Hip Int 2019:1120700019865530. [PMID: 31328577 DOI: 10.1177/1120700019865530] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION The purpose of this study was to retrospectively evaluate blood metal ion levels and leukocyte profiles in patients with modular dual-mobility hip implant (MDM) during a postoperative follow-up up to 2 years. METHODS We recruited 49 patients in a retrospective cohort study and had postoperative follow-up up to 2 years. Blood concentrations of chromium (Cr), cobalt (Co) and serum cytokines were measured. Flow cytometry was used to quantify the subpopulations of leukocytes, including CD14+ and CD16+ monocytes, CD3+ T lymphocytes, CD19+ B lymphocytes, CD4+ Helper T-cells and CD45+RA memory vs. naïve T-cells. RESULTS Clinical performances of implants were good during 2 years of follow-up. Cr levels were normal in all patients and only detectable in 1 patient (1.4µg/L, ref < 5.0µg/L). Co levels were mildly elevated in 4 patients at 1 year (mean 1.375µg/L, range 1.2-1.7µg/L, ref < 1.0µg/L) and in 2 patients at 2-year follow-up (both 1.2µg/L). Interestingly, Co level observed in 3 patients at 1 year converted to undetectable at their 2-year follow-up. Percentages of B cells, T cells and their subpopulations were within normal levels. There was no increase of CD16+ inflammatory monocytes. DISCUSSION With the recent introduction of MDM systems there is potential for metal ion release from the interface between the acetabular shell and CoCr liner. Clinical results have been good and metal levels undetectable or within acceptable ranges at 1-2 years. There was no evidence of activated immune response, as manifested by constant circulating leukocyte profiles and no increase of CD16+ inflammatory monocytes.
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Affiliation(s)
- David Markel
- 1 The CORE Institute, Novi, MI
- 2 Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA
- 3 Ascension Providence Hospital Orthopedic Research Laboratory, Southfield, MI, USA
| | - Theresa Bou-Akl
- 3 Ascension Providence Hospital Orthopedic Research Laboratory, Southfield, MI, USA
| | - Maria Rossi
- 3 Ascension Providence Hospital Orthopedic Research Laboratory, Southfield, MI, USA
| | | | - Bin Wu
- 3 Ascension Providence Hospital Orthopedic Research Laboratory, Southfield, MI, USA
| | - Wei-Ping Ren
- 2 Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA
- 3 Ascension Providence Hospital Orthopedic Research Laboratory, Southfield, MI, USA
- 4 John D. Dingle VA Medical Center, Detroit, MI, USA
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Mozaffari HR, Molavi M, Lopez-Jornet P, Sadeghi M, Safaei M, Imani MM, Sharifi R, Moradpoor H, Golshah A, Jamshidy L. Salivary and Serum Interferon-Gamma/Interleukin-4 Ratio in Oral Lichen Planus Patients: A Systematic Review and Meta-Analysis. ACTA ACUST UNITED AC 2019; 55:medicina55060257. [PMID: 31181785 PMCID: PMC6630336 DOI: 10.3390/medicina55060257] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 02/07/2023]
Abstract
Background and Objectives: Interferon-gamma (IFN-γ)/interleukin-4 (IL-4) ratio may indicate a change in the immune response with a potential pathological effect presented in oral lichen planus (OLP) patients. Herein, this meta-analysis evaluated the role of serum and salivary interferon-gamma/interleukin-4 ratio in the severity and development of OLP. Materials and Methods: The Scopus, Cochrane Library, PubMed, and Web of Science databases were systematically searched to retrieve the relevant studies published up from the database inception to March 2019. The crude mean difference (MD) and 95% confidence interval (CI) were calculated by RevMan 5.3 software using a random-effects model. A sensitivity analysis was performed on the results using the CMA 2.0 software. A total of 98 studies were retrieved from the databases, of which at last seven studies were included in this meta-analysis. Results: The findings showed that the pooled MDs of serum and salivary IFN-γ/IL-4 ratio were −0.22 (95% CI: −1.16, 0.72; p = 0.64) and 0.17 (95% CI: −1.50, 1.84; p = 0.84) in OLP patients compared to controls, respectively. In addition, the pooled MDs of serum and salivary IFN-γ/IL-4 ratio were −0.15 (95% CI: −0.53, 0.23; p = 0.43) and −0.39 (95% CI: −0.63, −0.15; p = 0.001) in patients with erythematous/ulcerative subtype compared to patients with reticular subtype, respectively. Conclusions: In conclusion, the results of meta-analysis demonstrated that serum and salivary IFN-γ/IL-4 ratio cannot play a major role in OLP development and severity.
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Affiliation(s)
- Hamid Reza Mozaffari
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran.
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran.
| | - Maryam Molavi
- Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran.
| | - Pia Lopez-Jornet
- Facultad de Medicina y Odontologia Universidad de Murcia, Hospital Morales Meseguer, Clinica Odontologic Adv Marques Velez s/n, 30008 Murcia, Spain.
| | - Masoud Sadeghi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran.
| | - Mohsen Safaei
- Oral and Dental Sciences Research Laboratory, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran.
| | - Mohammad Moslem Imani
- Department of Orthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran.
| | - Roohollah Sharifi
- Department of Endodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran.
| | - Hedaiat Moradpoor
- Department of Prosthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran.
| | - Amin Golshah
- Department of Orthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran.
| | - Ladan Jamshidy
- Department of Prosthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran.
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Zhang K, Yang J, Ao N, Jin S, Qi R, Shan F, Du J. Methionine enkephalin (MENK) regulates the immune pathogenesis of type 2 diabetes mellitus via the IL-33/ST2 pathway. Int Immunopharmacol 2019; 73:23-40. [PMID: 31078923 DOI: 10.1016/j.intimp.2019.04.054] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 04/25/2019] [Accepted: 04/25/2019] [Indexed: 12/18/2022]
Abstract
The incidence and mortality of type 2 diabetes mellitus (T2DM) rank among the top ten worldwide. Emerging studies indicate pathological roles for the immune system in inflammation, insulin resistance and islet β-cell damage in subjects with T2DM. Methionine enkephalin (MENK) is present in endocrine cells of the pancreas and has been suggested to be an important mediator between the immune and neuroendocrine systems. Therefore, it may play a role in modulating insulin secretion from islet cells. Since little is known about the effect of MENK on T2DM, therefore it was the aim of this study to characterize the role and possible mechanism of action of MENK on plasma glucose and serum insulin levels in T2DM rats and INS-1 cells in vivo and in vitro. MENK significantly decreased the plasma glucose level and increased the serum insulin concentration in T2DM rats. It also increased the serum levels of the cytokines IL-5 and IL-10, while decreased TNF-α and IL-2 levels. We further confirmed that MENK regulated glucose metabolism by upregulating opioid receptor expression and modulating the IL-33/ST2 and MyD88-TRAF6-NF-κB p65 signaling pathways. Based on these results, an intraperitoneal injection of MENK represents a potentially new approach for T2DM.
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Affiliation(s)
- Keying Zhang
- Department of Endocrinology, No. 4 Teaching Hospital, China Medical University, Shenyang 110032, China
| | - Jing Yang
- Department of Endocrinology, No. 4 Teaching Hospital, China Medical University, Shenyang 110032, China
| | - Na Ao
- Department of Endocrinology, No. 4 Teaching Hospital, China Medical University, Shenyang 110032, China
| | - Shi Jin
- Department of Endocrinology, No. 4 Teaching Hospital, China Medical University, Shenyang 110032, China
| | - Ruiqun Qi
- Department of Dermatology, No. 1 Teaching Hospital, China Medical University, Shenyang 110001, China
| | - Fengping Shan
- Department of Immunology, School of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Jian Du
- Department of Endocrinology, No. 4 Teaching Hospital, China Medical University, Shenyang 110032, China.
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Astroglia in Sepsis Associated Encephalopathy. Neurochem Res 2019; 45:83-99. [PMID: 30778837 PMCID: PMC7089215 DOI: 10.1007/s11064-019-02743-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/25/2019] [Accepted: 01/28/2019] [Indexed: 01/07/2023]
Abstract
Cellular pathophysiology of sepsis associated encephalopathy (SAE) remains poorly characterised. Brain pathology in SAE, which is manifested by impaired perception, consciousness and cognition, results from multifactorial events, including high levels of systemic cytokines, microbial components and endotoxins, which all damage the brain barriers, instigate neuroinflammation and cause homeostatic failure. Astrocytes, being the principal homeostatic cells of the central nervous system contribute to the brain defence against infection. Forming multifunctional anatomical barriers, astroglial cells maintain brain-systemic interfaces and restrict the damage to the nervous tissue. Astrocytes detect, produce and integrate inflammatory signals between immune cells and cells of brain parenchyma, thus regulating brain immune response. In SAE astrocytes are present in both reactive and astrogliopathic states; balance between these states define evolution of pathology and neurological outcomes. In humans pathophysiology of SAE is complicated by frequent presence of comorbidities, as well as age-related remodelling of the brain tissue with senescence of astroglia; these confounding factors further impact upon SAE progression and neurological deficits.
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Merlo J, Cutrera AP, Zenuto RR. Assessment of Trade-Offs between Simultaneous Immune Challenges in a Slow-Living Subterranean Rodent. Physiol Biochem Zool 2019; 92:92-105. [PMID: 30601103 DOI: 10.1086/701320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The coexistence of two or more infectious agents in the same host is common in nature. Given this, the study of trade-offs within the immune system itself is key to understanding how immune defenses act in wild species in their natural environment. Here we assessed the possible trade-off between an inflammatory response (induced by phytohemagglutinin [PHA]; involving innate and adaptive responses in the study species) and an antibody response (induced by sheep red blood cells [SRBC]; adaptive response) in a slow-living subterranean rodent, the Talas tuco-tuco (Ctenomys talarum Thomas, 1898). According to life-history theory, slow-living species should rely more heavily on adaptive immunity, which develops more slowly than an innate response but is beneficial against repeated infections. Individual physiological condition (estimated by measuring levels of infection and immune, nutritional, and stress parameters) was analyzed during immune challenges. Contrary to what was expected, we found that the magnitude and energetic costs of both immune responses were similar when stimulated alone or simultaneously. Variation in natural antibodies, neutrophils, basophils, total leukocytes, and the ratio of neutrophils to lymphocytes in relation to the different treatments was also detected. In particular, natural antibodies were negatively affected by the induction of both immune challenges simultaneously and an increase of neutrophil counts was detected in all animals with the exception of those challenged with SRBC, while the pattern of variation of basophils, total leukocytes, and ratio of neutrophils to lymphocytes was not clearly associated with any triggered immune response. In general, our results suggest the absence of an energetic or resource-based trade-off between the immune responses triggered by PHA and SRBC in C. talarum.
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Zheng S, Jin X, Chen M, Shi Q, Zhang H, Xu S. Hydrogen sulfide exposure induces jejunum injury via CYP450s/ROS pathway in broilers. CHEMOSPHERE 2019; 214:25-34. [PMID: 30253253 DOI: 10.1016/j.chemosphere.2018.09.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 08/30/2018] [Accepted: 09/01/2018] [Indexed: 06/08/2023]
Abstract
Hydrogen sulfide (H2S) is generally recognized as a highly poisonous environmental and industrial pollutant. Previous toxicological studies of H2S are mainly focused on the nervous and cardiovascular system. There are few reports on the H2S toxicity effects on jejunum to our knowledge. Our study examined the morphological changes and antioxidant functions of broiler jejunum after the 42-day exposure to H2S. Effects of H2S on morphological damage and immune function in the broiler jejunum were analyzed from the perspective of CYP450s and oxidative stress via transcriptomics and quantitative real-time PCR (qRT-PCR). It was found that the activities of GPx, CAT, SOD, and T-AOC and the level of GSH were observably decreased (P < 0.05), while the contents of MDA and H2O2 were remarkably increased (P < 0.05) in the jejunums of broilers exposed to H2S, which undergone a process of oxidative stress, and typical inflammatory changes and apoptosis could be observed. Transcriptional profiling results showed that 208 genes were significantly up-regulated while 295 genes were remarkably down-regulated in H2S group. The expression of CYP450s, inflammation and apoptosis-related genes were also significantly increased. In conclusion, H2S led to the redox homeostasis disorder through CYP450s differential expression in broiler jejunum. The jejunal inflammatory response, apoptosis along with the immune dysfunction were subsequently observed, which eventually caused jejunal morphology and functional damage. The present study further enriches and perfects the mechanism theory of H2S toxicity on broilers, which may be valuable for the risk assessment of H2S and human health protection.
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Affiliation(s)
- Shufang Zheng
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xi Jin
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Menghao Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Qunxiang Shi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, PR China.
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
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Su Y, Zhang X, Xin H, Li S, Li J, Zhang R, Li X, Li J, Bao J. Effects of prior cold stimulation on inflammatory and immune regulation in ileum of cold-stressed broilers. Poult Sci 2018; 97:4228-4237. [DOI: 10.3382/ps/pey308] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 06/21/2018] [Indexed: 01/10/2023] Open
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