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Lagarde CB, Thapa K, Cullen NM, Hawes ML, Salim K, Benz MC, Dietrich SR, Burow BE, Bunnell BA, Martin EC, Collins-Burow BM, Lynch RM, Hoang VT, Burow ME, Fang JS. Obesity and leptin in breast cancer angiogenesis. Front Endocrinol (Lausanne) 2024; 15:1465727. [PMID: 39439572 PMCID: PMC11493622 DOI: 10.3389/fendo.2024.1465727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/04/2024] [Indexed: 10/25/2024] Open
Abstract
At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.
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Affiliation(s)
- Courtney B. Lagarde
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Kapil Thapa
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Nicole M. Cullen
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Mackenzie L. Hawes
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Khudeja Salim
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Megan C. Benz
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Sophie R. Dietrich
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- United States Department of Agriculture Southern Regional Research Center, New Orleans, LA, United States
| | - Brandon E. Burow
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Bruce A. Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Elizabeth C. Martin
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Bridgette M. Collins-Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Ronald M. Lynch
- Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Van T. Hoang
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Matthew E. Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jennifer S. Fang
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
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Yuliana ME, Chou HC, Su ECY, Chuang HC, Huang LT, Chen CM. Uteroplacental insufficiency decreases leptin expression and impairs lung development in growth-restricted newborn rats. Pediatr Res 2024; 95:1503-1509. [PMID: 38049649 DOI: 10.1038/s41390-023-02946-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/16/2023] [Indexed: 12/06/2023]
Abstract
BACKGROUND The study aimed to analyze the effect of uteroplacental insufficiency (UPI) on leptin expression and lung development of intrauterine growth restriction (IUGR) rats. METHODS On day 17 of pregnancy, time-dated Sprague-Dawley rats were randomly divided into either an IUGR group or a control group. Uteroplacental insufficiency surgery (IUGR) and sham surgery (control) were conducted. Offspring rats were spontaneously delivered on day 22 of pregnancy. On postnatal days 0 and 7, rats' pups were selected at random from the control and IUGR groups. Blood was withdrawn from the heart to determine leptin levels. The right lung was obtained for leptin and leptin receptor levels, immunohistochemistry, proliferating cell nuclear antigen (PCNA), western blot, and metabolomic analyses. RESULTS UPI-induced IUGR decreased leptin expression and impaired lung development, causing decreased surface area and volume in offspring. This results in lower body weight, decreased serum leptin levels, lung leptin and leptin receptor levels, alveolar space, PCNA, and increased alveolar wall volume fraction in IUGR offspring rats. The IUGR group found significant relationships between serum leptin, radial alveolar count, von Willebrand Factor, and metabolites. CONCLUSION Leptin may contribute to UPI-induced lung development during the postnatal period, suggesting supplementation as a potential treatment. IMPACT The neonatal rats with intrauterine growth restriction (IUGR) caused by uteroplacental insufficiency (UPI) showed decreased leptin expression and impaired lung development. UPI-induced IUGR significantly decreased surface area and volume in lung offspring. This is a novel study that investigates leptin expression and lung development in neonatal rats with IUGR caused by UPI. If our findings translate to IUGR infants, leptin may contribute to UPI-induced lung development during the postnatal period, suggesting supplementation as a potential treatment.
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Affiliation(s)
- Merryl Esther Yuliana
- International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsiu-Chu Chou
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Emily Chia-Yu Su
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Research Center for Artificial Intelligence in Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsiao-Chi Chuang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Liang-Ti Huang
- Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chung-Ming Chen
- International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan.
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Al-Ghadban S, Walczak SG, Isern SU, Martin EC, Herbst KL, Bunnell BA. Enhanced Angiogenesis in HUVECs Preconditioned with Media from Adipocytes Differentiated from Lipedema Adipose Stem Cells In Vitro. Int J Mol Sci 2023; 24:13572. [PMID: 37686378 PMCID: PMC10487727 DOI: 10.3390/ijms241713572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/25/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
Lipedema is a connective tissue disorder characterized by increased dilated blood vessels (angiogenesis), inflammation, and fibrosis of the subcutaneous adipose tissue. This project aims to gain insights into the angiogenic processes in lipedema using human umbilical vein endothelial cells (HUVECs) as an in vitro model. HUVECs were cultured in conditioned media (CM) collected from healthy (non-lipedema, AQH) and lipedema adipocytes (AQL). The impacts on the expression levels of multiple endothelial and angiogenic markers [CD31, von Willebrand Factor (vWF), angiopoietin 2 (ANG2), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMPs), NOTCH and its ligands] in HUVECs were investigated. The data demonstrate an increased expression of CD31 and ANG2 at both the gene and protein levels in HUVECs treated with AQL CM in 2D monolayer and 3D cultures compared to untreated cells. Furthermore, the expression of the vWF, NOTCH 4, and DELTA-4 genes decreased. In contrast, increased VEGF, MMP9, and HGF gene expression was detected in HUVECs treated with AQL CM cultured in a 2D monolayer. In addition, the results of a tube formation assay indicate that the number of formed tubes increased in lipedema-treated HUVECs cultured in a 2D monolayer. Together, the data indicate that lipedema adipocyte-CM promotes angiogenesis through paracrine-driven mechanisms.
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Affiliation(s)
- Sara Al-Ghadban
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
| | - Samantha G. Walczak
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
| | - Spencer U. Isern
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
| | - Elizabeth C. Martin
- Department of Medicine, Section of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA;
| | | | - Bruce A. Bunnell
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
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Ali S, Alam R, Ahsan H, Khan S. Role of adipokines (omentin and visfatin) in coronary artery disease. Nutr Metab Cardiovasc Dis 2023; 33:483-493. [PMID: 36653284 DOI: 10.1016/j.numecd.2022.11.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 11/18/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022]
Abstract
AIMS Adipose tissue is considered as an endocrine organ that releases bioactive factors known as adipokines which contribute to the pathogenesis of rotundity-linked metabolic and cardiovascular complications. Rotundity is a major predisposer for the development and progression of coronary artery disease (CAD). DATA SYNTHESIS The literature survey from various databases such as Pubmed/Medline, DOAJ, Scopus, Clarivate analytics/Web of Science and Google Scholar were used to prepare this article. The epidemic of rotundity has gained significant attention to understand the biology of adipocytes and the metabolism of adipose tissue in obese individuals. In CAD, visfatin/NAMPT was primarily indicated as a clinical marker of atherosclerosis, endothelial dysfunction and vascular injury having a prognostic significance. Visfatin/NAMPT is a factor that promotes vascular inflammation and atherosclerosis. Omentin is an anti-inflammatory and anti-atherogenic adipokine regulating cardiovascular functions. CONCLUSIONS This review highlights and summarizes the scientific information pertaining to the role of the adipokines - omentin and visfatin in CAD.
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Affiliation(s)
- Saif Ali
- Department of Biochemistry, Integral Institute of Medical Sciences and Research, Integral University, Lucknow, India
| | - Roshan Alam
- Department of Biochemistry, Integral Institute of Medical Sciences and Research, Integral University, Lucknow, India
| | - Haseeb Ahsan
- Department of Biochemistry, Faculty of Dentistry, Jamia Millia Islamia, Jamia Nagar, New Delhi, India
| | - Saba Khan
- Department of Biochemistry, Integral Institute of Medical Sciences and Research, Integral University, Lucknow, India.
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Li R, Dong F, Zhang L, Ni X, Lin G. Role of adipocytokines in endometrial cancer progression. Front Pharmacol 2022; 13:1090227. [PMID: 36578551 PMCID: PMC9791063 DOI: 10.3389/fphar.2022.1090227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Endometrial cancer is considered a significant barrier to increasing life expectancy and remains one of the most common malignant cancers among women in many countries worldwide. The increasing mortality rates are potentially proportional to the increasing obesity incidence. Adipose tissue secretes numerous adipocytokines, which may play important roles in endometrial cancer progression. In this scenario, we describe the role of adipocytokines in cell proliferation, cell invasion, cell adhesion, inflammation, angiogenesis, and anti-apoptotic action. A better understanding of the mechanisms of these adipocytokines may open up new therapeutic avenues for women with endometrial cancer. In the future, larger prospective studies focusing on adipocytokines and specific inhibitors should be directed at preventing the rapidly increasing prevalence of gynecological malignancies.
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Affiliation(s)
- Ran Li
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Fang Dong
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Ling Zhang
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Xiuqin Ni
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Guozhi Lin
- Department of Obstetrics and Gynecology, Second Affiliated Hospital to Shandong First Medical University, Taian, China,*Correspondence: Guozhi Lin,
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Cui Q, Zhang Y, Tian N, Yang J, Ya D, Xiang W, Zhou Z, Jiang Y, Deng J, Yang B, Lin X, Li Q, Liao R. Leptin Promotes Angiogenesis via Pericyte STAT3 Pathway upon Intracerebral Hemorrhage. Cells 2022; 11:cells11172755. [PMID: 36078162 PMCID: PMC9454866 DOI: 10.3390/cells11172755] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 11/22/2022] Open
Abstract
Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin potentiates angiogenesis and plays a beneficial role in stroke. However, the proangiogenic effect of leptin on ICH has not been adequately explored. Moreover, leptin triggers post-ICH angiogenesis through pericyte, an important component of forming new blood vessels, which remains unclear. Here, we reported that exogenous leptin infusion dose-dependent promoted vascular endothelial cells survival and proliferation at chronic stage of ICH mice. Additionally, leptin robustly ameliorated pericytes loss, enhanced pericytes proliferation and migration in ICH mice in vivo, and in ICH human brain microvascular pericytes (HBVPC) in vitro. Notably, we showed that pericytes-derived pro-angiogenic factors were responsible for enhancing the survival, proliferation and tube formation followed leptin treatment in human brain microvascular endothelial cells (HCMEC/D3)/HBVPC co-culture models. Importantly, considerable improvements in neurobehavioral function and hostile microenvironment were observed in leptin treatment ICH mice, indicating that better vascular functionality post ICH improves outcome. Mechanistically, this study unveiled that leptin boost post-ICH angiogenesis potentially through modulation of leptin receptor (leptinR)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pericyte. Thus, leptin may be a lucrative option for the treatment of ICH.
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Affiliation(s)
- Qi Cui
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Yingmei Zhang
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Ning Tian
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Jiaxin Yang
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Dongshan Ya
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Wenjing Xiang
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Zixian Zhou
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Yanlin Jiang
- Department of Pharmacology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Jungang Deng
- Department of Pharmacology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Bin Yang
- Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Xiaohui Lin
- Department of Geriatrics, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Qinghua Li
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
| | - Rujia Liao
- Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China
- Correspondence: ; Tel.: +86-0773-2833025
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Harris BHL, Macaulay VM, Harris DA, Klenerman P, Karpe F, Lord SR, Harris AL, Buffa FM. Obesity: a perfect storm for carcinogenesis. Cancer Metastasis Rev 2022; 41:491-515. [PMID: 36038791 PMCID: PMC9470699 DOI: 10.1007/s10555-022-10046-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/08/2022] [Indexed: 12/14/2022]
Abstract
Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.
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Affiliation(s)
- Benjamin H L Harris
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
- St Anne's College, 56 Woodstock Rd, Oxford, OX2 6HS, UK.
| | - Valentine M Macaulay
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK
| | | | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK
| | - Simon R Lord
- Early Phase Clinical Trials Unit, Churchill Hospital, Oxford, OX3 7LE, UK
| | - Adrian L Harris
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
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Intermittent Fasting: Potential Bridge of Obesity and Diabetes to Health? Nutrients 2022; 14:nu14050981. [PMID: 35267959 PMCID: PMC8912812 DOI: 10.3390/nu14050981] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Obesity has been an escalating worldwide health problem for decades, and it is likely a risk factor of prediabetes and diabetes. Correlated with obesity, the number of diabetic patients is also remarkable. A modest weight loss (5–10%) is critical to alleviate the risk of any other metabolic disease. Reduced energy intake has been an essential factor for weight loss reduction. As a new behavior intervention to lose weight, intermittent fasting (IF) attracts considerable attention and has become a popular strategy among young people. IF is a diet pattern that cycles between periods of fasting and eating on a regular schedule, involving various types, mainly Intermittent Energy Restriction and Time-Restricted Fasting. Accumulating evidence shows that short-term IF has a greatly positive effect in animal studies and contributes favorable benefits in human trials as well. Nevertheless, as an emerging, diverse, and relatively premature behavior intervention, there are still limited studies considering patients with obesity and type 2 diabetes mellitus. It is also a controversial intervention for the treatment of metabolic disease and cancer. The risks and challenges appear consequently. Additionally, whether intermittent fasting can be applied to long-term clinical treatment, and whether it has side effects during the long-term period or not, demands more large-scale and long-term experiments.
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Franchini F, Palatucci G, Colao A, Ungaro P, Macchia PE, Nettore IC. Obesity and Thyroid Cancer Risk: An Update. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19031116. [PMID: 35162142 PMCID: PMC8834607 DOI: 10.3390/ijerph19031116] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/07/2023]
Abstract
Thyroid cancer (TC) is the most common endocrine malignancy worldwide and its incidence has increased dramatically in recent years. In parallel, the prevalence of overweight and obesity has also increased, suggesting a possible link between these two diseases. Indeed, low-grade chronic inflammation, altered cytokine levels, insulin resistance, oxidative stress, and hormonal changes that occur in obese patients are all factors that contribute to the occurrence and growth of TC. In this review, the most recent evidence supporting the potential role of the mechanisms linking obesity to TC will be discussed.
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Affiliation(s)
- Fabiana Franchini
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Giuseppe Palatucci
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Paola Ungaro
- National Research Council–Institute for Experimental Endocrinology & Oncology ‘Gaetano Salvatore’, 80145 Napoli, Italy;
| | - Paolo Emidio Macchia
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Immacolata Cristina Nettore
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
- Correspondence: ; Tel.: +39-081-7463848; Fax: +39-081-7462108
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10
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Hao R, Liu Y, Li XM. Leptin's concentration in tears and dry eye: a clinical observational study. Int J Ophthalmol 2021; 14:83-88. [PMID: 33469488 DOI: 10.18240/ijo.2021.01.12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 07/27/2020] [Indexed: 11/23/2022] Open
Abstract
AIM To investigate the concentration of leptin in tears and its correlation with dry eye symptoms and signs. METHODS The study enrolled individuals (n=39) responding to an advertising or dry eye patients (n=58) from the Ophthalmology Department. Tear samples were collected for leptin concentration measuring. Ocular Surface Disease Index (OSDI), tear meniscus height (TMH), tear break up time (TBUT), cornea fluorescein staining, Schirmer test (ST) and impression cytology (IC) were assessed. Leptin concentration in tears of dry eye patients and healthy controls, and its correlation with clinical features of dry eye disease (DED) were analyzed. RESULTS Age, body mass index (BMI), OSDI scores and cornea fluorescein staining scores showed a negative correlation with leptin concentration in tears (r=-0.340, P=0.001; r=-0.332, P=0.001; r=-0.258, P=0.011; r=-0.424, P<0.001, respectively). ST showed positive correlation with leptin concentration in tears (r=0.206, P=0.045). No significant difference was observed in leptin concentration between dry eye patients and controls (P=0.682). Multivariate linear regression analysis revealed that dry eye, OSDI, corneal fluorescein staining scores and ST correlated with leptin concentration in tears. CONCLUSION This is the first study measuring leptin concentration in tears. The correlation between leptin concentration and DED symptoms and signs reveal that leptin level correlated with the dry eye, potentially contributing to repair of ocular damage and dry eye improvement.
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Affiliation(s)
- Ran Hao
- Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China
| | - Yan Liu
- Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China
| | - Xue-Min Li
- Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China
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11
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Serum leptin is associated with increased pulse pressure and the development of arterial stiffening in adult men: results of an eight-year follow-up study. Hypertens Res 2021; 44:1444-1450. [PMID: 34385686 PMCID: PMC8568692 DOI: 10.1038/s41440-021-00718-x] [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: 01/26/2021] [Revised: 06/16/2021] [Accepted: 07/03/2021] [Indexed: 02/07/2023]
Abstract
High leptin levels are associated with an unfavorable cardiometabolic risk profile. A number of studies found a positive association between leptin and vascular damage, but to date, no observational study has evaluated a potential predictive role of leptin for arterial stiffening. Therefore, the aim of this study was to estimate the role of leptin in the incidence of arterial stiffening (pulse pressure >60 mmHg) and changes in pulse pressure in an 8-year follow-up of a sample of adult men (The Olivetti Heart Study). The analysis included 460 men without baseline arterial stiffening and antihypertensive treatment at baseline and at follow-up (age: 50.0 years, BMI: 26.5 kg/m2). At the end of the follow-up period, the incidence of arterial stiffening was 8%. Baseline leptin was significantly greater in the group that developed arterial stiffening and was significantly correlated with pulse pressure changes over time (p < 0.05). According to the median plasma leptin distribution of the whole population, the sample was stratified into two groups: one with leptin levels above the median and the other with leptin levels below the median. Those who had baseline leptin levels above the median had a greater risk of developing arterial stiffening (odds ratio: 2.5, p < 0.05) and a greater increase in pulse pressure over time (beta: 2.1, p < 0.05), also after adjustment for confounders. The results of this prospective study indicate a predictive role of circulating leptin levels for vascular damage, independent of body weight and blood pressure.
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Wu Q, Xie X, Zhang K, Niang B, Liu Y, Zhang C, Huang T, Huang H, Li W, Zhang J, Liu Y. Reduced expression of ppGalNAc-T4 promotes proliferation of human breast cancer cells. Cell Biol Int 2020; 45:320-333. [PMID: 33079401 DOI: 10.1002/cbin.11488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/06/2020] [Accepted: 10/18/2020] [Indexed: 12/24/2022]
Abstract
Breast cancer, one of the most frequently diagnosed and aggressive malignancies, is the major cause of cancer-related death greatly threatening women health. Polypeptide N-acetylgalactosaminyltransferase 4 (ppGalNAc-T4), responsible for the initial step of mucin-type O-glycosylation, has been reported to be implicated in diverse types of human tumors. However, the biological role of ppGalNAc-T4 in breast cancer is still undetermined. In this study, we investigate the effects and mechanism of ppGalNAc-T4 to breast cancer cell proliferation. From analysis of high throughput RNA sequencing datasets of Gene Expression Omnibus and ArrayExpress, a positive correlation between ppGalNAc-T4 and the recurrence-free survival was observed in multigroup of human breast cancer datasets. Moreover, transcriptomes analysis using RNA-sequencing in MCF7 cells revealed that cell cycle-related genes induced the effects of ppGalNAc-T4 on breast cancer cell proliferation. Additionally, investigations showed that ppGalNAc-T4 impaired cell proliferation in MCF-7 and MDA-MB-231 breast cells. Furthermore, our results suggested that the ppGalNAc-T4 knockout activated Notch signaling pathway and enhanced cell proliferation. Collectively, our data indicated that ppGalNAc-T4 affected the proliferation of human breast cancer cells, which appears to be a novel target for understanding the underlying molecular mechanism of breast cancer.
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Affiliation(s)
- Qiong Wu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Xueqin Xie
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Keren Zhang
- Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China
| | - Bachir Niang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Yimin Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Cheng Zhang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Tianmiao Huang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Huang Huang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Wenli Li
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Jianing Zhang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Yubo Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
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Leptin levels predict the development of left ventricular hypertrophy in a sample of adult men: the Olivetti Heart Study. J Hypertens 2020; 39:692-697. [PMID: 33060451 DOI: 10.1097/hjh.0000000000002687] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE A higher leptin (LPT) is associated with a greater cardiometabolic risk. Some studies also showed a positive association between LPT and cardiovascular organ damage but no consistent data are available about a predictive role of LPT on cardiac remodelling. Hence, the aim of this study was to evaluate the potential role of LPT on the incidence of left ventricular hypertrophy (LVH) in a sample of adult men. METHODS The study population was made up of 439 individuals (age: 51 years) without LVH at baseline, participating in The Olivetti Heart Study. The ECG criteria were adopted to exclude LVH at baseline and echocardiogram criteria for diagnosis of LVH at follow-up were considered. RESULTS At baseline, LPT was significantly and positively correlated with BMI, waist circumference, ECG indices, SBP and DBP but not with age and renal function. At the end of the 8-year follow-up period, there was an incidence of 23% in LVH by echocardiography. Individuals who developed LVH had higher baseline age, LPT, BMI, waist circumference, blood pressure and ECG indices (P < 0.05). Furthermore, those that had LPT above the median had greater risk to develop LVH (odds ratio: 1.7; P < 0.05). This association was also confirmed after adjustment for main confounders, among which changes in blood pressure and anthropometric indices. CONCLUSION The results of this study suggest a predictive role of circulating LPT levels on cardiac remodelling expressed by echocardiographic LVH, independently of body weight and blood pressure changes over the years.
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Zhao J, Wen J, Wang S, Yao J, Liao L, Dong J. Association between adipokines and thyroid carcinoma: a meta-analysis of case-control studies. BMC Cancer 2020; 20:788. [PMID: 32819324 PMCID: PMC7441682 DOI: 10.1186/s12885-020-07299-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 08/13/2020] [Indexed: 02/07/2023] Open
Abstract
Background The incidence of thyroid carcinoma is increasing all over the world. Some studies have suggested that the change of adipokines expression can induce thyroid carcinoma. However, other studies have come to the opposite conclusion. Therefore, we studied the relationship between adipokines and thyroid carcinoma. Methods Databases—PubMed, Cochrane Library, SinoMed, CNKI, Wanfang, and clinical trial registries were searched. A meta-analysis was then performed through a fixed or random-effects model to calculate I values for heterogeneity analysis. Results Twenty-nine articles were finally included for analysis. The level of serum tumor necrosis factor-alpha (TNF-α) [standardized mean difference (SMD) =1.31, 95% confidence interval (95% CI): 0.35 to 2.28, I2 = 98%, P = 0.008] and the ratio of TNF-α immunoreactivity in tissues [odds ratios (OR) =6.36, 95% CI: 1.92 to 21.05, I2 = 66%, P = 0.002] in thyroid carcinoma are significantly higher than those in control. The serum interleukin-6 (IL-6) in patients with thyroid carcinoma is higher than that in control (SMD = 1.04, 95% CI: 0.40 to 1.67, I2 = 96%, P = 0.001). There is no significant difference of the ratio of IL-6 immunoreactivity in tissues between carcinoma and control (OR = 1.23, 95% CI: 0.62 to 2.43, I2 = 86%, P = 0.55). The ratio of leptin immunoreactivity in tissues is significantly associated with the risk of thyroid carcinoma (OR = 12.21, 95% CI: 3.36 to 44.40, I2 = 85%, P < 0.00001). However, after analyzing the expression level of serum adiponectin in three studies, no significant difference is found between thyroid carcinoma and the control (P = 0.81). Conclusions Adipokines (TNF-α, IL-6 and leptin) show a strong relationship between elevated concentrations (in serum and/or tissue) and thyroid carcinoma. However, the association between adiponectin and thyroid carcinoma needs further research.
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Affiliation(s)
- Junyu Zhao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji-nan, 250014, China.,Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250014, China
| | - Jing Wen
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Ji-nan, 250000, China
| | - Shengnan Wang
- Department of Endocrinology and Metabology, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji-nan, 250014, China
| | - Jinming Yao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji-nan, 250014, China.,Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250014, China
| | - Lin Liao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji-nan, 250014, China. .,Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250014, China.
| | - Jianjun Dong
- Department of Endocrinology and Metabology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China.
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The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis. PPAR Res 2020; 2020:3608315. [PMID: 32855630 PMCID: PMC7443046 DOI: 10.1155/2020/3608315] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/24/2020] [Indexed: 12/31/2022] Open
Abstract
PPARs are ligand-activated transcriptional factors that belong to the nuclear receptor superfamily. Among them, PPAR alpha and PPAR gamma are prone to exert an antiangiogenic effect, whereas PPAR beta/delta has an opposite effect in physiological and pathological conditions. Angiogenesis has been known as a hallmark of cancer, and our recent works also demonstrate that vascular-specific PPAR beta/delta overexpression promotes tumor angiogenesis and progression in vivo. In this review, we will mainly focus on the role of PPAR beta/delta in tumor angiogenesis linked to the tumor microenvironment to further facilitate tumor progression and metastasis. Moreover, the crosstalk between PPAR beta/delta and its downstream key signal molecules involved in tumor angiogenesis will also be discussed, and the network of interplay between them will further be established in the review.
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Panza S, Russo U, Giordano F, Leggio A, Barone I, Bonofiglio D, Gelsomino L, Malivindi R, Conforti FL, Naimo GD, Giordano C, Catalano S, Andò S. Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression. Biomolecules 2020; 10:biom10060886. [PMID: 32526957 PMCID: PMC7356667 DOI: 10.3390/biom10060886] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/27/2020] [Accepted: 06/06/2020] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.
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Affiliation(s)
- Salvatore Panza
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Umberto Russo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Antonella Leggio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Rocco Malivindi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Francesca Luisa Conforti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
| | - Giuseppina Daniela Naimo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
- Correspondence: (S.C.); (S.A.); Tel.: +39-0984-496207 (S.C.); +39-0984-496201 (S.A.)
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
- Correspondence: (S.C.); (S.A.); Tel.: +39-0984-496207 (S.C.); +39-0984-496201 (S.A.)
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Sabol RA, Villela VA, Denys A, Freeman BT, Hartono AB, Wise RM, Harrison MAA, Sandler MB, Hossain F, Miele L, Bunnell BA. Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling. Int J Mol Sci 2020; 21:ijms21082722. [PMID: 32326381 PMCID: PMC7216284 DOI: 10.3390/ijms21082722] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/10/2020] [Accepted: 04/10/2020] [Indexed: 12/17/2022] Open
Abstract
Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell’s (ER+BCCs) response to radiotherapy (RT) were evaluated. We determined that BCCs had a decreased apoptotic index and increased surviving fraction following RT when co-cultured with obASCs compared to lnASCs or non-co-cultured cells. Further, obASCs reduced oxidative stress and induced IL-6 expression in co-cultured BCCs after radiation. obASCs produce increased levels of leptin relative to ASCs from normal-weight individuals (lnASCs). obASCs upregulate the expression of IL-6 compared to non-co-cultured BCCs, but BCCs co-cultured with leptin knockdown obASCs did not upregulate IL-6. The impact of shLeptin obASCs on radiation resistance of ER+BCCs demonstrate a decreased radioprotective ability compared to shControl obASCs. Key NOTCH signaling players were enhanced in ER+BBCs following co-culture with shCtrl obASCs but not shLep obASCs. This work demonstrates that obesity-altered ASCs, via enhanced secretion of leptin, promote IL-6 and NOTCH signaling pathways in ER+BCCs leading to radiation resistance.
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Affiliation(s)
- Rachel A. Sabol
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Vidal A. Villela
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Alexandra Denys
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Benjamin T. Freeman
- Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA 70112, USA;
| | - Alifiani B. Hartono
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Rachel M. Wise
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Mark A. A. Harrison
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Maxwell B. Sandler
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Fokhrul Hossain
- Louisiana State University Health Sciences Center (LSUHSC), Department of Genetics, New Orleans, LA 70112, USA; (F.H.); (L.M.)
- Louisiana Cancer Research Center (LCRC), Stanley S. Scott Cancer Center, LSUSHC, New Orleans, LA 70112, USA
| | - Lucio Miele
- Louisiana State University Health Sciences Center (LSUHSC), Department of Genetics, New Orleans, LA 70112, USA; (F.H.); (L.M.)
- Louisiana Cancer Research Center (LCRC), Stanley S. Scott Cancer Center, LSUSHC, New Orleans, LA 70112, USA
| | - Bruce A. Bunnell
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
- Department of Pharmacology, Tulane University, New Orleans, LA 70112, USA
- Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, LA 70433, USA
- Correspondence: ; Tel.: +1-504-988-7071
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Lu HY, Zu YX, Jiang XW, Sun XT, Liu TY, Li RL, Wu Q, Zhang YS, Zhao QC. Novel ADAM-17 inhibitor ZLDI-8 inhibits the proliferation and metastasis of chemo-resistant non-small-cell lung cancer by reversing Notch and epithelial mesenchymal transition in vitro and in vivo. Pharmacol Res 2019; 148:104406. [PMID: 31442576 DOI: 10.1016/j.phrs.2019.104406] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 07/21/2019] [Accepted: 08/19/2019] [Indexed: 01/09/2023]
Abstract
Acquired drug-resistant non-small cell lung cancer (NSCLC) has strong proliferation ability and is prone to epithelial-mesenchymal transition (EMT) and subsequent metastasis. Notch pathway mediates cell survival and EMT and is involved in the induction of multidrug resistance (MDR). ZLDI-8 is an inhibitor of Notch activating/cleaving enzyme ADAM-17 we found before. However, the effects of ZLDI-8 on resistant NSCLC was unclear. Here, we demonstrated for the first time that ZLDI-8 could induce apoptosis in lung cancer, especially in chemotherapy-resistant non-small cell lung cancer cells, and also inhibit migration, invasion and EMT phenotype of drug-resistant lung cancer. ZLDI-8 inhibits the Notch signaling pathway, thereby regulating the expression of survival/apoptosis and EMT-related proteins. Moreover, ZLDI-8 suppresses multidrug-resistant lung cancer xenograft growth in vivo and blocks metastasis in a tail vein injection mice model. Therefore, ZLDI-8 is expected to be an effective agent in the treatment of drug-resistant lung cancer.
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Affiliation(s)
- Hong-Yuan Lu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Yu-Xin Zu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xiao-Wen Jiang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xiao-Tong Sun
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Tian-Yi Liu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ruo-Lan Li
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Qiong Wu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ying-Shi Zhang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Qing-Chun Zhao
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, China.
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Avgerinos KI, Spyrou N, Mantzoros CS, Dalamaga M. Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism 2019; 92:121-135. [PMID: 30445141 DOI: 10.1016/j.metabol.2018.11.001] [Citation(s) in RCA: 898] [Impact Index Per Article: 149.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/02/2018] [Accepted: 11/03/2018] [Indexed: 02/07/2023]
Abstract
Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.
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Affiliation(s)
| | - Nikolaos Spyrou
- 251 Airforce General Hospital, Kanellopoulou 3, 11525, Athens, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527 Athens, Greece.
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20
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Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice. Sci Rep 2019; 9:2479. [PMID: 30792482 PMCID: PMC6385507 DOI: 10.1038/s41598-019-39380-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 01/23/2019] [Indexed: 01/13/2023] Open
Abstract
Intermittent fasting (IF) is an effective dietary intervention to counteract obesity-associated metabolic abnormalities. Previously, we and others have highlighted white adipose tissue (WAT) browning as the main underlying mechanism of IF-mediated metabolic benefits. However, whether IF retains its efficacy in different models, such as genetically obese/diabetic animals, is unknown. Here, leptin-deficient ob/ob mice were subjected to 16 weeks of isocaloric IF, and comprehensive metabolic phenotyping was conducted to assess the metabolic effects of IF. Unlike our previous study, isocaloric IF-subjected ob/ob animals failed to exhibit reduced body weight gain, lower fat mass, or decreased liver lipid accumulation. Moreover, isocaloric IF did not result in increased thermogenesis nor induce WAT browning in ob/ob mice. These findings indicate that isocaloric IF may not be an effective approach for regulating body weight in ob/ob animals, posing the possible limitations of IF to treat obesity. However, despite the lack of improvement in insulin sensitivity, isocaloric IF-subjected ob/ob animals displayed improved glucose tolerance as well as higher postprandial insulin level, with elevated incretin expression, suggesting that isocaloric IF is effective in improving nutrient-stimulated insulin secretion. Together, this study uncovers the insulinotropic effect of isocaloric IF, independent of adipose thermogenesis, which is potentially complementary for the treatment of type 2 diabetes.
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Zhang Y, Coarfa C, Dong X, Jiang W, Hayward-Piatkovskyi B, Gleghorn JP, Lingappan K. MicroRNA-30a as a candidate underlying sex-specific differences in neonatal hyperoxic lung injury: implications for BPD. Am J Physiol Lung Cell Mol Physiol 2019; 316:L144-L156. [PMID: 30382766 PMCID: PMC6383497 DOI: 10.1152/ajplung.00372.2018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/22/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Premature male neonates are at a greater risk of developing bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. The role of miRNAs in mediating sex biases in BPD is understudied. Analysis of the pulmonary transcriptome revealed that a large percentage of angiogenesis-related differentially expressed genes are miR-30a targets. We tested the hypothesis that there is differential expression of miR-30a in vivo and in vitro in neonatal human pulmonary microvascular endothelial cells (HPMECs) upon exposure to hyperoxia. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% fraction of inspired oxygen (FiO2), postnatal day ( PND) 1-5] and euthanized on PND 7 and 21. HPMECs (18-24-wk gestation donors) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. miR-30a expression was increased in both males and females in the acute phase ( PND 7) after hyperoxia exposure. However, at PND 21 (recovery phase), female mice showed significantly higher miR-30a expression in the lungs compared with male mice. Female HPMECs showed greater expression of miR-30a in vitro upon exposure to hyperoxia. Delta-like ligand 4 (Dll4) was an miR-30a target in HPMECs and showed sex-specific differential expression. miR-30a increased angiogenic sprouting in vitro in female HPMECs. Lastly, we show decreased expression of miR-30a and increased expression of DLL4 in human BPD lung samples compared with controls. These results support the hypothesis that miR-30a could, in part, contribute to the sex-specific molecular mechanisms in play that lead to the sexual dimorphism in BPD.
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Affiliation(s)
- Yuhao Zhang
- Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine , Houston, Texas
| | - Cristian Coarfa
- Advanced Technology Cores, Baylor College of Medicine , Houston, Texas
| | - Xiaoyu Dong
- Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine , Houston, Texas
| | - Weiwu Jiang
- Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine , Houston, Texas
| | | | - Jason P Gleghorn
- Department of Biological Sciences, University of Delaware , Newark, Delaware
- Department of Biomedical Engineering, University of Delaware , Newark, Delaware
| | - Krithika Lingappan
- Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine , Houston, Texas
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Spyrou N, Avgerinos KI, Mantzoros CS, Dalamaga M. Classic and Novel Adipocytokines at the Intersection of Obesity and Cancer: Diagnostic and Therapeutic Strategies. Curr Obes Rep 2018; 7:260-275. [PMID: 30145771 DOI: 10.1007/s13679-018-0318-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW In this review, we investigate the role of classic and novel adipocytokines in cancer pathogenesis synopsizing the mechanisms underlying the association between adipocytokines and malignancy. Special emphasis is given on novel adipocytokines as new evidence is emerging regarding their entanglement in neoplastic development. RECENT FINDINGS Recent data have emphasized the role of the triad of overweight/obesity, insulin resistance and adipocytokines in cancer. In the setting of obesity, classic and novel adipocytokines present independent and joint effects on activation of major intracellular signaling pathways implicated in cell proliferation, expansion, survival, adhesion, invasion, and metastasis. Until now, more than 15 adipocytokines have been associated with cancer, and this list continues to expand. While the plethora of circulating pro-inflammatory adipocytokines, such as leptin, resistin, extracellular nicotinamide phosphoribosyl transferase, and chemerin are elevated in malignancies, some adipocytokines such as adiponectin and omentin-1 are generally decreased in cancers and are considered protective against carcinogenesis. Elucidating the intertwining of inflammation, cellular bioenergetics, and adiposopathy is significant for the development of preventive, diagnostic, and therapeutic strategies against cancer. Novel more effective and safe adipocytokine-centered therapeutic interventions may pave the way for targeted oncotherapy.
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Affiliation(s)
- Nikolaos Spyrou
- 251 Airforce General Hospital, Kanellopoulou 3, 11525, Athens, Greece
| | | | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
- Section of Endocrinology, VA Boston Healthcare System, Boston, MA, USA
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527, Athens, Greece.
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23
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Zhang X, Li X, Yang H, Cui Z. Biochemical mechanism of phytoremediation process of lead and cadmium pollution with Mucor circinelloides and Trichoderma asperellum. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2018; 157:21-28. [PMID: 29605641 DOI: 10.1016/j.ecoenv.2018.03.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 03/11/2018] [Accepted: 03/23/2018] [Indexed: 05/27/2023]
Abstract
This study focused on the bioremediation mechanisms of lead (0, 100, 500, 1000 mg kg-1) and cadmium (0,10,50,100 mg kg-1) contaminated soil using two indigenous fungi selected from mine tailings as the phytostimulation of Arabidopsis thaliana. The two fungal strains were characterized as Mucor circinelloides (MC) and Trichoderma asperellum (TA) by internal transcribed spacer sequencing at the genetic levels. Our research revealed that Cadmium was more toxic to plant growth than lead and meanwhile, MC and TA can strengthen A. thaliana tolerance to cadmium and lead with 40.19-117.50% higher root length and 58.31-154.14% shoot fresh weight of plant compared to non-inoculation. In this study, TA exhibited a higher potential to the inactivation of cadmium; however, MC was more effective in lead passivation. There was a direct correlation between the type of fungi, heavy metal content, heavy metal type and oxidative damage in plant. Both lead and cadmium induced oxidative damage as indicated by increased superoxide dismutase and catalase activities, while the antioxidant levels were significantly higher in fungal inoculated plants compared with those non-inoculated. The analysis of soil enzyme activity and taxonomic richness uncovered that the dominant structures of soil microbial community were altered by exogenous microbial agents. MC enhanced higher microbial diversity and soil enzyme activity than TA. The two indigenous fungi lessened several limiting factors with respect to phytoremediation technology, such as soil chemistry, contamination level and transformation, and metal solubility.
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Affiliation(s)
- Xu Zhang
- School of Environmental Science and Engineering, Shandong University, Ji'nan 250100, China
| | - Xinxin Li
- School of Environmental Science and Engineering, Shandong University, Ji'nan 250100, China
| | - Huanhuan Yang
- School of Life Science, Shandong University, Ji'nan 250100, China
| | - Zhaojie Cui
- School of Environmental Science and Engineering, Shandong University, Ji'nan 250100, China.
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24
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Zhang Y, Li D, Jiang Q, Cao S, Sun H, Chai Y, Li X, Ren T, Yang R, Feng F, Li BA, Zhao Q. Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells. Cell Death Dis 2018; 9:743. [PMID: 29970890 PMCID: PMC6030059 DOI: 10.1038/s41419-018-0804-6] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/17/2018] [Accepted: 06/19/2018] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of multi-drug resistance (MDR). In the present study, we demonstrated the discovery of a novel inhibitor for Notch activating/cleaving enzyme ADAM-17, named ZLDI-8; it inhibited the cleavage of NOTCH protein, consequently decreased the expression of pro-survival/anti-apoptosis and EMT related proteins. ZLDI-8 treatment enhanced the susceptibility of HCC cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel. ZLDI-8 treatment enhanced the effect of Sorafenib on inhibiting tumor growth in nude HCC-bearing mice model. These results suggest that ZLDI-8 can be a promising therapeutic agent to enhance Sorafenib's anti-tumor effect and to overcome the MDR of HCC patients.
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Affiliation(s)
- Yingshi Zhang
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110840, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Dandan Li
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110840, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Qiyu Jiang
- Research Center For Clinical And Transitional Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, China
| | - Shuang Cao
- Hubei Key Laboratory of Novel Chemical Reactor and Green Chemical Technology, Wuhan Institute of Technology, Wuhan, 430073, China
| | - Huiwei Sun
- Research Center For Clinical And Transitional Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, China
| | - Yantao Chai
- Research Center For Clinical And Transitional Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, China
| | - Xiaojuan Li
- Research Center For Clinical And Transitional Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, China
| | - Tianshu Ren
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110840, China
| | - Ruichuang Yang
- Research Center For Clinical And Transitional Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, China
| | - Fan Feng
- Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing, 100039, China.
| | - Bo-An Li
- Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing, 100039, China.
| | - Qingchun Zhao
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110840, China.
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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25
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Sahoo AK, Das JK, Nayak S. Isolation, culture, characterization, and osteogenic differentiation of canine endometrial mesenchymal stem cell. Vet World 2017; 10:1533-1541. [PMID: 29391698 PMCID: PMC5771182 DOI: 10.14202/vetworld.2017.1533-1541] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 12/04/2017] [Indexed: 01/09/2023] Open
Abstract
Aim In this study, the canine endometrium tissue is characterized for its stem cell properties such as adherence to tissue culture plate (plasticity), short population doubling time, serial clonal passaging, long-term culturing properties, stem cell marker expression, and multilineage differentiation potential. Materials and Methods The present work describes a novel isolation protocol for obtaining mesenchymal stem cells from the uterine endometrium and is compared with cells derived from umbilical cord matrix as a positive control. These cells are clonogenic, can undergo several population doublings in vitro, and can be differentiated to the osteocytes in mature mesenchymal tissues when grown in osteogenic differentiation media as detected by Alizarin Red-S staining. Results It is reported for the first time that the cells derived from the canine endometrium (e-multipotent stem cells [MSCs]) were able to differentiate into a heterologous cell type: Osteocytes, thus demonstrating the presence of MSCs. Thus, the endometrium may be told as a potential source of MSCs which can be used for various therapeutic purposes. Conclusion The endometrium can be used as a potential source of MSCs, which can be used for various therapeutic purposes.
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Affiliation(s)
- A K Sahoo
- Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, OUAT, Bhubaneswar - 751 003, Odisha, India
| | - J K Das
- Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, OUAT, Bhubaneswar - 751 003, Odisha, India
| | - S Nayak
- Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, OUAT, Bhubaneswar - 751 003, Odisha, India
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26
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Mechanick JI, Zhao S, Garvey WT. Leptin, An Adipokine With Central Importance in the Global Obesity Problem. Glob Heart 2017; 13:113-127. [PMID: 29248361 DOI: 10.1016/j.gheart.2017.10.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 10/25/2017] [Indexed: 02/08/2023] Open
Abstract
Leptin has central importance in the global obesity and cardiovascular disease problem. Leptin is principally secreted by adipocytes and acts in the hypothalamus to suppress appetite and food intake, increase energy expenditure, and regulate body weight. Based on clinical translation of specific and networked actions, leptin affects the cardiovascular system and may be a marker and driver of cardiometabolic risk factors with interventions that are actionable by cardiologists. Leptin subnetwork analysis demonstrates a statistically significant role for ethnoculturally and socioeconomically appropriate lifestyle intervention in cardiovascular disease. Emergent mechanistic components and potential diagnostic or therapeutic targets include hexokinase 3, urocortins, clusterin, sialic acid-binding immunoglobulin-like lectin 6, C-reactive protein, platelet glycoprotein VI, albumin, pentraxin 3, ghrelin, obestatin prepropeptide, leptin receptor, neuropeptide Y, and corticotropin-releasing factor receptor 1. Emergent associated symptoms include weight change, eating disorders, vascular necrosis, chronic fatigue, and chest pain. Leptin-targeted therapies are reported for lipodystrophy and leptin deficiency, but they are investigational for leptin resistance, obesity, and other chronic diseases.
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Affiliation(s)
- Jeffrey I Mechanick
- Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Shan Zhao
- Basepaws Inc., Redondo Beach, CA, USA
| | - W Timothy Garvey
- Department of Nutritional Sciences and Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Geriatric Research Education and Clinical Center, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
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Sun X, Wei J, Tang Y, Wang B, Zhang Y, Shi L, Guo J, Hu F, Li X. Leptin-induced migration and angiogenesis in rheumatoid arthritis is mediated by reactive oxygen species. FEBS Open Bio 2017; 7:1899-1908. [PMID: 29226077 PMCID: PMC5715350 DOI: 10.1002/2211-5463.12326] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 09/03/2017] [Accepted: 09/20/2017] [Indexed: 01/18/2023] Open
Abstract
Rheumatoid arthritis (RA) is a progressive autoimmune disease affecting the joints. In this study, we investigated the role of the pro‐angiogenic factor leptin in regulating reactive oxygen species (ROS) to promote cell migration and angiogenesis in RA. We showed that leptin triggered RA fibroblast‐like synoviocyte (FLS) migration by increased ROS expression. Additionally, leptin enhanced human umbilical vein endothelial cell (HUVEC) tube formation in a ROS/hypoxia‐inducible factor‐1α‐dependent manner, accompanied by increased production of vascular endothelial growth factor and interleukin (IL)‐6. We also revealed that antagonists of tumor necrosis factor, IL‐6 and IL‐1β down‐regulated ROS production of RA FLS induced by leptin, which subsequently attenuated RA FLS migration and HUVEC tube formation. These findings demonstrated that leptin might play an important role in RA FLS migration and HUVEC angiogenesis.
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Affiliation(s)
- Xiaotong Sun
- Department of Immunology College of Basic Medical Science Dalian Medical University Liaoning China
| | - Jing Wei
- Department of Immunology College of Basic Medical Science Dalian Medical University Liaoning China
| | - Yawei Tang
- Department of Immunology College of Basic Medical Science Dalian Medical University Liaoning China
| | - Bing Wang
- Department of Immunology College of Basic Medical Science Dalian Medical University Liaoning China
| | - Yan Zhang
- Department of Rheumatology and Immunology The Second Affiliated Hospital of Dalian Medical University Liaoning China
| | - Lei Shi
- College of Basic Medical Science Dalian Medical University Liaoning China
| | - Jianping Guo
- Department of Rheumatology and Immunology Peking University People's Hospital Beijing China
| | - Fanlei Hu
- Department of Rheumatology and Immunology Peking University People's Hospital Beijing China
| | - Xia Li
- Department of Immunology College of Basic Medical Science Dalian Medical University Liaoning China
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28
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Jiang H, Chen Y, Chen G, Tian X, Tang J, Luo L, Huang M, Yan B, Ao X, Zhou W, Wang L, Bai X, Zhang Z, Wang L, Xian CJ. Leptin accelerates the pathogenesis of heterotopic ossification in rat tendon tissues via mTORC1 signaling. J Cell Physiol 2017; 233:1017-1028. [PMID: 28407241 DOI: 10.1002/jcp.25955] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 04/11/2017] [Indexed: 12/12/2022]
Abstract
Leptin, an adipocyte-derived cytokine associated with bone metabolism, is believed to play a critical role in the pathogenesis of heterotopic ossification (HO). The effect and underlying action mechanism of leptin were investigated on osteogenic differentiation of tendon-derived stem cells (TDSCs) in vitro and the HO formation in rat tendons. Isolated rat TDSCs were treated with various concentrations of leptin in the presence or absence of mTORC1 signaling specific inhibitor rapamycin in vitro. A rat model with Achilles tenotomy was employed to evaluate the effect of leptin on HO formation together with or without rapamycin treatment. In vitro studies with TDSCs showed that leptin increased the expression of osteogenic biomarkers (alkaline phosphatase, runt-related transcription factor 2, osterix, osteocalcin) and enhanced mineralization of TDSCs via activating the mTORC1 signal pathway (as indicated by phosphorylation of p70 ribosomal S6 kinase 1 and p70 ribosomal S6). However, mTORC1 signaling blockade with rapamycin treatment suppressed leptin-induced osteogenic differentiation and mineralization. In vivo studies showed that leptin promoted HO formation in the Achilles tendon after tenotomy, and rapamycin treatment blocked leptin-induced HO formation. In conclusion, leptin can promote TDSC osteogenic differentiation and heterotopic bone formation via mTORC1 signaling in both vitro and vivo model, which provides a new potential therapeutic target for HO prevention.
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Affiliation(s)
- Huaji Jiang
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Yuhui Chen
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Guorong Chen
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Xinggui Tian
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Jiajun Tang
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Lei Luo
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Minjun Huang
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Bin Yan
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Xiang Ao
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Wen Zhou
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Liping Wang
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
| | - Xiaochun Bai
- Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China.,Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongmin Zhang
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Liang Wang
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Academy of Orthopaedics of Guangdong Province, Guangzhou, Guangdong, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, Guangdong, China
| | - Cory J Xian
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
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Daley-Brown D, Oprea-Iles G, Vann KT, Lanier V, Lee R, Candelaria PV, Quarshie A, Pattillo R, Gonzalez-Perez RR. Type II Endometrial Cancer Overexpresses NILCO: A Preliminary Evaluation. DISEASE MARKERS 2017; 2017:8248175. [PMID: 28659656 PMCID: PMC5474242 DOI: 10.1155/2017/8248175] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 04/27/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The expression of NILCO molecules (Notch, IL-1, and leptin crosstalk outcome) and the association with obesity were investigated in types I and II endometrial cancer (EmCa). Additionally, the involvement of NILCO in leptin-induced invasiveness of EmCa cells was investigated. METHODS The expression of NILCO mRNAs and proteins were analyzed in EmCa from African-American (n = 29) and Chinese patients (tissue array, n = 120 cases). The role of NILCO in leptin-induced invasion of Ishikawa and An3ca EmCa cells was investigated using Notch, IL-1, and leptin signaling inhibitors. RESULTS NILCO molecules were expressed higher in type II EmCa, regardless of ethnic background or obesity status of patients. NILCO proteins were mainly localized in the cellular membrane and cytoplasm of type II EmCa. Additionally, EmCa from obese African-American patients showed higher levels of NILCO molecules than EmCa from lean patients. Notably, leptin-induced EmCa cell invasion was abrogated by NILCO inhibitors. CONCLUSION Type II EmCa expressed higher NILCO molecules, which may suggest it is involved in the progression of the more aggressive EmCa phenotype. Obesity was associated with higher expression of NILCO molecules in EmCa. Leptin-induced cell invasion was dependent on NILCO. Hence, NILCO might be involved in tumor progression and could represent a new target/biomarker for type II EmCa.
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MESH Headings
- Adenocarcinoma, Papillary/complications
- Adenocarcinoma, Papillary/diagnosis
- Adenocarcinoma, Papillary/ethnology
- Adenocarcinoma, Papillary/genetics
- Aged
- Antibodies/pharmacology
- Asian People
- Black People
- Carcinoma, Endometrioid/complications
- Carcinoma, Endometrioid/diagnosis
- Carcinoma, Endometrioid/ethnology
- Carcinoma, Endometrioid/genetics
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cystadenocarcinoma, Serous/complications
- Cystadenocarcinoma, Serous/diagnosis
- Cystadenocarcinoma, Serous/ethnology
- Cystadenocarcinoma, Serous/genetics
- Diamines/pharmacology
- Disease Progression
- Endometrial Neoplasms/complications
- Endometrial Neoplasms/diagnosis
- Endometrial Neoplasms/ethnology
- Endometrial Neoplasms/genetics
- Endometrium/metabolism
- Endometrium/pathology
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Interleukin-1/antagonists & inhibitors
- Interleukin-1/genetics
- Interleukin-1/metabolism
- Leptin/genetics
- Leptin/metabolism
- Middle Aged
- Neoplasm Staging
- Obesity/complications
- Obesity/diagnosis
- Obesity/ethnology
- Obesity/genetics
- Protein Isoforms/antagonists & inhibitors
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- Receptor, Notch1/antagonists & inhibitors
- Receptor, Notch1/genetics
- Receptor, Notch1/metabolism
- Signal Transduction
- Thiazoles/pharmacology
- Black or African American
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Affiliation(s)
- Danielle Daley-Brown
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Gabriela Oprea-Iles
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Kiara T. Vann
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Viola Lanier
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Regina Lee
- Department of Obstetrics and Gynecology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Pierre V. Candelaria
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Alexander Quarshie
- Department of Community Health & Preventive Medicine, Morehouse School of Medicine, Atlanta, GA, USA
| | - Roland Pattillo
- Department of Obstetrics and Gynecology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Ruben Rene Gonzalez-Perez
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA
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30
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Candelaria PV, Rampoldi A, Harbuzariu A, Gonzalez-Perez RR. Leptin signaling and cancer chemoresistance: Perspectives. World J Clin Oncol 2017; 8:106-119. [PMID: 28439492 PMCID: PMC5385432 DOI: 10.5306/wjco.v8.i2.106] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 12/20/2016] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.
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31
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Wauman J, Zabeau L, Tavernier J. The Leptin Receptor Complex: Heavier Than Expected? Front Endocrinol (Lausanne) 2017; 8:30. [PMID: 28270795 PMCID: PMC5318964 DOI: 10.3389/fendo.2017.00030] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 02/01/2017] [Indexed: 12/31/2022] Open
Abstract
Under normal physiological conditions, leptin and the leptin receptor (ObR) regulate the body weight by balancing food intake and energy expenditure. However, this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism. Leptin, therefore, can act as a metabolic switch connecting the body's nutritional status to high energy consuming processes. We provide an extensive overview of current structural insights on the leptin-ObR interface and ObR activation, coupling to signaling pathways and their negative regulation, and leptin functioning under normal and pathophysiological conditions (obesity, autoimmunity, cancer, … ). We also discuss possible cross-talk with other receptor systems on the receptor (extracellular) and signaling cascade (intracellular) levels.
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Affiliation(s)
- Joris Wauman
- Cytokine Receptor Laboratory, Faculty of Medicine and Health Sciences, Department of Biochemistry, Ghent University, Ghent, Belgium
- VIB Medical Biotechnology Center, VIB, Ghent, Belgium
| | - Lennart Zabeau
- Cytokine Receptor Laboratory, Faculty of Medicine and Health Sciences, Department of Biochemistry, Ghent University, Ghent, Belgium
- VIB Medical Biotechnology Center, VIB, Ghent, Belgium
| | - Jan Tavernier
- Cytokine Receptor Laboratory, Faculty of Medicine and Health Sciences, Department of Biochemistry, Ghent University, Ghent, Belgium
- VIB Medical Biotechnology Center, VIB, Ghent, Belgium
- *Correspondence: Jan Tavernier,
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