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1
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Crecca E, Di Giuseppe G, Camplone C, Vigiano Benedetti V, Melaiu O, Mezza T, Cencioni C, Spallotta F. The multifaceted role of agents counteracting metabolic syndrome: A new hope for gastrointestinal cancer therapy. Pharmacol Ther 2025; 270:108847. [PMID: 40216262 DOI: 10.1016/j.pharmthera.2025.108847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/27/2025] [Accepted: 04/03/2025] [Indexed: 04/24/2025]
Abstract
Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.
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Affiliation(s)
- Elena Crecca
- Institute of System Analysis and Informatics "Antonio Ruberti", National Research Council (IASI-CNR), 00185 Rome, Italy
| | - Gianfranco Di Giuseppe
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Claudia Camplone
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, 00185 Rome, Italy; Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
| | | | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Teresa Mezza
- Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy; Pancreas Unit, CEMAD Digestive Diseases Center, Internal Medicine and Gastroenterology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Chiara Cencioni
- Institute of System Analysis and Informatics "Antonio Ruberti", National Research Council (IASI-CNR), 00185 Rome, Italy.
| | - Francesco Spallotta
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, 00185 Rome, Italy; Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy.
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AL-Noshokaty TM, Abdelhamid R, Abdelmaksoud NM, Khaled A, Hossam M, Ahmed R, Saber T, Khaled S, Elshaer SS, Abulsoud AI. Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential. Toxicol Rep 2025; 14:101895. [PMID: 39911322 PMCID: PMC11795145 DOI: 10.1016/j.toxrep.2025.101895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/07/2025] Open
Abstract
Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.
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Affiliation(s)
- Tohada M. AL-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rehab Abdelhamid
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Aya Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mariam Hossam
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Razan Ahmed
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Toka Saber
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shahd Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed I. Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt
- Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
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3
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Kelly CA, Sipos JA. Approach to the Patient With Thyroid Nodules: Considering GLP-1 Receptor Agonists. J Clin Endocrinol Metab 2025; 110:e2080-e2087. [PMID: 39400117 DOI: 10.1210/clinem/dgae722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/28/2024] [Accepted: 10/11/2024] [Indexed: 10/15/2024]
Abstract
Glucagon-like peptide 1 receptor agonists (GLP1RAs) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the US Food and Drug Administration recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RAs and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.
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Affiliation(s)
- Clare A Kelly
- Division of Endocrinology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106 USA
| | - Jennifer A Sipos
- Division of Endocrinology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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4
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Fawzy MS, Alenezy A, Jishu JA, Khan I, Dessouky A, Abdelmaksoud A, Limbach KE, Toraih EA. Survival Benefits of GLP-1 Receptor Agonists in Patients with Neuroendocrine Neoplasms: A Large-Scale Propensity-Matched Cohort Study. Cancers (Basel) 2025; 17:1593. [PMID: 40361517 PMCID: PMC12072167 DOI: 10.3390/cancers17091593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 05/04/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025] Open
Abstract
Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies that consist of two major subtypes: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Glucagon-like peptide-1 receptor agonists (GLP-1Ra) have demonstrated favorable results in preclinical studies, but their impact on NEN outcomes remains unexplored. Methods: Using the TriNetX US Research Network, we identified adult patients with NEN and either diabetes or obesity. After 1:1 propensity score matching based on demographics, comorbidities, procedures, and medication use, we compared survival outcomes between patients who received GLP-1Ra after NEN diagnosis and those who did not. Results: Among 32,464 eligible patients, 3139 received GLP-1Ra and 29,325 did not. After propensity matching, each cohort included 3043 patients with well-balanced baseline characteristics. During follow-up periods extending up to 15 years, all-cause mortality occurred in 356 (11.7%) GLP-1Ra users versus 753 (24.7%) non-users, representing a 13.0% absolute risk reduction (p < 0.001). GLP-1Ra use was associated with significantly improved survival (HR = 0.56, 95%CI = 0.49-0.63, p < 0.001). Both well-differentiated (HR = 0.52) and poorly differentiated tumors (HR = 0.56) showed significant improvement. Among primary sites, lung NENs demonstrated the most pronounced benefit (HR = 0.42). Tirzepatide showed the strongest association with reduced mortality (HR = 0.16), followed by semaglutide (HR = 0.27) and dulaglutide (HR = 0.52). Results: In this large propensity-matched study, GLP-1Ra use was associated with a 44.3% reduction in mortality risk among NEN patients with diabetes or obesity. The magnitude of the observed benefit suggests a potential role for GLP-1Ra as adjunctive therapy in this patient population. Prospective clinical trials are warranted to confirm these findings and explore underlying mechanisms.
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Affiliation(s)
- Manal S. Fawzy
- Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia;
| | - Awwad Alenezy
- Department of Family and Community Medicine, Faculty of Medicine, Northern Border University, Arar 91431, Saudi Arabia
| | - Jessan A. Jishu
- School of Medicine, Tulane University, 1430 Tulane Ave., New Orleans, LA 70112, USA;
| | - Issa Khan
- SUNY Upstate Medical University, New York, NY 13210, USA
| | - Ahmad Dessouky
- Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed Abdelmaksoud
- Department of Internal Medicine, University of California, Riverside, CA 92521, USA
| | - Kristen E. Limbach
- Department of Surgery, School of Medicine, Tulane University, 1430 Tulane Ave., New Orleans, LA 70112, USA;
| | - Eman A. Toraih
- Department of Surgery, School of Medicine, Tulane University, 1430 Tulane Ave., New Orleans, LA 70112, USA;
- Department of Cardiovascular Perfusion, Interprofessional Research, College of Health Professions, SUNY Upstate Medical University, New York, NY 13210, USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
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Ruggeri RM, Grossrubatscher EM, Ciocca E, Hasballa I, Jaafar S, Oldani M, Rubino M, Russo F, Isidori AM, Colao A, Faggiano A. Incretins and SGLT-2 inhibitors in diabetic patients with neuroendocrine tumors: current updates and future directions. Rev Endocr Metab Disord 2025:10.1007/s11154-025-09958-5. [PMID: 40175622 DOI: 10.1007/s11154-025-09958-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 04/04/2025]
Abstract
Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.
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Affiliation(s)
- Rosaria M Ruggeri
- Endocrinology, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, Messina, Italy
| | | | - Eleonora Ciocca
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Iderina Hasballa
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132, Genoa, Italy
| | - Simona Jaafar
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Monica Oldani
- Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy
| | - Manila Rubino
- Onco-Endocrinology Unit, European Institute of Oncology, Milan, Italy
| | - Flaminia Russo
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy.
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Lin A, Ding Y, Li Z, Jiang A, Liu Z, Wong HZH, Cheng Q, Zhang J, Luo P. Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence. Biomark Res 2025; 13:50. [PMID: 40140925 PMCID: PMC11948983 DOI: 10.1186/s40364-025-00765-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a primary first-line treatment for type 2 diabetes. This has raised concerns about their impact on cancer risk, spurring extensive research. This review systematically examines the varied effects of GLP-1RAs on the risk of different types of tumors, including overall cancer risk and specific cancers such as thyroid, pancreatic, reproductive system, liver, and colorectal cancers. The potential biological mechanisms underlying their influence on cancer risk are complex, involving metabolic regulation, direct antitumor effects, immune modulation, and epigenetic changes. A systematic comparison with other antidiabetic agents reveals notable differences in their influence on cancer risk across drug classes. Additionally, critical factors that shape the relationship between GLP-1RAs and cancer risk are thoroughly analyzed, including patient demographics, comorbidities, treatment regimens, and lifestyle factors, offering essential insights for developing individualized treatment protocols. Despite significant research progress, critical gaps remain. Future research should prioritize elucidating the molecular mechanisms behind the antitumor effects, refining individualized treatment strategies, investigating early tumor prevention applications, assessing potential benefits for non-diabetic populations, advancing the development of novel therapies, establishing robust safety monitoring frameworks, and building precision medicine decision-making platforms. These efforts aim to establish novel roles for GLP-1RAs in cancer prevention. and treatment, thereby advancing the progress of precision medicine.
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Affiliation(s)
- Anqi Lin
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, Jiangsu Province, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Yanxi Ding
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Zhengrui Li
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Hank Z H Wong
- Li Ka Shing, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China.
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
| | - Peng Luo
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, Jiangsu Province, 222000, China.
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
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7
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Ungvari Z, Bartha Á, Ungvari A, Fekete M, Bianchini G, Győrffy B. Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types. GeroScience 2025:10.1007/s11357-024-01494-5. [PMID: 39777709 DOI: 10.1007/s11357-024-01494-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient's cancer risk profile.
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Affiliation(s)
- Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral College/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary
| | - Áron Bartha
- Dept. of Bioinformatics, Semmelweis University, 1094, Budapest, Hungary
| | - Anna Ungvari
- Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.
| | - Monika Fekete
- Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary
| | | | - Balázs Győrffy
- Dept. of Bioinformatics, Semmelweis University, 1094, Budapest, Hungary
- Dept. of Biophysics, Medical School, University of Pecs, H-7624, Pecs, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117, Budapest, Hungary
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8
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Ibrahim SS, Ibrahim RS, Arabi B, Brockmueller A, Shakibaei M, Büsselberg D. The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer. Cancer Metastasis Rev 2024; 43:1297-1314. [PMID: 38801466 PMCID: PMC11554930 DOI: 10.1007/s10555-024-10192-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists have garnered significant attention for their therapeutic potential in addressing the interconnected health challenges of diabetes, obesity, and cancer. The role of GLP-1R in type 2 diabetes mellitus (T2DM) is highlighted, emphasizing its pivotal contribution to glucose homeostasis, promoting β-cell proliferation, and facilitating insulin release. GLP-1R agonists have effectively managed obesity by reducing hunger, moderating food intake, and regulating body weight. Beyond diabetes and obesity, GLP-1R agonists exhibit a multifaceted impact on cancer progression across various malignancies. The mechanisms underlying these effects involve the modulation of signaling pathways associated with cell growth, survival, and metabolism. However, the current literature reveals a lack of in vivo studies on specific GLP-1R agonists such as semaglutide, necessitating further research to elucidate its precise mechanisms and effects, particularly in cancer. While other GLP-1R agonists have shown promising outcomes in mitigating cancer progression, the association between some GLP-1R agonists and an increased risk of cancer remains a topic requiring more profound investigation. This calls for more extensive research to unravel the intricate relationships between the GLP-1R agonist and different cancers, providing valuable insights for clinicians and researchers alike.
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Affiliation(s)
| | | | - Batoul Arabi
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, 24144, Qatar
| | - Aranka Brockmueller
- Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Mehdi Shakibaei
- Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Dietrich Büsselberg
- Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, 24144, Qatar.
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9
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Mirghani HO. Glucagon-like peptide-1 agonists: Role of the gut in hypoglycemia unawareness, and the rationale in type 1 diabetes. World J Diabetes 2024; 15:2167-2172. [PMID: 39582561 PMCID: PMC11580574 DOI: 10.4239/wjd.v15.i11.2167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/30/2024] [Accepted: 09/05/2024] [Indexed: 10/16/2024] Open
Abstract
Type 1 diabetes is increasing and the majority of patients have poor glycemic control. Although advanced technology and nanoparticle use have greatly enhanced insulin delivery and glucose monitoring, weight gain and hypoglycemia remain major challenges and a constant source of concern for patients with type 1 diabetes. Type 1 diabetes shares some pathophysiology with type 2 diabetes, and an overlap has been reported. The above observation created great interest in glucagon-like peptide-1 receptor agonists (GLP-1) as adjuvants for type 1 diabetes. Previous trials confirmed the positive influence of GLP-1 agonists on β cell function. However, hypoglycemia unawareness and dysregulated glucagon response have been previously reported in patients with recurrent hypoglycemia using GLP-1 agonists. Jin et al found that the source of glucagon dysregulation due to GLP-1 agonists resides in the gut. Plausible explanations could be gut nervous system dysregulation or gut microbiota disruption. This review evaluates the potential of GLP-1 agonists in managing type 1 diabetes, particularly focusing on their impact on glycemic control, weight management, and glucagon dysregulation. We provide a broader insight into the problem of type 1 diabetes mellitus management in the light of recent findings and provide future research directions.
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Affiliation(s)
- Hyder O Mirghani
- Internal Medicine, University of Tabuk, Tabuk 51941, Tabuk, Saudi Arabia
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10
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Ji L, He X, Min X, Yang H, Wu W, Xu H, Chen J, Mei A. Glucagon-like peptide-1 receptor agonists in neoplastic diseases. Front Endocrinol (Lausanne) 2024; 15:1465881. [PMID: 39371922 PMCID: PMC11449759 DOI: 10.3389/fendo.2024.1465881] [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: 07/18/2024] [Accepted: 08/28/2024] [Indexed: 10/08/2024] Open
Abstract
Glucagon-like peptide-1 receptor agonist (GLP-1RA), a novel hypoglycemic agent for the treatment of type 2 diabetes, has well-known effects such as lowering blood sugar, ameliorating inflammation, reducing weight, and lowering blood lipids. It has also been shown that it can influence the proliferation and survival of cells and has a certain effect on the prognosis of some neoplastic diseases. In this study, the potential effects of GLP-1RAs on the occurrence and development of tumors were reviewed to provide new ideas for the prevention and treatment of tumors in patients.
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Affiliation(s)
- Lisan Ji
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Xianzhen He
- Children’s Medical Center, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xinwen Min
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Handong Yang
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Wenwen Wu
- School of Public Health, Hubei University of Medicine, Shiyan, Hubei, China
| | - Hao Xu
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Jun Chen
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
- Virology Key Laboratory of Shiyan City, Hubei University of Medicine, Shiyan, China
| | - Aihua Mei
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
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Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, Gao J. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther 2024; 9:234. [PMID: 39289339 PMCID: PMC11408715 DOI: 10.1038/s41392-024-01931-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 09/19/2024] Open
Abstract
The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.
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Affiliation(s)
- Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yucheng Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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12
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Guo Z, Ashrafizadeh M, Zhang W, Zou R, Sethi G, Zhang X. Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance. Cancer Metastasis Rev 2024; 43:29-53. [PMID: 37453022 DOI: 10.1007/s10555-023-10125-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
The metastasis is a multistep process in which a small proportion of cancer cells are detached from the colony to enter into blood cells for obtaining a new place for metastasis and proliferation. The metastasis and cell plasticity are considered major causes of cancer-related deaths since they improve the malignancy of cancer cells and provide poor prognosis for patients. Furthermore, enhancement in the aggressiveness of cancer cells has been related to the development of drug resistance. Metastasis of pancreatic cancer (PC) cells has been considered one of the major causes of death in patients and their undesirable prognosis. PC is among the most malignant tumors of the gastrointestinal tract and in addition to lifestyle, smoking, and other factors, genomic changes play a key role in its progression. The stimulation of EMT in PC cells occurs as a result of changes in molecular interaction, and in addition to increasing metastasis, EMT participates in the development of chemoresistance. The epithelial, mesenchymal, and acinar cell plasticity can occur and determines the progression of PC. The major molecular pathways including STAT3, PTEN, PI3K/Akt, and Wnt participate in regulating the metastasis of PC cells. The communication in tumor microenvironment can provide by exosomes in determining PC metastasis. The components of tumor microenvironment including macrophages, neutrophils, and cancer-associated fibroblasts can modulate PC progression and the response of cancer cells to chemotherapy.
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Affiliation(s)
- Zhenli Guo
- Department of Oncology, First Affiliated Hospital, Gannan Medical University, 128 Jinling Road, Ganzhou City, Jiangxi Province, 341000, China
| | - Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Wei Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Rongjun Zou
- Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, Guangdong, China
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Gautam Sethi
- Department of Pharmacology, National University of Singapore, 16 Medical Drive, Singapore, 117600, Singapore.
| | - Xianbin Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
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13
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Baran O, Akgun MY, Kayhan A, Evran S, Ozbek A, Akyoldas G, Samanci MY, Demirel N, Sonmez D, Serin H, Kocak A, Kemerdere R, Tanriverdi T. The association between calreticulin and glucagon-like peptide-1 expressions with prognostic factors in high-grade gliomas. J Cancer Res Ther 2024; 20:25-32. [PMID: 38554294 DOI: 10.4103/jcrt.jcrt_1519_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/26/2022] [Indexed: 04/01/2024]
Abstract
OBJECTIVE The aim of this study is to present the expressions of Calreticulin (CALR) and Glucagon-like peptide-1 (GLP-1) in high-grade gliomas and to further show the relation between the levels of these molecules and Ki-67 index, presence of Isocitrate dehydrogenase (IDH)-1 mutation, and tumor grade. PATIENTS AND METHODS A total of 43 patients who underwent surgical resection due to high-grade gliomas (HGG) (grades III and IV) were included. The control group comprised 27 people who showed no gross pathology in the brain during the autopsy procedures. Adequately sized tumor samples were removed from each patient during surgery, and cerebral tissues were removed from the control subjects during the autopsy procedures. Each sample was stored at -80°C as rapidly as possible until the enzyme assay. RESULTS Patients with high-grade gliomas showed significantly higher levels of CALR and significantly lower levels of GLP-1 when compared to control subjects (P = 0.001). CALR levels were significantly higher, GLP-1 levels were significantly lower in grade IV gliomas than those in grade III gliomas (P = 0.001). Gliomas with negative IDH-1 mutations had significantly higher CALR expressions and gliomas with positive IDH-1 mutations showed significantly higher GLP-1 expressions (P = 0.01). A positive correlation between Ki-67 and CALR and a negative correlation between Ki-67 and GLP-1 expressions were observed in grade IV gliomas (P = 0.001). CONCLUSIONS Our results showed that higher CALR and lower GLP-1 expressions are found in HGGs compared to normal cerebral tissues.
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Affiliation(s)
- Oguz Baran
- Department of Neurosurgery, Koç University Hospital, Istanbul, Turkey
| | | | - Ahmet Kayhan
- Department of Neurosurgery, Haseki Research and Training Hospital, Istanbul, Turkey
| | - Sevket Evran
- Department of Neurosurgery, Haseki Research and Training Hospital, Istanbul, Turkey
| | - Arif Ozbek
- Department of Neurosurgery, Medipol Mega University Hospital, Istanbul, Turkey
| | - Goktug Akyoldas
- Department of Neurosurgery, Koç University Hospital, Istanbul, Turkey
| | | | - Nail Demirel
- Department of Neurosurgery, Istanbul Research and Training Hospital, Istanbul, Turkey
| | - Derya Sonmez
- Clinical Biochemistry Laboratory, Istanbul Research and Training Hospital, Istanbul, Turkey
| | - Huriye Serin
- Clinical Biochemistry Laboratory, Istanbul Research and Training Hospital, Istanbul, Turkey
| | - Ayhan Kocak
- Department of Neurosurgery, Taksim Research and Training Hospital, Istanbul, Turkey
| | - Rahsan Kemerdere
- Department of Neurosurgery, Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Taner Tanriverdi
- Department of Neurosurgery, Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
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Du Y, Zhu J, Guo Z, Wang Z, Wang Y, Hu M, Zhang L, Yang Y, Wang J, Huang Y, Huang P, Chen M, Chen B, Yang C. Metformin adverse event profile: a pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS) from 2004 to 2022. Expert Rev Clin Pharmacol 2024; 17:189-201. [PMID: 38269492 DOI: 10.1080/17512433.2024.2306223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 01/12/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND Metformin has the potential for treating numerous diseases, but there are still many unrecognized and unreported adverse events (AEs). METHODS We selected data from the United States FDA Adverse Event Reporting System (FAERS) database from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2022 for disproportionality analysis to assess the association between metformin and related adverse events. RESULTS In this study 10,500,295 case reports were collected from the FAERS database, of which 56,674 adverse events related to metformin were reported. A total of 643 preferred terms (PTs) and 27 system organ classes (SOCs) that were significant disproportionality conforming to the four algorithms simultaneously were included. The SOCs included metabolic and nutritional disorders (p = 0.00E + 00), gastrointestinal disorders (p = 0.00E + 00) and others. PT levels were screened for adverse drug reaction (ADR) signals such as acute pancreatitis (p = 0.00E + 00), melas syndrome, pemphigoid (p = 0.00E + 00), skin eruption (p = 0.00E + 00) and drug exposure during pregnancy (p = 0.00E + 00). CONCLUSION Most of our results were consistent with the specification, but some new signals of adverse reactions such as acute pancreatitis were not included. Therefore, further studies are needed to validate unlabeled adverse reactions and provide important support for clinical monitoring and risk identification of metformin.
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Affiliation(s)
- Yikuan Du
- Central Laboratory, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, People's Republic of China
| | - Jinfeng Zhu
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Zhuoming Guo
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Zhenjie Wang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Yuni Wang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Mianda Hu
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Lingzhi Zhang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Yurong Yang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Jinjin Wang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Yixing Huang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Peiying Huang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Mianhai Chen
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Bo Chen
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
| | - Chun Yang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
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Alanteet A, Attia H, Alfayez M, Mahmood A, Alsaleh K, Alsanea S. Liraglutide attenuates obese-associated breast cancer cell proliferation via inhibiting PI3K/Akt/mTOR signaling pathway. Saudi Pharm J 2024; 32:101923. [PMID: 38223522 PMCID: PMC10784703 DOI: 10.1016/j.jsps.2023.101923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/13/2023] [Indexed: 01/16/2024] Open
Abstract
This study aims to explore the anti-proliferative, pro-apoptotic, and anti-migration activities of liraglutide (LGT) in MCF-7 breast cancer (BC) cells in subjects with obesity, particularly its effects on the PI3K/Akt/mTOR/AMPK pathway. The role of AMPK/SIRT-1, an essential regulator of adipokine production, in the effect of LGT on the production of adipose-derived adipokine was also assessed. MCF-7 cells were incubated in conditioned medium (CM) generated from adipose-derived stem cells (ADSCs) of obese subjects. MCF-7 cells were then treated with LGT for 72 h. Anti-proliferative, pro-apoptotic, and anti-migration activities were investigated using alamarBlue, annexin V stain, and scratch assay, respectively. Protein levels of phosphorylated PI3K, p-Akt, p-mTOR, and p-AMPK were investigated using immunoblotting. Levels of adipokines in ADSCs were determined using RT-PCR before and after transfection of ADSCs using the specific small interference RNA sequences for AMPK and SIRT-1. LGT evoked anti-proliferative, apoptotic, and potential anti-migratory properties on MCF-7 cells incubated in CM from obese ADSCs and significantly mitigated the activity of the PI3K/Akt/mTOR survival pathway-but not AMPK-in MCF-7 cells. Furthermore, the anti-proliferative effects afforded by LGT were similar to those mediated by LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor). Our results reveal that transfection of AMPK/SIRT-1 genes did not affect the beneficial role of LGT in the expression of adipokines in ADSCs. In conclusion, LGT elicits anti-proliferative, apoptotic, and anti-migratory effects on BC cells in obese conditions by suppressing the activity of survival pathways; however, this effect is independent of the AMPK/SIRT1 pathway in ADSCs or AMPK in BC cells.
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Affiliation(s)
- Alaa Alanteet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Hala Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Musaed Alfayez
- Anatomy Department, Stem Cell Unit, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Amer Mahmood
- Anatomy Department, Stem Cell Unit, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Khalid Alsaleh
- College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sary Alsanea
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Mazzieri A, Basta G, Calafiore R, Luca G. GLP-1 RAs and SGLT2i: two antidiabetic agents associated with immune and inflammation modulatory properties through the common AMPK pathway. Front Immunol 2023; 14:1163288. [PMID: 38053992 PMCID: PMC10694219 DOI: 10.3389/fimmu.2023.1163288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 10/30/2023] [Indexed: 12/07/2023] Open
Abstract
Immune cells and other cells respond to nutrient deprivation by the classic catabolic pathway of AMPK (Adenosine monophosphate kinase). This kinase is a pivotal regulator of glucose and fatty acids metabolism, although current evidence highlights its role in immune regulation. Indeed AMPK, through activation of Foxo1 (Forkhead box O1) and Foxo3 (Forkhead box O3), can regulate FOXP3, the key gene for differentiation and homeostasis of Tregs (T regulators lymphocytes). The relevance of Tregs in the onset of T1D (Type 1 diabetes) is well-known, while their role in the pathogenesis of T2D (Type 2 diabetes) is not fully understood yet. However, several studies seem to indicate that Tregs may oppose the progression of diabetic complications by mitigating insulin resistance, atherosclerosis, and damage to target organs (as in kidney disease). Hence, AMPK and AMPK-activating agents may play a role in the regulation of the immune system. The connection between metformin and AMPK is historically known; however, this link and the possible related immune effects are less studied about SGLT2i (Sodium-glucose co-transport 2 inhibitors) and GLP1-RAs (Glucagon-like peptide-1 receptor agonists). Actual evidence shows that the negative caloric balance, induced by SGLT2i, can activate AMPK. Conversely and surprisingly, an anabolizing agent like GLP-1RAs can also upregulate this kinase through cAMP (Cyclic adenosine monophosphate) accumulation. Therefore, both these drugs can likely lead to the activation of the AMPK pathway and consequential proliferation of Tregs. These observations seem to confirm not only the metabolic but also the immunoregulatory effects of these new antidiabetic agents.
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Affiliation(s)
- Alessio Mazzieri
- Translational Medicine and Surgery, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Basta
- Division of Internal Medicine and Endocrine and Metabolic Sciences (MISEM), Laboratory for Endocrine Cell Transplants and Biohybrid Organs, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Riccardo Calafiore
- Diabetes Research Foundation, Confindustria Umbria, Perugia, Italy
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giovanni Luca
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Division of Medical Andrology and Endocrinology of Reproduction, Saint Mary Hospital, Terni, Italy
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17
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Cuttica CM, Briata IM, DeCensi A. Novel Treatments for Obesity: Implications for Cancer Prevention and Treatment. Nutrients 2023; 15:3737. [PMID: 37686769 PMCID: PMC10490004 DOI: 10.3390/nu15173737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
It is now established that obesity is related to a higher incidence of cancer during a lifespan. The effective treatment of obesity opens up new perspectives in the treatment of a relevant modifiable cancer risk factor. The present narrative review summarizes the correlations between weight loss in obesity and cancer. The current knowledge between obesity treatment and cancer was explored, highlighting the greatest potential for its use in the treatment of cancer in the clinical setting. Evidence for the effects of obesity therapy on proliferation, apoptosis, and response to chemotherapy is summarized. While more studies, including large, long-term clinical trials, are needed to adequately evaluate the relationship and durability between anti-obesity treatment and cancer, collaboration between oncologists and obesity treatment experts is increasingly important.
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Affiliation(s)
| | - Irene Maria Briata
- Division of Medical Oncology, E.O. Ospedali Galliera, 16128 Genoa, Italy; (I.M.B.); (A.D.)
| | - Andrea DeCensi
- Division of Medical Oncology, E.O. Ospedali Galliera, 16128 Genoa, Italy; (I.M.B.); (A.D.)
- Wolfson Institute of Population Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, UK
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18
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Ma B, Wang X, Ren H, Li Y, Zhang H, Yang M, Li J. High glucose promotes the progression of colorectal cancer by activating the BMP4 signaling and inhibited by glucagon-like peptide-1 receptor agonist. BMC Cancer 2023; 23:594. [PMID: 37370018 PMCID: PMC10304216 DOI: 10.1186/s12885-023-11077-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND The detailed molecular mechanism between type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) is still uncertain. Bone morphogenetic protein 4 (BMP4) dysregulation is implicated in T2DM and CRC, respectively. This study aims to investigate whether BMP4 can mediate the interaction of CRC with T2DM. METHODS We firstly explored the expression of BMP4 in The Cancer Genome Altas (TCGA) databases and CRC patients with or without DM from the Shanghai Tenth People's Hospital. The diabetic model of CRC cell lines in vitro and the mice model in vivo were developed to explore the BMP4 expression during CRC with or without diabetes. Further inhibition of BMP4 to observe its effects on CRC. Also, glucagon-like peptide-1 receptor agonist (GLP-1RA) was used to verify the underlying mechanism of hypoglycemic drugs on CRC via BMP4. RESULTS BMP4 expression was upregulated in CRC patients, and significantly higher in CRC patients with diabetes (P < 0.05). High glucose-induced insulin resistance (IR)-CRC cells and diabetic mice with metastasis model of CRC had increased BMP4 expression, activated BMP4-Smad1/5/8 pathway, and improved proliferative and metastatic ability mediated by epithelial-mesenchymal transition (EMT). And, treated CRC cells with exogenously BMP inhibitor-Noggin or transfected with lentivirus (sh-BMP4) could block the upregulated metastatic ability of CRC cells induced by IR. Meanwhile, GLP-1R was downregulated by high glucose-induced IR while unregulated by BMP4 inhibitor noggin, and treated GLP-1RA could suppress the proliferation of CRC cells induced by IR through downregulated BMP4. CONCLUSIONS BMP4 increased by high glucose promoted the EMT of CRC. The mechanism of the BMP4/Smad pathway was related to the susceptible metastasis of high glucose-induced IR-CRC. The commonly used hypoglycemic drug, GLP-1RA, inhibited the growth and promoted the apoptosis of CRC through the downregulation of BMP4. The result of our study suggested that BMP4 might serve as a therapeutic target in CRC patients with diabetes.
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Affiliation(s)
- Bingwei Ma
- Colorectal Cancer Central, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai, 200072, China
| | - Xingchun Wang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University, 301 Middle Yanchang Road, Shanghai, 200072, China
- Thyroid Research Center of Shanghai, Shanghai Tenth People's Hospital, 301 Middle Yanchang Road, Shanghai, 200072, China
| | - Hui Ren
- School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
| | - Yingying Li
- School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
| | - Haijiao Zhang
- Department of Gastrointestinal Surgery, Huadong Hospital affiliated with Fudan University, 221 West Yanan Road, Shanghai, 200040, China
| | - Muqing Yang
- Department of General Surgery, Tenth People's Hospital of Tongji University, 301 Middle Yanchang Road, Shanghai, 200072, China
| | - Jiyu Li
- Geriatric Cancer Center, Huadong Hospital Affiliated to Fudan University, 221 West Yanan Road, Shanghai, 200040, China.
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Ruze R, Chen Y, Xu R, Song J, Yin X, Wang C, Xu Q. Obesity, diabetes mellitus, and pancreatic carcinogenesis: Correlations, prevention, and diagnostic implications. Biochim Biophys Acta Rev Cancer 2023; 1878:188844. [PMID: 36464199 DOI: 10.1016/j.bbcan.2022.188844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/13/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022]
Abstract
The prevalence of obesity, diabetes mellitus (DM), and pancreatic cancer (PC) has been consistently increasing in the last two decades worldwide. Sharing various influential risk factors in genetics and environmental inducers in pathogenesis, the close correlations of these three diseases have been demonstrated in plenty of clinical studies using multiple parameters among different populations. On the contrary, most measures aimed to manage and treat obesity and DM effectively reduce the risk and prevent PC occurrence, yet certain drugs can inversely promote pancreatic carcinogenesis instead. Most importantly, an elevation of blood glucose with or without a reduction in body weight, along with other potential tools, may provide valuable clues for detecting PC at an early stage in patients with obesity and DM, favoring a timely intervention and prolonging survival. Herein, the epidemiological and etiological correlations among these three diseases and the supporting clinical evidence of their connections are first summarized to favor a better and more thorough understanding of obesity- and DM-related pancreatic carcinogenesis. After comparing the distinct impacts of different weight-lowering and anti-diabetic treatments on the risk of PC, the possible diagnostic implications of hyperglycemia and weight loss in PC screening are also addressed in detail.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China.
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China.
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20
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Chen J, Mei A, Wei Y, Li C, Qian H, Min X, Yang H, Dong L, Rao X, Zhong J. GLP-1 receptor agonist as a modulator of innate immunity. Front Immunol 2022; 13:997578. [PMID: 36569936 PMCID: PMC9772276 DOI: 10.3389/fimmu.2022.997578] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a 30-amino acid hormone secreted by L cells in the distal ileum, colon, and pancreatic α cells, which participates in blood sugar regulation by promoting insulin release, reducing glucagon levels, delaying gastric emptying, increasing satiety, and reducing appetite. GLP-1 specifically binds to the glucagon-like peptide-1 receptor (GLP-1R) in the body, directly stimulating the secretion of insulin by pancreatic β-cells, promoting proliferation and differentiation, and inhibiting cell apoptosis, thereby exerting a glycemic lowering effect. The glycemic regulating effect of GLP-1 and its analogues has been well studied in human and murine models in the circumstance of many diseases. Recent studies found that GLP-1 is able to modulate innate immune response in a number of inflammatory diseases. In the present review, we summarize the research progression of GLP-1 and its analogues in immunomodulation and related signal pathways.
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Affiliation(s)
- Jun Chen
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Aihua Mei
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Yingying Wei
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chunlei Li
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Hang Qian
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Xinwen Min
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Handong Yang
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoquan Rao
- Department of Cardiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
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21
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Deng J, Guo Y, Du J, Gu J, Kong L, Tao B, Li J, Fu D. The Intricate Crosstalk Between Insulin and Pancreatic Ductal Adenocarcinoma: A Review From Clinical to Molecular. Front Cell Dev Biol 2022; 10:844028. [PMID: 35252207 PMCID: PMC8891560 DOI: 10.3389/fcell.2022.844028] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/21/2022] [Indexed: 12/14/2022] Open
Abstract
Increased insulin level (or "hyperinsulinemia") is a common phenomenon in pancreatic ductal adenocarcinoma (PDA) patients and signals poor clinical outcomes. Insulin is safe in low PDA risk population, while insulin significantly promotes PDA risk in high PDA risk population. The correlation between insulin and PDA is a reciprocal self-reinforcing relationship. On the one hand, pancreatic cancer cells synthesize multiple molecules to cause elevated peripheral insulin resistance, thus enhancing hyperinsulinemia. On the other hand, insulin promotes pancreatic cancer initiation and sustains PDA development by eliciting tumorigenic inflammation, regulating lipid and glucose metabolic reprogram, overcoming apoptosis through the crosstalk with IGF-1, stimulating cancer metastasis, and activating tumor microenvironment formation (inflammation, fibrosis, and angiogenesis). Currently, taking glucose sensitizing agents, including metformin, SGLT-2 inhibitor, and GLP-1 agonist, is an effective way of lowering insulin levels and controlling PDA development at the same time. In the future, new drugs targeting insulin-related signal pathways may pave a novel way for suppressing PDA initiation and progression.
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Affiliation(s)
| | | | | | | | | | | | - Ji Li
- Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Fudan University, Shanghai, China
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Seo YG. Side Effects Associated with Liraglutide Treatment for Obesity as Well as Diabetes. J Obes Metab Syndr 2021; 30:12-19. [PMID: 33071241 PMCID: PMC8017323 DOI: 10.7570/jomes20059] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/25/2020] [Accepted: 08/02/2020] [Indexed: 02/06/2023] Open
Abstract
Liraglutide is a glucagon-like peptide-1 receptor agonist used as a treatment for type 2 diabetes mellitus, which has been expanded for use at a higher dose in weight control. Therefore, it is necessary to consider adverse reactions of the drug at high doses as well as at lower doses after the indication has been expanded. Body mass index criteria for patients prescribed the drug in the real world tend to be applied less rigorously, which may increase the number of adverse reactions due to over-prescription. Liraglutide treatment was found effective and safe in some studies, while others have warned about its risks. Therefore, this review summarizes the current data available on side effects associated with liraglutide.
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Affiliation(s)
- Young-Gyun Seo
- Department of Family Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea
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23
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Alanteet AA, Attia HA, Shaheen S, Alfayez M, Alshanawani B. Anti-Proliferative Activity of Glucagon-Like Peptide-1 Receptor Agonist on Obesity-Associated Breast Cancer: The Impact on Modulating Adipokines' Expression in Adipocytes and Cancer Cells. Dose Response 2021; 19:1559325821995651. [PMID: 33746653 PMCID: PMC7903831 DOI: 10.1177/1559325821995651] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 01/27/2021] [Accepted: 01/27/2021] [Indexed: 01/04/2023] Open
Abstract
Obesity is associated with high risk and poor prognosis of breast cancer (BC). Obesity promotes BC cells proliferation via modulating the production of adipokines, including adiponectin (anti-neoplastic adipokine), leptin (carcinogenic adipokine) and inflammatory mediators. In the present study we investigated the anti-proliferative effects of liraglutide (LG; anti-diabetic and weight reducing drug) on MCF-7 human BC cells cultured in obese adipose tissue-derived stem cells-conditioned medium (ADSCs-CM) and whether this effect is mediated via modulating the adipokines in ADSCs and cancer cells. Proliferation was investigated using AlamarBlue viability test, colony forming assay and cell cycle analysis. Levels and expression of adipokines and their receptors were assayed using ELISA and RT-PCR. LG caused 48% inhibition of MCF-7 proliferation in obese ADSCs-CM, reduced the colony formation and induced G0/G1 phase arrest. LG also decreased the levels of inflammatory mediators, suppressed the expression of leptin, while increased mRNA levels of adiponectin and their receptors in obese ADSCs and cancer cells cultured in obese ADCSs-CM. In conclusion, LG could mitigate BC cell growth in obese subjects; therefore it could be used for clinical prevention and/or treatment of BC in obese subjects. It may assist to improve treatment outcomes and, reduce the mortality rate in obese patients with BC.
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Affiliation(s)
- Alaa A Alanteet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hala A Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.,Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Sameerah Shaheen
- Anatomy Department and Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Musaed Alfayez
- Anatomy Department and Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Bisher Alshanawani
- Plastic Surgery Unit, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
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Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y, Zhang Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne) 2021; 12:721135. [PMID: 34497589 PMCID: PMC8419463 DOI: 10.3389/fendo.2021.721135] [Citation(s) in RCA: 205] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.
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Affiliation(s)
- Xin Zhao
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Minghe Wang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Zhitong Wen
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Zhihong Lu
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Lijuan Cui
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Chao Fu
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Huan Xue
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
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Eftekhari S, Montazeri H, Tarighi P. Synergistic anti-tumor effects of Liraglutide, a glucagon-like peptide-1 receptor agonist, along with Docetaxel on LNCaP prostate cancer cell line. Eur J Pharmacol 2020; 878:173102. [DOI: 10.1016/j.ejphar.2020.173102] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/27/2020] [Accepted: 04/06/2020] [Indexed: 12/29/2022]
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Dimitrios P, Michael D, Vasilios K, Konstantinos S, Konstantinos I, Ioanna Z, Konstantinos P, Spyridon B, Asterios K. Liraglutide as Adjunct to Insulin Treatment in Patients with Type 1 Diabetes: A Systematic Review and Meta-analysis. Curr Diabetes Rev 2020; 16:313-326. [PMID: 31203802 DOI: 10.2174/1573399815666190614141918] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/24/2019] [Accepted: 05/03/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND A few Randomized Controlled Trials (RCTs) have evaluated the use of liraglutide in Type 1 Diabetes (T1D). Through the present systematic review and meta-analysis, we aim at critically appraising and summarizing those RCTs, providing precise effect estimates. METHODS We searched major databases and grey literature from their inception to October 2018, for RCTs with a duration ≥ 12 weeks, comparing liraglutide with placebo or any other comparator as adjunct to insulin in patients with T1D, investigating major efficacy and safety endpoints. This review is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. RESULTS We included 5 trials with 2,445 randomized participants. Liraglutide provided modest reductions in HbA1c, with liraglutide 1.8 mg producing the greatest decrease (MD = -0.24%, 95% CI -0.32 to -0.16, I2=0%). Significant weight reduction, up to 4.87 kg with liraglutide 1.8 mg was also observed (95% CI -5.31 to -4.43, I2=0%). Decrease in total daily insulin dose, primarily driven by a decrease in bolus insulin requirements, was demonstrated. Liraglutide decreased non-significantly the odds for severe hypoglycemia (OR=0.80, 95% CI 0.57-1.14, I2=0%), while it increased significantly the odds for gastrointestinal adverse events (for nausea, OR=4.70, 95% CI 3.68-6.00, I2=37%, and for vomiting, OR=2.50, 95% CI 1.54-4.72, I2=27%). A significant increase in heart rate was also demonstrated. No association with diabetic ketoacidosis or malignancies was identified. CONCLUSION In patients with T1D, liraglutide might prove be an adjunct to insulin, improving glycemic control, inducing body weight loss and decreasing exogenous insulin requirements and severe hypoglycemia.
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Affiliation(s)
- Patoulias Dimitrios
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Doumas Michael
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
- VAMC and George Washington University, Washington, DC, United States
| | - Kotsis Vasilios
- Third Department of Internal Medicine, General Hospital "Papageorgiou", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stavropoulos Konstantinos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Imprialos Konstantinos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Zografou Ioanna
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Petidis Konstantinos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Bakatselos Spyridon
- First Department of Internal Medicine, General Hospital "Hippokration", Thessaloniki, Greece
| | - Karagiannis Asterios
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
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Krause GC, Lima KG, Levorse V, Haute GV, Gassen RB, Garcia MC, Pedrazza L, Donadio MVF, Luft C, de Oliveira JR. Exenatide induces autophagy and prevents the cell regrowth in HepG2 cells. EXCLI JOURNAL 2019; 18:540-548. [PMID: 31611738 PMCID: PMC6785771 DOI: 10.17179/excli2019-1415] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 07/18/2019] [Indexed: 12/20/2022]
Abstract
The incidence of hepatocellular carcinoma (HCC) keeps rising year by year, and became the second leading cause of cancer-related death. Some studies have found that liraglutide, a GLP-1 analog, may decrease the tumor cells proliferation. Due to this, the aim of this work is to investigate the antiproliferative potential of exenatide, another GLP-1 analog. Cell proliferation was assessed by direct count with Trypan blue dye exclusion. Flow cytometry was used to determinate autophagy and nuclear staining. Morphometric analysis was used to verify senescence and apoptosis. The mechanism that induced cell growth inhibition was analyzed by Western Blot. Treatment with exenatide significantly decreases cell proliferation and increases autophagy, both in relation to control and liraglutide. In addition, mTOR inhibition was greater in cells treated with exenatide. In relation to chronic treatment, exenatide does not allow cellular regrowth by preventing some resistance mechanism that the cells can acquire. These results suggest that exenatide has a potent anti-proliferative activity via mTOR modulation and, among the GLP-1 analogs tested, could be in the future an alternative for HCC treatment.
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Affiliation(s)
- Gabriele Catyana Krause
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Kelly Goulart Lima
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Vitor Levorse
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Gabriela Viegas Haute
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Rodrigo Benedetti Gassen
- Laboratório de Imunologia Celular e Molecular, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Maria Cláudia Garcia
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Leonardo Pedrazza
- Ubiquitylation and Cell Signaling Lab. IDIBELL, Department de Ciències Fisiològiques, Universitat de Barcelona, L'Hospitalet de Llobregat - Barcelona, Spain
| | - Márcio Vinícius Fagundes Donadio
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
- Laboratório de Atividade Física em Pediatria, Centro Infant, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Carolina Luft
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
- Laboratório de Atividade Física em Pediatria, Centro Infant, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Jarbas Rodrigues de Oliveira
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
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Alwhaibi A, Verma A, Adil MS, Somanath PR. The unconventional role of Akt1 in the advanced cancers and in diabetes-promoted carcinogenesis. Pharmacol Res 2019; 145:104270. [PMID: 31078742 PMCID: PMC6659399 DOI: 10.1016/j.phrs.2019.104270] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/03/2019] [Accepted: 05/08/2019] [Indexed: 12/15/2022]
Abstract
Decades of research have elucidated the critical role of Akt isoforms in cancer as pro-tumorigenic and metastatic regulators through their specific effects on the cancer cells, tumor endothelial cells and the stromal cells. The pro-cancerous role of Akt isoforms through enhanced cell proliferation and suppression of apoptosis in cancer cells and the cells in the tumor microenvironment is considered a dogma. Intriguingly, studies also indicate that the Akt pathway is essential to protect the endothelial-barrier and prevent aberrant vascular permeability, which is also integral to tumor perfusion and metastasis. To complicate this further, a flurry of recent reports strongly indicates the metastasis suppressive role of Akt, Akt1 in particular in various cancer types. These reports emanated from different laboratories have elegantly demonstrated the paradoxical effect of Akt1 on cancer cell epithelial-to-mesenchymal transition, invasion, tumor endothelial-barrier disruption, and cancer metastasis. Here, we emphasize on the specific role of Akt1 in mediating tumor cell-vasculature reciprocity during the advanced stages of cancers and discuss how Akt1 differentially regulates cancer metastasis through mechanisms distinct from its pro-tumorigenic effects. Since Akt is integral for insulin signaling, endothelial function, and metabolic regulation, we also attempt to shed some light on the specific effects of diabetes in modulating Akt pathway in the promotion of tumor growth and metastasis.
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Affiliation(s)
- Abdulrahman Alwhaibi
- Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and the Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Arti Verma
- Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and the Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Mir S Adil
- Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and the Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Payaningal R Somanath
- Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and the Charlie Norwood VA Medical Center, Augusta, GA, USA; Department of Medicine, Vascular Biology Center and Cancer Center, Augusta University, USA.
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Chen B, Zhou W, Zhao W, Yuan P, Tang C, Wang G, Leng J, Ma J, Wang X, Hui Y, Wang Q. Oxaliplatin reverses the GLP-1R-mediated promotion of intrahepatic cholangiocarcinoma by altering FoxO1 signaling. Oncol Lett 2019; 18:1989-1998. [PMID: 31423269 DOI: 10.3892/ol.2019.10497] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 04/25/2019] [Indexed: 12/26/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, with a 5-year survival rate of <10%; effective drug treatment for ICC is currently lacking. Glucagon-like peptide-1 receptor (GLP-1R) is upregulated in ICC; however, the functions of GLP-1R in ICC remain unknown. In this study, the upregulation of GLP-1R was confirmed in ICC cells using reverse transcription-quantitative polymerase chain reaction and western blot analysis, and GLP-1R was determined to promote the migration and invasion of ICC cells using Transwell assays. This tumor-promoting effect depended on the upregulation of epithelial-mesenchymal transformation-associated proteins, which was mediated by the FoxO1 signaling pathway. It was also indicated that following oxaliplatin treatment, the effects of GLP-1R on EMT and invasion were reversed. This functional reversion was associated with the reduced phosphorylation of S256 in forkhead box O1 (FoxO1) and an increase in the levels of unphosphorylated FoxO1. These findings suggest that incretin-based therapies may increase the risk of ICC metastasis and should not be used solely for the treatment of patients with ICC.
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Affiliation(s)
- Bendong Chen
- Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Wenyan Zhou
- Department of Intensive Care Unit, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Wenchao Zhao
- Department of Hepato-Biliary-Pancreatic Surgery, Sixth Medical Center of People's Liberation Army General Hospital, Beijing 100043, P.R. China
| | - Peng Yuan
- Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Chaofeng Tang
- Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Genwang Wang
- Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Junzhi Leng
- Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Jinlong Ma
- Department of Postgraduate, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Xiaowen Wang
- Department of Postgraduate, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Yongfeng Hui
- Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Qi Wang
- Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
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Zhang H, Pan YZ, Cheung M, Cao M, Yu C, Chen L, Zhan L, He ZW, Sun CY. LAMB3 mediates apoptotic, proliferative, invasive, and metastatic behaviors in pancreatic cancer by regulating the PI3K/Akt signaling pathway. Cell Death Dis 2019; 10:230. [PMID: 30850586 PMCID: PMC6408539 DOI: 10.1038/s41419-019-1320-z] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/08/2018] [Accepted: 12/17/2018] [Indexed: 12/19/2022]
Abstract
The poor prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is partially attributed to the invasive and metastatic behavior of this disease. Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, an extracellular matrix protein secreted by cultured human keratinocytes. In addition, LAMB3 is involved in the invasive and metastatic abilities of some types of cancer, including colon, pancreas, lung, cervix, stomach, and prostate cancer, but the role and mechanism of LAMB3 in PDAC have not been previously determined. Herein, we tentatively investigated the role of LAMB3 in the malignant biological behavior of PDAC. In this study, we demonstrated that LAMB3 is upregulated in PDAC. Inhibition of LAMB3 abrogated the tumorigenic outcomes of PI3K/Akt signaling pathway activation, including those involving cell cycle arrest, cell apoptosis, proliferation, invasion and migration in vitro, and tumor growth and liver metastasis in vivo. Our results showed that LAMB3 could mediate cell cycle arrest and apoptosis in PDAC cells and alter the proliferative, invasive, and metastatic behaviors of PDAC by regulating the PI3K/Akt signaling pathway. LAMB3 may be a novel therapeutic target for the treatment of PDAC in the future.
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Affiliation(s)
- Hong Zhang
- Guizhou Medical University, Guiyang, Guizhou, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- Key Laboratory of Hepatobiliary-Pancreas-Spleen Surgery of Guizhou Medical University, Guiyang, Guizhou, China
- Ontario Cancer Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Yao-Zhen Pan
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- Key Laboratory of Hepatobiliary-Pancreas-Spleen Surgery of Guizhou Medical University, Guiyang, Guizhou, China
| | - May Cheung
- Ontario Cancer Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Mary Cao
- Ontario Cancer Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Chao Yu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- Key Laboratory of Hepatobiliary-Pancreas-Spleen Surgery of Guizhou Medical University, Guiyang, Guizhou, China
| | - Ling Chen
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- Key Laboratory of Hepatobiliary-Pancreas-Spleen Surgery of Guizhou Medical University, Guiyang, Guizhou, China
| | - Lei Zhan
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- Key Laboratory of Hepatobiliary-Pancreas-Spleen Surgery of Guizhou Medical University, Guiyang, Guizhou, China
| | - Zhi-Wei He
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- Key Laboratory of Hepatobiliary-Pancreas-Spleen Surgery of Guizhou Medical University, Guiyang, Guizhou, China
| | - Cheng-Yi Sun
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
- Key Laboratory of Hepatobiliary-Pancreas-Spleen Surgery of Guizhou Medical University, Guiyang, Guizhou, China.
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Lin WJ, Ma XF, Hao M, Zhou HR, Yu XY, Shao N, Gao XY, Kuang HY. Liraglutide attenuates the migration of retinal pericytes induced by advanced glycation end products. Peptides 2018; 105:7-13. [PMID: 29746877 DOI: 10.1016/j.peptides.2018.05.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 05/03/2018] [Accepted: 05/06/2018] [Indexed: 01/08/2023]
Abstract
Retinal pericyte migration represents a novel mechanism of pericyte loss in diabetic retinopathy (DR), which plays a crucial role in the early impairment of the blood-retinal barrier (BRB). Glucagon-like peptide-1 (GLP-1) has been shown to protect the diabetic retina in the early stage of DR; however, the relationship between GLP-1 and retinal pericytes has not been discussed. In this study, advanced glycation end products (AGEs) significantly increased the migration of primary bovine retinal pericytes without influencing cell viability. AGEs also significantly enhanced phosphatidylinositol 3-kinase (PI3K)/Akt activation, and changed the expressions of migration-related proteins, including phosphorylated focal adhesion kinase (p-FAK), matrix metalloproteinase (MMP)-2 and vinculin. PI3K inhibition significantly attenuated the AGEs-induced migration of retinal pericytes and reversed the overexpression of MMP-2. Glucagon-like peptide-1 receptor (Glp1r) was expressed in retinal pericytes, and liraglutide, a GLP-1 analog, significantly attenuated the migration of pericytes by Glp1r and reversed the changes in p-Akt/Akt, p-FAK/FAK, vinculin and MMP-2 levels induced by AGEs, indicating that the protective effect of liraglutide was associated with the PI3K/Akt pathway. These results provided new insights into the mechanism underlying retinal pericyte migration. The early use of liraglutide exerts a potential bebefical effect on regulating pericyte migration, which might contribute to mechanisms that maintain the integrity of vascular barrier and delay the development of DR.
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Affiliation(s)
- Wen-Jian Lin
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xue-Fei Ma
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Hao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huan-Ran Zhou
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xin-Yang Yu
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ning Shao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xin-Yuan Gao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hong-Yu Kuang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Lu R, Yang J, Wei R, Ke J, Tian Q, Yu F, Liu J, Zhang J, Hong T. Synergistic anti-tumor effects of liraglutide with metformin on pancreatic cancer cells. PLoS One 2018; 13:e0198938. [PMID: 29897998 PMCID: PMC5999272 DOI: 10.1371/journal.pone.0198938] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 05/29/2018] [Indexed: 12/13/2022] Open
Abstract
Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively. RT-PCR and western blot analyses were used to determine the mRNA and protein levels of related molecules. Results showed that combination treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) significantly decreased cell viability and colony formation, caused cell cycle arrest, upregulated the level of pro-apoptotic proteins Bax and cleaved caspase-3, and inhibited cell migration in the cells, although their single treatment did not exhibit such effects. Combination index value for cell viability indicated a synergistic interaction of liraglutide and metformin. Moreover, the combined treatment with liraglutide and metformin could activate the phosphorylation of AMP-activated protein kinase (AMPK) more potently than their single treatment in the cells. These results suggest that liraglutide in combination with metformin has a synergistic anti-tumor effect on the pancreatic cancer cells, which may be at least partly due to activation of AMPK signaling. Our study provides new insights into the treatment of patients with type 2 diabetes and pancreatic cancer.
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Affiliation(s)
- Ran Lu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jing Ke
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Qing Tian
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Fei Yu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Junling Liu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jingjing Zhang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
- * E-mail:
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Wang H, Liu Y, Tian Q, Yang J, Lu R, Zhan S, Haukka J, Hong T. Incretin-based therapies and risk of pancreatic cancer in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 2018; 20:910-920. [PMID: 29193572 DOI: 10.1111/dom.13177] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/07/2017] [Accepted: 11/25/2017] [Indexed: 01/04/2023]
Abstract
AIMS To perform a meta-analysis of randomized controlled trials (RCTs), including 6 recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with type 2 diabetes (T2DM). MATERIALS AND METHODS For the period January 1, 2007 to May 1, 2017, the PubMed, Embase, Cochrane Central Register and ClininalTrials.gov databases were searched for RCTs in people with T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of ≥52 weeks. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate. RESULTS A total of 33 studies (n = 79 971), including the 6 CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered incretin drugs compared with controls (Peto odds ratio [OR] 0.67, 95% confidence interval [CI] 0.44-1.02). In the 6 CVOTs, 79 pancreatic cancer events were identified in 55 248 participants. Pooled estimates of the 6 CVOTs showed an identical tendency (Peto OR 0.65, 95% CI 0.42-1.01). Notably, in the subgroup of participants who received treatment and follow-up for ≥104 weeks, 84 pancreatic cancer events were identified in 59 919 participants, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62, 95% CI 0.41-0.95). CONCLUSIONS Treatment with incretin drugs was not associated with an increased risk of pancreatic cancer in people with T2DM. Instead, it might protect against pancreatic malignancy in patients treated for ≥104 weeks.
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Affiliation(s)
- Haining Wang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Ye Liu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Qing Tian
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Ran Lu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Siyan Zhan
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
| | - Jari Haukka
- Clinicum Department of Public Health, University of Helsinki, Helsinki, Finland
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
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Chen P, Shi X, Xu X, Lin Y, Shao Z, Wu R, Huang L. Liraglutide ameliorates early renal injury by the activation of renal FoxO1 in a type 2 diabetic kidney disease rat model. Diabetes Res Clin Pract 2018; 137:173-182. [PMID: 29355652 DOI: 10.1016/j.diabres.2017.09.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 08/27/2017] [Accepted: 09/18/2017] [Indexed: 02/06/2023]
Abstract
AIMS The aim of this study was to investigate the effects of liraglutide on renal injury and the renal expression of FoxO1 in type 2 diabetic rats. METHODS Type 2 diabetic rats model was induced by a high-sugar and high-fat diet and intraperitoneal injection of low-dose Streptozotocin (STZ) (30 mg/kg). Five weeks after STZ injection, diabetic rats were randomly treated with or without subcutaneous injection of liraglutide (0.2 mg/kg/12 h) for eight weeks. Diabetes-related physical and biochemical indicators, renal histopathological and ultrastructural changes, the expression of renal transforming growth factor beta-1 (TGF-β1), fibronectin (FN), type IV collagen (Col IV), protein kinase B (Akt), forkhead box protein O1 (FoxO1) and manganese superoxide dismutase (MnSOD) were measured. RESULTS Rats in DN group showed a significant increase in fasting blood glucose, HbA1c, kidney to body weight index, serum creatinine (Scr), blood urea nitrogen (BUN), urinary albumin excretion, mesangial matrix index, glomerular basement membrane (GBM) thickening, podocyte foot process fusion, the mRNA and protein levels of renal TGF-β1, FN and Col IV and a dramatic decrease in the mRNA and protein levels of renal MnSOD, all of which were significantly ameliorated by liraglutide. In addition, liraglutide also increased the expression of FoxO1 mRNA and reduced renal phosphorylation levels of Akt and FoxO1 protein. CONCLUSIONS These results suggest that liraglutide may exert a renoprotective effect by a FoxO1-mediated upregulation of renal MnSOD expression in the early DKD.
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Affiliation(s)
- Pin Chen
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, Fujian, China; Department of Endocrinology, Fuzhou General Hospital, Fuzhou 350025, Fujian, China
| | - Xiaozhi Shi
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, Fujian, China; Department of Endocrinology, Fuzhou General Hospital, Fuzhou 350025, Fujian, China
| | - Xiangjin Xu
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, Fujian, China; Department of Endocrinology, Fuzhou General Hospital, Fuzhou 350025, Fujian, China.
| | - Yiyang Lin
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou 350025, Fujian, China
| | - Zhulin Shao
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou 350025, Fujian, China
| | - Rongdan Wu
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, Fujian, China; Department of Endocrinology, Fuzhou General Hospital, Fuzhou 350025, Fujian, China
| | - Lihong Huang
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, Fujian, China; Department of Endocrinology, Fuzhou General Hospital, Fuzhou 350025, Fujian, China
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Sinclair P, Docherty N, le Roux CW. Metabolic Effects of Bariatric Surgery. Clin Chem 2018; 64:72-81. [PMID: 29162562 DOI: 10.1373/clinchem.2017.272336] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 10/26/2017] [Indexed: 02/06/2023]
Abstract
Abstract
BACKGROUND
Obesity can be defined as a chronic subcortical brain disease, as there is an important neurophysiological component to its etiology based on changes in the functioning of those areas of the brain controlling food intake and reward. Extensive metabolic changes accompany bariatric surgery-based treatment of obesity. Consequently, the term “metabolic” surgery is being increasingly adopted in relation to the beneficial effects these procedures have on chronic diseases like type 2 diabetes.
CONTENT
In the present review, we focus on the key biochemical and physiological changes induced by metabolic surgery and highlight the beneficial effects accrued systemically with the use of an organ-based approach. Understanding the impact on and interactions between the gut, brain, adipose tissue, liver, muscle, pancreas, and kidney is key to understanding the sum of the metabolic effects of these operations.
SUMMARY
Further mechanistic studies are essential to assess the true potential of metabolic surgery to treat metabolic comorbidities of obesity beyond type 2 diabetes. Approaches that may mitigate the metabolic side effects of surgery also require attention. Understanding the positive impact of metabolic surgery on metabolic health may result in a wider acceptance of this intervention as treatment for metabolic, comorbid conditions.
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Affiliation(s)
- Piriyah Sinclair
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland
| | - Neil Docherty
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland
- Gastrosurgical Laboratory, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Carel W le Roux
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland
- Gastrosurgical Laboratory, Sahlgrenska Academy, University of Gothenburg, Sweden
- Investigative Medicine, Imperial College London, UK
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He L, Zhang S, Zhang X, Liu R, Guan H, Zhang H. Effects of insulin analogs and glucagon-like peptide-1 receptor agonists on proliferation and cellular energy metabolism in papillary thyroid cancer. Onco Targets Ther 2017; 10:5621-5631. [PMID: 29200876 PMCID: PMC5703165 DOI: 10.2147/ott.s150701] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purpose This study was aimed to investigate the expressions of the insulin receptor (IR), insulin-like growth factor receptor (IGF-1R), and glucagon-like peptide-1 receptor (GLP-1R) in normal thyroid tissue, papillary thyroid cancer (PTC) tissues, and PTC cells, and to examine the possible role of insulin analogs and GLP-1R agonists in cell proliferation and energy metabolism in PTC cells. Methods The expressions of IR, IGF-1R, and GLP-1R in PTC tissues and PTC cell lines were detected by immunohistochemistry and western blotting, respectively. Cell proliferation was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Levels of members of the phosphoinositol-3 kinase/AKT serine/threonine kinase (Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (Erk) signaling pathways were measured by western blotting. Energy metabolism of PTC cell lines was analyzed using a Seahorse Extracellular Flux analyzer. Results Three receptors could be detected in both PTC tissues and PTC cell lines. Expressions of IGF-1R and GLP-1R were more obvious in PTC than in normal thyroid cells. Neither insulin, four insulin analogs, and two GLP-1R agonists showed significant effects on the proliferation of PTC cells, nor did they influence the levels of Akt/p-Akt and Erk/p-Erk. None of these antidiabetic agents could change the mitochondrial respiration and glycolysis levels in PTC cell lines. Conclusion Both PTC tissues and the PTC cell lines express IR, IGF-1R, and GLP-1R. However, insulin analogs and GLP-1R agonists, which are commonly used to treat patients with diabetes, may not influence cell proliferation, the phosphoinositol-3 kinase/Akt and mitogen-activated protein kinase/Erk pathways, or energy metabolism in PTC cells. For now, it is not necessary to avoid use of these antidiabetic agents in patients with PTC.
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Affiliation(s)
- Liang He
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning
| | - Siliang Zhang
- Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, Liaoning
| | - Xiaowen Zhang
- Department of Endocrinology and Metabolism, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, People's Republic of China
| | - Rui Liu
- Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, Liaoning
| | - Haixia Guan
- Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, Liaoning
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning
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Liraglutide, a glucagon-like peptide-1 analog, induce autophagy and senescence in HepG2 cells. Eur J Pharmacol 2017; 809:32-41. [DOI: 10.1016/j.ejphar.2017.05.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 05/03/2017] [Accepted: 05/09/2017] [Indexed: 02/06/2023]
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Abstract
AIM Glucagon-like peptide-1 (GLP-1) receptor agonists are a kind of very popular antidiabetes drugs. They promote cell proliferation and survival through activation of signaling pathways in human islet cells involving phosphate idylinositol 3 kinase (PI3K) and extracellular regulated kinases 1 and 2 (ERK1/2), which are frequently activated in human colon cancer cells. Then, it is possible that taking GLP-1 receptor (GLP-1R) agonists persistently would induce proliferation of β cells as well as colon cancer cells. So, clarifying the effects and mechanisms of GLP-1R agonists on colon cancer cells has important clinical implications. MATERIALS AND METHODS We investigated GLP-1R expression in human colon cancer tissue samples with immunohistochemisty analysis and explored the effects of exendin-4, a GLP-1 receptor agonist, on colon cancer cells in vitro and in vivo. RESULTS The results showed lack of GLP-1R expression in both human colon cancer tissues and colon cancer cell lines. Exendin-4 did not enhance the proliferation and migration of colon cancer cell lines in vitro, and nor did it inhibit apoptosis induced by cytotoxic agents such as 5-fluorouracil (5-FU) or irinotecan. In addition, exendin-4 did not promote the propagation of colon cancer cells in vivo. CONCLUSION Our study suggests that GLP-1R agonists do not modify the growth or survival of human colon cancer cells and may be safe for diabetic patients with colon cancer.
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Affiliation(s)
- He Wenjing
- a Department of Endocrinology , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
- b Institute of Urology, The First Affiliated Hospital of Nanchang University , Nanchang , China
| | - Yu Shuang
- a Department of Endocrinology , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
| | - Li Weisong
- c Department of Pathology , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
| | - Xiao Haipeng
- a Department of Endocrinology , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
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Tuccori M, Convertino I, Galiulo MT, Marino A, Capogrosso-Sansone A, Blandizzi C. Diabetes drugs and the incidence of solid cancers: a survey of the current evidence. Expert Opin Drug Saf 2017; 16:1133-1148. [PMID: 28748718 DOI: 10.1080/14740338.2017.1361401] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The evaluation of the relationship between the use of antidiabetic drug and the occurrence of cancer is extremely challenging, both from the clinical and pharmacoepidemiological standpoint. This narrative review described the current evidence supporting a relationship between the use of antidiabetic drugs and the incidence of solid cancers. Areas covered: Data from pharmacoepidemiological studies on cancer incidence were presented for the main antidiabetic drugs and drug classes, including human insulin and insulin analogues, metformin, sulfonylureas, glinides, alpha-glucosidase inhibitors, thiazolidinediones, incretin mimetics, and sodium glucose co-transporter 2 inhibitors. The relationship between the use of antidiabetics and the incidence of solid cancer was described in strata by any cancer and by organ-specific cancer and by drug and by drug classes. Information supporting biological evidence and putative mechanisms were also provided. Expert opinion: The history of exploration of the relationship between antidiabetic drugs and the risk of solid cancers has showed several issues. Unrecognized biases and misinterpretations of study results have had important consequences that delayed the identification of actual risk and benefits of the use of antidiabetic drugs associated with cancer occurrence or progression. The lesson learned from the past should address the future research in this area, since in the majority of cases findings are controversial and confirmatory studies are warranted.
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Affiliation(s)
- Marco Tuccori
- a Unit of Adverse Drug Reaction Monitoring , University Hospital of Pisa , Pisa , Italy
| | - Irma Convertino
- b Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Maria Teresa Galiulo
- b Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Alessandra Marino
- b Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | | | - Corrado Blandizzi
- a Unit of Adverse Drug Reaction Monitoring , University Hospital of Pisa , Pisa , Italy.,b Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
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Xia R, Chen SX, Qin Q, Chen Y, Zhang WW, Zhu RR, Deng AM. Oridonin Suppresses Proliferation of Human Ovarian Cancer Cells via Blockage of mTOR Signaling. Asian Pac J Cancer Prev 2017; 17:667-71. [PMID: 26925661 DOI: 10.7314/apjcp.2016.17.2.667] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Oridonin, an ent-kaurane diterpenoid compound isolated from the traditional Chinese herb Rabdosia rubescens, has shown various pharmacological and physiological effects such as anti-tumor, anti-bacterial, and anti-inflammatory properties. However, the effect of oridonin on human ovarian cancer cell lines has not been determined. In this study, we demonstrated that oridonin inhibited ovarian cancer cell proliferation, migration and invasion in a dose-dependent manner. Furthermore, we showed oridonin inhibited tumor growth of ovarian cancer cells (SKOV3) in vivo. We then assessed mechanisms and found that oridonin specifically abrogated the phosphorylation/activation of mTOR signaling. In summary, our results indicate that oridonin is a potential inhibitor of ovarian cancer by blocking the mTOR signaling pathway.
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Affiliation(s)
- Rong Xia
- Department of Transfusion, Huashan Hospital, Fudan University, Shanghai, P. R. China E-mail :
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Pérez-Segura P, Palacio JE, Vázquez L, Monereo S, de Las Peñas R, de Icaya PM, Grávalos C, Lecube A, Blasco A, García-Almeida JM, Barneto I, Goday A. Peculiarities of the obese patient with cancer: a national consensus statement by the Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology. Clin Transl Oncol 2017; 19:682-694. [PMID: 28074400 DOI: 10.1007/s12094-016-1601-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 12/16/2016] [Indexed: 12/14/2022]
Abstract
The relationship between obesity and cancer is clear and is present at all times during course of the disease. The importance of obesity in increasing the risk of developing cancer is well known, and some of the most prevalent tumours (breast, colorectal, and prostate) are directly related to this risk increase. However, there is less information available on the role that obesity plays when the patient has already been diagnosed with cancer. Certain data demonstrate that in some types of cancer, obese patients tolerate the treatments more poorly. Obesity is also known to have an impact on the prognosis, favouring lower survival rates or the appearance of secondary tumours. In this consensus statement, we will analyse the scientific evidence on the role that obesity plays in patients already diagnosed with cancer, and the available data on how obesity control can improve the quality of daily life for the cancer patient.
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Affiliation(s)
- P Pérez-Segura
- Servicio de Oncología Médica, Hospital Clínico Universitario San Carlos, Calle Profesor Martín Lagos, s/n, 28040, Madrid, Spain.
| | - J E Palacio
- Servicio de Endocrinología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Tenerife, Spain
| | - L Vázquez
- Servicio de Oncología Médica, Complejo Hospitalario de Pontevedra, Pontevedra, Spain
| | - S Monereo
- Servicio de Endocrinología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - R de Las Peñas
- Servicio de Oncología Médica, Consorcio Hospitalario Provincial de Castellón, Castellón de la Plana, Castellón, Spain
| | - P Martínez de Icaya
- Servicio de Endocrinología, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain
| | - C Grávalos
- Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - A Lecube
- Servicio de Endocrinología, Hospital Arnau de Vilanova, Lleida, Spain
| | - A Blasco
- Servicio de Oncología Médica, Consorcio Hospital General Universitario de Valencia, Valencia, Spain
| | - J M García-Almeida
- Servicio de Endocrinología, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - I Barneto
- Servicio de Oncología Médica, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - A Goday
- Servicio de Endocrinología, Hospital del Mar, Barcelona, Spain.,Departament de Medicina, IMIM Institut Mar de Investigacions Mediques, CiberOBN, Universitat Autònoma de Barcelona, Barcelona, Spain
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42
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He W, Yu S, Wang L, He M, Cao X, Li Y, Xiao H. Exendin-4 inhibits growth and augments apoptosis of ovarian cancer cells. Mol Cell Endocrinol 2016; 436:240-9. [PMID: 27496641 DOI: 10.1016/j.mce.2016.07.032] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 07/16/2016] [Accepted: 07/26/2016] [Indexed: 12/23/2022]
Abstract
Glucagon-like peptide (GLP)-1 promotes proliferation and survival in β-cell; however, whether GLP-1 receptor agonists promote growth of human ovarian cancer cells remain unknown. We aimed to explore the effects of GLP-1 agents on ovarian cancer cells. GLP-1 receptor expression in human ovarian cancer tissues was detected by immunohistochemical analysis. The effects of exendin-4, a GLP-1R agonist, were investigated on proliferation, migration and invasion, apoptosis in vitro and tumor formation in nude mice of ovarian cancer cells. Our study demonstrated that GLP-1R expressed in both human ovarian cancer tissues and cell lines. Exendin-4 inhibited growth, migration and invasion and enhanced apoptosis of ovarian cancer cells through inhibition of the PI3K/Akt pathway. And exendin-4 attenuated tumor formation by ovarian cancer cells in vivo. Our study suggests that GLP-1R agonists do not promote the growth of ovarian cancer and may even have anticancer effect on selected diabetic patients with ovarian cancer.
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Affiliation(s)
- Wenjing He
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Shuang Yu
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Liantang Wang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mian He
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaopei Cao
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Yanbing Li
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Haipeng Xiao
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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Nomiyama T, Yanase T. GLP-1 receptor agonist as treatment for cancer as well as diabetes: beyond blood glucose control. Expert Rev Endocrinol Metab 2016; 11:357-364. [PMID: 30058925 DOI: 10.1080/17446651.2016.1191349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Recent studies indicate that cancer is a new complication of diabetes. In Japan, cancer is the most critical cause of death in patients with type 2 diabetes. Areas covered: Unlike diabetic angiopathies, diabetes does not accelerate the onset and progression of cancer, even though diabetes and cancer exhibit very similar pathophysiological features including obesity, insulin resistance, chronic inflammation, oxidative stress, and decreased adipokine imbalance. Agonists to glucagon-like peptide-1 (GLP-1) receptor are a newly identified therapy for type 2 diabetes. These drugs exert their effects by enhancing glucose-induced insulin secretion and inhibiting appetite. However, the relationship between GLP-1 receptor agonists and cancer is controversial. Expert commentary: GLP-1 receptor agonist may possess anti-cancer effect in several kind of cancers.
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Affiliation(s)
- Takashi Nomiyama
- a Department of Endocrinology and Diabetes Mellitus, School of Medicine , Fukuoka University , Fukuoka , Japan
| | - Toshihiko Yanase
- a Department of Endocrinology and Diabetes Mellitus, School of Medicine , Fukuoka University , Fukuoka , Japan
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Yang J, Gong X, Ouyang L, He W, Xiao R, Tan L. PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway. Oncol Lett 2016; 12:1139-1143. [PMID: 27446408 DOI: 10.3892/ol.2016.4688] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 04/08/2016] [Indexed: 02/07/2023] Open
Abstract
Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger factor 2 (PREX2) is a novel regulator of the small guanosine triphosphatase Rac, and has been observed to be implicated in human cancer by inhibiting the activity of phosphatase and tensin homolog (PTEN), thus upregulating the activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. However, the exact role of PREX2 in pancreatic cancer has not been reported to date. In the present study, the expression levels of PREX2 were observed to be frequently increased in pancreatic cancer specimens compared with those in their matched adjacent normal tissues. In addition, PREX2 expression was also frequently upregulated in several pancreatic cancer cell lines, including AsPC-1, BxPC-3, PANC-1 and CFAPC-1, compared with that in the normal pancreatic epithelial cell line HPC-Y5. Overexpression of PREX2 significantly promoted the proliferation, invasion and migration of pancreatic cancer PANC-1 cells, while small interfering RNA-induced knockdown of PREX2 expression significantly inhibited the proliferation, invasion and migration of these cells. Investigation of the molecular mechanism revealed that the overexpression of PREX2 upregulated the phosphorylation levels of PTEN, indicating that the activity of PTEN was reduced, which further increased the phosphorylation levels of AKT, which indicated that the activity of the PI3K signaling pathway was upregulated. By contrast, knockdown of PREX2 upregulated the activity of PTEN and inhibited the activity of the PI3K signaling pathway. In conclusion, the present study demonstrated that PREX2 regulates the proliferation, invasion and migration of pancreatic cancer cells, probably at least via modulation of the activity of PTEN and the PI3K signaling pathway.
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Affiliation(s)
- Jianyi Yang
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Xuejun Gong
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Lu Ouyang
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Wen He
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Rou Xiao
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Li Tan
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
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Smits MM, van Raalte DH, Tonneijck L, Muskiet MHA, Kramer MHH, Cahen DL. GLP-1 based therapies: clinical implications for gastroenterologists. Gut 2016; 65:702-11. [PMID: 26786687 DOI: 10.1136/gutjnl-2015-310572] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/23/2015] [Indexed: 12/13/2022]
Abstract
The gut-derived incretin hormone, glucagon-like peptide 1 (GLP-1) lowers postprandial blood glucose levels by stimulating insulin and inhibiting glucagon secretion. Two novel antihyperglycaemic drug classes augment these effects; GLP-1 receptor agonists and inhibitors of the GLP-1 degrading enzyme dipeptidyl peptidase 4. These so called GLP-1 based or incretin based drugs are increasingly used to treat type 2 diabetes, because of a low risk of hypoglycaemia and favourable effect on body weight, blood pressure and lipid profiles. Besides glucose control, GLP-1 functions as an enterogastrone, causing a wide range of GI responses. Studies have shown that endogenous GLP-1 and its derived therapies slow down digestion by affecting the stomach, intestines, exocrine pancreas, gallbladder and liver. Understanding the GI actions of GLP-1 based therapies is clinically relevant; because GI side effects are common and need to be recognised, and because these drugs may be used to treat GI disease.
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Affiliation(s)
- Mark M Smits
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Daniel H van Raalte
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Lennart Tonneijck
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Marcel H A Muskiet
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Mark H H Kramer
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Djuna L Cahen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Zhang Y, Xu F, Liang H, Cai M, Wen X, Li X, Weng J. Exenatide inhibits the growth of endometrial cancer Ishikawa xenografts in nude mice. Oncol Rep 2015; 35:1340-8. [PMID: 26648451 DOI: 10.3892/or.2015.4476] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 10/06/2015] [Indexed: 11/05/2022] Open
Abstract
Studies have showed that diabetes is one of the high risk factors of endometrial cancer; however, no reports describe the anti- or pro-cancer effect of a new kind of anti-diabetes drug, glucagon-like peptide-1 receptor agonist exenatide (exendin-4), on endometrial cancer. To investigate whether exenatide promotes or inhibits the growth of endometrial cancer, we used the subcutaneous human endometrial cancer cell Ishikawa xenografts in nude mouse model, and divided them into control group and exenatide-treated group. The tumor growth rate in exenatide group was slower than that in control group, and the apoptosis rate of exenatide group was higher than that in control group. In vitro, exendin-4 also attenuated Ishikawa cell viability and clone formation rate, but promoted cell apoptosis. There was an increase of phosphorylated-AMPK protein, a decrease of phosphorylated-mTOR protein both in vivo and in vitro after exenatide or exendin-4 treatment. Moreover, when treated with exendin-4 plus AICAR, an AMPK activator, cell apoptosis increased with higher ratio of phosphorylayed-AMPK/AMPK, lower ratio of phosphorylated-mTOR/mTOR and higher expression of cleaved caspase-3 than those in exendin-4 alone group, and the results were the opposite when treated with exendin-4 plus compound C, an AMPK inhibitor. Our results suggest that exenatide could attenuate the growth of endometrial cancer Ishikawa xenografts in nude mice, and AMPK may be the target of the mechanism.
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Affiliation(s)
- Yu Zhang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Fen Xu
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Hua Liang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Mengyin Cai
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Xinqiao Wen
- Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Xiaomao Li
- Department of Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Jianping Weng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
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CASES ANAINES, OHTSUKA TAKAO, KIMURA HIDEYO, ZHENG BIAO, SHINDO KOJI, ODA YOSHINAO, MIZUMOTO KAZUHIRO, NAKAMURA MASAFUMI, TANAKA MASAO. Significance of expression of glucagon-like peptide 1 receptor in pancreatic cancer. Oncol Rep 2015; 34:1717-25. [DOI: 10.3892/or.2015.4138] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 06/29/2015] [Indexed: 11/05/2022] Open
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Madi A, Bransburg-Zabary S, Maayan-Metzger A, Dar G, Ben-Jacob E, Cohen IR. Tumor-associated and disease-associated autoantibody repertoires in healthy colostrum and maternal and newborn cord sera. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2015; 194:5272-81. [PMID: 25917091 PMCID: PMC4432729 DOI: 10.4049/jimmunol.1402771] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 03/31/2015] [Indexed: 02/07/2023]
Abstract
In this work, we studied autoantibody repertoires and Ig isotypes in 71 mothers and their 104 healthy newborns (including twins and triplets delivered term or premature). Newborns receive maternal IgG Abs via the placenta before birth, but developing infants must produce their own IgM and IgA Abs. We used an Ag microarray analysis to detect binding to a selection of 295 self-Ags, compared with 27 standard foreign Ags. The magnitude of binding to specific self-Ags was found to be not less than that to the foreign Ags. As expected, each newborn shared with its mother a similar IgG repertoire-manifest as early as the 24th week of gestation. IgM and IgA autoantibody repertoires in cord sera were highly correlated among the newborns and differed from their mothers' repertoires; the latter differed in sera and milk. The autoantibodies bound to self-Ags known to be associated with tumors and to autoimmune diseases. Thus, autoantibody repertoires in healthy humans--the immunological homunculus--arise congenitally, differ in maternal milk and sera, and mark the potential of the immune system to attack tumors, beneficially, or healthy tissues, harmfully; regulation of the tissue site, the dynamics, and the response phenotype of homuncular autoimmunity very likely affects health.
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Affiliation(s)
- Asaf Madi
- Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel; Department of Neonatology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 5262100 Ramat Gan, Israel
| | - Sharron Bransburg-Zabary
- Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel
| | - Ayala Maayan-Metzger
- Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Department of Neonatology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 5262100 Ramat Gan, Israel
| | - Gittit Dar
- School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel
| | - Eshel Ben-Jacob
- School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel; Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; and
| | - Irun R Cohen
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
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49
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Kang CM, Lee JH. Pathophysiology after pancreaticoduodenectomy. World J Gastroenterol 2015; 21:5794-5804. [PMID: 26019443 PMCID: PMC4438013 DOI: 10.3748/wjg.v21.i19.5794] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Revised: 02/25/2015] [Accepted: 04/17/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreaticoduodenectomy (PD) will result in removal of important multiorgans in upper intestinal tract and subsequently secondary physiologic change. In the past, surgeons just focused on the safety of surgical procedure; however, PD is regarded as safe and widely applied to treatment of periampullary lesions. Practical issues after PD, such as, effect of duodenectomy, metabolic surgery-like effect, alignment effect of gastrointestinal continuity, and non-alcoholic fatty liver disease were summarized and discussed.
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50
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Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse Effects of GLP-1 Receptor Agonists. Rev Diabet Stud 2015; 11:202-30. [PMID: 26177483 DOI: 10.1900/rds.2014.11.202] [Citation(s) in RCA: 256] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.
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Affiliation(s)
- Theodosios D Filippatos
- Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Thalia V Panagiotopoulou
- Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Moses S Elisaf
- Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
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