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Ziqubu K, Mazibuko-Mbeje SE, Dludla PV. Regulation of adipokine and batokine secretion by dietary flavonoids, as a prospective therapeutic approach for obesity and its metabolic complications. Biochimie 2025; 230:95-113. [PMID: 39551425 DOI: 10.1016/j.biochi.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 10/27/2024] [Accepted: 11/13/2024] [Indexed: 11/19/2024]
Abstract
Traditionally recognised as the energy reservoir and main site of adaptive thermogenesis, white and brown adipose tissues are complex endocrine organs regulating systemic energy metabolism via the secretion of bioactive molecules, termed "adipokines" and "batokines", respectively. Due to its significant role in regulating whole-body energy metabolism and other physiological processes, adipose tissue has been increasingly explored as a feasible therapeutic target for obesity. Flavonoids are one of the most significant plant polyphenolic compounds holding a great potential as therapeutic agents for combating obesity. However, understanding their mechanisms of action remains largely insufficient to formulate therapeutic theories. This review critically discusses scientific evidence highlighting the role of flavonoids in ameliorating obesity-related metabolic complications, including adipose tissue dysfunction, inflammation, insulin resistance, hepatic steatosis, and cardiovascular comorbidities in part by modulating the release of adipokines and batokines. Further discussion advocates for the use of therapeutics targeting these bioactive molecules as a potential avenue for developing effective treatment for obesity and its adverse metabolic diseases such as type 2 diabetes.
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Affiliation(s)
- Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | | | - Phiwayinkosi V Dludla
- Cochrane South Africa, South African Medical Research Council, Tygerberg 7505, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa
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Mo L, Yang C, Dai Y, Liu W, Gong Y, Guo Y, Zhu Y, Cao Y, Xiao X, Du S, Lu S, He J. Novel drug delivery systems for hirudin-based product development and clinical applications. Int J Biol Macromol 2025; 287:138533. [PMID: 39657884 DOI: 10.1016/j.ijbiomac.2024.138533] [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: 09/23/2024] [Revised: 11/26/2024] [Accepted: 12/06/2024] [Indexed: 12/12/2024]
Abstract
Hirudin, a natural biological polypeptide macromolecule secreted by the salivary glands of medicinal leech, is a specific thrombin inhibitor with multiple favourable bioactivities, including anti-coagulation, anti-fibrotic, and anti-tumour. Despite several anticoagulants have been widely applied in clinic, hirudin shows advantages in reducing the incidence of bleeding side effects by virtue of its high specificity in binding to thrombin. As a result, hirudin has been tested in clinical practice to prevent and treat several complex diseases. However, the application of this polypeptide macromolecule is compromised by its low bioavailability and bioactivity due to poor serum stability and susceptibility to protease degradation in vivo. To overcome these drawbacks, several studies have proposed novel drug delivery systems (NDDSs) to prevent the degradation and increase the targeting efficiency of hirudin. This systematic review summarises the clinical research on hirudin, including its classification and bioactivities, and highlights the opportunities and challenges in the clinical use of hirudin. The NDDSs designed to enhance the bioavailability and bioactivity of hirudin are discussed to explore its application in the treatment of related diseases. This review may considerably contribute to the advancement of delivery science and technology, particularly in the context of polypeptide-based therapeutics.
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Affiliation(s)
- Liqing Mo
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Can Yang
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Yingxuan Dai
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Wei Liu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Yuhong Gong
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Yujie Guo
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan, 430061, PR China
| | - Yuxi Zhu
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Pediatrics, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH 44106, USA
| | - Yan Cao
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan, 430061, PR China
| | - Xuecheng Xiao
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan, 430061, PR China
| | - Shi Du
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
| | - Shan Lu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan, 430061, PR China.
| | - Jianhua He
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan, 430061, PR China.
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Markova I, Hüttl M, Gayova N, Miklankova D, Cerna K, Kavanova M, Skaroupkova P, Cacanyiova S, Malinska H. Visceral Adipose Tissue Inflammation and Vascular Complications in a Rat Model with Severe Dyslipidemia: Sex Differences and PAI-1 Tissue Involvement. Biomolecules 2024; 15:19. [PMID: 39858414 PMCID: PMC11763299 DOI: 10.3390/biom15010019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
We investigated the sex-dependent effects of inflammatory responses in visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT), as well as hematological status, in relation to cardiovascular disorders associated with prediabetes. Using male and female hereditary hypertriglyceridemic (HHTg) rats-a nonobese prediabetic model featuring dyslipidemia, hepatic steatosis, and insulin resistance-we found that HHTg females exhibited more pronounced hypertriglyceridemia than males, while HHTg males had higher non-fasting glucose levels. Additionally, HHTg females had higher platelet counts, larger platelet volumes, and lower antithrombin inhibitory activity. Regarding low-grade chronic inflammation, HHTg males exhibited increased serum leptin and leukocyte levels, while females had increased serum interleukin-6 (IL-6). Both sexes had increased circulating plasminogen activator inhibitor-1 (PAI-1), higher PAI-1 gene expression in VAT and PVAT, and elevated intercellular adhesion molecule-1 (ICAM-1) gene expression in the aorta, contributing to endothelial dysfunction in the HHTg strain. However, HHTg females had lower tumor necrosis factor alpha (TNFα) gene expression in the aorta. Severe dyslipidemia in this prediabetic model was associated with hypercoagulation and low-grade chronic inflammation. The increase in PAI-1 expression in both VAT and PVAT seems to indicate a link between inflammation and vascular dysfunction. Despite the more pronounced dyslipidemia and procoagulation status in females, their milder inflammatory response may reflect an association between reduced cardiovascular damage and prediabetes.
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Affiliation(s)
- Irena Markova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; (I.M.); (M.H.); (N.G.); (D.M.); (K.C.); (P.S.)
| | - Martina Hüttl
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; (I.M.); (M.H.); (N.G.); (D.M.); (K.C.); (P.S.)
| | - Natalie Gayova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; (I.M.); (M.H.); (N.G.); (D.M.); (K.C.); (P.S.)
| | - Denisa Miklankova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; (I.M.); (M.H.); (N.G.); (D.M.); (K.C.); (P.S.)
| | - Kristyna Cerna
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; (I.M.); (M.H.); (N.G.); (D.M.); (K.C.); (P.S.)
| | - Martina Kavanova
- Department of Laboratory Methods, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic;
| | - Petra Skaroupkova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; (I.M.); (M.H.); (N.G.); (D.M.); (K.C.); (P.S.)
| | - Sona Cacanyiova
- Centre of Experimental Medicine, Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia;
| | - Hana Malinska
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; (I.M.); (M.H.); (N.G.); (D.M.); (K.C.); (P.S.)
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Mizukami Y, Kawao N, Ohira T, Okada K, Yamao H, Matsuo O, Kaji H. Effects of plasminogen activator inhibitor-1 deficiency on bone disorders and sarcopenia caused by adenine-induced renal dysfunction in mice. PLoS One 2024; 19:e0311902. [PMID: 39388484 PMCID: PMC11469609 DOI: 10.1371/journal.pone.0311902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 09/27/2024] [Indexed: 10/12/2024] Open
Abstract
Chronic kidney disease (CKD) is a significant global health issue and often involves CKD-mineral and bone disorder (MBD) and sarcopenia. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. PAI-1 has been implicated in the pathogenesis of osteoporosis and muscle wasting induced by inflammatory conditions. However, the roles of PAI-1 in CKD-MBD and sarcopenia remain unknown. Therefore, the present study investigated the roles of PAI-1 in bone loss and muscle wasting induced by adenine in PAI-1-deficient mice. CKD was induced in PAI-1+/+ and PAI-1-/- mice by administration of adenine for ten weeks. Muscle wasting was assessed by grip strength test, quantitative computed tomography (CT) analysis and muscle weight measurement. Osteoporosis was assessed by micro-CT analysis of femoral microstructural parameters. PAI-1 deficiency did not affect adenine-induced decreases in body weight and food intake or renal dysfunction in male or female mice. PAI-1 deficiency also did not affect adenine-induced decreases in grip strength, muscle mass in the lower limbs, or the tissue weights of the gastrocnemius, soleus, and tibialis anterior muscles in male or female mice. PAI-1 deficiency aggravated trabecular bone loss in CKD-induced male mice, but significantly increased trabecular bone in CKD-induced female mice. On the other hand, PAI-1 deficiency did not affect cortical bone loss in CKD-induced mice. In conclusion, PAI-1 is not critical for the pathophysiology of CKD-MBD or CKD-induced sarcopenia in mice. However, PAI-1 may be partly related to bone metabolism in trabecular bone in the CKD state with sex differences.
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Affiliation(s)
- Yuya Mizukami
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Naoyuki Kawao
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Takashi Ohira
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Kiyotaka Okada
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Hisatoshi Yamao
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Osamu Matsuo
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Hiroshi Kaji
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
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Abu-Nejem R, Hannon TS. Insulin Dynamics and Pathophysiology in Youth-Onset Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:2411-2421. [PMID: 38963882 DOI: 10.1210/clinem/dgae463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/28/2024] [Accepted: 07/03/2024] [Indexed: 07/06/2024]
Abstract
Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic β-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.
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Affiliation(s)
- Rozan Abu-Nejem
- Department of Pediatrics, Divisions of Pediatric Endocrinology and Diabetology and Pediatric Health Services Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tamara S Hannon
- Department of Pediatrics, Divisions of Pediatric Endocrinology and Diabetology and Pediatric Health Services Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Zhang X, Tian L, Majumdar A, Scheller EL. Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations. Compr Physiol 2024; 14:5521-5579. [PMID: 39109972 PMCID: PMC11725182 DOI: 10.1002/cphy.c230016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Linda Tian
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Erica L. Scheller
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
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Martins Kattah F, Janjusevic M, Figueiredo N, Santos Oliveira E, Carielo Lima G, Dâmaso AR, Oyama LM, Fluca AL, de Melo PRE, Aderuza Horst M, Aleksova A, Campos Corgosinho F. HOMA-IR as a Predictor of PAI-1 Levels in Women with Severe Obesity. Biomedicines 2024; 12:1222. [PMID: 38927429 PMCID: PMC11200361 DOI: 10.3390/biomedicines12061222] [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: 04/23/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Obesity is a chronic inflammatory disorder that increases the risk of cardiovascular diseases (CVDs). Given the high CVD mortality rate among individuals with obesity, early screening should be considered. Plasminogen activator inhibitor (PAI-1), a cytokine that links obesity and CVDs, represents a promising biomarker. However, PAI-1 is not part of the clinical routine due to its high cost. Therefore, it is necessary to find good predictors that would allow an indirect assessment of PAI-1. METHODS This study enrolled 47 women with severe obesity (SO). The obtained anthropometric measurements included weight, height, neck (NC), waist (WC), and hip circumference (HC). Blood samples were collected to analyse glucose and lipid profiles, C-reactive protein, liver markers, adiponectin, and PAI-1 (determined by ELISA immunoassay). Homeostasis model assessment-adiponectin (HOMA-AD), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), triglyceride-glucose index (TyG), and atherogenic index of plasma (AIP) were calculated. The women were grouped according to PAI-1 levels. The data were analysed using IBM SPSS Statistics, version 21. The significance level for the analysis was set at 5%. RESULTS Women with SO who have higher levels of PAI-1 have lower values of high-density lipoprotein cholesterol (HDL) (p = 0.037) and QUICKI (0.020) and higher values of HOMA-AD (0.046) and HOMA-IR (0.037). HOMA-IR was demonstrated to be a good predictor of PAI-1 in this sample (B = 0.2791; p = 0.017). CONCLUSIONS HOMA-IR could be used as a predictor of PAI-1 levels, pointing out the relevance of assessing glycaemic parameters for the prevention of CVDs in women with SO.
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Affiliation(s)
- Fabiana Martins Kattah
- Faculty of Nutrition, Federal University of Goias, Goiânia 74605-080, Brazil; (E.S.O.); (G.C.L.); (M.A.H.)
| | - Milijana Janjusevic
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Department of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); or (A.A.)
| | - Nayra Figueiredo
- Faculty of Medicine, Federal University of Goias, Goiania 74605-080, Brazil;
| | - Emilly Santos Oliveira
- Faculty of Nutrition, Federal University of Goias, Goiânia 74605-080, Brazil; (E.S.O.); (G.C.L.); (M.A.H.)
| | - Glaucia Carielo Lima
- Faculty of Nutrition, Federal University of Goias, Goiânia 74605-080, Brazil; (E.S.O.); (G.C.L.); (M.A.H.)
| | - Ana Raimunda Dâmaso
- Paulista Medicine School, Federal University of São Paulo, São Paulo 04023-062, Brazil; (A.R.D.); (L.M.O.)
| | - Lila Missae Oyama
- Paulista Medicine School, Federal University of São Paulo, São Paulo 04023-062, Brazil; (A.R.D.); (L.M.O.)
| | - Alessandra Lucia Fluca
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Department of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); or (A.A.)
| | | | - Maria Aderuza Horst
- Faculty of Nutrition, Federal University of Goias, Goiânia 74605-080, Brazil; (E.S.O.); (G.C.L.); (M.A.H.)
| | - Aneta Aleksova
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Department of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); or (A.A.)
| | - Flávia Campos Corgosinho
- Faculty of Nutrition, Federal University of Goias, Goiânia 74605-080, Brazil; (E.S.O.); (G.C.L.); (M.A.H.)
- Faculty of Medicine, Federal University of Goias, Goiania 74605-080, Brazil;
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Okada K, Niwa Y, Fukuhara K, Ohira T, Mizukami Y, Kawao N, Matsuo O, Kaji H. Plasminogen activator inhibitor-1 is involved in glucocorticoid-induced decreases in angiogenesis during bone repair in mice. J Bone Miner Metab 2024; 42:282-289. [PMID: 38704516 DOI: 10.1007/s00774-024-01510-w] [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: 12/27/2023] [Accepted: 03/25/2024] [Indexed: 05/06/2024]
Abstract
INTRODUCTION Glucocorticoids delay fracture healing and induce osteoporosis. Angiogenesis plays an important role in bone repair after bone injury. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of plasminogen activators and an adipocytokine that regulates metabolism. However, the mechanisms by which glucocorticoids delay bone repair remain unclear. MATERIALS AND METHODS Therefore, we herein investigated the roles of PAI-1 and angiogenesis in glucocorticoid-induced delays in bone repair after femoral bone injury using PAI-1-deficient female mice intraperitoneally administered dexamethasone (Dex). RESULTS PAI-1 deficiency significantly attenuated Dex-induced decreases in the number of CD31-positive vessels at damaged sites 4 days after femoral bone injury in mice. PAI-1 deficiency also significantly ameliorated Dex-induced decreases in the number of CD31- and endomucin-positive type H vessels and CD31-positive- and endomucin-negative vessels at damaged sites 4 days after femoral bone injury. Moreover, PAI-1 deficiency significantly mitigated Dex-induced decreases in the expression of vascular endothelial growth factor as well as hypoxia inducible factor-1α, transforming growth factor-β1, and bone morphogenetic protein-2 at damaged sites 4 days after femoral bone injury. CONCLUSION The present results demonstrate that Dex-reduced angiogenesis at damaged sites during the early bone-repair phase after femoral bone injury partly through PAI-1 in mice.
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Affiliation(s)
- Kiyotaka Okada
- Department of Arts and Science, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Yuto Niwa
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Kazusa Fukuhara
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Takashi Ohira
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Yuya Mizukami
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Osamu Matsuo
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan.
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Mizukami Y, Kawao N, Ohira T, Hashimoto D, Okada K, Matsuo O, Kaji H. Roles of Plasminogen Activator Inhibitor-1 in Heterotopic Ossification Induced by Achilles Tenotomy in Thermal Injured Mice. Calcif Tissue Int 2024; 114:535-549. [PMID: 38467838 DOI: 10.1007/s00223-024-01193-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/02/2024] [Indexed: 03/13/2024]
Abstract
Heterotopic ossification (HO) is the process by which ectopic bone forms at an extraskeletal site. Inflammatory conditions induce plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis, which regulates osteogenesis. In the present study, we investigated the roles of PAI-1 in the pathophysiology of HO induced by trauma/burn treatment using PAI-1-deficient mice. PAI-1 deficiency significantly promoted HO and increased the number of alkaline phosphatase (ALP)-positive cells in Achilles tendons after trauma/burn treatment. The mRNA levels of inflammation markers were elevated in Achilles tendons of both wild-type and PAI-1-deficient mice after trauma/burn treatment and PAI-1 mRNA levels were elevated in Achilles tendons of wild-type mice. PAI-1 deficiency significantly up-regulated the expression of Runx2, Osterix, and type 1 collagen in Achilles tendons 9 weeks after trauma/burn treatment in mice. In in vitro experiments, PAI-1 deficiency significantly increased ALP activity and mineralization in mouse osteoblasts. Moreover, PAI-1 deficiency significantly increased ALP activity and up-regulated osteocalcin expression during osteoblastic differentiation from mouse adipose-tissue-derived stem cells, but suppressed the chondrogenic differentiation of these cells. In conclusion, the present study showed that PAI-1 deficiency promoted HO in Achilles tendons after trauma/burn treatment partly by enhancing osteoblast differentiation and ALP activity in mice. Endogenous PAI-1 may play protective roles against HO after injury and inflammation.
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Affiliation(s)
- Yuya Mizukami
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan
| | - Takashi Ohira
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan
| | - Daiki Hashimoto
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan
| | - Kiyotaka Okada
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan
| | - Osamu Matsuo
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan.
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10
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Li Z, Kegui H, Piao W, Xuejiu W, Lim KT, Jin H. PAI-1 transfected-conditioned media promotes osteogenic differentiation of hBMSCs. Cell Biol Int 2024. [PMID: 38654436 DOI: 10.1002/cbin.12166] [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: 07/27/2023] [Revised: 02/28/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
Reconstruction of injured bone remains challenging in the clinic owing to the lack of suitable bone grafts. The utilization of PAI-1 transfected-conditioned media (P-CM) has demonstrated its ability to facilitate the differentiation process of mesenchymal stem cells (MSCs), potentially serving as a crucial mediator in tissue regeneration. This research endeavored to explore the therapeutic potential of P-CM concerning the differentiation of human bone marrow mesenchymal stem cells (hBMSCs). To assess new bone formation, a rat calvaria critical defect model was employed, while in vitro experiments involved the use of the alizarin Red-S mineral induction test. In the rat calvaria critical defect model, P-CM treatment resulted in significan new bone formation. In vitro, P-CM treated hBMSCs displayed robust osteogenesis compared to the control group, as demonstrated by the mineral induction test using alizarin Red-S. P-CM with hydroxyapatite/β-tricalcium phosphate/fibrin gel treatment significantly exhibited new bone formation, and the expression of osteogenic associated markers was enhanced in the P-CM-treated group. In conclusion, results demonstrate that P-CM treatment significantly enhanced the osteogenic differantiation efficiency and new bone formation, thus could be used as an ideal therapeutic biomolecule for constructing bone-specific implants, especially for orthopedic and dental applications.
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Affiliation(s)
- Zhang Li
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Hou Kegui
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Wang Piao
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Wang Xuejiu
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Ki-Taek Lim
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, South Korea
| | - Hexiu Jin
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
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11
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Conte C, Cipponeri E, Roden M. Diabetes Mellitus, Energy Metabolism, and COVID-19. Endocr Rev 2024; 45:281-308. [PMID: 37934800 PMCID: PMC10911957 DOI: 10.1210/endrev/bnad032] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/30/2023] [Accepted: 11/01/2023] [Indexed: 11/09/2023]
Abstract
Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.
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Affiliation(s)
- Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome 00166, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Elisa Cipponeri
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Neuherberg 85764, Germany
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12
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Simental-Mendía LE, Simental-Mendía M, Sahebkar A, Atkin SL, Jamialahmadi T. Effect of Fibrate Treatment on Circulating Adipokine Levels: A Systematic Review and Meta-analysis of Randomized Clinical Trials. Arch Med Res 2024; 55:102957. [PMID: 38266418 DOI: 10.1016/j.arcmed.2024.102957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 01/03/2024] [Accepted: 01/11/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND Fibrates are widely used in the treatment of dyslipidemia and associated metabolic abnormalities; however, their effects on adipokines are unclear. AIM OF THE STUDY This meta-analysis of clinical trials aimed to evaluate the effect of fibrates on circulating adipokine levels. METHODS Only randomized controlled trials investigating the impact/effect of fibrate treatment on circulating adipokine levels were included from searches in PubMed-Medline, SCOPUS, ClinicalTrials.gov, Web of Science, and Google Scholar databases. A random effects model and the generic inverse variance method were used for the meta-analysis. Sensitivity analysis was conducted using the leave-one-out method. RESULTS This meta-analysis of 22 clinical trials showed a significant reduction on/in leptin (WMD: -1.58 ng/mL, 95% CI: -2.96, -0.20, p = 0.02, I2 = 0%), plasminogen activator inhibitor-1 (PAI-1) (WMD: -13.86 ng/mL, 95% CI: -26.70, -1.03, p = 0.03, I2 = 99%), and visfatin (WMD: -1.52 ng/mL, 95% CI: -2.49, -0.56, p = 0.002, I2 = 0%) after fibrate therapy; no significant effect was observed on adiponectin (WMD: -0.69 µg/ml, 95% CI: -1.40, 0.02, p = 0.06, I2 = 83%) and resistin (WMD: -2.27 ng/mL, 95% CI: -7.11, 2.57, p = 0.36, I2 = 0%). The sensitivity analysis was robust only for visfatin, while the effect size was sensitive to one arm for leptin, four for adiponectin, and two for PAI-1. CONCLUSION This meta-analysis showed that fibrate treatment significantly improves adipokine levels with a decrease in leptin, PAI-1, and visfatin, suggesting potential additional clinical therapeutic benefits through/of fibrate treatment on adipose tissue.
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Affiliation(s)
- Luis E Simental-Mendía
- Biomedical Research Unit, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico.
| | - Mario Simental-Mendía
- Department of Orthopedics and Traumatology, Hospital Universitario Dr. José E. González, Faculty of Medicine, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Stephen L Atkin
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
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13
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Pezzino S, Luca T, Castorina M, Puleo S, Latteri S, Castorina S. Role of Perturbated Hemostasis in MASLD and Its Correlation with Adipokines. Life (Basel) 2024; 14:93. [PMID: 38255708 PMCID: PMC10820028 DOI: 10.3390/life14010093] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/04/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, making it one of the most prevalent chronic liver disorders. MASLD encompasses a range of liver pathologies, from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) with inflammation, hepatocyte damage, and fibrosis. Interestingly, the liver exhibits close intercommunication with fatty tissue. In fact, adipose tissue could contribute to the etiology and advancement of MASLD, acting as an endocrine organ that releases several hormones and cytokines, with the adipokines assuming a pivotal role. The levels of adipokines in the blood are altered in people with MASLD, and recent research has shed light on the crucial role played by adipokines in regulating energy expenditure, inflammation, and fibrosis in MASLD. However, MASLD disease is a multifaceted condition that affects various aspects of health beyond liver function, including its impact on hemostasis. The alterations in coagulation mechanisms and endothelial and platelet functions may play a role in the increased vulnerability and severity of MASLD. Therefore, more attention is being given to imbalanced adipokines as causative agents in causing disturbances in hemostasis in MASLD. Metabolic inflammation and hepatic injury are fundamental components of MASLD, and the interrelation between these biological components and the hemostasis pathway is delineated by reciprocal influences, as well as the induction of alterations. Adipokines have the potential to serve as the shared elements within this complex interrelationship. The objective of this review is to thoroughly examine the existing scientific knowledge on the impairment of hemostasis in MASLD and its connection with adipokines, with the aim of enhancing our comprehension of the disease.
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Affiliation(s)
- Salvatore Pezzino
- Mediterranean Foundation “GB Morgagni”, 95125 Catania, Italy (M.C.); (S.C.)
| | - Tonia Luca
- Mediterranean Foundation “GB Morgagni”, 95125 Catania, Italy (M.C.); (S.C.)
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy;
| | | | - Stefano Puleo
- Mediterranean Foundation “GB Morgagni”, 95125 Catania, Italy (M.C.); (S.C.)
| | - Saverio Latteri
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy;
| | - Sergio Castorina
- Mediterranean Foundation “GB Morgagni”, 95125 Catania, Italy (M.C.); (S.C.)
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy;
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14
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Di Sarli Gutiérrez L, Castro MC, Farromeque Vásquez S, Villagarcía HG, González Arbeláez L, Rojano B, Schinella G, Maiztegui B, Francini F. Protective Effect of Monoterpene Isoespintanol in a Rat Model of Prediabetes Induced by Fructose. Pharmaceuticals (Basel) 2023; 17:47. [PMID: 38256882 PMCID: PMC10819293 DOI: 10.3390/ph17010047] [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: 09/11/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 01/24/2024] Open
Abstract
A high-fructose diet (HFD) induces murine alterations like those recorded in human prediabetes. Protective effects of isoespintanol (monoterpene isolated from Oxandra cf. xylopioides) on changes induced by HFD were evaluated. Animals were maintained for 21 days with a standard diet (C), 10% fructose (F), and F plus isoespintanol (FI, 10 mg/kg, i.p.). Glycemia, triglyceridemia, total and HDL-cholesterol, and insulin resistance index (IRX) were determined. Intraperitoneal glucose tolerance test (IGTT) was performed. In the liver, we measured glycogen, lipogenic gene expression (SREBP-1c, GPAT, FAS, and CPT1), oxidative stress (GSH and 3'-nitrotyrosine content), inflammation markers (iNOS, TNF-α, and PAI-1 gene expression; iNOS and COX-2 protein levels), p-eNOS, p-Akt, and p-GSK3β protein levels. Isoespintanol corrected enhanced triglycerides, lipogenic genes, and IRX, and reduced HDL-cholesterol induced by HFD. Increased liver glycogen and inflammatory markers and decreased GSH, p-Akt, and p-GSK3β measured in F rats were reversed by isoespintanol, and p-eNOS/e-NOS and iNOS/GADPH ratios were normalized. Isoespintanol restored glucose tolerance (IGTT) compared to F rats. These results demonstrate for the first time that isoespintanol prevents endocrine-metabolic alterations induced by HFD in prediabetic rats. These effects could be mediated by Akt/eNOS and Akt/GSK3β pathways, suggesting its possible use as a therapeutic tool for the prevention of diabetes at early stages of its development (prediabetes).
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Affiliation(s)
- Luciana Di Sarli Gutiérrez
- CENEXA (Centre for Experimental and Applied Endocrinology, UNLP CONICET CCT La Plata, CEAS CICPBA), School of Medicine, Street 60 and 120, La Plata 1900, Argentina; (L.D.S.G.); (M.C.C.); (S.F.V.); (H.G.V.); (B.M.)
| | - María Cecilia Castro
- CENEXA (Centre for Experimental and Applied Endocrinology, UNLP CONICET CCT La Plata, CEAS CICPBA), School of Medicine, Street 60 and 120, La Plata 1900, Argentina; (L.D.S.G.); (M.C.C.); (S.F.V.); (H.G.V.); (B.M.)
| | - Sherley Farromeque Vásquez
- CENEXA (Centre for Experimental and Applied Endocrinology, UNLP CONICET CCT La Plata, CEAS CICPBA), School of Medicine, Street 60 and 120, La Plata 1900, Argentina; (L.D.S.G.); (M.C.C.); (S.F.V.); (H.G.V.); (B.M.)
| | - Hernán Gonzalo Villagarcía
- CENEXA (Centre for Experimental and Applied Endocrinology, UNLP CONICET CCT La Plata, CEAS CICPBA), School of Medicine, Street 60 and 120, La Plata 1900, Argentina; (L.D.S.G.); (M.C.C.); (S.F.V.); (H.G.V.); (B.M.)
| | - Luisa González Arbeláez
- CIC (Centre for Cardiovascular Research, UNLP CONICET CCT La Plata), School of Medicine, Street 60 and 120, La Plata 1900, Argentina;
| | - Benjamín Rojano
- Food Science Laboratory, Faculty of Sciences, National University of Colombia, Medellín Campus, Medellin 050034, Colombia;
| | - Guillermo Schinella
- School of Medicine, UNLP, Street 60 and 120, La Plata 1900, Argentina;
- Institute of Health Sciences, UNAJ-CICPBA, Av. Calchaquí 6200, Florencio Varela 1888, Argentina
| | - Bárbara Maiztegui
- CENEXA (Centre for Experimental and Applied Endocrinology, UNLP CONICET CCT La Plata, CEAS CICPBA), School of Medicine, Street 60 and 120, La Plata 1900, Argentina; (L.D.S.G.); (M.C.C.); (S.F.V.); (H.G.V.); (B.M.)
| | - Flavio Francini
- CENEXA (Centre for Experimental and Applied Endocrinology, UNLP CONICET CCT La Plata, CEAS CICPBA), School of Medicine, Street 60 and 120, La Plata 1900, Argentina; (L.D.S.G.); (M.C.C.); (S.F.V.); (H.G.V.); (B.M.)
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15
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Gumede N, Khathi A. The role of fibrinolysis in the development of prediabetes-associated coronary heart disease: a focus on the plasminogen activator inhibitor -1 and its potential use as a predictive marker in diet-induced prediabetes. Front Nutr 2023; 10:1256427. [PMID: 38024366 PMCID: PMC10652797 DOI: 10.3389/fnut.2023.1256427] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular diseases (CVD). However, the onset of T2DM is preceded by prediabetes, which is associated with sedentary lifestyles and consumption of high-calorie diets. Studies have shown that impaired glucose homeostasis creates an environment for developing T2DM-related complications. Using a high-fat-high-carbohydrate diet-induced prediabetes animal model, this study sought to assess the risk factors of coronary heart disease (CHD) in diet-induced prediabetes and identify biomarkers that can be used for early detection of prediabetes-associated CHD. Methods Male Sprague Dawley rats were randomly grouped into two groups and were kept on different diets for 20 weeks (n = 6 in each group). One group was fed standard rat chow to serve as a non-prediabetes (NPD) control, while the other group consumed a high-fat-high-carbohydrate diet to induce prediabetes (PD). Post induction, the homeostasis model assessment- insulin resistance (HOMA-IR) and glycated haemoglobin (HbA1c) was used to test for insulin resistance. Body weight, mean arterial pressure (MAP), resting heart rate (HR), inflammatory cytokines (C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6)), lipids (total cholesterol (TC), triglyceride (TG), lipoproteins (HDL, LDL, VLDL)), endothelial function (endothelial nitric oxide (eNOS), endothelin -1 (ET-1)), fibrinolysis (plasminogen activator inhibitor-1 (PAI-1)) were all measured to assess the risk of CHD. All data were expressed as means ± S.E.M. Statistical comparisons were performed with Graph Pad. Instat Software using Student's two-sided t-test. The Pearson correlation coefficient and linear regression were calculated to assess the association. The value of p < 0.05 was considered statistically significant. Results There was significant insulin resistance accompanied by significantly increased HbA1c and body weight in PD compared to NPD. Simultaneously, there was a significant increase in inflammatory cytokines in PD compared to NPD. This was accompanied by significantly increased TG and VLDL and endothelial dysfunction in PD. The association between HOMA-IR and PAI-1 was insignificantly positive in NPD, whereas a significantly strong positive association was observed in PD. Conclusion There is a positive correlation between insulin resistance and PAI-1 during prediabetes; therefore, suggesting that prediabetes increases the risk of developing vascular thrombosis. The current therefore study warrants further investigation on PAI-1 and other markers of fibrinolysis for the early detection of thrombosis and risk of CHD in prediabetes.
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Affiliation(s)
- Nompumelelo Gumede
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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16
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Hou X, Zhang R, Yang M, Niu N, Zong W, Yang L, Li H, Hou R, Wang X, Wang L, Liu X, Shi L, Zhao F, Wang L, Zhang L. Characteristics of Transcriptome and Metabolome Concerning Intramuscular Fat Content in Beijing Black Pigs. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:15874-15883. [PMID: 37847170 DOI: 10.1021/acs.jafc.3c02669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2023]
Abstract
To study the characteristics of genes and metabolites related to intramuscular fat (IMF) content with less influence by breed background and individual differences, the skeletal muscle samples from 40 Beijing black pigs with either high or low IMF content were used to perform transcriptome and metabolome analyses. About 99 genes (twofold-change) were differentially expressed. Up-regulated genes in the high IMF pigs were mainly related to fat metabolism. The key genes in charge of IMF deposition are ADIPOQ, CIDEC, CYP4B1, DGAT2, LEP, OPRL1, PLIN1, SCD, and THRSP. KLHL40, TRAFD1, and HSPA6 were novel candidate genes for the IMF trait due to their high abundances. In the low IMF pigs, the differentially expressed genes involved in virus resistance were up-regulated. About 16 and 18 differential metabolites (1.5 fold-change) were obtained in the positive and negative modes, respectively. Pigs with low IMF had weaker fatty acid oxidation due to the down-regulation of various carnitines. Differentially expressed genes were more important in determining IMF deposition than differential metabolites because relatively few differential metabolites were obtained, and they were merely the products under the physiological status of diverged IMF content. This study provided valuable information for further studies on IMF deposition.
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Affiliation(s)
- Xinhua Hou
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Run Zhang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Man Yang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Naiqi Niu
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Wencheng Zong
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Liyu Yang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Huihui Li
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Renda Hou
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Xiaoqing Wang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Ligang Wang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Xin Liu
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Lijun Shi
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Fuping Zhao
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Lixian Wang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Longchao Zhang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
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Simiczyjew A, Wądzyńska J, Pietraszek-Gremplewicz K, Kot M, Ziętek M, Matkowski R, Nowak D. Melanoma cells induce dedifferentiation and metabolic changes in adipocytes present in the tumor niche. Cell Mol Biol Lett 2023; 28:58. [PMID: 37481560 PMCID: PMC10363323 DOI: 10.1186/s11658-023-00476-3] [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: 03/15/2023] [Accepted: 06/30/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND One of the factors that affect the progression of melanoma is the tumor microenvironment, which consists of cellular elements, extracellular matrix, acidification, and a hypoxic state. Adipocytes are one of the types of cell present in the niche and are localized in the deepest layer of the skin. However, the relationship between fat cells and melanoma remains unclear. METHODS We assessed the influence of melanoma cells on adipocytes using an indirect coculture system. We estimated the level of cancer-associated adipocyte (CAA) markers through quantitative PCR analysis. The fibroblastic phenotype of CAAs was confirmed by cell staining and western blotting analysis. The lipid content was estimated by lipid detection in CAAs using LipidSpot and by quantitative analysis using Oil Red O. The expression of proteins involved in lipid synthesis, delipidation, and metabolic processes were assessed through quantitative PCR or western blotting analysis. Lactate secretion was established using a Lactate-Glo™ assay. Proteins secreted by CAAs were identified in cytokine and angiogenesis arrays. The proliferation of melanoma cells cocultured with CAAs was assessed using an XTT proliferation assay. Statistical analysis was performed using a one-way ANOVA followed by Tukey's test in GraphPad Prism 7 software. RESULTS Obtained CAAs were identified by decreased levels of leptin, adiponectin, resistin, and FABP4. Adipocytes cocultured with melanoma presented fibroblastic features, such as a similar proteolytic pattern to that of 3T3L1 fibroblasts and increased levels of vimentin and TGFβRIII. Melanoma cells led to a reduction of lipid content in CAAs, possibly by downregulation of lipid synthesis pathways (lower FADS, SC4MOL, FASN) or enhancement of lipolysis (higher level of phosphorylation of ERK and STAT3). Adipocytes cocultured with melanoma cells secreted higher IL6 and SerpinE1 levels and produced less CCL2, CXCL1, and angiogenic molecules. CAAs also showed metabolic changes comprising the increased secretion of lactate and enhanced production of glucose, lactate, and ion transporters. In addition, changes in adipocytes observed following melanoma coculture resulted in a higher proliferation rate of cancer cells. CONCLUSIONS Melanoma cells led to decreased lipid content in adipocytes, which might be related to enhanced delipidation or reduction of lipid synthesis. Fibroblast-like CAAs showed metabolic changes that may be the reason for accelerated proliferation of melanoma cells.
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Affiliation(s)
- Aleksandra Simiczyjew
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, 50-383, Wroclaw, Poland.
| | - Justyna Wądzyńska
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, 50-383, Wroclaw, Poland
| | | | - Magdalena Kot
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, 50-383, Wroclaw, Poland
| | - Marcin Ziętek
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Plac Hirszfelda 12, 53-413, Wroclaw, Poland
- Lower Silesian Oncology, Pulmonology, and Hematology Center, Plac Hirszfelda 12, 53-413, Wroclaw, Poland
| | - Rafał Matkowski
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Plac Hirszfelda 12, 53-413, Wroclaw, Poland
- Lower Silesian Oncology, Pulmonology, and Hematology Center, Plac Hirszfelda 12, 53-413, Wroclaw, Poland
| | - Dorota Nowak
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, 50-383, Wroclaw, Poland
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Maiztegui B, Villagarcía HG, Román CL, Flores LE, Prieto JM, Castro MC, Massa ML, Schinella GR, Francini F. Dietary Supplementation with Yerba Mate ( Ilex paraguariensis) Infusion Increases IRS-1 and PI3K mRNA Levels and Enhances Insulin Sensitivity and Secretion in Rat Pancreatic Islets. PLANTS (BASEL, SWITZERLAND) 2023; 12:2620. [PMID: 37514235 PMCID: PMC10383281 DOI: 10.3390/plants12142620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/30/2023]
Abstract
"Yerba mate" (YM), an aqueous extract of Ilex paraguariensis, has antioxidant, diuretic, cardio-protective and hypoglycaemic properties. Since its effect on the pancreatic islets remains unclear, we evaluated insulin sensitivity and glucose-stimulated insulin secretion (GSIS) in rats consuming YM or tap water (C) for 21 days. Glucose tolerance, glycemia, triglyceridemia, insulinemia, TBARS and FRAP serum levels were evaluated. GSIS and mRNA levels of insulin signaling pathway and inflammatory markers were measured in isolated pancreatic islets from both groups. In C rats, islets were incubated with YM extract or its phenolic components to measure GSIS. YM improved glucose tolerance, enhanced GSIS, increased FRAP plasma levels and islet mRNA levels of IRS-1 and PI3K (p110), and decreased TBARS plasma levels and islet gene expression of TNF-α and PAI-1. Islets from C rats incubated with 100 µg/mL dry YM extract, 1 µM chlorogenic acid, 0.1 and 1 µM rutin, 1 µM caffeic acid or 1 µM quercetin showed an increase in GSIS. Our results suggest that YM enhances glucose tolerance because of its positive effects on GSIS, oxidative stress rate and insulin sensitivity in rat islets, suggesting that long-term dietary supplementation with YM may improve glucose homeostasis in pre-diabetes or type 2 diabetes.
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Affiliation(s)
- Bárbara Maiztegui
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), La Plata 1900, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata 1900, Argentina
| | - Hernán Gonzalo Villagarcía
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), La Plata 1900, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata 1900, Argentina
| | - Carolina Lisi Román
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), La Plata 1900, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata 1900, Argentina
| | - Luis Emilio Flores
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), La Plata 1900, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata 1900, Argentina
| | - José María Prieto
- Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK
| | - María Cecilia Castro
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), La Plata 1900, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata 1900, Argentina
| | - María Laura Massa
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), La Plata 1900, Argentina
| | - Guillermo R Schinella
- Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata 1900, Argentina
- Instituto de Ciencias de la Salud, UNAJ-CICPBA, Florencio Varela 1888, Argentina
| | - Flavio Francini
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), La Plata 1900, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata 1900, Argentina
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19
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Xu ZH, Xiong CW, Miao KS, Yu ZT, Zhang JJ, Yu CL, Huang Y, Zhou XD. Adipokines regulate mesenchymal stem cell osteogenic differentiation. World J Stem Cells 2023; 15:502-513. [PMID: 37424950 PMCID: PMC10324509 DOI: 10.4252/wjsc.v15.i6.502] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/26/2023] [Accepted: 04/24/2023] [Indexed: 06/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into various tissue cell types including bone, adipose, cartilage, and muscle. Among those, osteogenic differentiation of MSCs has been widely explored in many bone tissue engineering studies. Moreover, the conditions and methods of inducing osteogenic differentiation of MSCs are continuously advancing. Recently, with the gradual recognition of adipokines, the research on their involvement in different pathophysiological processes of the body is also deepening including lipid metabolism, inflammation, immune regulation, energy disorders, and bone homeostasis. At the same time, the role of adipokines in the osteogenic differentiation of MSCs has been gradually described more completely. Therefore, this paper reviewed the evidence of the role of adipokines in the osteogenic differentiation of MSCs, emphasizing bone formation and bone regeneration.
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Affiliation(s)
- Zhong-Hua Xu
- Department of Orthopedics, Jintan Hospital Affiliated to Jiangsu University, Changzhou 213200, Jiangsu Province, China
| | - Chen-Wei Xiong
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Kai-Song Miao
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Zhen-Tang Yu
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Jun-Jie Zhang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Chang-Lin Yu
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Yong Huang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Xin-Die Zhou
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Department of Orthopedics, Gonghe County Hospital of Traditional Chinese Medicine, Hainan Tibetan Autonomous Prefecture 811800, Qinghai Province, China
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20
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Johnston EK, Abbott RD. Adipose Tissue Paracrine-, Autocrine-, and Matrix-Dependent Signaling during the Development and Progression of Obesity. Cells 2023; 12:407. [PMID: 36766750 PMCID: PMC9913478 DOI: 10.3390/cells12030407] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/19/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
Obesity is an ever-increasing phenomenon, with 42% of Americans being considered obese (BMI ≥ 30) and 9.2% being considered morbidly obese (BMI ≥ 40) as of 2016. With obesity being characterized by an abundance of adipose tissue expansion, abnormal tissue remodeling is a typical consequence. Importantly, this pathological tissue expansion is associated with many alterations in the cellular populations and phenotypes within the tissue, lending to cellular, paracrine, mechanical, and metabolic alterations that have local and systemic effects, including diabetes and cardiovascular disease. In particular, vascular dynamics shift during the progression of obesity, providing signaling cues that drive metabolic dysfunction. In this review, paracrine-, autocrine-, and matrix-dependent signaling between adipocytes and endothelial cells is discussed in the context of the development and progression of obesity and its consequential diseases, including adipose fibrosis, diabetes, and cardiovascular disease.
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Affiliation(s)
| | - Rosalyn D. Abbott
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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21
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Gui M, Zhao B, Huang J, Chen E, Qu H, Mao E. Pathogenesis and Therapy of Coagulation Disorders in Severe Acute Pancreatitis. J Inflamm Res 2023; 16:57-67. [PMID: 36636248 PMCID: PMC9831125 DOI: 10.2147/jir.s388216] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/12/2022] [Indexed: 01/07/2023] Open
Abstract
Ischemia superimposed upon pancreatic edema leads to acute necrotizing pancreatitis. One possible mechanism contributing to ischemia is intravascular thrombogenesis since fibrin deposits have been detected in pancreatic capillaries by electron microscope. Current experimental and clinical data provided compelling evidence that the disorders in the blood coagulation system play a critical role in the pathogenesis of severe acute pancreatitis (SAP). This leads to microcirculatory failure of intra- and extrapancreatic organs and multiple organ failure and increases the case fatality rate. However, the mechanism of coagulopathy underlying SAP is not yet clear, although some anticoagulant drugs have entered clinical practice showing improvement in prognosis. Thus, enhanced understanding of the process might improve the treatment strategies with safety and high efficacy. Herein, the pathogenesis of the coagulation system of SAP was reviewed with a focus on the coagulation pathway, intercellular interactions, and complement system, thereby illustrating some anticoagulant therapies and potential therapeutic targets.
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Affiliation(s)
- Menglu Gui
- Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Bing Zhao
- Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Jun Huang
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Erzhen Chen
- Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Hongping Qu
- Department of Critical Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Enqiang Mao
- Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China,Correspondence: Enqiang Mao, Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Huangpu District, Shanghai, People’s Republic of China, Tel +86 13501747906, Email
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22
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Requena P, Pérez-Díaz C, Mustieles V, Peinado FM, León J, Pérez-Carrascosa FM, Frederiksen H, Salcedo-Bellido I, Barrios-Rodríguez R, Arrebola JP. Associations of circulating levels of phthalate metabolites with cytokines and acute phase reactants in a Spanish human cohort. ENVIRONMENTAL RESEARCH 2023; 216:114470. [PMID: 36241073 DOI: 10.1016/j.envres.2022.114470] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/12/2022] [Accepted: 09/28/2022] [Indexed: 06/16/2023]
Abstract
The associations between human phthalate exposure and the onset of chronic diseases with an immunological component (e.g., metabolic syndrome, cancer) remain unclear, partly due to the uncertainties in the underlying mechanisms. This study investigates cross-sectional associations of the concentrations of 10 phthalate metabolites with 19 cytokines and acute phase proteins in 213 serum samples of Spanish adults. The associations were explored by Spearman's correlation, multivariable linear regression, and weighted quantile sum regression analyses. In the multivariable analyses, levels of plasminogen activator inhibitor (PAI)-1 were positively associated with mono-n-butyl phthalate (fold-change per one IQR increase in phthalate levels, 95% Confidence Interval: 1.65, 1.45-1.88) and mono-iso-butyl phthalate (3.07, 2.39-3.95), mono-ethyl phthalate (2.05, 1.62-2.61), as well as categorized mono-iso-decyl and mono-benzyl phthalates. The same phthalates also were significantly associated with leptin, interleukin (IL)-18 and monocyte chemoattractant protein-1. Moreover, the proinflammatory markers IL-1β, IL-17, IL-8, IL-6, IL-12, tumor necrosis factor, and lipopolysaccharide-binding protein showed positive and negative associations with, respectively, mono-(2-ethyl-hexyl) and mono-methyl phthalates. Finally, phthalate mixtures were positively associated with PAI-1, leptin, IL-18, IL-12, IL-8 and IL-1β. Despite the cross-sectional design limitation, these associations point to relevant subclinical immuno-inflammatory actions of these pollutants, warranting confirmation in future studies.
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Affiliation(s)
- Pilar Requena
- Universidad de Granada, Department of Preventive Medicine and Public Health, Campus de Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria (ibs.GRANADA), Avda. de Madrid, 15. Pabellón de Consultas Externas 2, 2a Planta, 18012, Granada, Spain.
| | - Celia Pérez-Díaz
- Universidad de Granada, Department of Preventive Medicine and Public Health, Campus de Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria (ibs.GRANADA), Avda. de Madrid, 15. Pabellón de Consultas Externas 2, 2a Planta, 18012, Granada, Spain.
| | - Vicente Mustieles
- Instituto de Investigación Biosanitaria (ibs.GRANADA), Avda. de Madrid, 15. Pabellón de Consultas Externas 2, 2a Planta, 18012, Granada, Spain; Universidad de Granada, Department of Radiology and Physical Medicine, Avda. del Conocimiento 11, 18016, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11. Planta 0, 28029, Madrid, Spain.
| | - Francisco M Peinado
- Instituto de Investigación Biosanitaria (ibs.GRANADA), Avda. de Madrid, 15. Pabellón de Consultas Externas 2, 2a Planta, 18012, Granada, Spain; Universidad de Granada, Department of Radiology and Physical Medicine, Avda. del Conocimiento 11, 18016, Granada, Spain.
| | - Josefa León
- Hospital Universitario San Cecilio, Digestive System Clinical Management Unit, Av. del Conocimiento, s/n, 18016, Granada, Spain.
| | - Francisco M Pérez-Carrascosa
- Universidad de Granada, Department of Preventive Medicine and Public Health, Campus de Cartuja s/n, 18071, Granada, Spain.
| | - Hanne Frederiksen
- Department of Growth and Reproduction, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
| | - Inmaculada Salcedo-Bellido
- Universidad de Granada, Department of Preventive Medicine and Public Health, Campus de Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria (ibs.GRANADA), Avda. de Madrid, 15. Pabellón de Consultas Externas 2, 2a Planta, 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11. Planta 0, 28029, Madrid, Spain.
| | - Rocío Barrios-Rodríguez
- Universidad de Granada, Department of Preventive Medicine and Public Health, Campus de Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria (ibs.GRANADA), Avda. de Madrid, 15. Pabellón de Consultas Externas 2, 2a Planta, 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11. Planta 0, 28029, Madrid, Spain.
| | - Juan Pedro Arrebola
- Universidad de Granada, Department of Preventive Medicine and Public Health, Campus de Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria (ibs.GRANADA), Avda. de Madrid, 15. Pabellón de Consultas Externas 2, 2a Planta, 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11. Planta 0, 28029, Madrid, Spain.
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23
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Heubner L, Petrick PL, Güldner A, Bartels L, Ragaller M, Mirus M, Rand A, Tiebel O, Beyer-Westendorf J, Rößler M, Schmitt J, Koch T, Spieth PM. Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome. Sci Rep 2022; 12:18418. [PMID: 36319681 PMCID: PMC9626466 DOI: 10.1038/s41598-022-22107-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/10/2022] [Indexed: 11/26/2022] Open
Abstract
Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients' characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge-midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25-92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1-60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000-9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26-2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.Trial registration DRKS-ID DRKS00027856.
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Affiliation(s)
- Lars Heubner
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Paul Leon Petrick
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Andreas Güldner
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Lea Bartels
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Maximillian Ragaller
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Martin Mirus
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Axel Rand
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Oliver Tiebel
- Institute of Clinical Chemistry, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Jan Beyer-Westendorf
- Division of Hematology and Hemostasis, Department of Medicine I Thrombosis Research, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Martin Rößler
- Center for Evidence-Based Healthcare (ZEGV), University Hospital "Carl Gustav Carus" and "Carl Gustav Carus" Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Jochen Schmitt
- Center for Evidence-Based Healthcare (ZEGV), University Hospital "Carl Gustav Carus" and "Carl Gustav Carus" Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Thea Koch
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Peter Markus Spieth
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany.
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24
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Ojeda ML, Nogales F, Carreras O, Pajuelo E, Gallego-López MDC, Romero-Herrera I, Begines B, Moreno-Fernández J, Díaz-Castro J, Alcudia A. Different Effects of Low Selenite and Selenium-Nanoparticle Supplementation on Adipose Tissue Function and Insulin Secretion in Adolescent Male Rats. Nutrients 2022; 14:nu14173571. [PMID: 36079831 PMCID: PMC9459699 DOI: 10.3390/nu14173571] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/20/2022] [Accepted: 08/26/2022] [Indexed: 11/23/2022] Open
Abstract
Adolescence is a period of intense growth and endocrine changes, and obesity and insulin-resistance processes during this period have lately been rising. Selenium (Se) homeostasis is related to lipid metabolism depending on the form and dose of Se. This study tests the actions of low-dose selenite and Se nanoparticles (SeNPs) on white (WAT) and brown adipose tissue (BAT) deposition, insulin secretion, and GPx1, IRS-1 and FOXO3a expression in the WAT of adolescent rats as regards oxidative stress, adipocyte length and adipokine secretion. Four groups of male adolescent rats were treated: control (C), low selenite supplementation (S), low SeNP supplementation (NS) and moderate SeNP supplementation (NSS). Supplementation was received orally through water intake; NS and NSS rats received two- and tenfold more Se than C animals, respectively. SeNPs were obtained by reducing Se tetrachloride in the presence of ascorbic acid. For the first time in vivo, it was demonstrated that low selenite supplementation contributed to increased adipogenesis via the insulin signaling pathway and LCN2 modulation, while low SeNP administration prevented fat depots in WAT via the decrease in insulin signaling and FOXO3a autophagy in WAT, lowering inflammation. These effects were independent of GPx1 expression or activity in WAT. These findings provide data for dietary approaches to prevent obesity and/or anorexia during adolescence. These findings may be relevant to future studies looking at a nutritional approach aimed at pre-venting obesity and/or anorexia in adolescence.
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Affiliation(s)
- María Luisa Ojeda
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Fátima Nogales
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
- Correspondence: ; Tel.: +34-954556518
| | - Olimpia Carreras
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Eloísa Pajuelo
- Department of Microbiology and Parasitology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | | | - Inés Romero-Herrera
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Belén Begines
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Jorge Moreno-Fernández
- Department of Physiology, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, 18071 Granada, Spain
| | - Javier Díaz-Castro
- Department of Physiology, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, 18071 Granada, Spain
| | - Ana Alcudia
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
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25
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Heubner L, Greiner M, Vicent O, Beyer-Westendorf J, Tiebel O, Scholz U, Güldner A, Mirus M, Fries D, Koch T, Spieth PM. Predictive ability of viscoelastic testing using ClotPro® for short-term outcome in patients with severe Covid-19 ARDS with or without ECMO therapy: a retrospective study. Thromb J 2022; 20:48. [PMID: 36038895 PMCID: PMC9421107 DOI: 10.1186/s12959-022-00403-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 08/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND SARS-CoV-2 infections are suspected to trigger the coagulation system through various pathways leading to a high incidence of thromboembolic complications, hypercoagulation and impaired fibrinolytic capacity were previously identified as potentially mechanisms. A reliable diagnostic tool for detecting both is still under discussion. This retrospective study is aimed to examine the prognostic relevance of early viscoelastic testing compared to conventional laboratory tests in COVID-19 patients with acute respiratory distress syndrome (ARDS). METHODS All mechanically ventilated patients with COVID-19 related ARDS treated in our intensive care unit (ICU) between January and March 2021 were included in this study. Viscoelastic testing (VET) was performed using the ClotPro® system after admission to our ICU. Prevalence of thromboembolic events was observed by standardized screening for venous and pulmonary thromboembolism using complete compression ultrasound and thoracic computed tomography pulmonary angiography at ICU admission, respectively. We examined associations between the severity of ARDS at admission to our ICU, in-hospital mortality and the incidence of thromboembolic events comparing conventional laboratory analysis and VET. ECMO related coagulopathy was investigated in a subgroup analysis. The data were analyzed using the Mann-Whitney U test. RESULTS Of 55 patients enrolled in this study, 22 patients required treatment with ECMO. Thromboembolic complications occurred in 51% of all patients. Overall hospital mortality was 55%. In patients with thromboembolic complications, signs of reduced fibrinolytic capacity could be detected in the TPA assay with prolonged lysis time, median 460 s (IQR 350-560) vs 359 s (IQR 287-521, p = 0.073). Patients with moderate to severe ARDS at admission to our ICU showed increased maximum clot firmness as a sign of hypercoagulation in the EX-test (70 vs 67 mm, p < 0.05), FIB-test (35 vs 24 mm, p < 0.05) and TPA-test (52 vs 36 mm, p < 0.05) as well as higher values of inflammatory markers (CRP, PCT and IL6). ECMO patients suffered more frequently from bleeding complications (32% vs 15%). CONCLUSION Although, the predictive value for thromboembolic complications or mortality seems limited, point-of-care viscoelastic coagulation testing might be useful in detecting hypercoagulable states and impaired fibrinolysis in critically ill COVID-19 ARDS patients and could be helpful in identifying patients with a potentially very severe course of the disease.
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Affiliation(s)
- Lars Heubner
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Marvin Greiner
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Oliver Vicent
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Jan Beyer-Westendorf
- Division of Hematology and Hemostasis, Department of Medicine I, Thrombosis Research University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Oliver Tiebel
- Institute of Clinical Chemistry, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Ute Scholz
- MVZ Labor Dr. Reising-Ackermann Und Kollegen, Center of Hemostasis, Leipzig, Germany
| | - Andreas Güldner
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Martin Mirus
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Dietmar Fries
- Department for General and Surgical Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria
| | - Thea Koch
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Peter Markus Spieth
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany.
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Nawaz S, Chinnadurai R, Al Chalabi S, Evans P, Kalra PA, Syed AA, Sinha S. Obesity and Chronic Kidney Disease A Current Review. Obes Sci Pract 2022; 9:61-74. [PMID: 37034567 PMCID: PMC10073820 DOI: 10.1002/osp4.629] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 06/02/2022] [Accepted: 07/04/2022] [Indexed: 11/08/2022] Open
Abstract
Background Obesity poses significant challenges to healthcare globally, particularly through its bi-directional relationship with co-morbid metabolic conditions such as type 2 diabetes and hypertension. There is also emerging evidence of an association between obesity and chronic kidney disease (CKD) which is less well characterized. Methods A literature search of electronic libraries was conducted to identify and present a narrative review of the interplay between obesity and CKD. Findings Obesity may predispose to CKD directly as it is linked to the histopathological finding of obesity-related glomerulopathy and indirectly through its widely recognized complications such as atherosclerosis, hypertension, and type 2 diabetes. The biochemical and endocrine products of adipose tissue contribute to pathophysiological processes such as inflammation, oxidative stress, endothelial dysfunction, and proteinuria. The prevention and management of obesity may prove critical in counteracting both the development and advancement of CKD. Moreover, measures of abdominal adiposity such as waist circumference, are generally associated with worse morbidity and mortality in individuals receiving maintenance hemodialysis. Conclusion Obesity is a risk factor for the onset and progression of CKD and should be recognized as a potential target for a preventative public health approach to reduce CKD rates within the general population. Future research should focus on the use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors in patients with CKD and obesity due to their multi-faceted actions on major outcomes.
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Affiliation(s)
- Saira Nawaz
- Faculty of Biology Medicine and Health University of Manchester Manchester UK
| | - Rajkumar Chinnadurai
- Faculty of Biology Medicine and Health University of Manchester Manchester UK
- Department of Renal Medicine Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Salford UK
| | - Saif Al Chalabi
- Faculty of Biology Medicine and Health University of Manchester Manchester UK
- Department of Renal Medicine Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Salford UK
| | - Philip Evans
- Department of Renal Medicine Liverpool University Hospitals NHS Foundation Trust Liverpool UK
| | - Philip A Kalra
- Faculty of Biology Medicine and Health University of Manchester Manchester UK
- Department of Renal Medicine Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Salford UK
| | - Akheel A. Syed
- Faculty of Biology Medicine and Health University of Manchester Manchester UK
- Department of Diabetes Endocrinology and Obesity Medicine Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Salford UK
| | - Smeeta Sinha
- Faculty of Biology Medicine and Health University of Manchester Manchester UK
- Department of Renal Medicine Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Salford UK
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Roumiguié M, Estève D, Manceau C, Toulet A, Gilleron J, Belles C, Jia Y, Houël C, Pericart S, LeGonidec S, Valet P, Cormont M, Tanti JF, Malavaud B, Bouloumié A, Milhas D, Muller C. Periprostatic Adipose Tissue Displays a Chronic Hypoxic State that Limits Its Expandability. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:926-942. [PMID: 35358473 DOI: 10.1016/j.ajpath.2022.03.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/15/2022] [Accepted: 03/08/2022] [Indexed: 06/14/2023]
Abstract
White adipose tissue accumulates at various sites throughout the body, some adipose tissue depots exist near organs whose function they influence in a paracrine manner. Prostate gland is surrounded by a poorly characterized adipose depot called periprostatic adipose tissue (PPAT), which plays emerging roles in prostate-related disorders. Unlike all other adipose depots, PPAT secretes proinflammatory cytokines even in lean individuals and does not increase in volume during obesity. These unique features remain unexplained because of the poor structural and functional characterization of this tissue. This study characterized the structural organization of PPAT in patients compared with abdominopelvic adipose tissue (APAT), an extraperitoneal adipose depot, the accumulation of which is correlated to body mass index. Confocal microscopy followed by three-dimensional reconstructions showed a sparse vascular network in PPAT when compared with that in APAT, suggesting that this tissue is hypoxic. Unbiased comparisons of PPAT and APAT transcriptomes found that most differentially expressed genes were related to the hypoxia response. High levels of the hypoxia-inducible factor 2α confirmed the presence of an adaptive response to hypoxia in PPAT. This chronic hypoxic state was associated with inflammation and fibrosis, which were not further up-regulated by obesity. This fibrosis and inflammation explain the failure of PPAT to expand in obesity and open new mechanistic avenues to explain its role in prostate-related disorders, including cancer.
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Affiliation(s)
- Mathieu Roumiguié
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France; Département d'Urologie, Institut Universitaire du Cancer, Toulouse, France
| | - David Estève
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Cécile Manceau
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France; Département d'Urologie, Institut Universitaire du Cancer, Toulouse, France
| | - Aurélie Toulet
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Jérôme Gilleron
- Université Côte d'Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Chloé Belles
- Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, INSERM, Toulouse, France
| | - Yiyue Jia
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Cynthia Houël
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Sarah Pericart
- Département d'Anatomo-Pathologie, Institut Universitaire du Cancer, Toulouse, France
| | - Sophie LeGonidec
- Institut RESTORE, Université de Toulouse, Centre national de la recherche scientifique U-5070, Etablissement Français du Sang, Ecole Nationale Vétérinaire de Toulouse, INSERM U1301, Toulouse, France
| | - Philippe Valet
- Institut RESTORE, Université de Toulouse, Centre national de la recherche scientifique U-5070, Etablissement Français du Sang, Ecole Nationale Vétérinaire de Toulouse, INSERM U1301, Toulouse, France
| | - Mireille Cormont
- Université Côte d'Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Jean-François Tanti
- Université Côte d'Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Bernard Malavaud
- Département d'Urologie, Institut Universitaire du Cancer, Toulouse, France
| | - Anne Bouloumié
- Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, INSERM, Toulouse, France
| | - Delphine Milhas
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France.
| | - Catherine Muller
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France.
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28
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Egido-Turrión C, Rossi E, Ollauri-Ibáñez C, Pérez-García ML, Sevilla MA, Bastida JM, González-Porras JR, Rodríguez-Barbero A, Bernabeu C, Lopez-Novoa JM, Pericacho M. Functional Alterations Involved in Increased Bleeding in Hereditary Hemorrhagic Telangiectasia Mouse Models. Front Med (Lausanne) 2022; 9:871903. [PMID: 35665360 PMCID: PMC9160577 DOI: 10.3389/fmed.2022.871903] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/06/2022] [Indexed: 12/11/2022] Open
Abstract
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal-dominant genetic disorder involving defects in two predominant genes known as endoglin (ENG; HHT-1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT-2). It is characterized by mucocutaneous telangiectases that, due to their fragility, frequently break causing recurrent epistaxis and gastrointestinal bleeding. Because of the severity of hemorrhages, the study of the hemostasis involved in these vascular ruptures is critical to find therapies for this disease. Our results demonstrate that HHT patients with high bleeding, as determined by a high Epistaxis Severity Score (ESS), do not have prolonged clotting times or alterations in clotting factors. Considering that coagulation is only one of the processes involved in hemostasis, the main objective of this study was to investigate the overall mechanisms of hemostasis in HHT-1 (Eng+/−) and HHT-2 (Alk1+/−) mouse models, which do not show HHT vascular phenotypes in the meaning of spontaneous bleeding. In Eng+/− mice, the results of in vivo and in vitro assays suggest deficient platelet-endothelium interactions that impair a robust and stable thrombus formation. Consequently, the thrombus could be torn off and dragged by the mechanical force exerted by the bloodstream, leading to the reappearance of hemorrhages. In Alk1+/− mice, an overactivation of the fibrinolysis system was observed. These results support the idea that endoglin and Alk1 haploinsufficiency leads to a common phenotype of impaired hemostasis, but through different mechanisms. This contribution opens new therapeutic approaches to HHT patients' epistaxis.
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Affiliation(s)
- Cristina Egido-Turrión
- Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Elisa Rossi
- Université de Paris, Innovative Therapies in Haemostasis, INSERM, Paris, France
| | - Claudia Ollauri-Ibáñez
- Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - María L. Pérez-García
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Internal Medicine, Complejo Asistencial Universitario de Salamanca (CAUSA)-SACYL, Salamanca, Spain
| | - María A. Sevilla
- Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - José María Bastida
- Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA)-SACYL, Salamanca, Spain
| | - José Ramón González-Porras
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA)-SACYL, Salamanca, Spain
| | - Alicia Rodríguez-Barbero
- Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - José M. Lopez-Novoa
- Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Miguel Pericacho
- Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- *Correspondence: Miguel Pericacho
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29
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Liu L, Shi Z, Ji X, Zhang W, Luan J, Zahr T, Qiang L. Adipokines, adiposity, and atherosclerosis. Cell Mol Life Sci 2022; 79:272. [PMID: 35503385 PMCID: PMC11073100 DOI: 10.1007/s00018-022-04286-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/11/2022] [Accepted: 04/03/2022] [Indexed: 12/12/2022]
Abstract
Characterized by a surplus of whole-body adiposity, obesity is strongly associated with the prognosis of atherosclerosis, a hallmark of coronary artery disease (CAD) and the major contributor to cardiovascular disease (CVD) mortality. Adipose tissue serves a primary role as a lipid-storage organ, secreting cytokines known as adipokines that affect whole-body metabolism, inflammation, and endocrine functions. Emerging evidence suggests that adipokines can play important roles in atherosclerosis development, progression, as well as regression. Here, we review the versatile functions of various adipokines in atherosclerosis and divide these respective functions into three major groups: protective, deteriorative, and undefined. The protective adipokines represented here are adiponectin, fibroblast growth factor 21 (FGF-21), C1q tumor necrosis factor-related protein 9 (CTRP9), and progranulin, while the deteriorative adipokines listed include leptin, chemerin, resistin, Interleukin- 6 (IL-6), and more, with additional adipokines that have unclear roles denoted as undefined adipokines. Comprehensively categorizing adipokines in the context of atherosclerosis can help elucidate the various pathways involved and potentially pave novel therapeutic approaches to treat CVDs.
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Affiliation(s)
- Longhua Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai, People's Republic of China.
| | - Zunhan Shi
- School of Kinesiology, Shanghai University of Sport, Shanghai, People's Republic of China
| | - Xiaohui Ji
- School of Kinesiology, Shanghai University of Sport, Shanghai, People's Republic of China
| | - Wenqian Zhang
- School of Kinesiology, Shanghai University of Sport, Shanghai, People's Republic of China
| | - Jinwen Luan
- School of Kinesiology, Shanghai University of Sport, Shanghai, People's Republic of China
| | - Tarik Zahr
- Department of Pharmacology, Columbia University, New York, NY, USA
| | - Li Qiang
- Department of Pathology and Cellular Biology and Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
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30
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Reyes-Barrera J, Medina-Urrutia AX, Jorge-Galarza E, Osorio-Alonso H, Arellano-Buendía AS, Olvera-Mayorga G, Sánchez-Ortiz NA, Torres-Tamayo M, Tovar Palacio AR, Torre-Villalvazo I, Juárez-Rojas JG. Uric acid is associated with morpho-functional adipose tissue markers in apparently healthy subjects. Clin Chim Acta 2022; 531:368-374. [DOI: 10.1016/j.cca.2022.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/26/2022]
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31
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A Comparative Study on the Adipogenic Differentiation of Mesenchymal Stem/Stromal Cells in 2D and 3D Culture. Cells 2022; 11:cells11081313. [PMID: 35455993 PMCID: PMC9029885 DOI: 10.3390/cells11081313] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 02/04/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSC) are capable of renewing the progenitor cell fraction or differentiating in a tissue-specific manner. Adipogenic differentiation of adipose-tissue-derived MSC (adMSC) is important in various pathological processes. Adipocytes and their progenitors are metabolically active and secrete molecules (adipokines) that have both pro- and anti-inflammatory properties. Cell culturing in 2D is commonly used to study cellular responses, but the 2D environment does not reflect the structural situation for most cell types. Therefore, 3D culture systems have been developed to create an environment considered more physiological. Since knowledge about the effects of 3D cultivation on adipogenic differentiation is limited, we investigated its effects on adipogenic differentiation and adipokine release of adMSC (up to 28 days) and compared these with the effects in 2D. We demonstrated that cultivation conditions are crucial for cell behavior: in both 2D and 3D culture, adipogenic differentiation occurred only after specific stimulation. While the size and structure of adipogenically stimulated 3D spheroids remained stable during the experiment, the unstimulated spheroids showed signs of disintegration. Adipokine release was dependent on culture dimensionality; we found upregulated adiponectin and downregulated pro-inflammatory factors. Our findings are relevant for cell therapeutic applications of adMSC in complex, three-dimensionally arranged tissues.
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32
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Bruno ME, Mukherjee S, Stromberg AJ, Saito H, Starr ME. Visceral fat-specific regulation of plasminogen activator inhibitor-1 in aged septic mice. J Cell Physiol 2022; 237:706-719. [PMID: 34369600 PMCID: PMC8810697 DOI: 10.1002/jcp.30551] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 01/03/2023]
Abstract
Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our previous work demonstrated that visceral adipose tissues (VAT) are a major source of PAI-1, especially in the aged (murine endotoxemia), that circulating PAI-1 protein levels match the trajectory of PAI-1 transcript levels in VAT (clinical sepsis), and that PAI-1 in both VAT and plasma are positively associated with acute kidney injury (AKI) in septic patients. In the current study utilizing preclinical sepsis models, PAI-1 tissue distribution was examined and cellular sources, as well as mechanisms mediating PAI-1 induction in VAT, were identified. In aged mice with sepsis, PAI-1 gene expression was significantly higher in VAT than in other major organs. VAT PAI-1 gene expression correlated with PAI-1 protein levels in both VAT and plasma. Moreover, VAT and plasma levels of PAI-1 were positively associated with AKI markers, modeling our previous clinical data. Using explant cultures of VAT, we determined that PAI-1 is secreted robustly in response to recombinant transforming growth factor β (TGFβ) and tumor necrosis factor α (TNFα) treatment; however, neutralization was effective only for TNFα indicating that TGFβ is not an endogenous modulator of PAI-1. Within VAT, TNFα was localized to neutrophils and macrophages. PAI-1 protein levels were fourfold higher in stromal vascular fraction (SVF) cells compared with mature adipocytes, and among SVF cells, both immune and nonimmune compartments expressed PAI-1 in a similar fashion. PAI-1 was localized predominantly to macrophages within the immune compartment and preadipocytes and endothelial cells within the nonimmune compartment. Collectively, these results indicate that induction and secretion of PAI-1 from VAT is facilitated by a complex interaction among immune and nonimmune cells. As circulating PAI-1 contributes to AKI in sepsis, understanding PAI-1 regulation in VAT could yield novel strategies for reducing systemic consequences of PAI-1 overproduction.
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Affiliation(s)
- Maria E.C. Bruno
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Sujata Mukherjee
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Arnold J. Stromberg
- Department of Statistics, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Hiroshi Saito
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Marlene E. Starr
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA
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33
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Okada K, Kawao N, Nakai D, Wakabayashi R, Horiuchi Y, Okumoto K, Kurashimo S, Takafuji Y, Matsuo O, Kaji H. Role of Macrophages and Plasminogen Activator Inhibitor-1 in Delayed Bone Repair Induced by Glucocorticoids in Mice. Int J Mol Sci 2022; 23:478. [PMID: 35008904 PMCID: PMC8745285 DOI: 10.3390/ijms23010478] [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: 12/06/2021] [Revised: 12/24/2021] [Accepted: 12/29/2021] [Indexed: 11/16/2022] Open
Abstract
Glucocorticoids delay fracture healing and induce osteoporosis. However, the mechanisms by which glucocorticoids delay bone repair have yet to be clarified. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of plasminogen activators and an adipocytokine that regulates metabolism. We herein investigated the roles of macrophages in glucocorticoid-induced delays in bone repair after femoral bone injury using PAI-1-deficient female mice intraperitoneally administered with dexamethasone (Dex). Dex significantly decreased the number of F4/80-positive macrophages at the damaged site two days after femoral bone injury. It also attenuated bone injury-induced decreases in the number of hematopoietic stem cells in bone marrow in wild-type and PAI-1-deficient mice. PAI-1 deficiency significantly weakened Dex-induced decreases in macrophage number and macrophage colony-stimulating factor (M-CSF) mRNA levels at the damaged site two days after bone injury. It also significantly ameliorated the Dex-induced inhibition of macrophage phagocytosis at the damaged site. In conclusion, we herein demonstrated that Dex decreased the number of macrophages at the damaged site during early bone repair after femoral bone injury partly through PAI-1 and M-CSF in mice.
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Affiliation(s)
- Kiyotaka Okada
- Department of Arts and Sciences, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan;
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan; (N.K.); (D.N.); (R.W.); (Y.T.); (O.M.)
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan; (N.K.); (D.N.); (R.W.); (Y.T.); (O.M.)
| | - Daisho Nakai
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan; (N.K.); (D.N.); (R.W.); (Y.T.); (O.M.)
| | - Rei Wakabayashi
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan; (N.K.); (D.N.); (R.W.); (Y.T.); (O.M.)
| | - Yoshitaka Horiuchi
- Life Science Research Institute, Kindai University, Osaka 589-8511, Japan; (Y.H.); (K.O.); (S.K.)
| | - Katsumi Okumoto
- Life Science Research Institute, Kindai University, Osaka 589-8511, Japan; (Y.H.); (K.O.); (S.K.)
| | - Shinji Kurashimo
- Life Science Research Institute, Kindai University, Osaka 589-8511, Japan; (Y.H.); (K.O.); (S.K.)
| | - Yoshimasa Takafuji
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan; (N.K.); (D.N.); (R.W.); (Y.T.); (O.M.)
| | - Osamu Matsuo
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan; (N.K.); (D.N.); (R.W.); (Y.T.); (O.M.)
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan; (N.K.); (D.N.); (R.W.); (Y.T.); (O.M.)
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34
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Ren Y, Zhao H, Yin C, Lan X, Wu L, Du X, Griffiths HR, Gao D. Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation. Front Endocrinol (Lausanne) 2022; 13:873699. [PMID: 35909571 PMCID: PMC9329830 DOI: 10.3389/fendo.2022.873699] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 06/17/2022] [Indexed: 11/18/2022] Open
Abstract
Chronic low-grade inflammation in adipose tissue (AT) is a hallmark of obesity and contributes to various metabolic disorders, such as type 2 diabetes and cardiovascular diseases. Inflammation in ATs is characterized by macrophage infiltration and the activation of inflammatory pathways mediated by NF-κB, JNK, and NLRP3 inflammasomes. Adipokines, hepatokines and myokines - proteins secreted from AT, the liver and skeletal muscle play regulatory roles in AT inflammation via endocrine, paracrine, and autocrine pathways. For example, obesity is associated with elevated levels of pro-inflammatory adipokines (e.g., leptin, resistin, chemerin, progranulin, RBP4, WISP1, FABP4, PAI-1, Follistatin-like1, MCP-1, SPARC, SPARCL1, and SAA) and reduced levels of anti-inflammatory adipokines such as adiponectin, omentin, ZAG, SFRP5, CTRP3, vaspin, and IL-10. Moreover, some hepatokines (Fetuin A, DPP4, FGF21, GDF15, and MANF) and myokines (irisin, IL-6, and DEL-1) also play pro- or anti-inflammatory roles in AT inflammation. This review aims to provide an updated understanding of these organokines and their role in AT inflammation and related metabolic abnormalities. It serves to highlight the molecular mechanisms underlying the effects of these organokines and their clinical significance. Insights into the roles and mechanisms of these organokines could provide novel and potential therapeutic targets for obesity-induced inflammation.
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Affiliation(s)
- Yakun Ren
- Institute of Molecular and Translational Medicine, Xian Jiaotong University Health Science Center, Xi’an, China
| | - Hao Zhao
- School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
| | - Chunyan Yin
- Department of Pediatrics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xi Lan
- Institute of Molecular and Translational Medicine, Xian Jiaotong University Health Science Center, Xi’an, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
| | - Litao Wu
- Institute of Molecular and Translational Medicine, Xian Jiaotong University Health Science Center, Xi’an, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
| | - Xiaojuan Du
- Institute of Molecular and Translational Medicine, Xian Jiaotong University Health Science Center, Xi’an, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
| | - Helen R. Griffiths
- Swansea University Medical School, Swansea University, Swansea, United Kingdom
| | - Dan Gao
- Institute of Molecular and Translational Medicine, Xian Jiaotong University Health Science Center, Xi’an, China
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Center, Xi’an, China
- *Correspondence: Dan Gao,
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Ehara H, Takafuji Y, Tatsumi K, Okada K, Mizukami Y, Kawao N, Matsuo O, Kaji H. Role of plasminogen activator inhibitor-1 in muscle wasting induced by a diabetic state in female mice. Endocr J 2021; 68:1421-1428. [PMID: 34248092 DOI: 10.1507/endocrj.ej21-0142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [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
Muscle wasting is a complication in patients with diabetes and leads to a reduced quality of life. However, the detailed mechanisms of diabetes-induced muscle wasting remain unknown. Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that suppresses plasminogen activator activity, is involved in the pathophysiology of various diseases, including diabetes. In the present study, we examined the role of endogenous PAI-1 in the decrease in muscle mass and the impaired grip strength induced by the diabetic state by employing streptozotocin (STZ)-treated PAI-1-deficient female mice. The analyses of skeletal muscles and grip strength were performed in PAI-1-deficient and wild-type mice 4 weeks after the induction of a diabetic state by STZ administration. PAI-1 deficiency did not affect muscle mass in the lower limbs measured by quantitative computed tomography or tissue weights of the tibialis anterior, gastrocnemius and soleus muscles of female mice with or without STZ treatment. On the other hand, PAI-1 deficiency significantly aggravated grip strength decreased by STZ in female mice. PAI-1 deficiency did not affect the mRNA levels of Pax7, MyoD, myogenin or myosin heavy chain in either the tibialis anterior or soleus muscles of female mice with or without STZ treatment. In conclusion, we revealed for the first time that PAI-1 deficiency aggravates grip strength impaired by the diabetic state in female mice, although it did not affect diabetes-decreased muscle mass.
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Affiliation(s)
- Hiroki Ehara
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Yoshimasa Takafuji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Kohei Tatsumi
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Kiyotaka Okada
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Yuya Mizukami
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Osamu Matsuo
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
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Holm JB, Rosendahl AH, Borgquist S. Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer. Cancers (Basel) 2021; 13:cancers13246286. [PMID: 34944905 PMCID: PMC8699696 DOI: 10.3390/cancers13246286] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/07/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Breast cancer is the second most common cancer in women worldwide. The risk of developing breast cancer depends on various mechanisms, such as age, heredity, reproductive factors, physical inactivity, and obesity. Obesity increases the risk of breast cancer and worsens outcomes for breast cancer patients. The rate of obesity is increasing worldwide, stressing the need for awareness of the association between obesity and breast cancer. In this review, we outline the biomarkers—including cellular and soluble factors—in the breast, associated with obesity, that affect the risk of breast cancer and breast cancer prognosis. Through these biomarkers, we aim to better identify patients with obesity with a higher risk of breast cancer and an inferior prognosis. Abstract Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed.
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Affiliation(s)
- Jonas Busk Holm
- Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark
- Correspondence: (J.B.H.); (S.B.)
| | - Ann H. Rosendahl
- Department of Clinical Sciences Lund, Oncology, Lund University, Skåne University Hospital, Barngatan 4, 221 85 Lund, Sweden;
| | - Signe Borgquist
- Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark
- Department of Clinical Sciences Lund, Oncology, Lund University, Skåne University Hospital, Barngatan 4, 221 85 Lund, Sweden;
- Correspondence: (J.B.H.); (S.B.)
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Ehara H, Tatsumi K, Takafuji Y, Kawao N, Ishida M, Okada K, Mackman N, Kaji H. Role of tissue factor in delayed bone repair induced by diabetic state in mice. PLoS One 2021; 16:e0260754. [PMID: 34855855 PMCID: PMC8638858 DOI: 10.1371/journal.pone.0260754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/17/2021] [Indexed: 11/19/2022] Open
Abstract
Background Tissue factor (TF) is the primary activator of the extrinsic coagulation protease cascade. Although TF plays roles in various pathological states, such as thrombosis, inflammatory diseases, cancer, and atherosclerosis, its involvement in bone metabolism remains unknown. Materials and methods The present study examined the roles of TF in delayed bone repair induced by a diabetic state in mice using wild-type (WT) and low TF-expressing (LTF) male mice. A diabetic state was induced by intraperitoneal injections of streptozotocin (STZ). Results A prolonged diabetic state significantly reduced total and trabecular bone mineral densities (BMD) as well as cortical bone thickness in WT and LTF mice; these BMD parameters were similar between WT and LTF mice treated with or without STZ. The diabetic state induced in WT mice delayed the repair of the femur following injury. The diabetic state induced in LTF mice was associated with further delays in bone repair. In in vitro experiments, TF significantly decreased receptor activator of nuclear factor-κB ligand-induced osteoclast formation and osteoclastogenic gene expression in RAW264.7 cells. However, it did not affect the gene expression levels of runt-related transcription factor 2 and osterix as well as alkaline phosphatase activity in mouse primary osteoblasts. Conclusion Low TF state was associated with enhanced bone repair delay induced by diabetic state in mice. The TF-induced suppression of bone remodeling may be a contributing factor to the protective effects of TF against delayed bone repair in a diabetic state.
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Affiliation(s)
- Hiroki Ehara
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Kohei Tatsumi
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara, Japan
| | - Yoshimasa Takafuji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Masayoshi Ishida
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Kiyotaka Okada
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Nigel Mackman
- Department of Medicine, Division of Hematology, UNC Blood Research Institute, University of North Carolina, Chapel Hill, NC, United States of America
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
- * E-mail:
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Mandujano-Lázaro G, Galaviz-Hernández C, Reyes-López CA, Almanza-Pérez JC, Giacoman-Martínez A, López-Camarillo C, Huang F, Marchat LA. A Short S-Equol Exposure Has a Long-Term Inhibitory Effect on Adipogenesis in Mouse 3T3-L1 Cells. APPLIED SCIENCES 2021; 11:9657. [DOI: 10.3390/app11209657] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2025]
Abstract
In the search for new drugs against obesity, the chronic disease that threatens human health worldwide, several works have focused on the study of estrogen homologs because of the role of estrogen receptors (ERs) in adipocyte growth. The isoflavone equol, an ERβ agonist, has shown beneficial metabolic effects in in vivo and in vitro assays; however, additional studies are required to better characterize its potential for body weight control. Here, we showed that the treatment of 3T3-L1 cells with 10 μM of S-equol for the first three days of the adipocyte differentiation protocol was able to prevent cells becoming semi-rounded and having a lipid droplet formation until the seventh day of culture; moreover, lipid accumulation was reduced by about 50%. Congruently, S-equol induced a reduction in mRNA expression of the adipogenic markers C/EBPα and PPARγ, and adipokines secretion, mainly Adiponectin, Leptin, Resistin, and MCP-1, while the release of PAI-1 was augmented. Moreover, it also reduced the expression of ERα and attenuated the subexpression of ERβ associated with adipogenesis. Altogether, our data suggested that S-equol binding to ERβ affects the transcriptional program that regulates adipogenesis and alters adipocyte functions. Future efforts will focus on studying the impact of S-equol on ER signaling pathways.
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Affiliation(s)
- Gilberto Mandujano-Lázaro
- Laboratorio 2 de Biomedicina Molecular, ENMH, Instituto Politécnico Nacional, Ciudad de México 07320, Mexico
| | | | - César A. Reyes-López
- Laboratorio de Bioquímica Estructural, ENMH, Instituto Politécnico Nacional, Ciudad de México 07320, Mexico
| | - Julio C. Almanza-Pérez
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Abraham Giacoman-Martínez
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Sede Sur, Ciudad de México 14330, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México 03100, Mexico
| | - Fengyang Huang
- Laboratorio de Farmacología y Toxicología, Hospital Infantil de México Federico Gómez, Ciudad de México 06720, Mexico
| | - Laurence A. Marchat
- Laboratorio 2 de Biomedicina Molecular, ENMH, Instituto Politécnico Nacional, Ciudad de México 07320, Mexico
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Paniagua-Sancho M, Quiros Y, Casanova AG, Blanco-Gozalo V, Agüeros-Blanco C, Benito-Hernández A, Ramos-Barron MA, Gómez-Alamillo C, Arias M, Sancho-Martínez SM, López-Hernández FJ. Urinary Plasminogen Activator Inhibitor-1: A Biomarker of Acute Tubular Injury. Am J Nephrol 2021; 52:714-724. [PMID: 34518454 DOI: 10.1159/000518455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/12/2021] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Acute kidney injury (AKI) is a threatening, multiaetiological syndrome encompassing a variety of forms and damage patterns. AKI lacks sufficiently specific diagnostic tools to evaluate the distinct combination of pathophysiological events underlying each case, which limits personalized and optimized handling. Therefore, a pathophysiological diagnosis based on new urinary biomarkers is sought for practical (readiness and noninvasiveness) and conceptual reasons, as the urine is a direct product of the kidneys. However, biomarkers found in the urine may also have extrarenal origin, thus conveying pathophysiological information from other organs or tissues. Urinary plasminogen activator inhibitor-1 (PAI-1) has been associated to AKI, although its origin and traffic to the urine are not known. METHODS Herein, we studied the blood or renal origin of urinary PAI-1 (uPAI-1) in experimental AKI in Wistar rats, by means of the in situ renal perfusion method. For this purpose, urine was collected while the kidneys of rats with AKI showing increased uPAI-1 excretion, and controls, were in situ perfused with a saline solution. RESULTS Our results show that during perfusion, PAI-1 remained in the urine of AKI rats, suggesting that renal cells shed this protein directly to the urine. PAI-1 is also significantly increased in the urine of AKI patients. Its low correlation with other urinary markers such as NGAL or NAG suggests that PAI-1 provides complementary and distinct phenotypical information. CONCLUSION In conclusion, uPAI-1 is a biomarker produced by damaged kidneys following AKI, whose precise pathophysiological meaning in AKI needs to be further investigated.
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Affiliation(s)
- María Paniagua-Sancho
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
- Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain
| | - Yaremi Quiros
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain
- Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Soria, Spain
| | - Alfredo G Casanova
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
- Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain
| | - Víctor Blanco-Gozalo
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
- Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain
| | - Consuelo Agüeros-Blanco
- Department of Nephrology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Santander, Spain
| | - Adalberto Benito-Hernández
- Department of Nephrology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Santander, Spain
| | - María A Ramos-Barron
- Department of Nephrology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Santander, Spain
| | - Carlos Gómez-Alamillo
- Department of Nephrology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Santander, Spain
| | - Manuel Arias
- Department of Nephrology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Santander, Spain
| | - Sandra M Sancho-Martínez
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
- Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain
- Group of Biomedical Research on Critical Care (BioCritic), Valladolid, Spain
- Spanish Renal Research Network (REDinREN), Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco J López-Hernández
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
- Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain
- Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Soria, Spain
- Group of Biomedical Research on Critical Care (BioCritic), Valladolid, Spain
- Spanish Renal Research Network (REDinREN), Instituto de Salud Carlos III, Madrid, Spain
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Shen JX, Couchet M, Dufau J, de Castro Barbosa T, Ulbrich MH, Helmstädter M, Kemas AM, Zandi Shafagh R, Marques M, Hansen JB, Mejhert N, Langin D, Rydén M, Lauschke VM. 3D Adipose Tissue Culture Links the Organotypic Microenvironment to Improved Adipogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100106. [PMID: 34165908 PMCID: PMC8373086 DOI: 10.1002/advs.202100106] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/06/2021] [Indexed: 05/15/2023]
Abstract
Obesity and type 2 diabetes are strongly associated with adipose tissue dysfunction and impaired adipogenesis. Understanding the molecular underpinnings that control adipogenesis is thus of fundamental importance for the development of novel therapeutics against metabolic disorders. However, translational approaches are hampered as current models do not accurately recapitulate adipogenesis. Here, a scaffold-free versatile 3D adipocyte culture platform with chemically defined conditions is presented in which primary human preadipocytes accurately recapitulate adipogenesis. Following differentiation, multi-omics profiling and functional tests demonstrate that 3D adipocyte cultures feature mature molecular and cellular phenotypes similar to freshly isolated mature adipocytes. Spheroids exhibit physiologically relevant gene expression signatures with 4704 differentially expressed genes compared to conventional 2D cultures (false discovery rate < 0.05), including the concerted expression of factors shaping the adipogenic niche. Furthermore, lipid profiles of >1000 lipid species closely resemble patterns of the corresponding isogenic mature adipocytes in vivo (R2 = 0.97). Integration of multi-omics signatures with analyses of the activity profiles of 503 transcription factors using global promoter motif inference reveals a complex signaling network, involving YAP, Hedgehog, and TGFβ signaling, that links the organotypic microenvironment in 3D culture to the activation and reinforcement of PPARγ and CEBP activity resulting in improved adipogenesis.
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Affiliation(s)
- Joanne X. Shen
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
| | - Morgane Couchet
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Jérémy Dufau
- InsermInstitute of Metabolic and Cardiovascular Diseases (I2MC)UMR1297Toulouse31432France
- Université de ToulouseUniversité Paul SabatierFaculté de Médecine, I2MCUMR1297Toulouse31432France
| | - Thais de Castro Barbosa
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Maximilian H. Ulbrich
- Renal DivisionDepartment of MedicineUniversity Hospital Freiburg and Faculty of MedicineUniversity of FreiburgFreiburg79106Germany
- BIOSS Centre for Biological Signalling StudiesUniversity of FreiburgFreiburg79104Germany
| | - Martin Helmstädter
- Renal DivisionDepartment of MedicineUniversity Hospital Freiburg and Faculty of MedicineUniversity of FreiburgFreiburg79106Germany
| | - Aurino M. Kemas
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
| | - Reza Zandi Shafagh
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
- Division of Micro‐ and NanosystemsKTH Royal Institute of TechnologyStockholm100 44Sweden
| | - Marie‐Adeline Marques
- InsermInstitute of Metabolic and Cardiovascular Diseases (I2MC)UMR1297Toulouse31432France
- Université de ToulouseUniversité Paul SabatierFaculté de Médecine, I2MCUMR1297Toulouse31432France
| | - Jacob B. Hansen
- Department of BiologyUniversity of CopenhagenCopenhagen2100Denmark
| | - Niklas Mejhert
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Dominique Langin
- InsermInstitute of Metabolic and Cardiovascular Diseases (I2MC)UMR1297Toulouse31432France
- Université de ToulouseUniversité Paul SabatierFaculté de Médecine, I2MCUMR1297Toulouse31432France
- Toulouse University HospitalsDepartment of BiochemistryToulouse31079France
| | - Mikael Rydén
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Volker M. Lauschke
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
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Olszańska J, Pietraszek-Gremplewicz K, Nowak D. Melanoma Progression under Obesity: Focus on Adipokines. Cancers (Basel) 2021; 13:cancers13092281. [PMID: 34068679 PMCID: PMC8126042 DOI: 10.3390/cancers13092281] [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: 04/09/2021] [Revised: 05/01/2021] [Accepted: 05/05/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Obesity is a rapidly growing public health problem and the reason for numerous diseases in the human body, including cancer. This article reviews the current knowledge of the effect of molecules secreted by adipose tissue-adipokines on melanoma progression. We also discuss the role of these factors as markers of incidence, metastasis, and melanoma patient survival. Understanding the functions of adipokines will lead to knowledge of whether and how obesity promotes melanoma growth. Abstract Obesity is a growing problem in the world and is one of the risk factors of various cancers. Among these cancers is melanoma, which accounts for the majority of skin tumor deaths. Current studies are looking for a correlation between obesity and melanoma. They suspect that a potential cause of its development is connected to the biology of adipokines, active molecules secreted by adipose tissue. Under physiological conditions, adipokines control many processes, including lipid and glucose homeostasis, insulin sensitivity, angiogenesis, and inflammations. However, when there is an increased amount of fat in the body, their secretion is dysregulated. This article reviews the current knowledge of the effect of adipokines on melanoma growth. This work focuses on the molecular pathways by which adipose tissue secreted molecules modify the angiogenesis, migration, invasion, proliferation, and death of melanoma cells. We also discuss the role of these factors as markers of incidence, metastasis, and melanoma patient survival. Understanding the functions of adipokines will lead to knowledge of whether and how obesity promotes melanoma growth. Further studies may contribute to the innovations of therapies and the use of adipokines as predictive and/or prognostic biomarkers.
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Zwischenberger BA, Balasuriya BK, Harris DD, Nataraj N, Owen AM, Bruno MEC, Mukherjee S, Ortiz-Soriano V, O’Connor W, Ke C, Stromberg AJ, Chang PK, Neyra JA, Saito H, Starr ME. Adipose-Derived Inflammatory and Coagulant Mediators in Patients With Sepsis. Shock 2021; 55:596-606. [PMID: 32496420 PMCID: PMC8994194 DOI: 10.1097/shk.0000000000001579] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Results from preclinical sepsis studies using rodents are often criticized as not being reproducible in humans. Using a murine model, we previously reported that visceral adipose tissues (VAT) are highly active during the acute inflammatory response, serving as a major source of inflammatory and coagulant mediators. The purpose of this study was to determine whether these findings are recapitulated in patients with sepsis and to evaluate their clinical significance. VAT and plasma were obtained from patients undergoing intra-abdominal operations with noninflammatory conditions (control), local inflammation, or sepsis. In mesenteric and epiploic VAT, gene expression of pro-inflammatory (TNFα, IL-6, IL-1α, IL-1β) and pro-coagulant (PAI-1, PAI-2, TSP-1, TF) mediators was increased in sepsis compared with control and local inflammation groups. In the omentum, increased expression was limited to IL-1β, PAI-1, and PAI-2, showing a depot-specific regulation. Histological analyses showed little correlation between cellular infiltration and gene expression, indicating a resident source of these mediators. Notably, a strong correlation between PAI-1 expression in VAT and circulating protein levels was observed, both being positively associated with markers of acute kidney injury (AKI). In another cohort of septic patients stratified by incidence of AKI, circulating PAI-1 levels were higher in those with versus without AKI, thus extending these findings beyond intra-abdominal cases. This study is the first to translate upregulation of VAT mediators in sepsis from mouse to human. Collectively, the data suggest that development of AKI in septic patients is associated with high plasma levels of PAI-1, likely derived from resident cells within VAT.
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Affiliation(s)
- Brittany A. Zwischenberger
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Beverly K. Balasuriya
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Dwight D. Harris
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Nisha Nataraj
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Allison M. Owen
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
- Department of Physiology, University of Kentucky, Lexington, Kentucky
| | - Maria E. C. Bruno
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Sujata Mukherjee
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | | | - William O’Connor
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky
| | - Chenlu Ke
- Department of Statistics, University of Kentucky, Lexington, Kentucky
| | | | - Phillip K. Chang
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Javier A. Neyra
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Hiroshi Saito
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
- Department of Physiology, University of Kentucky, Lexington, Kentucky
| | - Marlene E. Starr
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
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Ishida M, Kawao N, Mizukami Y, Takafuji Y, Kaji H. Serpinb1a suppresses osteoclast formation. Biochem Biophys Rep 2021; 26:101004. [PMID: 33997318 PMCID: PMC8100536 DOI: 10.1016/j.bbrep.2021.101004] [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: 03/10/2021] [Revised: 04/12/2021] [Accepted: 04/19/2021] [Indexed: 11/25/2022] Open
Abstract
Serpinb1a, a serine protease inhibitor family protein, has been implicated in immunoregulation and several metabolic disorders, such as diabetes and obesity; however, its roles in bone remain unknown. Therefore, we herein investigated the physiological functions of Serpinb1a in osteoclastic and osteoblastic differentiation using mouse cell lines. Serpinb1a overexpression markedly reduced the number of tartrate-resistant acid phosphatase (TRAP)- and calcitonin receptor-positive multinucleated cells increased by receptor activator nuclear factor κB ligand (RANKL) in mouse preosteoclastic RAW 264.7 cells. Moreover, it significantly decreased the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), TRAP and cathepsin K in these cells. Regarding osteoblasts, Serpinb1a overexpression significantly reduced the mRNA levels of alkaline phosphatase (ALP) and osteocalcin as well as ALP activity induced by bone morphogenetic protein-2 (BMP-2) in mouse mesenchymal ST2 cells, although it did not alter osteoblast differentiation in mouse osteoblastic MC3T3-E1 cells. Concerning the pathophysiological relevance of Serpinb1a, Serpinb1a mRNA levels were decreased in the soleus and gastrocnemius muscles of mice 4 weeks after bilateral sciatic nerve resection. In conclusion, we herein revealed for the first time that Serpinb1a inhibited osteoclast formation induced by RANKL in RAW 264.7 cells and suppressed BMP-2-induced ALP activity in ST2 cells.
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Affiliation(s)
- Masayoshi Ishida
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Yuya Mizukami
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Yoshimasa Takafuji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
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Morrow GB, Whyte CS, Mutch NJ. A Serpin With a Finger in Many PAIs: PAI-1's Central Function in Thromboinflammation and Cardiovascular Disease. Front Cardiovasc Med 2021; 8:653655. [PMID: 33937363 PMCID: PMC8085275 DOI: 10.3389/fcvm.2021.653655] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/23/2021] [Indexed: 12/27/2022] Open
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily. PAI-1 is the principal inhibitor of the plasminogen activators, tissue plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA). Turbulence in the levels of PAI-1 tilts the balance of the hemostatic system resulting in bleeding or thrombotic complications. Not surprisingly, there is strong evidence that documents the role of PAI-1 in cardiovascular disease. The more recent uncovering of the coalition between the hemostatic and inflammatory pathways has exposed a distinct role for PAI-1. The storm of proinflammatory cytokines liberated during inflammation, including IL-6 and TNF-α, directly influence PAI-1 synthesis and increase circulating levels of this serpin. Consequently, elevated levels of PAI-1 are commonplace during infection and are frequently associated with a hypofibrinolytic state and thrombotic complications. Elevated PAI-1 levels are also a feature of metabolic syndrome, which is defined by a cluster of abnormalities including obesity, type 2 diabetes, hypertension, and elevated triglyceride. Metabolic syndrome is in itself defined as a proinflammatory state associated with elevated levels of cytokines. In addition, insulin has a direct impact on PAI-1 synthesis bridging these pathways. This review describes the key physiological functions of PAI-1 and how these become perturbed during disease processes. We focus on the direct relationship between PAI-1 and inflammation and the repercussion in terms of an ensuing hypofibrinolytic state and thromboembolic complications. Collectively, these observations strengthen the utility of PAI-1 as a viable drug target for the treatment of various diseases.
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Affiliation(s)
- Gael B Morrow
- Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom.,Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Claire S Whyte
- Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom
| | - Nicola J Mutch
- Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom
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45
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Junren C, Xiaofang X, Huiqiong Z, Gangmin L, Yanpeng Y, Xiaoyu C, Yuqing G, Yanan L, Yue Z, Fu P, Cheng P. Pharmacological Activities and Mechanisms of Hirudin and Its Derivatives - A Review. Front Pharmacol 2021; 12:660757. [PMID: 33935784 PMCID: PMC8085555 DOI: 10.3389/fphar.2021.660757] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022] Open
Abstract
Hirudin, an acidic polypeptide secreted by the salivary glands of Hirudo medicinalis (also known as "Shuizhi" in traditional Chinese medicine), is the strongest natural specific inhibitor of thrombin found so far. Hirudin has been demonstrated to possess potent anti-thrombotic effect in previous studies. Recently, increasing researches have focused on the anti-thrombotic activity of the derivatives of hirudin, mainly because these derivatives have stronger antithrombotic activity and lower bleeding risk. Additionally, various bioactivities of hirudin have been reported as well, including wound repair effect, anti-fibrosis effect, effect on diabetic complications, anti-tumor effect, anti-hyperuricemia effect, effect on cerebral hemorrhage, and others. Therefore, by collecting and summarizing publications from the recent two decades, the pharmacological activities, pharmacokinetics, novel preparations and derivatives, as well as toxicity of hirudin were systematically reviewed in this paper. In addition, the clinical application, the underlying mechanisms of pharmacological effects, the dose-effect relationship, and the development potential in new drug research of hirudin were discussed on the purpose of providing new ideas for application of hirudin in treating related diseases.
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Affiliation(s)
- Chen Junren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xie Xiaofang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhang Huiqiong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Gangmin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yin Yanpeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cao Xiaoyu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Gao Yuqing
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Yanan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhang Yue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Peng Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China.,West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Peng Cheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Marco A, Marco P. Improvement in the cardiovascular profile of patients with morbid obesity following bariatric surgery: Effect on hypercoagulability. Medicine (Baltimore) 2021; 100:e25280. [PMID: 33761732 PMCID: PMC9281975 DOI: 10.1097/md.0000000000025280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 03/03/2021] [Indexed: 01/05/2023] Open
Abstract
Obesity is an inflammatory state related to vascular endothelium dysfunction. It generates a biological situation of hypercoagulability increasing the risk of thrombosis. This prothrombotic condition could be improved by bariatric surgery.The main objective was to analyze the impact of bariatric surgery on cardiovascular risk factors (CVRF) associated with changes in thrombin generation and procoagulant activity of microparticles (MP).We present a prospective longitudinal study including consecutive patients candidate for bariatric surgery. We performed 3 sequential clinical visits: at inclusion, before surgery after completing the modified fasting phase, and 6 months after surgery. We analyzed CVRF, thrombin generation, and MP activity. The data analysis was performed using a logistic regression model to determine changes over time of hemostatic parameters and body mass index (BMI). McNemar test for binary variables was used to analyze the CVRF.We included 94 patients (66 women), with an average age of 45.7 ± 10.1 years. The mean BMI reduction at the end of the follow-up was 15.5 ± 4.2 kg/m2. We detected a statistically significant improvement in CVRF: hypertension, diabetes mellitus, dyslipidemia, and obstructive sleep apnea, as well as a significant reduction in thrombin generation capacity and procoagulant MP activity.Massive weight loss induced by bariatric surgery improves the cardiovascular profile, associated with a reduction in the hypercoagulable status.
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Affiliation(s)
- Ana Marco
- Hematology and Hemotherapy Service, Thrombosis and Hemostasis Department, University General Hospital
- Biomedical Research Institute
| | - Pascual Marco
- Hematology and Hemotherapy Service, Thrombosis and Hemostasis Department, University General Hospital
- Biomedical Research Institute
- Clinical Medicine Department, Miguel Hernández University, Alicante, Spain
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Soni S, Torvund M, Mandal CC. Molecular insights into the interplay between adiposity, breast cancer and bone metastasis. Clin Exp Metastasis 2021; 38:119-138. [PMID: 33591548 DOI: 10.1007/s10585-021-10076-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 02/03/2021] [Indexed: 01/20/2023]
Abstract
Cancer is a complex disease, with various pre-existing health ailments enhancing its pathology. In cancer, the extracellular environment contains various intrinsic physiological factors whose levels are altered with aging and pre-existing conditions. In obesity, the tumor microenvironment and metastases are enriched with factors that are both derived locally, and from other physiological compartments. Similarly, in obesity, the cancer cell environment both at the site of origin and at the secondary site i.e., metastatic niche, contains significantly more phenotypically-altered adipocytes than that of un-obese cancer patients. Indeed, obesity has been linked with cancer progression, metastasis, and therapy resistance. Adipocytes not only interact with tumor cells, but also with adjacent stromal cells at primary and metastatic sites. This review emphasizes the importance of bidirectional interactions between adipocytes and breast tumor cells in breast cancer progression and its bone metastases. This paper not only chronicles the role of various adipocyte-derived factors in tumor growth, but also describes the significance of adipocyte-derived bone metastatic factors in the development of bone metastasis of breast cancer. It provides a molecular view of the interplay between the adipocytes and tumor cells involved in breast cancer bone metastasis. However, more research is needed to determine if targeting cancer-associated adipocytes holds promise as a potential therapeutic approach for breast cancer bone metastasis treatment. Interplay between adipocytes and breast cancer cells at primary cancer site and metastatic bone microenvironment. AMSC Adipose-derived mesenchymal stem cell, CAA Cancer associated adipocytes, CAF Cancer associated fibroblast, BMSC Bone marrow derived mesenchymal stem cell, BMA Bone marrow adipocyte.
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Affiliation(s)
- Sneha Soni
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan, 305817, India
| | - Meaghan Torvund
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan, 305817, India.
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Kitamura H, Hashimoto M. USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes. Int J Mol Sci 2021; 22:1209. [PMID: 33530560 PMCID: PMC7865608 DOI: 10.3390/ijms22031209] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/22/2021] [Accepted: 01/23/2021] [Indexed: 12/13/2022] Open
Abstract
Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.
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Affiliation(s)
- Hiroshi Kitamura
- Laboratory of Veterinary Physiology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan;
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Altered acylated ghrelin response to food intake in congenital generalized lipodystrophy. PLoS One 2021; 16:e0244667. [PMID: 33411809 PMCID: PMC7790291 DOI: 10.1371/journal.pone.0244667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 12/14/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Patients with congenital generalized lipodystrophy (CGL) have very low levels of leptin and are described as having a voracious appetite. However, a direct comparison between CGL and eutrophic individuals is lacking, regarding both appetite parameters and acylated ghrelin, the hormone form that is active in acute food intake stimulation. The objective of the present study was to address whether and in what extent the subjective appetite parameters and acylated ghrelin response to a meal are affected in CGL individuals, in comparison to eutrophic individuals. Additionally, an obese group was included in the study, to allow the comparison between a leptin-resistant and a leptin-deficient condition on these aspects. METHODS Eutrophic controls (EUT, n = 10), obese subjects (OB, n = 10) and CGL (n = 11) were fasted overnight and then received an ad libitum meal. Blood was collected and the visual analogue scale was applied before and 90 minutes after the meal. An additional blood sample was collected at 60 minutes for ghrelin determination. RESULTS The CGL patients showed low fasting levels of leptin and adiponectin, dyslipidemia, and insulin resistance. The caloric intake was similar among the 3 groups. However, both CGL (p = 0.02) and OB (p = 0.04) had shorter satiation times than EUT. The CGL patients also had lower satiety time (p = 0.01) and their sensation of hunger was less attenuated by the meal (p = 0.03). Fasting acylated ghrelin levels were lower in CGL than in EUT (p = 0.003). After the meal, the levels tended to decrease in EUT but not in CGL and OB individuals. CONCLUSION The data indicate that, although not hyperphagic, the CGL patients present appetite disturbances in relation to eutrophic individuals. Their low fasting levels of acylated ghrelin and the absence of the physiological drop after meal intake suggest a role of these disturbances in hunger attenuation and satiety but not in acute satiation.
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50
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Chaurasia B, Talbot CL, Summers SA. Adipocyte Ceramides-The Nexus of Inflammation and Metabolic Disease. Front Immunol 2020; 11:576347. [PMID: 33072120 PMCID: PMC7538607 DOI: 10.3389/fimmu.2020.576347] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/20/2020] [Indexed: 12/21/2022] Open
Abstract
Adipose depots are heterogeneous tissues that store and sense fuel levels. Through the secretion of lipids, cytokines, and protein hormones (adipokines), they communicate with other organ systems, informing them of the organism's nutritional status. The adipose tissues include diverse types of adipocytes (white, beige, and brown) distinguished by the number/size of lipid droplets, mitochondrial density, and thermogenic capacity. Moreover, they include a spectrum of immune cells that modulate metabolic activity and tissue remodeling. The unique characteristics and interplay of these cells control the production of ceramides, a class of nutrient signals derived from fat and protein metabolism that modulate adipocyte function to regulate glucose and lipid metabolism. The excessive accumulation of ceramides contributes to the adipose tissue inflammation and dysfunction that underlies cardiometabolic disease. Herein we review findings on this important class of lipid species and discuss their role at the convergence point that links overnutrition/inflammation to key features of the metabolic syndrome.
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Affiliation(s)
- Bhagirath Chaurasia
- Division of Endocrinology, Department of Internal Medicine, Carver College of Medicine and the Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, United States
| | - Chad Lamar Talbot
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT, United States
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT, United States
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