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Soh LJ, Lee SY, Roebuck MM, Wong PF. Unravelling the interplay between ER stress, UPR and the cGAS-STING pathway: Implications for osteoarthritis pathogenesis and treatment strategy. Life Sci 2024; 357:123112. [PMID: 39378929 DOI: 10.1016/j.lfs.2024.123112] [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: 04/29/2024] [Revised: 09/20/2024] [Accepted: 10/03/2024] [Indexed: 10/10/2024]
Abstract
Osteoarthritis (OA) is a debilitating chronic degenerative disease affecting the whole joint organ leading to pain and disability. Cellular stress and injuries trigger inflammation and the onset of pathophysiological changes ensue after irreparable damage and inability to resolve inflammation, impeding the completion of the healing process. Extracellular matrix (ECM) degradation leads to dysregulated joint tissue metabolism. The reparative effort induces the proliferation of hypertrophic chondrocytes and matrix protein synthesis. Aberrant protein synthesis leads to endoplasmic reticulum (ER) stress and chondrocyte apoptosis with consequent cartilage matrix loss. These events in a vicious cycle perpetuate inflammation, hindering the restoration of normal tissue homeostasis. Recent evidence suggests that inflammatory responses and chondrocyte apoptosis could be caused by the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling axis in response to DNA damage. It has been reported that there is a crosstalk between ER stress and cGAS-STING signalling in cellular senescence and other diseases. Based on recent evidence, this review discusses the role of ER stress, Unfolded Protein Response (UPR) and cGAS-STING pathway in mediating inflammatory responses in OA.
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Affiliation(s)
- Li-Jen Soh
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Siam-Yee Lee
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Margaret M Roebuck
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK; Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L3 9TA, UK
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
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Kim JH, Yu H, Kang JH, Hong EH, Kang MH, Seong M, Cho H, Shin YU. MicroRNA Regulation for Inflammasomes in High Glucose-Treated ARPE-19 Cells. J Ophthalmol 2024; 2024:3654690. [PMID: 39220230 PMCID: PMC11366061 DOI: 10.1155/2024/3654690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 07/22/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
Purpose This study aimed to evaluate the expression of microRNAs (miRNAs) and inflammasomes in diabetes-induced retinal cells and to determine their role in the pathogenesis of diabetic retinopathy (DR). Methods To establish diabetes-induced cell models, ARPE-19 cells were treated with high glucose. The expression levels of five miRNAs (miR-185, miR-17, miR-20a, miR-15a, and miR-15b) were measured in high glucose-treated ARPE-19 cells using real-time quantitative polymerase chain reaction. Western blotting was performed to measure inflammasome expression in cellular models. miR-17 was selected as the target miRNA, and inflammasome expression was measured following the transfection of an miR-17 mimic into high glucose-treated ARPE-19 cells. Results In high glucose-treated ARPE-19 cells, miRNA expression was substantially downregulated, whereas that of inflammasome components was significantly increased. Following the transfection of the miR-17 mimic into high glucose-treated ARPE-19 cells, the levels of inflammasome components were significantly decreased. Conclusions This study investigated the relationship between miRNAs and inflammasomes in diabetes-induced cells using high glucose-treated ARPE-19 cells. These findings suggested that miR-17 suppresses inflammasomes, thereby reducing the subsequent inflammatory response and indicating that miRNAs and inflammasomes could serve as new therapeutic targets for DR.
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Affiliation(s)
- Ji Hong Kim
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
- Department of OphthalmologyHanyang University Seoul Hospital, Seoul, Republic of Korea
| | - Hyoseon Yu
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
| | - Ji Hye Kang
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
| | - Eun Hee Hong
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
- Department of OphthalmologyHanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- Hanyang Institute of Bioscience and BiotechnologyHanyang University, Seoul, Republic of Korea
| | - Min Ho Kang
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
- Department of OphthalmologyHanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
| | - Mincheol Seong
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
- Department of OphthalmologyHanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- NOON Eye Clinic, Guri, Gyeonggi-do, Republic of Korea
| | - Heeyoon Cho
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
- Department of OphthalmologyHanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- NOON Eye Clinic, Guri, Gyeonggi-do, Republic of Korea
| | - Yong Un Shin
- Department of OphthalmologyHanyang University College of Medicine, Seoul, Republic of Korea
- Department of OphthalmologyHanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- Hanyang Institute of Bioscience and BiotechnologyHanyang University, Seoul, Republic of Korea
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Jeong JS, Kim JW, Kim JH, Kim CY, Chung EH, Cho YE, Hong EJ, Kwon HJ, Ko JW, Kim TW. The absence of thioredoxin-interacting protein in alveolar cells exacerbates asthma during obesity. Redox Biol 2024; 73:103193. [PMID: 38781728 PMCID: PMC11145548 DOI: 10.1016/j.redox.2024.103193] [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: 05/02/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024] Open
Abstract
Obesity is associated with an increased incidence of asthma. However, the mechanisms underlying this association are not fully understood. In this study, we investigated the role of thioredoxin-interacting protein (TXNIP) in obesity-induced asthma. Asthma was induced by intranasal injection of a protease from Aspergillus oryzae in normal diet (ND)- or high fat diet (HFD)-fed mice to investigate the symptoms. We measured TXNIP expression in the lungs of patients with asthma and in ND or HFD asthmatic mice. To explore the role of TXNIP in asthma pathogenesis, we induced asthma in the same manner in alveolar type 2 cell-specific TXNIP deficient (TXNIPCre) mice. In addition, the expression levels of pro-inflammatory cytokines were compared based on TXNIP gene expression in A549 cells stimulated with recombinant human tumor necrosis factor alpha. Compared to ND-fed mice, HFD-fed mice had elevated levels of free fatty acids and adipokines, resulting in high reactive oxygen species levels and more severe asthma symptoms. TXNIP expression was increased in both, asthmatic patients and HFD asthmatic mice. However, in experiments using TXNIPCre mice, despite being TXNIP deficient, TXNIPCre mice exhibited exacerbated asthma symptoms. Consistent with this, in vitro studies showed highest expression levels of pro-inflammatory cytokines in TXNIP-silenced cells. Overall, our findings suggest that increased TXNIP levels in obesity-induced asthma is compensatory to protect against inflammatory responses.
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Affiliation(s)
- Ji-Soo Jeong
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea
| | - Jeong-Won Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea
| | - Jin-Hwa Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea
| | - Chang-Yeop Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea; Inhalation Toxicology, Jeongeup Campus, KIT, Jeongeupsi, Jelabukdo, 580-185, Republic of Korea
| | - Eun-Hye Chung
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea
| | - Young-Eun Cho
- Andong National University, Andong, 36729, Republic of Korea
| | - Eui-Ju Hong
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea
| | - Hyo-Jung Kwon
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea
| | - Je-Won Ko
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea.
| | - Tae-Won Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon, 34131, Republic of Korea.
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Augustine-Wofford K, Connaughton VP, McCarthy E. Are Hyperglycemia-Induced Changes in the Retina Associated with Diabetes-Correlated Changes in the Brain? A Review from Zebrafish and Rodent Type 2 Diabetes Models. BIOLOGY 2024; 13:477. [PMID: 39056672 PMCID: PMC11273949 DOI: 10.3390/biology13070477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/28/2024]
Abstract
Diabetes is prevalent worldwide, with >90% of the cases identified as Type 2 diabetes. High blood sugar (hyperglycemia) is the hallmark symptom of diabetes, with prolonged and uncontrolled levels contributing to subsequent complications. Animal models have been used to study these complications, which include retinopathy, nephropathy, and peripheral neuropathy. More recent studies have focused on cognitive behaviors due to the increased risk of dementia/cognitive deficits that are reported to occur in older Type 2 diabetic patients. In this review, we collate the data reported from specific animal models (i.e., mouse, rat, zebrafish) that have been examined for changes in both retina/vision (retinopathy) and brain/cognition, including db/db mice, Goto-Kakizaki rats, Zucker Diabetic Fatty rats, high-fat diet-fed rodents and zebrafish, and hyperglycemic zebrafish induced by glucose immersion. These models were selected because rodents are widely recognized as established models for studying diabetic complications, while zebrafish represent a newer model in this field. Our goal is to (1) summarize the published findings relevant to these models, (2) identify similarities in cellular mechanisms underlying the disease progression that occur in both tissues, and (3) address the hypothesis that hyperglycemic-induced changes in retina precede or predict later complications in brain.
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Affiliation(s)
| | - Victoria P. Connaughton
- Department of Biology, American University, Washington, DC 20016, USA; (K.A.-W.); (E.M.)
- Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA
| | - Elizabeth McCarthy
- Department of Biology, American University, Washington, DC 20016, USA; (K.A.-W.); (E.M.)
- Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA
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Yi YS. MicroRNA-mediated epigenetic regulation of inflammasomes in inflammatory responses and immunopathologies. Semin Cell Dev Biol 2024; 154:227-238. [PMID: 36437174 DOI: 10.1016/j.semcdb.2022.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 11/18/2022] [Accepted: 11/19/2022] [Indexed: 11/27/2022]
Abstract
Inflammation represents the first-line defense mechanism of the host against pathogens and cellular stress. One of the most critical inflammatory responses is characterized by the activation of inflammasomes, intracellular multiprotein complexes that induce inflammatory signaling pathways in response to various pathogen-associated molecular patterns or danger-associated molecular patterns under physiological and pathological conditions. Inflammasomes are tightly regulated in normal cells, and dysregulation of these complexes is observed in various pathological conditions, especially inflammatory diseases and cancers. Epigenetic regulation has been suggested as a key mechanism in modulating inflammasome activity, and microRNAs (miRNAs) have been implicated in the post-transcriptional regulation of inflammasomes. Therefore, miRNA-mediated epigenetic regulation of inflammasomes in pathological conditions has received considerable attention, and current strategies for targeting inflammasomes have been shown to be effective in the treatment of diseases associated with inflammasome activation. This review summarizes recent studies suggesting the roles of miRNAs in the epigenetic control of inflammasomes and highlights the potential of miRNAs as a therapeutic tool for treating human diseases.
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Affiliation(s)
- Young-Su Yi
- Department of Life Sciences, Kyonggi University, Suwon 16227, South Korea.
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Xu Y, Yang Y, Chen X, Jiang D, Zhang F, Guo Y, Hu B, Xu G, Peng S, Wu L, Hu J. NLRP3 inflammasome in cognitive impairment and pharmacological properties of its inhibitors. Transl Neurodegener 2023; 12:49. [PMID: 37915104 PMCID: PMC10621314 DOI: 10.1186/s40035-023-00381-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/09/2023] [Indexed: 11/03/2023] Open
Abstract
Cognitive impairment is a multifactorial and multi-step pathological process that places a heavy burden on patients and the society. Neuroinflammation is one of the main factors leading to cognitive impairment. The inflammasomes are multi-protein complexes that respond to various microorganisms and endogenous danger signals, helping to initiate innate protective responses in inflammatory diseases. NLRP3 inflammasomes produce proinflammatory cytokines (interleukin IL-1β and IL-18) by activating caspase-1. In this review, we comprehensively describe the structure and functions of the NLRP3 inflammasome. We also explore the intrinsic relationship between the NLRP3 inflammasome and cognitive impairment, which involves immune cell activation, cell apoptosis, oxidative stress, mitochondrial autophagy, and neuroinflammation. Finally, we describe NLRP3 inflammasome antagonists as targeted therapies to improve cognitive impairment.
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Affiliation(s)
- Yi Xu
- The Second Affiliated Hospital of Nanchang University, Department of the Second Clinical Medical College of Nanchang University, Nanchang, 330006, China
| | - Yanling Yang
- The Second Affiliated Hospital of Nanchang University, Department of the Second Clinical Medical College of Nanchang University, Nanchang, 330006, China
| | - Xi Chen
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Danling Jiang
- Department of Ultrasound Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Fei Zhang
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yao Guo
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Bin Hu
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Guohai Xu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Shengliang Peng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
| | - Lidong Wu
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
| | - Jialing Hu
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- Department of Thyroid and Hernia Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
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Pimenta R, Camargo JA, Gonçalves GL, Ghazarian V, Candido P, Guimarães VR, Romão P, Chiovatto C, da Silva KS, Dos Santos GA, Silva IA, Nahas WC, Leite KR, Pessoa AFM, Viana NI, Reis ST. Overexpression of miR-17-5p may negatively impact p300/CBP factor-associated inflammation in a hypercholesterolemic advanced prostate cancer model. Mol Biol Rep 2023; 50:7333-7345. [PMID: 37439896 DOI: 10.1007/s11033-023-08638-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/26/2023] [Indexed: 07/14/2023]
Abstract
BACKGROUND Previously, we demonstrated that cholesterol triggers the increase in p300/CBP-associated factor (PCAF), targeted by miR-17-5p. The p300, IL-6, PCAF, and miR-17-5p genes have important and contradictory roles in inflammation and prostate cancer (PCa). This study aimed to demonstrate the potential anti-inflammatory effect of miR-17-5 in an advanced PCa model with diet-induced hypercholesterolemia. METHODS AND RESULTS In vitro, using the PC-3 cell line, we show that induction of miR-17-5p reduces p300 and PCAF expression, increases apoptosis, and decreases cell migration. Furthermore, we demonstrate that supplementing this same cell with cholesterol (2 µg/mL) triggers increased p300, IL-6, and PCAF. In vivo, after establishing the hypercholesterolemic (HCOL) model, xenografts were treated with miR-17-5p. Increased expression of this miR after intratumoral injections attenuated tumor growth in the control and HCOL animals and reduced cell proliferation. CONCLUSION Our results demonstrate that inducing miR-17-5p expression suppresses tumor growth and inflammatory mediator expression. Further studies should be conducted to fully explore the role of miR-17-5p and the involvement of inflammatory mediators p300, PCAF, and IL-6.
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Affiliation(s)
- Ruan Pimenta
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil.
- D'Or Institute for Research and Education (IDOR), Sao Paulo, Brazil.
| | - Juliana A Camargo
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
| | - Guilherme L Gonçalves
- Laboratory of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, 05508-000, Brazil
| | - Vitória Ghazarian
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
| | - Patrícia Candido
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
| | - Vanessa R Guimarães
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
| | - Poliana Romão
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
| | - Caroline Chiovatto
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
- Centro Universitário São Camilo, São Paulo, 04263-200, Brazil
| | - Karina Serafim da Silva
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
- Centro Universitário São Camilo, São Paulo, 04263-200, Brazil
| | - Gabriel A Dos Santos
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
- D'Or Institute for Research and Education (IDOR), Sao Paulo, Brazil
| | - Iran A Silva
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
| | - William C Nahas
- Uro-Oncology Group, Urology Department, University of Sao Paulo Medical School and Institute of Cancer Estate of Sao Paulo (ICESP), Sao Paulo, SP, 01246-000, Brazil
| | - Kátia R Leite
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
| | - Ana Flávia Marçal Pessoa
- Natural Products and Derivatives Laboratory, Department of Surgery, University of São Paulo Medical School, São Paulo, SP, 01246-903, Brazil
| | - Nayara I Viana
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
- Universidade do Estado de Minas Gerais - UEMG, Avenida Juca Stockler, Passos, MG, 1130, Brasil
| | - Sabrina T Reis
- Laboratorio de Investigação Médica 55 (LIM55), Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, 2° floor, room 2145, Sao Paulo, Sao Paulo, SP, BR, SP, 01246- 903, Brazil
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Kim DK, Han D, Bae J, Kim H, Lee S, Kim JS, Jeong YG, Shin J, Park HW. Verapamil-loaded supramolecular hydrogel patch attenuates metabolic dysfunction-associated fatty liver disease via restoration of autophagic clearance of aggregated proteins and inhibition of NLRP3. Biomater Res 2023; 27:4. [PMID: 36670488 PMCID: PMC9854054 DOI: 10.1186/s40824-023-00342-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/15/2023] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Obesity, a serious threat to public health, is linked to chronic metabolic complications including insulin resistance, type-2 diabetes, and metabolic dysfunction-associated fatty liver disease (MAFLD). Current obesity medications are challenged by poor effectiveness, poor patient compliance, and potential side effects. Verapamil is an inhibitor of L-type calcium channels, FDA-approved for the treatment of hypertension. We previously investigated the effect of verapamil on modulating autophagy to treat obesity-associated lipotoxicity. This study aims to develop a verapamil transdermal patch and to evaluate its anti-obesity effects. METHODS Verapamil is loaded in biomimetic vascular bundle-like carboxymethyl pullulan-based supramolecular hydrogel patches cross-linked with citric acid and glycerol linkages (CLCMP). The investigation was then carried out to determine the therapeutic effect of verapamil-loaded CLCMP (Vera@CLCMP) on diet-induced obese mice. RESULTS Vera@CLCMP hydrogel patches with hierarchically organized and anisotropic pore structures not only improved verapamil bioavailability without modifying its chemical structure but also enhanced verapamil release through the stratum corneum barrier. Vera@CLCMP patches exhibit low toxicity and high effectiveness at delivering verapamil into the systemic circulation through the dermis in a sustained manner. Specifically, transdermal administration of this patch into diet-induced obese mice drastically improved glucose tolerance and insulin sensitivity and alleviated metabolic derangements associated with MAFLD. Furthermore, we uncovered a distinct molecular mechanism underlying the anti-obesity effects associated with the hepatic NLR family pyrin domain-containing 3 (NLRP3) inflammasome and autophagic clearance by the vera@CLCMP hydrogel patches. CONCLUSION The current study provides promising drug delivery platforms for long-term family treatment of chronic diseases, including obesity and metabolic dysfunctions.
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Affiliation(s)
- Do Kyung Kim
- grid.411143.20000 0000 8674 9741Department of Anatomy, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Daewon Han
- grid.411143.20000 0000 8674 9741Department of Cell Biology, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Jeongyun Bae
- grid.411143.20000 0000 8674 9741Department of Cell Biology, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Haeil Kim
- grid.411143.20000 0000 8674 9741Department of Cell Biology, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Solji Lee
- grid.411143.20000 0000 8674 9741Department of Cell Biology, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Jong-Seok Kim
- grid.411143.20000 0000 8674 9741Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Young-Gil Jeong
- grid.411143.20000 0000 8674 9741Department of Anatomy, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Jongdae Shin
- grid.411143.20000 0000 8674 9741Department of Cell Biology, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea ,grid.411143.20000 0000 8674 9741Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
| | - Hwan-Woo Park
- grid.411143.20000 0000 8674 9741Department of Cell Biology, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea ,grid.411143.20000 0000 8674 9741Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, 35365 Republic of Korea
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Chen W, Wang X, Sun Q, Zhang Y, Liu J, Hu T, Wu W, Wei C, Liu M, Ding Y, Liu D, Chong Y, Wang P, Zhu H, Cui W, Zhang J, Li Q, Yang F. The upregulation of NLRP3 inflammasome in dorsal root ganglion by ten-eleven translocation methylcytosine dioxygenase 2 (TET2) contributed to diabetic neuropathic pain in mice. J Neuroinflammation 2022; 19:302. [PMID: 36527131 PMCID: PMC9756585 DOI: 10.1186/s12974-022-02669-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in dorsal root ganglion (DRG) contributes to pain hypersensitivity in multiple neuropathic pain models, but the function of the NLRP3 in diabetic neuropathic pain (DNP) and the regulation mechanism are still largely unknown. Epigenetic regulation plays a vital role in the controlling of gene expression. Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a DNA demethylase that contributes to transcriptional activation. TET2 is also involved in high glucose (HG)-induced pathology. METHODS DNP was induced in mice via the intraperitoneal injection of streptozotocin (STZ) for five consecutive days and the mechanical threshold was evaluated in STZ-diabetic mice by using von Frey hairs. The expression level of the NLRP3 pathway and TET2 in DRG were determined through molecular biology experiments. The regulation of the NLRP3 pathway by TET2 was examined in in vitro and in vivo conditions. RESULTS In the present research, we first established the DNP model and found that NLRP3 pathway was activated in DRG. The treatment of NLRP3 inhibitor MCC950 alleviated the mechanical allodynia of DNP mice. Then we revealed that in STZ-diabetic mice DRG, the genomic DNA was demethylated, and the expression of DNA demethylase TET2 was increased evidently. Using RNA-sequencing analysis, we found that the expression of Txnip, a gene that encodes a thioredoxin-interacting protein (TXNIP) which mediates NLRP3 activation, was elevated in the DRG after STZ treatment. In addition, knocking down of TET2 expression in DRG using TET2-siRNA suppressed the mRNA expression of Txnip and subsequently inhibited the expression/activation of NLRP3 inflammasome in vitro and in vivo as well as relieved the pain sensitivity of DNP animals. CONCLUSION The results suggested that the upregulation of the TXNIP/NLRP3 pathway by TET2 in DRG was involved in the pain hypersensitivity of the DNP model.
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Affiliation(s)
- Wen Chen
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China ,grid.24695.3c0000 0001 1431 9176International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Xiaotong Wang
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Qingyu Sun
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Yurui Zhang
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Jing Liu
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Tingting Hu
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Weihua Wu
- grid.24696.3f0000 0004 0369 153XDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Chao Wei
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Meng Liu
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Yumeng Ding
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Dianxin Liu
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Yingzi Chong
- grid.24696.3f0000 0004 0369 153XDepartment of Anesthesiology Beijing Tian Tan Hospital, Capital Medical University, Beijing, 100070 China
| | - Peipei Wang
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Hongwei Zhu
- grid.24696.3f0000 0004 0369 153XBeijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053 China
| | - Weihua Cui
- grid.24696.3f0000 0004 0369 153XDepartment of Anesthesiology Beijing Tian Tan Hospital, Capital Medical University, Beijing, 100070 China
| | - Jiannan Zhang
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Qian Li
- grid.24696.3f0000 0004 0369 153XDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China ,grid.24696.3f0000 0004 0369 153XAdvanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China ,grid.24696.3f0000 0004 0369 153XKey Laboratory of Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, 100069 China
| | - Fei Yang
- grid.24696.3f0000 0004 0369 153XDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China ,grid.24696.3f0000 0004 0369 153XAdvanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China
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10
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Askari S, Azizi F, Javadpour P, Karimi N, Ghasemi R. Endoplasmic reticulum stress as an underlying factor in leading causes of blindness and potential therapeutic effects of 4-phenylbutyric acid: from bench to bedside. EXPERT REVIEW OF OPHTHALMOLOGY 2022. [DOI: 10.1080/17469899.2022.2145945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Sahar Askari
- Neuroscience Research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Azizi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Pegah Javadpour
- Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasser Karimi
- Eye and Skull Base Research Centers, The Five Senses Institute, Iran University of Medical Sciences, Tehran, Iran5Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rasoul Ghasemi
- Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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11
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Aoki S, Inoue Y, Shinozawa A, Tanaka K, Shirasuna K, Iwata H. miR-17-5p in bovine oviductal fluid affects embryo development. Mol Cell Endocrinol 2022; 551:111651. [PMID: 35452772 DOI: 10.1016/j.mce.2022.111651] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/03/2022] [Accepted: 04/16/2022] [Indexed: 11/22/2022]
Abstract
This study identified microRNAs (miRNAs) in bovine oviductal fluids (OFs) and examined the effect of miR-17-5p in OFs on embryonic development to the blastocyst stage. Small RNA-seq of extracellular vesicles of OFs revealed 242 miRNAs. Additionally, analyzing expressions of randomly selected OF-miRNAs with RT-qPCR in the culture medium of oviductal epithelial cells indicated that the abundance of miRNAs in OFs increased during the luteal phase. miR-17-5p mimic-treated eight-cell-stage zona pellucida-free embryos showed improved embryonic development to the blastocyst stage. The effect of the miR-17-5p mimic was confirmed using a dual-luciferase assay and immunostaining. In addition, RNA-seq of the miR-17-5p mimic- or control-treated embryos revealed differentially expressed genes (DEGs), suggesting possible pathways that overlapped with the in silico-predicted pathways for miR-17-5p targeting genes. Furthermore, ingenuity pathway analysis of DEG predicted miR-17 to be a significant upstream regulator. Our results suggest that miR-17-5p in OFs regulates embryonic development in bovines.
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Affiliation(s)
- Sogo Aoki
- Department of Animal Science, Graduate School of Agriculture, Tokyo University of Agriculture, Funako, 1737, Atsugi City, Kanagawa, Japan
| | - Yuki Inoue
- Department of Animal Science, Graduate School of Agriculture, Tokyo University of Agriculture, Funako, 1737, Atsugi City, Kanagawa, Japan
| | - Akihisa Shinozawa
- NODAI Genome Research Center, Tokyo University of Agriculture, Sakuragaoka 1-1-1, Setagaya, Tokyo, Japan
| | - Keisuke Tanaka
- NODAI Genome Research Center, Tokyo University of Agriculture, Sakuragaoka 1-1-1, Setagaya, Tokyo, Japan
| | - Koumei Shirasuna
- Department of Animal Science, Graduate School of Agriculture, Tokyo University of Agriculture, Funako, 1737, Atsugi City, Kanagawa, Japan
| | - Hisataka Iwata
- Department of Animal Science, Graduate School of Agriculture, Tokyo University of Agriculture, Funako, 1737, Atsugi City, Kanagawa, Japan.
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12
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Mohamed IN, Li L, Ismael S, Ishrat T, El-Remessy AB. Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response. World J Diabetes 2021; 12:1979-1999. [PMID: 35047114 PMCID: PMC8696646 DOI: 10.4239/wjd.v12.i12.1979] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/01/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis. Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease (NAFLD), retinopathy, critical limb ischemia, and impaired angiogenesis. Sterile inflammation driven by high-fat diet, increased formation of reactive oxygen species, alteration of intracellular calcium level and associated release of inflammatory mediators, are the main common underlying forces in the pathophysiology of NAFLD, ischemic retinopathy, stroke, and aging brain. This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein (TXNIP) to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states. Finally, the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.
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Affiliation(s)
- Islam N Mohamed
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California North State University, Elk Grove, CA 95758, United States
| | - Luling Li
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California North State University, Elk Grove, CA 95758, United States
| | - Saifudeen Ismael
- Department of Anatomy and Neurobiology, and Neuroscience Institute, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, and Neuroscience Institute, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Azza B El-Remessy
- Department of Pharmacy, Doctors Hospital of Augusta, Augusta, GA 30909, United States
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13
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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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14
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Aslani M, Mortazavi-Jahromi SS, Mirshafiey A. Cytokine storm in the pathophysiology of COVID-19: Possible functional disturbances of miRNAs. Int Immunopharmacol 2021; 101:108172. [PMID: 34601331 PMCID: PMC8452524 DOI: 10.1016/j.intimp.2021.108172] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease.
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Affiliation(s)
- Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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15
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Short-term high-fat feeding exacerbates degeneration in retinitis pigmentosa by promoting retinal oxidative stress and inflammation. Proc Natl Acad Sci U S A 2021; 118:2100566118. [PMID: 34667124 DOI: 10.1073/pnas.2100566118] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2021] [Indexed: 12/22/2022] Open
Abstract
A high-fat diet (HFD) can induce hyperglycemia and metabolic syndromes that, in turn, can trigger visual impairment. To evaluate the acute effects of HFD feeding on retinal degeneration, we assessed retinal function and morphology, inflammatory state, oxidative stress, and gut microbiome in dystrophic retinal degeneration 10 (rd10) mice, a model of retinitis pigmentosa, fed an HFD for 2 to 3 wk. Short-term HFD feeding impaired retinal responsiveness and visual acuity and enhanced photoreceptor degeneration, microglial cell activation, and Müller cell gliosis. HFD consumption also triggered the expression of inflammatory and oxidative markers in rd10 retinas. Finally, an HFD caused gut microbiome dysbiosis, increasing the abundance of potentially proinflammatory bacteria. Thus, HFD feeding drives the pathological processes of retinal degeneration by promoting oxidative stress and activating inflammatory-related pathways. Our findings suggest that consumption of an HFD could accelerate the progression of the disease in patients with retinal degenerative disorders.
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16
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Non-coding RNAs: The key regulators in NLRP3 inflammasome-mediated inflammatory diseases. Int Immunopharmacol 2021; 100:108105. [PMID: 34481143 DOI: 10.1016/j.intimp.2021.108105] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/03/2021] [Accepted: 08/26/2021] [Indexed: 02/07/2023]
Abstract
Inflammasomes are multiprotein complexes responding to various microbes and endogenous danger signals, contributing to initiating the innate protective response of inflammatory diseases. NLRP3 inflammasome is a crucial regulator of pro-inflammatory cytokines (IL-1β and IL-18) production through activating caspase-1. Non-coding RNAs (ncRNAs) are a class of RNA transcripts lacking the ability to encode peptides or proteins. Its dysregulation leads to the development and progression of inflammation in diseases. Recently, accumulating evidence has indicated that NLRP3 inflammasome activation could be modulated by ncRNAs (lncRNAs, miRNAs, and circRNAs) in a variety of inflammatory diseases. This review focuses on the substantial role and function of ncRNAs in the NLRP3 inflammasome activation, providing novel insight for the future therapeutic approach of inflammatory diseases.
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17
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Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook. Int J Mol Sci 2021; 22:ijms22052754. [PMID: 33803178 PMCID: PMC7963165 DOI: 10.3390/ijms22052754] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.
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18
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A Comparison of Gene Expression Changes in the Blood of Individuals Consuming Diets Supplemented with Olives, Nuts or Long-Chain Omega-3 Fatty Acids. Nutrients 2020; 12:nu12123765. [PMID: 33302351 PMCID: PMC7762614 DOI: 10.3390/nu12123765] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/02/2020] [Accepted: 12/04/2020] [Indexed: 12/13/2022] Open
Abstract
Background: The Mediterranean diet, which is rich in olive oil, nuts, and fish, is considered healthy and may reduce the risk of chronic diseases. Methods: Here, we compared the transcriptome from the blood of subjects with diets supplemented with olives, nuts, or long-chain omega-3 fatty acids and identified the genes differentially expressed. The dietary genes obtained were subjected to network analysis to determine the main pathways, as well as the transcription factors and microRNA interaction networks to elucidate their regulation. Finally, a gene-associated disease interaction network was performed. Results: We identified several genes whose expression is altered after the intake of components of the Mediterranean diets compared to controls. These genes were associated with infection and inflammation. Transcription factors and miRNAs were identified as potential regulators of the dietary genes. Interestingly, caspase 1 and sialophorin are differentially expressed in the opposite direction after the intake of supplements compared to Alzheimer’s disease patients. In addition, ten transcription factors were identified that regulated gene expression in supplemented diets, mild cognitive impairment, and Alzheimer’s disease. Conclusions: We identified genes whose expression is altered after the intake of the supplements as well as the transcription factors and miRNAs involved in their regulation. These genes are associated with schizophrenia, neoplasms, and rheumatic arthritis, suggesting that the Mediterranean diet may be beneficial in reducing these diseases. In addition, the results suggest that the Mediterranean diet may also be beneficial in reducing the risk of dementia.
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19
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Zhang Y, Yang S, Fu J, Liu A, Liu D, Cao S. Inhibition of endoplasmic reticulum stress prevents high-fat diet mediated atrial fibrosis and fibrillation. J Cell Mol Med 2020; 24:13660-13668. [PMID: 33135380 PMCID: PMC7754029 DOI: 10.1111/jcmm.15816] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 06/17/2020] [Accepted: 08/08/2020] [Indexed: 12/14/2022] Open
Abstract
Obesity is a significant risk factor for atrial fibrillation (AF), which is the most common sustained arrhythmia with increased mortality and morbidity. High-fat diet (HFD)-induced obesity is associated with the activation of endoplasmic reticulum stress (ERS). However, the role of ERS in HFD-induced AF remains elusive. Human atrium samples were examined for the ERS activation test. C57BL/6J mice were divided into four groups, including the control group, the HFD group, the 4-phenylbutyric acid (4-PBA) group, and the HFD + 4-PBA group. At the age of 4 weeks, the HFD group and the HFD + 4-PBA group were given HFD to construct the obesity model, while the other two groups were given a normal diet (ND). Transesophageal programmed electrical stimulation was conducted to evaluate the AF inducibility and duration. Atrial fibrosis and ERS activation were also investigated.We found that CHOP and GRP-78 protein were significantly higher in overweight patients than the controls (both P < 0.05). AF inducibility and duration of the HFD group were significantly higher than the other groups (both P < 0.05), while there was no difference between those groups (P > 0.05). The mice of the HFD group had significantly higher collagen volume fraction (CVF%) than the other groups (P < 0.05). ERS marker protein of GRP78, p-PERK, ATF6 and CHOP protein expression level was increased in the HFD group, which were significantly mitigated in the HFD + 4-PBA group. In summary, HFD-induced ERS activation facilitates atrial fibrosis and AF. The inhibition of ERS might alleviate atrial fibrosis and reduce the incidence of AF-associated obesity.
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Affiliation(s)
- Yan Zhang
- Department of General Practice/VIP Medical ServiceBeijing HospitalNational Center of GerontologyBeijingChina
- Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingChina
| | - Shuwen Yang
- Department of General Practice/VIP Medical ServiceBeijing HospitalNational Center of GerontologyBeijingChina
- Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingChina
| | - Jing Fu
- Department of General Practice/VIP Medical ServiceBeijing HospitalNational Center of GerontologyBeijingChina
- Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingChina
| | - Annan Liu
- Department of General Practice/VIP Medical ServiceBeijing HospitalNational Center of GerontologyBeijingChina
- Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingChina
| | - Deping Liu
- Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingChina
- Department of CardiologyBeijing HospitalNational Center of GerontologyBeijingChina
| | - Suyan Cao
- Department of General Practice/VIP Medical ServiceBeijing HospitalNational Center of GerontologyBeijingChina
- Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingChina
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20
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Wang Q, Cang Z, Shen L, Peng W, Xi L, Jiang X, Ge X, Xu B, Huang S. circ_0037128/miR-17-3p/AKT3 axis promotes the development of diabetic nephropathy. Gene 2020; 765:145076. [PMID: 32860899 DOI: 10.1016/j.gene.2020.145076] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/01/2020] [Accepted: 08/19/2020] [Indexed: 12/26/2022]
Abstract
Circular RNAs (circRNAs) play vital roles in the development of diabetic nephropathy (DN). In this study, we investigated the function of circ_0037128 and molecular mechanism via which it regulates diabetic nephropathy development. It was found that expression of circ_0037128 was significantly increased in mouse DN model and high glucose treated mesangial cells (MCs), and circ_0037128 loss-of-function led to reduced cell proliferation and fibrosis in vitro. Moreover, miR-17-3p acts as competitive endogenous RNA (ceRNA) that directly interacts with circ_0037128 through its miRNA response elements (MREs). Consistently, expression of miR-17-3p was remarkably down-regulated in DN model, and negatively regulated cell proliferation and fibrosis. Further investigations revealed that AKT3 was the putative target of miR-17-3p, whose expression was elevated in DN model. In conclusion, we have characterized the function of a novel circ_0037128 and illustrated the significance of circ_0037128-miR-17-3p-AKT3 axis in DN pathogenesis.
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Affiliation(s)
- Qianqian Wang
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Zheng Cang
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Lisha Shen
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Wenfang Peng
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Liuqing Xi
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Xiaohong Jiang
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Xiaoxu Ge
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Bojin Xu
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Shan Huang
- Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.
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21
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Poli G, Fabi C, Bellet MM, Costantini C, Nunziangeli L, Romani L, Brancorsini S. Epigenetic Mechanisms of Inflammasome Regulation. Int J Mol Sci 2020; 21:E5758. [PMID: 32796686 PMCID: PMC7460952 DOI: 10.3390/ijms21165758] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/05/2020] [Accepted: 08/08/2020] [Indexed: 02/07/2023] Open
Abstract
The innate immune system represents the host's first-line defense against pathogens, dead cells or environmental factors. One of the most important inflammatory pathways is represented by the activation of the NOD-like receptor (NLR) protein family. Some NLRs induce the assembly of large caspase-1-activating complexes called inflammasomes. Different types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections; sterile cell damage or other stressors, such as metabolic imbalances. Epigenetic regulation has been recently suggested to provide a complementary mechanism to control inflammasome activity. This regulation can be exerted through at least three main mechanisms, including CpG DNA methylation, histones post-translational modifications and noncoding RNA expression. The repression or promotion of expression of different inflammasomes (NLRP1, NLRP2, NLRP3, NLRP4, NLRP6, NLRP7, NLRP12 and AIM2) through epigenetic mechanisms determines the development of pathologies with variable severity. For example, our team recently explored the role of microRNAs (miRNAs) targeting and modulating the components of the inflammasome as potential biomarkers in bladder cancer and during therapy. This suggests that the epigenetic control of inflammasome-related genes could represent a potential target for further investigations of molecular mechanisms regulating inflammatory pathways.
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Affiliation(s)
- Giulia Poli
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy; (M.M.B.); (C.C.); (L.R.); (S.B.)
| | - Consuelo Fabi
- Department of Surgical and Biomedical Sciences, Urology and Andrology Clinic, University of Perugia, 05100 Terni, Italy;
| | - Marina Maria Bellet
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy; (M.M.B.); (C.C.); (L.R.); (S.B.)
| | - Claudio Costantini
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy; (M.M.B.); (C.C.); (L.R.); (S.B.)
| | - Luisa Nunziangeli
- Polo d’Innovazione di Genomica, Genetica e Biologia, 05100 Terni, Italy;
| | - Luigina Romani
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy; (M.M.B.); (C.C.); (L.R.); (S.B.)
| | - Stefano Brancorsini
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy; (M.M.B.); (C.C.); (L.R.); (S.B.)
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22
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Mohamed IN, Sheibani N, El-Remessy AB. Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model. Int J Mol Sci 2020; 21:ijms21113983. [PMID: 32492941 PMCID: PMC7312035 DOI: 10.3390/ijms21113983] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/29/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and interaction with thioredoxin-interacting protein (TXNIP). Here, the specific contribution of TXNIP and the impact of HFD on retinal leukostasis, barrier dysfunction and microvascular degeneration were investigated. Wild-type (WT) and TXNIP knockout (TKO) mice were fed with normal diet or 60% HFD for 8–18 weeks. TXNIP was overexpressed or silenced in human retinal endothelial cells (REC). At 8 weeks, HFD significantly induced retinal leukostasis and breakdown of the blood–retina barrier in WT mice, but not in TKO mice. In parallel, HFD also induced retinal expression of adhesion molecules and cleaved IL-1β in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1β, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1β receptor significantly suppressed TXNIP-induced expression of NLRP3-inflammasome and adhesion molecules in HREC. Ex-vivo assay showed that leukocytes isolated from WT-HFD, but not from TKO-HFD, induced leukostasis and cell death. At 18 weeks, HFD triggered development of degenerated (acellular) capillaries and decreased branching density in WT but not in TKO mice. Together, HFD-induced obesity triggered early retinal leukostasis and microvascular dysfunction at least in part via TXNIP-NLRP3-inflammasome activation.
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Affiliation(s)
- Islam N. Mohamed
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California North State University, Elk Grove, CA 95758, USA;
- Research Service Line, Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Nader Sheibani
- Departments of Ophthalmology and Visual Sciences, Cell and Regenerative Biology, and Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Azza B. El-Remessy
- Research Service Line, Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Department of Surgery, 820 South Wood Street, University of Illinois at Chicago, Chicago, IL 60612, USA
- Correspondence: or
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Expression of miRNA-223 and NLRP3 gene in IgA patients and intervention of traditional Chinese medicine. Saudi J Biol Sci 2020; 27:1521-1526. [PMID: 32489289 PMCID: PMC7254046 DOI: 10.1016/j.sjbs.2020.04.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/14/2020] [Accepted: 04/17/2020] [Indexed: 11/20/2022] Open
Abstract
Objective The purpose of this study was to investigate the expression of miRNA-223 and NLRP3 in IgA patients and the intervention of traditional Chinese medicine (TCM), so as to realize the basic pathological changes of IgA patients, the expression of miRNA-223 and NLRP3 in IgA patients and the changes of patients' body indexes before and after the treatment of TCM. Methods Firstly, according to the clinical data, patients with IgA nephropathy were divided into different groups according to their pathological changes. After that, the chemical sections and staining steps of the immune kidney were carried out. Immunohistochemical pv-9000 two-step method was used to stain it. By this method, miRNA-223 and NLRP3 genes in kidney were determined. After that, the image analysis method was used for semi quantitative experiment. Finally, the intervention of TCM was used to study the changes of indicators before and after treatment. Results miRNA-223 and NLRP3 genes could be found mainly in the cytoplasm of renal tubular epithelial cells and the interstitium of monocyte in renal tissue, and there were significant differences between miRNA-223 and NLRP3 genes in the expression levels of proteinuria alone, hematuria albuminuria alone and hematuria alone. There was a positive correlation between miRNA-223 and NLRP3 expression and 24-hour urinary protein in IgA nephropathy. In addition, it also had positive correlation with MCP-1 and IL-18. Conclusion This study could provide some direction and guidance for clinical diagnosis and treatment of IgA nephropathy.
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24
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Advances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators. Biochem Pharmacol 2020; 175:113863. [PMID: 32081791 DOI: 10.1016/j.bcp.2020.113863] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/13/2020] [Indexed: 12/15/2022]
Abstract
NLRP3 inflammasome is an intracellular protein complex that initiates cellular injury via assembly of NLRP3, ASC and caspase-1 in response to microbial infection and sterile stressors. The importance of NLRP3 inflammasome in immunity and human diseases has been well documented. Up to now, targeted inhibition of the assembly of NLRP3 inflammasome complex and of its activation was thought to be therapeutic strategy for associated diseases. Recent studies show that a host of molecules such as NIMA-related kinase 7 (Nek7) and DEAD-box helicase 3 X-linked (DDX3X) and a large number of biological mediators including cytokines, microRNAs, nitric oxide, carbon monoxide, nuclear factor erythroid-2 related factor 2 (Nrf2) and cellular autophagy participate in the activation and inactivation of NLRP3 inflammasome. This review summarizes current understanding of the molecular basis of NLRP3 inflammasome activation and inactivation. This knowledge may lead to development of new therapies directed at NLRP3 inflammasome related diseases.
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25
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Lim RR, Wieser ME, Ganga RR, Barathi VA, Lakshminarayanan R, Mohan RR, Hainsworth DP, Chaurasia SS. NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy. Int J Mol Sci 2020; 21:E899. [PMID: 32019187 PMCID: PMC7037099 DOI: 10.3390/ijms21030899] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/22/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.
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Affiliation(s)
- Rayne R. Lim
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
- Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA
- Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA
| | - Margaret E. Wieser
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
| | - Rama R. Ganga
- Surgery, University of Missouri, Columbia, MO 652011, USA;
| | | | | | - Rajiv R. Mohan
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
- Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA
- Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 652011, USA;
| | - Dean P. Hainsworth
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 652011, USA;
| | - Shyam S. Chaurasia
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
- Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA
- Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA
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26
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Zamani P, Oskuee RK, Atkin SL, Navashenaq JG, Sahebkar A. MicroRNAs as important regulators of the NLRP3 inflammasome. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2020; 150:50-61. [PMID: 31100298 DOI: 10.1016/j.pbiomolbio.2019.05.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 05/13/2019] [Indexed: 12/28/2022]
Abstract
Inflammasomes are a group of cytosolic multi-protein signaling complexes that regulate maturation of the interleukin (IL)-1 family cytokines IL-1β and IL-18 through activation of inflammatory caspase-1. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is the best characterized and consists of several key components that are assembled and activated in response to different endogenous and exogenous signals. The NLRP3 inflammasome is common to a number of human inflammatory diseases and its targeting may lead to novel anti-inflammatory therapy. NLRP3 inflammasome activation is tightly regulated by different mechanisms especially post-transcriptional modulation via microRNAs (miRNA). MicroRNAs are small endogenous noncoding RNAs that are 21-23 nucleotides in length and control the expression of various genes through binding to the 3'-untranslated regions of the respective mRNA and subsequent post-transcriptional regulation. MicroRNAs have recently been recognized as crucial regulators of the NLRP3 inflammasome. In this review, we summarize the current understanding of the role of miRNAs in the regulation of NLRP3 inflammasome complexes and their impact on the pathogenesis of inflammatory disease processes.
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Affiliation(s)
- Parvin Zamani
- Nanotechnology Research Center, Student Research Committee, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Kazemi Oskuee
- Targeted Drug Delivery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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27
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Coucha M, Shanab AY, Sayed M, Vazdarjanova A, El-Remessy AB. Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion. Int J Mol Sci 2019; 20:ijms20163969. [PMID: 31443163 PMCID: PMC6721134 DOI: 10.3390/ijms20163969] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 12/29/2022] Open
Abstract
Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases.
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Affiliation(s)
- Maha Coucha
- Augusta Biomedical Research Corporation, Augusta, GA 30901, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
- Department of Pharmaceutical Sciences, South University, School of Pharmacy, Savannah, GA 31406, USA
| | - Ahmed Y Shanab
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Mohamed Sayed
- Augusta Biomedical Research Corporation, Augusta, GA 30901, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Almira Vazdarjanova
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
- Department of Pharmacology and Toxicology, Augusta University, Augusta, GA 30901, USA
| | - Azza B El-Remessy
- Augusta Biomedical Research Corporation, Augusta, GA 30901, USA.
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
- Department of Pharmacy, Doctors Hospital of Augusta, Augusta, GA 30909, USA.
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28
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Ji ZR, Xue WL, Zhang L. Schisandrin B Attenuates Inflammation in LPS-Induced Sepsis Through miR-17-5p Downregulating TLR4. Inflammation 2019; 42:731-739. [PMID: 30506107 DOI: 10.1007/s10753-018-0931-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
To investigate the mechanism of Schisandrin B (Sch B) on the inflammation in LPS-induced sepsis. Sepsis mouse model was established by injecting LPS. qRT-PCR and western blot were used to measure the expression of miR-17-5p and TLR4. ELISA was used to test the concentrations of IL-1β and TNF-α. Sch B could increase miR-17-5p expression, promote inflammation, and decrease TLR4 expression in sepsis mice and LPS-induced macrophages. Moreover, miR-17-5p could negatively regulate TLR4. Overexpression of miR-17-5p suppressed the concentrations of inflammatory factors (IL-1β and TNF-α) in LPS induced-macrophages, while pcDNA-TLR4 could change the inhibition effect. Additionally, miR-17-5p inhibitor changed the inhibitory effects of Sch B on TLR4 expression and the concentrations of IL-1β and TNF-α in LPS induced-macrophages. Sch B could attenuate inflammation in LPS-induced sepsis through miR-17-5p downregulating TLR4.
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Affiliation(s)
- Zhi-Rong Ji
- Department of Traditional Chinese Medicine, People's Hospital of Ningxia Hui Autonomous Region, the First Affiliated Hospital of Northwest University for Nationalities, Yinchuan, 750000, Ningxia, China
| | - Wei-Liang Xue
- Department of Emergency, People's Hospital of Ningxia Hui Autonomous Region, the First Affiliated Hospital of Northwest University for Nationalities, No.301 Zhengyuan North Street, Yinchuan, 750000, Ningxia, China.
| | - Ling Zhang
- Department of Emergency, People's Hospital of Ningxia Hui Autonomous Region, the First Affiliated Hospital of Northwest University for Nationalities, No.301 Zhengyuan North Street, Yinchuan, 750000, Ningxia, China
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29
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Vencken S, Foged C, Ramsey JM, Sweeney L, Cryan SA, MacLoughlin RJ, Greene CM. Nebulised lipid-polymer hybrid nanoparticles for the delivery of a therapeutic anti-inflammatory microRNA to bronchial epithelial cells. ERJ Open Res 2019; 5:00161-2018. [PMID: 30972350 PMCID: PMC6452044 DOI: 10.1183/23120541.00161-2018] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 02/19/2019] [Indexed: 12/22/2022] Open
Abstract
Modulation of microRNAs (miRNAs), endogenous regulators of gene expression, is a promising strategy for tackling inflammatory lung diseases. In this proof-of-concept study, we tested delivery of miR-17 to bronchial epithelial cells (BECs) using nebulised lipid-polymer hybrid nanoparticles (LPNs). The primary aim was to reduce the induced secretion of miR-17's target, i.e. the pro-inflammatory chemokine interleukin (IL)-8. Synthetic miR-17 mimics were loaded into LPNs composed of poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid 1,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP) using a double emulsion solvent evaporation method and nebulised using the Aerogen Solo nebuliser. The physicochemical, aerosol, inflammatory and cytotoxic properties of LPNs were characterised. The effect of LPNs on lipopolysaccharide (LPS)-induced IL-8 production from human NuLi-1 BECs was tested by ELISA. The z-average, polydispersity index and ζ-potential of the LPNs and the aerodynamic properties of nebulised suspensions were in a range optimal for deposition in the bronchi and bronchioles post-inhalation. Cytotoxic and pro-inflammatory effects were minimal for LPNs loaded with a model cargo. Nebulisation did not affect the physicochemical or functional properties of the LPNs. Nebulised miR-17-loaded LPNs downregulated LPS-induced IL-8 secretion by >40% in BECs. This study suggests that DOTAP-modified PLGA LPNs are efficient and well-tolerated carriers for delivery of miRNA mimics to BECs.
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Affiliation(s)
- Sebastian Vencken
- Lung Biology Group, Dept of Clinical Microbiology, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Camilla Foged
- Dept of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Joanne M Ramsey
- Drug Delivery and Advanced Materials Team and Tissue Engineering Research Group, School of Pharmacy and Dept of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | - Sally-Ann Cryan
- Drug Delivery and Advanced Materials Team and Tissue Engineering Research Group, School of Pharmacy and Dept of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland.,Trinity Centre for Bioengineering, Trinity College Dublin, Dublin, Ireland.,SFI Centre for Research in Medical Devices (CURAM), Royal College of Surgeons in Ireland, Dublin and NUI Galway, Galway, Ireland
| | | | - Catherine M Greene
- Lung Biology Group, Dept of Clinical Microbiology, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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Consumption of a high fat diet promotes protein O-GlcNAcylation in mouse retina via NR4A1-dependent GFAT2 expression. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3568-3576. [PMID: 30254013 DOI: 10.1016/j.bbadis.2018.09.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 08/29/2018] [Accepted: 09/08/2018] [Indexed: 01/30/2023]
Abstract
The incidence of type 2 diabetes, the most common cause of diabetic retinopathy (DR), is rapidly on the rise in developed countries due to overconsumption of calorie rich diets. Using an animal model of diet-induced obesity/pre-diabetes, we evaluated the impact of a diet high in saturated fat (HFD) on O-GlcNAcylation of retinal proteins, as dysregulated O-GlcNAcylation contributes to diabetic complications and evidence supports a role in DR. Protein O-GlcNAcylation was increased in the retina of mice fed a HFD as compared to littermates receiving control chow. Similarly, O-GlcNAcylation was elevated in retinal Müller cells in culture exposed to the saturated fatty acid palmitate or the ceramide analog Cer6. One potential mechanism responsible for elevated O-GlcNAcylation is increased flux through the hexosamine biosynthetic pathway (HBP). Indeed, inhibition of the pathway's rate-limiting enzyme glutamine-fructose-6-phosphate amidotransferase (GFAT) prevented Cer6-induced O-GlcNAcylation. Importantly, expression of the mRNA encoding GFAT2, but not GFAT1 was elevated in both the retina of mice fed a HFD and in retinal cells in culture exposed to palmitate or Cer6. Notably, expression of nuclear receptor subfamily 4 group A member 1 (NR4A1) was increased in the retina of mice fed a HFD and NR4A1 expression was sufficient to promote GFAT2 mRNA expression and O-GlcNAcylation in retinal cells in culture. Whereas palmitate or Cer6 addition to culture medium enhanced NR4A1 and GFAT2 expression, chemical inhibition of NR4A1 transactivation repressed Cer6-induced GFAT2 mRNA expression. Overall, the results support a model wherein HFD increases retinal protein O-GlcNAcylation by promoting NR4A1-dependent GFAT2 expression.
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31
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Ye Z, Liu G, Guo J, Su Z. Hypothalamic endoplasmic reticulum stress as a key mediator of obesity-induced leptin resistance. Obes Rev 2018. [PMID: 29514392 DOI: 10.1111/obr.12673] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity is an epidemic disease that is increasing worldwide and is a major risk factor for many metabolic diseases. However, effective agents for the prevention or treatment of obesity remain limited. Therefore, it is urgent to clarify the pathophysiological mechanisms underlying the development and progression of obesity and exploit potential agents to cure and prevent this disease. According to a recent study series, obesity is associated with the development of endoplasmic reticulum stress and the activation of its stress responses (unfolded protein response) in metabolically active tissues, which contribute to the development of obesity-related insulin and leptin resistance, inflammation and energy imbalance. Hypothalamic endoplasmic reticulum stress is the central mechanism underlying the development of obesity-associated leptin resistance and disruption of energy homeostasis; thus, targeting endoplasmic reticulum stress offers a promising therapeutic strategy for improving leptin sensitivity, increasing energy expenditure and ultimately combating obesity. In this review, we highlight the relationship between and mechanism underlying hypothalamic endoplasmic reticulum stress and obesity-associated leptin resistance and energy imbalance and provide new insight regarding strategies for the treatment of obesity.
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Affiliation(s)
- Z Ye
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China.,Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou, China
| | - G Liu
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - J Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
| | - Z Su
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China.,Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou, China
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32
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Mohamed IN, Sarhan NR, Eladl MA, El-Remessy AB, El-Sherbiny M. Deletion of Thioredoxin-interacting protein ameliorates high fat diet-induced non-alcoholic steatohepatitis through modulation of Toll-like receptor 2-NLRP3-inflammasome axis: Histological and immunohistochemical study. Acta Histochem 2018; 120:242-254. [PMID: 29482933 DOI: 10.1016/j.acthis.2018.02.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/03/2018] [Accepted: 02/15/2018] [Indexed: 12/20/2022]
Abstract
Endemic prevalence of obesity is associated with alarming increases in non-alcoholic steatohepatitis (NASH) with limited available therapeutics. Toll-like receptor2 (TLR2) and Nod-like receptor protein 3 (NLRP3) Inflammasome are implicated in hepatic steatosis, inflammation and fibrosis; the histological landmark stages of NASH. TXNIP, a member of α-arrestin family activates NLRP3 in response to various danger stimuli. The aim of current work was to investigate the effect of TXNIP genetic deletion on histological manifestations of high fat diet-induced steatohepatitis and activation of TLR2-NLRP3-inflammasome axis. Wild-type mice (WT) and TXNIP knock out (TKO) littermates were randomized to normal diet (WT-ND and TKO-ND) or high fat diet (HFD, 60% fat) (WT-HFD and TKO-HFD). After 8-weeks, liver samples from all groups were evaluated by histological, immunohistochemical and western blot analysis. HFD resulted in significant induction of micro and macrovesicular hepatic steatosis, that was associated with increased inflammatory immune cell infiltration in WT-HFD compared with WT-ND and TKO-ND controls, but not in TKO-HFD group. In parallel, WT-HFD group showed significant fibrosis and α-SMA expression; a marker of pro-fibrotic stellate-cell activation, in areas surrounding the central vein and portal circulation, versus all other groups. Western blot revealed increased activation of TLR2-NLRP3 inflammasome pathway and downstream IL-1β and TNFα in WT-HFD group, but not in TKO-HFD group. IL-1β expression coincided within the same areas of steatosis, inflammatory cell infiltration, collagen deposition and α-SMA expression in WT-HFD mice, that was significantly reduced in TKO-HFD mice. In conclusion, TXNIP deletion ameliorates the HFD-induced steatosis, inflammatory and fibrotic response via modulation of TLR2-NLRP3 inflammasome axis. Targeting TXNIP-TLR2-NLRP3 pathway may provide potential therapeutic modalities for NASH treatment.
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Affiliation(s)
- Islam N Mohamed
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, USA; Augusta Biomedical Research Corporation, Charlie Norwood VA Medical Center, Augusta, GA, USA.
| | - Nahla Reda Sarhan
- Department of Histology & Cell Biology, Faculty of Medicine, Mansoura University, Egypt.
| | - Mohamed Ahmed Eladl
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, United Arab Emirates; Department of Anatomy & Embryology, Faculty of Medicine, Mansoura University, Egypt.
| | - Azza B El-Remessy
- Augusta Biomedical Research Corporation, Charlie Norwood VA Medical Center, Augusta, GA, USA.
| | - Mohamed El-Sherbiny
- Department of Medicine, Al-Maarefa College, Riyadh, Saudi Arabia; Department of Anatomy & Embryology, Faculty of Medicine, Mansoura University, Egypt.
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Huang N, Li W, Wang X, Qi S. MicroRNA-17-5p aggravates lipopolysaccharide-induced injury in nasal epithelial cells by targeting Smad7. BMC Cell Biol 2018; 19:1. [PMID: 29433423 PMCID: PMC5809994 DOI: 10.1186/s12860-018-0152-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 01/16/2018] [Indexed: 01/07/2023] Open
Abstract
Background Globally, rhinitis is one of the most common chronic disorders. Despite availability of drugs to manage the symptomatology of rhinitis, researchers still focus on identification of novel molecular targets for better management. MicroRNAs are implicated in many biological and pathological processes. However, the role of miR-17-5p in rhinitis remains unexplored. This study aimed to explore the role of miR-17-5p in lipopolysaccharide (LPS)-induced injury of nasal epithelial RPMI2650 cells and to elucidate the possible underlying molecular mechanism. Results LPS damaged RPMI2650 cells by inhibiting cell proliferation, promoting apoptosis, and stimulating the release of inflammatory cytokines. miR-17-5p expression was significantly increased in RPMI2650 cells following treatment with LPS. Furthermore, it was found that overexpression of miR-17-5p led to aggravation of LPS-induced injury. miR-17-5p negatively regulated expression of Smad7; overexpression of Smad7 protected the RPMI2650 cells by inactivating NF-κB and Wnt/β catenin pathways and vice versa. Conclusions Overexpression of miR-17-5p aggravated LPS-induced damage of RPMI2650 cells. Expression of Smad7 was negatively regulated by miR-17-5p; Smad7 expression inactivated NF-κB and Wnt/β catenin pathways.
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Affiliation(s)
- Nan Huang
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wenjing Li
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaolong Wang
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shanshan Qi
- Department of Allergy, Wuhan No.1 Hospital, No. 215, Zhongshan Avenue, Wuhan, 430022, China.
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Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia. Antioxidants (Basel) 2017; 6:antiox6030047. [PMID: 28661427 PMCID: PMC5618075 DOI: 10.3390/antiox6030047] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 05/25/2017] [Accepted: 06/23/2017] [Indexed: 12/21/2022] Open
Abstract
Background: Previous work demonstrated that high-fat diet (HFD) triggered thioredoxin-interacting protein (TXNIP) and that silencing TXNIP prevents diabetes-impaired vascular recovery. Here, we examine the impact of genetic deletion of TXNIP on HFD-impaired vascular recovery using hind limb ischemia model. Methods: Wild type mice (WT, C57Bl/6) and TXNIP knockout mice (TKO) were fed either normal chow diet (WT-ND and TKO-ND) or 60% high-fat diet (WT-HFD and TKO-HFD). After four weeks of HFD, unilateral hind limb ischemia was performed and blood flow was measured using Laser doppler scanner at baseline and then weekly for an additional three weeks. Vascular density, nitrative stress, infiltration of CD68+ macrophages, and expression of inflammasome, vascular endothelial growth factor (VEGF), VEGF receptor-2 were examined by slot blot, Western blot and immunohistochemistry. Results: By week 8, HFD caused similar increases in weight, cholesterol and triglycerides in both WT and TKO. At week 4 and week 8, HFD significantly impaired glucose tolerance in WT and to a lesser extent in TKO. HFD significantly impaired blood flow and vascular density (CD31 labeled) in skeletal muscle of WT mice compared to ND but not in TKO. HFD and ischemia significantly induced tyrosine nitration, and systemic IL-1β and infiltration of CD68+ cells in skeletal muscle from WT but not from TKO. HFD significantly increased cleaved-caspase-1 and IL-1 β compared to ND. Under both ND, ischemia tended to increase VEGF expression and increased VEGFR2 activation in WT only but not TKO. Conclusion: Similar to prior observation in diabetes, HFD-induced obesity can compromise vascular recovery in response to ischemic insult. The mechanism involves increased TXNIP-NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome activation, nitrative stress and impaired VEGFR2 activation. Deletion of TXNIP restored blood flow, reduced nitrative stress and blunted inflammasome-mediated inflammation; however, it did not impact VEGF/VEGFR2 in HFD. Targeting TXNIP-NLRP3 inflammasome can provide potential therapeutic target in obesity-induced vascular complication.
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