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Uzun O, Heybeli C, Kutlu FSA, Celebioglu Pekiner M, Yıldırım F, Cavdar C, Sarioglu S. Relationship between complement and macrophage markers with kidney survival in patients with diabetic nephropathy. Acta Diabetol 2025:10.1007/s00592-025-02521-3. [PMID: 40338344 DOI: 10.1007/s00592-025-02521-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 04/21/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease (ESKD) worldwide. Macrophages and the complement system have interrelated roles in DN. We aimed to determine associations between macrophage and complement markers with the progression of DN. METHODS This retrospective cohort study included patients diagnosed with sole DN by kidney biopsy. Using immunohistochemistry, CD68+ and CD163+ cells and complement markers were counted in glomerular and tubulointerstitial areas. The primary outcome was evolution to ESKD and/or doubling serum creatinine (SCr). RESULTS Forty-six patients were included. The median SCr at baseline was 2.7 (1.41-3.1) mg/dL. During the median follow-up of 32 months (range 6-54), 50% of patients reached the primary outcome. Most of the clinical and histological findings were comparable between progressors and non-progressors, while progressors had a higher median number of glomerular CD68+ cells and a higher percentage of glomerulosclerosis. After adjustments for age, sex, and SCr, the median glomerular CD68+ cell number was the sole independent predictor of progression. Glomerular C4d was associated with nephrotic-range proteinuria but not with the progression of kidney failure. CONCLUSIONS Glomerular CD68+ cell count may serve as a promising predictor of kidney disease progression among patients with DN. Glomerular C4d was associated with nephrotic-range proteinuria but not with the progression of kidney failure.
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Affiliation(s)
- Ozcan Uzun
- Yalova Research and Training Hospital, Yalova, Turkey
| | - Cihan Heybeli
- Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey.
| | | | | | | | - Caner Cavdar
- Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Sulen Sarioglu
- Department of Pathology, Dokuz Eylül University School of Medicine, Izmir, Turkey
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Dousdampanis P, Aggeletopoulou I, Mouzaki A. The role of M1/M2 macrophage polarization in the pathogenesis of obesity-related kidney disease and related pathologies. Front Immunol 2025; 15:1534823. [PMID: 39867890 PMCID: PMC11758166 DOI: 10.3389/fimmu.2024.1534823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 12/19/2024] [Indexed: 01/28/2025] Open
Abstract
Obesity is a rapidly growing health problem worldwide, affecting both adults and children and increasing the risk of chronic diseases such as type 2 diabetes, hypertension and cardiovascular disease (CVD). In addition, obesity is closely linked to chronic kidney disease (CKD) by either exacerbating diabetic complications or directly causing kidney damage. Obesity-related CKD is characterized by proteinuria, lipid accumulation, fibrosis and glomerulosclerosis, which can gradually impair kidney function. Among the immune cells of the innate and adaptive immune response involved in the pathogenesis of obesity-related diseases, macrophages play a crucial role in the inflammation associated with CKD. In obese individuals, macrophages enter a pro-inflammatory state known as M1 polarization, which contributes to chronic inflammation. This polarization promotes tissue damage, inflammation and fibrosis, leading to progressive loss of kidney function. In addition, macrophage-induced oxidative stress is a key feature of CKD as it also promotes cell damage and inflammation. Macrophages also contribute to insulin resistance in type 2 diabetes by releasing inflammatory molecules that impair glucose metabolism, complicating the management of diabetes in obese patients. Hypertension and atherosclerosis, which are often associated with obesity, also contribute to the progression of CKD via immune and inflammatory pathways. Macrophages influence blood pressure regulation and contribute to vascular inflammation, particularly via the renin-angiotensin system. In atherosclerosis, macrophages accumulate in arterial plaques, leading to chronic inflammation and plaque instability, which may increase the risk of CVD in CKD patients. This review focuses on the involvement of macrophages in CKD and highlights their role as a critical link between CKD and other pathologies. Targeting macrophage polarization and the ensuing macrophage-induced inflammation could be an effective therapeutic strategy for CKD and related diseases and improve outcomes for patients with obesity-related kidney disease.
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Affiliation(s)
| | - Ioanna Aggeletopoulou
- Laboratory of Immunohematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Laboratory of Immunohematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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Wu Z, Hou Q, Chi H, Liu J, Mei Y, Chen T, Yang K, Zheng J, Xu J, Wei F, Wang L. Single-cell RNA sequencing reveals a distinct profile of bone immune microenvironment and decreased osteoclast differentiation in type 2 diabetic mice. Genes Dis 2024; 11:101145. [PMID: 39281831 PMCID: PMC11399629 DOI: 10.1016/j.gendis.2023.101145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/07/2023] [Accepted: 09/16/2023] [Indexed: 09/18/2024] Open
Abstract
The pathogenic effects of type 2 diabetes on bone tissue are gaining attention, but the cellular and molecular mechanisms underlying osteoimmunology are still unclear in diabetes-related bone diseases. We delineated the single-cell transcriptome of bone marrow cells from both wide type and type 2 diabetes mice, which provided the first detailed global profile of bone marrow cells and revealed a distinct bone immune microenvironment at the genetic level under type 2 diabetic condition. It was observed that osteoclast activity was inhibited due to a dysregulated cytokine network, which ultimately led to decreased osteoclast formation and differentiation. In type 2 diabetes mice, a specific C d 36 + cluster (cluster 18, monocytes/macrophages 2) was identified as the precursor of osteoclasts with diminished differentiation potential. AP-1 was demonstrated to be the key transcription factor in the underlying mechanism.
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Affiliation(s)
- Zimei Wu
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Qiaodan Hou
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Heng Chi
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Jihong Liu
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
- Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, China
| | - Yixin Mei
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Tingting Chen
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Kunkun Yang
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Jingna Zheng
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Jing Xu
- Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, China
| | - Fuxin Wei
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Lin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
- Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, China
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He X, Peng L, Zhou L, Liu H, Hao Y, Li Y, Lv Z, Zeng B, Guo X, Guo R. A biphasic drug-releasing microneedle with ROS scavenging and angiogenesis for the treatment of diabetic ulcers. Acta Biomater 2024; 189:270-285. [PMID: 39362454 DOI: 10.1016/j.actbio.2024.09.045] [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: 07/03/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024]
Abstract
Diabetic ulcers are one of the common complications in diabetic patients. Delayed wound healing is associated with persistent pro-inflammatory M1 polarization, reduced angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Wound healing consists of multiple phases and therefore requires treatment tailored to each phase. In this study, a biphasic drug-releasing microneedle (MN) was fabricated to achieve early ROS scavenging and late accelerated angiogenesis to promote wound healing. Vascular endothelial growth factor (VEGF) was first encapsulated in methacryloylated sulfonated chitosan (SCSMA) microspheres (V@MP), and then V@MP was loaded into hyaluronic acid (HA) microneedles along with cerium dioxide nanoparticles (CONPs). Rapid dissolution of HA rapidly releases the CONPs to clear ROS, whereas the V@MP stays in the wound. SCSMA slow degradation prolongs the release of VEGF, thereby promoting angiogenesis. In vitro and in vivo studies have shown that this biphasic drug-releasing smart microneedle improves cell proliferation and migration, effectively scavenges ROS, promotes angiogenesis and tissue regeneration, and synergistically promotes M2 macrophage polarization. It provides a new delivery mode for nano-enzymes and growth factors that could be multifunctional and synergistic in the treatment of diabetic ulcers. STATEMENT OF SIGNIFICANCE: In our study, we present a microneedle (V@MP/C@MN) that can release drugs biphasically, which showed good repair ability in diabetic ulcer model. Large amounts of CONPs were rapidly released to alleviate oxidative stress during the inflammation of the wound, and V@MP stayed in the wound for a long period of time to release VEGF and promote angiogenesis in the late stage of wound healing. The results indicated that V@MP/C@MN could promote cell proliferation and migration, effectively scavenge ROS, promote angiogenesis and tissue regeneration, and synergistically promote M2 macrophage polarization, which could play a multifunctional and synergistic role in the treatment of diabetic ulcers.
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Affiliation(s)
- Xinyue He
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Key Laboratory of Regenerative Medicine of Ministry of Education, Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
| | - Lianghong Peng
- Department of Ophthalmology, General Hospital of Southern Theater Command, PLA, Guangzhou 510010, China
| | - Liming Zhou
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Key Laboratory of Regenerative Medicine of Ministry of Education, Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
| | - Huiling Liu
- Head Department of Oral and Maxillofacial Surgery, Leiden University Medical Centre, Amsterdam, De Boelelaan 1117, the Netherlands
| | - Yifan Hao
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Key Laboratory of Regenerative Medicine of Ministry of Education, Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
| | - Yuhan Li
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Key Laboratory of Regenerative Medicine of Ministry of Education, Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
| | - Zijin Lv
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Key Laboratory of Regenerative Medicine of Ministry of Education, Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
| | - Baohui Zeng
- Department of Ultrasound, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Xinmin Guo
- Department of Ultrasound, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China.
| | - Rui Guo
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Key Laboratory of Regenerative Medicine of Ministry of Education, Guangdong Provincial Engineering and Technological Research Centre for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China.
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Eitner A, Rutte V, Marintschev I, Hofmann GO, Schaible HG. Enhanced joint pain in diabetic patients with knee osteoarthritis is associated with increased synovitis, synovial immune cell infiltration, and erythrocyte extravasation. Front Endocrinol (Lausanne) 2024; 15:1477384. [PMID: 39469580 PMCID: PMC11513275 DOI: 10.3389/fendo.2024.1477384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 09/30/2024] [Indexed: 10/30/2024] Open
Abstract
Objective Diabetes mellitus (DM) is an important risk factor for the development of osteoarthritis (OA), increasing OA progression and OA pain. To gain insight into the underlying mechanisms of how DM exacerbates OA processes and OA pain, this study analyzed histological differences of synovial tissues from non-DM and DM patients with OA and correlated these differences with knee pain severity. Materials and methods Synovial tissue was obtained from 12 non-DM and 10 DM patients with advanced knee OA who underwent total knee arthroplasty. Synovial inflammation was assessed using the Synovitis score developed by Krenn. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was used to assess knee pain intensity and disability in OA patients. The number of mast cells, macrophages, nerve fibers, capillaries, larger vessels and erythrocyte extravasation were analyzed microscopically in histological and immunostained synovial sections from non-DM and DM patients. Association analyses were performed to determine associations between OA knee pain and synovial changes affected by DM. Results Synovial tissue from OA patients with DM had a higher synovitis score, more erythrocyte extravasation, and contained higher numbers of mast cells and macrophages compared to non-DM patients. The number of capillaries and vessels in the lining/sublining layer of the synovial tissue was reduced in DM patients. OA patients with DM had more severe knee pain compared to non-DM patients. The KOOS pain score was associated with the synovitis score, the number of tissue macrophages, and the number of mast cells in the synovial tissue (adjusted for age, sex, and BMI). In addition, the erythrocyte extravasation score was associated with the KOOS pain score and with the synovitis score. Conclusion The study suggests that increased OA progression and pain severity in patients with DM result from more pronounced synovitis and synovial vascular leakage and increased infiltration of macrophages and mast cells.
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Affiliation(s)
- Annett Eitner
- Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Veronika Rutte
- Institute of Physiology 1/Neurophysiology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Ivan Marintschev
- Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Gunther O. Hofmann
- Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Hans-Georg Schaible
- Institute of Physiology 1/Neurophysiology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
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Zhang W, Chen W, Lei J, Li J, Yang M, Li L. The Expression of MAFB Gene in Circulating Monocytes Is Related to Chronic Inflammatory Status in T2DM Patients. Inflammation 2024; 47:1837-1852. [PMID: 38602607 DOI: 10.1007/s10753-024-02012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/16/2024] [Accepted: 03/22/2024] [Indexed: 04/12/2024]
Abstract
Immune cell-mediated chronic inflammation is one of the causes of type 2 diabetes mellitus (T2DM). Therefore, identifying inflammatory markers in circulating immune cells is highly important for predicting insulin resistance (IR) and the occurrence of T2DM. In this study, we discovered that differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) from T2DM patients were associated with innate immunity and chronic inflammatory responses through bulk transcriptome sequencing (bulk RNA-seq). Gene integration analysis revealed that nine DEGs were upregulated, and receiver operating characteristic (ROC) curve analysis revealed that V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), a candidate biomarker, has a certain predictive value for T2DM. In population-based cohort studies, we found that MAFB expression was significantly upregulated in the PBMCs of T2DM patients and was significantly correlated with homeostasis model assessment of IR (HOMA-IR), tumor necrosis factor-α (TNF-α), adiponectin (Adipoq), etc. We further evaluated the sensitivity and specificity of MAFB and other clinical parameters for predicting and diagnosing T2DM and found that MAFB expression in PBMCs had a positive effect on the prediction and diagnosis of T2DM. Finally, single-cell RNA sequencing (scRNA-seq) analysis revealed that the increase in MAFB expression was mainly in nonclassical monocytes. Our results suggest that increased MAFB expression in circulating monocytes may mediate chronic inflammatory status in patients with T2DM. Therefore, MAFB gene expression in circulating monocytes has certain clinical significance for predicting and assisting in the diagnosis of T2DM.
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Affiliation(s)
- Wanliang Zhang
- The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Wenyun Chen
- The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Jingwei Lei
- The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Jie Li
- The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Mengliu Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ling Li
- The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
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7
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Siwan E, Wong J, Brooks BA, Shinko D, Baker CJ, Deshpande N, McLennan SV, Twigg SM, Min D. Deep Immune and RNA Profiling Revealed Distinct Circulating CD163+ Monocytes in Diabetes-Related Complications. Int J Mol Sci 2024; 25:10094. [PMID: 39337580 PMCID: PMC11432403 DOI: 10.3390/ijms251810094] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/06/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
CD163, a scavenger receptor with anti-inflammatory function expressed exclusively on monocytes/macrophages, is dysregulated in cases of diabetes complications. This study aimed to characterize circulating CD163+ monocytes in the presence (D+Comps) or absence (D-Comps) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D+Comps or D-Comps. Out of 10,868 differentially expressed genes identified between D+Comps and D-Comps, 885 were up-regulated and 190 were down-regulated with a ≥ 1.5-fold change. In D+Comps, 'regulation of centrosome cycle' genes were enriched 6.7-fold compared to the reference genome. MIR27A, MIR3648-1, and MIR23A, the most up-regulated and CD200R1, the most down-regulated gene, were detected in D+Comps from the list of 75 'genes of interest'. CD163+ monocytes in D+Comps had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD86. A gene-protein network identified down-regulated TLR4 and CD11b as 'hub-nodes'. In conclusion, this study reports novel insights into CD163+ monocyte dysregulation in diabetes-related complications. Enriched centrosome cycle genes and up-regulated miRNAs linked to apoptosis, coupled with down-regulated monocyte activation, recruitment, and immune regulation, suggest functionally distinct CD163+ monocytes in cases of diabetes complications. Further investigation is needed to confirm their role in diabetes-related tissue damage.
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Affiliation(s)
- Elisha Siwan
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkin Centre, The University of Sydney, Sydney, NSW 2006, Australia; (E.S.); (J.W.); (C.J.B.); (S.V.M.); (S.M.T.)
| | - Jencia Wong
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkin Centre, The University of Sydney, Sydney, NSW 2006, Australia; (E.S.); (J.W.); (C.J.B.); (S.V.M.); (S.M.T.)
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia;
| | - Belinda A. Brooks
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia;
| | - Diana Shinko
- Sydney Cytometry, The University of Sydney, Sydney, NSW 2006, Australia;
| | - Callum J. Baker
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkin Centre, The University of Sydney, Sydney, NSW 2006, Australia; (E.S.); (J.W.); (C.J.B.); (S.V.M.); (S.M.T.)
| | - Nandan Deshpande
- Sydney Informatics Hub, The University of Sydney, Sydney, NSW 2006, Australia;
| | - Susan V. McLennan
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkin Centre, The University of Sydney, Sydney, NSW 2006, Australia; (E.S.); (J.W.); (C.J.B.); (S.V.M.); (S.M.T.)
- NSW Health Pathology, Sydney, NSW 2050, Australia
| | - Stephen M. Twigg
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkin Centre, The University of Sydney, Sydney, NSW 2006, Australia; (E.S.); (J.W.); (C.J.B.); (S.V.M.); (S.M.T.)
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia;
| | - Danqing Min
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkin Centre, The University of Sydney, Sydney, NSW 2006, Australia; (E.S.); (J.W.); (C.J.B.); (S.V.M.); (S.M.T.)
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia;
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Sierra-Silvestre E, Smith RE, Andrade RJ, Kennedy B, Coppieters MW. Microstructural changes in the median and ulnar nerve in people with and without diabetic neuropathy in their hands: A cross-sectional diffusion MRI study. Eur J Radiol 2024; 181:111721. [PMID: 39260209 DOI: 10.1016/j.ejrad.2024.111721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 05/29/2024] [Accepted: 09/03/2024] [Indexed: 09/13/2024]
Abstract
PURPOSE Diffusion weighted imaging (DWI) has revealed microstructural changes in lower limb nerves in people with diabetic neuropathy. Microstructural changes in upper limb nerves using DWI in people with diabetes have not yet been explored. METHODS This cross-sectional study aimed to quantify and compare the microstructure of the median and ulnar nerve in people without diabetes (n = 10), people with diabetes without distal symmetrical polyneuropathy (DSPN; n = 10), people with DSPN in the lower limbs only (DSPN FEET ONLY; n = 12), and people with DSPN in the upper and lower limbs (DSPN HANDS & FEET; n = 9). DSPN diagnosis included electrodiagnosis and corneal confocal microscopy. Tensor metrics, such as fractional anisotropy, radial diffusivity and axial diffusivity, and constrained spherical deconvolution metrics, such as dispersion and complexity, were calculated. Linear mixed-models were used to quantify DWI metrics from multiple models in median and ulnar nerves across the groups, and to evaluate potential differences in metrics at the wrist and elbow based on the principle of a distal-to-proximal disease progression. RESULTS Tensor metrics revealed microstructural abnormalities in the median and ulnar nerve in people with DSPN HANDS & FEET, and also already in DSPN FEET ONLY. There were significant negative correlations between electrodiagnostic parameters and tensor metrics. A distal-to-proximal pattern was more pronounced in the median nerve. Non-tensor metrics showed early microstructural changes in people with diabetes without DSPN. CONCLUSION Compared to people without diabetes, microstructural changes in upper limb nerves can be identified in people with diabetes with and without DSPN, even before symptoms occur.
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Affiliation(s)
- Eva Sierra-Silvestre
- School of Health Sciences and Social Work, Griffith University, Brisbane, Australia; Amsterdam Movement Sciences - Program Musculoskeletal Health, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK. https://twitter.com/esiesil
| | - Robert E Smith
- The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia; The Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
| | - Ricardo J Andrade
- School of Health Sciences and Social Work, Griffith University, Brisbane, Australia; Movement - Interactions - Performance (MIP), Nantes University, Nantes, France. https://twitter.com/jacobofhume
| | - Ben Kennedy
- Mermaid Beach Radiology, Gold Coast, Australia
| | - Michel W Coppieters
- School of Health Sciences and Social Work, Griffith University, Brisbane, Australia; Amsterdam Movement Sciences - Program Musculoskeletal Health, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. https://twitter.com/michelcoppie
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Eid SA, Elzinga SE, Guo K, Hinder LM, Hayes JM, Pacut CM, Koubek EJ, Hur J, Feldman EL. Transcriptomic profiling of sciatic nerves and dorsal root ganglia reveals site-specific effects of prediabetic neuropathy. Transl Res 2024; 270:24-41. [PMID: 38556110 PMCID: PMC11166517 DOI: 10.1016/j.trsl.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/01/2024] [Accepted: 03/24/2024] [Indexed: 04/02/2024]
Abstract
Peripheral neuropathy (PN) is a severe and frequent complication of obesity, prediabetes, and type 2 diabetes characterized by progressive distal-to-proximal peripheral nerve degeneration. However, a comprehensive understanding of the mechanisms underlying PN, and whether these mechanisms change during PN progression, is currently lacking. Here, gene expression data were obtained from distal (sciatic nerve; SCN) and proximal (dorsal root ganglia; DRG) injury sites of a high-fat diet (HFD)-induced mouse model of obesity/prediabetes at early and late disease stages. Self-organizing map and differentially expressed gene analyses followed by pathway enrichment analysis identified genes and pathways altered across disease stage and injury site. Pathways related to immune response, inflammation, and glucose and lipid metabolism were consistently dysregulated with HFD-induced PN, irrespective of injury site. However, regulation of oxidative stress was unique to the SCN while dysregulated Hippo and Notch signaling were only observed in the DRG. The role of the immune system and inflammation in disease progression was supported by an increase in the percentage of immune cells in the SCN with PN progression. Finally, when comparing these data to transcriptomic signatures from human patients with PN, we observed conserved pathways related to metabolic dysregulation across species, highlighting the translational relevance of our mouse data. Our findings demonstrate that PN is associated with distinct site-specific molecular re-programming in the peripheral nervous system, identifying novel, clinically relevant therapeutic targets.
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Affiliation(s)
- Stéphanie A. Eid
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sarah E. Elzinga
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kai Guo
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lucy M. Hinder
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - John M. Hayes
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Crystal M. Pacut
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Emily J. Koubek
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Junguk Hur
- Department of Biomedical Sciences, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202, USA
| | - Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
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10
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Su W, Yin Y, Zhao J, Hu R, Zhang H, Hu J, Ren R, Zhang Y, Wang A, Lyu Z, Mu Y, Cheng Y. Exosomes derived from umbilical cord-derived mesenchymal stem cells exposed to diabetic microenvironment enhance M2 macrophage polarization and protect against diabetic nephropathy. FASEB J 2024; 38:e23798. [PMID: 38989582 DOI: 10.1096/fj.202400359r] [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: 02/15/2024] [Revised: 05/07/2024] [Accepted: 06/24/2024] [Indexed: 07/12/2024]
Abstract
The role of mesenchymal-stem-cell-derived exosomes (MSCs-Exo) in the regulation of macrophage polarization has been recognized in several diseases. There is emerging evidence that MSCs-Exo partially prevent the progression of diabetic nephropathy (DN). This study aimed to investigate whether exosomes secreted by MSCs pre-treated with a diabetic environment (Exo-pre) have a more pronounced protective effect against DN by regulating the balance of macrophages. Exo-pre and Exo-Con were isolated from the culture medium of UC-MSCs pre-treated with a diabetic mimic environment and natural UC-MSCs, respectively. Exo-pre and Exo-Con were injected into the tail veins of db/db mice three times a week for 6 weeks. Serum creatinine and serum urea nitrogen levels, the urinary protein/creatinine ratio, and histological staining were used to determine renal function and morphology. Macrophage phenotypes were analyzed by immunofluorescence, western blotting, and quantitative reverse transcription polymerase chain reaction. In vitro, lipopolysaccharide-induced M1 macrophages were incubated separately with Exo-Con and Exo-pre. We performed microRNA (miRNA) sequencing to identify candidate miRNAs and predict their target genes. An miRNA inhibitor was used to confirm the role of miRNAs in macrophage modulation. Exo-pre were more potent than Exo-Con at alleviating DN. Exo-pre administration significantly reduced the number of M1 macrophages and increased the number of M2 macrophages in the kidney compared to Exo-Con administration. Parallel outcomes were observed in the co-culture experiments. Moreover, miR-486-5p was distinctly expressed in Exo-Con and Exo-pre groups, and it played an important role in macrophage polarization by targeting PIK3R1 through the PI3K/Akt pathway. Reducing miR-486-5p levels in Exo-pre abolished macrophage polarization modulation. Exo-pre administration exhibited a superior effect on DN by remodeling the macrophage balance by shuttling miR-486-5p, which targets PIK3R1.
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Affiliation(s)
- Wanlu Su
- School of Medicine, Nankai University, Tianjin, China
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Jian Zhao
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Ruofan Hu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Haixia Zhang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Jia Hu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Rui Ren
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yue Zhang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Anning Wang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhaohui Lyu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yiming Mu
- School of Medicine, Nankai University, Tianjin, China
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yu Cheng
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China
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11
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Han M, Li J, Wu Y, Tang Z. Potential immune-related therapeutic mechanisms of multiple traditional Chinese medicines on type 2 diabetic nephropathy based on bioinformatics, network pharmacology and molecular docking. Int Immunopharmacol 2024; 133:112044. [PMID: 38648716 DOI: 10.1016/j.intimp.2024.112044] [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: 02/21/2024] [Revised: 03/27/2024] [Accepted: 04/06/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND The prevalence of type 2 diabetic nephropathy (T2DN) ranges from 20 % to 40 % among individuals with type 2 diabetes. Multiple immune pathways play a pivotal role in the pathogenesis of T2DN. This study aimed to investigate the immunomodulatory effects of active ingredients derived from 14 traditional Chinese medicines (TCMs) on T2DN. METHODS By removing batch effect on the GSE30528 and GSE96804 datasets, we employed a combination of weighted gene co-expression network analysis, least absolute shrinkage and selection operator analysis, protein-protein interaction network analysis, and the CIBERSORT algorithm to identify the active ingredients of TCMs as well as potential hub biomarkers associated with immune cells. Functional analysis was conducted using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and gene set variation analysis (GSVA). Additionally, molecular docking was employed to evaluate interactions between active ingredients and potential immunotherapy targets. RESULTS A total of 638 differentially expressed genes (DEGs) were identified in this study, comprising 5 hub genes along with 4 potential biomarkers. Notably, CXCR1, CXCR2, and FOS exhibit significant associations with immune cells while displaying robust or favorable affinities towards the active ingredients kaempferol, quercetin, and luteolin. Furthermore, functional analysis unveiled intricate involvement of DEGs, hub genes and potential biomarkers in pathways closely linked to immunity and diabetes. CONCLUSION The potential hub biomarkers and immunotherapy targets associated with immune cells of T2DN comprise CXCR1, CXCR2, and FOS. Furthermore, kaempferol, quercetin, and luteolin demonstrate potential immunomodulatory effects in modulating T2DN through the regulation of CXCR1, CXCR2, and FOS expression.
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MESH Headings
- Diabetic Nephropathies/drug therapy
- Diabetic Nephropathies/genetics
- Diabetic Nephropathies/immunology
- Humans
- Molecular Docking Simulation
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/genetics
- Drugs, Chinese Herbal/therapeutic use
- Drugs, Chinese Herbal/chemistry
- Drugs, Chinese Herbal/pharmacology
- Medicine, Chinese Traditional
- Computational Biology
- Network Pharmacology
- Protein Interaction Maps
- Receptors, Interleukin-8B/genetics
- Receptors, Interleukin-8B/metabolism
- Receptors, Interleukin-8A/genetics
- Receptors, Interleukin-8A/metabolism
- Gene Regulatory Networks/drug effects
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Affiliation(s)
- Mingzheng Han
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Jiale Li
- Department of Blood Transfusion, Yuexi Hospital of the Sixth Affiliated Hospital, Sun Yat-sen University (Xinyi People's Hospital), Xinyi, China
| | - Yijin Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Zhaoxin Tang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
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12
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Jaffey JA, Kreisler R, Graves TK, Al-Nakkash L, Backus RC, Allison L. Ex Vivo Immune Function and Modulatory Effects of Calcitriol in Dogs with Naturally Occurring Diabetes Mellitus. Vet Sci 2024; 11:193. [PMID: 38787165 PMCID: PMC11125998 DOI: 10.3390/vetsci11050193] [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: 02/23/2024] [Revised: 04/10/2024] [Accepted: 04/21/2024] [Indexed: 05/25/2024] Open
Abstract
Human patients with type 1 diabetes mellitus (T1DM) are susceptible to several long-term complications that are related to glycemic control and immune dysregulation. Immune function remains relatively unexplored in dogs with naturally occurring diabetes mellitus (NODM). Calcitriol improves various aspects of immune function in a variety of species, but its effect in diabetic dogs remains unexplored. Therefore, the objectives of this study were to (i) evaluate immune function in dogs with NODM and determine if differences exist based on the level of clinical control and (ii) assess the immunomodulatory effects of calcitriol. Twenty diabetic dogs (clinically controlled, n = ten, not controlled, n = ten) and 20 non-diabetic, healthy control dogs were included in this prospective, case-control study. Whole blood was incubated with calcitriol (10-7 M) or negative control, after which the samples were divided for phagocytosis and leukocyte cytokine response experiments. The phagocytosis of opsonized Escherichia coli (E. coli) was evaluated with flow cytometry. The samples for leukocyte cytokine response evaluations were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or phosphate buffer solution (PBS; negative control), and tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10 were measured in supernatant using a canine-specific multiplex bead-based assay. The leukocytes from diabetic dogs produced higher concentrations of IL-10 (p = 0.01), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) than the control dogs while controlling for the intervention and stimulant. Calcitriol decreased the supernatant concentrations of TNF-α (p < 0.001) and IL-8 (p = 0.04) with concomitant increases in IL-6 (p = 0.005). Diabetic dogs had a lower percentage of leukocytes undergoing phagocytosis (p < 0.0001) but a higher number of bacteria phagocytized per cell (p = 0.001) when compared to the control dogs. Calcitriol had no effect on phagocytic capacity. Lastly, the status of clinical control in diabetic dogs did not yield differences in immune function. These results support that dogs with NODM exhibit immune dysregulation and warrant additional investigation.
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Affiliation(s)
- Jared A. Jaffey
- Department of Specialty Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA; (T.K.G.); (L.A.)
| | - Rachael Kreisler
- Department of Pathology and Population Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA;
| | - Thomas K. Graves
- Department of Specialty Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA; (T.K.G.); (L.A.)
| | - Layla Al-Nakkash
- Department of Physiology, Midwestern University, College of Graduate Studies, Glendale, AZ 85308, USA;
| | - Robert C. Backus
- Department of Veterinary Medicine and Surgery, University of Missouri, College of Veterinary Medicine, Columbia, MO 65211, USA;
| | - Lauren Allison
- Department of Specialty Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA; (T.K.G.); (L.A.)
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13
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Panda S, Arora A, Luthra K, Mohan A, Vikram NK, Kumar Gupta N, Singh A. Hyperglycemia modulates M1/M2 macrophage polarization in chronic diabetic patients with pulmonary tuberculosis infection. Immunobiology 2024; 229:152787. [PMID: 38271857 DOI: 10.1016/j.imbio.2024.152787] [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: 08/31/2023] [Revised: 01/05/2024] [Accepted: 01/12/2024] [Indexed: 01/27/2024]
Abstract
Increased susceptibility to bacterial infections like tuberculosis (TB) is one of the complications of type 2 diabetes, however the underlying mechanisms remains poorly characterized. To explore how chronic hyperglycemia in diabetes affects progression of active TB, we examined mRNA expression of M1 (proinflammatory) and M2 (anti-inflammatory) cytokines/markers, in monocyte-derived macrophages obtained from patients with PTB + DM (pulmonary TB + diabetes mellitus type 2), patients with DM alone, patients with PTB alone, and healthy individuals (controls). Our findings indicate a dysregulated cytokine response in patients with both PTB and DM, characterized by decreased expression levels of interferon-gamma (IFN-γ) and inducible nitric oxide synthase (iNOS), along with increased expression levels of interleukin-1 beta (IL-1β) and CD206. Furthermore, we observed a positive correlation of IL-1β and CD206 expression with levels of glycosylated hemoglobin (HbA1c) in both PTB + DM and DM groups, while IFN-γ showed a positive correlation with HbA1c levels, specifically in the PTB + DM group. Additionally, M1 cytokines/markers, IL-1β and iNOS were found to be significantly associated with the extent of sputum positivity in both PTB and PTB + DM groups, suggesting it to be a function of increased bacterial load and hence severity of infection. Our data demonstrates that tuberculosis in individuals with PTB + DM is characterized by altered M1/M2 cytokine responses, indicating that chronic inflammation associated with type 2 diabetes may contribute to increased immune pathology and inadequate control of tuberculosis infection.
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Affiliation(s)
- Sudhasini Panda
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi -110029, India
| | - Alisha Arora
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi -110029, India
| | - Kalpana Luthra
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi -110029, India
| | - Anant Mohan
- Department of Pulmonary Medicine, All India Institute of Medical Sciences, New Delhi -110029, India
| | - Naval K Vikram
- Department of Medicine, All India Institute of Medical Sciences, New Delhi -110029, India
| | - Neeraj Kumar Gupta
- Department of Pulmonary Medicine, VMMC and Safdarjung Hospital, New Delhi -110029, India
| | - Archana Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi -110029, India.
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14
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Youssef N, Noureldein MH, Riachi ME, Haddad A, Eid AA. Macrophage polarization and signaling in diabetic kidney disease: a catalyst for disease progression. Am J Physiol Renal Physiol 2024; 326:F301-F312. [PMID: 38153850 DOI: 10.1152/ajprenal.00266.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/29/2023] [Accepted: 12/16/2023] [Indexed: 12/30/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes affecting millions of people worldwide. Macrophages, a critical immune cell type, are central players in the development and progression of DKD. In this comprehensive review, we delve into the intricate role of macrophages in DKD, examining how they can become polarized into proinflammatory M1 or anti-inflammatory M2 phenotypes. We explore the signaling pathways involved in macrophage recruitment and polarization in the kidneys, including the key cytokines and transcription factors that promote M1 and M2 polarization. In addition, we discuss the latest clinical studies investigating macrophages in DKD and explore the potential of hypoglycemic drugs for modulating macrophage polarization. By gaining a deeper understanding of the mechanisms that regulate macrophage polarization in DKD, we may identify novel therapeutic targets for this debilitating complication of diabetes. This review provides valuable insights into the complex interplay between macrophages and DKD, shedding light on the latest developments in this important area of research. This review aims to enhance understanding of the role that macrophages play in the pathogenesis of DKD.
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Affiliation(s)
- Natalie Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamed H Noureldein
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mansour E Riachi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Antony Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
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15
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Ma JY, Xia TJ, Li S, Yin S, Luo SM, Li G. Germline cell de novo mutations and potential effects of inflammation on germline cell genome stability. Semin Cell Dev Biol 2024; 154:316-327. [PMID: 36376195 DOI: 10.1016/j.semcdb.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/05/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
Uncontrolled pathogenic genome mutations in germline cells might impair adult fertility, lead to birth defects or even affect the adaptability of a species. Understanding the sources of DNA damage, as well as the features of damage response in germline cells are the overarching tasks to reduce the mutations in germline cells. With the accumulation of human genome data and genetic reports, genome variants formed in germline cells are being extensively explored. However, the sources of DNA damage, the damage repair mechanisms, and the effects of DNA damage or mutations on the development of germline cells are still unclear. Besides exogenous triggers of DNA damage such as irradiation and genotoxic chemicals, endogenous exposure to inflammation may also contribute to the genome instability of germline cells. In this review, we summarized the features of de novo mutations and the specific DNA damage responses in germline cells and explored the possible roles of inflammation on the genome stability of germline cells.
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Affiliation(s)
- Jun-Yu Ma
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.
| | - Tian-Jin Xia
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China; College of Life Sciences, Qingdao Agricultural University, Qingdao, China
| | - Shuai Li
- Center for Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Shen Yin
- College of Life Sciences, Qingdao Agricultural University, Qingdao, China.
| | - Shi-Ming Luo
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.
| | - Guowei Li
- Center for Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China.
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16
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Tang S, An X, Sun W, Zhang Y, Yang C, Kang X, Sun Y, Jiang L, Zhao X, Gao Q, Ji H, Lian F. Parallelism and non-parallelism in diabetic nephropathy and diabetic retinopathy. Front Endocrinol (Lausanne) 2024; 15:1336123. [PMID: 38419958 PMCID: PMC10899692 DOI: 10.3389/fendo.2024.1336123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/23/2024] [Indexed: 03/02/2024] Open
Abstract
Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes of end-stage renal disease (ESRD) and blindness, respectively, in the adult working population, and they are major public health problems with social and economic burdens. The parallelism between the two in the process of occurrence and development manifests in the high overlap of disease-causing risk factors and pathogenesis, high rates of comorbidity, mutually predictive effects, and partial concordance in the clinical use of medications. However, since the two organs, the eye and the kidney, have their unique internal environment and physiological processes, each with specific influencing molecules, and the target organs have non-parallelism due to different pathological changes and responses to various influencing factors, this article provides an overview of the parallelism and non-parallelism between DN and DR to further recognize the commonalities and differences between the two diseases and provide references for early diagnosis, clinical guidance on the use of medication, and the development of new drugs.
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Affiliation(s)
- Shanshan Tang
- College of Traditional Chinese Medicine, Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Xuedong An
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenjie Sun
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuehong Zhang
- Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Cunqing Yang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaomin Kang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuting Sun
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Linlin Jiang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuefei Zhao
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Qing Gao
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hangyu Ji
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengmei Lian
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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17
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Wang M, Zhang Q, Lou S, Jin L, Wu G, Wu W, Tang Q, Wang Y, Long X, Huang P, Luo W, Liang G. Inhibition of MD2 by natural product-drived JM-9 attenuates renal inflammation and diabetic nephropathy in mice. Biomed Pharmacother 2023; 168:115660. [PMID: 37806092 DOI: 10.1016/j.biopha.2023.115660] [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: 07/26/2023] [Revised: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 10/10/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the severe complications of diabetes mellitus-related microvascular lesions, which remains the leading cause of end-stage kidney disease. The genesis and development of DKD is closely related to inflammation. Myeloid differentiation 2 (MD2) mediates hyperlyciemia-induced renal inflammation and DKD development and is considered as a potential therapeutic target of DKD. Here, we identified a new small-molecule MD2 inhibitor, JM-9. In vitro, JM-9 suppressed high glucose (HG) and palmitic acid (PA)-induced inflammation in MPMs, accompanied by inhibition of MD2 activation and the downstream TLR4/MyD88-MAPKs/NFκB pro-inflammatory signaling pathway. Macrophage-derived factors increased the fibrotic and inflammatory responses in renal tubular epithelial cells, which were inhibited by treating macrophages with JM-9. Then, we investigated the therapeutic effects against DKD in streptozotocin-induced type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mouse models. Treatment with JM-9 prevented renal inflammation, fibrosis, and dysfunction by targeting MD2 in both T1DM and T2DM models. Our results show that JM-9, a new small-molecule MD2 inhibitor, protects against DKD by targeting MD2 and inhibiting MD2-mediated inflammation. In summary, JM-9 is a potential therapeutic agent for DKD.
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Affiliation(s)
- Minxiu Wang
- Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Qianhui Zhang
- Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shuaijie Lou
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Leiming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China
| | - Gaojun Wu
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wenqi Wu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Qidong Tang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaohong Long
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ping Huang
- Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Wu Luo
- Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Guang Liang
- Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China.
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18
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Dou F, Liu Q, Lv S, Xu Q, Wang X, Liu S, Liu G. FN1 and TGFBI are key biomarkers of macrophage immune injury in diabetic kidney disease. Medicine (Baltimore) 2023; 102:e35794. [PMID: 37960829 PMCID: PMC10637504 DOI: 10.1097/md.0000000000035794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 10/04/2023] [Indexed: 11/15/2023] Open
Abstract
The pathogenesis of diabetic kidney disease (DKD) is complex, and the existing treatment methods cannot control disease progression well. Macrophages play an important role in the development of DKD. This study aimed to search for biomarkers involved in immune injury induced by macrophages in DKD. The GSE96804 dataset was downloaded and analyzed by the CIBERSORT algorithm to understand the differential infiltration of macrophages between DKD and normal controls. Weighted gene co-expression network analysis was used to explore the correlation between gene expression modules and macrophages in renal tissue of DKD patients. Protein-protein interaction network and machine learning algorithm were used to screen the hub genes in the key modules. Subsequently, the GSE30528 dataset was used to further validate the expression of hub genes and analyze the diagnostic effect by the receiver operating characteristic curve. The clinical data were applied to explore the prognostic significance of hub genes. CIBERSORT analysis showed that macrophages increased significantly in DKD renal tissue samples. A total of ten modules were generated by weighted gene co-expression network analysis, of which the blue module was closely associated with macrophages. The blue module mainly played an important role in biological processes such as immune response and fibrosis. Fibronectin 1 (FN1) and transforming growth factor beta induced (TGFBI) were identified as hub genes of DKD patients. Receiver operating characteristic curve analysis was performed in the test cohort: FN1 and TGFBI had larger area under the curve values (0.99 and 0.88, respectively). Clinical validation showed that 2 hub genes were negatively correlated with the estimated glomerular filtration rate in DKD patients. In addition, FN1 and TGFBI showed a strong positive correlation with macrophage alternative activation. FN1 and TGFBI are promising biomarkers for the diagnosis and treatment of DKD patients, which may participate in immune response and fibrosis induced by macrophages.
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Affiliation(s)
- Fulin Dou
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, China
| | - Qingzhen Liu
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, China
| | - Shasha Lv
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, China
| | - Qiaoying Xu
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, China
| | - Xueling Wang
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, China
| | - Shanshan Liu
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, China
| | - Gang Liu
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, China
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
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Vichare R, Crelli C, Liu L, McCallin R, Cowan A, Stratimirovic S, Herneisey M, Pollock JA, Janjic JM. Folate-conjugated near-infrared fluorescent perfluorocarbon nanoemulsions as theranostics for activated macrophage COX-2 inhibition. Sci Rep 2023; 13:15229. [PMID: 37709807 PMCID: PMC10502124 DOI: 10.1038/s41598-023-41959-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 09/04/2023] [Indexed: 09/16/2023] Open
Abstract
Activated macrophages play a critical role in the orchestration of inflammation and inflammatory pain in several chronic diseases. We present here the first perfluorocarbon nanoemulsion (PFC NE) that is designed to preferentially target activated macrophages and can deliver up to three payloads (two fluorescent dyes and a COX-2 inhibitor). Folate receptors are overexpressed on activated macrophages. Therefore, we introduced a folate-PEG-cholesterol conjugate into the formulation. The incorporation of folate conjugate did not require changes in processing parameters and did not change the droplet size or fluorescent properties of the PFC NE. The uptake of folate-conjugated PFC NE was higher in activated macrophages than in resting macrophages. Flow cytometry showed that the uptake of folate-conjugated PFC NE occurred by both phagocytosis and receptor-mediated endocytosis. Furthermore, folate-conjugated PFC NE inhibited the release of proinflammatory cytokines (TNF-α and IL-6) more effectively than nonmodified PFC NE, while drug loading and COX-2 inhibition were comparable. The PFC NEs reported here were successfully produced on multiple scales, from 25 to 200 mL, and by using two distinct processors (microfluidizers: M110S and LM20). Therefore, folate-conjugated PFC NEs are viable anti-inflammatory theranostic nanosystems for macrophage drug delivery and imaging.
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Affiliation(s)
- Riddhi Vichare
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA
| | - Caitlin Crelli
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA
| | - Lu Liu
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA
| | - Rebecca McCallin
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA
| | - Abree Cowan
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA
| | - Stefan Stratimirovic
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA
| | - Michele Herneisey
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA
| | - John A Pollock
- Department of Biological Sciences, School of Science and Engineering, Duquesne University, Pittsburgh, PA, 15282, USA
| | - Jelena M Janjic
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA.
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Li X, Liu J, Zeng M, Yang K, Zhang S, Liu Y, Yin X, Zhao C, Wang W, Xiao L. GBP2 promotes M1 macrophage polarization by activating the notch1 signaling pathway in diabetic nephropathy. Front Immunol 2023; 14:1127612. [PMID: 37622120 PMCID: PMC10445759 DOI: 10.3389/fimmu.2023.1127612] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
Background Diabetic nephropathy (DN) is one of the most common diabetic complications, which has become the primary cause of end-stage renal disease (ESRD) globally. Macrophage infiltration has been proven vital in the occurrence and development of DN. This study was designed to investigate the hub genes involved in macrophage-mediated inflammation of DN via bioinformatics analysis and experimental validation. Methods Gene microarray datasets were obtained from the Gene Expression Omnibus (GEO) public website. Integrating the CIBERSORT, weighted gene co-expression network analysis (WGCNA) and DEGs, we screened macrophage M1-associated key genes with the highest intramodular connectivity. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) regression was utilized to further mine hub genes. GSE104954 acted as an external validation to predict the expression levels and diagnostic performance of these hub genes. The Nephroseq online platform was employed to evaluate the clinical implications of these hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to elucidate the dominant biological functions and signal pathways. Finally, we conducted experiments to verify the role of GBP2 in M1 macrophage-mediated inflammatory response and the underlying mechanism of this role. Results Sixteen DEGs with the highest connectivity in M1 macrophages-associated module (paleturquoise module) were determined. Subsequently, we identified four hub genes through LASSO regression analysis, including CASP1, MS4A4A, CD53, and GBP2. Consistent with the training set, expression levels of these four hub genes manifested memorably elevated and the ROC curves indicated a good diagnostic accuracy with an area under the curve of greater than 0.8. Clinically, enhanced expression of these four hub genes predicted worse outcomes of DN patients. Given the known correlation between the first three hub genes and macrophage-mediated inflammation, experiments were performed to demonstrate the effect of GBP2, which proved that GBP2 contributed to M1 polarization of macrophages by activating the notch1 signaling pathway. Conclusion Our findings detected four hub genes, namely CASP1, MS4A4A, CD53, and GBP2, may involve in the progression of DN via pro-inflammatory M1 macrophage phenotype. GBP2 could be a promising prognostic biomarker and intervention target for DN by regulating M1 polarization.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Li Xiao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, Changsha, China
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Yan J, Li X, Liu N, He JC, Zhong Y. Relationship between Macrophages and Tissue Microenvironments in Diabetic Kidneys. Biomedicines 2023; 11:1889. [PMID: 37509528 PMCID: PMC10377233 DOI: 10.3390/biomedicines11071889] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/23/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Increasing evidence has suggested that inflammation is a key microenvironment involved in the development and progression of DN. Studies have confirmed that macrophage accumulation is closely related to the progression to human DN. Macrophage phenotype is highly regulated by the surrounding microenvironment in the diabetic kidneys. M1 and M2 macrophages represent distinct and sometimes coexisting functional phenotypes of the same population, with their roles implicated in pathological changes, such as in inflammation and fibrosis associated with the stage of DN. Recent findings from single-cell RNA sequencing of macrophages in DN further confirmed the heterogeneity and plasticity of the macrophages. In addition, intrinsic renal cells interact with macrophages directly or through changes in the tissue microenvironment. Macrophage depletion, modification of its polarization, and autophagy could be potential new therapies for DN.
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Affiliation(s)
- Jiayi Yan
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xueling Li
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ni Liu
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - John Cijiang He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yifei Zhong
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Yasuda K, Noma H, Mimura T, Nonaka R, Sasaki S, Suganuma N, Shimura M. Effects of Intravitreal Ranibizumab Injection on Peripheral Retinal Microcirculation and Cytokines in Branch Retinal Vein Occlusion with Macular Edema. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1053. [PMID: 37374257 DOI: 10.3390/medicina59061053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/26/2023] [Accepted: 05/28/2023] [Indexed: 06/29/2023]
Abstract
Background and Objectives: To investigate peripheral blood flow in retinal vessels and vessel diameters after intravitreal ranibizumab injection (IRI) and the relationship between these parameters and cytokines in branch retinal vein occlusion (BRVO) with macular edema. Materials and Methods: We assessed relative flow volume (RFV) and the width of the main and branch retinal arteries and veins in the occluded and non-occluded regions before and after IRI in 37 patients with BRVO and macular edema. Measurements were made using laser speckle flowgraphy (LSFG). When performing IRI, we obtained samples of aqueous humor and analyzed them using the suspension array method to evaluate vascular endothelial growth factor (VEGF), placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, and interferon-inducible 10-kDa protein (IP-10). Results: In both retinal regions, before and after IRI, the RFV in the main artery and vein showed a significant correlation with the summed RFV in the respective branch vessels 1 and 2. In the occluded region, the RFV in the main vein was significantly negatively correlated with MCP-1, PDGF-AA, IL-6, and IL-8; the RFV in branch vein 1 was significantly negatively correlated with PlGF, MCP-1, IL-6, and IL-8; PDGF-AA was significantly negatively correlated with the width of the main and branch veins; and the RFVs of the main artery and vein decreased significantly from before to 1 month after IRI. Conclusions: Contrary to expectations, the study found that anti-VEGF therapy does not affect RFV in arteries and veins in patients with BRVO and macular edema. Furthermore, retinal blood flow is poor in patients with high MCP-1, IL-6, and IL-8. Finally, high PDGF-AA may result in smaller venous diameters and reduced retinal blood flow.
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Affiliation(s)
- Kanako Yasuda
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan
| | - Hidetaka Noma
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan
| | - Tatsuya Mimura
- Department of Ophthalmology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8606, Japan
| | - Ryota Nonaka
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan
| | - Shotaro Sasaki
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan
| | - Noboru Suganuma
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan
| | - Masahiko Shimura
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan
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Zhou H, Mu L, Yang Z, Shi Y. Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy. Front Immunol 2023; 14:1113212. [PMID: 36969169 PMCID: PMC10030848 DOI: 10.3389/fimmu.2023.1113212] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/22/2023] [Indexed: 03/10/2023] Open
Abstract
Background The study aimed to identify core biomarkers related to diagnosis and immune microenvironment regulation and explore the immune molecular mechanism of diabetic nephropathy (DN) through bioinformatics analysis. Methods GSE30529, GSE99325, and GSE104954 were merged with removing batch effects, and different expression genes (DEGs) were screened at a criterion |log2FC| >0.5 and adjusted P <0.05. KEGG, GO, and GSEA analyses were performed. Hub genes were screened by conducting PPI networks and calculating node genes using five algorithms with CytoHubba, followed by LASSO and ROC analysis to accurately identify diagnostic biomarkers. In addition, two different GEO datasets, GSE175759 and GSE47184, and an experiment cohort with 30 controls and 40 DN patients detected by IHC, were used to validate the biomarkers. Moreover, ssGSEA was performed to analyze the immune microenvironment in DN. Wilcoxon test and LASSO regression were used to determine the core immune signatures. The correlation between biomarkers and crucial immune signatures was calculated by Spearman analysis. Finally, cMap was used to explore potential drugs treating renal tubule injury in DN patients. Results A total of 509 DEGs, including 338 upregulated and 171 downregulated genes, were screened out. "chemokine signaling pathway" and "cell adhesion molecules" were enriched in both GSEA and KEGG analysis. CCR2, CX3CR1, and SELP, especially for the combination model of the three genes, were identified as core biomarkers with high diagnostic capabilities with striking AUC, sensitivity, and specificity in both merged and validated datasets and IHC validation. Immune infiltration analysis showed a notable infiltration advantage for APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. In addition, the correlation analysis showed that CCR2, CX3CR1, and SELP were strongly and positively correlated with checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. Finally, dilazep was screened out as an underlying compound for DN analyzed by CMap. Conclusions CCR2, CX3CR1, and SELP are underlying diagnostic biomarkers for DN, especially in their combination. APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation may participate in the occurrence and development of DN. At last, dilazep may be a promising drug for treating DN.
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Affiliation(s)
- Huandi Zhou
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Kidney Disease, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lin Mu
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Kidney Disease, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Nephrology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhifen Yang
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Kidney Disease, Hebei Medical University, Shijiazhuang, Hebei, China
- Gynecology and Obstetrics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yonghong Shi
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Kidney Disease, Hebei Medical University, Shijiazhuang, Hebei, China
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Rajlic S, Treede H, Münzel T, Daiber A, Duerr GD. Early Detection Is the Best Prevention-Characterization of Oxidative Stress in Diabetes Mellitus and Its Consequences on the Cardiovascular System. Cells 2023; 12:583. [PMID: 36831253 PMCID: PMC9954643 DOI: 10.3390/cells12040583] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/05/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023] Open
Abstract
Previous studies demonstrated an important role of oxidative stress in the pathogenesis of cardiovascular disease (CVD) in diabetic patients due to hyperglycemia. CVD remains the leading cause of premature death in the western world. Therefore, diabetes mellitus-associated oxidative stress and subsequent inflammation should be recognized at the earliest possible stage to start with the appropriate treatment before the onset of the cardiovascular sequelae such as arterial hypertension or coronary artery disease (CAD). The pathophysiology comprises increased reactive oxygen and nitrogen species (RONS) production by enzymatic and non-enzymatic sources, e.g., mitochondria, an uncoupled nitric oxide synthase, xanthine oxidase, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Considering that RONS originate from different cellular mechanisms in separate cellular compartments, adequate, sensitive, and compartment-specific methods for their quantification are crucial for early detection. In this review, we provide an overview of these methods with important information for early, appropriate, and effective treatment of these patients and their cardiovascular sequelae.
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Affiliation(s)
- Sanela Rajlic
- Department of Cardiothoracic and Vascular Surgery, University of Medicine Mainz, 55131 Mainz, Germany
| | - Hendrik Treede
- Department of Cardiothoracic and Vascular Surgery, University of Medicine Mainz, 55131 Mainz, Germany
| | - Thomas Münzel
- Center for Cardiology, Department of Cardiology, Molecular Cardiology, University Medical Center, 55131 Mainz, Germany
| | - Andreas Daiber
- Center for Cardiology, Department of Cardiology, Molecular Cardiology, University Medical Center, 55131 Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
| | - Georg Daniel Duerr
- Department of Cardiothoracic and Vascular Surgery, University of Medicine Mainz, 55131 Mainz, Germany
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25
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Kushnir OY, Yaremii IM, Pantsiuk KA, Vivsyannuk VV, Tymkul DM, Vlasova KV, Vlasova OV. CARBOHYDRATES METABOLISM IN THE BLOOD OF RATS WITH IMPAIRED GLUCOSE TOLERANCE UNDER LONG TERM MELATONIN INJECTIONS. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2023; 76:1761-1767. [PMID: 37740968 DOI: 10.36740/wlek202308109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2023]
Abstract
OBJECTIVE The aim: To determine the influence of melatonin on the glucose level and content of malondialdehyde, activities of pyruvate kinase and glucose-6-phosphate dehydrogenase enzymes in the blood; histochemical features of glycogen distribution in liver of rats with impaired glucose tolerance. PATIENTS AND METHODS Materials and methods: Diabetes in rats was induced by intra-abdominal injection of a 5% solution of alloxan monohydrate at the rate of 170 mg/kg of body weight. Four days after animals were divided into rats with impaired glucose tolerance and melatonin-group with impaired glucose tolerance (5 mg/ kg «Sigma» USA, daily and intraperitoneal for 42 days starting from 5th day). Impaired glucose tolerance was determined by measurement of glucose profiles - fasting <5.6 mmol/l; postprandial (2h post-load) 7.8 - 11.0 mmol/l. Histochemical examination of the liver was performed according to the standard method of PAS-reaction staining. Statistical analysis was performed using Statistica 10 StatSoft Inc. RESULTS Results: Pyruvate kinase activity in erythrocytes and optical density of glycogen in hepatocytes of animals with impaired glucose tolerance decreased on 18% and 11%, activity of glucose-6-phosphate dehydrogenase and content of malondialdehyde increased on 35% and 23%, respectively compared with the control. We have reached the recovery of the pyruvate kinase and normalization of glucose-6-phosphate dehydrogenase activities, malondialdehyde levels, glucose profiles in the blood as well as glycogen distribution in the liver caused by melatonin injections. CONCLUSION Conclusions: We have determined that long term melatonin injections did better glucose tolerance in rats.
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Affiliation(s)
| | | | | | | | - Diana M Tymkul
- BUKOVYNIAN STATE MEDICAL UNIVERSITY, CHERNIVTSI, UKRAINE
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Banu S, Sur D. Role of Macrophage in Type 2 Diabetes Mellitus: Macrophage Polarization a New Paradigm for Treatment of Type 2 Diabetes Mellitus. Endocr Metab Immune Disord Drug Targets 2023; 23:2-11. [PMID: 35786198 DOI: 10.2174/1871530322666220630093359] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 11/22/2022]
Abstract
Metabolic diseases such as type 2 diabetes mellitus are usually associated with meta-inflammation. β-cell failure is a marked feature observed in the pathogenesis of type 2 diabetes mellitus. Type 2 diabetes mellitus (T2DM) is a heterogeneous situation that is accompanied by not only defective insulin secretion but also peripheral insulin resistance. β-cells are the primary organ for insulin secretion; hence, it is crucial to maintain a significant β-cell mass in response to a variety of changes. Insulin resistance is a chief cause of T2DM, leading to increased free fatty acid (FFA) levels, which in turn elevates β-cell mass and insulin secretion as compensation for insulin insensitivity. It has recently been established that amplified numbers of innate immune cells, cytokines, and chemokines result in detrimental effects on islets in chronic conditions. Macrophage migration inhibitory factor (MIF) is the lymphokine that prevents arbitrary migration of macrophages and assembles macrophages at inflammatory loci. Inflammation is known to trigger monocytes to differentiate into macrophages. Progress of complications associated with type 2 diabetes mellitus, as indicated through recent findings, is also dependent on the buildup of macrophages in tissues vulnerable to diabetic injury. The present article scientifically evaluates the present knowledge concerning the mechanisms of monocyte and macrophage-mediated injury recruitment in complications associated with type 2 diabetes mellitus. It also describes some of the established and experimental therapies that might bring about a reduction in these inflammatory complications. Recent discoveries in the field of drug delivery have facilitated phenotype-specific targeting of macrophages. This review highlights the pathophysiology of type 2 diabetes mellitus, how macrophage induces type 2 diabetes mellitus and potential therapeutics for type 2 diabetes mellitus via macrophage-specific delivery.
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Affiliation(s)
- Sarmin Banu
- Division of Pharmacology, Guru Nanak College of Pharmaceutical Science and Technology, 157/F Nilgunaj Road, Panihati, Kolkata 700114, India
| | - Debjeet Sur
- Division of Pharmacology, Guru Nanak College of Pharmaceutical Science and Technology, 157/F Nilgunaj Road, Panihati, Kolkata 700114, India
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Yuniartha R, Arfian N, Setyaningsih WAW, Kencana SMS, Sari DCR, Sari DCR, Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia, Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia, Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia, Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Accelerated Senescence and Apoptosis in the Rat Liver during the Progression of Diabetic Complications. Malays J Med Sci 2022; 29:46-59. [PMID: 36818894 PMCID: PMC9910368 DOI: 10.21315/mjms2022.29.6.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/25/2022] [Indexed: 12/25/2022] Open
Abstract
Background Chronic hyperglycaemia of diabetes causes long-term damage and impaired function of multiple organs. However, the pathological changes in the liver following long-term diabetes remain unclear. This study aimed to determine the pathological complications of long-term diabetes in the rat liver. Methods Intraperitoneal injection of streptozotocin (STZ) was used to induce diabetes in rats at a single dose (60 mg/kg body weight [BW]). Rats were euthanised at 1 month (DM1 group), 2 months (DM2 group) and 4 months (DM4 group) following diabetes induction with six rats in each group. Immunohistochemistry was performed against SOD1, CD68, p53 and p16 antibodies. Messenger RNA (mRNA) expressions of SOD1, SOD2, GPx, CD68, p53, p21 and caspase-3 genes were measured by reverse transcription-polymerase chain reaction. Results Hepatic p53 mRNA expression was significantly higher in DM1, DM2 and DM4 groups compared to the control group. The p21 and caspase-3 mRNA expressions were significantly upregulated in the DM2 and DM4 groups. The p16-positive cells were obviously increased, particularly in the DM4 group. Bivariate correlation analysis showed mRNA expressions of p21 and caspase-3 genes were positively correlated with the p53 gene. Conclusion Diabetic rats exhibited increased apoptosis and senescence in the liver following a longer period of hyperglycaemia.
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Sutradhar S, Deb A, Singh SS. Protective efficacy of melatonin and insulin against LPS caused toxicity in diabetic mice. Immunopharmacol Immunotoxicol 2022; 44:902-914. [PMID: 35736957 DOI: 10.1080/08923973.2022.2093739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Context: Deregulated glucose homeostasis leads to a life-threatening metabolic disorder known as diabetes. The insulin deficiency and hyperglycaemic condition related to diabetes cause dysregulation of the immune system.Objective: This study evaluated the combined efficacy of melatonin and insulin in attenuation of lipopolysaccharide (LPS) caused inflammation, macrophage functional impairment, and oxidative stress in the spleen of diabetic mice.Materials and Methods: Multiple low doses of streptozotocin (50mg/kg B. wt.) were administered intraperitoneally to induce diabetes. Diabetes mice were divided into two sets. Set-1 contained control, diabetes, diabetes insulin (2IU/100g B.wt.) treated, diabetes melatonin (100µg/100g. B.wt.) treated, and diabetes melatonin and insulin treated groups of mice. In set II, the same number of groups as those of set I were given a single dose of LPS (50µg/mice) 24 hours before euthanization.Results and Discussion: LPS caused a significant increase in oxidative stress, circulatory proinflammatory cytokines, significant suppression of antioxidant defense system, and phagocytic index in diabetic mice. Melatonin and insulin significantly improved the adverse effects caused by LPS treatment in diabetic mice. The present study noted that combined treatment of melatonin and insulin was more effective in attenuating LPS-induced devastating effects in laboratory mice.Conclusions: The present study may suggest a combinatorial approach in the therapeutic use of melatonin and insulin to improve such devastating conditions.
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Affiliation(s)
- Sangita Sutradhar
- Molecular Endocrine Research Lab., Department of Zoology, Tripura University, Suryamaninagar, India
| | - Anindita Deb
- Molecular Endocrine Research Lab., Department of Zoology, Tripura University, Suryamaninagar, India
| | - Shiv Shankar Singh
- Molecular Endocrine Research Lab., Department of Zoology, Tripura University, Suryamaninagar, India
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Shen Y, Zhang Y, Zhou Z, Wang J, Han D, Sun J, Chen G, Tang Q, Sun W, Chen L. Dysfunction of macrophages leads to diabetic bone regeneration deficiency. Front Immunol 2022; 13:990457. [PMID: 36311779 PMCID: PMC9613949 DOI: 10.3389/fimmu.2022.990457] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 10/03/2022] [Indexed: 11/22/2022] Open
Abstract
Insufficient bone matrix formation caused by diabetic chronic inflammation can result in bone nonunion, which is perceived as a worldwide epidemic, with a substantial socioeconomic and public health burden. Macrophages in microenvironment orchestrate the inflammation and launch the process of bone remodeling and repair, but aberrant activation of macrophages can drive drastic inflammatory responses during diabetic bone regeneration. In diabetes mellitus, the proliferation of resident macrophages in bone microenvironment is limited, while enhanced myeloid differentiation of hematopoietic stem cells (HSCs) leads to increased and constant monocyte recruitment and thus macrophages shift toward the classic pro-inflammatory phenotype, which leads to the deficiency of bone regeneration. In this review, we systematically summarized the anomalous origin of macrophages under diabetic conditions. Moreover, we evaluated the deficit of pro-regeneration macrophages in the diabetic inflammatory microenvironment. Finally, we further discussed the latest developments on strategies based on targeting macrophages to promote diabetic bone regeneration. Briefly, this review aimed to provide a basis for modulating the biological functions of macrophages to accelerate bone regeneration and rescue diabetic fracture healing in the future.
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Affiliation(s)
- Yufeng Shen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
| | - Yifan Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
| | - Zheng Zhou
- Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
| | - Jinyu Wang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
| | - Dong Han
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
| | - Jiwei Sun
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
| | - Guangjin Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
| | - Wei Sun
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
- *Correspondence: Lili Chen, ; Wei Sun,
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillary Development and Regeneration, Wuhan, China
- *Correspondence: Lili Chen, ; Wei Sun,
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Msheik Z, El Massry M, Rovini A, Billet F, Desmoulière A. The macrophage: a key player in the pathophysiology of peripheral neuropathies. J Neuroinflammation 2022; 19:97. [PMID: 35429971 PMCID: PMC9013246 DOI: 10.1186/s12974-022-02454-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 03/29/2022] [Indexed: 12/22/2022] Open
Abstract
Macrophages are present in all mammalian tissues and coexist with various cell types in order to respond to different environmental cues. However, the role of these cells has been underestimated in the context of peripheral nerve damage. More importantly, macrophages display divergent characteristics, associated with their origin, and in response to the modulatory effects of their microenvironment. Interestingly, the advent of new techniques such as fate mapping and single-cell transcriptomics and their synergistic use has helped characterize in detail the origin and fate of tissue-resident macrophages in the peripheral nervous system (PNS). Furthermore, these techniques have allowed a better understanding of their functions from simple homeostatic supervisors to chief regulators in peripheral neuropathies. In this review, we summarize the latest knowledge about macrophage ontogeny, function and tissue identity, with a particular focus on PNS-associated cells, as well as their interaction with reactive oxygen species under physiological and pathological conditions. We then revisit the process of Wallerian degeneration, describing the events accompanying axon degeneration, Schwann cell activation and most importantly, macrophage recruitment to the site of injury. Finally, we review these processes in light of internal and external insults to peripheral nerves leading to peripheral neuropathies, the involvement of macrophages and the potential benefit of the targeting of specific macrophages for the alleviation of functional defects in the PNS.
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Ito S, Nakashima M, Ishikiriyama T, Nakashima H, Yamagata A, Imakiire T, Kinoshita M, Seki S, Kumagai H, Oshima N. Effects of L-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy. Kidney Blood Press Res 2022; 47:277-290. [PMID: 35104825 DOI: 10.1159/000522013] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 01/13/2022] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION In diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs), and triggers their activation. METHODS We orally administered L-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of L-carnitine on kidney mitochondrial reactive oxygen species (mtROS) production, circulating mtDNA content, and kidney CD11bhigh/CD11blow Mφ functions. RESULTS In db/db mice, mtROS production increased in proximal tubular cells and kidney CD11blow Mφs; both Mφ types showed enhanced TLR9 expression. L-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11blow Mφs (p < 0.01), with improved SOD2 expression in the kidney (p < 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (p < 0.01), thereby lowering tumor necrosis factor-α production in CD11bhigh Mφs (p < 0.05) and ROS production by CD11blow Mφs (p < 0.01). Collectively, these changes alleviated DN symptoms. CONCLUSION The positive effects of L-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.
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Affiliation(s)
- Seigo Ito
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Masahiro Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Takuya Ishikiriyama
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Akira Yamagata
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Toshihiko Imakiire
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Shuhji Seki
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Hiroo Kumagai
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Naoki Oshima
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
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Kulkarni A, Anderson CM, Mirmira RG, Tersey SA. Role of Polyamines and Hypusine in β Cells and Diabetes Pathogenesis. Metabolites 2022; 12:344. [PMID: 35448531 PMCID: PMC9028953 DOI: 10.3390/metabo12040344] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
The polyamines-putrescine, spermidine, and spermine-are polycationic, low molecular weight amines with cellular functions primarily related to mRNA translation and cell proliferation. Polyamines partly exert their effects via the hypusine pathway, wherein the polyamine spermidine provides the aminobutyl moiety to allow posttranslational modification of the translation factor eIF5A with the rare amino acid hypusine (hydroxy putrescine lysine). The "hypusinated" eIF5A (eIF5Ahyp) is considered to be the active form of the translation factor necessary for the translation of mRNAs associated with stress and inflammation. Recently, it has been demonstrated that activity of the polyamines-hypusine circuit in insulin-producing islet β cells contributes to diabetes pathogenesis under conditions of inflammation. Elevated levels of polyamines are reported in both exocrine and endocrine cells of the pancreas, which may contribute to endoplasmic reticulum stress, oxidative stress, inflammatory response, and autophagy. In this review, we have summarized the existing research on polyamine-hypusine metabolism in the context of β-cell function and diabetes pathogenesis.
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Affiliation(s)
| | | | | | - Sarah A. Tersey
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; (A.K.); (C.M.A.); (R.G.M.)
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Strath LJ, Sorge RE. Racial Differences in Pain, Nutrition, and Oxidative Stress. Pain Ther 2022; 11:37-56. [PMID: 35106711 PMCID: PMC8861224 DOI: 10.1007/s40122-022-00359-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/21/2022] [Indexed: 12/12/2022] Open
Abstract
Investigating the disproportionate rates of chronic pain and their related comorbidities between Black and non-Hispanic White (White) individuals is a growing area of interest, both in the healthcare community and in general society. Researchers have identified racial differences in chronic pain prevalence and severity, but still very little is known about the mechanisms underlying them. Current explanations for these differences have primarily focused on socioeconomic status and unequal healthcare between races as causal factors. Whereas these factors are informative, a racial gap still exists between Black and White individuals when these factors are controlled for. One potential cause of this racial gap in chronic pain is the differences in nutrition and dietary intake between groups. Certain foods play a key role in the inflammatory and oxidative stress pathways in the human body and could potentially influence the severity of the pain experience. Here, we review the previous literature on the surrounding topics and propose a potential mechanism to explain racial differences in the chronic pain population, based on established racial differences in diet and oxidative stress.
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Affiliation(s)
- Larissa J Strath
- Department of Psychology, The University of Alabama at Birmingham, 1300 University Blvd, Birmingham, AL, 35294, USA
| | - Robert E Sorge
- Department of Psychology, The University of Alabama at Birmingham, 1300 University Blvd, Birmingham, AL, 35294, USA.
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34
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Agrafioti P, Morin-Baxter J, Tanagala KKK, Dubey S, Sims P, Lalla E, Momen-Heravi F. Decoding the role of macrophages in periodontitis and type 2 diabetes using single-cell RNA-sequencing. FASEB J 2022; 36:e22136. [PMID: 35032412 PMCID: PMC8881186 DOI: 10.1096/fj.202101198r] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/14/2021] [Accepted: 12/17/2021] [Indexed: 02/03/2023]
Abstract
Macrophages are resident myeloid cells in the gingival tissue which control homeostasis and play a pivotal role in orchestrating the immune response in periodontitis. Cell heterogeneity and functional phenotypes of macrophage subpopulations in periodontitis remain elusive. Here, we isolated gingival tissue from periodontitis-affected and healthy sites of patients with and without type 2 diabetes mellitus (T2DM). We then used single-cell RNA-sequencing (scRNA-seq) to define the heterogeneity of tissue-resident macrophages in gingival tissue in health vs. periodontitis. scRNA-seq demonstrated an unforeseen gene expression heterogeneity among macrophages in periodontitis and showed transcriptional and signaling heterogeneity of identified subsets in an independent cohort of patients with periodontitis and T2DM. Our bioinformatic inferences indicated divergent expression profiles in macrophages driven by transcriptional regulators CIITA, RELA, RFX5, and RUNX2. Macrophages in periodontitis expressed both pro-inflammatory and anti-inflammatory markers and their polarization was not mutually exclusive. The majority of macrophages in periodontitis expressed the monocyte lineage marker CD14, indicating their bone marrow lineage. We also found high expression and activation of RELA, a subunit of the NF-κB transcription factor complex, in gingival macrophages of periodontitis patients with T2DM. Our data suggested that heterogeneity and hyperinflammatory activation of macrophages may be relevant to the pathogenesis and outcomes of periodontitis, and may be further augmented in patients with T2DM.
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Affiliation(s)
- Panagiota Agrafioti
- Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA,Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA
| | - Joshua Morin-Baxter
- Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA,Fu Foundation School of Engineering and Applied Science, Columbia University, New York, New York, USA
| | - Kranthi K. K. Tanagala
- Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA,Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA
| | - Sunil Dubey
- Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA,Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA
| | - Peter Sims
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA,Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, New York, USA
| | - Evanthia Lalla
- Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA
| | - Fatemeh Momen-Heravi
- Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA,Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA,Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA
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Balogh M, Janjic JM, Shepherd AJ. Targeting Neuroimmune Interactions in Diabetic Neuropathy with Nanomedicine. Antioxid Redox Signal 2022; 36:122-143. [PMID: 34416821 PMCID: PMC8823248 DOI: 10.1089/ars.2021.0123] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 01/03/2023]
Abstract
Significance: Diabetes is a major source of neuropathy and neuropathic pain that is set to continue growing in prevalence. Diabetic peripheral neuropathy (DPN) and pain associated with diabetes are not adequately managed by current treatment regimens. Perhaps the greatest difficulty in treating DPN is the complex pathophysiology, which involves aspects of metabolic disruption and neurotrophic deficits, along with neuroimmune interactions. There is, therefore, an urgent need to pursue novel therapeutic options targeting the key cellular and molecular players. Recent Advances: To that end, cellular targeting becomes an increasingly compelling drug delivery option as our knowledge of neuroimmune interactions continues to mount. These nanomedicine-based approaches afford a potentially unparalleled specificity and longevity of drug targeting, using novel or established compounds, all while minimizing off-target effects. Critical Issues: The DPN therapeutics directly targeted at the nervous system make up the bulk of currently available treatment options. However, there are significant opportunities based on the targeting of non-neuronal cells and neuroimmune interactions in DPN. Future Directions: Nanomedicine-based agents represent an exciting opportunity for the treatment of DPN with the goals of improving the efficacy and safety profile of analgesia, as well as restoring peripheral neuroregenerative capacity. Antioxid. Redox Signal. 36, 122-143.
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Affiliation(s)
- Mihály Balogh
- Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jelena M. Janjic
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, USA
| | - Andrew J. Shepherd
- Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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36
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Rojas A, Lindner C, Schneider I, Gonzàlez I, Araya H, Morales E, Gómez M, Urdaneta N, Araya P, Morales MA. Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer. World J Gastrointest Oncol 2021; 13:1997-2012. [PMID: 35070037 PMCID: PMC8713306 DOI: 10.4251/wjgo.v13.i12.1997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/10/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Iván Schneider
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Hernan Araya
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Erik Morales
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Anatomía Patologica, Hospital Regional de Talca, Talca 34600000, Chile
| | - Milibeth Gómez
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Nelson Urdaneta
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Paulina Araya
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Miguel Angel Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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Ito S, Nakashima H, Ishikiriyama T, Nakashima M, Yamagata A, Imakiire T, Kinoshita M, Seki S, Kumagai H, Oshima N. Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy. Am J Physiol Renal Physiol 2021; 321:F757-F770. [PMID: 34719947 DOI: 10.1152/ajprenal.00191.2021] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 10/19/2021] [Indexed: 12/24/2022] Open
Abstract
The pathogenesis of diabetic nephropathy (DN) is related to macrophage (Mφ) recruitment to the kidneys, tumor necrosis factor-α (TNF-α) production, and oxidative stress. Toll-like receptor 9 (TLR9) activation is reportedly involved in systemic inflammation, and it exacerbates this condition in metabolic syndrome. Therefore, we hypothesized that TLR9 plays a role in the pathogenesis of DN. Two subsets of kidney Mφs in DN model (db/db) mice were analyzed using flow cytometry to evaluate their distribution and TLR9 expression and function. Mice were administered the CCR2 antagonist INCB3344 for 8 wk; changes in Mφ distribution and function and its therapeutic effects on DN pathology were examined. Bone marrow-derived CD11bhigh (BM-Mφ) and tissue-resident CD11blow Mφs (Res-Mφ) were identified in the mouse kidneys. As DN progressed, the BM-Mφ number, TLR9 expression, and TNF-α production increased significantly. In Res-Mφs, reactive oxygen species (ROS) production and phagocytic activity were enhanced. INCB3344 decreased albuminuria, serum creatinine level, BM-Mφ abundance, TLR9 expression, and TNF-α production by BM-Mφs and ROS production by Res-Mφs. Both increased activation of BM-Mφ via TLR9 and TNF-α production and increased ROS production by Res-Mφs were involved in DN progression. Thus, inactivating Mφs and their TLR9 expression by INCB3344 is a potential therapeutic strategy for DN.NEW & NOTEWORTHY We classified kidney macrophages (Mφs) into bone marrow-derived Mφs (BM-Mφs) expressing high CD11b and tissue-specific resident Mφ (Res-Mφs) expressing low CD11b. In diabetic nephropathy (DN) model mice, Toll-like receptor 9 (TLR9) expression and TNF-α production via TLR9 activation in BM-Mφs and ROS production in Res-Mφs were enhanced. Furthermore, CCR2 antagonist suppressed the kidney infiltration of BM-Mφs and their function and the ROS production by Res-Mφs, with concomitant TLR9 suppression. Our study presents a new therapeutic strategy for DN.
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Affiliation(s)
- Seigo Ito
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Takuya Ishikiriyama
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Masahiro Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Akira Yamagata
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Toshihiko Imakiire
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Shuhji Seki
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | - Hiroo Kumagai
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Naoki Oshima
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Japan
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There Is Strength in Numbers: Quantitation of Fc Gamma Receptors on Murine Tissue-Resident Macrophages. Int J Mol Sci 2021; 22:ijms222212172. [PMID: 34830050 PMCID: PMC8620503 DOI: 10.3390/ijms222212172] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/29/2021] [Accepted: 11/03/2021] [Indexed: 11/17/2022] Open
Abstract
Many of the effector functions of antibodies rely on the binding of antibodies/immune complexes to cellular Fcγ receptors (FcγRs). Since the majority of innate immune effector cells express both activating and inhibitory Fc receptors, the outcome of the binding of immune complexes to cells of a given population is influenced by the relative affinities of the respective IgG subclasses to these receptors, as well as by the numbers of activating and inhibitory FcγRs on the cell surface. A group of immune cells that has come into focus more recently is the various subsets of tissue-resident macrophages. The central functions of FcγRs on tissue macrophages include the clearance of opsonized pathogens, the removal of small immune complexes from the circulation and the depletion of antibody-opsonized cells in the therapy of autoimmunity and cancer. Despite these essential functions of FcγRs on tissue-resident macrophages, an in-depth quantification of FcγRs is lacking. Thus, the aim of our current study was to quantify the various Fcγ receptors on macrophages in murine liver, lung, kidney, brain, skin and spleen. Our study identified a pronounced heterogeneity between FcγR expression patterns of the different tissue macrophages, which may reflect their specialized functions within their unique niches in different organ environments.
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Malladi N, Johny E, Uppulapu SK, Tiwari V, Alam MJ, Adela R, Banerjee SK. Understanding the Activation of Platelets in Diabetes and Its Modulation by Allyl Methyl Sulfide, an Active Metabolite of Garlic. J Diabetes Res 2021; 2021:6404438. [PMID: 35127948 PMCID: PMC8808240 DOI: 10.1155/2021/6404438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/22/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a chronic metabolic disorder associated with higher risk of having cardiovascular disease. Platelets play a promising role in the pathogenesis of cardiovascular complications in diabetes. Since last several decades, garlic and its bioactive components are extensively studied in diabetes and its complications. Our aim was to explore the antiplatelet property of allyl methyl sulfide (AMS) focusing on ameliorating platelet activation in diabetes. METHOD We used streptozotocin- (STZ-) induced diabetic rats as model for type 1 diabetes. We have evaluated the effect of allyl methyl sulfide on platelet activation by administrating AMS to diabetic rats for 10 weeks. Flow cytometry-based analysis was used to evaluate the platelet activation, platelet aggregation, platelet macrophage interaction, and endogenous ROS generation in the platelets obtained from control, diabetes, and AMS- and aspirin-treated diabetic rats. RESULTS AMS treatment for 10 weeks effectively reduced the blood glucose levels in diabetic rats. Three weeks of AMS (50 mg/kg/day) treatment did not reduce the activation of platelets but a significant (p < 0.05) decrease was observed after 10 weeks of treatment. Oral administration of AMS significantly (p < 0.05) reduced the baseline and also reduced ADP-induced aggregation of platelets after 3 and 10 weeks of treatment. Furthermore, 10 weeks of AMS treatment in diabetic rats attenuated the endogenous ROS content (p < 0.05) of platelets and platelet macrophage interactions. The inhibition of platelet activation in diabetic rats after AMS treatment was comparable with aspirin treatment (30 mg/kg/day). CONCLUSION We observed an inhibitory effect of allyl methyl sulfide on platelet aggregation, platelet activation, platelet macrophage interaction, and increased ROS levels in type 1 diabetes. Our data suggests that AMS can be useful to control cardiovascular complication in diabetes via inhibition of platelet activation.
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Affiliation(s)
- Navya Malladi
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati, 781101 Assam, India
| | - Ebin Johny
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Guwahati, 781101 Assam, India
| | - Shravan K. Uppulapu
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati, 781101 Assam, India
| | - Vikas Tiwari
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati, 781101 Assam, India
| | - Md Jahangir Alam
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati, 781101 Assam, India
| | - Ramu Adela
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Guwahati, 781101 Assam, India
| | - Sanjay K. Banerjee
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati, 781101 Assam, India
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Eliezer M, Sculean A, Miron RJ, Nemcovsky C, Bosshardt DD, Fujioka-Kobayashi M, Weinreb M, Moses O. Cross-linked hyaluronic acid slows down collagen membrane resorption in diabetic rats through reducing the number of macrophages. Clin Oral Investig 2021; 26:2401-2411. [PMID: 34608575 DOI: 10.1007/s00784-021-04206-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/26/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVES We previously showed that accelerated degradation of collagen membranes (CMs) in diabetic rats is associated with increased infiltration of macrophages and blood vessels. Since pre-implantation immersion of CMs in cross-linked high molecular weight hyaluronic acid (CLHA) delays membrane degradation, we evaluated here its effect on the number of macrophages and endothelial cells (ECs) within the CM as a possible mechanism for inhibition of CM resorption. MATERIALS AND METHODS Diabetes was induced with streptozotocin in 16 rats, while 16 healthy rats served as control. CM discs were labeled with biotin, soaked in CLHA or PBS, and implanted under the scalp. Fourteen days later, CMs were embedded in paraffin and the number of macrophages and ECs within the CMs was determined using antibodies against CD68 and transglutaminase II, respectively. RESULTS Diabetes increased the number of macrophages and ECs within the CMs (∼2.5-fold and fourfold, respectively). Immersion of CMs in CLHA statistically significantly reduced the number of macrophages (p < 0.0001) in diabetic rats, but not that of ECs. In the healthy group, CLHA had no significant effect on the number of either cells. Higher residual collagen area and membrane thickness in CLHA-treated CMs in diabetic animals were significantly correlated with reduced number of macrophages but not ECs. CONCLUSIONS Immersion of CM in CLHA inhibits macrophage infiltration and reduces CM degradation in diabetic animals. CLINICAL RELEVANCE The combination of CLHA and CM may represent a valuable approach when guided tissue regeneration or guided bone regeneration procedures are performed in diabetic patients.
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Affiliation(s)
- Meizi Eliezer
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Anton Sculean
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Richard J Miron
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Carlos Nemcovsky
- Department of Periodontology and Dental Implantology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dieter D Bosshardt
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland.,Robert K. Schenk Laboratory of Oral Histology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Masako Fujioka-Kobayashi
- Department of Cranio-Maxillofacial Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Miron Weinreb
- Department of Oral Biology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ofer Moses
- Department of Periodontology and Dental Implantology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.
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Zhang D, Wu Y, Li Z, Chen H, Huang S, Jian C, Yu A. MiR-144-5p, an exosomal miRNA from bone marrow-derived macrophage in type 2 diabetes, impairs bone fracture healing via targeting Smad1. J Nanobiotechnology 2021; 19:226. [PMID: 34340698 PMCID: PMC8327443 DOI: 10.1186/s12951-021-00964-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/13/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Patients with diabetes have an increased risk of nonunion and delayed union of fractures. Macrophages have been shown as a key player in diabetic complications. However, it remains obscure how diabetic milieu affects macrophage-derived exosomes and its implications on osteogenic differentiation of BMSCs. In this study, we aim to define the impact of diabetic milieu on macrophage-derived exosomes, role of extracellular vesicles in intercellular communication with BMSCs, and subsequent effects on osteogenic differentiation and fracture repair. RESULTS The osteogenic potential and the ability of fracture repair of exosomes derived from diabetic bone marrow-derived macrophages (dBMDM-exos) were revealed to be lower, as compared with non-diabetic bone marrow-derived macrophages (nBMDM-exos) in vitro and in vivo. Interestingly, miR-144-5p levels were sharply elevated in dBMDM-exos and it could be transferred into BMSCs to regulate bone regeneration by targeting Smad1. In addition, the adverse effects of dBMDM-exos on the osteogenic potential and the ability of fracture repair were reversed through the suppression of miR-144-5p inhibition in vitro and vivo. CONCLUSIONS The results demonstrated an important role of exosomal miR-144-5p in bone regeneration, offering insight into developing new strategy for the improvement of fracture healing in patients with diabetes mellitus.
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Affiliation(s)
- Dong Zhang
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, China
| | - Yifan Wu
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, China
| | - Zonghuan Li
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, China
| | - Hairen Chen
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, China
| | - Siyuan Huang
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, China
| | - Chao Jian
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, China.
| | - Aixi Yu
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, China.
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Glucose regulates expression of pro-inflammatory genes, IL-1β and IL-12, through a mechanism involving hexosamine biosynthesis pathway-dependent regulation of α-E catenin. Biosci Rep 2021; 41:229052. [PMID: 34139004 PMCID: PMC8243339 DOI: 10.1042/bsr20211066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 01/09/2023] Open
Abstract
High glucose levels are associated with changes in macrophage polarisation and evidence indicates that the sustained or even short-term high glucose levels modulate inflammatory responses in macrophages. However, the mechanism by which macrophages can sense the changes in glucose levels are not clearly understood. We find that high glucose levels rapidly increase the α-E catenin protein level in RAW264.7 macrophages. We also find an attenuation of glucose-induced increase in α-E catenin when hexosamine biosynthesis (HB) pathway is inhibited either with glutamine depletion or with the drugs azaserine and tunicamycin. This indicates the involvement of HB pathway in this process. Then, we investigated the potential role of α-E catenin in glucose-induced macrophage polarisation. We find that the reduction in α-E catenin level using siRNA attenuates the glucose-induced changes of both IL-1β and IL-12 mRNA levels under LPS-stimulated condition but does not affect TNF-α expression. Together this indicates that α-E catenin can sense the changes in glucose levels in macrophages via HB pathway and also can modulate the glucose-induced gene expression of inflammatory markers such as IL-1β and IL-12. This identifies a new part of the mechanism by which macrophages are able to respond to changes in glucose levels.
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Chang J, Yan J, Li X, Liu N, Zheng R, Zhong Y. Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease. Front Med (Lausanne) 2021; 8:661076. [PMID: 33859992 PMCID: PMC8042139 DOI: 10.3389/fmed.2021.661076] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.
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Affiliation(s)
- Jingsheng Chang
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiayi Yan
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xueling Li
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ni Liu
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Zheng
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Zhong
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34 + Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction. Int J Mol Sci 2021; 22:ijms22031423. [PMID: 33572602 PMCID: PMC7866997 DOI: 10.3390/ijms22031423] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/24/2021] [Accepted: 01/28/2021] [Indexed: 01/01/2023] Open
Abstract
Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of BM-derived CD34+ stem cells purified from sternal biopsies of patients undergoing coronary bypass surgery with or without DM (CAD and CAD-DM patients) was sequenced. The results evidenced 10566 expressed genes whose 79% were protein-coding genes, and 21% non-coding RNA. We identified 139 differentially expressed genes (p-value < 0.05 and |log2 FC| > 0.5) between the two comparing groups of CAD and CAD-DM patients. Gene Set Enrichment Analysis (GSEA), based on Gene Ontology biological processes (GO-BP) terms, led to the identification of fourteen overrepresented biological categories in CAD-DM samples. Most of the biological processes were related to lymphocyte activation, chemotaxis, peptidase activity, and innate immune response. Specifically, HSPCs from CAD-DM patients displayed reduced expression of genes coding for proteins regulating antibacterial and antivirus host defense as well as macrophage differentiation and lymphocyte emigration, proliferation, and differentiation. However, within the same biological processes, a consistent number of inflammatory genes coding for chemokines and cytokines were up-regulated. Our findings suggest that DM induces transcriptional alterations in HSPCs, which are potentially responsible of progeny dysfunction.
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Xu J, Shi X, Pan Y. The Association of Aspartate Aminotransferase/Alanine Aminotransferase Ratio with Diabetic Nephropathy in Patients with Type 2 Diabetes. Diabetes Metab Syndr Obes 2021; 14:3831-3837. [PMID: 34522109 PMCID: PMC8434854 DOI: 10.2147/dmso.s330741] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 08/27/2021] [Indexed: 12/15/2022] Open
Abstract
PURPOSE To investigate the relationship between aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT) and diabetic nephropathy (DN). PATIENTS AND METHODS A total of 402 patients with type 2 diabetes mellitus were divided into three groups, such as normoalbuminuria (n = 196), microalbuminuria (n = 131) and macroalbuminuria (n = 75) groups. Basic information and laboratory results were collected. Serum AST/ALT, tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-4, IL-6, IL-10 and interferon- γ (INF- γ) were also measured. DN was defined as microalbuminuria or macroalbuminuria. The estimated glomerular filtration rate (eGFR) was calculated using the following formula: 186 × (serum creatinine)-1.154× (age)-0.203× (0.742 if female). RESULTS The AST/ALT in the macroalbuminuria group was higher than in the microalbuminuria and normoalbuminuria groups. The concentrations of tumor necrosis factor-α (TNF-α), IL-2, IL-4, IL-10 and INF-γ in the macroalbuminuria group were significantly higher than those in the two other groups. Multivariate logistical analysis showed that after adjusting confounding factors, TNF-α and high AST/ALT were independent risks for DN and macroalbuminuria. Furthermore, the AST/ALT had significantly positive correlation with TNF-α (r = 0.101, P = 0.048), IL-4 (r = 0.185, P = 0.005) and IL-6 (r = 0.274, P < 0.001) levels. CONCLUSION This study showed that high AST/ALT was an independent risk factor for the DN. Additionally, AST/ALT was positively correlated with inflammation cytokines, such as TNF-α, IL-4 and IL-6 levels.
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Affiliation(s)
- Jing Xu
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Xiaomin Shi
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Youjin Pan
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
- Correspondence: Youjin Pan Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Lucheng District, Wenzhou, Zhejiang Province, People’s Republic of ChinaTel +86 15068256508Fax +86 577-85678813 Email
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Retinal Microcirculation and Cytokines as Predictors for Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Branch Retinal Vein Occlusion. J Clin Med 2020; 10:jcm10010058. [PMID: 33375281 PMCID: PMC7796037 DOI: 10.3390/jcm10010058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/22/2020] [Accepted: 12/22/2020] [Indexed: 11/16/2022] Open
Abstract
Purpose: To investigate the relationship between retinal blood flow, presence or absence of recurrence of macular edema, and levels of cytokines, after intravitreal ranibizumab injection (IRI) in patients with branch retinal vein occlusion (BRVO). Methods: In 47 patients with BRVO and macular edema, we used laser speckle flowgraphy (LSFG) to measure the relative flow volume (RFV) of the retinal arteries and veins passing through the optic disc in the occluded and non-occluded regions of the retina before and after IRI. Aqueous humor samples were obtained at the time of IRI. Levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, IL-12 (p70), IL-13 and interferon-inducible 10-kDa protein (IP-10) were measured by the suspension array method. Patients were categorized into two groups on the basis of whether or not macular edema recurred at 2 months after IRI: the nonrecurrent group, n = 24; and the recurrent group, n = 23. Results: In the veins of the occluded region, RFV showed a significant difference between baseline and 1 month after IRI (p < 0.001) in the recurrent group and the percent change of RFV showed a significant difference between the recurrent and nonrecurrent groups (p = 0.005). Furthermore, we found a significant negative correlation between RFV in the veins of the occluded region and aqueous levels of MCP-1, IL-8 and IP-10 at baseline (p = 0.029, p = 0.035, and p = 0.039, respectively). In the recurrent group, the arteries and veins of the non-occluded and occluded regions showed no significant association between RFV and the aqueous levels of any factors. Conclusions: These findings suggested that a decrease in RFV in the veins of the occluded region might be associated with the recurrence of macular edema and that the recurrence might depend on the change in RFV in the veins of the occluded region rather than the levels of cytokines.
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Mizui T, Noma H, Yasuda K, Kanemaki T, Goto H, Shimura M. Intravitreal ranibizumab reduced ocular blood flow and aqueous cytokine levels and improved retinal morphology in patients with diabetic macular edema. Sci Rep 2020; 10:21713. [PMID: 33303870 PMCID: PMC7728747 DOI: 10.1038/s41598-020-78792-3] [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: 06/20/2020] [Accepted: 11/23/2020] [Indexed: 11/30/2022] Open
Abstract
We investigated the relationship between aqueous cytokine levels, changes in ocular blood flow, and morphological and functional improvements after intravitreal ranibizumab injection (IRI) in treatment-naïve eyes with center-involving diabetic macular edema (DME). Thirty-three eligible patients with DME (33 eyes) were recruited. At the first IRI, we collected a sample of aqueous humor from each eye and measured levels of the cytokines/chemokines. Mean blur rate (MBR) was used to evaluate retinal and choroidal flow by laser speckle flowgraphy at the time of the first IRI and 1 month later. One month after IRI, both retinal and choroidal MBR had significantly decreased from baseline. The reduction ratio of the retinal MBR was significantly correlated with aqueous levels of monocyte chemotactic protein (MCP)-1 and interleukin-8, and with reduction of central macular thickness, but not with improvement of best corrected visual acuity. The reduction ratio of choroidal MBR showed no statistical correlation with any cytokine levels or changes in clinical parameters. We conclude that IRI reduces both retinal and choroidal blood flow in treatment-naïve DME. Reduction of retinal blood flow correlated with regression of morphological pathology, which is regulated by the initial aqueous levels of some cytokines.
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Affiliation(s)
- Toru Mizui
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan
| | - Hidetaka Noma
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan.
| | - Kanako Yasuda
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan
| | - Tomoe Kanemaki
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan
| | - Hiroshi Goto
- Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan
| | - Masahiko Shimura
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan
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Han J, Pang X, Zhang Y, Peng Z, Shi X, Xing Y. Hirudin Protects Against Kidney Damage in Streptozotocin-Induced Diabetic Nephropathy Rats by Inhibiting Inflammation via P38 MAPK/NF-κB Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:3223-3234. [PMID: 32848363 PMCID: PMC7425656 DOI: 10.2147/dddt.s257613] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/26/2020] [Indexed: 12/31/2022]
Abstract
Background Inflammation-induced podocyte apoptosis plays an important role in kidney injury during diabetic nephropathy (DN). Hirudin (HIR), a natural compound extracted from leeches, can inhibit inflammation. However, whether HIR can protect the kidneys against inflammation during DN is unknown. In the present study, we aimed to study the effects of HIR on kidney damage in a DN rat model and explore its anti-inflammatory properties. Methods A streptozotocin-induced DN rat model was generated, and HIR was administered subcutaneously. Immortal podocytes and primary peritoneal macrophages were used for vitro studies. Hematoxylin and eosin staining was used to evaluate renal pathological changes; quantitative polymerase chain reaction and immunoblotting were used to detect gene expression; and TUNEL staining was used to detect apoptotic cells. Results Our results showed that HIR protected against renal injury, as indicated by kidney weight/body weight, serum creatinine, renal pathological changes, blood urea nitrogen, and detection of urine proteins. Notably, HIR treatment reduced macrophage infiltration, pro-inflammatory cytokine expression, and podocyte apoptosis in the kidney tissues of DN rats. In vitro, high glucose (HG) induced the activation of M1 macrophages, which was accompanied by increased podocyte apoptosis. HIR could decrease HG-induced podocyte apoptosis and suppress pro-inflammatory cytokine expression in podocytes in vitro. This was achieved via inhibition of p38 MAPK/NF-κB activation in renal tissues and podocytes. Conclusion HIR could inhibit inflammation via the p38 MAPK/NF-κB pathway, prevent podocyte apoptosis, and protect against kidney damage in a DN rat model.
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Affiliation(s)
- Jiarui Han
- Department of Nephropathy, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China.,Department of Nephropathy, The Second Hospital Affiliated to Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Xinxin Pang
- Department of Nephropathy, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China.,Department of Nephropathy, The Second Hospital Affiliated to Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Yage Zhang
- Department of Nephropathy, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China.,Department of Nephropathy, The Second Hospital Affiliated to Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Zining Peng
- Department of Nephropathy, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China.,Department of Nephropathy, The Second Hospital Affiliated to Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Xiujie Shi
- Department of Nephropathy, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China.,Department of Nephropathy, The Second Hospital Affiliated to Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Yufeng Xing
- Department of Nephropathy, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China.,Department of Nephropathy, The Second Hospital Affiliated to Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
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Shi C, Wang Q, Rao Z, Shi Y, Wei S, Wang H, Lu X, Wang P, Lu L, Zhou H, Cheng F. Diabetes induces hepatocyte pyroptosis by promoting oxidative stress-mediated NLRP3 inflammasome activation during liver ischaemia and reperfusion injury. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:739. [PMID: 32647664 PMCID: PMC7333130 DOI: 10.21037/atm-20-1839] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Although diabetes mellitus has been reported to aggravate liver ischaemia and reperfusion (IR) injury, the basic mechanism remains largely unknown. The object of the present study was to determine the role of oxidative stress and hepatocellular pyroptosis in liver IR injury in diabetic mice. Methods Db/db and C57BL/6 mice at 8 weeks of age were subjected to liver IR injury. Liver injury and hepatocyte cell death were analyzed. A NOD-like receptor family pyrin domain-containing 3 protein (NLRP3) inflammasome antagonist (CY09) and a reactive oxygen species (ROS) antagonist (N-Acetyl-L-cysteine, NAC) were used to determine the role of ROS-mediated hepatocellular pyroptosis in diabetic mice post-IR. Results Aggravated liver IR injury was found in db/db mice compared to C57BL/6 control mice, as demonstrated by increased serum alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) levels, liver architecture damage and Suzuki scores. Interestingly, IR induces the pyroptosis of hepatocytes in db/db mice, as evidenced by enhanced NLRP3 inflammasome activation, increased numbers of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive hepatocytes and increased gene expression of interleukin-1β (IL-1β) and IL-18 in livers post-IR. The inhibitory effect of CY09, an NLRP3 antagonist, efficiently abrogated the exacerbation effects of diabetes on liver IR injury in db/db mice. Furthermore, increased ROS expression was detected in db/db mice compared to control mice after IR. ROS scavenging by NAC pretreatment markedly inhibited hepatocellular NLRP3 inflammasome activation and pyroptosis in the db/db mice post-IR, indicating that ROS play an essential role in mediating hepatocyte pyroptosis in the setting of diabetes mellitus. Conclusions Our results demonstrate that diabetes induces hepatocyte pyroptosis by promoting oxidative stress-mediated NLRP3 inflammasome activation during liver IR injury. Strategies targeting ROS and NLRP3 inflammasome activation would be beneficial for preventing liver IR injury in diabetic patients.
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Affiliation(s)
- Chengyu Shi
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.,School of Medical, Southeast University, Nanjing, China
| | - Zhuqing Rao
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yong Shi
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Song Wei
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.,School of Medical, Southeast University, Nanjing, China
| | - Hao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Xu Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Ping Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.,School of Medical, Southeast University, Nanjing, China.,Department of General Surgery, People's Hospital of Qinghai Province, Xining, Qinghai, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Feng Cheng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.,NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
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Pereira BP, do Valle GT, Salles BCC, Costa KCM, Ângelo ML, Torres LHL, Novaes RD, Ruginsk SG, Tirapelli CR, de Araújo Paula FB, Ceron CS. Pyrrolidine dithiocarbamate reduces alloxan-induced kidney damage by decreasing nox4, inducible nitric oxide synthase, and metalloproteinase-2. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1899-1910. [PMID: 32440769 DOI: 10.1007/s00210-020-01906-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 05/10/2020] [Indexed: 12/18/2022]
Abstract
We examined the effect of the NFκB inhibitor pyrrolidine-1-carbodithioic acid (PDTC) on inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2) activity, and oxidative and inflammatory kidney damage in alloxan-induced diabetes. Two weeks after diabetes induction (alloxan-130 mg/kg), control and diabetic rats received PDTC (100 mg/kg) or vehicle for 8 weeks. Body weight, glycemia, urea, and creatinine were measured. Kidney changes were measured in hematoxylin/eosin sections and ED1 by immunohistochemistry. Kidney thiobarbituric acid reactive substances (TBARS), superoxide anion (O2-), and nitrate/nitrite (NOx) levels, and catalase and superoxide dismutase (SOD) activities were analyzed. Also, kidney nox4 and iNOS expression, and NFkB nuclear translocation were measured by western blot, and MMP-2 by zymography. Glycemia and urea increased in alloxan rats, which were not modified by PDTC treatment. However, PDTC attenuated kidney structural alterations and macrophage infiltration in diabetic rats. While diabetes increased both TBARS and O2- levels, PDTC treatment reduced TBARS in diabetic and O2- in control kidneys. A decrease in NOx levels was found in diabetic kidneys, which was prevented by PDTC. Diabetes reduced catalase activity, and PDTC increased catalase and SOD activities in both control and diabetic kidneys. PDTC treatment reduced MMP-2 activity and iNOS and p65 NFκB nuclear expression found increased in diabetic kidneys. Our results show that the NFκB inhibitor PDTC reduces renal damage through reduction of Nox4, iNOS, macrophages, and MMP-2 in the alloxan-induced diabetic model. These findings suggest that PDTC inhibits alloxan kidney damage via antioxidative and anti-inflammatory mechanisms.
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Affiliation(s)
- Bruna Pinheiro Pereira
- Departamento de Alimentos e Medicamentos, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais,, Brazil
| | - Gabriel Tavares do Valle
- Escola de Enfermagem de Ribeirão Preto (EERP), Universidade de São Paulo - USP, Sao Paulo, Brazil
| | - Bruno César Côrrea Salles
- Departamento de Análises Clínicas, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais, Brazil
| | - Karla Cristinne Mancini Costa
- Departamento de Alimentos e Medicamentos, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais,, Brazil
| | - Marilene Lopes Ângelo
- Departamento de Alimentos e Medicamentos, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais,, Brazil
| | - Larissa Helena Lobo Torres
- Departamento de Alimentos e Medicamentos, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais,, Brazil
| | - Rômulo Dias Novaes
- Departamento de Biologia Estrutural, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais, Brazil
| | - Sílvia Graciela Ruginsk
- Departamento de Ciências Fisiológicas, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais, Brazil
| | - Carlos Renato Tirapelli
- Escola de Enfermagem de Ribeirão Preto (EERP), Universidade de São Paulo - USP, Sao Paulo, Brazil
| | | | - Carla Speroni Ceron
- Departamento de Alimentos e Medicamentos, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais,, Brazil.
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