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Dash UK, Mazumdar D, Singh S. High Mobility Group Box Protein (HMGB1): A Potential Therapeutic Target for Diabetic Encephalopathy. Mol Neurobiol 2024; 61:8188-8205. [PMID: 38478143 DOI: 10.1007/s12035-024-04081-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/28/2024] [Indexed: 09/21/2024]
Abstract
HMGB (high mobility group B) is one of the ubiquitous non-histone nuclear protein superfamilies that make up the HMG (high mobility group) protein group. HMGB1 is involved in a variety of physiological and pathological processes in the human body, including a structural role in the cell nucleus as well as replication, repair, DNA transcription, and assembly of nuclear proteins. It functions as a signaling regulator in the cytoplasm and a pro-inflammatory cytokine in the extracellular environment. Among several studies, HMGB1 protein is also emerging as a crucial factor involved in the development and progression of diabetic encephalopathy (DE) along with other factors such as hyperglycaemia-induced oxidative and nitrosative stress. Diabetes' chronic side effect is DE, which manifests as cognitive and psychoneurological dysfunction. The HMGB1 is released outside to the extracellular medium in diabetes condition through active or passive routes, where it functions as a damage-associated molecular pattern (DAMP) molecule to activate several signaling pathways by interacting with receptors for advanced glycosylation end-products (RAGE)/toll like receptors (TLR). HMGB1 reportedly activates inflammatory pathways, disrupts the blood-brain barrier, causes glutamate toxicity and oxidative stress, and promotes neuroinflammation, contributing to the development of cognitive impairment and neuronal damage which is suggestive of the involvement of HMGB1 in the enhancement of the diabetes-induced encephalopathic condition. Additionally, HMGB1 is reported to induce insulin resistance, further exacerbating the metabolic dysfunction associated with diabetes mellitus (DM). Thus, the present review explores the possible pathways associated with DM-induced hyperactivation of HMGB1 ultimately leading to DE.
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Affiliation(s)
- Udit Kumar Dash
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, 495009, India
| | - Debashree Mazumdar
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, 495009, India
| | - Santosh Singh
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, 495009, India.
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Tylutka A, Morawin B, Torz N, Osmólska J, Łuszczki K, Jarmużek P, Zembron-Lacny A. Association of adipose tissue inflammation and physical fitness in older adults. Immun Ageing 2024; 21:64. [PMID: 39342343 PMCID: PMC11438273 DOI: 10.1186/s12979-024-00468-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/06/2024] [Indexed: 10/01/2024]
Abstract
An active lifestyle is of key importance for reduction of obesity and inflammation, as well as circulating levels of adipokines. Therefore, the aim of our study was to assess the relationship of physical fitness with chronic inflammatory status, and to evaluate biomarkers useful in the analysis of adipose tissue dysfunction. Sixty-three older adults (69.6 ± 5.1 years) were allocated to a high n = 31 (women n = 23 and men n = 8 male) or low physical fitness n = 32 (women n = 29 and men n = 3) group based on gait speed values (1.4-1.8 m/s or ≤ 1.3 m/s). The gait speed correlated with hand grip strength (rs = 0.493, p = 0.0001) and with leptin level (R = -0.372, p = 0.003), which shows the benefits of physical activity on muscle strength and circulating adipokines. In low physical fitness group, 58.1% individuals had adiponectin to leptin ratio (Adpn/Lep) < 0.5 revealing dysfunction of adipose tissue and high cardiometabolic risk; 20% of the group were obese with BMI ≥ 30 kg/m2. In high physical fitness group, 25.8% of individuals had Adpn/Lep ≥ 1.0 i.e., within the reference range. Markers of systemic inflammation were significantly related to physical fitness: CRP/gait speed (rs = -0.377) and HMGB-1/gait speed (rs = -0.264). The results of the ROC analysis for Adpn (AUC = 0.526), Lep (AUC = 0.745) and HMGB-1 (AUC = 0.689) indicated their diagnostic potential for clinical prognosis in older patients. The optimal threshold values corresponded to 1.2 μg/mL for Adpn (sensitivity 74.2%, specificity 41.9%, OR = 1.4, 95%Cl 0.488-3.902), 6.7 ng/mL for Lep (sensitivity 56.2%, specificity 93.5%, OR = 14.8, 95%Cl 3.574-112.229), 2.63 mg/L for CRP (sensitivity 51.6%, specificity 84.3%, OR = 4.4, 95% Cl 1.401- 16.063) and 34.2 ng/mL for HMGB-1 (sensitivity 62.0%, specificity 86.6%, OR = 12.0, 95%Cl 3.254-61.614). The highest sensitivity and specificity were observed for Leptin and HMGB-1. The study revealed changes in inflammatory status in older adults at various levels of physical fitness and demonstrated diagnostic usefulness of adipokines in the assessment of adipose tissue inflammation.
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Affiliation(s)
- Anna Tylutka
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, 28 Zyty Str, Zielona Gora, 65-417, Poland
| | - Barbara Morawin
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, 28 Zyty Str, Zielona Gora, 65-417, Poland
| | - Natalia Torz
- Student Research Group, University of Zielona Gora, Collegium Medicum University of Zielona Gora, 28 Zyty Str, Zielona Gora, 65-417, Poland
| | - Joanna Osmólska
- Student Research Group, University of Zielona Gora, Collegium Medicum University of Zielona Gora, 28 Zyty Str, Zielona Gora, 65-417, Poland
| | - Kacper Łuszczki
- Student Research Group, University of Zielona Gora, Collegium Medicum University of Zielona Gora, 28 Zyty Str, Zielona Gora, 65-417, Poland
| | - Paweł Jarmużek
- Department of Nervous System Diseases, Collegium Medicum University of Zielona Gora, Neurosurgery Center University Hospital in Zielona Gora, Zielona Gora, Poland
| | - Agnieszka Zembron-Lacny
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, 28 Zyty Str, Zielona Gora, 65-417, Poland.
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Hong EP, Han SW, Kim BJ, Youn DH, Rhim JK, Jeon JP, Park JJ. Target Gene-Based Association Study of High Mobility Group Box Protein 1 in Intracranial Aneurysms in Koreans. Brain Sci 2024; 14:969. [PMID: 39451983 PMCID: PMC11505682 DOI: 10.3390/brainsci14100969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Objective: We investigated the effect of high mobility group box 1 (HMGB1) on intracranial aneurysms (IAs) by analyzing single-nucleotide polymorphisms (SNPs) based on genome-wide association study (GWAS) data. HMGB1 mRNA and protein expression levels in plasma were also analyzed. Methods: This study was a comprehensive analysis of a GWAS dataset, including 250 patients with IAs and 294 controls. The HMGB1 gene region was targeted within SNP rs3742305 ± 10 kbp. Multivariate logistic regression analysis determined its association with IAs after adjusting for relevant clinical factors. HMGB1 mRNA expression was analyzed in the plasma of 24 patients selected from the GWAS dataset. The HMGB1 protein was analyzed by Western blotting. Results: A total of seven polymorphisms, including rs1360485, rs185382445, rs2039338, rs1045411, rs3742305, rs2249825, and rs189034241, were observed. Two SNPs, including rs1045411 (UTR-3) and rs3742305 (intron), showed strong linkage disequilibrium (r2 = 0.99). However, none of the seven SNPs associated with IAs had an adjusted p-value of < 0.0016 on multiple comparison analysis. HMGB1 mRNA levels (2-ΔCt) did not differ significantly between patients with IAs and the control subjects [1.07 (1.00-1.15) in patients with IAs vs. 1.05 (0.94-1.12) in controls; p = 0.67)]. Also, no significant difference in the degree of plasma HMGB1 protein expression was seen between the two groups (p = 0.82). Conclusions: The number of SNPs associated with HMGB1 and the degree of HMGB1 mRNA and protein expression were not significantly different between patients diagnosed with IAs and the controls.
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Affiliation(s)
- Eun Pyo Hong
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon 24254, Republic of Korea; (E.P.H.); (S.W.H.); (B.J.K.); (D.H.Y.)
| | - Sung Woo Han
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon 24254, Republic of Korea; (E.P.H.); (S.W.H.); (B.J.K.); (D.H.Y.)
| | - Bong Jun Kim
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon 24254, Republic of Korea; (E.P.H.); (S.W.H.); (B.J.K.); (D.H.Y.)
| | - Dong Hyuk Youn
- Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon 24254, Republic of Korea; (E.P.H.); (S.W.H.); (B.J.K.); (D.H.Y.)
| | - Jong Kook Rhim
- Department of Neurosurgery, Jeju National University College of Medicine, Jeju 63241, Republic of Korea;
| | - Jin Pyeong Jeon
- Department of Neurosurgery, Hallym University College of Medicine, Chuncheon 24253, Republic of Korea;
| | - Jeong Jin Park
- Department of Neurology, Konkuk University Medical Center, Seoul 05030, Republic of Korea
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Zheng X, Wang Q, Xu X, Huang X, Chen J, Huo X. Associations of insulin sensitivity and immune inflammatory responses with child blood lead (Pb) and PM 2.5 exposure at an e-waste recycling area during the COVID-19 lockdown. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2024; 46:296. [PMID: 38980420 DOI: 10.1007/s10653-024-02066-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/04/2024] [Indexed: 07/10/2024]
Abstract
Fine particular matter (PM2.5) and lead (Pb) exposure can induce insulin resistance, elevating the likelihood of diabetes onset. Nonetheless, the underlying mechanism remains ambiguous. Consequently, we assessed the association of PM2.5 and Pb exposure with insulin resistance and inflammation biomarkers in children. A total of 235 children aged 3-7 years in a kindergarten in e-waste recycling areas were enrolled before and during the Corona Virus Disease 2019 (COVID-19) lockdown. Daily PM2.5 data was collected and used to calculate the individual PM2.5 daily exposure dose (DED-PM2.5). Concentrations of whole blood Pb, fasting blood glucose, serum insulin, and high mobility group box 1 (HMGB1) in serum were measured. Compared with that before COVID-19, the COVID-19 lockdown group had lower DED-PM2.5 and blood Pb, higher serum HMGB1, and lower blood glucose and homeostasis model assessment of insulin resistance (HOMA-IR) index. Decreased DED-PM2.5 and blood Pb levels were linked to decreased levels of fasting blood glucose and increased serum HMGB1 in all children. Increased serum HMGB1 levels were linked to reduced levels of blood glucose and HOMA-IR. Due to the implementation of COVID-19 prevention and control measures, e-waste dismantling activities and exposure levels of PM2.5 and Pb declined, which probably reduced the association of PM2.5 and Pb on insulin sensitivity and diabetes risk, but a high level of risk of chronic low-grade inflammation remained. Our findings add new evidence for the associations among PM2.5 and Pb exposure, systemic inflammation and insulin resistance, which could be a possible explanation for diabetes related to environmental exposure.
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Affiliation(s)
- Xiangbin Zheng
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 855 East Xingye Avenue, Guangzhou, 511443, Guangdong, China
- Center for Reproductive Medicine, Clinical Research Center, Shantou Central Hospital, Shantou, 515041, Guangdong, China
| | - Qihua Wang
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 855 East Xingye Avenue, Guangzhou, 511443, Guangdong, China
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Xiaofan Huang
- Center for Reproductive Medicine, Clinical Research Center, Shantou Central Hospital, Shantou, 515041, Guangdong, China
| | - Jiaxue Chen
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Xia Huo
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 855 East Xingye Avenue, Guangzhou, 511443, Guangdong, China.
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Liu B, Liu Y, Li S, Chen P, Zhang J, Feng L. Depletion of placental brain-derived neurotrophic factor (BDNF) is attributed to premature ovarian insufficiency (POI) in mice offspring. J Ovarian Res 2024; 17:141. [PMID: 38982490 PMCID: PMC11232340 DOI: 10.1186/s13048-024-01467-4] [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: 12/11/2023] [Accepted: 06/29/2024] [Indexed: 07/11/2024] Open
Abstract
INTRODUCTION Premature ovarian insufficiency (POI) is one of the causes of female infertility. Unexplained POI is increasingly affecting women in their reproductive years. However, the etiology of POI is diverse and remains elusive. We and others have shown that brain-derived neurotrophic factor (BDNF) plays an important role in adult ovarian function. Here, we report on a novel role of BDNF in the Developmental Origins of POI. METHODS Placental BDNF knockout mice were created using CRISPR/CAS9. Homozygous knockout (cKO(HO)) mice didn't survive, while heterozygous knockout (cKO(HE)) mice did. BDNF reduction in cKO(HE) mice was confirmed via immunohistochemistry and Western blots. Ovaries were collected from cKO(HE) mice at various ages, analyzing ovarian metrics, FSH expression, and litter sizes. In one-month-old mice, oocyte numbers were assessed using super-ovulation, and oocyte gene expression was analyzed with smart RNAseq. Ovaries of P7 mice were studied with SEM, and gene expression was confirmed with RT-qPCR. Alkaline phosphatase staining at E11.5 and immunofluorescence for cyclinD1 assessed germ cell number and cell proliferation. RESULTS cKO(HE) mice had decreased ovarian function and litter size in adulthood. They were insensitive to ovulation induction drugs manifested by lower oocyte release after superovulation in one-month-old cKO(HE) mice. The transcriptome and SEM results indicate that mitochondria-mediated cell death or aging might occur in cKO(HE) ovaries. Decreased placental BDNF led to diminished primordial germ cell proliferation at E11.5 and ovarian reserve which may underlie POI in adulthood. CONCLUSION The current results showed decreased placental BDNF diminished primordial germ cell proliferation in female fetuses during pregnancy and POI in adulthood. Our findings can provide insights into understanding the underlying mechanisms of POI.
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Affiliation(s)
- Bin Liu
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China
- Department of Reproduction, School of Medicine, Xinhua Hospital, Shanghai Jiao-Tong University, Shanghai, China
| | - Yongjie Liu
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shuman Li
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Pingping Chen
- Department of Reproduction, School of Medicine, Xinhua Hospital, Shanghai Jiao-Tong University, Shanghai, China
| | - Jun Zhang
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Liping Feng
- Department of Obstetrics and Gynaecology, Duke University, Durham, NC, USA.
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Wang W, Ma C, Zhang Q, Jiang Y. TMT-labeled quantitative malonylome analysis on the longissimus dorsi muscle of Laiwu pigs reveals the role of ACOT7 in fat deposition. J Proteomics 2024; 298:105129. [PMID: 38395145 DOI: 10.1016/j.jprot.2024.105129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/29/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024]
Abstract
The Laiwu pig is an indigenous fatty pig breed distributed in North China, characterized by an extremely high level of intramuscular fat (IMF) content (9% ∼ 12%), but the regulatory mechanism underlying intramuscular fat deposition in skeletal muscle is still unknown. In this study, the TMT-labeled quantitative malonylome of the longissimus dorsi muscle in Laiwu pigs at the fastest IMF deposition stage (240 d vs 120 d) was compared to analyze the molecular mechanism of IMF variation in pigs. In Laiwu pigs aged 240 days/120 days, we identified 291 malonylated lysine sites across 188 proteins in the longissimus dorsi muscle. Among these, 38 sites across 31 proteins exhibited differential malonylation. Annotation analysis and enrichment analysis were performed for differentially malonylated proteins (DMPs). These DMPs were mainly clustered into 12 GO functional categories accounting for 5 biological processes, 4 cellular components and 3 molecular functions, and 2 signaling pathways by KEGG enrichment analysis. The function of differentially malonylated protein ACOT7 in the process of fat deposition was further investigated during the differentiation of 3 T3-L1 cells. The results showed that the protein level of ACOT7 in 3 T3-L1 cells decreased but the malonylated level of ACOT7 increased significantly. The malonyl-CoA that is synthesized by ACSF3 affected the malonylation level of ACOT7 in 3 T3-L1 cells. SIGNIFICANCE: The intramuscular fat (IMF) content, by affecting sensory quality traits of meat, such as tenderness, flavor and juiciness, plays an important role in meat quality. Using TMT-based quantitative malonylated proteome analysis, we identified malonylated proteins in LD muscle samples in two stages (120 d and 240 d) of development and further identified differentially malonylated proteins, such as SLC25A4, ANXA5, TPM3 and ACOT7, that are associated with intramuscular fat deposition and fat metabolism in pigs. These differentially malonylated proteins could serve as candidates for elucidating the molecular mechanism of IMF deposition in pigs. In addition, we found that the malonyl-CoA in 3 T3-L1 cells is mainly synthesized by ACSF3, affecting the malonylated level of ACOT7. The study provides some data concerning the role of protein malonylation in regulating the variation in porcine IMF content.
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Affiliation(s)
- Wenlei Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, No. 61 Daizong Street, Taian 271018, PR China.
| | - Cai Ma
- Department of Medical Genetics and Cell Biology, Binzhou Medical University, No. 346 Guanhai Road, Yantai 264003, PR China.
| | - Qin Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, No. 61 Daizong Street, Taian 271018, PR China.
| | - Yunliang Jiang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, No. 61 Daizong Street, Taian 271018, PR China.
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Zhang Q, Lu C, Lu F, Liao Y, Cai J, Gao J. Challenges and opportunities in obesity: the role of adipocytes during tissue fibrosis. Front Endocrinol (Lausanne) 2024; 15:1365156. [PMID: 38686209 PMCID: PMC11056552 DOI: 10.3389/fendo.2024.1365156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/01/2024] [Indexed: 05/02/2024] Open
Abstract
Obesity is a chronic disease that affects the energy balance of the whole body. In addition to increasing fat mass, tissue fibrosis occurred in white adipose tissue in obese condition. Fibrosis is the over-activation of fibroblasts leading to excessive accumulation of extracellular matrix, which could be caused by various factors, including the status of adipocytes. The morphology of adipocytes responds rapidly and dynamically to nutrient fluctuations. Adaptive hypertrophy of normal adipocytes protects peripheral organs from damage from lipotoxicity. However, the biological behavior of hypertrophic adipocytes in chronic obesity is abnormally altered. Adipocytes lead to fibrotic remodeling of the extracellular matrix by inducing unresolved chronic inflammation, persistent hypoxia, and increasing myofibroblast numbers. Moreover, adipocyte-induced fibrosis not only restricts the flexible expansion and contraction of adipose tissue but also initiates the development of various diseases through cellular autonomic and paracrine effects. Regarding anti-fibrotic therapy, dysregulated intracellular signaling and epigenetic changes represent potential candidate targets. Thus, modulation of adipocytes may provide potential therapeutic avenues for reversing pathological fibrosis in adipose tissue and achieving the anti-obesity purpose.
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Affiliation(s)
- Qian Zhang
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chongxuan Lu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Feng Lu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yunjun Liao
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Junrong Cai
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianhua Gao
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Listyoko AS, Okazaki R, Harada T, Inui G, Yamasaki A. Impact of obesity on airway remodeling in asthma: pathophysiological insights and clinical implications. FRONTIERS IN ALLERGY 2024; 5:1365801. [PMID: 38562155 PMCID: PMC10982419 DOI: 10.3389/falgy.2024.1365801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/07/2024] [Indexed: 04/04/2024] Open
Abstract
The prevalence of obesity among asthma patients has surged in recent years, posing a significant risk factor for uncontrolled asthma. Beyond its impact on asthma severity and patients' quality of life, obesity is associated with reduced lung function, increased asthma exacerbations, hospitalizations, heightened airway hyperresponsiveness, and elevated asthma-related mortality. Obesity may lead to metabolic dysfunction and immune dysregulation, fostering chronic inflammation characterized by increased pro-inflammatory mediators and adipocytokines, elevated reactive oxygen species, and reduced antioxidant activity. This chronic inflammation holds the potential to induce airway remodeling in individuals with asthma and obesity. Airway remodeling encompasses structural and pathological changes, involving alterations in the airway's epithelial and subepithelial layers, hyperplasia and hypertrophy of airway smooth muscle, and changes in airway vascularity. In individuals with asthma and obesity, airway remodeling may underlie heightened airway hyperresponsiveness and increased asthma severity, ultimately contributing to the development of persistent airflow limitation, declining lung function, and a potential increase in asthma-related mortality. Despite efforts to address the impact of obesity on asthma outcomes, the intricate mechanisms linking obesity to asthma pathophysiology, particularly concerning airway remodeling, remain incompletely understood. This comprehensive review discusses current research investigating the influence of obesity on airway remodeling, to enhance our understanding of obesity's role in the context of asthma airway remodeling.
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Affiliation(s)
- Aditya Sri Listyoko
- Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
- Pulmonology and Respiratory Medicine Department, Faculty of Medicine, Brawijaya University-Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Ryota Okazaki
- Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Tomoya Harada
- Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Genki Inui
- Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Akira Yamasaki
- Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
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Kumar V, Stewart JH. Obesity, bone marrow adiposity, and leukemia: Time to act. Obes Rev 2024; 25:e13674. [PMID: 38092420 DOI: 10.1111/obr.13674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/07/2023] [Accepted: 11/13/2023] [Indexed: 02/28/2024]
Abstract
Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients.
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Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - John H Stewart
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
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Rubas NC, Peres R, Kunihiro BP, Allan NP, Phankitnirundorn K, Wells RK, McCracken T, Lee RH, Umeda L, Conching A, Juarez R, Maunakea AK. HMGB1 mediates microbiome-immune axis dysregulation underlying reduced neutralization capacity in obesity-related post-acute sequelae of SARS-CoV-2. Sci Rep 2024; 14:355. [PMID: 38172612 PMCID: PMC10764757 DOI: 10.1038/s41598-023-50027-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
While obesity is a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC, "long-COVID"), the mechanism(s) underlying this phenomenon remains poorly understood. To address this gap in knowledge, we performed a 6-week longitudinal study to examine immune activity and gut microbiome dysbiosis in post-acute stage patients recovering from SARS-CoV-2 infection. Self-reported symptom frequencies and blood samples were collected weekly, with plasma assessed by ELISA and Luminex for multiple biomarkers and immune cell profiling. DNA from stool samples were collected at the early stage of recovery for baseline assessments of gut microbial composition and diversity using 16S-based metagenomic sequencing. Multiple regression analyses revealed obesity-related PASC linked to a sustained proinflammatory immune profile and reduced adaptive immunity, corresponding with reduced gut microbial diversity. In particular, enhanced signaling of the high mobility group box 1 (HMGB1) protein was found to associate with this dysregulation, with its upregulated levels in plasma associated with significantly impaired viral neutralization that was exacerbated with obesity. These findings implicate HMGB1 as a candidate biomarker of PASC, with potential applications for risk assessment and targeted therapies.
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Affiliation(s)
- Noelle C Rubas
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
- Deparment of Molecular Biosciences and Bioengineering, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Rafael Peres
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Braden P Kunihiro
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Nina P Allan
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Krit Phankitnirundorn
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Riley K Wells
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
- Deparment of Molecular Biosciences and Bioengineering, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Trevor McCracken
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Rosa H Lee
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Lesley Umeda
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
- Deparment of Molecular Biosciences and Bioengineering, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | | | - Ruben Juarez
- Hawai'i Integrated Analytics, Honolulu, HI, USA
- Deparment of Economics and UHERO, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Alika K Maunakea
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA.
- Hawai'i Integrated Analytics, Honolulu, HI, USA.
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11
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Khan MI, Ashfaq F, Alsayegh AA, Hamouda A, Khatoon F, Altamimi TN, Alhodieb FS, Beg MMA. Advanced glycation end product signaling and metabolic complications: Dietary approach. World J Diabetes 2023; 14:995-1012. [PMID: 37547584 PMCID: PMC10401445 DOI: 10.4239/wjd.v14.i7.995] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/08/2023] [Accepted: 04/27/2023] [Indexed: 07/12/2023] Open
Abstract
Advanced glycation end products (AGEs) are a heterogeneous collection of compounds formed during industrial processing and home cooking through a sequence of nonenzymatic glycation reactions. The modern western diet is full of heat-treated foods that contribute to AGE intake. Foods high in AGEs in the contemporary diet include processed cereal products. Due to industrialization and marketing strategies, restaurant meals are modified rather than being traditionally or conventionally cooked. Fried, grilled, baked, and boiled foods have the greatest AGE levels. Higher AGE-content foods include dry nuts, roasted walnuts, sunflower seeds, fried chicken, bacon, and beef. Animal proteins and processed plant foods contain furosine, acrylamide, heterocyclic amines, and 5-hydroxymethylfurfural. Furosine (2-furoil-methyl-lysine) is an amino acid found in cooked meat products and other processed foods. High concentrations of carboxymethyl-lysine, carboxyethyl-lysine, and methylglyoxal-O are found in heat-treated nonvegetarian foods, peanut butter, and cereal items. Increased plasma levels of AGEs, which are harmful chemicals that lead to age-related diseases and physiological aging, diabetes, and autoimmune/inflammatory rheumatic diseases such as systemic lupus erythematosus and rheumatoid arthritis. AGEs in the pathophysiology of metabolic diseases have been linked to individuals with diabetes mellitus who have peripheral nerves with high amounts of AGEs and diabetes has been linked to increased myelin glycation. Insulin resistance and hyperglycemia can impact numerous human tissues and organs, leading to long-term difficulties in a number of systems and organs, including the cardiovascular system. Plasma AGE levels are linked to all-cause mortality in individuals with diabetes who have fatal or nonfatal coronary artery disease, such as ventricular dysfunction. High levels of tissue AGEs are independently associated with cardiac systolic dysfunction in diabetic patients with heart failure compared with diabetic patients without heart failure. It is widely recognized that AGEs and oxidative stress play a key role in the cardiovascular complications of diabetes because they both influence and are impacted by oxidative stress. All chronic illnesses involve protein, lipid, or nucleic acid modifications including crosslinked and nondegradable aggregates known as AGEs. Endogenous AGE formation or dietary AGE uptake can result in additional protein modifications and stimulation of several inflammatory signaling pathways. Many of these systems, however, require additional explanation because they are not entirely obvious. This review summarizes the current evidence regarding dietary sources of AGEs and metabolism-related complications associated with AGEs.
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Affiliation(s)
- Mohammad Idreesh Khan
- Department of Clinical Nutrition, College of Applied Health Sciences in Ar Rass, Qassim University, Ar Rass 51921, Saudi Arabia
| | - Fauzia Ashfaq
- Clinical Nutrition Department, Applied Medical Sciences College, Jazan University, Jazan 82817, Saudi Arabia
| | - Abdulrahman A Alsayegh
- Clinical Nutrition Department, Applied Medical Sciences College, Jazan University, Jazan 82817, Saudi Arabia
| | - Alshaimaa Hamouda
- Clinical Nutrition Department, Applied Medical Sciences College, Jazan University, Jazan 82817, Saudi Arabia
| | - Fahmida Khatoon
- Department of Biochemistry, College of Medicine, University of Hail, Hail 2240, Saudi Arabia
| | - Tahani Nasser Altamimi
- Department of Family and Community Medicine, College of Medicine, University of Hail, Hail 2240, Saudi Arabia
| | - Fahad Saad Alhodieb
- Department of Clinical Nutrition, College of Applied Health Sciences in Ar Rass, Qassim University, Ar Rass 51921, Saudi Arabia
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12
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Kamiya H, Komatsu S, Nishibeppu K, Ohashi T, Konishi H, Shiozaki A, Kubota T, Fujiwara H, Otsuji E. Obesity paradox as a new insight from postoperative complications in gastric cancer. Sci Rep 2023; 13:10116. [PMID: 37344511 DOI: 10.1038/s41598-023-36968-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/13/2023] [Indexed: 06/23/2023] Open
Abstract
The obesity paradox is reported to exist in various diseases. However, obesity is a pivotal issue in gastric cancer (GC) patients because of the surgical difficulty related to postoperative abdominal infectious complications (PAIC). This study clarified the existence of the obesity paradox in GC. Between 1997 and 2015, 1536 consecutive patients underwent curative gastrectomy. Of all patients, 18.6% (285/1536) were obese and tended to have a better prognosis (P = 0.073). In patients without PAIC, obesity was a significant prognostic factor for 5-year overall survival (P = 0.017). PAIC was an independent poor prognostic factor in both obese and non-obese patients (P < 0.001; hazard ratio [HR] 4.22 and 1.82). In pStage II-III patients, there was a large and significant prognostic difference between non-PAIC and PAIC obese patients (P = 0.006; 5-year overall survival: 69.7% vs. 43.8%) related to the higher incidence of peritoneal recurrence in PAIC obese patients (P = 0.035; 31% vs. 10%). Whereas, there was a small prognostic difference between non-PAIC and PAIC non-obese patients (P = 0.102; 5-year overall survival: 56.5% vs. 51.9%). Although the obesity paradox is present in GC, PAIC had a more negative prognostic impact through peritoneal recurrence in obese GC patients.
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Affiliation(s)
- Hajime Kamiya
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Keiji Nishibeppu
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery (Gastric Surgery Division), Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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13
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Shen P, Sun Y, Jiang X, Zhou X, Nian B, Wang W, Zhang J. Interaction of bioactive kaempferol with HMGB1: Investigation by multi-spectroscopic and molecular simulation methods. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 292:122360. [PMID: 36724682 DOI: 10.1016/j.saa.2023.122360] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 12/12/2022] [Accepted: 01/09/2023] [Indexed: 06/18/2023]
Abstract
Chronic and persistent inflammation associated with excessive high mobility group protein 1 (HMGB1) is a risk factor for various diseases. Dietary intake of kaempferol has been proven to be effective in reducing HMGB1 levels and the degree of inflammation, but the structural mechanism remains unclear. In this context, we first investigated the interaction between bioactive kaempferol and HMGB1 using multi-spectroscopic and molecular simulation techniques. The surface plasmon resonance (SPR) data indicated that kaempferol binds directly to HMGB1 with a Kd value of 2.89 × 10-5 M. Binding of kaempferol with HMGB1 led to the intrinsic fluorescence quenching and modest secondary structure change of HMGB1 supported by fluorescence spectrometry and circular dichroism (CD). Using dynamic light scattering (DLS), it was found that kaempferol induced the aggregation of HMGB1 protein complex to form larger particles. On HMGB1-activated RAW264.7 cells, kaempferol co-incubation exhibited a remarkable inhibitory effect on nitric oxide (NO) release with an IC50 value of 5.02 μM, which was lower than that of quercetin. In silico, kaempferol binds to HMGB1 mainly through hydrogen bonds and hydrophobic forces. Collectively, our study showed kaempferol as a potential HMGB1 inhibitor, mainly acting by direct binding to HMGB1 and inducing its conformational changes, which provides clues for the treatment of chronic inflammation by kaempferol.
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Affiliation(s)
- Pingping Shen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yueming Sun
- The Affiliated Baiyun Hospital of Guizhou Medical University, Guizhou 550025, PR China
| | - Xuewa Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xiaoyang Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Binbin Nian
- RWTH Aachen University, Aachen 52062, Germany
| | - Weiwei Wang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210046, PR China
| | - Jian Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, PR China.
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14
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Asprosin Enhances Cytokine Production by a Co-Culture of Fully Differentiated Mature Adipocytes and Macrophages Leading to the Exacerbation of the Condition Typical of Obesity-Related Inflammation. Int J Mol Sci 2023; 24:ijms24065745. [PMID: 36982813 PMCID: PMC10056564 DOI: 10.3390/ijms24065745] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/09/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
Asprosin, a fasting-induced, glucogenic, and orexigenic adipokine, has gained popularity in recent years as a potential target in the fight against obesity and its complications. However, the contribution of asprosin to the development of moderate obesity-related inflammation remains still unknown. The present study aimed to evaluate the effect of asprosin on the inflammatory activation of adipocyte–macrophage co-cultures at various stages of differentiation. The study was performed on co-cultures of the murine 3T3L1 adipocyte and the RAW264.7 macrophage cell lines treated with asprosin before, during, and after 3T3L1 cell differentiation, with or without lipopolysaccharide (LPS) stimulation. Cell viability, overall cell activity, and the expression and release of key inflammatory cytokines were analyzed. In the concentration range of 50–100 nM, asprosin increased the pro-inflammatory activity in the mature co-culture and enhanced the expression and release of tumor necrosis factor α (TNF-α), high-mobility group box protein 1 (HMGB1), and interleukin 6 (IL-6). Macrophage migration was also increased, which could be related to the upregulated expression and release of monocyte chemoattractant protein-1 (MCP-1) by the adipocytes. In summary, asprosin exerted a pro-inflammatory effect on the mature adipocyte–macrophage co-culture and may contribute to the spread of moderate obesity-associated inflammation. Nevertheless, further research is needed to fully elucidate this process.
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15
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Morais JBS, Dias TMDS, Cardoso BEP, de Paiva Sousa M, Sousa TGVD, Araújo DSCD, Marreiro DDN. Adipose Tissue Dysfunction: Impact on Metabolic Changes? Horm Metab Res 2022; 54:785-794. [PMID: 35952684 DOI: 10.1055/a-1922-7052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Adipose tissue is a metabolically dynamic organ that is the primary site of storage for excess energy, but it serves as an endocrine organ capable of synthesizing a number of biologically active compounds that regulate metabolic homeostasis. However, when the capacity of expansion of this tissue exceeds, dysfunction occurs, favoring ectopic accumulation of fat in the visceral, which has been implicated in several disease states, most notably obesity. This review highlights the mechanisms involved in the structure of adipose tissue, tissue expandability, adipocyte dysfunction, as well as the impact of these events on the manifestation of important metabolic disorders associated with adipose tissue dysfunction. A literature search using Pubmed, Web of Science, Scopus, and Cochrane databases were used to identify relevant studies, using clinical trials, experimental studies in animals and humans, case-control studies, case series, letters to the editor, and review articles published in English, without restrictions on year of publication. The excessive ectopic lipid accumulation leads to local inflammation and insulin resistance. Indeed, overnutrition triggers uncontrolled inflammatory responses white adipose tissue, leading to chronic low-grade inflammation, therefore fostering the progression of important metabolic disorders. Thus, it is essential to advance the understanding of the molecular mechanisms involved in adipose tissue dysfunction in order to mitigate the negative metabolic consequences of obesity.
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16
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Arredondo-Hernandez R, Siebe C, Castillo-Rojas G, Ponce de León S, López-Vidal Y. The synergistic interaction of systemic inflammation, dysbiosis and antimicrobial resistance promotes growth restriction in children with acute severe malnutrition: An emphasis on Escherichia coli. FRONTIERS IN ANTIBIOTICS 2022; 1:1001717. [PMID: 39816412 PMCID: PMC11732057 DOI: 10.3389/frabi.2022.1001717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 10/05/2022] [Indexed: 01/18/2025]
Abstract
A healthy development is denied to millions of children worldwide as harsh life conditions manifest themselves in an altered inflammation-prone microbiome crosstalk environment. Keynote of this tragedy is that insufficient nutritious amino acid blocks lipids-intake to sustain diverse microbiota, and promotes the generalist strategy followed by Escherichia coli -besides other proteobacteria- of shifting gut metabolism, subverting the site specificity of first immune reaction. Furthermore, it could be hypothesized that selective success lies in their ability to induce inflammation, since this phenomenon also fuels horizontal gene transfer (HGT). In this review, we dilucidate how immune mechanisms of environmental enteric dysfunction affect overgrowth restriction, infectious morbidity rate, and acquired lifelong risks among severe acute malnourished children. Also, despite acknowledging complexities of antimicrobial resistant enrichment, we explore and speculate over the links between virulence regulation and HGT as an indissociable part in the quest for new inflammatory niches by open genome bacteria, particularly when both collide in the most vulnerable.
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Affiliation(s)
- Rene Arredondo-Hernandez
- Laboratorio de Microbioma, División de Investigación y División de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Christina Siebe
- Instituto de Geología, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Gonzalo Castillo-Rojas
- Programa de Inmunología Molecular Microbiana, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Samuel Ponce de León
- Laboratorio de Microbioma, División de Investigación y División de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Yolanda López-Vidal
- Programa de Inmunología Molecular Microbiana, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Endothelial Dysfunction, HMGB1, and Dengue: An Enigma to Solve. Viruses 2022; 14:v14081765. [PMID: 36016387 PMCID: PMC9414358 DOI: 10.3390/v14081765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Dengue is a viral infection caused by dengue virus (DENV), which has a significant impact on public health worldwide. Although most infections are asymptomatic, a series of severe clinical manifestations such as hemorrhage and plasma leakage can occur during the severe presentation of the disease. This suggests that the virus or host immune response may affect the protective function of endothelial barriers, ultimately being considered the most relevant event in severe and fatal dengue pathogenesis. The mechanisms that induce these alterations are diverse. It has been suggested that the high mobility group box 1 protein (HMGB1) may be involved in endothelial dysfunction. This non-histone nuclear protein has different immunomodulatory activities and belongs to the alarmin group. High concentrations of HMGB1 have been detected in patients with several infectious diseases, including dengue, and it could be considered as a biomarker for the early diagnosis of dengue and a predictor of complications of the disease. This review summarizes the main features of dengue infection and describes the known causes associated with endothelial dysfunction, highlighting the involvement and possible relationship between HMGB1 and DENV.
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18
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Giusti L, Tesi M, Ciregia F, Marselli L, Zallocco L, Suleiman M, De Luca C, Del Guerra S, Zuccarini M, Trerotola M, Eizirik DL, Cnop M, Mazzoni MR, Marchetti P, Lucacchini A, Ronci M. The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved. Cells 2022; 11:2465. [PMID: 35954309 PMCID: PMC9368307 DOI: 10.3390/cells11152465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 11/24/2022] Open
Abstract
Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D.
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Affiliation(s)
- Laura Giusti
- School of Pharmacy, University of Camerino, 62032 Camerino, Italy
| | - Marta Tesi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Federica Ciregia
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Rheumatology, GIGA Research, CHU de Liège, University of Liège, 4000 Liège, Belgium
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | | | - Mara Suleiman
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Carmela De Luca
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Silvia Del Guerra
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Mariachiara Zuccarini
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Marco Trerotola
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Decio L. Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | | | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Antonio Lucacchini
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Maurizio Ronci
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
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19
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Leisengang S, Gluding D, Hörster J, Peek V, Ott D, Rummel C, Schmidt MJ. Expression of adipokines and adipocytokines by epidural adipose tissue in cauda equina syndrome in dogs. J Vet Intern Med 2022; 36:1373-1381. [PMID: 35838307 PMCID: PMC9308421 DOI: 10.1111/jvim.16483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/15/2022] [Indexed: 11/28/2022] Open
Abstract
Background Compression of epidural adipose tissue (EAT) within the scope of cauda equina syndrome (CES) could lead to an enhanced expression of inflammatory mediators, possibly contributing to pain amplification in dogs. Objectives To analyze expression of inflammatory adipo(‐cyto)kines within the EAT of dogs with CES. Animals Client‐owned dogs: 15 dogs with CES and 9 dogs euthanized for unrelated medical reasons (controls). Methods Prospective, experimental study. Epidural adipose tissue and subcutaneous adipose tissue were collected during dorsal laminectomy and used for real‐time quantitative polymerase chain reaction. Tissue explants were cultured for measurements of inflammation‐induced release of cytokines. Results Results show a CES‐associated upregulation of the cytokines tumor necrosis factor alpha (TNFα: mean ± SD: 18.88 ± 11.87, 95% CI: 10.90‐26.86 vs 9.66 ± 5.22, 95% CI: 5.29‐14.02, *: P = .04) and interleukin‐ (IL‐) 10 (20.1 ± 9.15, 95% CI: 14.82‐25.39 vs 11.52 ± 6.82, 95% CI: 5.82‐17.22, *: P = .03), whereas the expression of the adipokine leptin was attenuated in EAT of dogs with CES (3.07 ± 2.29, 95% CI: 1.80‐3.34 vs 9.83 ± 8.42, 95% CI: 3.36‐16.30, **: P = .007). Inflammatory stimulation of EAT explant cultures resulted in an enhanced release of IL‐6 (LPS: 5491.55 ± 4438, 95% CI: 833.7‐10 149; HMGB1: 1001.78 ± 522.2, 95% CI: 518.8‐1485; PBS: 310.9 ± 98.57, 95% CI: 228.5‐393.3, ***: P < .001). Conclusion and Clinical Importance Expression profile of inflammatory adipo(‐cyto)kines by EAT is influenced from compressive forces acting in dogs with CES and might contribute to amplification of pain.
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Affiliation(s)
- Stephan Leisengang
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany.,Center for Mind, Brain and Behavior - CMBB, Philipps University Marburg & Justus Liebig University Giessen, Giessen, Germany.,Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Dennis Gluding
- Department of Veterinary Clinical Sciences, Clinic for Small Animals (Surgery), Justus Liebig University Giessen, Giessen, Germany
| | - Julia Hörster
- Department of Veterinary Clinical Sciences, Small Animal Clinic - Neurosurgery, Neuroradiology and Clinical Neurology, Justus Liebig University Giessen, Giessen, Germany
| | - Verena Peek
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Daniela Ott
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Christoph Rummel
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany.,Center for Mind, Brain and Behavior - CMBB, Philipps University Marburg & Justus Liebig University Giessen, Giessen, Germany
| | - Martin J Schmidt
- Department of Veterinary Clinical Sciences, Small Animal Clinic - Neurosurgery, Neuroradiology and Clinical Neurology, Justus Liebig University Giessen, Giessen, Germany
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20
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Genkel VV, Dolgushin II, Baturina IL, Savochkina AY, Nikushkina KV, Minasova AA, Pykhova LR, Kuznetcova AS, Shaposhnik II. Relationships between serum HMGB1 concentration and subpopulation composition of circulating monocytes in patients with subclinical atherosclerosis. MEDICAL IMMUNOLOGY (RUSSIA) 2022; 24:807-820. [DOI: 10.15789/1563-0625-rbs-2508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Chronic non-infectious inflammation of low intensity is the most important mechanism of development and progression in atherosclerosis. Under the conditions of persistent non-resolving inflammation observed in the vascular wall and atherosclerotic plaque (ASB), permanent tissue damage occurs, thus leading to increased formation of endogenous danger-associated molecular patterns (DAMPs). The non-histone chromosomal protein HMGB1 may be regarded as a prototypical DAMPs. HMGB1 acts as a DAMP if entering the extracellular space, causing inflammation by its binding to pattern-recognizing receptors (TLR2, TLR4, RAGE, CD36, etc.). A number of clinical studies have revealed higher HMGB1 levels in the blood of patients with coronary heart disease and atherosclerotic disease of the lower limb arteries, as well as its interrelations with the burden of coronary artery atherosclerosis. Currently, the mechanisms of HMGB1-mediated atherosclerosis progression are studied only fragmentary. The aim of our study was to investigate relationships between the serum HMGB1 level and subsets of circulating monocyte subpopulations in patients with subclinical atherosclerosis.The study enrolled patients aged 40-64 years with subclinical atherosclerosis of peripheral arteries. Serum HMGB1 concentration was determined using enzyme immunoassay kits (Human HMGB1/HMG-1 ELISA Kit, NBP2-62766, Novus Biologicals, USA). The serum HMGB1 threshold was 18.75 pg/ml, whereas the measurement range was 31.25 to 2000 pg/ml. Phenotyping of the blood monocyte subpopulations was performed by flow cytometry using Navios 6/2 device (Beckman Coulter, USA).An increase in serum HMGB1 concentration was associated with decreased number of classical M2 monocytes, and an increase in intermediate and M1 monocytes. Moreover, an increase in HMGB1 concentration was associated with higher numbers of classical, intermediate, and non-classical monocytes expressing CD36 and TLR2. Increased HMGB1 concentration (from Q1 to Q4) correlated with higher numbers of classical (p = 0.001) and intermediate monocytes (p = 0.006) but not with non-classical phenotypes (p = 0.147). Upon increase of HMGB1 concentration (Q1 to Q4), we have found an increase in the number of classical (p < 0.0001), intermediate (p < 0.0001), and non-classical (p < 0.0001), CD36-expressing monocytes. An increased number of intermediate (p = 0.022; p1, 4 = 0.034) and non-classical, TLR2-expressing monocytes was also revealed (p = 0.002; p1, 4 = 0.035). By mean of correlation analysis, IL-1β concentrations showed direct correlation with the number of M1 monocytes (r = 0.268; p = 0.035) and inverse relation with the number of M2 monocytes (r = -0.376; p = 0.003).Increased serum HMGB1 concentration in patients with subclinical atherosclerosis was associated with decreased numbers of classical and M2 monocytes, as well as higher numbers of intermediate and M1 monocytes, like as with increased contents of intermediate and non-classical monocytes expressing CD36 and TLR2. IL-1β levels directly correlated with HMGB1 concentration and the number of Mi-monocytes.
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21
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Divella R, Gadaleta Caldarola G, Mazzocca A. Chronic Inflammation in Obesity and Cancer Cachexia. J Clin Med 2022; 11:2191. [PMID: 35456284 PMCID: PMC9027625 DOI: 10.3390/jcm11082191] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 12/14/2022] Open
Abstract
Chronic inflammation has long been linked to obesity and related conditions such as type 2 diabetes and metabolic syndrome. According to current research, the increased risk of cancer in people with certain metabolic diseases may be due to chronic inflammation. Adipocytokines, which are pro-inflammatory cytokines secreted in excess, are elevated in many chronic metabolic diseases. Cytokines and inflammatory mediators, which are not directly linked to DNA, are important in tumorigenesis. Cachexia, a type of metabolic syndrome linked to the disease, is associated with a dysregulation of metabolic pathways. Obesity and cachexia have distinct metabolic characteristics, such as insulin resistance, increased lipolysis, elevated free fatty acids (FFA), and ceramide levels, which are discussed in this section. The goal of this research project is to create a framework for bringing together our knowledge of inflammation-mediated insulin resistance.
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Affiliation(s)
- Rosa Divella
- ASD Nordic Walking Apulia Lifestyle, Corso Giuseppe Di Vittorio 14, 70024 Gravina in Puglia, Italy
| | | | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
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22
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Liu S, Wang X, Kai Y, Tian C, Guo S, He L, Zhai D, Song X. Clinical significance of high mobility group box 1/toll-like receptor 4 in obese diabetic patients. Endocr J 2022; 69:235-242. [PMID: 34657898 DOI: 10.1507/endocrj.ej21-0381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
High mobility group box 1 (HMGB1) is an alarmin that may link to obesity and type 2 diabetes mellitus (T2DM). The present study analyzed the correlation between HMGB1/ Toll-like receptor 4 (TLR4) and certain biochemical parameters in obese (OB) diabetic patients. 40 normal glucose tolerant subjects (NGT) and 40 patients with newly diagnosed T2DM were enrolled. All patients were further divided into non-obese NGT (NGT-NOB), obese NGT (NGT-OB), non-obese T2DM (T2DM-NOB) and obese T2DM (T2DM-OB) groups according to body mass index (BMI).The levels of HMGB1 in serum were quantified using ELISA, whereas the mRNA expression levels of TLR4 in peripheral blood mononuclear cells were assessed using reverse transcription-quantitative PCR. The results suggested that the levels of HMGB1 and TLR4 were higher in NGT-OB and T2DM-NOB groups compared with those in NGT-NOB group. Similarly, the levels of these two markers were higher in T2DM-OB group compared with those in NGT-OB group. Correlation analysis indicated that the levels of HMGB1 and TLR4 were positively correlated with triglyceride (TG), fasting plasma glucose (FPG) levels and BMI, whereas a negative correlation between HMGB1 and high density lipoprotein (HDL) was noted. Linear regression analysis suggested that HMGB1 was associated with FPG and TG levels, whereas TLR4 was strongly associated with TG levels and BMI. The results demonstrated that the expression levels of HMGB1 and TLR4 in patients with T2DM or obesity were increased, which were associated with glycolipid metabolism disorders. Therefore, the HMGB1/TLR4 may serve a role in inflammatory process associated with obesity and T2DM.
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Affiliation(s)
- Shuai Liu
- Department of Blood Transfusion, the Third Affiliated Hospital of Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Xianchun Wang
- Clinical laboratory, the Third Affiliated Hospital of Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Yue Kai
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
| | - Chenrui Tian
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
| | - Sheng Guo
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
| | - Ling He
- Department of Ophthalmology, the 371 Affiliated Hospital of Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Desheng Zhai
- Department of Epidemiology and Biostatistics, School of Public Health, Xinxiang Medical University, Henan Xinxiang, 453003, China
| | - Xiangfeng Song
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Henan Xinxiang, 453003, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Henan Xinxiang, 453000, China
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Wrba L, Halbgebauer R, Roos J, Huber-Lang M, Fischer-Posovszky P. Adipose tissue: a neglected organ in the response to severe trauma? Cell Mol Life Sci 2022; 79:207. [PMID: 35338424 PMCID: PMC8956559 DOI: 10.1007/s00018-022-04234-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/17/2022] [Accepted: 03/07/2022] [Indexed: 01/01/2023]
Abstract
Despite the manifold recent efforts to improve patient outcomes, trauma still is a clinical and socioeconomical issue of major relevance especially in younger people. The systemic immune reaction after severe injury is characterized by a strong pro- and anti-inflammatory response. Besides its functions as energy storage depot and organ-protective cushion, adipose tissue regulates vital processes via its secretion products. However, there is little awareness of the important role of adipose tissue in regulating the posttraumatic inflammatory response. In this review, we delineate the local and systemic role of adipose tissue in trauma and outline different aspects of adipose tissue as an immunologically active modifier of inflammation and as an immune target of injured remote organs after severe trauma.
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Affiliation(s)
- Lisa Wrba
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
- Department of Trauma, Orthopedic, Plastic and Hand Surgery, University Hospital of Augsburg, Augsburg, Germany
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Julian Roos
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Eythstr. 24, 89075, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Pamela Fischer-Posovszky
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Eythstr. 24, 89075, Ulm, Germany.
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24
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Assumpção JAF, Pasquarelli-do-Nascimento G, Duarte MSV, Bonamino MH, Magalhães KG. The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy. J Biomed Sci 2022; 29:12. [PMID: 35164764 PMCID: PMC8842976 DOI: 10.1186/s12929-022-00796-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
Obesity is nowadays considered a pandemic which prevalence's has been steadily increasingly in western countries. It is a dynamic, complex, and multifactorial disease which propitiates the development of several metabolic and cardiovascular diseases, as well as cancer. Excessive adipose tissue has been causally related to cancer progression and is a preventable risk factor for overall and cancer-specific survival, associated with poor prognosis in cancer patients. The onset of obesity features a state of chronic low-grade inflammation and secretion of a diversity of adipocyte-derived molecules (adipokines, cytokines, hormones), responsible for altering the metabolic, inflammatory, and immune landscape. The crosstalk between adipocytes and tumor cells fuels the tumor microenvironment with pro-inflammatory factors, promoting tissue injury, mutagenesis, invasion, and metastasis. Although classically established as a risk factor for cancer and treatment toxicity, recent evidence suggests mild obesity is related to better outcomes, with obese cancer patients showing better responses to treatment when compared to lean cancer patients. This phenomenon is termed obesity paradox and has been reported in different types and stages of cancer. The mechanisms underlying this paradoxical relationship between obesity and cancer are still not fully described but point to systemic alterations in metabolic fitness and modulation of the tumor microenvironment by obesity-associated molecules. Obesity impacts the response to cancer treatments, such as chemotherapy and immunotherapy, and has been reported as having a positive association with immune checkpoint therapy. In this review, we discuss obesity's association to inflammation and cancer, also highlighting potential physiological and biological mechanisms underlying this association, hoping to clarify the existence and impact of obesity paradox in cancer development and treatment.
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Affiliation(s)
| | | | - Mariana Saldanha Viegas Duarte
- Immunology and Tumor Biology Program - Research Coordination, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - Martín Hernan Bonamino
- Immunology and Tumor Biology Program - Research Coordination, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
- Vice - Presidency of Research and Biological Collections (VPPCB), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Kelly Grace Magalhães
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil.
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Selejan SR, Linz D, Mauz M, Hohl M, Huynh AKD, Speer T, Wintrich J, Kazakov A, Werner C, Mahfoud F, Böhm M. Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome. Basic Res Cardiol 2022; 117:36. [PMID: 35834066 PMCID: PMC9283368 DOI: 10.1007/s00395-022-00943-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 06/22/2022] [Accepted: 06/26/2022] [Indexed: 01/31/2023]
Abstract
Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (- 62%) in SHRob as compared with controls. RDN reduced RAGE expression (- 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (- 57% CML and - 51% HMGB1) with reduced pro-inflammatory NFkB activation (- 96%), IL-6 production (- 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (- 33%), collagen type I content (- 72%), accompanied by reduced LA myocyte hypertrophy (- 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.
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Affiliation(s)
- Simina-Ramona Selejan
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Dominik Linz
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Muriel Mauz
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Mathias Hohl
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Anh Khoa Dennis Huynh
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Thimoteus Speer
- Klinik für Innere Medizin IV (Nephrologie und Hochdruckkrankheiten), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg/Saar, Germany
| | - Jan Wintrich
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Andrey Kazakov
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Christian Werner
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Felix Mahfoud
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
| | - Michael Böhm
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrbergerstr. 100, Geb. 41.1 (IMED), 66421 Homburg/Saar, Germany
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26
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HMGB-1 in Psoriasis. Biomolecules 2021; 12:biom12010060. [PMID: 35053208 PMCID: PMC8774071 DOI: 10.3390/biom12010060] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/10/2021] [Accepted: 12/29/2021] [Indexed: 11/20/2022] Open
Abstract
Psoriasis is a multifactorial pathology linked to systemic inflammation. Enhanced keratinocytes proliferation and a minor maturation state of the cells are typical features. Perivascular T cells, dendritic cells, macrophages, and neutrophilic granulocytes are part of the scenario completed by apoptosis dysregulation. Several proinflammatory mediators, alarmins and growth factors are increased too, both in the skin and the patients’ blood. HMGB1 is important as an alarmin in several inflammatory conditions. Released after cellular damage, HMGB1 acts as a danger signal. Several studies have considered its role in psoriasis pathogenesis. We evaluated its level in psoriasis and the potential of the alarmin blockade through standard therapies, biological treatments and using monoclonal antibodies. PV patients were shown to have significantly increased levels of HMGB1 both in lesional skin and in serum, which were linked, in some cases, to other pro-inflammatory markers and alarmins. In most cases these parameters were correlated with PASI score. Data demonstrated that blocking HMGB1 is effective in ameliorating psoriasis. Focusing on this approach could be valuable in terms of a therapeutic option for counteracting immune-related diseases in a way unthinkable until few years ago.
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27
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Di Salvo E, Di Gioacchino M, Tonacci A, Casciaro M, Gangemi S. Alarmins, COVID-19 and comorbidities. Ann Med 2021; 53:777-785. [PMID: 34042528 PMCID: PMC8168739 DOI: 10.1080/07853890.2021.1921252] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/16/2021] [Indexed: 02/07/2023] Open
Abstract
The coronavirus SARS-CoV-2, the aetiological agent of COVID-19 disease, is representing a worldwide threat for the medical community and the society at large so that it is being defined as "the twenty-first-century disease". Often associated with a severe cytokine storm, leading to more severe cases, it is mandatory to block such occurrence early in the disease course, to prevent the patients from having more severe, sometimes fatal, outcomes. In this framework, early detection of "danger signals", possibly represented by alarmins, can represent one of the most promising strategies to effectively tailor the disease and to better understand the underlying mechanisms eventually leading to death or severe consequences. In light of such considerations, the present article aims at evaluating the role of alarmins in patients affected by COVID-19 disease and the relationship of such compounds with the most commonly reported comorbidities. The conducted researches demonstrated yet poor literature on this specific topic, however preliminarily confirming a role for danger signals in the amplification of the inflammatory reaction associated with SARS-CoV-2 infection. As such, a number of chronic conditions, including metabolic syndrome, gastrointestinal and respiratory diseases, in turn, associated with higher levels of alarmins, both foster the infection and predispose to a worse prognosis. According to these preliminary data, prompt detection of high levels of alarmins in patients with COVID-19 and co-morbidities could suggest an immediate intense anti-inflammatory treatment.Key messageAlarmins have a role in the amplification of the inflammatory reaction associated with SARS-CoV-2 infectiona prompt detection of high levels of alarmins in patients with COVID-19 could suggest an immediate intense anti-inflammatory treatment.
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Affiliation(s)
- Eleonora Di Salvo
- Department of Veterinary Sciences, University of Messina, Messina, Italy
| | - Mario Di Gioacchino
- Center for Advanced Studies and Technology, G. d’Annunzio University, Chieti, Italy
- YDA – Institute for Clinical Immunotherapy and Advanced Biological Treatments, Pescara, Italy
| | - Alessandro Tonacci
- National Research Council of Italy (IFC-CNR), Clinical Physiology Institute, Pisa, Italy
| | - Marco Casciaro
- Department of Clinical and Experimental Medicine, Unit and School of Allergy and Clinical Immunology, University of Messina, Messina
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, Unit and School of Allergy and Clinical Immunology, University of Messina, Messina
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Rosita R, Yueniwati Y, Endharti AT, Widodo MA. High-Glucose and Free Fatty Acid-Induced Adipocytes Generate Increasing of HMGB1 and Reduced GLUT4 Expression. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background
High-mobility group box 1 protein (HMGB1) is released from necrotic adipocytes into the extracellular milieu as an inflammatory alarmin in obesity. Although the impact of excess nutrient on adipocytes is well known, it is not clear how specific its component drive cell-size and damaged of adipocytes, and how this relates to the risk of insulin resistance.
Objectives
The aim of this study was to determine HMGB1 level in adipocytes cultures after high glucose and/or FFA exposures and to assess GLUT4 expression. We determined cellular features of adipocytes that correlates to HMGB1 released and insulin resistance.
Methods
Differentiated adipocytes were exposed to high glucose and/or FFAs for 7 days. ELISA was performed on supernatant to assess the HMGB1 level. Total GLUT4 expression were quantified by immunofluorescense.
Results
High glucose and FFA-exposed cells have significant increase of HMGB1 level with decreased of cell size and necrotic adipocytes features. The total GLUT4 were reduced in HG-cells (p <0,045), but not in FFA cells. Hypertrophic adipocytes (p <0.05) and slight decrease of GLUT4 expression were showed on HG+FFA exposures with no increase of HMGB1 level. There was a significant correlation between cell size and HMGB1 level (R -0,637, p < 0.026)
Conclusion
The expression level studies between high glucose, FFA, and a combination of both on adipocytes results strongly suggest that high glucose is more damaging to adipocyte compared to FFA. Nevertheless, the combination of the two causes adipocyte dysfunction with general features of adipose tissue in obesity, suggested it can be used as a hypertrophic adipocytes model to study obesity in vitro.
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Chukwurah E, Farabaugh KT, Guan BJ, Ramakrishnan P, Hatzoglou M. A tale of two proteins: PACT and PKR and their roles in inflammation. FEBS J 2021; 288:6365-6391. [PMID: 33387379 PMCID: PMC9248962 DOI: 10.1111/febs.15691] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/14/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022]
Abstract
Inflammation is a pathological hallmark associated with bacterial and viral infections, autoimmune diseases, genetic disorders, obesity and diabetes, as well as environmental stresses including physical and chemical trauma. Among numerous proteins regulating proinflammatory signaling, very few such as Protein kinase R (PKR), have been shown to play an all-pervading role in inflammation induced by varied stimuli. PKR was initially characterized as an interferon-inducible gene activated by viral double-stranded RNA with a role in protein translation inhibition. However, it has become increasingly clear that PKR is involved in multiple pathways that promote inflammation in response to stress activation, both dependent on and independent of its cellular protein activator of PKR (PACT). In this review, we discuss the signaling pathways that contribute to the initiation of inflammation, including Toll-like receptor, interferon, and RIG-I-like receptor signaling, as well as inflammasome activation. We go on to discuss the specific roles that PKR and PACT play in such proinflammatory signaling, as well as in metabolic syndrome- and environmental stress-induced inflammation.
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Affiliation(s)
- Evelyn Chukwurah
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106
| | - Kenneth T. Farabaugh
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106
| | - Bo-Jhih Guan
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106
| | | | - Maria Hatzoglou
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106
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30
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Guzmán-Ruiz R, Tercero-Alcázar C, López-Alcalá J, Sánchez-Ceinos J, Malagón MM, Gordon A. The potential role of the adipokine HMGB1 in obesity and insulin resistance. Novel effects on adipose tissue biology. Mol Cell Endocrinol 2021; 536:111417. [PMID: 34339826 DOI: 10.1016/j.mce.2021.111417] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 12/19/2022]
Abstract
Discovery of the adipose tissue as a major source of signaling molecules almost three decades ago set a novel physiological paradigm that paved the way for the identification of metabolic organs as endocrine organs. Adipocytes, the main adipose tissue cell type, do not only represent the principal site of energy storage in form of triglycerides, but also produce a variety of molecules for short and long distance intercellular communication, named adipokines, which coordinate systemic responses. Although the best known adipokines identified and characterized hitherto are leptin and adiponectin, novel adipokines are continuously being described, what have significantly helped to elucidate the role of adipocyte biology in obesity and associated comorbidities. One of these novel adipokines is high-mobility group box 1 (HMGB1), a ubiquitous nuclear protein that has been recently reported to be dysregulated in obese dysfunctional adipocytes. Although the classical function of HMGB1 is related to inflammation and immunity, acting as an alarmin, novel advances evidence an active implication of HMGB1 in tissue remodeling and fibrosis. This review summarizes the current evidence on the mechanisms controlling HMGB1 release, as well as its role as a regulator of adipocyte function and extracellular matrix remodeling, with special emphasis on the potential of this novel adipokine as a target in the obesity treatment.
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Affiliation(s)
- R Guzmán-Ruiz
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofia University Hospital, 14014, Córdoba, Spain; CIBER Fisiopatología de La Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Spain.
| | - C Tercero-Alcázar
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofia University Hospital, 14014, Córdoba, Spain; CIBER Fisiopatología de La Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Spain
| | - J López-Alcalá
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofia University Hospital, 14014, Córdoba, Spain; CIBER Fisiopatología de La Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Spain
| | - J Sánchez-Ceinos
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofia University Hospital, 14014, Córdoba, Spain; CIBER Fisiopatología de La Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Spain
| | - M M Malagón
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofia University Hospital, 14014, Córdoba, Spain; CIBER Fisiopatología de La Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Spain
| | - A Gordon
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofia University Hospital, 14014, Córdoba, Spain; CIBER Fisiopatología de La Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Spain
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Zhao Y, Li W, Zhang D. Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus. Mol Med Rep 2021; 24:755. [PMID: 34476498 PMCID: PMC8436226 DOI: 10.3892/mmr.2021.12395] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 11/05/2020] [Indexed: 11/22/2022] Open
Abstract
Gycyrrhizic acid (GA), an inhibitor of high mobility group box 1 (HMGB1), inhibits inflammatory responses and is involved in the occurrence and development of several inflammation-related diseases. However, the role of GA in the atherosclerotic lesions caused by diabetes mellitus (DM) remains unknown. In the present study, Sprague Dawley rats were selected to desi=gn a diabetic atherosclerosis (AS) model. Rats from the DM-AS group were subsequently divided into DM-AS, DM-AS + GA (50 mg/kg) and DM-AS + GA (150 mg/kg) groups. Biochemical analyzers were used to measure levels of blood glucose, fasting insulin, total cholesterol, total triglyceride, low-density lipoprotein and high-density lipoprotein. The number of plaques was recorded after collection of thoracic aortas from the rats. The intimal thickness of arterial tissue was detected by hematoxylin and eosin staining. The expression levels of CD68 and α-smooth muscle actin (α-SMA) were detected by immunohistochemistry. The expression of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β in the serum of the rats was detected by ELISA. The expression of fatty acid synthetase, sterol regulatory element binding protein 1C, HMGB1 and receptor for advanced glycation end products (RAGE) was detected by western blotting. Reverse transcription quantitative PCR was used to detect the mRNA expression of HMGB1 and RAGE. The results demonstrated that GA treatment could decrease the body weight, blood glucose level and biochemical parameters of AS DM rats in a dose-dependent manner. In addition, GA decreased the intimal thickness of carotid artery and the formation of plaque in rats with diabetic AS. Furthermore, GA inhibited macrophage activation and decreased α-SMA expression in vascular smooth muscle cells, and decreased the expression of proteins (FAS and SREBP-1c) and inflammatory factors. Taken together, the findings from the present study demonstrated that GA may have a therapeutic effect on DM-associated AS. This study provides a theoretical basis for the treatment of diabetic AS.
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Affiliation(s)
- Yaodong Zhao
- Department of General Internal Medicine, The Fifth Affiliated Hospital of Zhengzhou University, Zhenzhou, Henan 450052, P.R. China
| | - Wei Li
- Department of General Internal Medicine, The Fifth Affiliated Hospital of Zhengzhou University, Zhenzhou, Henan 450052, P.R. China
| | - Daimin Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
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Coppola A, Capuani B, Pacifici F, Pastore D, Arriga R, Bellia A, Andreadi A, Di Daniele N, Lauro R, Della-Morte D, Sconocchia G, Lauro D. Activation of Peripheral Blood Mononuclear Cells and Leptin Secretion: New Potential Role of Interleukin-2 and High Mobility Group Box (HMGB)1. Int J Mol Sci 2021; 22:ijms22157988. [PMID: 34360753 PMCID: PMC8347813 DOI: 10.3390/ijms22157988] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/18/2021] [Accepted: 07/22/2021] [Indexed: 01/15/2023] Open
Abstract
Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1β from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.
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Affiliation(s)
- Andrea Coppola
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
| | - Barbara Capuani
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
| | - Francesca Pacifici
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
| | - Donatella Pastore
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
| | - Roberto Arriga
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
| | - Alfonso Bellia
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
- Department of Medical Sciences, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy
| | - Aikaterini Andreadi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
- Department of Medical Sciences, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy
| | - Nicola Di Daniele
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
- Department of Medical Sciences, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy
| | - Renato Lauro
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
| | - David Della-Morte
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Rome Open University, 00166 Rome, Italy
| | - Giuseppe Sconocchia
- Institute of Translational Pharmacology, National Research Council Rome, 00133 Rome, Italy;
| | - Davide Lauro
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (A.C.); (B.C.); (F.P.); (D.P.); (R.A.); (A.B.); (A.A.); (N.D.D.); (R.L.); (D.D.-M.)
- Department of Medical Sciences, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy
- Correspondence: ; Tel.: +39-(06)-2090-4666 or +39-(33)-773-5770; Fax: +39-(06)-20904668
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Roszkowski L, Ciechomska M. Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis. Cells 2021; 10:cells10081860. [PMID: 34440629 PMCID: PMC8392289 DOI: 10.3390/cells10081860] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/21/2022] Open
Abstract
Monocytes/macrophages play a central role in chronic inflammatory disorders, including rheumatoid arthritis (RA). Activation of these cells results in the production of various mediators responsible for inflammation and RA pathogenesis. On the other hand, the depletion of macrophages using specific antibodies or chemical agents can prevent their synovial tissue infiltration and subsequently attenuates inflammation. Their plasticity is a major feature that helps the switch from a pro-inflammatory phenotype (M1) to an anti-inflammatory state (M2). Therefore, understanding the precise strategy targeting pro-inflammatory monocytes/macrophages should be a powerful way of inhibiting chronic inflammation and bone erosion. In this review, we demonstrate potential consequences of different epigenetic regulations on inflammatory cytokines production by monocytes. In addition, we present unique profiles of monocytes/macrophages contributing to identification of new biomarkers of disease activity or predicting treatment response in RA. We also outline novel approaches of tuning monocytes/macrophages by biologic drugs, small molecules or by other therapeutic modalities to reduce arthritis. Finally, the importance of cellular heterogeneity of monocytes/macrophages is highlighted by single-cell technologies, which leads to the design of cell-specific therapeutic protocols for personalized medicine in RA in the future.
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Chiappalupi S, Salvadori L, Donato R, Riuzzi F, Sorci G. Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19-The Role of RAGE-RAS Crosstalk. Biomolecules 2021; 11:biom11060876. [PMID: 34204735 PMCID: PMC8231494 DOI: 10.3390/biom11060876] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 02/07/2023] Open
Abstract
The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin-angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed. .
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Affiliation(s)
- Sara Chiappalupi
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (S.C.); (F.R.)
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
| | - Laura Salvadori
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy
| | - Rosario Donato
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Correspondence: (R.D.); (G.S.); Tel.: +39-075-585-8258 (G.S.)
| | - Francesca Riuzzi
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (S.C.); (F.R.)
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Consorzio Interuniversitario Biotecnologie (CIB), 34127 Trieste, Italy
| | - Guglielmo Sorci
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (S.C.); (F.R.)
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Consorzio Interuniversitario Biotecnologie (CIB), 34127 Trieste, Italy
- Centro Universitario di Ricerca Sulla Genomica Funzionale (CURGeF), University of Perugia, 06132 Perugia, Italy
- Correspondence: (R.D.); (G.S.); Tel.: +39-075-585-8258 (G.S.)
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Rojas A, Lindner C, Gonzàlez I, Morales MA. Advanced-glycation end-products axis: A contributor to the risk of severe illness from COVID-19 in diabetes patients. World J Diabetes 2021; 12:590-602. [PMID: 33995847 PMCID: PMC8107984 DOI: 10.4239/wjd.v12.i5.590] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/29/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products (RAGE) in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus (DM). During the coronavirus disease 2019 (COVID-19) pandemic, many clinical reports have pointed out that DM increases the risk of COVID-19 complications, hospitalization requirements, as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate. In the present review, we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype, as well as the contribution of RAGE signaling in lung inflammation, may then lead to the increased mortality risk of COVID-19 in these patients. Additionally, the cross-talk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection, as well as the role of this multi-ligand receptor on the obesity-associated low-grade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19, are also discussed.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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Frisardi V, Matrone C, Street ME. Metabolic Syndrome and Autophagy: Focus on HMGB1 Protein. Front Cell Dev Biol 2021; 9:654913. [PMID: 33912566 PMCID: PMC8072385 DOI: 10.3389/fcell.2021.654913] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/18/2021] [Indexed: 12/11/2022] Open
Abstract
Metabolic syndrome (MetS) affects the population worldwide and results from several factors such as genetic background, environment and lifestyle. In recent years, an interplay among autophagy, metabolism, and metabolic disorders has become apparent. Defects in the autophagy machinery are associated with the dysfunction of many tissues/organs regulating metabolism. Metabolic hormones and nutrients regulate, in turn, the autophagy mechanism. Autophagy is a housekeeping stress-induced degradation process that ensures cellular homeostasis. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein with a nuclear and extracellular role that functions as an extracellular signaling molecule under specific conditions. Several studies have shown that HMGB1 is a critical regulator of autophagy. This mini-review focuses on the involvement of HMGB1 protein in the interplay between autophagy and MetS, emphasizing its potential role as a promising biomarker candidate for the early stage of MetS or disease's therapeutic target.
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Affiliation(s)
- Vincenza Frisardi
- Clinical and Nutritional Laboratory, Department of Geriatric and NeuroRehabilitation, Arcispedale Santa Maria Nuova (AUSL-IRCCS), Reggio Emilia, Italy
| | - Carmela Matrone
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maria Elisabeth Street
- Division of Paediatric Endocrinology and Diabetology, Paediatrics, Department of Mother and Child, Arcispedale Santa Maria Nuova (AUSL-IRCCS), Reggio Emilia, Italy
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Garay-Sevilla ME, Gomez-Ojeda A, González I, Luévano-Contreras C, Rojas A. Contribution of RAGE axis activation to the association between metabolic syndrome and cancer. Mol Cell Biochem 2021; 476:1555-1573. [PMID: 33398664 DOI: 10.1007/s11010-020-04022-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023]
Abstract
Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.
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Affiliation(s)
- Ma Eugenia Garay-Sevilla
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Gomez-Ojeda
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Ileana González
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Claudia Luévano-Contreras
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile.
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Roy D, Ramasamy R, Schmidt AM. Journey to a Receptor for Advanced Glycation End Products Connection in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: With Stops Along the Way in the Lung, Heart, Blood Vessels, and Adipose Tissue. Arterioscler Thromb Vasc Biol 2021; 41:614-627. [PMID: 33327744 PMCID: PMC7837689 DOI: 10.1161/atvbaha.120.315527] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 11/30/2020] [Indexed: 01/08/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide and the pandemic has yet to wane. Despite its associated significant morbidity and mortality, there are no definitive cures and no fully preventative measures to combat SARS-CoV-2. Hence, the urgency to identify the pathobiological mechanisms underlying increased risk for and the severity of SARS-CoV-2 infection is mounting. One contributing factor, the accumulation of damage-associated molecular pattern molecules, is a leading trigger for the activation of nuclear factor-kB and the IRF (interferon regulatory factors), such as IRF7. Activation of these pathways, particularly in the lung and other organs, such as the heart, contributes to a burst of cytokine release, which predisposes to significant tissue damage, loss of function, and mortality. The receptor for advanced glycation end products (RAGE) binds damage-associated molecular patterns is expressed in the lung and heart, and in priming organs, such as the blood vessels (in diabetes) and adipose tissue (in obesity), and transduces the pathological signals emitted by damage-associated molecular patterns. It is proposed that damage-associated molecular pattern-RAGE enrichment in these priming tissues, and in the lungs and heart during active infection, contributes to the widespread tissue damage induced by SARS-CoV-2. Accordingly, the RAGE axis might play seminal roles in and be a target for therapeutic intervention in SARS-CoV-2 infection.
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Affiliation(s)
- Divya Roy
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine (D.R., R.R., A.M.S.)
- New York Institute of Technology College of Osteopathic Medicine, Glen Head (D.R.)
| | - Ravichandran Ramasamy
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine (D.R., R.R., A.M.S.)
| | - Ann Marie Schmidt
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine (D.R., R.R., A.M.S.)
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Luo Y, Lin H. Inflammation initiates a vicious cycle between obesity and nonalcoholic fatty liver disease. IMMUNITY INFLAMMATION AND DISEASE 2020; 9:59-73. [PMID: 33332766 PMCID: PMC7860600 DOI: 10.1002/iid3.391] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/23/2020] [Accepted: 11/26/2020] [Indexed: 12/14/2022]
Abstract
Low‐level of chronic inflammation activation is characteristic of obesity. Nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity and is an emerging health problem, it originates from abnormal accumulation of triglycerides in the liver, and sometimes causes inflammatory reactions that could contribute to cirrhosis and liver cancer, thus its pathogenesis needs to be clarified for more treatment options. Once NAFLD is established, it contributes to systemic inflammation, the low‐grade inflammation is continuously maintained during NAFLD causing impaired resolution of inflammation in obesity, which subsequently exacerbates its severity. This study focuses on the effects of obesity‐induced inflammations, which are the underlying causes of the disease progression and development of more severe inflammatory and fibrotic stages. Understanding the relationship between obesity and NAFLD could help in establishing attractive therapeutic targets or diagnostic markers in obesity‐induced inflammation response and provides new approaches for the prevention and treatment of NAFLD in obesity.
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Affiliation(s)
- Yunfei Luo
- Department of Pathophysiology, Schools of Basic Sciences, Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, China
| | - Hui Lin
- Department of Pathophysiology, Schools of Basic Sciences, Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, China
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Abstract
The advanced glycosylation end product receptor (RAGE) acts as a recognition receptor and interacts with different types of ligands that form and accumulate in the tissues and circulation, such as diabetes, inflammation, insulin resistance, and obesity. In these environments, RAGE is expressed on the surface of various cells associated with tissue disturbance. This review mainly summarizes the characteristics of RAGE-related signalling, with a particular emphasis on the role of RAGE in the development of obesity. We also briefly describe the phenotypes and characteristics of macrophages and focus on the role of adipose tissue macrophages (ATMs) and the regulatory mechanisms in obesity, diabetes, and other related metabolic diseases. Besides, we will also elaborate on the prospect of new strategies for treating diabetes and obesity-related metabolic diseases by inhibiting RAGE signalling and regulating ATMs recruitment and polarization.
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Affiliation(s)
- Ziqian Feng
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Luochen Zhu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Jianbo Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
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Lin M, Long J, Li W, Yang C, Loughran P, O'Doherty R, Billiar TR, Deng M, Scott MJ. Hepatocyte high-mobility group box 1 protects against steatosis and cellular stress during high fat diet feeding. Mol Med 2020; 26:115. [PMID: 33238880 PMCID: PMC7687718 DOI: 10.1186/s10020-020-00227-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Circulating high-mobility group box 1 (HMGB1) plays important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Intracellular HMGB1 is critical for the biology of hepatocytes. However, the intracellular role of HMGB1 in hepatocellular steatosis is unknown. Therefore, we aimed to investigate the role of hepatocyte-specific HMGB1 (HC-HMGB1) in development of hepatic steatosis. METHODS Wild type (WT) C57BL/6 and HC-HMGB1-/- mice were fed high-fat diet (HFD) or low-fat diet (LFD) for up to 16 weeks. RESULTS As expected, HMGB1 translocated from nuclear into cytoplasm and released into circulation after HFD treatment. HC-HMGB1 deficiency significantly reduced circulating HMGB1, suggesting that hepatocyte is a major source of circulating HMGB1 during NAFLD. Unexpectedly, HC-HMGB1 deficiency promoted rapid weight gain with enhanced hepatic fat deposition compared with WT at as early as 4 weeks after HFD treatment. Furthermore, there was no difference between WT and HC-HMGB1-/- mice in glucose tolerance, energy expenditure, liver damage or systemic inflammation. Interestingly, hepatic gene expression related to free fatty acid (FFA) β-oxidation was significantly down-regulated in HC-HMGB1-/- mice compared with WT, and endoplasmic reticulum (ER) stress markers were significantly higher in livers of HC-HMGB1-/- mice. In vitro experiments using primary mouse hepatocytes showed absence of HMGB1 increased FFA-induced intracellular lipid accumulation, accompanied by increased ER-stress, significant downregulation of FFA β-oxidation, and reduced oxidative phosphorylation. CONCLUSIONS Our findings suggest that hepatocyte HMGB1 protects against dysregulated lipid metabolism via maintenance of β-oxidation and prevention of ER stress. This represents a novel mechanism for HMGB1-regulation of hepatocellular steatosis, and suggests that stabilizing HMGB1 in hepatocytes may be effective strategies for prevention and treatment of NAFLD.
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Affiliation(s)
- Minjie Lin
- Clinical Skills Training Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Jungke Long
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Wenbo Li
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Department of Plastic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Chenxuan Yang
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Tsinghua University School of Medicine, Beijing, 100084, China
| | - Patricia Loughran
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Robert O'Doherty
- The Center for Metabolism and Mitochondrial Medicine of University of Pittsburgh, Pittsburgh, PA, 15260, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Meihong Deng
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
- University of Pittsburgh, NW607 MUH, 3459 Fifth Ave, Pittsburgh, PA, 15213, USA.
| | - Melanie J Scott
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
- University of Pittsburgh, NW653 MUH, 3459 Fifth Ave, Pittsburgh, PA, 15213, USA.
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Yang L, Zhou L, Wang X, Wang W, Wang J. Inhibition of HMGB1 involved in the protective of salidroside on liver injury in diabetes mice. Int Immunopharmacol 2020; 89:106987. [PMID: 33217691 DOI: 10.1016/j.intimp.2020.106987] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/04/2020] [Accepted: 09/05/2020] [Indexed: 12/22/2022]
Abstract
High mobility group box 1 (HMGB1) is a nuclear protein that is released on injury triggers inflammation. This study aims to elucidate the effects of salidroside on diabetes-induced liver inflammation. The levels of glucose, inflammatory cytokines and hepatic functional parameters in serum and liver of type 2 diabetic db/db mice were examined. Immunohistochemistry, immunofluorescence and western blot tests were performed to determine the mechanisms underlying the action. Palmitic acid (PA) or HMGB1-stimulated was adopted as an in vitro cell model. Salidroside treatment improved glucose tolerance, lipid profiles while decreased the production of inflammatory cytokines. It also reduced the levels of serum biochemical markers. In addition, salidroside inhibited HMGB1 signaling pathway in db/db mice. In the salidroside treatment significantly inhibited PA or HMGB1 induced inflammatory signaling pathway, too. HMGB1 inhibitors and HMGB1 knockdown both hindered PA-induced HMGB1 signaling pathway, showing the same effect as salidroside. Salidroside treatment significantly alleviates insulin resistance, hyperglycemia and hepatic inflammation in db/db mice, and also showed beneficial to PA-stimulated. Salidroside proves to control hyperglycemia and hepatic inflammation via inhibiting HMGB1/RAGE/NF-κB and HMGB1/TLR4/NLRP3 signaling pathways.
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Affiliation(s)
- Limin Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province 450052, PR China.
| | - Lin Zhou
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province 450052, PR China.
| | - Xiaohui Wang
- Department of Ultrasonography, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province 450052, PR China.
| | - Wang Wang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, PR China.
| | - Jin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province 450052, PR China.
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Chen L, Zhu H, Su S, Harshfield G, Sullivan J, Webb C, Blumenthal JA, Wang X, Huang Y, Treiber FA, Kapuku G, Li W, Dong Y. High-Mobility Group Box-1 Is Associated With Obesity, Inflammation, and Subclinical Cardiovascular Risk Among Young Adults: A Longitudinal Cohort Study. Arterioscler Thromb Vasc Biol 2020; 40:2776-2784. [PMID: 32814439 PMCID: PMC7578115 DOI: 10.1161/atvbaha.120.314599] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE We aimed to characterize circulating HMGB1 (high-mobility group box-1) levels, one of the better-characterized damage-associated molecular patterns, with respect to age, sex, and race in the general population, and investigate the longitudinal associations of HMGB1 with inflammatory markers, obesity, and preclinical markers of cardiovascular disease. Approach and Results: The analyses included 489 participants (50% Blacks, aged 24.6±3.3 years at the first visit) with up to 4 follow-up visits (1149 samples) over a maximum of 8.5 years. Systolic blood pressure, diastolic blood pressure, carotid-femoral pulse wave velocity, and carotid intima-media thickness together with plasma HMGB1, hs-CRP (high-sensitivity C-reactive protein), IFN-γ (interferon-γ), IL-6 (interleukin-6), IL-10 (interleukin-10), and TNF-α (tumor necrosis factor-α) were measured at each visit. At baseline, plasma HMGB1 concentrations were higher in Blacks compared with Whites (3.86 versus 3.20 ng/mL, P<0.001), and in females compared with males (3.75 versus 3.30 ng/mL, P=0.005). HMGB1 concentrations increased with age (P=0.007), and higher levels of obesity measures (P<0.001). Without adjustment for age, sex, race, and body mass index, HMGB1 concentrations were positively associated with hs-CRP, IL-6, TNF-α, systolic blood pressure, diastolic blood pressure, and carotid-femoral pulse wave velocity (P<0.05) but not IL-10, IFN-γ or carotid intima-media thickness. After covariate adjustments, the associations of HMGB1 with hs-CRP, and carotid-femoral pulse wave velocity remained statistically significant (P<0.05). CONCLUSIONS This study demonstrates the age, sex, and race differences in circulating HMGB1. The increasing circulating concentrations of HMGB1 with age suggest a potential role of HMGB1 in the pathogenesis of chronic low-grade inflammation, obesity, and subclinical cardiovascular disease risk.
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Affiliation(s)
- Li Chen
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Haidong Zhu
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Shaoyong Su
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Gregory Harshfield
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Jennifer Sullivan
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Clinton Webb
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - James A. Blumenthal
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - Xiaoling Wang
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Ying Huang
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Frank A. Treiber
- College of Nursing, Medical University of South Carolina, Charleston, SC, USA
- College of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Gaston Kapuku
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Wenjun Li
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Yanbin Dong
- Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
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From cachexia to obesity: the role of host metabolism in cancer immunotherapy. Curr Opin Support Palliat Care 2020; 13:305-310. [PMID: 31389842 DOI: 10.1097/spc.0000000000000457] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Currently, several clinical trials in cancer therapy have demonstrated the success of immunomodulatory therapies. However, only a variable fraction of patients actually benefit from these treatments. The understanding of key mechanisms behind this response heterogeneity is one of the major unmet need and intense research field in immuno-oncology. This review will discuss the host metabolic dysfunctions derived from cachexia or obesity that can affect the response to cancer immunotherapy. RECENT FINDINGS Preclinical studies demonstrated that chronic inflammation, nutritional intake impairment and endocrine dysfunction may affect anticancer innate and adaptive immunity, both in cachexia and obesity. New emerging clinical findings have highlighted the impact of metabolic biomarkers in predicting response to immune checkpoint inhibitors in cancer patients. SUMMARY Patient's weight and inflammatory status could be relevant in the clinical decision-making process before starting cancer immunotherapy and for an effective patient selection and stratification in future clinical trials employing this class of anticancer agents.
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Wong SK, Chin KY, Ima-Nirwana S. Toll-like Receptor as a Molecular Link between Metabolic Syndrome and Inflammation: A Review. Curr Drug Targets 2020; 20:1264-1280. [PMID: 30961493 DOI: 10.2174/1389450120666190405172524] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/29/2019] [Accepted: 04/01/2019] [Indexed: 02/07/2023]
Abstract
Metabolic Syndrome (MetS) involves a cluster of five conditions, i.e. obesity, hyperglycaemia, hypertension, hypertriglyceridemia and low High-Density Lipoprotein (HDL) cholesterol. All components of MetS share an underlying chronic inflammatory aetiology, manifested by increased levels of pro-inflammatory cytokines. The pathogenic role of inflammation in the development of MetS suggested that toll-like receptor (TLR) activation may trigger MetS. This review summarises the supporting evidence on the interactions between MetS and TLR activation, bridged by the elevation of TLR ligands during MetS. The regulatory circuits mediated by TLR activation, which modulates signal propagation, leading to the state of chronic inflammation, are also discussed. Taken together, TLR activation could be the molecular basis in the development of MetS-induced inflammation.
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Affiliation(s)
- Sok Kuan Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Soelaiman Ima-Nirwana
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia
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Cámara-Quílez M, Barreiro-Alonso A, Rodríguez-Bemonte E, Quindós-Varela M, Cerdán ME, Lamas-Maceiras M. Differential Characteristics of HMGB2 Versus HMGB1 and their Perspectives in Ovary and Prostate Cancer. Curr Med Chem 2020; 27:3271-3289. [PMID: 30674244 DOI: 10.2174/0929867326666190123120338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 10/28/2018] [Accepted: 12/06/2018] [Indexed: 01/24/2023]
Abstract
We have summarized common and differential functions of HMGB1 and HMGB2 proteins with reference to pathological processes, with a special focus on cancer. Currently, several "omic" approaches help us compare the relative expression of these 2 proteins in healthy and cancerous human specimens, as well as in a wide range of cancer-derived cell lines, or in fetal versus adult cells. Molecules that interfere with HMGB1 functions, though through different mechanisms, have been extensively tested as therapeutic agents in animal models in recent years, and their effects are summarized. The review concludes with a discussion on the perspectives of HMGB molecules as targets in prostate and ovarian cancers.
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Affiliation(s)
- María Cámara-Quílez
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - Aida Barreiro-Alonso
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - Esther Rodríguez-Bemonte
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - María Quindós-Varela
- Translational Cancer Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Carretera del Pasaje s/n, 15006 A Coruña, Spain
| | - M Esperanza Cerdán
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - Mónica Lamas-Maceiras
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
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Rohde K, Schamarek I, Blüher M. Consequences of Obesity on the Sense of Taste: Taste Buds as Treatment Targets? Diabetes Metab J 2020; 44:509-528. [PMID: 32431111 PMCID: PMC7453985 DOI: 10.4093/dmj.2020.0058] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 03/25/2020] [Indexed: 12/19/2022] Open
Abstract
Premature obesity-related mortality is caused by cardiovascular and pulmonary diseases, type 2 diabetes mellitus, physical disabilities, osteoarthritis, and certain types of cancer. Obesity is caused by a positive energy balance due to hyper-caloric nutrition, low physical activity, and energy expenditure. Overeating is partially driven by impaired homeostatic feedback of the peripheral energy status in obesity. However, food with its different qualities is a key driver for the reward driven hedonic feeding with tremendous consequences on calorie consumption. In addition to visual and olfactory cues, taste buds of the oral cavity process the earliest signals which affect the regulation of food intake, appetite and satiety. Therefore, taste buds may play a crucial role how food related signals are transmitted to the brain, particularly in priming the body for digestion during the cephalic phase. Indeed, obesity development is associated with a significant reduction in taste buds. Impaired taste bud sensitivity may play a causal role in the pathophysiology of obesity in children and adolescents. In addition, genetic variation in taste receptors has been linked to body weight regulation. This review discusses the importance of taste buds as contributing factors in the development of obesity and how obesity may affect the sense of taste, alterations in food preferences and eating behavior.
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Affiliation(s)
- Kerstin Rohde
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
| | - Imke Schamarek
- Medical Department III (Endocrinology, Nephrology and Rheumatology), University of Leipzig, Leipzig, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
- Medical Department III (Endocrinology, Nephrology and Rheumatology), University of Leipzig, Leipzig, Germany
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Late Peaks of HMGB1 and Sepsis Outcome: Evidence For Synergy With Chronic Inflammatory Disorders. Shock 2020; 52:334-339. [PMID: 30239421 DOI: 10.1097/shk.0000000000001265] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
High mobility group box 1 (HMGB1) is released from macrophages as a late biomarker of sepsis. Conditions associated with pre-existing macrophage activation may modify HMGB1 expression. This study aimed to assess the impact of HMGB1 kinetics on 28-day mortality. In a sub-study of a previous randomized clinical trial among patients with systemic inflammatory response syndrome and gram-negative infections, patients were classified in early and late HMGB1 peak groups. Serial measurements of HMGB1, ferritin and interferon-gamma (IFNγ) were performed in all available sera. Two hundred ten patients were included; 118 (46.5%) had at least one inflammatory disease (diabetes, chronic obstructive pulmonary disease, chronic heart failure, or chronic renal disease). Mortality after 28 days was higher among patients with a late peak of HMGB1 (OR 2.640; P = 0.026). Co-existence of late peak and inflammatory disease synergistically impacted mortality (odds ratio of logistic regression analysis 3.17; P: 0.027). Late peak was concomitantly associated with higher values of ferritin (P = 0.035), and IFNγ (P = 0.002) among patients with hyperferritinemia. It is concluded that late HMGB1 peak was associated with worse prognosis, especially in patients with underlying chronic inflammatory conditions.
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St-Germain LE, Castellana B, Baltayeva J, Beristain AG. Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation. Int J Mol Sci 2020; 21:E3776. [PMID: 32471078 PMCID: PMC7312391 DOI: 10.3390/ijms21113776] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 05/26/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammation is often equated to the physiological response to injury or infection. Inflammatory responses defined by cytokine storms control cellular mechanisms that can either resolve quickly (i.e., acute inflammation) or remain prolonged and unabated (i.e., chronic inflammation). Perhaps less well-appreciated is the importance of inflammatory processes central to healthy pregnancy, including implantation, early stages of placentation, and parturition. Pregnancy juxtaposed with disease can lead to the perpetuation of aberrant inflammation that likely contributes to or potentiates maternal morbidity and poor fetal outcome. Maternal obesity, a prevalent condition within women of reproductive age, associates with increased risk of developing multiple pregnancy disorders. Importantly, chronic low-grade inflammation is thought to underlie the development of obesity-related obstetric and perinatal complications. While diverse subsets of uterine immune cells play central roles in initiating and maintaining healthy pregnancy, uterine leukocyte dysfunction as a result of maternal obesity may underpin the development of pregnancy disorders. In this review we discuss the current knowledge related to the impact of maternal obesity and obesity-associated inflammation on uterine immune cell function, utero-placental establishment, and pregnancy health.
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Affiliation(s)
- Lauren E. St-Germain
- The British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; (L.E.S.-G.); (B.C.); (J.B.)
- Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, BC V6Z 2K8, Canada
| | - Barbara Castellana
- The British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; (L.E.S.-G.); (B.C.); (J.B.)
- Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, BC V6Z 2K8, Canada
| | - Jennet Baltayeva
- The British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; (L.E.S.-G.); (B.C.); (J.B.)
- Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, BC V6Z 2K8, Canada
| | - Alexander G. Beristain
- The British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; (L.E.S.-G.); (B.C.); (J.B.)
- Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, BC V6Z 2K8, Canada
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Soliman NA, Abdel Ghafar MT, El Kolaley RM, Hafez YM, Abo Elgheit RE, Atef MM. Cross talk between Hsp72, HMGB1 and RAGE/ERK1/2 signaling in the pathogenesis of bronchial asthma in obese patients. Mol Biol Rep 2020; 47:4109-4116. [PMID: 32424522 DOI: 10.1007/s11033-020-05531-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/14/2020] [Indexed: 01/12/2023]
Abstract
BACKGROUND The incidence of obesity-related asthma has shown a remarkable increase. OBJECTIVES We aimed to explore the role of heat shock protein 72 (Hsp72) and receptor for advanced glycation end products (RAGE) axis with its downstream signaling in the pathogenesis of obesity-related asthma. METHODS We enrolled a total of 55 subjects and divided them into three groups. Groups I and II included healthy, normal weight (n = 15) and obese (n = 15) subjects, respectively. Twenty-five obese asthmatics (group III) were subdivided into group IIIa (10 patients with mild to moderate asthma) and group IIIb (15 patients with severe asthma). High mobility group box 1 (HMGB1), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and urinary Hsp72 were immunoassayed. Hydrogen peroxide (H2O2) and free fatty acids (FFAs) levels were photometrically measured. RAGE mRNA expression was relatively quantified by real-time PCR. RESULTS We found significant elevations of serum HMGB1, IL-8, MCP1, ERK1/2, FFAs, and H2O2 levels as well as urinary Hsp72 levels in obese subjects compared to healthy control. These were more evident in patients with severe asthma (group IIIb). Multivariate regression analysis identified Hsp72 and ERK1/2 as independent predictors of bronchial asthma severity. Receiver operating characteristic (ROC) curve analysis revealed that areas under the curve (AUC) for Hsp72 and ERK1/2 were 0.991 and 0.981, respectively, which denotes a strong predictive value for identifying the severity of bronchial asthma in obese patients. CONCLUSION The current study highlights the role of Hsp72 and HMGB1/RAGE/ERK1/2 signaling cascade in the pathogenesis of bronchial asthma and its link to obesity, which could be reflected on monitoring, severity grading, and management of this disease.
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Affiliation(s)
- Nema Ali Soliman
- Departments of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Muhammad Tarek Abdel Ghafar
- Departments of Clinical Pathology, Faculty of Medicine, Tanta University, Medical Campus, El-Gash St, Tanta, 31527, Egypt.
| | | | - Yasser Mostafa Hafez
- Departments of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rehab E Abo Elgheit
- Departments of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Marwa Mohamed Atef
- Departments of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
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